Pyrrolo [2, 3-c] pyridine compound and application thereof

Abstract

The invention provides a pyrrolo [2, 3-c] pyridine compound or a hydrate, a solvate, a prodrug, a stereoisomer or a tautomer of a pharmaceutically acceptable salt of the pyrrolo [2, 3-c] pyridine compound. The invention also provides processes for preparing the compounds of the invention and intermediate compounds useful in these processes; the compound provided by the invention can be used for preparing medicines for treating diseases related to bromodomain functions.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a new pyrrolo[2,3-c]pyridine compound and a preparation method thereof, as well as the application of a pharmaceutical composition containing the compound in pharmaceutical research, especially as a bromodomain inhibitor. Background Art

[0002] In recent years, tumors have become one of the leading causes of death worldwide. Tumors generally have low overall cure rates and high recurrence rates. Therefore, prevention, treatment, and inhibition of tumor recurrence have important scientific research value. The prevention and cure of tumors are of considerable urgency and challenge. Abnormal epigenetic regulation is one of the important factors leading to tumorigenesis.

[0003] A bromodomain is a protein domain that recognizes N-acetylated lysine residues. The BET (bromodomain and extraterminal domain) family of bromodomain-containing proteins includes four members (BRD2, BRD3, BRD4, and BRDt). Each member of the BET family uses two bromodomains to recognize N-acetylated lysine residues found primarily (but not exclusively) at the aminoterminal tail of histone proteins, regulating gene expression by recruiting transcription factors to specific genomic locations within chromatin. For example, BRD2 and BRD3 can function as transcriptional regulators of growth-promoting genes; bromodomain protein 4 (BRD4) is a member of the bromodomain and extraterminal (BET) family, and BRD4 regulates the expression of target genes by recruiting different transcriptional regulators, such as Mediator and positive transcription elongation factor b (P-TEFb). As a chromatin "adapter, reader" widely expressed in mammals, it can recognize acetylated proteins and bind to chromosomes throughout the mitotic process, recruit different chromatin modification proteins, and widely regulate gene expression, thereby playing an important role in regulating cell cycle progression, transcription, inflammation, etc. Recent studies have confirmed that BET bromodomains can be used as targets to treat a variety of cancers, atherosclerosis, inflammation, and HIV infection.

[0004] Recent studies have found that epigenetic abnormalities mediated by BRD4 protein are closely related to the overexpression of oncogenes and the growth and proliferation of cancer cells. BRD4 is a member of the Bromo and extra-terminal domain (BET) family of proteins. Due to its potential value in anti-tumor, it has attracted great attention from major pharmaceutical companies and research institutions. The dysregulated expression level or dysfunction of BRD4 is associated with the occurrence of midline carcinoma with rearrangement of the nuclear protein intestis gene (NMC), melanoma, acute myeloid leukemia, colon cancer, breast cancer, etc. BRD4 shRNA or BET inhibitors can induce cell cycle arrest, apoptosis and cell differentiation in the above tumors, showing strong anti-tumor activity. These findings indicate that BET proteins are expected to become new therapeutic targets for the above tumors and even other tumors. In addition, through the study of tool compounds such as JQ1, it was found that BRD4 inhibitors may have a wide range of applications in a variety of diseases such as viral infection, diabetes, metabolic diseases, liver diseases and Alzheimer's disease.

[0005] A series of patents for bromodomain protein inhibitors have been disclosed. Patent applications for selective BRD4 inhibitors include WO2013097052, WO2013158952, WO2014165127, WO2014206345, WO2016077378 and WO2015081189. The drug currently in Phase III clinical trials is Apabetalone, and the drugs in Phase II clinical trials include GSK-525762A, INCB-54329 and BMS986158. The compound Mivebresib (ABBV-075) is a pyridone BRD4 targeted inhibitor developed by AbbVie. It shows good DMPK properties and good biological activity in various tumor models. It is currently in Phase I clinical trials for the treatment of solid tumors and blood cancers.

[0006] BRD4 inhibitors have good application prospects as drugs in the pharmaceutical industry. In order to better meet market demand and solve problems such as patients' acquired resistance and drug toxicity and side effects, it is still necessary to continuously develop new drugs with bromodomain protein inhibitor activity, in order to obtain more efficient and less toxic drugs, further prolong patients' survival time and improve their quality of life. Summary of the invention

[0007] The purpose of the present invention is to provide a pyrrolo[2,3-c]pyridine compound having a significant inhibitory effect on bromodomain proteins. Biological in vitro experiments have shown that the compound of the present invention has a significant inhibitory effect on BRD4 binding activity, has significant anti-tumor activity, and has drug potential. Another purpose of the present invention is to provide a method for synthesizing the compound and its key intermediates.

[0008] The specific technical solutions of the present invention are as follows:

[0009] In a first aspect, the present invention provides a hydrate, solvate, prodrug, stereoisomer or tautomer of a pyrrolo[2,3-c]pyridine compound or a pharmaceutically acceptable salt thereof of general formula I:

[0010]

[0011] Wherein, L is selected from -O-, -S-, -NH-; preferably -O-;

[0012] M1, M2, and M3 are each independently selected from N or C, more preferably C;

[0013] Rg is independently selected from: absent or hydrogen, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2) n1 -NR6R7, -(CH2) n1-C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or hydrogen, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2) n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably hydrogen, halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably hydrogen, halogen, methyl, methoxy;

[0014] y is 0 or an integer from 1 to 5;

[0015] R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl;

[0016] Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl;

[0017] R4 is independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl;

[0018] n is an integer from 1 to 3, q ​​is an integer from 0, 1 to 6, and the maximum number q of substituents R4 is 2n, and when q≥2, the R4 substituents are the same or different;

[0019] m is an integer from 0, 1 to 6; preferably 0 or 1;

[0020] Z1 is selected from: O, S, NR b ,CRaR b NR b ,CRaR b ; Further, when Z1 is CRaR b When R b It can form a 3- to 7-membered ring together with the adjacent ring atoms of Z1, and a 3-membered ring is particularly preferred; when Z1 is NR b When R b Together with the atoms on the ring adjacent to Z1, it can form a 3- to 7-membered heterocyclic ring, and is particularly preferably a 4- to 5-membered heterocyclic ring;

[0021] Among them, Ra, R b are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferably Ra, R b Each independently is hydrogen, C 1-6 Alkyl, C2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferably Ra is hydrogen, methyl, R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane;

[0022] M4 and M5 are each independently selected from N or CRy, wherein Ry is selected from hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl; further, M4 and M5 are preferably CRy, wherein Ry is preferably hydrogen or methyl, and Ry is particularly preferably hydrogen;

[0023] X1 and X2 are independently selected from: O, S, NH or absent; further preferably, X1 and X2 are O or absent.

[0024] In a preferred embodiment of the present invention, the compound represented by the general formula I is a hydrate, solvate, prodrug, stereoisomer or tautomer of a pyrrolo[2,3-c]pyridine compound represented by the general formula II or a pharmaceutically acceptable salt thereof:

[0025]

[0026] in,

[0027] Rg is independently selected from: absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2)n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2) n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably halogen, methyl, methoxy;

[0028] y is an integer from 0 or 1 to 5; more preferably 0, 1 or 2;

[0029] R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl;

[0030] Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C1-6 Alkyl, more preferably hydrogen, methyl;

[0031] R4, R4′ are independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably R4 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl, and R4' is hydrogen, methyl;

[0032] m is an integer from 0, 1 to 6; preferably 0 or 1;

[0033] Ra, R b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferably Ra, R b Each independently is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferably Ra is hydrogen, methyl, R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane;

[0034] Further, R b It can form a 3- to 7-membered ring together with the adjacent ring atom directly connected to C, and a 3-membered ring is particularly preferred;

[0035] X2 is 0 or absent.

[0036] In a preferred embodiment of the present invention, the compound represented by the general formula I is a hydrate, solvate, prodrug, stereoisomer or tautomer of a pyrrolo[2,3-c]pyridine compound represented by the general formula III or a pharmaceutically acceptable salt thereof:

[0037]

[0038] in,

[0039] Rg is independently selected from: absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2)n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably halogen, methyl, methoxy;

[0040] y is an integer from 0 or 1 to 5; more preferably 0, 1 or 2;

[0041] R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl;

[0042] Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl;

[0043] R4, R4′ are independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably R4 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl, and R4' is hydrogen, methyl;

[0044] m is an integer from 0, 1 to 6; preferably 0 or 1;

[0045] Ra, R b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferably Ra, R b Each independently is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferably Ra is hydrogen, methyl, R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane;

[0046] Further, R b Together with the adjacent ring atom directly connected to N, it can form a 3- to 7-membered heterocyclic ring, and a 4- to 5-membered heterocyclic ring is particularly preferred.

[0047] In a preferred embodiment of the present invention, the compound represented by the general formula I is a hydrate, solvate, prodrug, stereoisomer or tautomer of a pyrrolo[2,3-c]pyridine compound represented by the general formula III-1 or a pharmaceutically acceptable salt thereof:

[0048]

[0049] in,

[0050] Rg is independently selected from: absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2)n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2) n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably halogen, methyl, methoxy;

[0051] y is an integer from 0 or 1 to 5; more preferably 0, 1 or 2;

[0052] R1, R2, and R3 are each independently selected from: hydrogen, C 1-6Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl;

[0053] Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl;

[0054] R4, R4′ are independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably R4 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl, and R4' is hydrogen, methyl;

[0055] m is an integer from 0, 1 to 6; preferably 0 or 1;

[0056] Ra, R b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferably Ra, R b Each independently is hydrogen, C1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferably Ra is hydrogen, methyl, R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane;

[0057] Further, R b Together with the adjacent ring atom directly connected to N, it can form a 3- to 7-membered heterocyclic ring, and a 4- to 5-membered heterocyclic ring is particularly preferred.

[0058] In a preferred embodiment of the present invention, the compound represented by the general formula I is a hydrate, solvate, prodrug, stereoisomer or tautomer of a pyrrolo[2,3-c]pyridine compound represented by the general formula IV or a pharmaceutically acceptable salt thereof:

[0059]

[0060] in,

[0061] Rg is independently selected from: absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1-C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2) n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably halogen, methyl, methoxy;

[0062] y is an integer from 0 or 1 to 5; more preferably 0, 1 or 2;

[0063] R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl;

[0064] Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl;

[0065] R4 is independently selected from hydrogen, C 1-6 Alkyl, C 3-8Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably R4 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl; more particularly preferably R4 is hydrogen, methyl;

[0066] q is an integer from 0, 1 to 4, and when q ≥ 2, the R4 substituents are the same or different;

[0067] m is an integer from 0, 1 to 6; preferably 0 or 1;

[0068] R b Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferred R b For hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferred R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane; more preferably R b For hydrogen.

[0069] In a preferred embodiment of the present invention, the compound represented by the general formula I is a hydrate, solvate, prodrug, stereoisomer or tautomer of a pyrrolo[2,3-c]pyridine compound represented by the general formula IV-1 or a pharmaceutically acceptable salt thereof:

[0070]

[0071] in,

[0072] Rg is independently selected from: absent or halogen, amino, nitro, cyano, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2) n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6Haloalkyl; Rg is more preferably halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably halogen, methyl, methoxy;

[0073] y is an integer from 0 or 1 to 5; more preferably 0, 1 or 2;

[0074] R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl;

[0075] Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl;

[0076] R4 is independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably R4 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl; more particularly preferably R4 is hydrogen, methyl;

[0077] q is an integer from 0, 1 to 4, and when q ≥ 2, the R4 substituents are the same or different;

[0078] m is an integer from 0, 1 to 6; preferably 0 or 1;

[0079] R b Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferred R b For hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferred R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane; more preferably R b For hydrogen.

[0080] In a preferred embodiment of the present invention, the hydrate, solvate, prodrug, stereoisomer or tautomer of the pyrrolo[2,3-c]pyridine compound of general formula I or a pharmaceutically acceptable salt thereof includes but is not limited to the following compounds:

[0081]

[0082]

[0083]

[0084] In a preferred embodiment of the present invention, the hydrate, solvate, prodrug, stereoisomer or tautomer of the pyrrolo[2,3-c]pyridine compound or a pharmaceutically acceptable salt thereof of the general formula I comprises the following compounds:

[0085]

[0086]

[0087] In the second aspect of the present invention, a method for preparing a pyrrolo[2,3-c]pyridine compound shown in formula I is provided. The compounds of the present application can be prepared by using a variety of methods known to those skilled in the art. The present application includes the use of the methods described herein and organic chemical synthesis methods or variations thereof understood by those skilled in the art for synthesis. Preferably, the method is not limited to the following method. The intermediate compounds used in the preparation process can be purchased or prepared with reference to the prior art; it is noted that in each embodiment, the intermediate is named SM compound or intermediate compound, and its structure is shown in the synthesis route, and its synthesis route is a generalized preparation route for the compounds of the present invention, and specific intermediate compounds such as SM-4, SM-7, SM-8, SM-9 and reaction conditions are determined according to the actual compound structure and preparation examples.

[0088] In a preferred embodiment of the present invention, a method for preparing a pyrrolo[2,3-c]pyridine compound of formula I is provided, and the synthesis route is as follows:

[0089]

[0090]

[0091] Wherein, R1, R2, R3, R4, Rg, L, y, M1, M2, M3, M4, M5, Z1, X1, X2, m, n, q in the intermediate compounds involved in the synthesis route are as defined in the general formula I of the first aspect of the present invention;

[0092] The preparation method includes but is not limited to the following steps:

[0093] Step 1) 5-bromo-2-methoxy-4-methyl-3-nitropyridine (SM-1) and N,N-dimethylformamide dimethyl acetal (DMFDMA) are heated in N,N-dimethylformamide (DMF) to react to obtain a reddish brown intermediate compound (SM-1a);

[0094] Step 2) The reddish brown intermediate compound (SM-1a) obtained in step 1 is dissolved in dichloromethane, and a cyclization reaction is carried out under the action of a catalyst zinc powder to prepare an intermediate compound 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-2);

[0095] Step 3) Add p-toluenesulfonyl chloride (P-TSCI), sodium hydroxide (NaOH), and tetrabutylammonium bromide (TBNB) to a dichloromethane solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-2) and stir to react to obtain a white intermediate compound (SM-3);

[0096] Step 4) The white intermediate compound (SM-3) obtained in step 3 is suspended in a mixed solvent of hydrochloric acid / ethanol / ethyl acetate to react to prepare a white intermediate compound (SM-3a);

[0097] Step 5) The intermediate compound SM-3a obtained in step 4 is reacted with an iodide (SM-4, i.e., R2-I, wherein R2 is defined in the general formula I, and the specific definition is determined according to the actual compound structure, such as when R2 is methyl, SM-4 is iodomethane CH3-I) to prepare a white intermediate compound 1;

[0098] Step 6) reacting the intermediate compound SM-5 with diboric acid pinacol ester under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2) to prepare a white intermediate compound (SM-6);

[0099] Step 7) reacting the compound intermediate 1 obtained in step 5 with the intermediate compound SM-6 obtained in step 6 under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2) to prepare a light yellow intermediate 2 compound;

[0100] Step 8) heating the compound intermediate 2 obtained in step 7 and the intermediate compound SM-7 to react to obtain the compound intermediate 3;

[0101] Step 9) Add glacial acetic acid (HOAc) dropwise to the compound intermediate 3 obtained in step 8 under the catalysis of zinc powder (Zn) to react to prepare compound intermediate 4;

[0102] Step 10) The compound intermediate 4 obtained in step 9 is dissolved in dichloromethane, and the intermediate compound SM-8, N,N-dimethylformamide (DMF), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), and triethylamine (Et3N) are added thereto and stirred for reaction to prepare the compound intermediate 5;

[0103] Step 11) reacting the compound intermediate 5 obtained in step 10 with an iodide (SM-9, i.e., R1-I, wherein R1 is defined in general formula I, and the specific definition is determined according to the actual compound structure, such as when R1 is methyl, SM-9 is iodomethane CH3-I) to prepare the target product I;

[0104] In a specific embodiment, if the substituent R1 of the obtained compound is H, the compound intermediate 5 obtained after completing the preparation process 1-10 is the target product I.

[0105] In a preferred embodiment of the present invention, a method for preparing a pyrrolo[2,3-c]pyridine compound of formula II is provided, and the synthesis route is as follows:

[0106]

[0107] Among them, R1, R2, R3, R4 (R4'), R a , R b , Rg, y, X2, m are as defined in the general formula II of the first aspect of the present invention;

[0108] The preparation method includes but is not limited to the following steps:

[0109] Step 1) 5-bromo-2-methoxy-4-methyl-3-nitropyridine (SM-1) and N,N-dimethylformamide dimethyl acetal (DMFDMA) are heated in N,N-dimethylformamide (DMF) to react to obtain a reddish brown intermediate compound (SM-1a);

[0110] Step 2) The reddish brown intermediate compound (SM-1a) obtained in step 1 is dissolved in dichloromethane, and a cyclization reaction is carried out under the action of a catalyst zinc powder to prepare an intermediate compound 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-2);

[0111] Step 3) Add p-toluenesulfonyl chloride (P-TSCI), sodium hydroxide (NaOH), and tetrabutylammonium bromide (TBNB) to a dichloromethane solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-2) and stir to react to obtain a white intermediate compound (SM-3);

[0112] Step 4) The white intermediate compound (SM-3) obtained in step 3 is suspended in a mixed solvent of hydrochloric acid / ethanol / ethyl acetate to react to obtain a white intermediate compound (SM-3a);

[0113] Step 5) The intermediate compound SM-3a obtained in step 4 is reacted with an iodide (SM-4, i.e., R2-I, wherein R2 is defined in the general formula I, and the specific definition is determined according to the actual compound structure, such as when R2 is methyl, SM-4 is iodomethane CH3-I) to prepare a white intermediate compound 1;

[0114] Step 6) reacting the intermediate compound SM-5 with diboric acid pinacol ester under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2) to prepare a white intermediate compound (SM-6);

[0115] Step 7) reacting the compound intermediate 1 obtained in step 5 with the intermediate compound SM-6 obtained in step 6 under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2) to prepare a light yellow intermediate 2 compound;

[0116] Step 8) heating the compound intermediate 2 obtained in step 7 and the phenol compound (SM-7) to react to prepare the compound intermediate 3;

[0117] Step 9) Add glacial acetic acid (HOAc) dropwise to the compound intermediate 3 obtained in step 8 under the catalysis of zinc powder (Zn) to react to prepare compound intermediate 4;

[0118] Step 10) The compound intermediate 4 obtained in step 9 is dissolved in dichloromethane, and a five-membered oxone compound (SM-8), N,N-dimethylformamide (DMF), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), and triethylamine (Et3N) are added thereto and stirred for reaction to obtain a compound intermediate 5;

[0119] Step 11) reacting the compound intermediate 5 obtained in step 10 with an iodide (SM-9, i.e., R1-I, wherein R1 is defined in the general formula II, and the specific definition is determined according to the actual compound structure, such as when R1 is methyl, SM-9 is iodomethane CH3-I) to prepare the target product II;

[0120] In a specific embodiment, if the substituent R1 of the obtained compound is H, the compound intermediate 5 obtained after completing the preparation process 1-10 is the target product II.

[0121] In a preferred embodiment of the present invention, a method for preparing a pyrrolo[2,3-c]pyridine compound shown in formula III is provided. After completing steps 1-8 of the preparation of the general formula II to obtain compound intermediate 3, compound intermediate 3 is subjected to Ts protection to obtain Ts-protected intermediate 5, which is reacted with a Boc-protected glycine compound (SM-8) to obtain compound intermediate 6. Intermediate 6 is subjected to trifluoroacetic acid (TFA) to remove the Boc protecting group to obtain compound intermediate 7. Intermediate 7 is subjected to a cyclization reaction under the action of triphosgene to obtain compound intermediate 8. Intermediate 8 is reacted with an alcohol compound (SM-9, i.e., R b -OH, where R b It is defined by the general formula III, and the specific definition is determined according to the actual compound structure. For example, when R b for When SM-9 is cyclopropylmethanol ) to obtain compound intermediate 9, intermediate 9 is deprotected by Ts under the action of a phenolic reagent (2,4-difluorophenol) to obtain compound intermediate 10, and compound intermediate 10 is reacted with an iodide (SM-10, i.e., R1-I, wherein R1 is defined by general formula III, and the specific definition is determined according to the actual compound structure, such as when R1 is methyl, SM-10 is methyl iodide CH3-I) to prepare the target product III;

[0122] The intermediate compound (SM) used in the preparation process can be purchased or prepared by referring to the prior art. It is noted that in each embodiment, the intermediate compound is named SM compound, and its structure is shown in the synthesis route. The synthesis route is a general preparation route for the compound of the present invention. The specific intermediate compounds such as SM-8, SM-9, SM-10 and the reaction conditions are determined according to the actual compound structure and preparation examples.

[0123] The synthetic route starting from intermediate 3 is as follows:

[0124]

[0125]

[0126] Among them, R1, R2, R3, R4 (R4'), R b , Rg, y, and m are as defined in the general formula III of the first aspect of the present invention;

[0127] The preparation method includes but is not limited to the following steps:

[0128] Step 9) adding p-toluenesulfonyl chloride (P-TSCI), sodium hydroxide (NaOH) and tetrabutylammonium bromide (TBNB) to a dichloromethane solution of intermediate 3, mixing and stirring to react, to prepare Ts-protected intermediate 4;

[0129] Step 10) Add glacial acetic acid (HOAc) dropwise to the compound intermediate 4 obtained in step 9 under the catalysis of zinc powder (Zn) to react to prepare compound intermediate 5;

[0130] Step 11) The compound intermediate 5 obtained in step 10 is reacted with a Boc-protected glycine compound (SM-8) in the presence of O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and triethylamine (Et3N) to prepare the compound intermediate 6;

[0131] Step 12) The intermediate 6 obtained in step 11 is dissolved in a dichloromethane solution, and trifluoroacetic acid is added to remove the Boc protecting group to prepare the compound intermediate 7;

[0132] Step 13) Add a dichloromethane solution of triphosgene to a dichloromethane solution of intermediate 7, dropwise add triethylamine, and stir to carry out a cyclization reaction to prepare compound intermediate 8;

[0133] Step 14) The intermediate 8 obtained in step 13, triphenylphosphine (PH3P), an alcohol compound (SM-9, i.e. R b -OH, where R b It is defined by the general formula III, and the specific definition is determined according to the actual compound structure. For example, when R b for When SM-9 is cyclopropylmethanol ) was placed in a reactor, dichloromethane was added to dissolve under nitrogen protection, diisopropyl azodicarboxylate (DIAD) was added dropwise to the solution and stirred for reaction to prepare compound intermediate 9;

[0134] Step 15) dissolving the compound intermediate 9 obtained in step 14 in N,N-dimethylformamide solution, stirring and reacting in the presence of a phenolic reagent (2,4-difluorophenol) and potassium carbonate, and removing the Ts protecting group to prepare the compound intermediate 10;

[0135] Step 16) reacting the intermediate compound 10 obtained in step 15 with an iodide (SM-10, i.e., R1-I, wherein R1 is defined in the general formula III, and the specific definition is determined according to the actual compound structure, such as when R1 is methyl, SM-9 is iodomethane CH3-I) to prepare the target product III;

[0136] In a specific embodiment, if the substituent R1 of the obtained compound is H, the compound intermediate 10 obtained after completing the preparation process 1-15 is the target product III.

[0137] In a preferred embodiment of the present invention, a method for preparing a pyrrolo[2,3-c]pyridine compound of formula III-1, after completing steps 1-9 of the preparation of the above general formula II to obtain the compound intermediate 4, continues to prepare the target product III-1, the synthetic route is as follows:

[0138]

[0139] Among them, R1, R2, R3, R4 (R4'), R b, Rg, y, and m are as defined in the general formula III-1 of the first aspect of the present invention; the intermediate compound (SM) used in the preparation process can be purchased or prepared by referring to the prior art; it is noted that in each embodiment, the intermediate compound is named SM compound, and its structure is shown in the synthesis route, and its synthesis route is a general preparation route for the compound of the present invention. Specific intermediate compounds such as SM-8, SM-9, SM-10 and reaction conditions are determined according to the actual compound structure and preparation examples.

[0140] In a specific embodiment, if the substituent R1 of the obtained compound is H, the compound intermediate 8 obtained after completing the preparation process 1-13 is the target product III-1.

[0141] In a preferred embodiment of the present invention, a method for preparing a pyrrolo[2,3-c]pyridine compound shown in formula IV, after completing the preparation steps 1-10 of the above general formula III to obtain compound intermediate 5, intermediate 5 is reacted with a Boc-protected glycine compound (SM-8) to prepare compound intermediate 6, intermediate 6 is deprotected by trifluoroacetic acid (TFA) to obtain compound intermediate 7, intermediate 7 is subjected to a cyclization reaction under the action of triphosgene (Trihosgen) to obtain compound intermediate 8, intermediate 8 is reacted with an alcohol compound (SM-9, i.e., R b -OH, where R b It is defined by the general formula III, and the specific definition is determined according to the actual compound structure. For example, when R b for When SM-9 is cyclopropylmethanol ) to obtain compound intermediate 9, intermediate 9 is deprotected by Ts under the action of a phenolic reagent (2,4-difluorophenol) to obtain compound intermediate 10, and compound intermediate 10 is reacted with an iodide (SM-10, i.e., R1-I, wherein R1 is defined by general formula IV, and the specific definition is determined according to the actual compound structure, such as when R1 is methyl, SM-10 is methyl iodide CH3-I) to prepare the target product IV;

[0142] The intermediate compound (SM) used in the preparation process can be purchased or prepared by referring to the prior art. It is noted that in each embodiment, the intermediate compound is named SM compound, and its structure is shown in the synthesis route. The synthesis route is a general preparation route for the compound of the present invention. The specific intermediate compounds such as SM-8, SM-9, SM-10 and the reaction conditions are determined according to the actual compound structure and preparation examples.

[0143] The synthetic route starting from intermediate 5 is as follows:

[0144]

[0145] Among them, R1, R2, R3, R4, R b , Rg, y, m, q are as defined in the general formula IV of the first aspect of the present invention;

[0146] The preparation method includes but is not limited to the following steps:

[0147] Step 11) The compound intermediate 5 obtained in step 10 is reacted with a Boc-protected glycine compound (SM-8) in the presence of O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and triethylamine (Et3N) to prepare the compound intermediate 6;

[0148] Step 12) The intermediate 6 obtained in step 11 is dissolved in a dichloromethane solution, and trifluoroacetic acid is added to remove the Boc protecting group to prepare the compound intermediate 7;

[0149] Step 13) Add a dichloromethane solution of triphosgene to a dichloromethane solution of intermediate 7, dropwise add triethylamine, and stir to carry out a cyclization reaction to prepare compound intermediate 8;

[0150] Step 14) The intermediate 8 obtained in step 13, triphenylphosphine (PH3P), an alcohol compound (SM-9, i.e. R b -OH, where R b It is defined by the general formula III, and the specific definition is determined according to the actual compound structure. For example, when R b for When SM-9 is cyclopropylmethanol ) was placed in a reactor, dichloromethane was added to dissolve under nitrogen protection, diisopropyl azodicarboxylate (DIAD) was added dropwise to the solution and stirred for reaction to prepare compound intermediate 9;

[0151] Step 15) dissolving the compound intermediate 9 obtained in step 14 in N,N-dimethylformamide solution, stirring and reacting in the presence of a phenolic reagent (2,4-difluorophenol) and potassium carbonate, and removing the Ts protecting group to prepare the compound intermediate 10;

[0152] Step 16) reacting the intermediate compound 10 obtained in step 15 with an iodide (SM-10, i.e., R1-I, wherein R1 is defined in the general formula III, and the specific definition is determined according to the actual compound structure, such as when R1 is methyl, SM-9 is iodomethane CH3-I) to prepare the target product IV;

[0153] In a specific embodiment, if the substituent R1 of the obtained compound is H, the compound intermediate 10 obtained after completing the preparation process 1-15 is the target product IV.

[0154] In a preferred embodiment of the present invention, a method for preparing a pyrrolo[2,3-c]pyridine compound of formula IV-1, after completing steps 1-9 of the preparation of the above general formula II to obtain the compound intermediate 4, continues to prepare the target product IV-1, the synthesis route is as follows:

[0155]

[0156] Among them, R1, R2, R3, R4, R b , Rg, y, and m are as defined in the general formula IV-1 of the first aspect of the present invention; the intermediate compound (SM) used in the preparation process can be purchased or prepared by referring to the prior art; it is noted that in each embodiment, the intermediate compound is named SM compound, and its structure is shown in the synthesis route, and its synthesis route is a general preparation route for the compound of the present invention. Specific intermediate compounds such as SM-8, SM-9, SM-10 and reaction conditions are determined according to the actual compound structure and preparation examples.

[0157] In a specific embodiment, if the substituent R1 of the obtained compound is H, the compound intermediate 8 obtained after completing the preparation process 1-13 is the target product IV-1.

[0158] The third aspect of the present invention provides a pharmaceutical composition, which comprises: a therapeutically effective amount of one or more of the hydrates, solvates, prodrugs, stereoisomers or tautomers of the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, excipient, adjuvant, auxiliary material or diluent.

[0159] Preferably, the drug combination can be used to treat diseases and indications related to BET bromodomain function.

[0160] Preferably, the BET bromodomain function-related diseases include but are not limited to inflammatory diseases, cancer or AIDS.

[0161] Preferably, a bromodomain inhibitor comprises an inhibitory effective amount of a pyrrolo[2,3-c]pyridine compound as shown in formula I of the present invention, or one or more of its pharmaceutically acceptable salts, tautomers, optical isomers, pharmaceutically acceptable solvates, and optionally a pharmaceutically acceptable carrier, excipient, adjuvant, auxiliary material or diluent.

[0162] The compounds of the present invention can be used directly for prevention and treatment, or preferably in the form of a pharmaceutical composition. Although the active ingredient can be administered alone, it is preferably in the form of a pharmaceutical preparation or composition. Therefore, the present invention provides a pharmaceutical preparation comprising a compound of the present invention and a pharmaceutically acceptable diluent, excipient or carrier (collectively referred to herein as "carrier" material). The pharmaceutical composition of the present invention can take the form of a pharmaceutical preparation described below. Therefore, the present invention relates to a pharmaceutical composition comprising at least one compound of formula I and a conventional excipient.

[0163] Pharmaceutical formulations of the present invention include those suitable for oral, parenteral [including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion) and intraarticular], inhalation (including fine particle powders or sprays that can be produced by means of various types of metered pressurized aerosols), nebulizer or inhaler, rectal, intraperitoneal and topical (including dermal, buccal, sublingual and intraocular) administration, although the most appropriate route may depend, for example, on the condition and state of the recipient.

[0164] In a fourth aspect, the present invention provides a use of a pyrrolo[2,3-c]pyridine compound as shown in formula I, which can be specifically used to prepare a bromodomain inhibitor for non-therapeutic inhibition of tumor cell growth in vitro or a combination thereof, and its use in the treatment or prevention of diseases in which BET plays a role.

[0165] Preferably, the pyrrolo[2,3-c]pyridine compounds of formula I described in the present invention are used for preparing drugs for treating or preventing diseases in which BET plays a role.

[0166] Preferably, the pyrrolo[2,3-c]pyridine compound of formula I described in the present invention is used for preparing ALK targeted drugs.

[0167] Preferably, the disease in which the BET plays a role includes an inflammatory disease or a cancer or an AIDS disease, and the specific cancer includes but is not limited to: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysproliferative changes) (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendotheliosarcoma (lymphagioendotheliosarcoma), lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and hyperplasia of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus , T-cell or B-cell origin lymphoid malignancies, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat adenoma, thyroid cancer, primary macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.Specific inflammatory diseases include, but are not limited to, Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous dermatoses, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, localized pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis and Wegener's granulomatosis. Particular AIDS diseases include, but are not limited to, individual obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, fatty liver, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy.

[0168] Preferably, the treatment refers to a method of alleviating or relieving the symptoms of a disease and its complications; the prevention refers to reducing or eliminating the symptoms or the onset of complications of a disease, condition or disorder.

[0169] Beneficial effects of the present invention: The present invention provides a pyrrolo[2,3-c]pyridine compound as shown in Formula I with a new mother core structure, which has a strong BET inhibitory effect and can be used to treat a series of diseases in which BET plays a role.

[0170] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (including embodiments) can be combined with each other to form new or preferred technical solutions.

[0171] Explanation of terms

[0172] Listed below are definitions of various terms used to describe this application. These definitions apply to the terms as used throughout the specification and claims, unless otherwise limited in specific cases, either individually or as part of a larger group.

[0173] The term "alkyl" in the present invention refers to a saturated straight or branched hydrocarbon group, which in certain embodiments contains 1 to 6 carbon atoms, C 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, or the like.

[0174] The term "halogenated" in the present invention refers to a group formed by a halogen atom replacing a hydrogen atom on a carbon atom, wherein the halogen atom includes but is not limited to F, Cl, Br, and I.

[0175] The term "alkoxy" in the present invention refers to -O-alkyl, wherein the alkyl is not limited to C 1-6 Alkyl and C 3-6 Specific examples of cycloalkyl include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and halogenated forms thereof.

[0176] The term "aryl" in the present invention refers to (i) an optionally substituted monocyclic or fused polycyclic aromatic carbocyclic ring (the ring structure has carbon atoms), preferably having 5 to 12 atoms per ring. Examples of aryl include phenyl, naphthyl, etc.; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety, wherein phenyl and C 5-7 Cycloalkyl or C 5-7 Cycloalkenyl groups are fused together to form a ring structure, for example tetrahydronaphthyl, indenyl or indanyl. This group can be a terminal group or a bridging group.

[0177] The term "arylalkyl" in the present invention is wherein the aryl and alkyl parts are as described above. Exemplary arylalkyl groups include benzyl, phenethyl, benzyl, naphthylmethyl and the like.

[0178] The term "heterocycloalkyl" of the present invention refers to a monocyclic or polycyclic non-aromatic ring system containing 2 to 6 ring carbon atoms and 1 to 3 ring heteroatoms, wherein the heteroatoms are selected from N, O, and S.

[0179] The term "cycloalkyl" in the present invention refers to a monovalent group of a monocyclic or polycyclic saturated or partially unsaturated carbocyclic compound, C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0180] The term "heteroaryl" of the present invention refers to a group containing an aromatic ring (preferably a 5-membered or 6-membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring and the remaining ring atoms being carbon atoms, wherein the heteroatoms are selected from N, S, and O. Examples of heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, and the like, and the group may be a terminal group or a bridging group.

[0181] The term "heteroarylalkyl" of the present invention wherein the aryl and alkyl moieties are as described above. Preferably the heteroarylalkyl contains a lower alkyl moiety. Exemplary heteroarylalkyls include pyrrolylmethyl, benzimidazolylmethyl, imidazolylmethyl, and the like.

[0182] The term "alkylamino" of the present invention refers to the group -N-alkyl, wherein the alkyl group is not limited to C 1-6 Alkyl and C 3-6Specific examples of cycloalkyl include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino and the like.

[0183] The "effective amount" mentioned in the present invention refers to a dose that can achieve the desired therapeutic effect in the desired subject without causing excessive negative effects. The specific dose can usually be determined by technicians in this field according to needs.

[0184] The term "treatment" as used herein refers to a method of alleviating or alleviating the symptoms of a disease and its complications; the term "prevention" as used herein refers to reducing or eliminating the symptoms or onset of complications of a disease, condition or disorder.

[0185] It should be understood that other terms not explained above but appearing in the present invention should be defined according to the common understanding of those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0186] Figure 1 : H NMR spectrum of intermediate 2 in Example 1 of the present invention.

[0187] Figure 2 : H NMR spectrum of intermediate 3 in Example 1 of the present invention.

[0188] Figure 3 : H NMR spectrum of intermediate 4 of Example 1 of the present invention.

[0189] Figure 4 : H NMR spectrum of compound 1 of Example 1 of the present invention.

[0190] Figure 5 : H-NMR spectrum of intermediate 4 of Example 33 of the present invention.

[0191] Figure 6 : H-NMR spectrum of intermediate 5 of Example 33 of the present invention.

[0192] Figure 7 : H-NMR spectrum of intermediate 6 of Example 33 of the present invention.

[0193] Figure 8 : H-NMR spectrum of intermediate 7 of Example 33 of the present invention.

[0194] Fig. 9 : H-NMR spectrum of intermediate 8 in Example 33 of the present invention.

[0195] Fig.10 : H NMR spectrum of compound 33 of Example 33 of the present invention. DETAILED DESCRIPTION

[0196] The present invention is further described below by way of examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention, so simple improvements to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0197] The structures of the compounds and intermediates are determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS); the accompanying drawings of the present specification list representative relevant intermediates and complete routes of compounds (such as Example 1 and Example 33). The intermediates prepared in other embodiments have the same or similar spectra. The specific compounds 1 H-NMR see the examples for characterization data.

[0198] The known starting materials of the present invention can be synthesized by methods known in the art, or purchased.

[0199] Example 1

[0200] Preparation of 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0201]

[0202] Step 1: Preparation of 2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethylene-1-amine (SM-1a)

[0203]

[0204] Take 5-bromo-2-methoxy-4-methyl-3-nitropyridine (SM-1, 50 g), N,N-dimethylformamide dimethyl acetal (81 g) and N,N-dimethylformamide (80 mL) and add them to a single-mouth bottle, mix well, and heat to 110 ° C for 2 hours. After the reaction is completed, cool to room temperature, add purified water (3000 mL) to the reaction solution, let it stand until the precipitate is solid, filter, collect the solid, and dry it at room temperature to obtain 55 g of brown-red solid, i.e. 2-(5-bromo-2-methoxy-3-nitropyridine-4-yl)-N,N-dimethylethylene-1-amine (SM-1a).

[0205] LCMS: m / z = 302.83 [M+H] + .

[0206] Step 2: Preparation of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-2)

[0207]

[0208] The brown-red solid (SM-1a, 55 g) obtained in the first step was dissolved in dichloromethane (1000 mL), purified water (1000 mL) and zinc powder (75 g) were added, and glacial acetic acid (50 mL) was slowly added dropwise while stirring, and the addition was completed over about 15 min; after the reaction was completed, diatomaceous earth was filtered, purified water (2000 mL) was added to the filtrate, and the pH was adjusted to about 7 with solid sodium bicarbonate, and diatomaceous earth was filtered again, and the filtrate was separated into phases to collect the dichloromethane layer, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; dichloromethane (100 mL) was added to the residue for washing, and the solid was collected by filtration to obtain 25 g of white solid powder, i.e. 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-2).

[0209] LCMS: m / z = 228.16 [M+H] + .

[0210] Step 3: Preparation of 4-bromo-7-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine (SM-3)

[0211]

[0212] To a solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-2, 23 g) in dichloromethane (500 mL) were added p-toluenesulfonyl chloride (23.2 g), sodium hydroxide (6.1 g) and tetrabutylammonium bromide (1.63 g), and the mixture was stirred at room temperature for about 4 hours. After the reaction was completed, the mixture was washed with water (500 mL), the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 (v / v)) to obtain 31 g of the target product as a white solid, i.e., 4-bromo-7-methoxy-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine (SM-3).

[0213] LCMS: m / z = 383.28 [M+H] + .

[0214] Step 4: Preparation of 4-bromo-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (SM-3a)

[0215]

[0216] The white solid obtained in the third step (SM-3, 15.2 g) was suspended in a mixture of 30% hydrochloric acid ethanol (30 mL) and ethyl acetate (50 mL). The mixture was heated and stirred at 45°C for about 5 hours. After the reaction was completed, the solvent was directly evaporated under reduced pressure to obtain a white residue, namely 4-bromo-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (SM-3a).

[0217] Step 5: Preparation of 4-bromo-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate I)

[0218]

[0219] To the white residue prepared in the fourth step (SM-3a) were added N,N-dimethylformamide (200 mL), potassium carbonate (16.5 g) and iodomethane (3.9 mL), and the mixture was stirred at room temperature overnight. After the reaction was completed, water (1000 mL) was added for dilution, and ethyl acetate was extracted twice (200 mL*2). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1 (v / v)) to obtain 13.15 g of a white solid, i.e., 4-bromo-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 1).

[0220] LCMS: m / z=381.36 [M+H] + .

[0221] Step 6: Preparation of 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (SM-6)

[0222]

[0223] Anhydrous sodium sulfate (5 g) and 4-fluoro-5-nitrophenylboronic acid (SM-5, 5 g) were added to a solution of pinacol (3.2 g) in diethyl ether (80 mL), and the mixture was stirred at room temperature for about 2 hours. After the reaction was completed, the sodium sulfate solid was filtered out and the filtrate was directly evaporated to dryness under reduced pressure to obtain 7 g of a slightly light pink translucent solid, i.e., 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (SM-6), which could be directly used in the next step without purification.

[0224] Step 7: Preparation of 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2)

[0225]

[0226] 4-Bromo-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 1, 3 g), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (SM-6, 3.15 g), tripotassium phosphate trihydrate (5.0 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.32 g) and toluene (40 mL) were added to a single-mouth bottle, and the reaction system was replaced with nitrogen and repeated three times. The mixture was stirred at 40 °C for 1 h. The mixture was stirred at 95°C for about 4 hours. After the reaction was completed, the mixture was diluted with purified water (200 mL), extracted with dichloromethane 3 times (200 mL*3), the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1 to 1:1 (v / v)) to obtain 3.44 g of a light yellow solid, i.e., 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2).

[0227] 1 H-NMR (600MHz, DMSO-d6) δ: 8.36-8.33 (m, 2H), 8.04 (d, J = 3.54Hz, 1H), 7.99 (d, = 8.34Hz, 2H), 7.76 (s, 1H ),7.67-7.64(m,1H),7.44(d,J=8.28Hz,2H),6.53(dd,J=3.18Hz,3.18Hz,1H),3.48(s,1H),2.39(s,3H);

[0228] LCMS: m / z=442.11[M+H] + .

[0229] Step 8: Preparation of 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3)

[0230]

[0231] The light yellow solid prepared in step 7 (intermediate 2, 0.9 g) was dissolved in N,N-dimethylformamide (15 mL) solution, 2,4-difluorophenol (SM-7, 0.75 g) and potassium carbonate (0.84 g) were added, and the mixture was heated at 110° C. for 2 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3). After the organic phases were combined, they were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.78 g of solid, i.e. 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0232] 1 H-NMR (600MHz, DMSO-d6) δ: 12.13 (s, 1H), 8.32 (d, J = 2.88Hz, 1H), 8.21 (dd, J = 9.12Hz, 2.88Hz, 1H), 7.57-7.53 (m, 1H), 7.50-7.46 ( m,2H),7.31(dd,J=2.76Hz,2.76Hz,1H),7.21-7.18(m,1H),6.97(d,J=9.06Hz,1H),6.31(dd,J=2.34Hz,2.34Hz,1H),3.59(s,3H);

[0233] LCMS: m / z=398.11[M+H] + .

[0234] Step 9: Preparation of 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4)

[0235]

[0236] 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3, 0.78 g) was dissolved in methanol / water (20 mL, V 甲醇 :V 水=5:1) mixed solvent, add excess zinc powder (0.64g), stir and slowly add excess glacial acetic acid (0.6mL); after the reaction is completed, filter through diatomaceous earth, wash with appropriate amount of dichloromethane, add saturated sodium bicarbonate solution (50mL) to the filtrate to adjust the pH value to about 7, filter through diatomaceous earth again, separate the filtrate into phases, collect the dichloromethane layer, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure; the residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 to 1:2 (v / v)) to obtain 0.65g of white solid, i.e. 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 4).

[0237] 1 H-NMR (600MHz, DMSO-d6) δ: 11.96 (s, 1H), 7.25-7.21 (m, 2H), 7.18 (s, 1H), 6.86-6.83 (m, 1H), 6.79-6.74 (m, 2H), 6. 72(d,J=2.76Hz,1H),6.58(dd,J=8.58Hz,2.76Hz,1H),6.21(dd,J=2.34Hz,2.34Hz,1H),5.10(s,2H),3.48(s,3H);

[0238] LCMS: m / z=368.12 [M+H] + .

[0239] Step 10: Preparation of 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 1)

[0240]

[0241] 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4, 110 mg) was dissolved in dichloromethane (3 mL) solution, succinic anhydride (SM-8, 57 mg) was added to the solution, and the mixture was stirred at room temperature for about 5 hours, and N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 140 mg) and triethylamine (0.3 mL), the mixture was stirred at room temperature for about 2-8 hours; after the reaction, the mixture was diluted with water and extracted with ethyl acetate 2-3 times, the organic phases were combined and washed with water once, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1 to 0: 1 (v / v)) to obtain 90 mg of a white solid, i.e., 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 1).

[0242] 1 H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 7.47-7.42 (m, 2H), 7.34 (s, 1H), 7.31-7.26 (m, 2H), 7.22 (dd, J = 8.70Hz, 2 .52Hz,1H),7.11-7.10(m,1H),6.93(d,J=8.70Hz,1H),6.33(dd,J=2.34Hz,2.34Hz,1H),3.55(s,3H),2.78(s,4H);

[0243] MS-ESI (m / z): 450.14 [M+H] + .

[0244] Example 2

[0245] Preparation of 1-(4-(4-chlorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0246]

[0247] Referring to steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-chlorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0248]

[0249] The light yellow solid prepared in step 7 (intermediate 2, 0.9 g) was dissolved in N,N-dimethylformamide (15 mL) solution, 4-chlorophenol (SM-7, 0.79 g) and potassium carbonate (0.84 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.75 g of solid, i.e. 4-(2-(4-chlorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0250] LCMS: m / z=396.36 [M+H] + .

[0251] After preparing 4-(2-(4-chlorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3), intermediate 3 was used as a raw material and the method of steps 9-10 of Example 1 was referred to to prepare the target product 1-(4-(4-chlorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (compound 2).

[0252] 1H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 7.47 (d, J = 2.52Hz, 1H), 7.35 (d, J = 9.00Hz, 2H), 7.31 (s, 1H), 7.30 (dd, J = 2.76Hz, 2.76Hz, 1H), 7. 28(dd,J=8.64Hz,2.52Hz,1H),7.14(d,J=8.70Hz,1H),6.97(d,J=9.00Hz,2H),6.31(dd,J=2.64Hz,2.16Hz,1H),3.51(s,3H),2.79(s,4H);

[0253] MS-ESI (m / z): 449.10 [M+H] + .

[0254] Example 3

[0255] Preparation of 1-(4-(4-bromophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0256]

[0257] Referring to steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-bromophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0258]

[0259] The light yellow solid prepared in step 7 (intermediate 2, 0.9 g) was dissolved in N,N-dimethylformamide (15 mL) solution, 4-bromophenol (SM-7, 1.03 g) and potassium carbonate (0.84 g) were added, and the mixture was heated at 110 ° C for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1 to 1: 1 (v / v)) to obtain 0.82 g of solid, i.e. 4-(2-(4-bromophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0260] LCMS: m / z=440.78 [M+H] + .

[0261] After preparing 4-(2-(4-bromophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3), intermediate 3 was used as a raw material and the method of steps 9-10 of Example 1 was referred to to prepare the target product 1-(4-(4-bromophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (compound 3).

[0262] 1 H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 7.49-7.46 (m, 3H), 7.31 (s, 1H), 7.30-7.29 (m, 1H), 7.27 (d, J = 2.52Hz, 1H),7.15(d,J=8.70Hz,1H),6.91(d,J=9.00Hz,2H),6.31(dd,J=2.64Hz,2.16Hz,1H),3.51(s,3H),2.79(s,4H);

[0263] MS-ESI (m / z): 493.15 [M+H] + .

[0264] Example 4

[0265] Preparation of 1-(4-(2,4-difluorophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0266]

[0267] 4-Bromo-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 1) was prepared by referring to Steps 1-5 of Example 1.

[0268] Step 6: Preparation of 2-(2-fluoro-4-methyl-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (SM-6)

[0269]

[0270] 1-Bromo-2-fluoro-4-methyl-5-nitrobenzene (SM-5, 3 g), bipyraclostrobin (4.88 g), potassium acetate (3.77 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.52 g) and dioxane (90 mL) were added to a 250 mL single-mouth bottle. The mixture was stirred overnight at 90 ° C under nitrogen protection. After the reaction was completed, the mixture was filtered with diatomaceous earth, and the filtrate was directly evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1 (v / v)) to obtain 2.9 g of an off-white solid, i.e., 2-(2-fluoro-4-methyl-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (SM-6).

[0271] Step 7 Preparation of 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2)

[0272]

[0273] Take 4-bromo-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 1, 2 g), 2-(2-fluoro-4-methyl-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (SM-6, 1.92 g), tripotassium phosphate trihydrate (3.34 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.21 g) and toluene (80 mL) and add them into a single-necked bottle. The reaction system was replaced with nitrogen and repeated three times, and the mixture was stirred at 90° C. overnight. After the reaction was completed, 200-mesh silica gel was directly added to mix the sample, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1 to 1:1 (v / v)) to obtain 2.43 g of a light yellow solid, namely 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 2).

[0274] LCMS: m / z=455.36 [M+H]+.

[0275] Step 8: Preparation of 4-(2-(2,4-difluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3)

[0276]

[0277] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 2,4-difluorophenol (SM-7, 0.85 g) and potassium carbonate (0.82 g) were added, and the mixture was heated at 100° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.66 g of solid, i.e. 4-(2-(2,4-difluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0278] LCMS: m / z=411.56 [M+H] + .

[0279] Step 9: Preparation of 4-(5-amino-2-(2,4-difluorophenoxy)-4-methylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4)

[0280]

[0281] 4-(2-(2,4-difluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3, 0.66 g) was dissolved in dichloromethane / methanol / water (100 mL, V 二氯甲烷 :V 甲醇 :V 水 =5:1:1) mixed solvent, add excess zinc powder (3g), and slowly drop excess glacial acetic acid (3mL) under stirring; after the reaction is completed, filter through diatomaceous earth and wash with appropriate amount of dichloromethane, add saturated sodium bicarbonate solution to the filtrate to adjust the pH value to about 7, filter through diatomaceous earth again, separate the filtrate into dichloromethane layers, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure; the residue is purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 30:1 (v / v)) to obtain 0.55g of white solid, i.e. 4-(5-amino-2-(2,4-difluorophenoxy)-4-methylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4).

[0282] LCMS: m / z=381.38 [M+H] + .

[0283] Step 10: Preparation of 1-(4-(2,4-difluorophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 1)

[0284]

[0285] 4-(5-Amino-2-(2,4-difluorophenoxy)-4-methylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4, 130 mg) was dissolved in dichloromethane (3 mL) solution, succinic anhydride (SM-8, 61 mg) was added to the solution, and the mixture was stirred at room temperature for about 1 hour, and N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 138 mg) and triethylamine (0.3 mL) were added thereto. ), the mixture was stirred at room temperature for about 2-8 hours; after the reaction, the mixture was diluted with water and extracted with ethyl acetate 2-3 times, the organic phases were combined and washed with water once, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=200:1 to 100:1 (v / v)) to obtain 93 mg of a white solid, i.e., 1-(4-(2,4-difluorophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 4).

[0286] 1 H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 7.45 (ddd, J = 11.34Hz, 8.82Hz, 3.00Hz, 1H), 7.31 (s, 1H), 7.30-7.29 (m, 2H), 7.27 (td, J = 9.18Hz, 5. 58Hz,1H),7.10-7.07(m,1H),6.78(s,1H),6.27(dd,J=2.64Hz,2.22Hz,1H),3.54(s,3H),2.89-2.83(m,2H),2.82-2.76(m,2H),2.03(s,3H);

[0287] MS-ESI (m / z): 464.13 [M+H] + .

[0288] Example 5

[0289] Preparation of 1-(4-(4-chlorophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0290]

[0291] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-chlorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0292]

[0293] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 4-chlorophenol (SM-7, 0.83 g) and potassium carbonate (0.85 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.67 g of solid, i.e. 4-(2-(4-chlorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0294] LCMS: m / z=410.11[M+H] + .

[0295] After preparing 4-(2-(4-chlorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3), intermediate 3 was used as a raw material and the method of steps 9-10 of Example 4 was referred to to prepare the target product 1-(4-(4-chlorophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (compound 5).

[0296] 1H-NMR (600MHz, DMSO-d6) δ: 12.03 (s, 1H), 7.36-7.33 (m, 3H), 7.28 (dd, J = 2.76Hz, 2.76Hz, 1H), 7.25 (s, 1H), 7.01 (s, 1H), 6.96(d,J=8.94Hz,2H),6.25(dd,J=2.28Hz,2.28Hz,1H),3.50(s,3H),2.90-2.84(m,2H),2.83-2.77(m,2H),2.07(s,3H);

[0297] MS-ESI (m / z): 463.22 [M+H] + .

[0298] Example 6

[0299] Preparation of 1-(2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl)pyrrolidine-2,5-dione

[0300]

[0301] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 6-methyl-4-(4-methyl-5-nitro-2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0302]

[0303] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, phenol (SM-7, 0.83 g) and potassium carbonate (0.85 g) were added, and the mixture was heated at 110 ° C for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1 to 1: 1 (v / v)) to obtain 0.67 g of solid, i.e. 6-methyl-4-(4-methyl-5-nitro-2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0304] LCMS: m / z=375.67 [M+H] + .

[0305] After preparing 6-methyl-4-(4-methyl-5-nitro-2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3), intermediate 3 was used as a raw material and the method of steps 9-10 of Example 4 was referred to to prepare the target product 1-(2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-phenoxyphenyl)pyrrolidine-2,5-dione (compound 6).

[0306] 1 H-NMR (600MHz, DMSO-d6) δ: 12.02 (s, 1H), 7.34-7.31 (m, 3H), 7.28 (dd, J = 2.76Hz, 2.76Hz, 1H), 7.26 (s, 1H), 7.07 (dd, J = 7.38Hz, 7.38Hz, 1H), 6 .96(dd,J=8.51Hz,0.96Hz,2H),6.94(s,1H),6.27(dd,J=2.28Hz,2.28Hz,1H),3.50(s,3H),2.90-2.84(m,2H),2.83-2.77(m,2H),2.05(s,3H);

[0307] MS-ESI (m / z): 428.16 [M+H] + .

[0308] Example 7

[0309] Preparation of 1-(4-(4-bromophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)2,5-diketopyrrolidine

[0310]

[0311] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-bromophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0312]

[0313] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 4-bromophenol (SM-7, 0.92 g) and potassium carbonate (0.85 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.72 g of solid, i.e. 4-(2-(4-bromophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0314] LCMS: m / z = 454.76 [M+H] + .

[0315] After preparing 4-(2-(4-bromophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3), intermediate 3 was used as a raw material and the method of steps 9-10 of Example 4 was referred to to prepare the target product 1-(4-(4-bromophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)2,5-diketopyrrolidine (compound 7).

[0316] 1 H-NMR (600MHz, DMSO-d6) δ: 12.04 (s, 1H), 7.47 (d, J = 8.94Hz, 2H), 7.35 (s, 1H), 7.28 (dd, J = 2.70Hz, 2.70Hz, 1H), 7.25 (s, 1H), 7.03 (s,1H),6.90(d,J=8.88Hz,2H),6.25(dd,J=2.22Hz,2.22Hz,1H),3.50(s,3H),2.90-2.84(m,2H),2.83-2.77(m,2H),2.07(s,3H);

[0317] MS-ESI (m / z): 507.23 [M+H] + .

[0318] Example 8

[0319] Preparation of 1-(4-(4-bromo-3-fluorophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0320]

[0321] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-bromo-3-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0322]

[0323] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 4-bromo-3-fluorophenol (SM-7, 0.92 g) and potassium carbonate (0.85 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.72 g of solid, i.e. 4-(2-(4-bromo-3-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0324] LCMS: m / z = 454.76 [M+H] + .

[0325] After preparing 4-(2-(4-bromo-3-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3), intermediate 3 was used as a raw material and the method of steps 9-10 of Example 4 was referred to to prepare the target product 1-(4-(4-bromo-3-fluorophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (compound 8).

[0326] 1H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 7.59 (dd, J = 8.58Hz, 8.58Hz, 1H), 7.37 (s,1H),7.29(dd,J=2.76Hz,2.76Hz,1H),7.25(s,1H),7.12(s,1H),7.01(dd,J=1 0.08Hz, 2.76Hz, 1H), 6.73 (ddd, J=8.82Hz, 2.76Hz, 0.90Hz, 1H), 6.24 (dd, J=2.64 Hz,2.10Hz,1H),3.50(s,3H),2.91-2.85(m,2H),2.83-2.77(m,2H),2.09(s,3H);

[0327] MS-ESI (m / z): 525.34 [M+H]+.

[0328] Example 9

[0329] Preparation of 1-(4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0330]

[0331] Referring to Steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(2-chloro-4-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in Step 8:

[0332]

[0333] The light yellow solid prepared in step 7 (intermediate 2, 0.9 g) was dissolved in N,N-dimethylformamide (15 mL) solution, 2-chloro-4-fluorophenol (SM-7, 0.83 g) and potassium carbonate (0.86 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.78 g of solid, i.e. 4-(2-(2-chloro-4-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0334] LCMS: m / z = 414.05 [M+H] + .

[0335] After preparing 4-(2-(2-chloro-4-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), intermediate 3 was used as a raw material and the method of steps 9-10 of Example 1 was referred to to prepare the target product 1-(4-(2-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 9).

[0336] 1 H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 7.47 (d, J = 2.52Hz, 1H), 7.40 (s, 1H), 7.31 (dd, J = 2.76Hz, 2.76Hz, 1H), 7.24 (dd, J = 8.76Hz, 2 .58Hz,1H),7.22-7.18(m,1H),7.17-7.15(m,1H),6.92(d,J=8.70Hz,1H),6.37(dd,J=2.28Hz,2.28Hz,1H),3.54(s,3H),2.78(s,4H);

[0337] MS-ESI (m / z): 467.19 [M+H] + .

[0338] Example 10

[0339] Preparation of 1-(4-(4-chloro-2-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0340]

[0341] Referring to steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-chloro-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0342]

[0343] The light yellow solid prepared in step 7 (intermediate 2, 0.9 g) was dissolved in N,N-dimethylformamide (15 mL) solution, 4-chloro-2-fluorophenol (SM-7, 0.85 g) and potassium carbonate (0.86 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.76 g of solid, i.e. 4-(2-(4-chloro-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0344] LCMS: m / z=414.21[M+H] + .

[0345] After preparing 4-(2-(4-chloro-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 1 was referred to to prepare the target product 1-(4-(4-chloro-2-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 10).

[0346] 1H-NMR (600MHz, DMSO-d6) δ: 12.08 (s, 1H), 7.60 (dd, J = 10.68Hz, 2.46Hz, 1H), 7.45 (d, J = 2.52Hz, 1H), 7.34 (s, 1H), 7.30 (dd, J = 2.76Hz, 2.76Hz ,1H),7.26-7.24(m,2H),7.17(dd,J=8.82Hz,8.82Hz,1H),7.04(d,J=8.70Hz,1H),6.31(dd,J=2.22Hz,2.22Hz,1H),3.54(s,3H),2.78(s,4H);

[0347] MS-ESI (m / z): 467.23 [M+H] + .

[0348] Embodiment 11

[0349] Preparation of 1-(4-(3-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0350]

[0351] Referring to steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(3-chloro-4-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0352]

[0353] The light yellow solid prepared in step 7 (intermediate 2, 0.9 g) was dissolved in N,N-dimethylformamide (15 mL) solution, 3-chloro-4-fluorophenol (SM-7, 0.85 g) and potassium carbonate (0.86 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.76 g of solid, i.e. 4-(2-(3-chloro-4-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0354] LCMS: m / z=414.08 [M+H] + .

[0355] After preparing 4-(2-(3-chloro-4-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 1 was referred to to prepare the target product 1-(4-(3-chloro-4-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 11).

[0356] 1 H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 7.46 (d, J = 2.52Hz, 1H), 7.36 (dd, J = 9 .06Hz, 9.06Hz, 1H), 7.34 (s, 1H), 7.31 (dd, J=2.76Hz, 2.76Hz, 1H), 7.28 (dd, J= 8.70Hz, 2.52Hz, 1H), 7.24 (dd, J=6.18Hz, 2.94Hz, 1H), 7.13 (d, J=8.70Hz, 1H), 7.00-6.97(m,1H),6.32(dd,J=2.58Hz,2.16Hz,1H),3.52(s,3H),2.79(s,4H);

[0357] MS-ESI (m / z): 467.45 [M+H]+.

[0358] Example 12

[0359] Preparation of 1-(4-(4-chloro-3-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0360]

[0361] Referring to steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-chloro-3-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0362]

[0363] The light yellow solid prepared in step 7 (intermediate 2, 0.9 g) was dissolved in N,N-dimethylformamide (15 mL) solution, 4-chloro-3-fluorophenol (SM-7, 0.85 g) and potassium carbonate (0.86 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.71 g of solid, i.e. 4-(2-(4-chloro-3-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0364] LCMS: m / z = 414.37 [M+H] + .

[0365] After preparing 4-(2-(4-chloro-3-fluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), intermediate 3 was used as a raw material and the method of steps 9-10 of Example 1 was referred to to prepare the target product 1-(4-(4-chloro-3-fluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 12).

[0366] 1 H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 7.50-7.47 (m, 2H), 7.32-7.30 (m, 3H), 7.23 (d, J = 8.70Hz, 1H), 7.06 (dd, J = 10.5 6Hz, 2.76Hz, 1H), 6.79 (ddd, J=8.88Hz, 2.82Hz, 1.08Hz, 1H), 6.31 (dd, J=2.58Hz, 2.10Hz, 1H), 3.51 (s, 3H), 2.80 (s, 4H);

[0367] MS-ESI (m / z): 467.32 [M+H] + .

[0368] Example 13

[0369] Preparation of 1-(4-(4-chloro-2-methylphenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0370]

[0371] Referring to Steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-chloro-2-methylphenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in Step 8:

[0372]

[0373] The light yellow solid prepared in step 7 (intermediate 2, 0.9 g) was dissolved in N,N-dimethylformamide (15 mL) solution, 4-chloro-2-methylphenol (SM-7, 0.85 g) and potassium carbonate (0.84 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.77 g of solid, i.e. 4-(2-(4-chloro-2-methylphenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0374] LCMS: m / z = 410.22 [M+H] + .

[0375] After preparing 4-(2-(4-chloro-2-methylphenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 1 was referred to to prepare the target product 1-(4-(4-chloro-2-methylphenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 13).

[0376] 1H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 7.46 (d, J = 2.46Hz, 1H), 7.34-7.33 (m, 2H), 7.31 (dd, J = 2.76Hz, 2.76Hz, 1H), 7.24 (dd, J = 8.70Hz, 2.52Hz, 1H), 7 .17(dd,J=8.70Hz,2.58Hz,1H),6.97(d,J=8.64Hz,1H),6.80(d,J=8.70Hz,1 H),6.33(dd,J=2.22Hz,2.22Hz,1H),3.52(s,3H),2.79(s,4H),2.13(s,3H);

[0377] MS-ESI (m / z): 463.51 [M+H] + .

[0378] Embodiment 14

[0379] Preparation of 1-(4-(4-chloro-2-methylphenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0380]

[0381] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-chloro-2-methylphenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0382]

[0383] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 4-chloro-2-methylphenol (SM-7, 0.85 g) and potassium carbonate (0.88 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.67 g of solid, i.e. 4-(2-(4-chloro-2-methylphenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0384] LCMS: m / z = 424.17 [M+H] + .

[0385] After preparing 4-(2-(4-chloro-2-methylphenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 4 was referred to to prepare the target product 1-(4-(4-chloro-2-methylphenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 14).

[0386] 1 H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 7.34 (s, 1H), 7.32 (dd, J = 2.64Hz, 0.54Hz, 1H), 7.30 (dd, J = 2.76Hz, 2.76Hz, 1H), 7.27 (s, 1H), 7.16 (ddd, J = 8.70 Hz,2.70Hz,0.42Hz,1H),6.84(s,1H),6.79(d,J=8.70Hz,1H),6.26(dd,J=2. 64Hz,2.10Hz,1H),3.51(s,3H),2.89-2.77(m,4H),2.13(s,3H),2.05(s,3H);

[0387] MS-ESI (m / z): 477.33 [M+H] + .

[0388] Embodiment 15

[0389] Preparation of 1-(4-(4-chloro-3-fluorophenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0390]

[0391] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-chloro-3-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0392]

[0393] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 4-chloro-3-fluorophenol (SM-7, 0.85 g) and potassium carbonate (0.95 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.65 g of solid, i.e. 4-(2-(4-chloro-3-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0394] LCMS: m / z = 428.09 [M+H] + .

[0395] After preparing 4-(2-(4-chloro-3-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 4 was referred to to prepare the target product 1-(4-(4-chloro-3-fluorophenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 15).

[0396] 1H-NMR (600MHz, DMSO-d6) δ: 12.04 (s, 1H), 7.49 (dd, J = 8.82Hz, 8.82Hz, 1H), 7.37(s,1H),7.29(dd,J=2.76Hz,2.76Hz,1H),7.26(s,1H),7.11(s,1H),7.0 5(dd,J=10.56Hz,2.76Hz,1H),6.78(ddd,J=8.88Hz,2.82Hz,1.08Hz,1H),6. 25(dd,J=2.64Hz,2.16Hz,1H),3.50(s,3H),2.92-2.76(m,4H),2.09(s,3H);

[0397] MS-ESI (m / z): 481.25 [M+H] + .

[0398] Example 16

[0399] Preparation of 1-(4-(2-chloro-4-methoxyphenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0400]

[0401] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(2-chloro-4-methoxyphenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0402]

[0403] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 2-chloro-4-methoxyphenol (SM-7, 0.90 g) and potassium carbonate (0.95 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.69 g of solid, i.e. 4-(2-(2-chloro-4-methoxyphenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0404] LCMS: m / z=440.13 [M+H] + .

[0405] After preparing 4-(2-(2-chloro-4-methoxyphenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 4 was referred to to prepare the target product 1-(4-(2-chloro-4-methoxyphenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 16).

[0406] 1 H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 7.30 (dd, J = 2.82Hz, 2.82Hz, 1H), 7.17 (d, J = 2.88Hz, 1H), 7.15 (d, J = 9.00Hz ,1H),6.93(dd,J=9.00Hz,3.00Hz,1H),6.61(s,1H),6.33(dd,J=2.58Hz,2.16Hz,1H),3.77(s,3H),3.55(s,3H),2.90-2.74(m,4H),2.01(s,3H);

[0407] MS-ESI (m / z): 493.12 [M+H]+.

[0408] Embodiment 17

[0409] Preparation of 1-(4-(3-chloro-4-fluorophenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0410]

[0411] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(3-chloro-4-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0412]

[0413] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 3-chloro-4-fluorophenol (SM-7, 0.85 g) and potassium carbonate (0.95 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.67 g of solid, i.e. 4-(2-(3-chloro-4-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0414] LCMS: m / z=428.15[M+H] + .

[0415] After preparing 4-(2-(3-chloro-4-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), intermediate 3 was used as a raw material and the method of steps 9-10 of Example 4 was referred to to prepare the target product 1-(4-(3-chloro-4-fluorophenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 17).

[0416] 1H-NMR (600MHz, DMSO-d6) δ: 12.04 (s, 1H), 7.37-7.34 (m, 2H), 7.29 (dd, J = 2.82Hz, 2.82Hz, 1H), 7.28 (s, 1H), 7.22 (dd, J = 6.18H z,2.94Hz,1H),7.01(s,1H),6.99-6.96(m,1H),6.26(dd,J=2.64Hz,2.16Hz,1H),3.51(s,3H),2.92-2.75(m,4H),2.07(s,3H);

[0417] MS-ESI (m / z): 481.16 [M+H]+.

[0418] Embodiment 18

[0419] Preparation of 1-(4-(3,4-dichlorophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0420]

[0421] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(3,4-dichlorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0422]

[0423] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 3,4-dichlorophenol (SM-7, 0.92 g) and potassium carbonate (0.95 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.71 g of solid, i.e. 4-(2-(3,4-dichlorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0424] LCMS: m / z = 444.27 [M+H] + .

[0425] After preparing 4-(2-(3,4-dichlorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 4 was referred to to prepare the target product 1-(4-(3,4-dichlorophenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 18).

[0426] 1 H-NMR (600MHz, DMSO-d6) δ: 12.04 (s, 1H), 7.52 (d, J = 8.88Hz, 1H), 7.37 (s, 1H), 7.29 (dd, J = 2.76Hz, 2.76Hz, 1H), 7.26 (s, 1H), 7.20 (d, J = 2 .82Hz,1H),7.11(s,1H),6.92(dd,J=8.88Hz,2.88Hz,1H),6.24(dd,J=2.58Hz,2.16Hz,1H),3.50(s,3H),2.92-2.76(m,4H),2.10(s,3H);

[0427] MS-ESI (m / z): 497.28 [M+H] + .

[0428] Embodiment 19

[0429] Preparation of 1-(4-(4-chloro-2-fluorophenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0430]

[0431] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-chloro-2-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0432]

[0433] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 4-chloro-2-fluorophenol (SM-7, 0.85 g) and potassium carbonate (0.88 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.68 g of solid, i.e. 4-(2-(4-chloro-2-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0434] LCMS: m / z = 428.24 [M+H] + .

[0435] After preparing 4-(2-(4-chloro-2-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 4 was referred to to prepare the target product 1-(4-(4-chloro-2-fluorophenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 19).

[0436] 1 H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 7.59 (dd, J = 10.68Hz, 2.46Hz, 1H), 7.33 (s, 1H), 7.29 (dd, J = 2.76Hz, 2.76Hz, 1H), 7.28 (s, 1H), 7.2 5-7.24(m,1H),7.16(dd,J=8.82z,8.82Hz,1H),6.91(s,1H),6.26(dd,J=2.28Hz,2.28Hz,1H),3.53(s,3H),2.91-2.75(m,4H),2.06(s,3H);

[0437] MS-ESI (m / z): 481.15 [M+H] + .

[0438] Embodiment 20

[0439] Preparation of 1-(4-(2-chloro-4-fluorophenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0440]

[0441] Referring to steps 1-7 of Example 4 above, 4-(2-fluoro-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(2-chloro-4-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0442]

[0443] The light yellow solid prepared in step 7 (intermediate 2, 0.8 g) was dissolved in N,N-dimethylformamide (20 mL) solution, 2-chloro-4-fluorophenol (SM-7, 0.85 g) and potassium carbonate (0.88 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.64 g of solid, i.e. 4-(2-(2-chloro-4-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one ((intermediate 3).

[0444] LCMS: m / z = 428.05 [M+H] + .

[0445] After preparing 4-(2-(2-chloro-4-fluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 4 was referred to to prepare the target product 1-(4-(2-chloro-4-fluorophenoxy)-2-methyl-5-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 20).

[0446] 1H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 7.57 (dd, J = 8.34Hz, 2.94Hz, 1H), 7.36 (s, 1H), 7.34 (s, 1H), 7.30 (dd, J = 2.76Hz, 2 .76Hz,1H),7.21-7.14(m,2H),6.79(s,1H),6.30(dd,J=2.58Hz,2.16Hz,1H),3.53(s,3H),2.91-2.76(m,4H),2.05(s,3H);

[0447] MS-ESI (m / z): 481.33 [M+H] + .

[0448] Embodiment 21

[0449] Preparation of 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylpyrrolidine-2,5-dione

[0450]

[0451] Referring to steps 1-9 of Example 1 above, 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 4) was prepared, and then 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylpyrrolidine-2,5-dione was prepared in step 10:

[0452]

[0453] 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4, 110 mg) was dissolved in dichloromethane (3 mL) solution, 3-methylsuccinic anhydride (SM-8, 100 mg) was added to the solution, and the mixture was stirred at room temperature for about 5 hours, and N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 230 mg) and triethylamine ( 0.3 mL), the mixture was stirred at room temperature overnight; after the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate, the organic phases were combined and washed once with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1 to 0: 1 (v / v)) to obtain 95 mg of a white solid, i.e., 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylpyrrolidine-2,5-dione (Compound 21).

[0454] 1 H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 7.47-7.43 (m, 2H), 7.34 (s, 1H), 7.31-7.30 (m, 1H), 7.29-7.26 (m, 1H), 7.23 (dd, J = 8.70Hz, 2.52H z,1H),7.11-7.07(m,1H),6.92(d,J=8.76Hz,1H),6.33(m,1H),3.55(s,3H),3.07-2.96(m,2H),2.49-2.47(m,1H),1.28(d,J=7.08Hz,3H);

[0455] MS-ESI (m / z): 464.13 [M+H] + .

[0456] Embodiment 22

[0457] Preparation of 1-(4-(2,6-dimethylphenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0458]

[0459] Referring to steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(2,6-dimethylphenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0460]

[0461] The light yellow solid prepared in step 7 (intermediate 2, 0.9 g) was dissolved in N,N-dimethylformamide (15 mL) solution, 2,6-dimethylphenol (SM-7, 0.92 g) and potassium carbonate (0.86 g) were added, and the mixture was heated at 110 ° C for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1 to 1: 1 (v / v)) to obtain 0.62 g of solid, i.e. 4-(2-(2,6-dimethylphenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0462] LCMS: m / z=389.75[M+H] + .

[0463] After preparing 4-(2-(2,6-dimethylphenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 1 was referred to to prepare the target product 1-(4-(2,6-dimethylphenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 22).

[0464] 1H-NMR (600MHz, DMSO-d6) δ: 12.11 (s, 1H), 7.404 (d, J = 2.34Hz, 1H), 7.402 (s, 1H), 7.34 (dd, J = 2.76Hz, 2.76Hz, 1H), 7.16 (d, J = 7 .50Hz,2H),7.12-7.08(m,2H),6.45(d,J=8.76Hz,1H),6.33(dd,J=2.28Hz,2.28Hz,1H),3.59(s,3H),2.76(s,4H)2.05(s,6H);

[0465] MS-ESI (m / z): 450.12 [M+H] + .

[0466] Embodiment 23

[0467] Preparation of 1-(4-(4-(hydroxymethyl)phenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0468]

[0469] Referring to steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-(hydroxymethyl)phenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0470]

[0471] The light yellow solid prepared in step 7 (intermediate 2, 0.5 g) was dissolved in N, N-dimethylformamide (5 mL) solution, p-hydroxybenzyl alcohol (SM-7, 0.42 g) and potassium carbonate (0.47 g) were added, and the mixture was heated at 90 ° C for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (200 mL), and extracted with ethyl acetate 3 times (50 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1 to 0: 1 (v / v)) to obtain 0.25 g of solid, i.e. 4-(2-(4-(hydroxymethyl)phenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0472] LCMS: m / z=391.55 [M+H] + .

[0473] After preparing 4-(2-(4-(hydroxymethyl)phenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3), Intermediate 3 was used as a raw material and the method of Steps 9-10 of Example 1 was referred to to prepare the target product 1-(4-(4-(hydroxymethyl)phenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 23).

[0474] 1 H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 7.44 (d, J = 2.46Hz, 1H), 7.33 (s, 1H), 7. 30(dd,J=2.70Hz,2.70Hz,1H),7.28(d,J=8.46Hz,2H),7.24(dd,J=8.70Hz,2.46Hz ,1H),7.02(d,J=8.64Hz,1H),6.95(d,J=8.52Hz,2H),6.34(dd,J=2.16HzHz,2.16 Hz, 1H), 5.13 (t, J = 5.70Hz, 1H), 4.43 (d, J = 5.64Hz, 2H), 3.52 (s, 3H), 2.79 (s, 4H);

[0475] MS-ESI (m / z): 444.15 [M+H]+.

[0476] Embodiment 24

[0477] Preparation of methyl 2-(4-(4-(2,5-dioxopyrrolidin-1-yl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)phenyl)acetate

[0478]

[0479] Referring to steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then methyl 2-(4-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophenoxy)phenyl)acetate (Intermediate 3) was prepared in step 8:

[0480]

[0481] The light yellow solid prepared in step 7 (intermediate 2, 0.5 g) was dissolved in N, N-dimethylformamide (5 mL) solution, p-hydroxybenzyl alcohol (SM-7, 0.65 g) and potassium carbonate (0.85 g) were added, and the mixture was heated at 90 ° C for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (200 mL), and extracted with ethyl acetate 3 times (50 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1 to 0: 1 (v / v)) to obtain 0.28 g of solid, i.e., methyl 2-(4-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophenoxy)phenyl)acetate (intermediate 3).

[0482] LCMS: m / z = 433.86 [M+H] + .

[0483] After preparing methyl 2-(4-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophenoxy)phenyl)acetate (Intermediate 3), intermediate 3 was used as a raw material and the method of steps 9-10 of Example 1 was referred to to prepare the target product methyl 2-(4-(4-(2,5-dioxypyrrolidin-1-yl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)phenyl)acetate (Compound 24).

[0484] 1 H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 7.45 (d, J = 2.52Hz, 1H), 7.32 (s, 1H), 7.30 (dd, J = 2.76Hz, 2.76Hz, 1H), 7.25 (dd, J = 8.70Hz, 2.52Hz, 1H), 7.22 (d,J=8.64Hz,2H),7.05(d,J=8.64Hz,1H),6.94(d,J=8.64Hz,2H),6.33(dd ,J=2.64Hz,2.16Hz,1H),3.62(s,3H),3.60(s,3H),3.51(s,3H)2.79(s,4H);

[0485] MS-ESI (m / z): 486.16 [M+H]+.

[0486] Embodiment 25

[0487] Preparation of 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3,3-dimethylpyrrolidine-2,5-dione

[0488]

[0489] Referring to steps 1-9 of Example 1 above, 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4) was prepared, and then 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3,3-dimethylpyrrolidine-2,5-dione was prepared in step 10:

[0490]

[0491] 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4, 150 mg) was dissolved in dichloromethane (5 mL) solution, 2,2-dimethylsuccinic anhydride (SM-8, 130 mg) was added to the solution, and the mixture was stirred at room temperature for about 5 hours, and N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 230 mg) and triethylamine (0 .3mL), the mixture was stirred at room temperature overnight; after the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate, the organic phases were combined and washed once with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1 to 0:1 (v / v)) to obtain 120 mg of a white solid, i.e., 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3,3-dimethylpyrrolidine-2,5-dione (Compound 25).

[0492] 1H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 7.47-7.44 (m, 2H), 7.34 (s, 1H), 7.31 (dd, J = 2.70Hz, 2.70Hz, 1H), 7.29-7.25 (m ,2H),7.10-7.08(m,1H),6.93(d,J=8.70Hz,1H),6.33(dd,J=2.28Hz,2.28Hz,1H),3.56(s,3H),2.73(s,2H),1.32(s,6H);

[0493] MS-ESI (m / z): 478.15 [M+H] + .

[0494] Embodiment 26

[0495] Preparation of 3-allyl-1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0496]

[0497] Referring to steps 1-9 of Example 1 above, 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 4) was prepared, and then 3-allyl-1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione was prepared in step 10:

[0498]

[0499] 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4, 110 mg) was dissolved in dichloromethane (3 mL) solution, allyl succinic anhydride (SM-8, 130 mg) was added to the solution, and the mixture was stirred at room temperature for about 5 hours, and then N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 230 mg) and triethylamine (0. 3 mL), the mixture was stirred at room temperature overnight; after the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate, the organic phases were combined and washed once with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1 to 0:1 (v / v)) to obtain 125 mg of a white solid, i.e., 3-allyl-1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 26).

[0500] 1 H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 7.47-7.45 (m, 1H), 7.42 (d, J = 1.78Hz, 1H), 7.35 (s, 1H), 7. 31-7.30(m,1H),7.30-7.25(m,1H),7.22(dd,J=8.70Hz,2.52Hz,1H),7.11-7.08(m,1H),6.93(d,J=8. 70Hz,1H),6.327-6.319(m,1H),5.87-5.80(m,1H),5.16(dd,J=17.10Hz,1.56Hz,1H),5.10(d,J=10. 2Hz,1H),3.13-3.09(m,1H),2.93(dd,J=17.88Hz,9.12Hz,1H),2.59-2.50(m,2H),2.42-2.37(m,1H);

[0501] MS-ESI (m / z): 490.15 [M+H] + .

[0502] Embodiment 27

[0503] Preparation of 1-(4-(4-acetylphenoxy)-3-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylpyrrolidine-2,5-dione

[0504]

[0505] Referring to steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-acetylphenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0506]

[0507] The light yellow solid prepared in step 7 (intermediate 2, 0.3 g) was dissolved in N,N-dimethylformamide (10 mL) solution, and p-4-hydroxyacetophenone (SM-7, 0.28 g) and potassium carbonate (0.28 g) were added, and the mixture was heated at 110° C. for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (100 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.22 g of solid, i.e. 4-(2-(4-acetylphenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0508] LCMS: m / z = 403.88 [M+H] + .

[0509] Step 9: Preparation of 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4)

[0510]

[0511] 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3, 0.22 g) was dissolved in methanol / water (10 mL, V 甲醇 :V 水=5:1) mixed solvent, add excess zinc powder (0.5g), and slowly dropwise add excess glacial acetic acid (0.5mL) under stirring; after the reaction is completed, filter through diatomaceous earth and wash with appropriate amount of dichloromethane, add saturated sodium bicarbonate solution (50mL) to the filtrate to adjust the pH value to about 7, filter through diatomaceous earth again, collect the dichloromethane layer of the filtrate by phase separation, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure; the residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 to 0:1 (v / v)) to obtain 0.18g of white solid, i.e. 4-(2-(4-acetylphenoxy)-5-aminophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 4).

[0512] LCMS: m / z=373.58 [M+H] + .

[0513] Step 10: Preparation of 1-(4-(4-acetylphenoxy)-3-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylpyrrolidine-2,5-dione

[0514]

[0515] 4-(2-(4-acetylphenoxy)-5-aminophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4, 180 mg) was dissolved in dichloromethane (5 mL) solution, methylsuccinic anhydride (SM-8, 60 mg) was added to the solution, and the mixture was stirred at room temperature for about 6 hours, and N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 270 mg) and triethylamine (0.3 mL) were added thereto. ), the mixture was stirred at room temperature for about 2-8 hours; after the reaction, the mixture was diluted with water and extracted twice with ethyl acetate, the organic phases were combined and washed once with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1 to 0:1 (v / v)) to obtain 130 mg of a white solid, i.e., 1-(4-(4-acetylphenoxy)-3-(6-methyl-7-oxo)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylpyrrolidine-2,5-dione (Compound 27).

[0516] 1H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 7.87 (d, J = 8.88Hz, 2H), 7.54 (d, J = 2.46Hz, 1H), 7.35 (dd, J = 8.64Hz, 2.52Hz, 1H), 7.31 (s, 1H), 7.30 -7.28(m,2H),6.95(d,J=8.88Hz,2H),6.33(dd,J=2.28Hz,2.28Hz,1H),3.49(s,3H),3.09-2.99(m,2H),2.48(s,3H),1.30(d,J=7.14Hz,3H);

[0517] MS-ESI (m / z): 470.16 [M+H] + .

[0518] Embodiment 28

[0519] Preparation of 1-(4-(4-(difluoromethyl)phenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylpyrrolidine-2,5-dione

[0520]

[0521] Referring to steps 1-8 of Example 23 above, 4-(2-(4-(hydroxymethyl)phenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared, and then 4-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophenoxy)benzaldehyde (Intermediate 3a) was prepared in step 9:

[0522]

[0523] The solid prepared in step 8 (intermediate 3, 0.25 g) was dissolved in dichloromethane (10 mL) solution, and Dess-Martin periodinane (0.32 g) was added and stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with water (200 mL), extracted twice with ethyl acetate (50 mL*2), and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1 to 75: 1 (v / v)) to obtain 0.21 g of solid, i.e., 4-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophenoxy)benzaldehyde (intermediate 3a).

[0524] LCMS: m / z = 389.78 [M+H] + .

[0525] Step 10: 4-(2-(4-(difluoromethyl)phenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3b)

[0526]

[0527] The intermediate 3a (0.21 g) was dissolved in dichloromethane (6 mL). After nitrogen replacement, the reaction bottle was placed in an ice-water bath and cooled to 0 degrees Celsius. Diethylaminosulfur trifluoride (DAST, 0.45 mL) was added dropwise to the mixture using a syringe. After the addition, the ice-water bath was removed, and 20 microliters of methanol was diluted with 2 mL of dichloromethane and injected into the reaction solution. The mixture was stirred at room temperature overnight. After the reaction was completed, a saturated sodium bicarbonate solution (10 mL) was added to the mixture and purified water ( The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 50:1 (v / v)) to obtain 0.18 g of a solid, i.e., 4-(2-(4-(difluoromethyl)phenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3b).

[0528] LCMS: m / z=411.66[M+H] + .

[0529] Step 11: Preparation of 4-(5-amino-2-(4-(difluoromethyl)phenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4)

[0530]

[0531] 4-(2-(4-(difluoromethyl)phenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3b, 0.18 g) was dissolved in methanol / water (10 mL, V 甲醇 :V 水=5:1) mixed solvent, add excess zinc powder (0.5 g), and slowly drop excess glacial acetic acid (0.5 mL) under stirring; after the reaction is completed, filter through diatomaceous earth and wash with an appropriate amount of dichloromethane, add saturated sodium bicarbonate solution (50 mL) to the filtrate to adjust the pH value to about 7, filter through diatomaceous earth again, separate the filtrate into phases, collect the dichloromethane layer, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure; the residue is purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 30:1 (v / v)) to obtain 0.12 g of white solid, i.e. 4-(5-amino-2-(4-(difluoromethyl)phenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4).

[0532] LCMS: m / z=381.76 [M+H] + .

[0533] Step 12: Preparation of 1-(4-(4-(difluoromethyl)phenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylpyrrolidine-2,5-dione

[0534]

[0535] 4-(5-amino-2-(4-(difluoromethyl)phenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4, 170 mg) was dissolved in dichloromethane (5 mL) solution, methylsuccinic anhydride (SM-8, 153 mg) was added to the solution, and the mixture was stirred at room temperature for about 2 hours, and N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 203 mg) and triethylamine (0 .3mL), and the mixture was stirred overnight; after the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate, the organic phases were combined and washed once with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1 to 0:1 (v / v)) to obtain 148 mg of a white solid, i.e., 1-(4-(4-(difluoromethyl)phenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylpyrrolidine-2,5-dione (Compound 28).

[0536] 1H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 7.52-7.50 (m, 3H), 7.32 (dd, J = 8.64Hz, 2.52Hz, 1H), 7.31 (s, 1H), 7.30 (dd, J = 2.76Hz, 2.76Hz, 1H), 7.21 (d ,J=8.70Hz,1H),7.03(d,J=8.70Hz,2H),6.33(dd,J=2.70Hz,2.16Hz,1H), 3.50(s,3H),3.09-2.98(m,2H),2.52-2.49(m,2H),1.30(d,J=7.08Hz,3H);

[0537] MS-ESI (m / z): 478.15 [M+H] + .

[0538] Embodiment 29

[0539] Preparation of N-(4-(4-(3-methyl-2,5-dioxopyrrolidin-1-yl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)phenyl)isobutyramide

[0540]

[0541] Referring to Steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(4-aminophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3a) was prepared in Step 8:

[0542]

[0543] The light yellow solid prepared in step 7 (intermediate 2, 0.6 g) was dissolved in N,N-dimethylformamide (10 mL) solution, p-aminophenol (SM-7, 0.44 g) and potassium carbonate (0.28 g) were added, and the mixture was replaced with nitrogen, and the mixture was heated at 90 ° C for 3 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (200 mL), and extracted with ethyl acetate 3 times (50 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1 to 0: 1 (v / v)) to obtain 0.39 g of solid, i.e. 4-(2-(4-aminophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3a).

[0544] LCMS: m / z = 376.57 [M+H] + .

[0545] Step 9: N-(4-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophenoxy)phenyl)isobutyramide (Intermediate 3)

[0546]

[0547] Isobutyric acid (0.18 g) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 474 mg) were placed in a 100 mL single-necked bottle, and dichloromethane / N,N-dimethylformamide (5 mL, V 二氯甲烷 :V N,N-二甲基甲酰胺 =1:1) mixed solvent and triethylamine (0.5 mL), stirred at room temperature for about 2 minutes, then added intermediate 3a (0.39 g), stirred at room temperature overnight, diluted with water after completion of the reaction, extracted twice with ethyl acetate (50 mL*2), dried over anhydrous sodium sulfate, and evaporated the solvent under reduced pressure; the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 to 0:1 (v / v)) to obtain 0.35 g of solid, i.e., N-(4-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophenoxy)phenyl)isobutyramide (intermediate 3).

[0548] LCMS: m / z=446.86 [M+H] + .

[0549] Step 10: Preparation of N-(4-(4-amino-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)phenyl)isobutyramide (Intermediate 4)

[0550]

[0551] N-(4-(2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-nitrophenoxy)phenyl)isobutyramide (Intermediate 3, 0.35 g) was dissolved in methanol / water (15 mL, V 甲醇 :V 水 =5:1) mixed solvent, add excess zinc powder (0.5 g), and slowly dropwise add excess glacial acetic acid (0.5 mL) under stirring; after completion of the reaction, filter through diatomaceous earth and wash with an appropriate amount of dichloromethane, separate the filtrate into phases, collect the dichloromethane layer, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure; the residue is purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 15:1 (v / v)) to obtain 0.28 g of a white solid, i.e., N-(4-(4-amino-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)phenyl)isobutyramide (intermediate 4).

[0552] LCMS: m / z=416.88 [M+H] + .

[0553] Step 11: Preparation of N-(4-(4-(3-methyl-2,5-dioxopyrrolidin-1-yl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)phenyl)isobutyramide

[0554]

[0555] N-(4-(4-amino-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)phenyl)acetamide (Intermediate 4, 380 mg) was dissolved in dichloromethane (6 mL) solution, methylsuccinic anhydride (SM-8, 310 mg) was added to the solution, and the mixture was stirred at room temperature for about 6 hours, and N,N-dimethylformamide (6 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 520 mg) and triethylamine (1.0 mL), and the mixture was stirred overnight; after the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate, the organic phases were combined and washed once with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 40:1 (v / v)) to obtain 320 mg of a white solid, i.e., N-(4-(4-(3-methyl-2,5-dioxopyrrolidin-1-yl)-2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenoxy)phenyl)isobutyramide (Compound 29).

[0556] 1 H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 9.81 (s, 1H), 7.58 (d, J = 9.00Hz, 2H), 7.43 (d, J=2.58Hz,1H),7.33(s,1H),7.30(dd,J=2.76Hz,2.76Hz,1H),7.23(dd,J=8.70Hz,2.52H z,1H),6.98-6.95(m,3H),6.34(dd,J=2.64Hz,2.10Hz,1H),3.53(s,3H),3.06-2.97(m,2 H),2.59-2.53(m,1H),2.50-2.47(m,1H),1.29(d,J=7.08Hz,3H)1.08(d,J=6.84Hz,6H);

[0557] MS-ESI (m / z): 513.21 [M+H] + .

[0558] Embodiment 30

[0559] Preparation of 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[0560]

[0561] Referring to steps 1-9 of Example 1 above, 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 4) was prepared, and then 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione was prepared in step 10:

[0562]

[0563] 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4, 150 mg) was dissolved in dichloromethane (5 mL) solution, 3-oxabicyclo[3.1.0]hexane-2,4-dione (SM-8, 120 mg) was added to the solution, and the mixture was stirred at room temperature for about 8 hours, and N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 230 mg) and tris(II) were added thereto. Ethylamine (0.3 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed once with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1 (v / v)) to obtain 80 mg of a white solid, namely 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Compound 30).

[0564] 1H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 7.46-7.42 (m, 1H), 7.39 (d, J = 2.58Hz, 1H), 7.31 ( s,1H),7.29(dd,J=2.76Hz,2.76Hz,1H),7.24(td,J=9.18Hz,5.58Hz,1H),7.19(dd,J=9.30 Hz,2.52Hz,1H),7.09-7.06(m,1H),6.88(d,J=8.70Hz,1H),6.30(dd,J=2.40Hz,2.40Hz,1H ),3.55(s,3H),2.70(dd,J=7.98Hz,3.54Hz,2H),1.86(q,J=3.72Hz,1H),1.63-1.59(m,1H);

[0565] MS-ESI (m / z): 462.12 [M+H] + .

[0566] Embodiment 31

[0567] Preparation of 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)imidazoline-2,4-dione

[0568]

[0569] Referring to steps 1-8 of Example 1 above, 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared, and then 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one was prepared in step 9:

[0570]

[0571] To a solution of intermediate 3 (3 g) in dichloromethane (40 mL) were added p-toluenesulfonyl chloride (1.58 g), sodium hydroxide (0.64 g) and tetrabutylammonium bromide (0.10 g), and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was diluted with water, extracted twice with ethyl acetate (200 mL*2), the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 1:1 (v / v)) to obtain 3.72 g of a white solid, i.e., 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 4).

[0572] 1 H-NMR (600MHz, DMSO-d6) δ: 8.29 (d, J = 2.88Hz, 1H), 8.23 ​​(dd, J = 9.18Hz, 2.88Hz, 1H), 8.00-7.97 (m, 3H), 7.72 (s, 1H), 7.57-7.53 (m, 1H), 7.52-7.48(m,1H),7.43(d,J=8.16Hz,2H),7.22-7.19(m,1H),6.96(d,J=9.06Hz,1H),6.60(d,J=3.54Hz,1H),3.48(s,3H),2.38(s,3H);

[0573] MS-ESI (m / z): 552.13 [M+H] + .

[0574] Step 10: Preparation of 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 5):

[0575]

[0576] Intermediate 4 (3.72 g) was dissolved in dichloromethane / methanol / water (50 mL, V 二氯甲烷 :V 甲醇 :V 水=5:1:1) mixed solvent, zinc powder (5 g) was added, glacial acetic acid (5 mL) was slowly added dropwise with stirring, and the mixture was stirred at room temperature after the addition was complete. After the reaction was completed, the mixture was filtered through diatomaceous earth and washed with an appropriate amount of dichloromethane. The filtrate was added with saturated sodium bicarbonate solution to adjust the pH value to about 7, and the mixture was filtered through diatomaceous earth again. The filtrate was separated into phases and the dichloromethane layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 20:1 (v / v)) to obtain 3.15 g of a solid, namely 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 5).

[0577] 1 H-NMR (600MHz, DMSO-d6) δ: 7.93 (d, J = 3.54Hz, 1H), 7.91 (d, J = 8.40Hz, 1H), 7.42-7.41 (m, 3H), 7.22-7.18 (m, 1H), 6.8 7-6.84(m,1H),6.81-6.76(m,2H),6.61-6.59(m,2H),6.46(d,J=3.48Hz,1H),5.12(s,2H),3.38(s,3H),2.38(s,3H);

[0578] MS-ESI (m / z): 522.14 [M+H] + .

[0579] Step 11: Preparation of tert-butyl (2-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-4-yl)phenyl)amino)-2-oxoethyl)carbamate (Intermediate 6):

[0580]

[0581] Boc-glycine (SM-8, 135 mg) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 175 mg) were placed in a single-necked bottle, and dichloromethane / N,N-dimethylformamide (6 mL, V 二氯甲烷 :V DMF=1:1) mixed solvent and triethylamine (0.3 mL) were stirred for 1-2 minutes, and then intermediate 5 (200 mg) was added, and the mixture was stirred at room temperature overnight; after the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate (50 mL*2), the organic phases were combined and washed once with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1 to 1:1 (v / v)) to obtain 235 mg of solid, i.e., tert-butyl (2-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin)-4-yl)phenyl)amino)-2-oxoethyl)carbamate (Intermediate 6).

[0582] LCMS: m / z=678.98 [M+H] + .

[0583] Step 12: Preparation of 2-amino-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (Intermediate 7):

[0584]

[0585] Intermediate 6 (235 mg) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (1 mL) was added dropwise under stirring at room temperature, and the reaction was continued under stirring at room temperature. After the reaction was completed, a saturated sodium bicarbonate solution was slowly added dropwise to the mixture until the mixture was slightly alkaline, purified water (50 mL) was added for dilution, and dichloromethane was extracted 3 times (50 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100:1 to 30:1 (v / v)) to obtain 170 mg of a solid, i.e., 2-amino-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide (Intermediate 7).

[0586] LCMS: m / z = 578.69 [M+H] + .

[0587] Step 13: Preparation of 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)imidazolidine-2,4-dione (Intermediate 8):

[0588]

[0589] Intermediate 7 (170 mg) was dissolved in dichloromethane (5 mL), and a dichloromethane (2 mL) solution of triphosgene (44 mg) was poured into the mixture at once under stirring at room temperature, and then triethylamine (0.2 mL) was added dropwise, and the mixture was stirred for reaction. After the reaction was completed, an appropriate amount of purified water was added to the mixture for dilution, and the mixture was extracted twice with ethyl acetate (50 mL*2). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1 to 50: 1 (v / v)) to obtain 130 mg of a solid, namely 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)imidazolidine-2,4-dione (Intermediate 8).

[0590] LCMS: m / z = 604.88 [M+H] + .

[0591] Step 14: Preparation of 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)imidazoline-2,4-dione (Compound 31):

[0592]

[0593] 2,4-difluorophenol (0.2 mL) and solid potassium carbonate (200 mg) were added to a solution of intermediate 8 (130 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at 80°C for 5 hours. After the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 30:1 (v / v)) to obtain 75 mg of a solid, namely 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)imidazoline-2,4-dione (Compound 31).

[0594] 1H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 8.32 (s, 1H), 7.51 (d, J = 2.58Hz, 1H), 7.45 (ddd, J = 11.40Hz, 8.82Hz, 3.00Hz, 1H), 7.35 (s, 1H), 7.32-7.3 0(m,2H),7.25(td,J=9.24Hz,5.64Hz,1H),7.10-7.07(m,1H),6.93(d,J= 8.70Hz, 1H), 6.35 (dd, J = 2.22Hz, 2.22Hz, 1H), 4.07 (s, 2H), 3.55 (s, 3H);

[0595] MS-ESI (m / z): 451.11 [M+H] + .

[0596] Embodiment 32

[0597] Preparation of (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazoline-2,4-dione

[0598]

[0599] Referring to steps 1-10 of Example 31, 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 5) was prepared;

[0600] Step 11: Preparation of tert-butyl (S)-(1-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1-oxopropane-2-yl)carbamate (Intermediate 6):

[0601]

[0602] Boc-L-alanine (SM-8, 580 mg) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 720 mg) were placed in a single-necked bottle, and dichloromethane / N,N-dimethylformamide (20 mL, V 二氯甲烷 :V DMF=1:1) mixed solvent and triethylamine (1.2 mL) were stirred for 2 minutes, and then intermediate 5 (800 mg) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction, the mixture was diluted with water and extracted with ethyl acetate 3 times (150 mL*3). The organic phases were combined and washed with water once, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1 to 1:1 (v / v)) to obtain 920 mg of solid, i.e., tert-butyl (S)-(1-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1-oxopropan-2-yl)carbamate (Intermediate 6).

[0603] LCMS: m / z = 692.53 [M+H] + .

[0604] Step 12: Preparation of (S)-2-amino-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)propanamide (Intermediate 7):

[0605]

[0606] Intermediate 6 (920 mg) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5 mL) was added dropwise under stirring at room temperature, and the reaction was continued under stirring at room temperature. After the reaction was completed, a saturated sodium bicarbonate solution was slowly added dropwise to the mixture until the mixture was slightly alkaline, purified water (100 mL) was added for dilution, and the mixture was extracted with dichloromethane 3 times (80 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100:1 to 30:1 (v / v)) to obtain 690 mg of a solid, namely (S)-2-amino-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)propanamide (Intermediate 7).

[0607] LCMS: m / z = 592.43 [M+H] + .

[0608] Step 13: Preparation of 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazolidine-2,4-dione (Intermediate 8):

[0609]

[0610] Intermediate 7 (690 mg) was dissolved in dichloromethane (15 mL), and a dichloromethane (5 mL) solution of triphosgene (180 mg) was poured into the mixture at once under stirring at room temperature, and then triethylamine (0.8 mL) was added dropwise, and the mixture was stirred for reaction. After the reaction was completed, an appropriate amount of purified water was added to the mixture for dilution, and the mixture was extracted twice with ethyl acetate (100 mL*2). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 to 0:1 (v / v)) to obtain 510 mg of a solid, namely 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazolidine-2,4-dione (Intermediate 8).

[0611] LCMS: m / z=618.32 [M+H] + .

[0612] Step 14: Preparation of (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazoline-2,4-dione (Compound 32):

[0613]

[0614] 2,4-difluorophenol (0.2 mL) and solid potassium carbonate (200 mg) were added to a solution of intermediate 8 (110 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 30:1 (v / v)) to obtain 60 mg of solid, i.e., 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)imidazoline-2,4-dione (Compound 32).

[0615] 1H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 8.47 (s, 1H), 7.51 (d, J = 2.52Hz ,1H),7.46-7.42(m,1H),7.35(s,1H),7.32-7.29(m,2H),7.27-7.23(m,1H ),7.10-7.06(m,1H),6.91(d,J=8.70Hz,1H),6.35(dd,J=2.40Hz,2.40Hz,1H),4.25(qd,J=6.78Hz,1.08Hz,1H),3.55(s,3H),1.35(d,6.96Hz,3H);

[0616] MS-ESI (m / z): 464.96 [M+H] + .

[0617] Embodiment 33

[0618] Preparation of (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-ethylimidazoline-2,4-dione

[0619]

[0620] Referring to steps 1-8 of Example 1 above, 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared, and then 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one was prepared in step 9:

[0621]

[0622] To a solution of intermediate 3 (3 g) in dichloromethane (40 mL) were added p-toluenesulfonyl chloride (1.58 g), sodium hydroxide (0.64 g) and tetrabutylammonium bromide (0.10 g), and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was diluted with water, extracted twice with ethyl acetate (200 mL*2), the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 1:1 (v / v)) to obtain 3.72 g of a white solid, i.e., 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 4).

[0623] 1 H-NMR (600MHz, DMSO-d6) δ: 8.29 (d, J = 2.88Hz, 1H), 8.23 ​​(dd, J = 9.18Hz, 2.88Hz, 1H), 8.00-7.97 (m, 3H), 7.72 (s, 1H), 7.57-7.53 (m, 1H), 7.52-7.48(m,1H),7.43(d,J=8.16Hz,2H),7.22-7.19(m,1H),6.96(d,J=9.06Hz,1H),6.60(d,J=3.54Hz,1H),3.48(s,3H),2.38(s,3H);

[0624] MS-ESI (m / z): 552.13 [M+H] + .

[0625] Step 10: Preparation of 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 5):

[0626]

[0627] Intermediate 4 (3.72 g) was dissolved in dichloromethane / methanol / water (50 mL, V 二氯甲烷 :V 甲醇 :V 水 =5:1:1) mixed solvent, zinc powder (5 g) was added, glacial acetic acid (5 mL) was slowly added dropwise with stirring, and the mixture was stirred at room temperature after the addition was complete. After the reaction was completed, the mixture was filtered through diatomaceous earth and washed with an appropriate amount of dichloromethane. The filtrate was added with saturated sodium bicarbonate solution to adjust the pH value to about 7, and the mixture was filtered through diatomaceous earth again. The filtrate was separated into phases and the dichloromethane layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 20:1 (v / v)) to obtain 3.15 g of a solid, namely 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 5).

[0628] 1H-NMR (600MHz, DMSO-d6) δ: 7.93 (d, J = 3.54Hz, 1H), 7.91 (d, J = 8.40Hz, 1H), 7.42-7.41 (m, 3H), 7.22-7.18 (m, 1H), 6.8 7-6.84(m,1H),6.81-6.76(m,2H),6.61-6.59(m,2H),6.46(d,J=3.48Hz,1H),5.12(s,2H),3.38(s,3H),2.38(s,3H);

[0629] MS-ESI (m / z): 522.14 [M+H] + .

[0630] Step 11: Preparation of tert-butyl (S)-(1-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1-oxobutan-2-yl)carbamate (Intermediate 6):

[0631]

[0632] BOC-L-2-aminobutyric acid (SM-8, 94 mg) was mixed with dichloromethane / N,N-dimethylformamide (6 mL, V 二氯甲烷 :V DMF =1:1) to prepare a solution, add O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 175 mg) and N,N-diisopropylethylamine (0.12 mL), stir for 1-2 minutes, add intermediate 5 (200 mg), and stir at room temperature overnight; after the reaction is completed, the mixture is diluted with water and extracted twice with ethyl acetate (100 mL*2), the organic phases are combined and washed once with water, and then washed with anhydrous sulfuric acid After drying over sodium, the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1 to 0:1 (v / v)) to obtain 250 mg of a solid, i.e., tert-butyl (S)-(1-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1-oxobutan-2-yl)carbamate (Intermediate 6).

[0633] 1H-NMR (600MHz, DMSO-d6) δ: 10.07 (s, 1H), 7.97 (d, J = 3.48Hz, 1H), 7.95 (d, J = 8.40Hz, 2H), 7.71 (d, J = 2 .34Hz,1H),7.57(dd,J=8.94Hz,2.64Hz,1H),7.53(s,1H),7.42(d,J=8.10Hz,2H),7.36-7.32(m,1H),7 .11-7.07(m,1H),7.00-6.98(m,2H),6.88(d,J=8.82Hz,1H),6.51(d,J=3.54Hz,1H),3.99-3.95(m,1H) ,3.43(s,3H),2.38(s,3H),1.72-1.65(m,1H),1.63-1.55(m,1H),1.38(s,9H),0.90(t,J=7.26Hz,3H);

[0634] MS-ESI (m / z): 707.19 [M+H] + .

[0635] Step 12: Preparation of (S)-2-amino-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)butyramide (Intermediate 7):

[0636]

[0637] Intermediate 6 (250 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added dropwise under stirring at room temperature, and the reaction was continued under stirring at room temperature. After the reaction was completed, a saturated sodium bicarbonate solution was slowly added dropwise to the mixture until the mixture was slightly alkaline, purified water (50 mL) was added for dilution, and the mixture was extracted with dichloromethane 3 times (50 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 20:1 (v / v)) to obtain 180 mg of a solid, namely (S)-2-amino-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)butanamide (Intermediate 7).

[0638] 1H-NMR (600MHz, DMSO-d6) δ: 7.97 (d, J = 3.54Hz, 1H), 7.95 (d, J = 8.40Hz, 2H), 7.75 (d, J = 2.58Hz, 1H), 7. 61(dd,J=8.88Hz,2.64Hz,1H),7.52(s,1H),7.42(d,J=8.10Hz,2H),7.36-7.32(m,1H),7.10-7.06(m, 1H),7.01-6.97(m,1H),6.88(d,J=8.88Hz,1H),6.52(d,J=3.54Hz,1H),3.99-3.95(m,1H),3.43(s,3H ),3.23(t,J=6.54Hz,1H),2.38(s,3H),1.69-1.63(m,1H),1.51-1.44(m,1H),0.90(t,J=7.38Hz,3H);

[0639] MS-ESI (m / z): 607.16 [M+H] + .

[0640] Step 13: Preparation of (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-ethylimidazolidine-2,4-dione (Intermediate 8):

[0641]

[0642] Intermediate 7 (180 mg) was dissolved in dichloromethane (5 mL), and a dichloromethane (2 mL) solution of triphosgene (44 mg) was poured into the mixture at once under stirring at room temperature, and then triethylamine (0.2 mL) was added dropwise, and the mixture was stirred for reaction. After the reaction was completed, an appropriate amount of purified water was added to the mixture for dilution, and the mixture was extracted twice with ethyl acetate (50 mL*2). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 0:1 (v / v)) to obtain 140 mg of a solid, namely (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-ethylimidazolidine-2,4-dione (Intermediate 8).

[0643] 1H-NMR (600MHz, DMSO-d6) δ: 8.55 (s, 1H), 8.00 (d, J = 3.54Hz, 1H), 7.96 (s, 1H) ),7.95(s,1H),7.57(s,1H),7.46-7.41(m,4H),7.33(dd,J=8.76Hz,2.52Hz ,1H),7.31-7.28(m,1H),7.11-7.08(m,1H),6.90(d,J=8.70Hz,1H),6.58(d ,J=3.54Hz,1H),4.20-4.18(m,1H),3.44(s,3H),2.38(s,3H),1.84-1.77(m,

[0644] 1H),1.65-1.72(m,1H),0.94(t,J=7.38Hz,3H); MS-ESI(m / z): 633.15[M+H] + .

[0645] Step 14: Preparation of (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-ethylimidazoline-2,4-dione (Compound 33):

[0646]

[0647] 2,4-difluorophenol (0.2 mL) and solid potassium carbonate (200 mg) were added to a solution of intermediate 8 (140 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at 80°C for 5 hours. After the reaction, the mixture was diluted with water and extracted twice with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 10:1 (v / v)) to obtain 90 mg of a solid, namely (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-ethylimidazoline-2,4-dione (Compound 33).

[0648] 1H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 8.54 (s, 1H), 7.48 (d, J = 2.58Hz, 1H), 7.46 -7.42(m,1H),7.35(s,1H),7.31-7.29(m,2H),7.25(td,J=9.24Hz,5.64Hz,1H),7.1 0-7.06(m,1H),6.91(d,J=8.70Hz,1H),6.34(dd,J=2.64Hz,2.16Hz,1H),4.20-4.18 (m,1H),3.32(s,3H),1.85-1.78(m,1H),1.73-1.66(m,1H),0.94(t,J=7.38Hz,3H);

[0649] MS-ESI (m / z): 479.16 [M+H] + .

[0650] Embodiment 34

[0651] Preparation of (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-isopropylimidazoline-2,4-dione

[0652]

[0653] Referring to step 1-10 of Example 33, intermediate 54-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one was prepared.

[0654] Step 11: Preparation of tert-butyl (S)-(1-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Intermediate 6):

[0655]

[0656] BOC-L-valine (SM-8, 100 mg) was mixed with dichloromethane / N,N-dimethylformamide (10 mL, V 二氯甲烷 :V DMF=1:1) to prepare a solution, add O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 175 mg) and N,N-diisopropylethylamine (0.15 mL), stir for 1-2 minutes, add intermediate 5 (200 mg), stir at room temperature overnight; after the reaction is completed, the mixture is diluted with water and extracted twice with ethyl acetate (100 mL*2), the organic phases are combined, washed once with water, and dried over anhydrous sodium sulfate The solvent was then evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1 to 0:1 (v / v)) to obtain 238 mg of a solid, i.e., tert-butyl (S)-(1-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (intermediate 6).

[0657] MS-ESI (m / z): 720.53 [M+H] + .

[0658] Step 12: Preparation of (S)-2-amino-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylbutanamide (Intermediate 7):

[0659]

[0660] Intermediate 6 (238 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added dropwise under stirring at room temperature, and the reaction was continued under stirring at room temperature. After the reaction was completed, a saturated sodium bicarbonate solution was slowly added dropwise to the mixture until the mixture was slightly alkaline, purified water (50 mL) was added for dilution, and dichloromethane was extracted 3 times (50 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 20:1 (v / v)) to obtain 160 mg of a solid, namely (S)-2-amino-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-3-methylbutanamide (Intermediate 7).

[0661] MS-ESI (m / z): 620.72 [M+H] + .

[0662] Step 13: Preparation of (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-isopropylimidazolidine-2,4-dione (Intermediate 8):

[0663]

[0664] Intermediate 7 (160 mg) was dissolved in dichloromethane (5 mL), and a dichloromethane (2 mL) solution of triphosgene (44 mg) was poured into the mixture at once under stirring at room temperature, and then triethylamine (0.2 mL) was added dropwise, and the mixture was stirred for reaction. After the reaction was completed, an appropriate amount of purified water was added to the mixture for dilution, and the mixture was extracted twice with ethyl acetate (50 mL*2). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 0:1 (v / v)) to obtain 133 mg of a solid, namely (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-isopropylimidazolidine-2,4-dione (Intermediate 8).

[0665] MS-ESI (m / z): 646.18 [M+H] + .

[0666] Step 14: Preparation of (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-isopropylimidazoline-2,4-dione (Compound 34):

[0667]

[0668] 2,4-difluorophenol (0.2 mL) and solid potassium carbonate (200 mg) were added to a solution of intermediate 8 (133 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at 80°C for 5 hours. After the reaction, the mixture was diluted with water and extracted twice with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 10:1 (v / v)) to obtain 78 mg of a solid, namely (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-isopropylimidazoline-2,4-dione (Compound 34).

[0669] 1 H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 8.55 (s, 1H), 7.46 (d, J = 2.58Hz, 1H), 7.45-7.4 3(m,1H),7.35(s,1H),7.31-7.27(m,2H),7.25(td,J=9.30Hz,5.64Hz,1H),7.10-7.06(m ,1H),6.92(d,J=8.76Hz,1H),6.33(dd,J=2.52Hz,2.52Hz,1H),4.14(dd,J=3.54Hz,1.20 Hz,1H),3.55(s,3H),2.16-2.11(m,1H),1.01(d,J=6.96Hz,3H),0.87(d,J=6.78Hz,3H);

[0670] MS-ESI (m / z): 493.16 [M+H] + .

[0671] Embodiment 35

[0672] Preparation of (S)-5-(tert-butyl)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)imidazoline-2,4-dione

[0673]

[0674] Refer to step 1-10 of Example 33 to prepare intermediate 5 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one. Step 11 Refer to Example 33, replace BOC-L-2-aminobutyric acid with (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (SM-8) and react with intermediate 5 to prepare intermediate 6;

[0675]

[0676] Using the prepared intermediate 6 as raw material, compound 35 was prepared according to the reaction conditions of steps 12-14 of example 33.

[0677] 1H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 8.47 (s, 1H), 7.51 (d, J = 2.48Hz, 1H), 7.46-7.42 (m, 1H), 7.35 (s, 1H), 7.33-7.30 (m, 2H), 7.27-7 .23(m,1H),7.10-7.06(m,1H),6.91(d,J=8.64Hz,1H),6.35(dd,J=2.40Hz,2.40Hz,1H), 4.40(d,J=1.08Hz,1H),3.53(s,3H),0.94(s,9H);

[0678] MS-ESI (m / z): 507.17 [M+H] + .

[0679] Embodiment 36

[0680] Preparation of (S)-5-((S)-sec-butyl)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)imidazolidine-2,4-dione

[0681]

[0682] Refer to steps 1-10 of Example 33 to prepare intermediate 5 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one. Step 11 Refer to Example 33, replace BOC-L-2-aminobutyric acid with (tert-butoxycarbonyl)-L-isoleucine (SM-8) and react with intermediate 5 to prepare intermediate 6;

[0683]

[0684] Continue to use the prepared intermediate 6 as raw material and refer to the reaction conditions of steps 12-14 of example 33 to prepare compound 36.

[0685] 1H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 8.43 (s, 1H), 7.52 (d, J = 2.52Hz, 1H), 7.46-7.42 (m,1H),7.36(s,1H),7.33-7.30(m,2H),7.27-7.23(m,1H),7.10-7.06(m,1H),6.92(d,J= 8.70Hz, 1H), 6.35 (dd, J=2.40Hz, 2.40Hz, 1H), 4.19 (dd, J=6.72Hz, 1.08Hz, 1H), 3.55 (s, 3 H),2.49-2.47(m,1H),1.57-1.54(m,2H),1.19(d,J=7.50Hz,3H),0.99(t,J=6.96Hz,3H);

[0686] MS-ESI (m / z): 507.32 [M+H] + .

[0687] Embodiment 37

[0688] Preparation of (R)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazolidine-2,4-dione

[0689]

[0690] Refer to step 1-10 of Example 33 to prepare intermediate 5 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one. Step 11 Refer to Example 33, replace BOC-L-2-aminobutyric acid with (tert-butyloxycarbonyl)-D-alanine (SM-8) and react with intermediate 5 to prepare intermediate 6;

[0691]

[0692] Continue to use the prepared intermediate 6 as raw material and refer to the reaction conditions of steps 12-14 of example 33 to prepare compound 37.

[0693] 1H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 8.47 (s, 1H), 7.51 (d, J = 2.52Hz ,1H),7.46-7.42(m,1H),7.35(s,1H),7.32-7.29(m,2H),7.27-7.23(m,1H ),7.10-7.06(m,1H),6.91(d,J=8.70Hz,1H),6.35(dd,J=2.40Hz,2.40Hz,1H),4.25(qd,J=6.78Hz,1.08Hz,1H),3.55(s,3H),1.35(d,6.96Hz,3H);

[0694] MS-ESI (m / z): 465.14 [M+H] + .

[0695] Embodiment 38

[0696] Preparation of (S)-2-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione

[0697]

[0698] Intermediate 5 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one was prepared by referring to Step 1-10 of Example 33.

[0699] Step 11: Preparation of tert-butyl (S)-2-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate (Intermediate 6)

[0700]

[0701] Boc-L-proline (SM-8, 120 mg) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 180 mg) were placed in a single-necked bottle, and dichloromethane / N,N-dimethylformamide (6 mL, V 二氯甲烷 :V DMF=1:1) mixed solvent and triethylamine (0.3 mL) were stirred for 2 minutes, and then intermediate 5 (200 mg) was added and stirred at room temperature for 5 hours. After the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate (50 mL*2). The organic phases were combined and washed once with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1 to 0:1 (v / v)) to obtain 302 mg of solid, i.e., tert-butyl (S)-2-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate (Intermediate 6).

[0702] LCMS: m / z = 718.42 [M+H] + .

[0703] Step 12: Preparation of (S)-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2-carboxamide (Intermediate 7)

[0704]

[0705] Intermediate 6 (302 mg) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (1 mL) was added dropwise under stirring at room temperature, and the reaction was continued under stirring at room temperature. After the reaction was completed, a saturated sodium bicarbonate solution was slowly added dropwise to the mixture until the mixture was slightly alkaline, purified water (50 mL) was added for dilution, and dichloromethane was extracted 3 times (50 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1 to 10:1 (v / v)) to obtain 185 mg of a solid, namely (S)-N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2-carboxamide (Intermediate 7).

[0706] LCMS: m / z=618.37 [M+H] + .

[0707] Step 13: Preparation of (S)-2-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (Intermediate 8)

[0708]

[0709] The intermediate 7 (185 mg) was dissolved in dichloromethane (5 mL), and a dichloromethane (2 mL) solution of triphosgene (45 mg) was poured into the mixture at once under stirring at room temperature, and then triethylamine (0.2 mL) was added dropwise, and the mixture was stirred for reaction. After the reaction was completed, an appropriate amount of purified water was added to dilute the mixture, and the mixture was extracted with ethyl acetate twice (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography After purification by precipitation (dichloromethane:methanol=100:1 to 50:1 (v / v)), 127 mg of a solid was obtained, namely (S)-2-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (Intermediate 8).

[0710] LCMS: m / z=644.75[M+H] + .

[0711] Step 14: Preparation of (S)-2-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione

[0712]

[0713] 2,4-difluorophenol (0.2 mL) and solid potassium carbonate (200 mg) were added to a solution of intermediate 8 (127 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 50:1 (v / v)) to obtain 59 mg of a solid, namely (S)-2-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (Compound 38).

[0714] 1H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 7.53 (d, J = 2.58Hz, 1H), 7.46-7.43 (m, 1H), 7.35 (s, 1H), 7.32 (d d,J=8.82Hz,2.58Hz,1H),7.30(dd,J=2.46Hz,2.46Hz,1H),7.26(td,J=9.24Hz,5.64Hz,1H),7.10-7.06(m ,1H),6.92(d,J=8.70Hz,1H),6.34(dd,J=2.58Hz,2.22Hz,1H),4.35(dd,J=9.24Hz,7.38Hz,1H),3.59-3. 55(m,4H),3.25-3.22(m,1H),2.18-2.13(m,1H),2.13-2.07(m,1H),2.06-1.98(m,1H),1.09-1.84(m,1H);

[0715] MS-ESI (m / z): 491.15 [M+H] + .

[0716] Embodiment 39

[0717] Preparation of (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-1,5-dimethylimidazoline-2,4-dione

[0718]

[0719] Refer to steps 1-10 of Example 33 to prepare intermediate 5 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one. Step 11 Refer to Example 33, replace BOC-L-2-aminobutyric acid with BOC-N-methyl-L-alanine (SM-8) and react with intermediate 5 to prepare intermediate 6;

[0720]

[0721] Continue to use the prepared intermediate 6 as raw material and refer to the reaction conditions of steps 12-14 of example 33 to prepare compound 39.

[0722] 1H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 7.51 (d, J = 2.52Hz, 1H), 7.47-7.43 (m, 1H), 7.36 (s, 1H), 7.32-7.28 (m, 2H), 7.28-7.24 (m, 1H), 7.10- 7.07(m,1H),6.91(d,J=8.70Hz,1H),6.36(dd,J=2.46Hz,2.46Hz,1H),4.25(q,J=6.84Hz,1H),3.56(s,3H),3.25(s,3H),1.35(d,6.96Hz,3H);

[0723] MS-ESI (m / z): 478.63 [M+H] + .

[0724] Embodiment 40

[0725] Preparation of (S)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-1,3-diazabicyclo[3.2.0]heptane-2,4-dione

[0726]

[0727] Refer to Step 1-10 of Example 38 to prepare Intermediate 5 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one. Step 11 Refer to Example 38, replace Boc-L-proline with (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (SM-8) and react with Intermediate 5 to prepare Intermediate 6;

[0728]

[0729] Using the prepared intermediate 6 as raw material, compound 40 was prepared according to the reaction conditions of steps 12-14 of example 38.

[0730] 1H-NMR (600MHz, DMSO-d6) δ: 12.07 (s, 1H), 7.59 (d, J = 2.58Hz, 1H), 7.45 (ddd, J = 11.40Hz, 8.82Hz, 3.00Hz, 1H), 7.37(dd,J=8.76Hz,2.52Hz,1H),7.36(s,1H),7.31(dd,J=2.76Hz,2.76Hz,1H),7.27(td,J=9.24Hz,5.58Hz,1H ),7.10-7.07(m,1H),6.95(d,J=8.70Hz,1H),6.34(dd,J=2.58Hz,2.22Hz,1H),4.88(dd,J=8.52Hz,7.20Hz,1H ),4.23(q,J=8.28Hz,1H),3.84(td,J=9.48Hz,4.62Hz,1H),3.56(s,3H),2.98-2.92(m,1H),2.75-2.70(m,1H);

[0731] MS-ESI (m / z): 477.13 [M+H] + .

[0732] Embodiment 41

[0733] Preparation of 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5,5-dimethylimidazoline-2,4-dione

[0734]

[0735] Refer to steps 1-10 of Example 33 to prepare intermediate 5 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one. Step 11 Refer to Example 33, replace BOC-L-2-aminobutyric acid with 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (SM-8) and react with intermediate 5 to prepare intermediate 6;

[0736]

[0737] Continue to use the prepared intermediate 6 as raw material and refer to the reaction conditions of steps 12-14 of example 33 to prepare compound 41.

[0738] 1H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 8.56 (s, 1H), 7.53 (d, J = 2.52Hz, 1H), 7.45 ( ddd,J=11.40Hz,8.88Hz,3.00Hz,1H),7.35(s,1H),7.33(dd,J=8.82Hz,2.58Hz,1H), 7.30(dd,J=2.76Hz,2.76Hz,1H),7.25(td,J=9.24Hz,5.58Hz,1H),7.10-7.07(m,1H) ,6.92(d,J=8.70Hz,1H),6.35(dd,J=2.28Hz,2.28Hz,1H),3.56(s,3H),1.40(s,6H);

[0739] MS-ESI (m / z): 479.15 [M+H] + .

[0740] Embodiment 42

[0741] Preparation of (S)-3-(4-(2,4-difluorophenoxy)-2-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-ethylimidazoline-2,4-dione

[0742]

[0743] Referring to steps 1-8 of Example 4 above, 4-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared.

[0744] Step 9: Preparation of 4-(2-(2,4-difluorophenoxy)-4-methyl-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4):

[0745]

[0746] To a solution of intermediate 3 (3 g) in dichloromethane (40 mL) were added p-toluenesulfonyl chloride (1.62 g), sodium hydroxide (0.66 g) and tetrabutylammonium bromide (0.12 g), and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was diluted with water, extracted twice with ethyl acetate (200 mL*2), the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 1:1 (v / v)) to obtain 3.58 g of a white solid, i.e., 4-(2-(2,4-difluorophenoxy)-4-methyl 5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 4).

[0747] LCMS: m / z = 565.32 [M+H] + .

[0748] Step 10: Preparation of 4-(5-amino-2-(2,4-difluorophenoxy)-4-methylphenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 5):

[0749]

[0750] Intermediate 4 (3.58 g) was dissolved in dichloromethane / methanol / water (50 mL, V 二氯甲烷 :V 甲醇 :V 水 =5:1:1) mixed solvent, zinc powder (5 g) was added, glacial acetic acid (5 mL) was slowly added dropwise with stirring, and the mixture was stirred at room temperature after the addition was complete. After the reaction was completed, the mixture was filtered through diatomaceous earth and washed with an appropriate amount of dichloromethane. The filtrate was added with saturated sodium bicarbonate solution to adjust the pH value to about 7, and the mixture was filtered through diatomaceous earth again. The filtrate was separated into phases and the dichloromethane layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 20:1 (v / v)) to obtain 3.02 g of a solid, namely 4-(5-amino-2-(2,4-difluorophenoxy)-4-methylphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 5).

[0751] LCMS: m / z=535.28 [M+H] + .

[0752] Referring to step 11 of Example 33, BOC-L-2-aminobutyric acid was reacted with intermediate 5 to prepare intermediate 6;

[0753]

[0754] Continue to use the prepared intermediate 6 as raw material and refer to the reaction conditions of steps 12-14 of example 33 to prepare compound 42.

[0755] 1 H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 8.47 (s, 1H), 7.45 (ddd, J = 11.40Hz, 8.82H z,2.94Hz,1H),7.31(s,1H),7.30-7.28(m,2H),7.27(td,J=9.06Hz,5.58Hz,1H),7.1 1-7.08(m,1H),6.78(s,1H),6.27(dd,J=2.64Hz,2.22Hz,1H),4.21-4.19(m,1H),3.3 2(s,3H),2.13(s,3H),1.85-1.78(m,1H),1.73-1.66(m,1H),0.94(t,J=7.38Hz,3H);

[0756] MS-ESI (m / z): 493.15 [M+H] + .

[0757] Embodiment 43

[0758] Preparation of (S)-1-(cyclopropylmethyl)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazoline-2,4-dione

[0759]

[0760] Referring to steps 1-13 of Example 32, 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazolidine-2,4-dione (Intermediate 8) was prepared.

[0761] Step 14: Preparation of (S)-1-(cyclopropylmethyl)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazolidine-2,4-dione (Intermediate 9):

[0762]

[0763] Intermediate 8 (400 mg), triphenylphosphine (255 mg) and cyclopropylmethanol (70 mg) were placed in a 50 mL three-necked flask. After nitrogen replacement, dichloromethane (10 mL) was added to dissolve the mixture. The reaction flask was placed in an ice-water bath for precooling for 5 minutes. Diisopropyl azodicarboxylate (196 mg) was diluted with dichloromethane (2 mL) and slowly added to the reaction solution with a syringe. After stirring for 5 minutes, the ice-water bath was removed and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated directly under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 0:1 (v / v)) to give 329 mg of a solid, namely (S)-1-(cyclopropylmethyl)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazolidine-2,4-dione (Intermediate 9).

[0764] LCMS: m / z=672.58 [M+H] + .

[0765] Step 15: Preparation of (S)-1-(cyclopropylmethyl)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazoline-2,4-dione

[0766]

[0767] 2,4-difluorophenol (0.3 mL) and solid potassium carbonate (300 mg) were added to a solution of intermediate 9 (210 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at 80°C for 3 hours. After the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 20:1 (v / v)) to obtain 72 mg of a solid, namely (S)-1-(cyclopropylmethyl)-3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-5-methylimidazoline-2,4-dione (Compound 43).

[0768] 1H-NMR (600MHz, DMSO-d6) δ: 12.06 (s, 1H), 7.53 (d, J = 2.58Hz, 1H), 7.45 (ddd, J = 11.34Hz, 8.82Hz, 2.94Hz, 1H), 7.35 (s, 1H), 7.34 (dd ,J=8.76Hz,2.58Hz,1H),7.30(dd,J=2.76Hz,2.76Hz,1H),7.26(td,J=9.18Hz,5.58Hz,1H),7.10-7.07(m,1H),6.92(d,J=8.76Hz,1 H),6.35(dd,J=2.28Hz,2.28Hz,1H),4.38(q,J=6.90Hz,1H),3.55(s,3H),3.43(dd,J=14.58Hz,6.72Hz,1H),3.06(dd,J=14.52Hz,7 .32Hz,1H),1.45(d,J=6.90Hz,3H),1.07-1.00(m,1H),0.55-0.51(m,1H),0.50-0.45(m,1H),0.35-0.32(m,1H),0.25-0.22(m,1H);

[0769] MS-ESI (m / z): 519.18 [M+H] + .

[0770] Embodiment 44

[0771] Preparation of 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-6,6-dimethyldihydropyrimidine-2,4(1H,3H)-dione

[0772]

[0773] Refer to step 1-10 of Example 33 to prepare intermediate 5 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one. Step 11 Refer to Example 33, replace BOC-L-2-aminobutyric acid with 3-((tert-butoxycarbonyl)amino)-3-methylbutyric acid (SM-8) and react with intermediate 5 to prepare intermediate 6;

[0774]

[0775] Continue to use the prepared intermediate 6 as raw material and refer to the reaction conditions of steps 12-14 of example 33 to prepare compound 44.

[0776] 1 H-NMR (600MHz, DMSO-d6) δ: 12.04 (s, 1H), 8.08 (s, 1H), 7.45 (ddd, J = 11.34Hz, 8.82Hz, 3.00Hz, 1H), 7.31 (s, 1H), 7.29 (dd, J = 2.82Hz, 2.82Hz ,1H),7.28-7.24(m,2H),7.12-7.08(m,2H),6.82(d,J=8.64Hz,1H),6.28(dd,J=2.64Hz,2.22Hz,1H),3.55(s,3H),2.73(s,2H),1.29(s,6H);

[0777] MS-ESI (m / z): 493.16 [M+H] + .

[0778] Embodiment 45

[0779] Preparation of 4-(2-(2,4-difluorophenoxy)-5-(2-oxopyrrolidin-1-yl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0780]

[0781] Intermediate 5 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one was prepared by referring to Step 1-10 of Example 33.

[0782] Step 11: Preparation of methyl 4-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)butyrate (Intermediate 6):

[0783]

[0784] Intermediate 5 (300 mg), sodium carbonate (91 mg) and potassium iodide (95 mg) were placed in a 25 mL round-bottom flask, acetonitrile (5 mL) was added, and finally methyl 4-bromobutyrate (105 mg) was added, and the mixture was stirred and refluxed at 90° C. for 8 hours; after the reaction, the mixture was diluted with purified water (100 mL) and extracted twice with ethyl acetate (50 mL*2), the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 200 mg of a solid, i.e., methyl 4-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)butyrate (Intermediate 6).

[0785] LCMS: m / z=621.68 [M+H] + .

[0786] Step 12: Preparation of 4-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)butyric acid (Intermediate 7)

[0787]

[0788] Intermediate 6 (200 mg) was dissolved in methanol (5 mL), solid sodium hydroxide (200 mg) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the mixture was diluted with purified water (50 mL) and adjusted to pH = 3 with 1M hydrochloric acid aqueous solution, extracted twice with ethyl acetate (50 mL * 2), the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 to 0: 1 (v / v)) to obtain 69 mg of solid, i.e. 4-((4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)butyric acid (Intermediate 7).

[0789] LCMS: m / z = 453.83 [M+H] + .

[0790] Step 13: Preparation of 4-(2-(2,4-difluorophenoxy)-5-(2-oxopyrrolidin-1-yl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0791]

[0792] The intermediate 7 (69 mg) was dissolved in N,N-dimethylformamide (3 mL), and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 100 mg) and triethylamine (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed once with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1 (v / v)) to obtain 30 mg of a solid, namely 4-(2-(2,4-difluorophenoxy)-5-(2-oxopyrrolidin-1-yl)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Compound 45).

[0793] 1 H-NMR (600MHz, DMSO-d6) δ: 12.03 (s, 1H), 7.81 (d, J = 2.70Hz, 1H), 7.58 (dd, J = 8.94H z,2.76Hz,1H),7.39-7.35(m,1H),7.30(s,1H),7.27(dd,J=2.76Hz,2.76Hz,1H),7. 09-7.05(m,1H),7.02-7.01(m,1H),6.92(d,J=8.88Hz,1H),6.29(dd,J=2.22Hz,2.2 2Hz,1H),3.86(t,J=6.96Hz,2H),3.54(s,3H),2.50-2.48(m,2H),2.09-2.04(m,2H);

[0794] MS-ESI (m / z): 436.14 [M+H] + .

[0795] Embodiment 46

[0796] Preparation of 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)pyrrolidine-2,5-dione

[0797]

[0798] Step 1: Preparation of methyl 3-bromo-4-(2,4-difluorophenoxy)benzoate (Intermediate 1):

[0799]

[0800] Take 3-bromo-4-fluorobenzoic acid methyl ester (SM-1, 5 g), 2,4-difluorophenol (SM-2, 3.3 g), potassium carbonate (6 g) and N,N-dimethylformamide (80 mL) and add them to the reactor, stir at 100°C for 2 hours; after the reaction, dilute the mixture with purified water (500 mL) and extract twice with ethyl acetate (100 mL*2), combine the organic phases and dry them over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure; the residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 15:1 (v / v)) to obtain 5.3 g of solid, i.e. 3-bromo-4-(2,4-difluorophenoxy)benzoic acid methyl ester (intermediate 1).

[0801] LCMS: m / z=342.88[M+H] + .

[0802] Step 2: Preparation of (3-bromo-4-(2,4-difluorophenoxy)phenyl)methanol (Intermediate 2)

[0803]

[0804] Anhydrous tetrahydrofuran (40 mL) and anhydrous zinc chloride (4.21 g) were added to the reactor, stirred at room temperature for 0.5 hours, sodium borohydride (1.17 g) was added in batches, and intermediate 1 (5.3 g) was added after continuing to stir at room temperature for 0.5 hours; the temperature was raised to 70°C and stirred and refluxed for 12 hours; after the reaction was completed, an appropriate amount of dilute hydrochloric acid was added to the mixture until the mixture became clear, purified water (300 mL) was added for dilution, and extracted with ethyl acetate 3 times (100 mL*3), the organic phases were combined and dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 15:1 to 1:1 (v / v)) to obtain 2.3 g of solid, i.e. (3-bromo-4-(2,4-difluorophenoxy)phenyl)methanol (intermediate 2).

[0805] LCMS: m / z=314.73 [M+H] + .

[0806] Step 3: Preparation of (4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (Intermediate 3)

[0807]

[0808] Intermediate 2 (2.3 g), bipyraclostrobin (3.7 g), potassium acetate (1.43 g), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (0.42 g) and dioxane (40 mL) were added to the reactor, and the reaction system was replaced with nitrogen and repeated three times, and the mixture was stirred at 85° C. overnight. After the reaction was completed, the mixture was filtered with diatomaceous earth, and the filtrate was directly evaporated to dryness under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1 to 10:1 (v / v)) to obtain 2.3 g of oily liquid, namely (4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (intermediate 3).

[0809] Step 4: Preparation of 4-(2-(2,4-difluorophenoxy)-5-(hydroxymethyl)phenyl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4)

[0810]

[0811] Intermediate 3 (2.3 g), 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (SM-3, 1.94 g), sodium carbonate (1.35 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.26 g) were placed in a reactor, dioxane (30 mL) and purified water (6 mL) were added, nitrogen was replaced in the reaction system and repeated three times, and the mixture was stirred at 85°C overnight; after the reaction was completed, the mixture was diluted with water The mixture was extracted twice with ethyl acetate (100 mL*2), the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1 (v / v)) to obtain 1.55 g of a solid, namely: 4-(2-(2,4-difluorophenoxy)-5-(hydroxymethyl)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 4).

[0812] LCMS: m / z = 536.92 [M+H] + .

[0813] Step 5: Preparation of 4-(5-(bromomethyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 5)

[0814]

[0815] Intermediate 4 (1.55 g) was dissolved in dichloromethane (30 mL), and the reaction flask was placed in an ice-water bath and pre-stirred for 5 minutes. Phosphorus tribromide (0.54 mL) was slowly added dropwise under stirring, and stirring was continued for 1 hour. After the reaction, the pH value of the mixture was adjusted to about 7 with a saturated sodium bicarbonate aqueous solution, the mixture was diluted with purified water (200 mL) and extracted twice with ethyl acetate (100 mL*2), the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1:1 to 0:1 (v / v)) to obtain 1.3 g of a solid, i.e., 4-(5-(bromomethyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 5).

[0816] LCMS: m / z = 599.45 [M+H] + .

[0817] Step 6: Preparation of 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)pyrrolidine-2,5-dione (Intermediate 6)

[0818]

[0819] Intermediate 5 (100 mg), succinimide (130 mg), potassium carbonate (100 mg) and N,N-dimethylformamide (5 mL) were added to a reaction flask and heated at 55° C. with stirring for 5 hours. After the reaction, the mixture was diluted with purified water (150 mL) and extracted twice with ethyl acetate (60 mL*2). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 to 0:1 (v / v)) to obtain 100 mg of a solid, namely 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)pyrrolidine-2,5-dione (Intermediate 6).

[0820] LCMS: m / z=617.67 [M+H] + .

[0821] Step 7: Preparation of 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)pyrrolidine-2,5-dione (Compound 46)

[0822]

[0823] A solution of intermediate 6 (100 mg) in N,N-dimethylformamide (5 mL) was prepared, 2,4-difluorophenol (0.5 mL) and solid potassium carbonate (300 mg) were added thereto, and the mixture was stirred at 80° C. for 5 hours; after the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate (50 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 20:1 (v / v)) to obtain 63 mg of solid, i.e., 1-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)pyrrolidine-2,5-dione (Compound 46).

[0824] 1H-NMR (600MHz, DMSO-d6) δ: 12.03 (s, 1H), 7.41 (d, J = 2.22Hz, 1H), 7.41-7.37 (m, 1H), 7.28-7.27 (m, 2H), 7.22 (dd, J = 8.46Hz, 2.22Hz, 1H ),7.16-7.12(m,1H),7.05-7.01(m,1H),6.79(d,J=8.46Hz,1H),6.24(dd,J=2.28Hz,2.28Hz,1H),4.56(s,2H),3.54(s,3H),2.68(s,4H);

[0825] MS-ESI (m / z): 464.13 [M+H]+.

[0826] Embodiment 47

[0827] Preparation of 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)imidazoline-2,4-dione

[0828]

[0829] Referring to Step 1-5 of Example 46, 4-(5-(bromomethyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 5) was prepared.

[0830] Step 6: Preparation of 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)imidazolidine-2,4-dione (Intermediate 6)

[0831]

[0832] Intermediate 5 (100 mg), hydantoin (130 mg), potassium carbonate (100 mg) and N,N-dimethylformamide (5 mL) were added to a reaction flask and heated at 55° C. with stirring for 3 hours. After the reaction, the mixture was diluted with purified water (150 mL) and extracted twice with ethyl acetate (60 mL*2). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 to 0:1 (v / v)) to obtain 90 mg of a solid, namely 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)imidazolidine-2,4-dione (Intermediate 6).

[0833] LCMS: m / z=618.74 [M+H]+.

[0834] Step 7: Preparation of 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)imidazoline-2,4-dione (Compound 47)

[0835]

[0836] A solution of intermediate 6 (90 mg) in N,N-dimethylformamide (5 mL) was prepared, 2,4-difluorophenol (0.2 mL) and solid potassium carbonate (200 mg) were added thereto, and the mixture was stirred at 80° C. for 5 hours. After the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 20:1 (v / v)) to obtain 44 mg of a solid, namely 3-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzyl)imidazoline-2,4-dione (Compound 47).

[0837] 1H-NMR (600MHz, DMSO-d6) δ: 12.03 (s, 1H), 8.32 (s, 1H), 7.40 (d, J = 2.28Hz, 1H), 7.41-7.38 (m, 1H), 7.27-7.26 (m, 2H), 7.23 (dd, J = 8.46Hz, 2.28 Hz,1H),7.15-7.12(m,1H),7.05-7.01(m,1H),6.79(d,J=8.46Hz,1H),6.24(dd,J=2.28Hz,2.28Hz,1H),4.57(s,2H),4.02(s,2H),3.54(s,3H);

[0838] MS-ESI (m / z): 465.12 [M+H]+.

[0839] Embodiment 48

[0840] Preparation of 3-(4-(2,6-dimethylphenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)imidazoline-2,4-dione

[0841]

[0842] Referring to steps 1-7 of Example 1 above, 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 2) was prepared, and then 4-(2-(2,6-dimethylphenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 3) was prepared in step 8:

[0843]

[0844] The light yellow solid prepared in step 7 (intermediate 2, 0.9 g) was dissolved in N,N-dimethylformamide (15 mL) solution, 2,6-dimethylphenol (SM-7, 0.72 g) and potassium carbonate (0.84 g) were added, and the mixture was heated at 110°C for 2 hours; after the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (150 mL), and extracted with ethyl acetate 3 times (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1 (v / v)) to obtain 0.58 g of solid, i.e. 4-(2-(2,6-dimethylphenoxy)-5-nitrophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (intermediate 3).

[0845] LCMS: m / z=389.55[M+H] + .

[0846] Continue to use the prepared intermediate 3 as raw material and refer to the reaction conditions of steps 9-14 of example 33 to prepare compound 48.

[0847] 1 H-NMR (600MHz, DMSO-d6) δ: 12.07(s,1H),8.35(s,1H),7.40(d,J=2.34Hz,1H),7.35(s,1H),7.32-7.30(m,2H),7.15(d,J=7.50H z,1H),7.02(d,J=7.50Hz,2H),6.93(d,J=8.70Hz,1H),6.35(dd,J=2.22Hz,2.22Hz,1H),4.07(s,2H),3.55(s,3H),2.15(s,6H);

[0848] MS-ESI (m / z): 443.14 [M+H] + .

[0849] Embodiment 49

[0850] Preparation of 1-(4-(4-acetylphenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0851]

[0852] Referring to Steps 1-9 of Example 27, 4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4) was prepared.

[0853] Step 10: Preparation of 1-(4-(4-acetylphenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione

[0854]

[0855] 4-(2-(4-acetylphenoxy)-5-aminophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Intermediate 4, 180 mg) was dissolved in dichloromethane (5 mL) solution, succinic anhydride (SM-8, 65 mg) was added to the solution, and the mixture was stirred at room temperature for about 5 hours, and N,N-dimethylformamide (3 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 240 mg) and triethylamine (0. 3mL), the mixture was stirred at room temperature for about 2-8 hours; after the reaction was completed, the mixture was diluted with water and extracted twice with ethyl acetate, the organic phases were combined and washed once with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 to 0:1 (v / v)) to obtain 98 mg of a white solid, i.e., 1-(4-(4-acetylphenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)pyrrolidine-2,5-dione (Compound 49).

[0856] 1 H-NMR (600MHz, DMSO-d6) δ: 12.05 (s, 1H), 7.87 (d, J = 8.88Hz, 2H), 7.54 (d, J = 2.46Hz, 1H), 7.37 (dd, J = 8.64Hz, 2.52Hz, 1H), 7. 32(s,1H),7.30-7.28(m,2H),6.94(d,J=8.88Hz,2H),6.31(dd,J=2.28Hz,2.28Hz,1H),3.51(s,3H),2.76(s,4H),2.48(s,3H);

[0857] MS-ESI (m / z): 456.27 [M+H] + .

[0858] Biological Examples

[0859] The present invention is further explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0860] Verification Example 1: In vitro enzymology experiment

[0861] The inhibitory activity of the compounds prepared in the above examples on BD1 and BD2 of the BRD4 protein was tested:

[0862] Specific experimental steps:

[0863] Preparation of 1.1x enzyme buffer:

[0864] One volume of 5x enzyme buffer was diluted with 4 volumes of distilled water; 5 mM HEPES, 10 mM MgCl2, 0.01% BRIJ-35, 1 mM EGTA, 2 mM DTT.

[0865] 2. Compound activity test method:

[0866] a) Prepare the compound DMSO stock solution and dilute it in a 1:4 gradient with DMSO. Use Echo 550 to transfer 0.1 μL of the compound dilution to the corresponding wells of a 384-well assay plate (784075, Greiner), with duplicate wells for each concentration;

[0867] b) Seal the assay plate and centrifuge the assay plate at 1000 rpm for 1 minute;

[0868] c) Add 5 μl of BRD4 protein solution (BRD4 BD1 or BRD4 BD2, final concentration of 1 nM) into the corresponding wells of a 384-well assay plate (784075, Greiner);

[0869] d) The test plate was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 15 minutes;

[0870] e) Add 5 μl of BRD4 protein substrate solution (for BRD4 BD1 test, the final concentration of the substrate is 5 nM; for BRD4 BD2 test, the final concentration of the substrate is 40 nM) to start the reaction;

[0871] f) Centrifuge the test plate at 1000 rpm for 1 minute. Seal the test plate and incubate at 25°C for 60 minutes;

[0872] g) Add 5 μl of Sa-XL665 solution and 5 μl of GST-Tb to each well of the detection plate;

[0873] h) Centrifuge the test plate at 1000 rpm for 1 minute, seal the test plate, and incubate at 25° C. for 60 minutes;

[0874] i) Fluorescence signals were read at 615 nm (Cryptate) and 665 nm (XL665) on an Envision 2104 plate reader.

[0875] 3. Data Analysis

[0876] 3.1 Calculate the ratio (665 / 615 nm) for each well.

[0877] 3.2 The inhibition rate is calculated as follows:

[0878] Inhibition rate = 100-(Signal cmpd -Signal Ave_PC) / (Signal Ave_VC -Signal Ave_PC )×100。

[0879] 3.3 Calculate the IC 50 value of the compound and plot the dose - effect curve of the compound:

[0880] Use GraphPad 6.0 to perform a non - linear regression curve (dose - effect relationship - variable slope) of the logarithm of the compound concentration against the inhibition rate to calculate the IC 50 value.

[0881] Y = lowest value+(highest value - lowest value) / (1 + 10^((LogIC 50 -X)*slope))

[0882] X: logarithm of the inhibitor concentration; Y: inhibition rate.

[0883] Calculate the IC 50 based on the calculated values, and the results are shown in Table 1.

[0884] Table 1 Inhibitory results of compound BRD4 protease IC 50 (nM) a

[0885]

[0886]

[0887] Note: The values in the table are the averages of 3 experiments; * indicates 0.01 < P < 0.05, ** indicates P < 0.01

[0888] The data in Table 1 show that the compounds of the present invention have a relatively obvious inhibitory effect on BRD4 (BD1 / BD2) protease; among them, the inhibitory effects of compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 19, 20, 23, 24, 26, 28, 29, 30, 38, 40 are extremely significantly different from the control group mivebresib (P < 0.01).

[0889] Verification Example 2: In vitro cell proliferation inhibition experiment

[0890] 1. In vitro proliferation inhibition experiment on LNCaP (human AR - positive prostate cancer cell line)

[0891] The specific experimental method is as follows:

[0892] LNCaP (human AR-positive prostate cancer cell line) was digested with trypsin for 3 minutes and then digested with RPMI1640 medium (complete medium) containing 10% serum. The cells were centrifuged at 1000rpm for 5 minutes, the supernatant was discarded, and the cells were resuspended in complete medium. The cell concentration was adjusted to 50 cells / μL, and 100 μL / well was inoculated in a 96-well plate, and a zero well containing only complete medium was reserved. After 30 hours of incubation in an incubator, the diluted target compound with different concentrations (twice the target concentration) was added to the 96-well plate at 100 μL / well, and the control group was added with 100 μL / well of complete medium. Three replicate wells were set for each concentration. After 72 hours of continuous incubation, 20 μL of CCK8 was added to each well; after incubation in an incubator for 2 hours, 450 nm was selected and the absorbance was measured by an enzyme reader; the formula: cell inhibition rate (%) = (1-A experiment / A control) × 100%, and the results of cell proliferation inhibition activity are shown in Table 2.

[0893] Table 2 Inhibition rate of LNCaP cell proliferation

[0894]

[0895] The data in Table 2 show that the compounds of the present invention have a significant inhibitory effect on the human AR-positive prostate cancer cell line LNCaP.

[0896] 2. In vitro proliferation inhibition experiment on HUVEC (human umbilical vein endothelial cell line)

[0897] The specific experimental method is:

[0898] HUVECs were digested with trypsin for 5 min, and then digested with DMEM high-glucose medium (complete medium) containing 10% serum. The cells were centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in complete medium. The cell concentration was adjusted to 15 cells / μL, and 100 μL / well was inoculated in a 96-well plate, and a zero well containing only complete medium was reserved. After culturing in an incubator for 24 h, the diluted target compound with different concentrations (twice the target concentration) was added to the 96-well plate at 100 μL / well, and the control group was added with 100 μL / well of complete medium, and three replicate wells were set for each concentration. After continuing to culture for 72 h, 20 μL of CCK8 was added to each well. After incubation in an incubator for 2 h, 450 nm was selected and the absorbance was measured by an enzyme reader. The formula: cell inhibition rate (%) = (1-A experiment / A control) × 100%, the results of cell proliferation inhibition activity are shown in Table 3.

[0899] Table 3 Inhibition rate of HUVEC cell proliferation

[0900]

[0901] The data in Table 3 show that, compared with the reference substance mivebresib (ABBV-075), the compounds of the present invention have generally low inhibitory action against normal human cell lines (human umbilical vein endothelial cell lines), but have good inhibitory effects on tumor cells. Therefore, the compounds of the present invention have good drug value.

Claims

1. A hydrate, solvate, prodrug, stereoisomer or tautomer of a pyrrolo[2,3-c]pyridine compound of formula I or a pharmaceutically acceptable salt thereof: in, L is selected from -O-, -S-, -NH-, preferably -O-; M1, M2, and M3 are each independently selected from N or C, more preferably C; Rg is independently selected from: absent or hydrogen, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2)n1-OH, -(CH2)n1-NR6R7, -(CH2)n1-C(O)NR6R7, -(CH2)n1-N(R6)C(O)R7, -(CH2)n1-C(O)R8, -(CH2)n1-C(O)OR8, -(CH2)n1-O-(CH2)n2-C(O)-(CH2)n3-C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 substituted with a haloalkyl, -(CH2)n1-NR6R7, -(CH2)n1-C(O)NR6R7, -(CH2)n1-N(R6)C(O)R7, -(CH2)n1-C(O)R8, -(CH2)n1-O-(CH2)n2-C(O)-(CH2)n3-C(O)OR8, -(CH2)n1-C(O)OR8 substituent; further, Rg is preferably absent or is hydrogen, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, -(CH2)n1-OH, -(CH2)n1-N(R6)C(O)R7, -(CH2)n1-C(O)R8, -(CH2)n1-C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably hydrogen, halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably hydrogen, halogen, methyl, methoxy; y is 0 or an integer from 1 to 5; R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl; Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl; R4 is independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl; n is an integer from 1 to 3, q ​​is an integer from 0, 1 to 6, and the maximum number q of substituents R4 is 2n, and when q≥2, the R4 substituents are the same or different; m is an integer from 0, 1 to 6; preferably 0 or 1; Z1 is selected from: O, S, NR b ,CRaR b NR b ,CRaR b ; Further, when Z1 is CRaR b When R b It can form a 3- to 7-membered ring together with the adjacent ring atoms of Z1, and a 3-membered ring is particularly preferred; when Z1 is NR b When R b Together with the atoms on the ring adjacent to Z1, it can form a 3- to 7-membered heterocyclic ring, and is particularly preferably a 4- to 5-membered heterocyclic ring; Among them, Ra, R b are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferably Ra, R b Each independently is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferably Ra is hydrogen, methyl, R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane; M4 and M5 are each independently selected from N or CRy, wherein Ry is selected from hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl; further, M4 and M5 are preferably CRy, wherein Ry is preferably hydrogen or methyl, and Ry is particularly preferably hydrogen; X1 and X2 are independently selected from: O, S, NH or absent; further preferably, X1 and X2 are O or absent.

2. The compound according to claim 1, which is a hydrate, solvate, prodrug, stereoisomer or tautomer of a compound represented by general formula II or a pharmaceutically acceptable salt thereof: in, Rg is independently selected from: absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2) n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably halogen, methyl, methoxy; y is an integer from 0 or 1 to 5; more preferably 0, 1 or 2; R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl; Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl; R4, R4′ are independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably R4 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl, and R4' is hydrogen, methyl; m is an integer from 0, 1 to 6; preferably 0 or 1; Ra, R b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferably Ra, R b Each independently is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferably Ra is hydrogen, methyl, R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane; Further, R b It can form a 3- to 7-membered ring together with the adjacent ring atom directly connected to C, and a 3-membered ring is particularly preferred; X2 is 0 or absent.

3. The compound according to claim 1, which is a hydrate, solvate, prodrug, stereoisomer or tautomer of the compound represented by general formula III or a pharmaceutically acceptable salt thereof: Rg is independently selected from: absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2) n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably halogen, methyl, methoxy; y is an integer from 0 or 1 to 5; more preferably 0, 1 or 2; R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl; in, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl; R4, R4′ are independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably R4 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl, and R4' is hydrogen, methyl; m is an integer from 0, 1 to 6; preferably 0 or 1; Ra, R b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferably Ra, R b Each independently is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferably Ra is hydrogen, methyl, R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane; Further, R b Together with the adjacent ring atom directly connected to N, it can form a 3- to 7-membered heterocyclic ring, and a 4- to 5-membered heterocyclic ring is particularly preferred.

4. The compound according to claim 1, which is a hydrate, solvate, prodrug, stereoisomer or tautomer of the compound represented by general formula III-1 or a pharmaceutically acceptable salt thereof: in, Rg is independently selected from: absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2) n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably halogen, methyl, methoxy; y is an integer from 0 or 1 to 5; more preferably 0, 1 or 2; R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl; Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl; R4, R4′ are independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably R4 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl, and R4' is hydrogen, methyl; m is an integer from 0, 1 to 6; preferably 0 or 1; Ra, R b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferably Ra, R b Each independently is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferably Ra is hydrogen, methyl, R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane; Further, R b Together with the adjacent ring atom directly connected to N, it can form a 3- to 7-membered heterocyclic ring, and a 4- to 5-membered heterocyclic ring is particularly preferred.

5. The compound according to claim 1, which is a hydrate, solvate, prodrug, stereoisomer or tautomer of a compound represented by general formula IV or a pharmaceutically acceptable salt thereof: in, Rg is independently selected from: absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2) n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably halogen, methyl, methoxy; y is an integer from 0 or 1 to 5; more preferably 0, 1 or 2; R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl; Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl; R4 is independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably R4 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl; more particularly preferably R4 is hydrogen, methyl; q is an integer from 0, 1 to 4, and when q ≥ 2, the R4 substituents are the same or different; m is an integer from 0, 1 to 6; preferably 0 or 1; R b Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferred R b For hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferred R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane; more preferably R b For hydrogen.

6. The compound according to claim 1, which is a hydrate, solvate, prodrug, stereoisomer or tautomer of the compound represented by general formula IV-1 or a pharmaceutically acceptable salt thereof: in, Rg is independently selected from: absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(CH2) n1 -OH, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, optionally substituted by one or more selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Haloalkyl, -(CH2) n1 -NR6R7, -(CH2) n1 -C(O)NR6R7, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -O-(CH2) n2 -C(O)-(CH2) n3 -C(O)OR8, -(CH2) n1 -C(O)OR8 substituent; further, Rg is preferably absent or halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, -(CH2) n1 -OH, -(CH2) n1 -N(R6)C(O)R7, -(CH2) n1 -C(O)R8, -(CH2) n1 -C(O)OR8; in the above groups, n1, n2, n3 are each independently an integer from 0, 1 to 6; R6, R7, R8 of each group are the same or different and are each independently selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl; Rg is more preferably halogen, -CF2H, -CH2-OH, methyl, methoxy, -C(O)CH3, -(CH2)-C(O)OCH3, -NHC(O)CH(CH3)2, and particularly preferably halogen, methyl, methoxy; y is an integer from 0 or 1 to 5; more preferably 0, 1 or 2; R1, R2, and R3 are each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl; Among them, R1 is more preferably hydrogen, methyl, cyano, methoxy, particularly preferably hydrogen, methyl, more preferably hydrogen; R2 is more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably methyl; R3 is further preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, particularly preferably hydrogen, C 1-6 Alkyl, more preferably hydrogen, methyl; R4 is independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, hydroxy, amino, nitro, cyano, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl; more preferably hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl; particularly preferably R4 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, tert-butyl, allyl; more particularly preferably R4 is hydrogen, methyl; q is an integer from 0, 1 to 4, and when q ≥ 2, the R4 substituents are the same or different; m is an integer from 0, 1 to 6; preferably 0 or 1; R b Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, cyano, halogen, C 1-6 Alkoxy, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl; further preferred R b For hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Alkoxy; particularly preferred R b is hydrogen, methyl, ethyl, propyl, methylcyclopropane; more preferably R b For hydrogen.

7. The pyrrolo[2,3-c]pyridine compound according to claim 1, characterized in that: The compound shown in formula I is a compound of any of the following structures: or a hydrate, solvate, prodrug, stereoisomer or tautomer of a pharmaceutically acceptable salt thereof.

8. The method for preparing a pyrrolo[2,3-c]pyridine compound according to claim 1, characterized in that: The following steps are involved: Step 1) 5-bromo-2-methoxy-4-methyl-3-nitropyridine (SM-1) and N,N-dimethylformamide dimethyl acetal (DMFDMA) are heated in N,N-dimethylformamide (DMF) to react to obtain a reddish brown intermediate compound (SM-1a); Step 2) The reddish brown intermediate compound (SM-1a) obtained in step 1 is dissolved in dichloromethane, and a cyclization reaction is carried out under the action of a catalyst zinc powder to prepare an intermediate compound 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-2); Step 3) Add p-toluenesulfonyl chloride (P-TSCI), sodium hydroxide (NaOH), and tetrabutylammonium bromide (TBNB) to a dichloromethane solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (SM-2) and stir to react to obtain a white intermediate compound (SM-3); Step 4) The white intermediate compound (SM-3) obtained in step 3 is suspended in a mixed solvent of hydrochloric acid / ethanol / ethyl acetate to react to obtain a white intermediate compound (SM-3a); Step 5) The intermediate compound SM-3a obtained in step 4 is reacted with an iodide (SM-4, i.e., R2-I, wherein R2 is defined in the general formula I, and the specific definition is determined according to the actual compound structure, such as when R2 is methyl, SM-4 is iodomethane CH3-I) to prepare a white intermediate compound 1; Step 6) reacting the intermediate compound SM-5 with diboric acid pinacol ester under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2) to prepare a white intermediate compound (SM-6); Step 7) reacting the compound intermediate 1 obtained in step 5 with the intermediate compound SM-6 obtained in step 6 under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2) to prepare a light yellow intermediate 2 compound; Step 8) heating the compound intermediate 2 obtained in step 7 and the intermediate compound SM-7 to react to obtain the compound intermediate 3; Step 9) Add glacial acetic acid (HOAc) dropwise to the compound intermediate 3 obtained in step 8 under the catalysis of zinc powder (Zn) to react to prepare compound intermediate 4; Step 10) The compound intermediate 4 obtained in step 9 is dissolved in dichloromethane, and the intermediate compound SM-8, N,N-dimethylformamide (DMF), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), and triethylamine (Et3N) are added thereto and stirred for reaction to prepare the compound intermediate 5; Step 11) reacting the compound intermediate 5 obtained in step 10 with an iodide (SM-9, i.e., R1-I, wherein R1 is defined in general formula I, and the specific definition is determined according to the actual compound structure, such as when R1 is methyl, SM-9 is iodomethane CH3-I) to prepare the target product I; The synthetic route is as follows: Among them, R1, R2, R3, R4, Rg, L, y, M1, M2, M3, M4, M5, Z1, X1, X2, m, n, q in the intermediate compounds involved in the synthesis route are as defined in the general formula I of the first aspect of the present invention.

9. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

10. Use of the compound according to any one of claims 1 to 7 for preparing a drug for treating bromodomain-related diseases.

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