Pyrrole amidopyridone compound, preparation method therefor and use thereof

Abstract

To provide a novel BRD enzyme inhibitor or degrading agent for the preparation of a therapeutic medicament for tumors or inflammatory diseases.SOLUTION: Disclosed are a pyrrole amidopyridone compound represented by general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer, a tautomer, a solvate, a polymorph, or a prodrug thereof, a preparation method therefor and use thereof in pharmacy.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims priority from Chinese patent application No. 201910200772.2 filed on March 17, 2019, and from Chinese patent application No. 201911073573.6 filed on November 6, 2019. This application cites the above-mentioned Chinese patent application in its entirety.

[0002] The present invention relates to the field of medicinal chemistry, specifically to pyrrole amide pyridone BET-BRD signal pathway inhibitor compounds, their preparation methods and uses. [Background technology]

[0003] Abnormal epigenetic regulation is one of the key factors in tumor development. Recent studies have found that epigenetic abnormalities mediated by BRD proteins are closely associated with the overexpression of oncogenes and are closely related to the growth and proliferation of cancer cells. BRD4 is a member of the BET protein family and has attracted great attention from major pharmaceutical companies and scientific research institutes due to its potential antitumor value.

[0004] BET proteins, also known as epigenetic recognition proteins, can recognize changes in epigenetic information of cellular histones and transmit signals such as stimulating cell division. Take leukemia as an example, mutations in the BET protein gene in blood cells disrupt the signal transmission, causing diseased cells to divide uncontrollably, thereby damaging human tissues and organs. The formation of BRD-NUT fusion proto-oncogenes by translocation of the bromodomain coding region of BRD3 / BRD4 and the chromatin of the NUT (nuclear protein of the testis) gene is the etiology of midline carcinoma, and is currently also direct evidence that the BRD4 protein is involved in the development of tumors. At the same time, studies have found that in models of hematopoietic cancers such as AML, Burkitt's lymphoma, multiple myeloma, and B-cell acute lymphoblastic leukemia, MYC can be directly silenced by preventing the binding of BRD4 at the MYC site. Since various isomers of MYC are known to be important regulators of cell proliferation and survival, and MYC is an oncogene that may be overexpressed in many cancers, bromodomain antagonism has provided the first opportunity to target MYC-induced tumorigenesis. Recently, it has been discovered that BRD4 also plays an important role in regulating the transcription of viral genes and has a certain relationship with the pathogenesis of viral tumors. These research results show that BRD4 plays an important role in various tumors, especially in tumors that are difficult to cure and have no effective treatments, and the study of its relationship with tumors has provided a new strategy for tumor treatment. By acting on small molecule compounds of the bromodomain of the BRD4 protein, it is possible to disrupt the specific binding of the bromodomain to acetylated lysine, affect the transcriptional regulation and other cellular processes of tumor cells, and realize targeted therapy of tumors.

[0005] Therefore, BRD4 protein is a very promising new epigenetic target, and small molecule inhibitors acting on the bromodomain of BRD4 protein also have broad prospects for use in tumor research, and may be used to develop new antitumor drugs. The reported selective inhibitors of BRD4 protein, such as JQ1 and IBET151, have crystal complexes that show that these small molecule inhibitors bind to the acetylated lysine recognition pocket of the bromodomain, thereby blocking the acetylation regulation mediated by the bromodomain, and the therapeutic effects of these inhibitors in some cancers have already been proven. At present, most of the known small molecule inhibitors of BRD4 protein have few structural types and are not sufficiently selective for the BD1 and BD2 bromodomains, which limits people's in-depth research into the biological functions of bromodomain-containing proteins and their antitumor potential. In addition, it is necessary to improve the effects of existing BRD protein inhibitors and further elucidate their mechanisms. Abbvie's ABBV744 is a selective inhibitor of BRD4-BD2, and is a selective inhibitor of BRD4-BD2. It has high selectivity and high killing effect against some leukemia and prostate cancer cell lines. At the same time, the ADME properties of ABBV744 need to be further optimized and improved. Therefore, finding a new small molecule BRD protein specific BD domain inhibitor or BRD protein degrader that is highly effective and highly selective is a hotspot of epigenetic anti-tumor research. Summary of the Invention

[0006] One of the technical problems that the present invention aims to solve is to provide a novel BRD enzyme inhibitor or decomposer in the manufacture of medicines for treating tumors or inflammatory diseases.

[0007] The methods to solve the above technical problems are as follows: A pyrrole amide pyridone compound represented by general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof,

[0008] [ka]

[0009] where: R1 is independently selected from hydrogen, C1-C8 alkyl, 3-8 membered cyclic hydrocarbon or heterocycloalkyl, alkoxyalkyl, alkylaminoalkyl, heterocyclylalkyl, arylalkyl, etc.; R2 is independently selected from hydrogen, C1-C6 alkyl;

[0010] X1 and X2 are each independently selected from CH or NH;

[0011] R3 and R5 are each independently selected from hydrogen, halogen, and C1-C6 alkyl;

[0012] R4, R6, and R7 are each independently selected from hydrogen, halogen, cyano, nitro, alkenyl, alkynyl, acylamino, ether or thioether, substituted or unsubstituted C1-C6 alkyl, 3-8 membered cyclic hydrocarbon or heterocycloalkyl, 5-10 membered aryl or heteroaryl, alkoxy, substituted or unsubstituted amino, alkylsulfone, alkylsulfoxide, alkylsulfonamide, alkylsulfinamide, urea, sulfonylurea, sulfinurea, etc.;

[0013] Alternatively, R6 and R7 may be joined via a carbon atom or a heteroatom to form a 3-8 membered saturated, unsaturated or partially unsaturated ring system.

[0014] One or more hydrogen atoms on any of the above groups may be replaced with a substituent including, but not limited to, deuterium, halogen, hydroxy, amino or cycloamino, cyano, nitro, sulfone or sulfonyl, C1-C8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, C1-C8 alkoxy or alkylthio, C1-C8 alkylamino, alkenyl, alkynyl, acyl or sulfonyl, urea or sulfonylurea, 5-8 membered aryl or heteroaryl; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O, P or S, the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, P or S, and the ring systems include saturated or partially unsaturated ring systems such as spiro rings, bridged rings, fused rings, fused rings, etc.

[0015] In a further embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, is preferably a compound of formula (II):

[0016] [ka]

[0017] wherein R8, R9 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, or R8 and R9 are connected together via a carbon atom or heteroatom to form a 3-8 membered saturated, unsaturated or partially unsaturated ring system; R10 is selected from hydrogen, C1-C10 alkyl, 3-10 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl; L is selected from O, S, NH, etc.; and R1, R2, R3, R4, R5, R6 are as defined above.

[0018] In yet a further embodiment, there is provided a compound represented by general formula (1), or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof, characterized in that:

[0019] R1 is preferably selected from substituted or unsubstituted C2-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl or heterocycloalkyl; R2 is preferably selected from hydrogen, C1-C6 alkyl; or R1 and R2 form a 4-8 membered nitrogen-containing heterocycle between them; more preferably selected from substituted or unsubstituted ethyl, ethoxyethyl, etc.;

[0020] R3, R5, and R6 are each independently selected from hydrogen, fluorine, and C1-C6 alkyl;

[0021] R4 is preferably selected from C1-C6 sulfonyl, C1-C6 sulfonylamide, C1-C6 sulfine, C1-C6 sulfinamide, C1-C6 sulfonimide, C1-C6 substituted alkyl;

[0022] R8 and R9 are each independently selected from hydrogen, C1-C3 alkyl, or form a 3-6 membered ring together;

[0023] R10 is preferably selected from hydrogen, C1-C8 alkyl, 3-8 membered cycloalkyl and heterocycloalkyl, 5-8 membered aryl and heteroaryl; more preferably,

[0024] [ka]

[0025] where Rd is selected from hydrogen, halogen, cyano, sulfonyl, sulfine, C1-C3 alkyl or alkoxy, and can form a 3-8 membered saturated or partially unsaturated ring system between Rd and a benzene ring or a cyclohexane ring or another Rd substituent; n=0-5, preferably selected from 2, 3.

[0026] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0027] [ka]

[0028] Wherein X1 is CH; X2 is NH;

[0029] R1 is hydrogen, C1-C8 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, C1-C8 alkyl substituted with 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, C1-C8 alkyl substituted with tetracycloalkyl or

[0030] [ka]

[0031] In the 3-8 membered heterocycloalkyl and the C1-C8 alkyl substituted with the 3-8 membered heterocycloalkyl, the heteroatom is N, O, S, -S(=O)-, or -S(=O) 2-, and the number of heteroatoms is 1, 2 or 3; said C1-C8 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, C1-C8 alkyl substituted with 3- to 8-membered cycloalkyl, C1-C8 alkyl substituted with 3- to 8-membered heterocycloalkyl, and

[0032] [ka]

[0033] is optionally substituted with one or more substituents, the substituents being independently selected from: halogen, cyano, hydroxy, =O, C1-C6 alkyl, C1-C6 alkyl-O-, C1-C6 alkyl-(SO 2 )-and

[0034] [ka]

[0035] When there are more than one substituents, they may be the same or different;

[0036] Ra and Rb are independently hydrogen or C1-C8 alkyl;

[0037] L1 is a linking bond, -(C1-C8 alkyl)-, -(C2-C6 alkynyl)-, or -(C1-C6 alkyl)-(CH 2 OCH 2 ) m1 -(C1-C6 alkyl)-;

[0038] m1 is 1, 2, 3 or 4;

[0039] L2 is a linking bond, -O-,

[0040] [ka]

[0041] and;

[0042] W is -CH 2 - or -C(=O)-;

[0043] R2 is hydrogen or C1-C6 alkyl;

[0044] Alternatively, R1 and R2 are linked together with the linked N to form: 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkyl substituted with one or more halogens; the heteroatoms of the 3-8 membered heterocycloalkyl and 3-8 membered heterocycloalkyl substituted with one or more halogens are, in addition to the N, further N, O, S, -S(=O)- and -S(=O) 2 -, and 0 to 2 heteroatoms selected from -; when there are multiple substituents, they may be the same or different;

[0045] R3 and R5 are independently hydrogen, halogen, or C1-C6 alkyl;

[0046] R4, R6 and R7 are independently hydrogen or -L-R10;

[0047] L is independently a bond, -O-, -(SO 2 )-or-(SO 2 )-NH- and (-NH-(SO 2 )-include);

[0048] R10 is independently C1-C6 alkyl, 6-10 membered aryl, C1-C6 alkyl substituted with one or more substituents, or 6-10 membered aryl substituted with one or more substituents; the substituents in the C1-C6 alkyl substituted with one or more substituents and the 6-10 membered aryl substituted with one or more substituents are independently halogen, hydroxy, cyano, or C1-C6 alkyl; when there are multiple substituents, they may be the same or different;

[0049] Alternatively, R6 and R7 may be linked together with the carbon atom to which they are linked to form: a 6-membered heterocyclo alkyl, or a 6-membered heterocycloalkyl substituted with one or more substituents, the heteroatoms in said 6-membered heterocycloalkyl being N, O, S, -S(=O)- and -S(=O) 2 -, and the number of heteroatoms is 1, 2 or 3; the substituents are independently C1-C6 alkyl or =O; and when there are multiple substituents, they may be the same or different.

[0050] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0051] R1 is C1-C8 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, C1-C8 alkyl substituted with 3- to 8-membered cycloalkyl, or

[0052] [ka]

[0053] For example, C1-C8 alkyl, 3-8 membered cycloalkyl or

[0054] [ka]

[0055] It is.

[0056] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof, are as follows (definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0057] R1 is C1-C8 alkyl, a 3- to 8-membered cycloalkyl, a 3- to 8-membered heterocycloalkyl, or a C1-C8 alkyl substituted with a 3- to 8-membered cycloalkyl; for example, C1-C8 alkyl or a 3- to 8-membered cycloalkyl.

[0058] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0059] R1 is

[0060] [ka]

[0061] It is.

[0062] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0063] m1 is 3.

[0064] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0065] L2 is a linking bond,

[0066] [ka]

[0067] It is.

[0068] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0069] R2 is hydrogen.

[0070] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0071] R1 and R2 are linked together with the linked N to form: a 3- to 8-membered heterocycloalkyl, or a 3- to 8-membered heterocycloalkyl substituted with one or more halogens.

[0072] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0073] R3 is hydrogen.

[0074] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0075] R5 is hydrogen.

[0076] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0077] R6 is hydrogen.

[0078] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0079] L is independently a linking bond, -O- or -(SO 2)-, for example a connecting bond or -(SO 2 )-.

[0080] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0081] L is independently -O-.

[0082] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0083] R10 is independently C1-C6 alkyl, C1-C6 alkyl substituted with one or more substituents.

[0084] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0085] R10 is independently a 6- to 10-membered aryl, or a 6- to 10-membered aryl substituted with one or more substituents.

[0086] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0087] R4 is hydrogen or -L-R10, for example, -L-R10, and for example, L is a linking bond or -(SO 2 )--, and / or R10 is C1-C6 alkyl, C1-C6 alkyl substituted with one or more substituents.

[0088] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0089] R7 is hydrogen or -L-R10, for example, -L-R10, or, for example, L is -O- and / or R10 is a 6-10 membered aryl or a 6-10 membered aryl substituted with one or more substituents.

[0090] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows: (wherein the definitions of undefined groups are as defined in any one of the embodiments of this application),

[0091] R6 and R7 are linked and together with the linked carbon atoms form: a 6-membered heterocycloalkyl, or a 6-membered heterocycloalkyl substituted with one or more substituents.

[0092] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0093] In R1, the substituents are independently: halogen, cyano, hydroxy, =O, C1-C6 alkyl, C1-C6 alkyl-O-, and C1-C6 alkyl-(SO 2 )-; for example, halogen, cyano, C1-C6 alkyl, C1-C6 alkyl-O- and C1-C6 alkyl-(SO 2 )-.

[0094] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0095] When R1 is C1-C8 alkyl and the C1-C8 alkyl is substituted with one or more substituents, the substituents are halogen, cyano, C1-C6 alkyl, C1-C6 alkyl-O- and C1-C6 alkyl-(SO 2 )- is selected from.

[0096] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0097] When R1 is a 3- to 8-membered cycloalkyl, a C1-C8 alkyl substituted with a 3- to 8-membered cycloalkyl, and the 3- to 8-membered cycloalkyl and the C1-C8 alkyl substituted with a 3- to 8-membered cycloalkyl are independently substituted with one or more substituents, the substituents are halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkyl-O-, and C1-C6 alkyl-(SO 2 )-; for example, halogen, C1-C6 alkyl or hydroxy, also for example, halogen.

[0098] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0099] When R1 is a C1-C8 alkyl substituted with a 3-8 membered cycloalkyl, and the C1-C8 alkyl substituted with a 3-8 membered cycloalkyl is substituted with one or more substituents, the substituents are halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkyl-O-, and C1-C6 alkyl-(SO 2 )-; for example, halogen or is hydroxy and also, for example, halogen.

[0100] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0101] [ka]

[0102] Wherein X1 is CH; X2 is NH;

[0103] R1 is C1-C8 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, C1-C8 alkyl substituted with 3- to 8-membered cycloalkyl, or

[0104] [ka]

[0105] In the 3-8 membered heterocycloalkyl, the heteroatoms are N, O, S, -S(=O)- and -S(=O) 2 -, wherein the number of heteroatoms is 1, 2 or 3; said C1-C8 alkyl, 3- to 8-membered cycloalkyl, C1-C8 alkyl substituted with 3- to 8-membered cycloalkyl, and

[0106] [ka]

[0107] is optionally substituted with one or more substituents, the substituents being independently selected from: halogen, cyano, hydroxy, =O, C1-C6 alkyl, C1-C6 alkyl-O-, and C1-C6 alkyl-(SO 2 )-; when there are multiple substituents, they may be the same or different;

[0108] L1 is a connecting bond, -(C1-C8 alkyl)-, -(C2-C6 alkynyl)-, -(C1-C6 alkyl)-(CH 2 OCH 2 ) m1 -(C1-C6 alkyl)-;

[0109] m1 is 1, 2, 3 or 4;

[0110] L2 is a linking bond,

[0111] [ka]

[0112] and;

[0113] W is -CH 2 - or -C(=O)-;

[0114] R2 is hydrogen;

[0115] Alternatively, R1 and R2 are linked together with the linked N to form: 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkyl substituted with one or more halogens; the heteroatoms of the 3-8 membered heterocycloalkyl and 3-8 membered heterocycloalkyl substituted with one or more halogens are, in addition to the N, further N, O, S, -S(=O)- and -S(=O) 2 -, and 0 to 2 heteroatoms selected from -; when there are multiple substituents, they may be the same or different;

[0116] R3 and R5 are independently hydrogen, halogen, or C1-C6 alkyl;

[0117] R6 is hydrogen;

[0118] R4 and R7 are independently hydrogen, -L-R10;

[0119] L is a linking bond, -O- or -(SO 2 )- and;

[0120] R10 is independently C1-C6 alkyl, 6-10 membered aryl, C1-C6 alkyl substituted with one or more substituents, or 6-10 membered aryl substituted with one or more substituents; the substituents in the C1-C6 alkyl substituted with one or more substituents and the 6-10 membered aryl substituted with one or more substituents are independently halogen, hydroxy, cyano, or C1-C6 alkyl; when there are multiple substituents, they may be the same or different;

[0121] Alternatively, R6 and R7 are linked together with the linked carbon atoms to form: a 6-membered heterocycloalkyl, or a 6-membered heterocycloalkyl substituted with one or more substituents, wherein the substituents are C1-C6 alkyl or =O.

[0122] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0123] X1 is CH; X2 is NH;

[0124] R1 is C1-C8 alkyl, 3-8 membered cycloalkyl; said C1-C8 alkyl, 3-8 membered cycloalkyl is optionally substituted with one or more substituents;

[0125] R2, R3, R5 and R6 are independently hydrogen;

[0126] R4 and R7 are independently hydrogen or -L-R10;

[0127] or R6 and R7 are linked together with the linked carbon atoms to form: a 6-membered heterocycloalkyl, or a 6-membered heterocycloalkyl substituted with one or more substituents, the substituents being C1-C6 alkyl or =O;

[0128] Preferably, R4 is C1-C6 alkyl or C1-C6 alkyl substituted with one or more substituents;

[0129] R7 is -L-R10; L is -O-; and R10 is a 6- to 10-membered aryl or a 6- to 10-membered aryl substituted with one or more substituents.

[0130] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0131] X1 is CH; X2 is NH;

[0132] R1 is C1-C8 alkyl or

[0133] [ka]

[0134] and;

[0135] R2, R3, R5 and R6 are independently hydrogen;

[0136] R4 and R7 are independently hydrogen or -L-R10;

[0137] or R6 and R7 are linked together with the linked carbon atoms to form: a 6-membered heterocycloalkyl, or a 6-membered heterocycloalkyl substituted with one or more substituents, the substituents being C1-C6 alkyl or =O;

[0138] Preferably, R1 is

[0139] [ka]

[0140] and;

[0141] R4 is -L-R10; L is a linking bond or -(SO 2 )-; R10 is C1-C6 alkyl or C1-C6 alkyl substituted with one or more substituents;

[0142] R7 is -L-R10; L is -O-; R10 is a 6-10 membered aryl or a 6-10 membered aryl substituted with one or more substituents;

[0143] or R6 and R7 are linked together with the linked carbon atoms to form: a 6-membered heterocycloalkyl, or a 6-membered heterocycloalkyl substituted with one or more substituents, the substituents being C1-C6 alkyl or =O;

[0144] More preferably, L1 is a linking bond;

[0145] L2 is

[0146] [ka]

[0147] It is.

[0148] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0149] When R1 is C1-C8 alkyl, C1-C8 alkyl substituted with 3-8 membered cycloalkyl, or C1-C8 alkyl substituted with 3-8 membered heterocycloalkyl, the C1-C8 alkyl in said C1-C8 alkyl, C1-C8 alkyl substituted with 3-8 membered cycloalkyl, and C1-C8 alkyl substituted with 3-8 membered heterocycloalkyl are independently C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or, for example, methyl, ethyl, or isopropyl.

[0150] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0151] When R1 is a 3- to 8-membered cycloalkyl or a C1-C8 alkyl substituted with a 3- to 8-membered cycloalkyl, the 3- to 8-membered cycloalkyl in the 3- to 8-membered cycloalkyl and the C1-C8 alkyl substituted with a 3- to 8-membered cycloalkyl is independently a 3- to 6-membered cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; or, for example, cyclopropyl, cyclobutyl, or cyclopentyl.

[0152] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0153] R1 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered heterocycloalkyl substituted When the 3-8 membered heterocycloalkyl and the 3-8 membered heterocycloalkyl substituted C1-C8 alkyl are independently 3-6 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1 or 2; for example,

[0154] [ka]

[0155] It is.

[0156] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0157] The substituent in R1 is C1-C6 alkyl, C1-C6 alkyl-O- or C1-C6 alkyl-(SO 2 )-, the C1-C6 alkyl, C1-C6 alkyl-O- and C1-C6 alkyl-(SO 2 )-C1-C6 alkyl is independently C 1 -C 4 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; also, for example, methyl or ethyl.

[0158] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0159] When Ra and / or Rb are independently C1-C8 alkyl, said C1-C8 alkyl is independently C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl; also, for example, methyl.

[0160] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0161] When L1 is -(C1-C8 alkyl)-, the C1-C8 alkyl is C1-C6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl. ; also, for example, n-butyl, n-pentyl or n-hexyl.

[0162] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0163] When L1 is -(C2-C6 alkynyl)-, the C2-C6 alkynyl is ethynyl, prop-1-ynyl,

[0164] [ka]

[0165] But-1-ynyl

[0166] [ka]

[0167] or pent-4-ynyl

[0168] [ka]

[0169] and, for example,

[0170] [ka]

[0171] Here, the a-terminal represents the connection with L2.

[0172] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0173] L1 is -(C1-C6 alkyl)-(CH 2 OCH 2 ) m1-(C1-C6 alkyl)-, said C1-C6 alkyl is independently 1 -C 4 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; also, for example, methyl, ethyl or n-propyl.

[0174] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0175] m1 is 2 or 3.

[0176] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0177] When R2 is C1-C6 alkyl, said C1-C6 alkyl is C1-C4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; also, for example, methyl, ethyl or isopropyl.

[0178] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0179] When R1 and R2 are linked together with the linked N to form: a 3- to 8-membered heterocycloalkyl, or a 3- to 8-membered heterocycloalkyl substituted with one or more halogens, In this case, the 3- to 8-membered heterocycloalkyl in the 3- to 8-membered heterocycloalkyl or the 3- to 8-membered heterocycloalkyl substituted with one or more halogens is independently a 3- to 6-membered heterocycloalkyl, where the heteroatom is the N; for example,

[0180] [ka]

[0181] It is.

[0182] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0183] When R10 is independently C1-C6 alkyl, or C1-C6 alkyl substituted with one or more substituents, said C1-C6 alkyl is independently C1-C4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or, for example, methyl or ethyl.

[0184] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0185] When R10 is independently a 6- to 10-membered aryl, or a 6- to 10-membered aryl substituted with one or more substituents, the 6- to 10-membered aryl in the 6- to 10-membered aryl, or the 6- to 10-membered aryl substituted with one or more substituents is independently phenyl or naphthyl.

[0186] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0187] When the substituents on R10 are C1-C6 alkyl, the substituents are independently C1-C4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; or, for example, methyl or ethyl.

[0188] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0189] When R and R are linked together with the carbon atom to which they are linked to form a 6-membered heterocycloalkyl, or a 6-membered heterocycloalkyl substituted with one or more substituents, the 6-membered heterocycloalkyl in the 6-membered heterocycloalkyl, 6-membered heterocycloalkyl substituted with one or more substituents, independently

[0190] [ka]

[0191] The b end represents a parallel connection to the benzene ring.

[0192] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0193] When R6 and R7 are linked together with the carbon atoms to which they are linked, they form a 6-membered heterocycloalkyl or a 6-membered heterocycloalkyl substituted with one or more substituents, and the substituent is C1-C6 alkyl, the C1-C6 alkyl is C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, or, for example, methyl or ethyl.

[0194] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0195] L1 is

[0196] [ka]

[0197] It is.

[0198] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0199] -L1-L2- is

[0200] [ka]

[0201] It is.

[0202] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application). ),

[0203] [ka]

[0204] teeth

[0205] [ka]

[0206] For example,

[0207] [ka]

[0208] It is.

[0209] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0210] R1 is C1-C8 alkyl or C1-C8 alkyl substituted with one or more substituents. For example, ethyl, isopropyl,

[0211] [ka]

[0212] It is.

[0213] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0214] When R1 is a 3- to 8-membered cycloalkyl or a 3- to 8-membered cycloalkyl substituted with one or more substituents, for example, cyclopropyl, cyclopentyl,

[0215] [ka]

[0216] It is.

[0217] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0218] When R1 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered heterocycloalkyl substituted with one or more substituents, for example,

[0219] [ka]

[0220] It is.

[0221] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0222] When R1 is C1-C8 alkyl substituted with 3-8 membered cycloalkyl, or C1-C8 alkyl substituted with 3-8 membered cycloalkyl substituted with one or more substituents, for example:

[0223] [ka]

[0224] It is.

[0225] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0226] R1 is

[0227] [ka]

[0228] or substituted with one or more substituents

[0229] [ka]

[0230] For example, if

[0231] [ka]

[0232] It is.

[0233] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0234] When R1 and R2 are linked together with the linked N to form: a 3- to 8-membered heterocycloalkyl, or a 3- to 8-membered heterocycloalkyl substituted with one or more halogens, If,

[0235] [ka]

[0236] teeth

[0237] [ka]

[0238] It is.

[0239] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0240] When R4 is -L-R10, L is independently a linking bond, and / or R10 is independently C1-C6 alkyl, C1-C6 alkyl substituted with one or more substituents, e.g.,

[0241] [ka]

[0242] It is.

[0243] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0244] R4 is -L-R10, where L is independently -(SO 2 )-, and / or R10 is independently C1-C6 alkyl or C1-C6 alkyl substituted with one or more substituents, e.g.,

[0245] [ka]

[0246] It is.

[0247] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0248] R4 is -L-R10, where L is independently -(SO 2 )-NH-; and / or R10 is independently C1-C6 alkyl or C1-C6 alkyl substituted with one or more substituents, e.g.,

[0249] [ka]

[0250] It is.

[0251] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0252] When R10 is independently 6-10 membered aryl substituted with one or more substituents, for example,

[0253] [ka]

[0254] It is.

[0255] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0256] When R7 is -O-R10, for example,

[0257] [ka]

[0258] It is.

[0259] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application). The pyrrole amide pyridone compound represented by formula I is represented by formula II-1 or II-2:

[0260] [ka]

[0261] wherein R1, R2, R3, R4, R5, R6, L and R10 are as defined above; R8 and R9 are independently C1-C6 alkyl (defined as: R6 and R7, taken together with the carbon atoms to which they are linked, form: a 6-membered heterocycloalkyl, or a 6-membered heterocycloalkyl substituted with one or more substituents, said substituents being C1-C6 alkyl);

[0262] Preferably, the pyrrole amide pyridone compound of formula I is as represented by formula II-1' or II-2':

[0263] [ka]

[0264] Wherein R1, R2, R4, R8, R9 are as defined above;

[0265] In formula II-1', R10 is C1-C6 alkyl or C1-C6 alkyl substituted with one or more substituents;

[0266] In II-2', R10 is a 6- to 10-membered aryl or a 6- to 10-membered aryl substituted with one or more substituents.

[0267] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0268] When R and R are linked together with the carbon atom to which they are linked to form: a 6-membered heterocycloalkyl, or a 6-membered heterocycloalkyl substituted with one or more substituents,

[0269] [ka]

[0270] teeth

[0271] [ka]

[0272] It is.

[0273] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0274] [ka]

[0275] but

[0276] [ka]

[0277] For example, if

[0278] [ka]

[0279] It is.

[0280] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0281] [ka]

[0282] but

[0283] [ka]

[0284] For example, if

[0285] [ka]

[0286] It is.

[0287] In some embodiments of the present invention, the definitions of some groups of the pyrrole amide pyridone compound represented by the general formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof are as follows (the definitions of groups that are not defined are as described in any one of the embodiments of the present application):

[0288] The pyrrole amide pyridone compound represented by formula I is selected from the following structures:

[0289] [ka]

[0290] [ka]

[0291] A method for preparing a compound of formula I, the method comprising schemes a to c: a) converting a compound represented by general formula (A) and a compound represented by general formula (B) into a compound represented by general formula (C) by a metal catalyzed coupling reaction; and b) hydrolyzing the compound of formula (C) under basic conditions to an intermediate compound of formula (D); and c) condensing the intermediate compound represented by general formula (D) with R1R2NH under the condition of a condensing agent to obtain a compound represented by general formula (I);

[0292] [ka]

[0293] The definitions of each of the above groups are as described above;

[0294] Preferably, each of the steps a), b), and c) is carried out in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethylsulfine, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, and the like. The solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

[0295] Preferably, the transition metal catalyst is: tris(dibenzylideneacetone)dipalladium (Pd 2(dba) 3 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, palladium acetate triphenylphosphine, [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride, bis(tri-o-benzylphosphine)palladium chloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, or combinations thereof; the catalyst ligand is selected from the group consisting of: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-benzylphosphine, or combinations thereof.

[0296] Preferably, the inorganic base is selected from the group consisting of: sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof; and the organic base is selected from the group consisting of: pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lithium hexamethyldisilylide, sodium hexamethyldisilylide, dimethylpyridine, or a combination thereof.

[0297] The present invention also provides a method for preparing the pyrrole amide pyridone compound represented by formula I, which includes method 1 or method 2;

[0298] Method 1 includes the steps of: in a solvent, in the presence of a base and a condensation reagent, carrying out a condensation reaction between a compound represented by formula D and R1R2NH as shown below to obtain a pyrrole amide pyridone compound represented by formula I;

[0299] [ka]

[0300] Method 2 includes the steps of: subjecting a compound represented by formula A' and a compound represented by formula B to a metal-catalyzed coupling reaction in a solvent in the presence of a base and a transition metal catalyst, as shown below, to obtain a pyrrole amide pyridone compound represented by formula I;

[0301] [ka]

[0302] Here, X1, X2, R1, R2, R3, R4, R5, R6 and R7 are as defined above.

[0303] In one embodiment of the present invention, the method 1 may further include a step of subjecting a compound represented by formula A and a compound represented by formula B to a metal-catalyzed coupling reaction in a solvent in the presence of a base and a transition metal catalyst to obtain a compound represented by formula C as shown below:

[0304] [ka]

[0305] Here, X1, X2, R1, R2, R3, R4, R5, R6 and R7 are as defined above.

[0306] In the preparation method, the operation and conditions of the condensation reaction can refer to the conventional operation and conditions for this type of reaction in the art.

[0307] In one embodiment of the present invention, the method 1 may further include a step of hydrolyzing the compound represented by formula C in a solvent in the presence of a base to obtain a compound represented by formula D as shown below;

[0308] [ka]

[0309] where X1, X2, R1, R2, R3, R4, R5, R6 and R7 are as defined above; Ra is C1-C6 alkyl (preferably C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; also, for example, methyl, ethyl or isopropyl).

[0310] The operation and conditions of the hydrolysis reaction can refer to conventional operations and conditions for this type of reaction in the art.

[0311] In one embodiment of the present invention, the method 1 may further include a step of subjecting a compound represented by formula A and a compound represented by formula B to a metal-catalyzed coupling reaction in a solvent in the presence of a base and a transition metal catalyst to obtain a compound represented by formula C as shown below;

[0312] [ka]

[0313] Here, X1, X2, R1, R2, R3, R4, R5, R6, R7 and Ra are as defined above.

[0314] The operation and conditions of the metal-catalyzed coupling reaction can refer to conventional operations and conditions for this type of reaction in the art. The present invention is preferably as follows:

[0315] In the metal-catalyzed coupling reaction, the transition metal catalyst is tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3), tetrakis(triphenylphosphine Palladium (Pd(PPh 3 ) 4 ), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, palladium acetate triphenylphosphine, [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride, bis(tri-o-benzylphosphine palladium chloride, 1,2-bis(diphenylphosphino)ethane palladium dichloride, or combinations thereof; said catalytic ligand is selected from the group consisting of: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-benzylphosphine, or combinations thereof.

[0316] The condensation reaction, hydrolysis reaction, and metal-catalyzed coupling reaction are each carried out in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethylsulfine, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

[0317] Here, in the condensation reaction, the solvent is preferably an amide solvent (for example, N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof).

[0318] Here, in the hydrolysis reaction, the solvent is preferably water or an alcohol-based solvent (eg, one or more of methanol, ethanol, isopropanol, butanol, and ethylene glycol).

[0319] In the metal-catalyzed coupling reaction, the solvent is preferably an alcohol-based solvent (e.g., one or more of methanol, ethanol, isopropanol, butanol, ethylene glycol), an amide-based solvent (e.g., N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof).

[0320] In the condensation reaction, hydrolysis reaction, and metal-catalyzed coupling reaction, the base can be an inorganic base and / or an organic base, the inorganic base being selected from sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof; the organic base being selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, dimethylpyridine, or a combination thereof.

[0321] The present invention provides compounds represented by formula D, formula C, formula A, and formula A',

[0322] [ka]

[0323] Here, X1, X2, R1, R2, R3, R4, R5, R6, R7 and Ra are as defined above.

[0324] In some embodiments of the present invention, the compound represented by formula D is selected from any of the following structures:

[0325] [ka]

[0326] In some embodiments of the present invention, the compound represented by formula C is selected from any of the following structures:

[0327] [ka]

[0328] In one embodiment of the present invention, the compound represented by formula A is

[0329] [ka]

[0330] It is.

[0331] In one embodiment of the present invention, the compound represented by formula A' is

[0332] [ka]

[0333] It is.

[0334] Another object of the present invention is to provide a medicine or a composition thereof for treating or preventing tumors or inflammatory diseases. The technical methods for achieving the above object are as follows:

[0335] A pharmaceutical composition for treating a tumor or an inflammatory disease, comprising a pyrrole amide pyridone compound represented by formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, crystalline polymorph, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0336] Another object of the present invention is to provide the use of said compound. The technical methods to achieve said object are as follows:

[0337] The present invention relates to the use of the pyrrole amide pyridone compound represented by the general formula (I) or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, crystalline polymorph, or prodrug thereof, in the manufacture of a drug for treating a disease associated with the activity or expression level of a protein such as BRD or c-Myc, particularly a tumor, an immune disease, and an inflammatory disease, wherein the tumor is independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, and the like. The immune and inflammatory diseases may be, independently, transplanted organ rejection, gout, rhinitis, alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma, arthritis, allergic dermatitis, Behcet's disease, herpetic skin disease, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease, liver cirrhosis, degenerative joint disease, dermatitis, dermatomyositis, eczema, enteritis, encephalitis, gastritis, nephritis, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease, and inflammatory bowel disease. The present invention is directed to a method for treating or preventing atopic dermatitis, including the treatment of rheumatoid arthritis, irritable bowel syndrome, Kawasaki disease, meningitis, multiple sclerosis, myocarditis, gravitational myasthenia, myocardial infarction, myositis, nephritis, osteomyelitis, pancreatitis, Parkinson's disease, pericarditis, pernicious anemia, pneumonia, primary biliary sclerosing cholangitis, polyarteritis nodosa, psoriasis, fibrosis, lupus erythematosus, tissue graft rejection, thyroiditis, type I diabetes mellitus, urethritis, uveitis, vasculitis, vitiligo, and Waldenstrom's macroglobulinemia.

[0338] The present invention relates to a pyrrole amide pyridone compound having a structure of general formula (I), which is a therapeutic drug with a new mechanism of action that can inhibit various tumor cells, particularly tumors associated with abnormalities in signal transduction pathways such as BRD / c-Myc, such as leukemia and prostate cancer.

[0339] The present invention further provides a pharmaceutical composition, which comprises the pyrrole amide pyridone compound represented by formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, and a pharma- ceutically acceptable carrier. The pyrrole amide pyridone compound represented by formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, is in a therapeutically effective amount.

[0340] The present invention further provides the use of a pyrrole amide pyridone compound represented by formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, crystalline polymorph or prodrug thereof, or said pharmaceutical composition in the manufacture of a BRD and / or c-Myc inhibitor.

[0341] The present invention further provides the use of a pyrrole amide pyridone compound represented by formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, crystalline polymorph or prodrug thereof, or said pharmaceutical composition, in the manufacture of a drug for treating or preventing a disease associated with the activity or expression level of BRD and / or c-Myc protein.

[0342] The pyrrole amide pyridone compound represented by the formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, or the pharmaceutical composition thereof, can inhibit various tumor cells, and in particular, can effectively kill tumors associated with abnormalities in signal transduction pathways such as BRD / c-Myc, such as leukemia and prostate cancer.

[0343] The present invention further provides use of the pyrrole amide pyridone compound of formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, crystalline polymorph or prodrug thereof, or the pharmaceutical composition, in the manufacture of a medicament for treating and / or preventing tumors and / or inflammatory diseases.

[0344] The present invention further provides a method for treating tumors and / or inflammatory diseases, comprising administering to a patient a therapeutically effective amount of a pyrrole amide pyridone compound represented by formula I, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, crystalline polymorph or prodrug thereof, or a pharmaceutical composition thereof.

[0345] The tumors are independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc. The immune disease and inflammatory disease are independently selected from transplanted organ rejection, gout, rhinitis, alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma, arthritis, allergic dermatitis, Behcet's disease, herpes skin disease, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease, cirrhosis of the liver, degenerative joint disease, dermatitis, dermatomyositis, eczema, enteritis, encephalitis, gastritis, nephritis, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease, and the like. The disease is selected from irritable bowel syndrome, Kawasaki disease, meningitis, multiple sclerosis, myocarditis, gravidarum myasthenia, myocal mycosis, myositis, nephritis, osteomyelitis, pancreatitis, Parkinson's disease, pericarditis, pernicious anemia, pneumonia, primary biliary sclerosing cholangitis, polyarteritis nodosa, psoriasis, fibrosis, lupus erythematosus, tissue graft rejection, thyroiditis, type I diabetes mellitus, urethritis, uveitis, vasculitis, vitiligo, and Waldenstrom's macroglobulinemia.

[0346] Within the scope of the present invention, the above technical features of the present invention and the following (e.g., examples, etc.) are specifically described. It should be understood that the disclosed technical features may also be combined with each other to form new or preferred technical solutions, which will not be detailed here due to space limitations.

[0347] The preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention, without violating the common general knowledge in the art.

[0348] All reagents and raw materials used in the present invention are commercially available.

[0349] The positive and progressive effects of the present invention are: the pyrrole amide pyridone compound having the structural characteristics represented by formula I provided by the present invention can inhibit various tumor cells, in particular, can effectively kill tumors associated with abnormalities in signal transduction pathways such as BRD / c-Myc, such as leukemia and prostate cancer, and is a therapeutic drug with a new mechanism of action. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0350] After extensive research, the inventors have prepared a novel compound having the structure represented by formula I, which has good BRD enzyme inhibitory or decomposing activity, and the compound produces specific inhibitory or decomposing effect on BRD enzyme at a very low concentration (can be as low as <10 nmol / L), has excellent inhibitory activity against BRD / c-MYc-related cell proliferation, and can be used to treat related diseases such as tumors caused by BRD / c-Myc mutation or abnormal expression. Based on the above findings, the inventors have completed the present invention.

[0351] term Unless otherwise defined, all scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claim category belongs. Unless otherwise noted, all patents, patent applications, and publications cited throughout this specification are incorporated herein by reference in their entirety.

[0352] It should be understood that the above brief description and the following detailed description are merely illustrative and interpretative, and are not intended to limit the scope of the present invention. In this application, the use of the singular includes the plural, unless otherwise specified. It should be noted that the singular form used in this specification and the claims includes the plural of the referenced item, unless otherwise clearly stated in the specification. It should also be noted that "or" and "or" mean "and / or" unless otherwise specified. Furthermore, the term "comprises" and other forms such as "contains", "includes", etc. are not limiting.

[0353] In the literature, definitions for standard chemical terms can be found (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise specified, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used in the descriptions relating to analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry herein are known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, reactions can be performed and purifications can be carried out according to manufacturer's kit instructions or methods known in the art or described herein. The above techniques and methods can generally be carried out according to conventional methods well known in the art, based on the descriptions in several general and more specific references cited and discussed herein. Herein, groups and substituents thereof can be chosen by one skilled in the art to provide stable structural moieties and compounds.

[0354] Where a substituent is depicted in a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent that results when the structural formula is written from right to left. For example, -CH 2 O-OCH 2- is equivalent to

[0355] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter. All literature or portions of literature documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are hereby incorporated by reference in their entirety.

[0356] Certain chemical groups defined herein are preceded by a shorthand symbol indicating the total number of carbon atoms present in that group. For example, C 1-6 Alkyl refers to an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the mnemonic does not include carbons that may exist in substituents of the group.

[0357] Except as set forth above, when used in the specification and claims of this application, the following terms have the meanings set forth below unless otherwise stated.

[0358] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine; "hydroxy" refers to -OH; "hydroxyalkyl" refers to an alkyl, as defined below, substituted with hydroxy (-OH); "carbonyl" refers to -C(=O)-; and "nitro" refers to -NO. 2 "Cyano" refers to -CN; "Amino" refers to -NH 2 "Substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, or heteroaralkyl, such as monoalkylamino, dialkylamino, alkylamido, aralkylamino, and heteroaralkylamino; "carboxy" refers to --COOH.

[0359] As used herein, the term "alkyl" as a group or part of another group (e.g., as used in groups such as halogen-substituted alkyl groups) refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, 1-12 (preferably 1-8, more preferably 1-6) carbon atoms, and attached to the remainder of the molecule through a single bond. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl.

[0360] As used herein, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, e.g., having 2-14 (preferably 2-10, preferably 2-6) carbon atoms, and attached to the remainder of the molecule through a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, and the like.

[0361] As used herein, the term "alkynyl" as a group or part of another group refers to a straight or branched hydrocarbon chain radical composed solely of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2-14 (preferably 2-10, more preferably 2-6) carbon atoms, and attached to the remainder of the molecule through a single bond, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.

[0362] As used herein, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group, consisting solely of carbon and hydrogen atoms, which may include fused, bridged, or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated, and which is attached to the remainder of the molecule by a single bond through any suitable carbon atom. Unless otherwise specified in this specification, the carbon atoms of a cycloalkyl group may be optionally oxidized. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro ... These include, but are not limited to, chlorooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl, and octahydro-2,5-methylene-cyclopentadienyl.

[0363] As used herein, the term "heterocyclic group" as a group or part of another group means a stable 3-20 membered non-aromatic cyclic group consisting of 2-14 carbon atoms and 1-6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise stated herein, a heterocyclic group may be a monocyclic, bicyclic, tricyclic, or higher ring system, including fused, bridged, or spiro ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclic group may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or fully saturated. A heterocyclic group may be attached to the remainder of the molecule by a single bond through a carbon atom or a heteroatom. In a fused ring-containing heterocyclic group, one or more of the rings may be an aryl or heteroaryl group as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azacyclobutyl, pyranyl, tetrahydropyranyl, thiolanyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinonyl, phthalimide, and the like.

[0364] In this application, the term "aryl" as a group or part of another group refers to a conjugated hydrocarbon ring system having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms. For the purposes of this invention, an aryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is connected to the remainder of the molecule by a single bond through an atom on the aromatic ring. Examples of aryl include phenyl, naphthyl, anthracenyl, phenanthryl, , fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-on-7-yl, and the like.

[0365] As used herein, the term "arylalkyl" refers to an alkyl group, as defined above, substituted with an aryl group, as defined above.

[0366] In this application, the term "heteroaryl" as a group or part of another group refers to a 5-16 membered conjugated ring system having 1-15 carbon atoms (preferably 1-10 carbon atoms) and 1-6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise stated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may be fused to a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is connected to the remainder of the molecule by a single bond through an atom on the aromatic ring. The nitrogen, carbon or sulfur atom in the heteroaryl may be optionally oxidized; the nitrogen atom may be optionally quaternized. For the purposes of the present invention, the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a stable 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.Examples of heteroaryl include thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzimidazolyl, benzopyra ... These include, but are not limited to, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-diazaphenanthryl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazole[1,2-a]pyridine, imidazole[1,2-b]pyridazine, imidazole[1,2-a]pyrazine and the like.

[0367] As used herein, the term "heteroarylalkyl" refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above.

[0368] As used herein, "optional" or "optionally" means that the subsequently described event or condition may, but does not necessarily, occur, and that the description is meant to include instances in which the event or condition occurs as well as instances in which the event or condition does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.

[0369] As used herein, the terms "moiety," "structural moiety," "chemical moiety," "group," and "chemical group" refer to specific fragments or functional groups within a molecule. A chemical moiety is generally considered to be a chemical entity that is embedded in or attached to a molecule.

[0370] "Stereoisomers" refer to compounds that have the same atomic configuration and are bonded by the same bonds, but differ in three-dimensional structure. The present invention encompasses various stereoisomers and mixtures thereof.

[0371] When compounds of the invention contain olefinic double bonds, the compounds of the invention, unless otherwise specified, are intended to include both E- and Z-geometric isomers.

[0372] "Tautomer" refers to an isomer formed by the migration of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are included within the scope of the present invention.

[0373] The compounds of the present invention, or their pharma- ceutically acceptable salts, may contain one or more chiral carbon atoms and may give rise to enantiomers, diastereomers and other stereoisomers. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, and their racemic and optically pure forms. In preparing the compounds of the present invention, racemates, diastereomers or enantiomers may be selected as starting materials or intermediates. Optically active isomers may be prepared using asymmetric synthesis or chiral reagents, or may be resolved using conventional techniques such as crystallization or chiral chromatography.

[0374] Conventional techniques for the preparation / isolation of individual isomers include asymmetric synthesis from suitable optically pure precursors, or resolution of the racemate (or a racemic salt or derivative) using chiral high performance liquid chromatography or the like; see, for example, Gerald Gubitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004;AM Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010;Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0375] In this application, the term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0376] "Pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic or organic acids that are capable of retaining the biological effectiveness of the free bases without other adverse effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, etc. These salts can be prepared by methods known in the art.

[0377] "Pharmaceutically acceptable base addition salts" refers to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acids without other adverse effects. Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, , zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines; substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins; such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, pyridine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts may be prepared by methods known in the art.

[0378] "Crystal polymorphism" refers to different solid crystalline phases produced by a compound of the invention due to the existence of two or more different molecular arrangements in the solid state. A compound of the invention may exist in more than one crystalline form, and the invention is intended to include various crystalline forms and mixtures thereof.

[0379] Generally, crystallization produces a solvate of the compound of the present invention. The term "solvate" as used in the present invention refers to an aggregate containing one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compound of the present invention may exist as a hydrate, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., and the corresponding solvated forms. The compound of the present invention may form a true solvate, but in some cases, it may also be possible to retain only water or a mixture of water and a portion of a solvent. The compound of the present invention may react in a solvent or be precipitated or crystallized from the solvent. Solvates of the compound of the present invention are also included within the scope of the present invention.

[0380] The present invention also includes prodrugs of the aforementioned compounds. In this application, the term "prodrug" refers to a compound that can be converted to a biologically active compound of the present invention under physiological conditions or by solvent degradation. Thus, the term "prodrug" refers to a pharma- ceutically acceptable metabolic precursor of a compound of the present invention. When administered to an individual in need, a prodrug may be inactive, but is converted to an active compound of the present invention in the body. Prodrugs are usually rapidly converted in the body, for example by hydrolysis in blood, to produce the parent compound of the present invention. Prodrug compounds typically offer advantages of solubility, tissue compatibility, or sustained release in mammalian organisms. Prodrugs include known amino and carboxy protecting groups. For specific methods of preparing prodrugs, see Saulnier, MG, et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, RB, et al., J. Med. Chem. 2000, 43, 475.

[0381] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the invention with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The vehicle includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, favor absorption of the active ingredient, and exert biological activity.

[0382] As used herein, the term "pharmacologically acceptable" refers to a material (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the invention and is relatively non-toxic. That is, the substance can be administered to an individual without eliciting an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

[0383] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, an adjuvant, carrier, excipient, lubricant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the relevant governmental authority as acceptable for human or veterinary use.

[0384] The "tumor" and "cell proliferation-related disease" according to the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, and other diseases.

[0385] As used herein, the terms "prophylactic," "prevention," and "prevent" include the possibility that a patient will reduce the occurrence or worsening of a disease or disorder.

[0386] As used herein, the term "treatment" and other similar synonyms include the following meanings: (i) preventing the occurrence of a disease or condition in a mammal, particularly where the mammal is susceptible to the disease or condition but has not been diagnosed as having the disease or condition; (ii) inhibiting the disease or condition, i.e. inhibiting its onset; (iii) alleviating the disease or condition, i.e. causing the regression of the disease or condition; or (iv) Relieving symptoms caused by a disease or condition.

[0387] As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutical effective amount" refers to an amount of at least one drug or compound sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated after administration. The result can be reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for use in treatment is the amount of a composition containing a compound disclosed herein that is required to provide a significant clinical symptom-alleviating effect. Techniques such as, for example, dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0388] As used herein, the terms "taking", "administering", "dosing" and the like refer to the method by which a compound or composition can be delivered to a desired site for biological effect. These methods include, but are not limited to, oral route, duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with application techniques that can be used with the compounds and methods described herein, for example, application techniques discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0389] As used herein, the terms "pharmaceutical combination," "drug combination," "co-administration," "administering other treatments," "administering other therapeutic agents," and the like refer to drug treatments obtained by mixing or combining two or more active ingredients, and include fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the combination of active ingredients in the form of a single entity or dosage, as described herein. The term "non-fixed combination" refers to the administration of at least one compound and at least one synergistic preparation to a patient simultaneously, in combination, or sequentially at variable intervals, in the form of separate entities, of at least one compound and at least one synergistic preparation as described herein. This also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0390] Those skilled in the art should understand that in the methods described below, functional groups of intermediates may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, fluorenyl and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable thiol protecting groups include -C(O)-R'' (where R'' is alkyl, aryl, or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxy protecting groups include alkyl, aryl, or aralkyl esters.

[0391] Protective groups can be introduced and removed according to standard techniques known to those skilled in the art and described herein. The use of protecting groups is described in detail in Greene, TW and PGM Wuts, Protective Groups in Organic Synthesis, Vol. 13, No. 1, pp. 111-115, 2003. Synthesis, (1999), 4th Ed., Wiley. The protecting group may be a polymer resin.

[0392] Those skilled in the art will recognize, according to conventions used in the art, the formulas used to describe the structures of radicals in this application.

[0393] [ka]

[0394] It will be understood that refers to the point through which the corresponding group is connected to another fragment, group of the compound.

[0395] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the described examples. In the following examples, for experimental methods whose conditions are not clearly described, they are usually selected according to conventional methods and conditions or according to product specifications.

[0396] [ka]

[0397] Step 1: Compound 1 (4g, 18.6mmol) and ethyl acetate azide (5.97g, 46.3mmol) were dissolved in anhydrous ethanol (200mL), sodium ethoxide (3.14g, 46.2mmol) was added thereto, and the mixture was reacted at room temperature overnight. The reaction solution was added with cold water, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 2 (1.8g, white solid). 1 H NMR (400 MHz, CDCl 3 ): δ8.60(d, J=2.0Hz, 1H), 8.13(d, J=2.4Hz, 1H), 7.10(s, 1H), 4.39(q, J=7.2Hz, 2H), 3.97(s, 3H), 1.41(t, J=7.2Hz, 3H).

[0398] Step 2: Compound 2 (1.8 g, 5.5 mmol) was dissolved in toluene (100 mL) and heated to 135° C. overnight. The reaction solution was concentrated to dryness to give crude product 3 (1.5 g, yellow solid), which was used directly in the next reaction. LC-MS: m / z 297.0 [M−H] + .

[0399] Step 3: Compound 3 (1.0 g, crude product) was dissolved in N,N-dimethylformamide (DMF) (15 mL), and then potassium carbonate (922 mg, 6.68 mmol) and 2-(2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (665 mg, 4.0 mmol) were added in sequence, and the mixture was allowed to react at room temperature overnight. Saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 4 (0.6 g, colorless oil). 1 H NMR (400 MHz, CDCl 3 ):δ8.11(s, 1H), 7.51(s, 1H), 6.45(s, 2H), 4.45(q, J=7.2Hz, 2H), 4.14(s, 3H), 3 .60(t, J=8.0Hz, 2H), 1.48(t, J=7.2Hz, 3H), 0.95(t, J=8.0Hz, 2H), 0.01(s, 9H).

[0400] Step 4: Compound 4 (0.6 g, 1.4 mmol) was dissolved in acetonitrile (30 mL), sodium iodide (315 mg, 2.1 mmol) and trimethylchlorosilane TMSCl (227 mg, 2.1 mmol) were added, and the mixture was reacted at room temperature for 1 hour, and then heated to 65° C. for 3 hours. The reaction solution was concentrated, sodium thiosulfate solution was added, extracted with dichloromethane, and the organic phase was concentrated to obtain compound 5 (0.5 g, white solid). LC-MS: m / z 415.1 [M+H] + .

[0401] Step 5: Compound 5 (0.5 g, 1.2 mmol) was dissolved in DMF (20 mL), and cesium carbonate (782 mg, 2.4 mmol) and methyl iodide (256 mg, 1.8 mmol) were added in sequence, and the reaction was allowed to proceed at room temperature overnight. A saturated ammonium chloride solution was added, and the di Extraction with dichloromethane, concentration of the organic phase, and purification of the residue by silica gel column chromatography gave compound 6 (320 mg, white solid). 1 H NMR (400 MHz, CDCl 3 ):δ7.70(s, 1H), 7.39(s, 1H), 6.37(s, 2H), 4.40(q, J=7.2Hz, 2H), 3.64(s, 3H), 3 .60(t, J=8.0Hz, 2H), 1.44(t, J=7.2Hz, 3H), 0.94(t, J=8.0Hz, 2H), 0.01(s, 9H).

[0402] Step 6: Compound 6 (320 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 5 hours. The reaction solution was concentrated, saturated sodium bicarbonate solution was added, extracted with dichloromethane, and the organic phase was concentrated to obtain intermediate A (200 mg, white solid). LC-MS: m / z 299.0 / 301.0 [M+H] + / [M+H+2] + .

[0403] [ka]

[0404] Step 1: Compound 1 (3.8 g, 16.8 mmol) was dissolved in N,N-dimethylformamide (DMF) (50 mL), cooled to 0° C., and sodium hydride (60% in mineral oil, 1.0 g, 24 mmol) was added in batches. After the addition was complete, stirring was continued for 30 minutes, after which p-toluenesulfonyl chloride (4.8 g, 25 mmol) was added and stirred at room temperature overnight. The reaction was quenched by adding ice water (200 mL), and the precipitated solid was filtered to obtain compound 2 (5.0 g, yellow solid). 1H NMR (DMSO-d6, 400MHz): δ8.18(d, J=3.6Hz, 1H), 8.00(s, 1H), 7.86(d, J=8.4Hz , 2H), 7.46(d, J=8.4Hz, 2H), 6.81(d, J=3.6Hz, 1H).3.82(s, 3H), 2.39(s, 3H). LC-MS:m / z380.9[M+H] + .

[0405] Step 2: Compound 2 (380 mg, 1.0 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to -70 ° C. in a dry ice acetone bath. Lithium diisopropylamide LDA (2 M, 1 mL, 2.0 mmol) was added dropwise, followed by stirring for 30 minutes, and ethyl chloroformate (162 mg, 1.5 mmol) was added dropwise at -50 ° C., and the reaction was continued for 2 hours while maintaining the temperature at -50 ° C. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain a crude product. The crude product was slurried in methanol to obtain compound 3 (400 mg, yellow solid). 1 H NMR (CDCl 3 , 400MHz): δ8.26(d, J=8.4Hz, 2H), 7.99(s, 1H), 7.38(d, J=8.4Hz, 2H), 7.08(s , 1H), 4.48(q, J=6.8Hz, 2H), 3.91(s, 3H), 2.47(s, 3H), 1.45(t, J=6.8Hz, 3H). LC-MS:m / z453.0[M+H] + .

[0406] Step 3: Compound 3 (1.3 g, 2.9 mmol) and sodium iodide (645 mg, 4.3 mmol) were dissolved in acetonitrile (50 mL), trimethylchlorosilane (465 mg, 4.3 mmol) was added at room temperature, and the mixture was stirred for 1 hour, after which 0.2 mL of water was added and the mixture was heated to 70° C. and reacted for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to obtain compound 4 (1.3 g, crude product, yellow solid). 1 H NMR (CDCl 3 , 4 00MHz): δ8.32(d, J=8.4Hz, 2H), 7.42(s, 1H), 7.38(d, J=8.0Hz, 2H), 6.99(s, 1H), 4.48(q, J=7.2Hz, 2H), 2.45(s, 3H), 1.45(t, J=7.2Hz, 3H).LC-MS: m / z438.9[M+H] + .

[0407] Step 4: Compound 4 (1.3 g, crude product) was dissolved in DMF (5 mL), and cesium carbonate (1.3 g, 3.9 mmol) and methyl iodide (550 mg, 3.9 mmol) were added. After stirring at room temperature overnight, water was added and extracted with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate B (1.2 g, white solid). 1 H NMR (CDCl 3 , 400MHz): δ8.48(d, J=8.0Hz, 2H), 7.39(d, J=8.4Hz, 2H), 7.26(s, 1H), 6.88(s , 1H), 4.46(q, J=7.2Hz, 2H), 3.56(s, 3H).2.45(s, 3H), 1.44(t, J=7.2Hz, 3H). LC-MS:m / z453.0[M+H] + .

[0408] Preparation of the Examples

[0409] Example 1: N-Ethyl-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0410] [ka]

[0411] Step 1: Intermediate A (100 mg, 0.34 mmol) was dissolved in ethanol (10 mL), water (5 mL) and sodium hydroxide (53 mg, 1.32 mmol) were added, and the mixture was heated to 80° C. and reacted for 4 hours. The reaction solution was concentrated to remove most of the ethanol, a small amount of water was added, and the pH value was adjusted to 3-4 with dilute hydrochloric acid, and the mixture was freeze-dried to obtain 7-bromo-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (90 mg, white solid). 1 H NMR (400MHz, DMSO_d6): δ13.13 (brs, 1H), 12.39 (s, 1H), 7.87 (s, 1H), 7.20 (s, 1H), 3.46 (s, 3H).

[0412] Step 2: 7-Bromo-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (90 mg, 0.33 mmol) was dissolved in DMF (5 mL), and ethylamine hydrochloride (54 mg, 0.67 mmol) and N,N-isopropylethyldiamine DIEA (213 mg, 1.65 mmol) were added in sequence, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU (250 mg, 0.66 mmol) was further added, and the reaction was allowed to proceed at room temperature overnight. Saturated ammonium chloride solution was added, extracted with dichloromethane, the organic phase was concentrated and the residue was purified by column chromatography to give 7-bromo-N-ethyl-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-amide (50 mg, white solid). LC-MS: m / z 298.0 [M+H] + .

[0413] Step 3: 7-Bromo-N-ethyl-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide (40 mg, 0.13 mmol) and (2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)boronic acid (51 mg, 0.16 mmol) were dissolved in DMF (10 mL) and successively treated with cesium carbonate (131 mg, 0.40 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride Pd(dppf)Cl 2 (20mg, 0.027mmol) was added and the mixture was heated to 100°C under nitrogen gas protection and reacted overnight. After cooling to room temperature, saturated ammonium chloride solution was added, extracted with dichloromethane, the organic phase was concentrated and the residue was purified by preparative chromatography to obtain compound N-ethyl-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-amide (15mg, white solid). LC-MS (M+H) 492.2. 1 H-NMR (DMSO-d6, 400MHz): δ10.85(s, 1H), 8.36(t, J=5.6Hz, 1H), 7.50(d, J=2.4Hz, 1H), 7.46(s, 1H), 7.37(dd, J=2.4, 8.8Hz, 1H), 7.27(s, 1H) , 6.97(d, J=9.2Hz, 2H), 6.32(d, J=8.8Hz, 1H), 4.98(s, 1H), 3.54(s, 3H), 3.22-3.27(m, 2H), 2.03(s, 6H), 1.45(s, 6H), 1.10(t, J=7.2Hz, 3H).

[0414] Example 2: N-Ethyl-5-methyl-4-oxo-7-(2,2,4-trimethyl-6-(methylsulfonyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0415] [ka]

[0416] Under the protection of nitrogen gas, 8-bromo-2,2,4-trimethyl-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (35 mg, 0.1 mmol) was dissolved in DMF (3 mL), and bis(pinacolato)diboron (51 mg, 0.2 mmol) was added, followed by cesium carbonate (98 mg, 0.3 mmol) and Pd(dppf)Cl. 2 (7 mg, 0.01 mmol) was added and the temperature was raised to 110° C. and stirred for 2 hours, after which 7-bromo-N-ethyl-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-amide (30 mg, 0.1 mmol) was added, followed by stirring overnight. Cooled to room temperature, water was added, extracted with dichloromethane DCM, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by preparative chromatography to obtain N-ethyl-5-methyl-4-oxo-7-(2,2,4-trimethyl-6-(methylsulfonyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-amide (3.6 mg , white solid) was obtained. LC-MS (M+H) 487.1. 1 H-NMR (CDCl 3 , 400MHz): δ11.29(br, 1H), 7.74(d, J=2.0Hz, 1H), 7.53(d, J=2.0Hz, 1H), 7.09-7.12(m,2H), 6.72(s, 1 H), 3.75(s, 3H), 3.53(q, J=7.2Hz, 2H), 3.48(s, 3H), 3.14(s, 3H), 1.47(s, 6H), 1.26(t, J=7.2Hz, 3H).

[0417] Example 3: N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0418] [ka]

[0419] Step 1: Intermediate A (500 mg, 1.68 mmol) and 2-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)propan-2-ol were dissolved in DMF (10 mL) and cesium carbonate (Cs 2 CO 3 (1.6 g, 4.91 mmol) and Pd(dppf)Cl 2 (245 mg, 0.33 mmol) was added, and the mixture was heated to 100° C. under nitrogen gas protection and stirred overnight. It was directly concentrated, and the residue was purified by column chromatography to give ethyl 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrole[3,2-c]pyridine-2-carboxylate (420 mg, white solid). LC-MS: m / z 493.5 [M+H] + .

[0420] Step 2: Sodium hydroxide NaOH (136 mg, 1.68 mmol) was added to a solution of ethyl 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (420 mg, 0.85 mmol) in ethanol / water (10 mL, volume ratio 1:1). The reaction was allowed to proceed at room temperature overnight. Most of the ethanol was spun off, water was added to dilute, the pH was adjusted to acidic, extracted with ethyl acetate, the organic phase was dried and concentrated to give 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (230 mg, white solid). LC-MS: m / z 465.3 [M+H] + .

[0421] Step 3: 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (28 mg, 0.060 mmol) and 3-(4-(5-aminopent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (18 mg, 0.050 mmol) were dissolved in DCM (2 mL) and treated with DIEA (36 mg, 0.28 mmol) and 1-n-propylphosphoric anhydride T 3 P (88 mg, 0.28 mmol) was added and stirred at room temperature for 2 hours. The reaction was stirred and concentrated directly, and the residue was purified by neutral preparative chromatography to give N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-amide (3 mg, white solid). LC-MS (M+H) 772.6. 1 H-NMR (CDCl3 , 400MHz): δ9.57(s, 1H), 8.63(s, 1H), 7.71(d, J=6.4Hz, 1H), 7.63(s, 1H), 7.23-7.52(m, 4H), 6.76(d, J=8.8Hz, 2H), 6.41(d, J=8 .8Hz, 1H), 5.17(brs, 1H), 4.25-4.60(m, 2H), 3.55-3.72(m, 5H), 2.79(brs, 2H), 2.57(brs, 2H), 1.96-2.17(m, 10H), 1.61(s, 6H).

[0422] Example 4: N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0423] [ka]

[0424] 3-(4-(5-aminopentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was used as raw material, and the process was the same as in Example 3. LC-MS (M+H) 776.6. 1 H-NMR (CDCl 3, 400MHz): δ9.67(s, 1H), 9.49(s, 1H), 7.72(d, J=7.2Hz, 1H), 7.58(d, J=2.0Hz, 1H), 7.51(s, 1H) , 7.26-7.45(m, 4H), 6.78(d, J=8.8Hz, 2H), 6.57(t, J=5.6Hz, 1H), 6.44(d, J=8.4Hz, 1H), 5.27-5. 35(m, 1H), 4.50(d, J=15.6Hz, 1H), 4.28(d, J=16.0Hz, 1H), 3.60-3.72(m, 5H), 3.10-3.15(m, 1H), 2.83-2.87(m, 2H), 2.71-2.76(m, 1H), 2.53-2.58(m, 1H), 2.04-2.35(m, 11H), 1.48-1.60(m, 8H).

[0425] Example 5: N-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxo)acetamido)butyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0426] [ka]

[0427] The raw material was N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxo)acetamide, and the process was the same as in Example 3. LC-MS (M+H) 849.5. 1 H-NMR (CDCl 3, 400MHz): δ9.87(brs, 1H), 9.53(s, 1H), 7.53-7.75(m, 4H), 7.20-7.33(m, 3H), 6.85(brs, 1H), 6.77(d, J=8.8Hz, 2H), 6.42(d, J=8.4Hz, 1H), 4.9 3-4.98(m, 1H), 4.61-4.66(m, 2H), 3.68(s, 3H), 3.34-3.57(m, 4H), 2.68 -2.86(m, 3H), 2.30-2.34(m, 1H), 1.90-2.15(m, 8H), 1.49-1.60(m, 8H).

[0428] Example 6: N-(3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)propyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0429] [ka]

[0430] The raw material was 4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride, and the process was the same as in Example 3. LC-MS (M+H) 923.7. 1 H-NMR (CDCl 3 , 400MHz): δ9.47(brs, 1H), 8 .72(s, 1H), 7.56(d, J=2.0Hz, 1H), 7.43(t, J=8.0Hz, 1H), 7.23-7.34(m, 2H), 7.04(d, J=7.2Hz, 1H), 6.87(d, J=8.4Hz, 1H), 6. 77(d, J=8.8Hz, 2H), 6.41-6.45(m, 2H), 4.87-4.91(m, 1H), 3.48-3.79(m, 17H), 3.34-3.36(m, 2H), 2.70-2.88(m, 3H), 2.26(br s, 1H), 2.10(s, 6H), 1.81-1.89(m, 4H), 1.59(s, 6H).

[0431] Example 7: N-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3-oxo-n-propoxy)ethoxy)ethoxy)ethyl)-5-methyl-4-oxo-7-(2,2,4-trimethyl-6-(methylsulfonyl))-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0432] [ka]

[0433] Step 1: Under the protection of nitrogen gas, 8-bromo-2,2,4-trimethyl-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (0.77 g, 2.2 mmol) was dissolved in DMF (20 mL) and bis(pinacolato)diboron (1.1 g, 4.4 mmol), cesium carbonate (2.1 g, 6.4 mmol) and Pd(dppf)Cl were added. 2(160 mg, 0.22 mmol) was added, the temperature was raised to 110° C. and stirred for 2 hours, after which intermediate A (1.0 g, 2.2 mmol) was added, followed by stirring overnight. Cooled to room temperature, water was added, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give ethyl 5-methyl-4-oxo-7-(2,2,4-trimethyl-6-(methylsulfonyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (212 mg, white solid). LC-MS: m / z 642.2 [MH] + .

[0434] Step 2: Sodium hydroxide (27 mg, 0.67 mmol) was added to a solution of the product obtained in step 1 (212 mg, 0.33 mmol) in ethanol / water (10 mL, 1:1 volume ratio). The reaction was allowed to proceed at room temperature overnight. Most of the ethanol was spun off, water was added to dilute, the pH was adjusted to acidic, extracted with ethyl acetate, the organic layer was dried and concentrated to give 5-methyl-4-oxo-7-(2,2,4-trimethyl-6-(methylsulfonyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (130 mg, white solid). LC-MS: m / z 460.2 [M+H] + .

[0435] Step 3: The product obtained in step 2 (46 mg, 0.10 mmol) and 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propionamide (48 mg, 0.10 mmol) were dissolved in DCM (2 mL) and DIEA (26 mg, 0. 20mmol) and T 3P (63 mg, 0.20 mmol) was added and the reaction was stirred at room temperature for 2 h. It was directly concentrated and the residue was purified by neutral preparative chromatography to give N-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3-oxo-n-propoxy)ethoxy)ethoxy)ethyl)-5-methyl-4-oxo-7-(2,2,4-trimethyl-6-(methylsulfonyl))-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-amide (5 mg, white solid). LC-MS (M+H) 918.3.

[0436] Example 8: N-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)n-hexyl)-6-methyl-7-oxy-4-(2,2,4-trimethyl-6-(methylsulfonyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0437] [ka]

[0438] The raw material was 4-(6-amino-n-hexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, and the process was the same as in Example 7. LC-MS (M+H) 799.3.

[0439] Example 9: 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-N-(2-methoxyethyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0440] [ka]

[0441] Step 1: Intermediate A (700 mg, 2.35 mmol), 2-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dihydro- (xaborolan-2-yl)phenyl)propan-2-ol (1.1 g, 2.75 mmol), cesium carbonate (2.3 g, 7.06 mmol), Pd(dppf)Cl 2 (400 mg, 0.55 mmol) was dissolved in DMF (15 mL), purged with nitrogen gas for 10 minutes, and heated to 100° C. under nitrogen gas protection overnight. It was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography to obtain ethyl 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (753 mg, white solid). LC-MS: m / z 493.4 [MH] + .

[0442] Step 2: Ethyl 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (753 mg, 1.53 mmol) was dissolved in ethanol (30 mL) and a solution of NaOH (183 mg, 4.59 mmol) in water (6 mL) was added and left at room temperature overnight. Concentrate, add dichloromethane and water to dissolve, adjust pH to 7 with 1M hydrochloric acid, shake, separate organic layer and concentrate to give 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (590 mg, pale yellow solid). LC-MS: m / z 465.4 [M+H] + .

[0443] Step 3: 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxyprop-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (80 mg, 0.17 mmol) was dissolved in DMF (3 mL), HATU (99 mg, 0.26 mmol) and DIEA (66 mg, 0.51 mmol) were added, and the mixture was stirred at room temperature for 5 minutes, and 2-methoxyethylamine (20 mg, 0.26 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Filtration and purification of the filtrate by preparative chromatography gave 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxyprop-2-yl)phenyl)-N-(2-methoxyethyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-amide (26.9 mg, white solid). LC-MS (M+H) 522.0. 1 H-NMR (DMSO-d6, 400MHz): δ10.95(s, 1H), 8.47(t, J=5.2Hz, 1H), 7.51(d, J=2.4Hz, 1H), 7.46(s, 1H), 7.38(dd, J=2.4, 8.4Hz, 1H), 7.29(d, J=2 .0Hz, 1H), 6.97(d, J=8.8Hz, 2H), 6.33(d, J=8.8Hz, 1H), 4.98(s, 1H), 3.55(s, 3H), 3.38-3.44(m, 4H), 3.27(s, 3H), 2.04(s, 6H), 1.46(s, 6H).

[0444] Example 10: 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-N-(2-(methylsulfonyl)ethyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0445] [ka]

[0446] The raw material was 2-methylsulfonylethylamine, and the process was the same as in Example 9. LC-MS (M+H) 570.0. 1 H-NMR (DMSO-d6, 400MHz): δ11.01 (d, J=1.6Hz, 1H), 8.66 (t, J=5.6Hz, 1H), 7.4 8(d, J=2.4Hz, 1H), 7.46(s, 1H), 7.36(dd, J=2.4, 8.4Hz, 1H), 7.29(d, J=2.0Hz , 1H), 6.97(d, J=9.2Hz, 2H), 6.31(d, J=8.4Hz, 1H), 4.97(s, 1H), 3.62-3.67(m , 2H), 3.54(s, 3H), 3.33-3.37(m, 2H), 3.02(s, 3H), 2.04(s, 6H), 1.45(s, 6H).

[0447] Example 11: N-(2,2-difluoroethyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0448] [ka]

[0449] The raw material was 2,2-difluoroethylamine, and the process was the same as in Example 9. LC-MS (M+H) 528.0. 1 H-NMR (DMSO-d6, 400MHz): δ11.09(s, 1H), 8.73(t, J=5.6Hz, 1H), 7.50(d, J=2. 0Hz, 1H), 7.47(s, 1H), 7.35-7.38(m, 2H), 6.96(d, J=9.2Hz, 2H), 6.32(d, J=8.4Hz, 1H), 5 .95-6.23(m, 1H), 4.98(s, 1H), 3.61-3.71(m, 2H), 3.55(s, 3H), 2.03(s, 6H), 1.45(s, 6H).

[0450] Example 12: N-(cyclopropylmethyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0451] [ka]

[0452] Cyclopropylmethylamine was used as raw material and the process was the same as in Example 9. LC-MS (M+H) 518.0. 1 H-NMR (DMSO-d6, 400MHz): δ10.93(s, 1H), 8.47(t, J=5.6Hz, 1H), 7.50(d, J=2.0Hz, 1H), 7.46(s, 1H), 7.37(dd, J=2.4, 8.8Hz, 1H), 7.29(d, J=1.6Hz, 1H), 6.97(d, J=9. 2Hz, 2H), 6.33(d, J=8.8Hz, 1H), 5.00(s, 1H), 3.55(s, 3H), 3.12(d, J=6.0Hz, 2H), 2 .04(s, 6H), 1.45(s, 6H), 0.81-0.86(m, 1H), 0.40-0.45(m, 2H), 0.18-0.22(m, 2H).

[0453] Example 13: 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-N-isopropyl-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0454] [ka]

[0455] The raw material was isopropylamine and the process was the same as in Example 9. LC-MS (M+H) 506.0. 1H-NMR (DMSO-d6, 400MHz): δ10.90(s, 1H), 8.17(d, J=7.6Hz, 1H), 7.51(d, J=2.0Hz, 1H), 7.47(s, 1H), 7.38(dd, J=2.0, 8.4Hz, 1H), 7.28(d, J=2.0Hz) , 1H), 6.98(d, J=9.2Hz, 2H), 6.33(d, J=8.8Hz, 1H), 5.02(s, 1H), 4.01-4. 07(m, 1H), 3.51(s, 3H), 2.03(s, 6H), 1.45(s, 6H), 1.14(d, J=6.8Hz, 6H).

[0456] Example 14: 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-N-(2,2,2-trifluoroethyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0457] [ka]

[0458] The raw material was 2,2,2-trifluoroethylamine, and the process was the same as in Example 9. LC-MS (M+H) 546.0. 1 H-NMR (DMSO-d6 / D 2 O, 400MHz): δ7.50(d, J=2.4Hz, 2H), 7.36-7.41(m, 2H), 6.97(d, J=9.2Hz, 2H), 6 .33(d, J=8.4Hz, 1H), 4.07-4.11(m, 2H), 3.56(s, 3H), 2.02(s, 6H), 1.46(s, 6H).

[0459] Example 15: N-(cyanomethyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0460] [ka]

[0461] The raw material was 2-aminoacetonitrile and the process was the same as in Example 9. LC-MS (M+H) 503.0. 1 H-NMR (CD 3 OD, 400MHz): δ7.60(d, J=2.4Hz, 1H), 7.50(s, 1H), 7.40-7.42(m, 2H), 6.82(d, J=8.8 Hz, 2H), 6.43(d, J=8.4Hz, 1H), 4.32(s, 2H), 3.70(s, 3H), 2.07(s, 6H), 1.56(s, 6H).

[0462] Example 16: N-cyclopropyl-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0463] [ka]

[0464] Cyclopropylamine was used as raw material and the process was the same as in Example 9. LC-MS (M+H) 504.0. 1 H-NMR (CD 3 OD, 400MHz): δ7.60(d, J=2.4Hz, 1H), 7.48(s, 1H), 7.41(dd, J=2.4, 8.8Hz, 1H), 7.35(s, 1H), 6.83(d, J=8.8Hz, 2H), 6. 44(d, J=8.8Hz, 1H), 3.69(s, 3H), 2.79-2.82(m, 1H), 2.08(s, 6H), 1.56(s, 6H), 0.77-0.80(m, 2H), 0.60-0.64(m, 2H).

[0465] Example 17: 2-(azetidine-1-carbonyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0466] [ka]

[0467] Azetidine was used as raw material and the process was the same as in Example 9. LC-MS (M+H) 504.0. 1 H-NMR (CD 3 OD, 400MHz): δ7.60(d, J=2.4Hz, 1H), 7.51(s, 1H), 7.41(dd, J=2.4, 8.4Hz, 1H), 7.14(s, 1H), 6.83(d, J=8.8Hz, 2H), 6.43(d, J=8.8Hz, 1H), 4.61(t, J=7.6Hz, 2H), 4.20(t, J=7.6 Hz, 2H), 3.70(s, 3H), 2.41-2.47(m, 2H), 2.08(s, 6H), 1.56(s, 6H).

[0468] Example 18: N-(3,3-difluorocyclobutyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0469] [ka]

[0470] The raw material was 3,3-difluorocyclobutylamine, and the process was the same as in Example 9. LC-MS (M+H) 554.0. 1 H-NMR (CD 3OD, 400MHz): δ7.60(d, J=2.0Hz, 1H), 7.49(s, 1H), 7.39-7.43(m, 2H), 6.83(d, J=9.2Hz, 2H), 6.44(d, J=8. 8Hz, 1H), 4.30-4.35(m, 1H), 3.70(s, 3H), 2.92-3.01(m, 2H), 2.66-2.74(m, 2H), 2.07(s, 6H), 1.56(s, 6H).

[0471] Example 19: 2-(3,3-difluoroazetidine-1-carbonyl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one

[0472] [ka]

[0473] 3,3-Difluoroazetidine was used as the raw material and the process was the same as in Example 9. LC-MS (M+H) 540.0. 1 H-NMR (CD 3 OD, 400MHz): δ7.60(d, J=2.0Hz, 1H), 7.52(s, 1H), 7.41(dd, J=2.4, 8.8Hz, 1H), 7.16(s, 1H), 6.83( d, J=8.8Hz, 2H), 6.43(d, J=8.8Hz, 1H), 4.40-5.00(m, 4H), 3.70(s, 3H), 2.08(s, 6H), 1.56(s, 6H).

[0474] Example 20: N-(1,3-difluoropropyl-2-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-amide

[0475] [ka]

[0476] The raw material was 1,3-difluoropropyl-2-amine hydrochloride, and the process was the same as in Example 9. LC-MS (M+H) 542.0.

[0477] Comparative compound 1: N-ethyl-4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropyl-2-yl)phenyl)-6-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridine-2-amide

[0478] [ka]

[0479] Using intermediate B as the raw material, the comparative compound 1 was obtained by the synthesis method according to the example of patent WO2017177955A1. LC-MS (M+H) 492.1. 1 H-NMR (CDCl 3 , 400MHz): δ10.89(s, 1H), 7.59(s, 1H), 7.17(s, 1H), 6.76-6.78(m, 4H), 6.40(d, J=8.8Hz, 1H), 5.46(bs, 1H), 3.73(s, 3H), 3.48-3.51(m, 2H), 2.07(s, 6H), 1.61(s, 6H), 1.25(t, J=7.8Hz, 3H).

[0480] Test Example 1: Detection of BRD4AlphaScreen

[0481] (1) 1x Assay buffer was prepared according to the requirements of the Reaction Biology Corp. (RBC) reagent kit. (2) Preparation of compound concentration gradient: The final detection concentrations of the test compounds all started from 10μM, and were diluted 3-fold to 10 concentrations, and a single-well test was set up for each concentration. The final detection concentration of the positive control compound (+)-JQ-1 started from 1μM, and was diluted 3-fold to 10 concentrations, and a double-well test was set up for each concentration. The gradient dilution was performed to the corresponding 1000-fold final concentration solution in a 384-well source plate, and then 20nL of the solution was transferred to a 384-well reaction plate for detection with Echo550. 20nL of 100% DMSO was transferred to the Max well, and 20nL of the highest concentration of the positive compound was transferred to the Min well. (3) 4x protein solution was prepared with 1x reaction solution. (4) 5μL of 4x protein solution was added to each well, centrifuged at 1000rpm for 1 minute, and incubated at room temperature for 15 minutes. (5) 4x polypeptide solution was prepared with 1x reaction solution. (6) 5μL of 4x polypeptide solution was added to each well of the reaction plate, centrifuged at 1000rpm for 1 minute. (7) 10μL of detection solution was added, centrifuged at 1000rpm for 60 seconds, gently shaken to mix, and incubated at room temperature for 60 minutes. (8) Data was read with EnVision. (9) The IC50 value of the compound for protein binding inhibition was obtained by fitting the dose-effect curve with the analysis software GraphPad Prism5 (specific data can be seen in Table 1).

[0482] [Table 1]

[0483] Results: Examples 1 to 20 provided by the present invention have inhibitory activity IC against BRD4-BD2. 50 The IC values ​​were all less than 10 nM, and most of the examples showed inhibitory activity IC 50The inhibitory activity of some examples against BRD4-BD1 was also stronger than that of the comparative compound; at the same time, the example compounds of the present invention maintained the relative selectivity against BRD4-BD2, with selectivity folds ranging from 10-fold to more than 400-fold.

[0484] Test Example 2: Test of the inhibitory activity of the example compounds against the proliferation of MV4-11 cells

[0485] Specific experimental steps: 1) Day 0: Seed cells in a 96-well plate, digest the cells with trypsin, suspend them in cell culture medium, detect the cell density by an automated cell counter, dilute the cells to an appropriate density with medium, add 100 μL of cell suspension into the 96-well plate, and use medium without cells as the control well, incubate at 37 °C, 5% CO 2 2) Day 1: Add drugs to treat cells test compounds, a total of 8 concentrations were tested, diluted 3 times, 10 μM was the starting concentration of the test compound. Specific steps: Prepare 200x compound mother solution, dilute with culture medium to a final concentration of 3x, immediately add 3 μL of 200x compound to 197 μL of culture medium, add 50 μL of diluted compound per well to cells in 96-well plate, and incubate at 37°C, 5% CO 2 3) Day 4: Cell viability detection was performed by first equilibrating the 96-well cell plate to room temperature, adding 40 μL of CellTiter-Glo® reagent to each well, mixing on a shaker for 2 min to completely lyse the cells, incubating at room temperature for 10 min to stabilize the luminescence signal, and reading the luminescence value on an Envision microplate reader; 4) Data processing was performed with GraphPad Prism 5.0 software to analyze the data, and the data was fitted using nonlinear S-curve regression to obtain the dose-effect curve, which allowed the IC 50 Values ​​were calculated: % inhibition = (DMSO treated cell wells - compound treated cell wells) / (DMSO treated cell wells - cell free medium wells) x 100. IC 50Values ​​were obtained using a four-parameter regression method using the microplate reader's software (see Table 2 for specific data).

[0486] [Table 2]

[0487] Results: The inhibitory activity of Examples 1 to 20 provided in the present invention against MV4-11 cell proliferation was IC 50 The IC values ​​were all less than 500 nM, and the inhibitory activity of some of the example compounds was 50 The value was less than 10 nM, indicating stronger cell proliferation inhibitory activity than the comparative compounds.

[0488] Test Example 3: Testing the inhibitory activity of example compounds against different enzymes

[0489] Using a BRD AlfaScreening method similar to Test Example 1 and a conventional test method for kinase inhibitors, some example compounds of the present invention were tested for inhibitory activity against various BRDs, such as BRD2 BD1 / 2, BRD3 BD1 / 2 and BRD-T BD1 / 2 enzymes, HDAC, EZH2, LSD1, G9a, etc., and various protein kinases, such as EGFR, VEGFR, PDGFR, FGFR, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, etc., and some example compounds, such as Examples 1, 11 and 18, showed good BRD-BD2 selectivity and kinase target selectivity, with the selectivity exceeding 100-fold.

[0490] Test Example 4: Testing the inhibitory activity of example compounds against the proliferation of different cell lines

[0491] In a manner similar to Test Example 2 and the literature, the proliferation inhibitory activity of some example compounds against different cell lines such as LNCAP (+R1881), SKM-1, 22RV1, DU145, MOLM13, MDA-PCA-2b, KASUMI 1, THP-1, KG-1, IEC6, H1299, etc. was tested. Some examples such as Example 1, Example 11, and Example 18 showed better proliferation inhibitory activity against most AML cell lines and prostate cancer cell lines, and the inhibitory activity IC 50 The IC50 values ​​for the growth inhibitory activity against the IEC6 and H1299 cell lines were less than 1000 nM, and even less than 100 nM for some cell lines, such as LNCAP, SKM-1, MOLM13, KASUMI 1, THP-1, and KG-1. 50 The activity exceeded 1000 nM, indicating high selectivity of cell proliferation inhibition.

[0492] Test Example 5: ADME Testing of Some Example Compounds

[0493] (1) Metabolic stability test: 150 μL of liver microsomes (final concentration is 0.5 mg / mL) were subjected to metabolic stability culture, and the system contained NADPH (final concentration is 1 mM), 1 μM of the test compound, and the positive control midazole or negative control atenolol. The reaction was terminated with acetonitrile containing tinidazole at 0, 5, 10, and 30 minutes, respectively. The mixture was vortexed for 1 min, centrifuged at 15000 rpm for 10 min, and 50 μL of the supernatant was sampled in a 96-well plate. The metabolic stability of the compound was calculated by measuring the relative decrease of the original drug (see Table 3 for specific data).

[0494] (2) Direct inhibition test (DI test): 100μL of human liver microsome system (final concentration 0.2mg / mL) was subjected to direct inhibition incubation, which contained NADPH (final concentration 1mM), 10μM of compound, positive inhibitor cocktail (ketoconazole 10μM, quinidine 10μM, sulfapyrazole 100μM, α-naphthoflavone 10μM, tranylcypromine 1000μM), negative control (0.1% DMSO BPS) and mixed probe substrate (midazolam 10μM, testosterone 100μM, dextromethorphan 10μM, diclofenac 20μM, phenacetin 100μM, mephenytoin 100μM), and the reaction was stopped after 20 minutes of incubation. Enzyme activity was calculated by measuring the relative production of metabolites.

[0495] [Table 3]

[0496] The stability of the example compounds 1, 11, and 18 in the metabolism of liver microsomes of rats, mice, and dogs was significantly improved in various genera compared with the comparative compound 1, and the microsome stability of mice and dogs was significantly improved compared with the comparative compound 1; and the inhibition IC of the examples 1 and 18 against the main metabolic enzymes CYP1A2, 2C8, 2C19, 3A4, etc. 50 All of the values ​​exceeded 15 μM, indicating high potential for drug discovery.

[0497] Test Example 6: Testing of in vivo pharmacokinetic parameters of example compounds in rats and mice

[0498] Six male SPF grade SD rats or Balb c mice (Shanghai B&K laboratory animals) were divided into two groups, and the test compounds were prepared into appropriate solutions or suspensions; one group was administered intravenously, and the other group was administered orally. Blood was collected by puncturing the jugular vein, and each sample was collected at approximately 0.2 mL / time point, and anticoagulated with sodium heparin. The blood collection times were 5, 15 and 30 minutes, 1, 2, 4, 6, 8 and 24 hours before and after administration; after collection, the blood samples were placed on ice and centrifuged to separate the plasma (centrifugation conditions: 8000 rpm / min, 6 minutes, 2-8°C), and the collected plasma was stored at -80°C before analysis. The plasma samples were analyzed by LC-MS / MS.

[0499] Using the blood drug concentration data, the pharmacokinetic parameter AUC 0-t , AUC 0-∞ , MRT 0-∞ , C max , T max , T 1 / 2 and V d The parameters, mean values, and standard deviations were calculated. Bioavailability (F) was calculated using the following formula.

[0500]

number

[0501] For samples with concentrations below the lower limit of quantification, C max Samples taken before reaching C are counted as zero. max After reaching this value, samples were calculated as not quantifiable (BLQ).

[0502] Results: Some of the example compounds of the present invention have good in vivo pharmacokinetic properties, for example, Example 1 and Example 18, when administered intragastrically to mice at a dose of 5 mg / kg, have excellent PK parameters, Cmax is more than 1.5 uM, T1 / 2 is more than 3 hours, and AUC(hr*nM) is more than 5000. The bioavailability of Example compounds 1 and 18 to mice is more than 40%, which is better than the bioavailability of comparative compound 1 (the bioavailability of comparative compound 1 in the mouse body is 25%). When administered intragastrically to beagle dogs at a dose of 10 mg / kg, the PK parameters are excellent, Cmax is more than 2.0 uM, T1 / 2 is more than 2 hours, and AUC(hr*nM) is more than 15000.

[0503] Test Example 7: Test on the growth inhibition of the compound of the present invention against MV4-11 tumor transplanted in nude mice

[0504] Actively growing tumor tissue was cut to approximately 1.5 mm 3 The tumors were then subcutaneously inoculated into the right armpit of nude mice under aseptic conditions. The diameters of the tumors subcutaneously inoculated into nude mice were measured with a caliper, and the average tumor volume was 130 mm. 3 When the animals reached the age of 10, they were randomly divided into groups. Example compound or Comparative compound 1 (prepared to the required concentration with water for injection containing 1% Tween 80 for use) was orally administered at a given dose every day for 3 consecutive weeks, and the vehicle control group was given the same amount of vehicle. Throughout the entire experiment, the diameter of the implanted tumor was measured twice a week, and the body weight of the mice was measured at the same time. The formula for calculating tumor volume (TV) was: TV=1 / 2×a×b 2where a and b are length and width, respectively. Based on the measurements, the relative tumor volume (RTV) was calculated using the formula: RTV = Vt / V0, where V0 was the tumor volume measured at the time of cage administration (i.e., d0), and Vt was the tumor volume at each measurement. The evaluation indexes of antitumor activity were: 1) relative tumor growth rate T / C (%), calculated as: T / C (%) = (TRTV / CRTV) × 100%, where TRTV is the RTV of the treatment group; CRTV is the RTV of the negative control group; 2) tumor volume growth inhibition rate GI%, calculated as: GI% = [1-(TVt-TV0) / (CVt-CT0)] × 100%, where TVt is the tumor volume measured at each time in the treatment group; TV0 is the tumor volume measured at the time of cage administration in the treatment group; CVt is the tumor volume measured at each time in the control group; CV0 is the tumor volume measured at the time of cage administration in the control group; 3) tumor weight inhibition rate, calculated as: tumor weight inhibition rate % = (W c -W T ) / Wc×100%, where W c is the tumor weight in the control group, and W T was the tumor weight of the treatment group.

[0505] Results: Some of the example compounds of the present invention exhibited excellent antitumor effects in animals. For example, Example 1 and Example 18 showed good tumor growth inhibitory effects when administered intragastrically at a low dose of 10 mg / kg to 30 mg / kg once a day for 21 days. and its T / C ratio was less than 40%; at high doses, such as 50mg / kg-100mg / kg, the tumor suppression effect was significant and well tolerated by all experimental animals. At the same doses, Example Compounds 1 and 18 had significant inhibitory effects on the growth of tumors transplanted into nude mice, and the inhibitory effects were superior to those of Comparative Compound 1 (at a dose of 15mpk, the tumor suppression rates of Example 1 and Example 18 were 82%, while the suppression rate of Comparative Compound 1 was about 60%).

[0506] All documents mentioned in the present invention are incorporated by reference into this application as if each document was individually incorporated by reference. Moreover, after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and equivalents thereof also fall within the scope of the appended claims of this application.

Claims

1. A pyrrole amide pyridone compound represented by general formula II-1, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or crystalline polymorph thereof. 【Chemistry 1】 R1 is C1-C8 alkyl or 【Chemistry 2】 and L1 is -(C1-C8 alkyl)- or -(C1-C6 alkyl)-(CH ２ OCH ２ ) ｍ１ -(C1-C6 alkyl)-; m1 is 1, 2, 3 or 4; L2 is a linking bond, or 【Chemistry 3】 and W is -CH ２ - or -C(=O)-; R2 is hydrogen; R3 and R5 are independently hydrogen; R4 is -L-R10; L is - (SO ２ )—wherein R10 is C1-C6 alkyl; A pyrrole amide pyridone compound, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or polymorph thereof, wherein R8 and R9 are independently C1-C6 alkyl.

2. The pyrrole amide pyridone compound represented by the general formula II-1 according to claim 1, wherein m1 is 3, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or polymorph thereof.

3. When R1 is C1-C8 alkyl, said C1-C8 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; Or, when L1 is -(C1-C8 alkyl)-, said C1-C8 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl; Or, L1 is -(C1-C6 alkyl)-(CH ２ OCH ２ ) ｍ１ When -(C1-C6 alkyl)-, said C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Or, m1 is 2 or 3; or R10 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. A pyrrole amide pyridone compound represented by general formula II-1 according to claim 1, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or polymorph thereof.

4. When R1 is C1-C8 alkyl, said C1-C8 alkyl is independently methyl, ethyl, or n-propyl; Or, when L1 is -(C1-C8 alkyl)-, said C1-C8 alkyl is n-butyl, n-pentyl, or n-hexyl; Or, L1 is -(C1-C6 alkyl)-(CH ２ OCH ２ ) ｍ１ -(C1-C6 alkyl)-, said C1-C6 alkyl is independently methyl, ethyl or n-propyl; Or, R10 is methyl or ethyl, the pyrrole amide pyridone compound represented by the general formula II-1 according to claim 3, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or polymorph thereof.

5. -L1-L2- is 【Chemistry 4】 and and / or 【Chemistry 5】 teeth 【Chemistry 6】 and And / or R4 is 【Chemistry 7】 The pyrrole amide pyridone compound represented by the general formula II-1 according to claim 1, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or polymorph thereof.

6. R1 is ethyl, isopropyl, 【Chemistry 8】 and and / or 【Chemistry 9】 teeth 【Chemistry 10】 The pyrrole amide pyridone compound represented by the general formula II-1 according to claim 1, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or polymorph thereof.

7. The pyrrole amide pyridone compound represented by the general formula II-1 according to claim 1, characterized in that the pyrrole amide pyridone compound represented by the general formula II-1 is selected from any of the following structures: A pyrrole amide pyridone compound represented by the general formula II-1 according to claim 1, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or polymorph thereof. 【Chemistry 11】 【Chemistry 12】

8. A method for preparing a pyrrole amide pyridone compound represented by formula I, comprising method 1 or method 2; Method 1 includes the steps of: in a solvent, in the presence of a base and a condensation reagent, carrying out a condensation reaction between a compound represented by formula D and R1R2NH as shown below to obtain a pyrrole amide pyridone compound represented by formula I; 【Chemistry 13】 Method 2 is a production method including the step of subjecting a compound represented by formula A' and a compound represented by formula B to a metal-catalyzed coupling reaction in a solvent in the presence of a base and a transition metal catalyst as shown below to obtain a pyrrole amide pyridone compound represented by formula I. 【Chemistry 14】 wherein R1, R2, R3, R4, and R5 are as defined in any one of claims 1 to 7; X1 is CH; X2 is NH; 【Chemistry 15】 teeth 【Chemistry 16】 It is.)

9. A pharmaceutical composition comprising a pyrrole amide pyridone compound represented by the general formula II-1 according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or crystalline polymorph thereof, and a pharma- ceutical acceptable carrier.

10. Use of a pyrrole amide pyridone compound represented by general formula II-1 according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or crystalline polymorph thereof, or a pharmaceutical composition according to claim 9, in the manufacture of a BRD and / or c-Myc inhibitor, a drug for treating or preventing a disease associated with the activity or expression level of BRD and / or c-Myc protein, or a medicament for treating or preventing a tumor, an immune disease, and / or an inflammatory disease; The tumor is selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, and pancreatic cancer; the immune disease and inflammatory disease are independently selected from transplanted organ rejection, gout, rhinitis, hair loss, Alzheimer's disease, appendicitis, atherosclerosis, asthma, arthritis, allergic dermatitis, Behcet's disease, herpetic skin disease, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease, and the like.

20. The use selected from pulmonary disease, cirrhosis of the liver, degenerative joint disease, dermatitis, dermatomyositis, eczema, enteritis, encephalitis, gastritis, nephritis, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease, irritable bowel syndrome, Kawasaki disease, meningitis, multiple sclerosis, myocarditis, gravitational myasthenia, myomycosis, myositis, nephritis, osteomyelitis, pancreatitis, Parkinson's disease, pericarditis, pernicious anemia, pneumonia, primary biliary sclerosing cholangitis, polyarteritis nodosa, psoriasis, fibrosis, lupus erythematosus, tissue graft rejection, thyroiditis, type I diabetes mellitus, urethritis, uveitis, vasculitis, vitiligo and Waldenstrom's macroglobulinemia.

11. A compound represented by formula D or formula C. 【Chemistry 17】 (wherein R3, R4, and R5 are as defined in any one of claims 1 to 7; Ra is C1-C6 alkyl; X1 is CH; X2 is NH; 【Chemistry 18】 teeth 【Chemistry 19】 It is.)

12. The compound represented by the formula D 【Chemistry 20】 and And / or the compound represented by formula C is 【Chemistry 21】 The compound of claim 11, which is represented by formula D or formula C.

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