阅读说明：本技术 具有bet抑制活性的化合物及其制备方法和用途 (Compound with BET inhibition activity, preparation method and application thereof ) 是由 夏林 耿美玉 叶艳 丁健 张琼 沈爱军 黄颖 刘红椿 杨浩然 艾菁 张敏敏 于 2019-02-01 设计创作，主要内容包括：本发明属于药物化学领域。具体地,本发明涉及一系列具有新型结构的BET(bromodomain and extra-terminal domain)抑制剂,尤其是靶向BRD4(Bromodomain-containing protein 4)的抑制剂,及其制备方法和用途。其结构如下列通式(I)所示。这些化合物或其立体异构体、外消旋物、几何异构体、互变异构体、前药、水合物、溶剂化物、晶型或其药学上可接受的盐及药物组合物,可用于治疗或/和预防由溴结构域蛋白介导的相关疾病。(The invention belongs to the field of pharmaceutical chemistry. In particular, the invention relates to a series of BET (branched and extra-tertiary domain) inhibitors with novel structures, in particular to inhibitors targeting BRD4 (Bromodomain-relating protein 4), and a preparation method and application thereof. The structure is shown in the following general formula (I). The compounds or stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates, crystal forms or pharmaceutically acceptable salts and pharmaceutical compositions thereof can be used for treating or/and preventing related diseases mediated by bromodomain proteins.)

A compound of formula (I) or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof,

in the formula (I), the compound is shown in the specification,

R₁selected from:

Y₁selected from the group consisting of CR₄' and N; wherein R is₄' is selected from H, D, hydroxy, halogen (e.g. F, Cl, Br, I), cyano and optionally substituted alkyl (e.g. C)_1-6Alkyl groups);

R₄selected from optionally substituted aryl (e.g. C)_6-14Aryl), optionally substituted heteroaryl (e.g., 5-12 membered heteroaryl), optionally substitutedCycloalkyl (e.g. C)_3-12Cycloalkyl), optionally substituted arylalkylene (e.g. C)_6-14Aryl radical C_1-3Alkylene), optionally substituted heteroarylalkylene (e.g. 5-12 membered heteroaryl C)_1-3Alkylene), and optionally substituted cycloalkylalkylene (e.g. C)_3-12Cycloalkyl radical C_1-3Alkylene groups);

Y₂selected from C, O and N; n represents 1 or 2, and R₅Each independently selected from H and optionally substituted alkyl (e.g. C)_1-8Alkyl groups);

ring A is selected from optionally substituted aromatic rings (e.g. C)_6-14An aromatic ring), an optionally substituted heteroaromatic ring (e.g., a 5-12 membered heteroaromatic ring), and an optionally substituted heterocyclic ring (e.g., a 3-12 membered heterocyclic ring);

ring B is selected from optionally substituted aromatic rings (e.g. C)_6-14An aromatic ring), an optionally substituted heteroaromatic ring (e.g., a 5-12 membered heteroaromatic ring), and an optionally substituted heterocyclic ring (e.g., a 3-12 membered heterocyclic ring);

R₇and R₇' each is independently selected from H, D, CN and optionally substituted alkyl (e.g. C)_1-8Alkyl groups);

R₂selected from H, D, optionally substituted alkyl (e.g. C)_1-8Alkyl) and optionally substituted cycloalkyl (e.g. C)_3-12Cycloalkyl groups);

R₃and R₃' each is independently selected from H, D, and optionally substituted alkyl (e.g. C)_1-8Alkyl), and R₃And R₃At least one of is not H; or R₃And R₃' together with the carbon to which they are attached form cycloalkyl (e.g. C)_3-12Cycloalkyl radicals, e.g. C_3-8Cycloalkyl, such as cyclopropyl);

X₁selected from the group consisting of CR_6aAnd N;

X₂selected from the group consisting of CR_6bAnd N;

X₃selected from the group consisting of CR_6cAnd N, and X₁、X₂And X₃At most two of N;

X₄selected from NR₈And O;

R_6a、R_6band R_6cEach is independentSelected from H, D, halogen (e.g. F, Cl, Br, I) and optionally substituted alkyl (e.g. C)_1-8Alkyl groups);

R₈selected from H, D, oxygen, hydroxy, optionally substituted alkyl (e.g. C)_1-8Alkyl), optionally substituted alkanoyl (e.g. C)_1-8Alkanoyl), optionally substituted alkoxycarbonyl (C)_1-8Alkoxycarbonyl), optionally substituted cycloalkyl (e.g. C)_3-12Cycloalkyl), optionally substituted heterocyclyl (e.g., 3-20 membered heterocyclyl), optionally substituted aryl (e.g., C)_6-14Aryl), optionally substituted heteroaryl (e.g., 5-12 membered heteroaryl), optionally substituted cycloalkylalkylene- (e.g., C)_3-12Cycloalkyl radical C_1-3Alkylene-), optionally substituted heterocyclylalkylene- (e.g. 3-20 membered heterocyclyl C)_1-3Alkylene-), optionally substituted arylalkylene- (e.g. C)_6-14Aryl radical C_1-3Alkylene-), and optionally substituted heteroarylalkylene- (e.g. C)_5-12Heteroaryl C_1-3Alkylene-).

The compound of claim 1, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

R₁selected from:

Y₁selected from the group consisting of CR₄' and N; wherein R is₄' is selected from H, D, hydroxy, F, Cl, Br, I, cyano, and C optionally substituted with 1-3 halogens (e.g., F, Cl, Br, I)_1-6Alkyl (e.g. C)_1-3Alkyl groups); preferably, R₄' is selected from H, D, hydroxy, F, Cl, cyano, methyl, ethyl, methyl substituted with 1-3 fluorines, and ethyl substituted with 1-3 fluorines; more preferably, R₄' is selected from H, D, hydroxy, F, cyano, methyl, and methyl substituted with 1-3 fluorines; most preferably, R₄' is selected from H, D and hydroxy;

R₄selected from optionally substituted C_6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C_3-8Cycloalkyl, optionally substituted C_6-10Aryl radical C_1-3Alkylene, optionally substituted 5-to 10-membered heteroaryl C_1-3Alkylene, and optionally substituted C_3-8Cycloalkyl radical C_1-3An alkylene group; preferably, R₄Selected from the group consisting of optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted benzyl, optionally substituted pyridylmethylene, optionally substituted pyrazinylmethylene, optionally substituted pyridazinylmethylene, optionally substituted pyrimidinyl methylene, optionally substituted cyclopropyl methylene, and optionally substituted cyclobutyl methylene; more preferably, R₄Selected from optionally substituted phenyl and optionally substituted pyridyl; for R₄Preferably, the substituents are one or more substituents independently selected from halogen (e.g., F, Cl, Br, I), C_1-6Alkyl (e.g. C)_1-4Alkyl group), C_1-6Alkoxy (e.g. C)_1-4Alkoxy), halo C_1-6Alkyl (e.g. halo C)_1-4Alkyl), halo C_1-6Alkoxy (e.g. halo C)_1-4Alkoxy), methanesulfonyl and cyano; more preferably, the substituents are one or more substituents independently selected from halogen (e.g. F, Cl, Br, I), C_1-2Alkyl radical, C_1-2Alkoxy, halo C_1-2Alkyl, halo C_1-2Alkoxy, methanesulfonyl and cyano groups; further preferably, the substituent is one or more groups independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, methyl substituted with 1 to 3 fluorines, ethyl substituted with 1 to 3 fluorines, methoxy substituted with 1 to 3 fluorines, ethoxy substituted with 1 to 3 fluorines, methanesulfonyl and cyano;

most preferably, R₄Selected from optionally substituted one or more halogen, C_1-6Phenyl substituted by alkyl or cyano, and optionally substituted by one or more halogens, C_1-6Alkyl-or cyano-substituted heteroaryl radicals, e.g. pyridineA group;

Y₂selected from C, O and N; n represents 1 or 2, and R₅Each independently selected from H and optionally substituted C_1-6An alkyl group; preferably, R₅Each independently selected from H and optionally substituted C_1-3An alkyl group; more preferably, R₅Each independently selected from H and methyl;

ring A is selected from optionally substituted 5-6 membered aromatic ring, optionally substituted 5-6 membered heteroaromatic ring, and optionally substituted 3-8 membered heterocyclic ring; preferably, ring a is selected from an optionally substituted benzene ring, an optionally substituted pyridine, an optionally substituted pyrrole, an optionally substituted furan, and an optionally substituted thiophene, an optionally substituted piperazine, and an optionally substituted pyrazine;

ring B is selected from optionally substituted 5-6 membered aromatic ring, optionally substituted 5-6 membered heteroaromatic ring, and optionally substituted 3-8 membered heterocyclic ring; preferably, ring B is selected from an optionally substituted benzene ring, an optionally substituted pyridine, an optionally substituted pyrrole, an optionally substituted furan, and an optionally substituted thiophene, an optionally substituted piperazine, and an optionally substituted pyrazine;

it is preferred for each of the cases of substitution in the a and B rings that the substituents are one or more, for example one or two, independently selected from the group consisting of: halogen, carboxyl, C_1-8Alkyl, -OR_dUnsubstituted or 1-3C_1-3Alkyl-substituted 5-to 10-membered heterocyclyl C_1-3Alkylene radical, C_1-3Alkylene radical NR_aR_bUnsubstituted or 1-3C_1-3Alkyl-substituted 5-to 10-membered heterocyclylcarbonyl, -halo-C_1-8Alkyl, cyano, -C (O) NR_aR_b、-NR_aR_b、-S(O)₂C_1-6Alkyl, -N (R)_a)S(O)₂R_b、-N(R_a)C(O)R_band-C (O) OC_1-6An alkyl group; r_dIs H, C_6-10Aryl radical, C_1-8Alkyl, halo C_1-8Alkyl, -NR_aR_bSubstituted C_1-8Alkyl, hydroxy substituted C_1-8Alkyl, or C_1-6Alkoxy-substituted C_1-8An alkyl group; wherein R is_aAnd R_bEach is independentSelected from hydrogen and C_1-8Alkyl, and halo C_1-8An alkyl group;

R₇and R₇' each is independently selected from H, D, CN and optionally substituted C_1-6Alkyl (e.g. C)_1-3Alkyl groups); preferably, R₇And R₇' independently from each other selected from H, D, CN, C_1-3Alkyl and halo C_1-3An alkyl group; more preferably, R₇And R₇' each is independently selected from H, D, CN, methyl, and methyl substituted with 1-3 halogens such as fluorine;

preferably, R₁Selected from:

more preferably, R₁Selected from:

wherein the content of the first and second substances,

Y₁selected from the group consisting of CR₄' and N; wherein R is₄' is selected from H, D, hydroxy, F, Cl, Br, I, cyano, and C optionally substituted with 1-3 halogens (e.g., F, Cl, Br, I)_1-6Alkyl (e.g. C)_1-3Alkyl groups); preferably, R₄' is selected from H, D, hydroxy, F, Cl, cyano, methyl, ethyl, methyl substituted with 1-3 fluorines, and ethyl substituted with 1-3 fluorines; more preferably, R₄' is selected from H, D, hydroxy, F, cyano, methyl, and methyl substituted with 1-3 fluorines; most preferably, R₄' is selected from H, D and hydroxy;

R₄selected from optionally substituted C_6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C_3-8Cycloalkyl, optionally substituted C_6-10Aryl radical C_1-3Alkylene, optionally substituted 5-to 10-membered heteroaryl C_1-3Alkylene, and optionally substituted C_3-8Cycloalkyl radical C_1-3An alkylene group; preferably, R₄Selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted benzyl, optionally substituted pyridylmethylene, optionally substituted pyrazinylmethylene, optionally substituted pyridazinylmethylene, optionally substituted pyrimidinyl methylene, optionally substituted cyclopropyl methylene and optionally substituted cyclobutyl methylene; more preferably, R₄Selected from optionally substituted phenyl and optionally substituted pyridyl; for R₄Preferably, the substituents are one or more substituents independently selected from halogen (e.g., F, Cl, Br, I), C_1-6Alkyl (e.g. C)_1-4Alkyl group), C_1-6Alkoxy (e.g. C)_1-4Alkoxy), halo C_1-6Alkyl (e.g. halo C)_1-4Alkyl), halo C_1-6Alkoxy (e.g. halo C)_1-4Alkoxy), methanesulfonyl and cyano; more preferably, the substituents are one or more substituents independently selected from halogen (e.g. F, Cl, Br, I), C_1-2Alkyl radical, C_1-2Alkoxy, halo C_1-2Alkyl, halo C_1-2Alkoxy, methanesulfonyl and cyano groups; further preferably, the substituent is one or more groups independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, methyl substituted with 1 to 3 fluorines, ethyl substituted with 1 to 3 fluorines, methoxy substituted with 1 to 3 fluorines, ethoxy substituted with 1 to 3 fluorines, methanesulfonyl and cyano;

most preferably, R₄Selected from optionally substituted one or more halogen, C_1-6Phenyl substituted by alkyl or cyano, and optionally substituted by one or more halogens, C_1-6Alkyl or cyano substituted heteroaryl such as pyridyl;

Y₂selected from C, O and N; n represents 1 or 2, and R₅Each independently selected from H and optionally substituted C_1-6An alkyl group; preferably, R₅Each independently selected from H and optionally substituted C_1-3An alkyl group; more preferably, R₅Each independently selected from H and methyl;

R₉selected from halogen, carboxyl, C_1-8Alkyl, -OR_dUnsubstituted or 1-3C_1-3Alkyl-substituted 5-to 10-membered heterocyclyl C_1-3Alkylene radical, C_1-3Alkylene radical NR_aR_bUnsubstituted or 1-3C_1-3Alkyl-substituted 5-to 10-membered heterocyclylcarbonyl, -halo-C_1-8Alkyl, cyano, -C (O) NR_aR_b、-NR_aR_b、-S(O)₂C_1-6Alkyl, -N (R)_a)S(O)₂R_b、-N(R_a)C(O)R_band-C (O) OC_1-6An alkyl group; r_dIs H, C_6-10Aryl radical, C_1-8Alkyl, halo C_1-8Alkyl, -NR_aR_bSubstituted C_1-8Alkyl, hydroxy substituted C_1-8Alkyl, or C_1-6Alkoxy-substituted C_1-8An alkyl group; wherein R is_aAnd R_bEach independently selected from hydrogen and C_1-8Alkyl and halo C_1-8An alkyl group;

preferably, R₉Selected from halogen, carboxyl, C_1-6Alkyl, -OR_dUnsubstituted or 1-3C_1-3Alkyl-substituted 5-to 8-membered heterocyclyl C_1-3Alkylene radical, C_1-3Alkylene radical NR_aR_bUnsubstituted or 1-3C_1-3Alkyl-substituted 5-8 membered heterocyclylcarbonyl, -halo-C_1-6Alkyl, cyano, -C (O) NR_aR_b、-NR_aR_b、-S(O)₂C_1-4Alkyl, -N (R)_a)S(O)₂R_b、-N(R_a)C(O)R_band-C (O) OC_1-4An alkyl group; r_dIs H, C_6-10Aryl radical, C_1-6Alkyl, halo C_1-6Alkyl, -NR_aR_bSubstituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl, or C_1-3Alkoxy-substituted C_1-6An alkyl group; wherein R is_aAnd R_bEach independently selected from hydrogen and C_1-6Alkyl, and halo C_1-6An alkyl group;

preferably, R₉Selected from halogen, carboxyl, C_1-4Alkyl radical, C_1-4Alkoxy radicalHalogen-substituted C_1-4Alkyl, halogen substituted C_1-4Alkoxy, cyano, -C (O) NR_aR_b、-N(R_a)C(O)R_bAnd C (O) OC_1-4Alkyl radical, R_aAnd R_bEach independently selected from hydrogen and C_1-4Alkyl, and halogen substituted C_1-4An alkyl group, a carboxyl group,

and m is R₉M is selected from 0, 1,2 and 3; preferably, m is 0, 1 or 2;

most preferably, R₁Selected from:

the compound of any one of the preceding claims, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

X₁is N or CH;

X₂is CR_6bOr N;

X₃is CR_6c；

R_6bAnd R_6cEach independently selected from H, D, halogen and optionally substituted C_1-6Alkyl radicals such as C_1-3An alkyl group; preferably, R_6bAnd R_6cEach independently selected from H, D, fluoro, methyl and methyl substituted with 1-3 halogens such as fluoro; more preferably, R_6a、R_6bAnd R_6cEach independently selected from H, D, fluoro, and methyl.

The compound of any one of the preceding claims, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

X₄selected from NR₈And O, wherein

R₈Selected from H, D, oxygen, hydroxylRadical, optionally substituted C_1-4Alkyl, optionally substituted C_1-4Alkanoyl, optionally substituted C_1-4Alkoxycarbonyl, optionally substituted C_3-8Cycloalkyl, optionally substituted 3-8 membered heterocyclic group (e.g., 3-8 membered heterocyclic group containing oxygen or nitrogen as a heteroatom), optionally substituted C_6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C_3-8Cycloalkyl radical C_1-3Alkylene- (e.g. C)_3-8Cycloalkylmethylene), optionally substituted 3-8 membered heterocyclyl C_1-3Alkylene-, optionally substituted C_6-10Arylalkylene- (e.g. benzyl), and optionally substituted 5-10 membered heteroaryl C_1-3Alkylene- (e.g. pyridyl C)_1-3Alkylene-, such as pyridylmethylene-);

preferably, R₈Selected from H, D, oxygen, hydroxy, methyl, ethyl, propyl such as isopropyl, hydroxyethyl, hydroxy-substituted propyl, C_1-2Alkoxy-substituted C_2-4Alkyl, methoxycarbonyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolanyl, tetrahydropyranyl, cyclopropanemethylene-, benzyl and pyridylmethylene;

for R₈Preferably, the substituents are one or more substituents independently selected from-OH, F, CN, -NH₂、C_1-6Alkoxy (e.g. C)_1-2Alkoxy), -NH (C)_1-3Alkoxy), and-N (C)_1-3Alkoxy group)₂A group of (1).

The compound of any one of the preceding claims, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

R₂selected from H, D, optionally substituted C_1-6Alkyl (e.g. C)_1-4Alkyl) and optionally substituted C_3-8Cycloalkyl (e.g. C)_3-6Cycloalkyl groups); for R₂Preferably, the substituents are one, two, three or more independently selected from D, halogen (e.g., F, Cl, Br and I) and hydroxyA group;

more preferably, R₂Selected from H, D, C optionally substituted by 1-3D, halogen such as fluorine and/or hydroxy_1-3Alkyl and C optionally substituted by 1-3 halogens, e.g. fluorine and/or hydroxy_3-4A cycloalkyl group;

further preferably, R₂Selected from H, D, methyl, ethyl, propyl, hydroxyethyl, -CHF₂、-CH₂F、-CF₃、CH₂CF₃And a cyclopropyl group.

The compound of any one of the preceding claims, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

R₃and R₃' each is independently selected from H, D, and optionally substituted C_1-6Alkyl (e.g. C)_1-3Alkyl), and R₃And R₃At least one of is not H;

preferably, R₃And R₃' each is independently selected from H, D, and C optionally substituted with one, two or more halogens (e.g., F, Cl, Br, and I)_1-3Alkyl (e.g., methyl, ethyl), and R₃And R₃At least one of is not H;

further preferably, R₃And R₃' each is independently selected from H, methyl and ethyl, and R₃And R₃At least one of is not H;

or further preferably, R₃And R₃' any of them is methyl and the other is H.

The compound of claim 1, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

R₁selected from:

Y₁selected from the group consisting of CR₄' and N; wherein R is₄' is selected from H, D, hydroxy, F, Cl, cyano, methyl, ethyl, methyl substituted with 1-3 fluorines, and ethyl substituted with 1-3 fluorines;

R₄selected from optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted C_3-8Cycloalkyl, optionally substituted benzyl, optionally substituted heteroarylalkylene, and optionally substituted C_3-8A cycloalkylalkylene group;

Y₂selected from C, O and N; n represents 1 or 2, and R₅Each independently selected from H and optionally substituted C_1-3An alkyl group;

ring A is selected from an optionally substituted benzene ring, and an optionally substituted 5-6 membered heteroaromatic ring;

ring B is selected from optionally substituted benzene ring, and optionally substituted 5-6 membered heteroaromatic ring such as pyridine ring;

R₇and R₇' each is independently selected from H, D, CN and optionally substituted C_1-3An alkyl group;

R₂selected from H, D, optionally substituted C_1-4Alkyl and optionally substituted C_3-4A cycloalkyl group;

R₃and R₃' each is independently selected from H, D, and optionally substituted C_1-6Alkyl (e.g. C)_1-3Alkyl), preferably each independently selected from H, D, methyl, and ethyl, and R₃And R₃At least one of is not H; or R₃And R₃' together with the attached carbon form a cyclopropyl group;

X₁selected from the group consisting of CR_6aAnd N;

X₂selected from the group consisting of CR_6bAnd N;

X₃selected from the group consisting of CR_6cAnd N, and X₁、X₂And X₃At most two of N;

X₄selected from NR₈And O;

R_6a、R_6band CR_6cEach independently selected from H, D,Halogen and optionally substituted C_1-3An alkyl group;

R₈selected from H, D, oxygen, hydroxy, optionally substituted C_1-6Alkyl, optionally substituted C_1-6Alkanoyl, optionally substituted C_1-6Alkylcarbonyl, optionally substituted C_3-8Cycloalkyl, optionally substituted 3-8 membered heterocyclyl and optionally substituted benzyl.

The compound of claim 1, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

R₁selected from:wherein the content of the first and second substances,

Y₁selected from the group consisting of CR₄' and N; wherein R is₄' is selected from H, D, hydroxy, F, Cl, cyano, methyl, ethyl, methyl substituted with 1-3 fluorines, and ethyl substituted with 1-3 fluorines;

R₄selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted C_3-4Cycloalkyl, optionally substituted benzyl, optionally substituted pyridylmethylene and optionally substituted C_3-4A cycloalkylmethylene group; for R₄Preferably, the substituents are one or more substituents independently selected from halogen, C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkyl, halo C_1-4Alkoxy, methanesulfonyl, and-CN;

Y₂selected from C, O and N; n represents 1 or 2, and R₅Each independently selected from H and optionally substituted C_1-3An alkyl group;

ring a is selected from an optionally substituted benzene ring, an optionally substituted pyridine, an optionally substituted pyrrole, an optionally substituted furan, and an optionally substituted thiophene;

ring B is selected from optionally substituted benzene rings, and optionally substituted pyridines;

for the case of substitution in the a and B rings, it is preferred that the substituents are one or more, for example one or two, independently selected from the following groups: halogen, carboxyl, C_1-8Alkyl, halo C_1-8Alkyl, cyano, -C (O) NR_aR_b、-OR_dUnsubstituted or 1-3C_1-3Alkyl-substituted 5-to 10-membered heterocyclyl C_1-3Alkylene radical, C_1-3Alkylene radical NR_aR_bUnsubstituted or 1-3C_1-3Alkyl-substituted 5-10 membered heteroarylcarbonyl, -NR_aR_b、-S(O)₂C_1-6Alkyl, -N (R)_a)S(O)₂R_b、-N(R_a)C(O)R_band-C (O) OC_1-8Alkyl radical, wherein R_aAnd R_bEach independently selected from hydrogen and C_1-8Alkyl and halo C_1-8An alkyl group; r_dIs H, C_6-10Aryl radical, C_1-8Alkyl, halo C_1-8Alkyl, -NR_aR_bSubstituted C_1-8Alkyl, hydroxy substituted C_1-8Alkyl or C_1-3Alkoxy-substituted C_1-8An alkyl group;

R₇and R₇' independently from each other selected from H, D, CN, C_1-3Alkyl and halo C_1-3An alkyl group;

R₂selected from H, D, C_1-2Alkyl and C substituted by 1-3 fluorine_1-2An alkyl group;

R₃and R₃' each is independently selected from H, D, and optionally substituted C_1-6Alkyl (e.g. C)_1-3Alkyl), preferably each independently selected from H, D, methyl, and ethyl, and R₃And R₃' at least one is not H;

X₁selected from the group consisting of CR_6aAnd N;

X₂selected from the group consisting of CR_6bAnd N;

X₃selected from the group consisting of CR_6cAnd N, and X₁、X₂And X₃At most two are N;

X₄selected from NR₈And O;

R_6a、R_6band CR_6cEach independently selected from H, D, F, Cl, methyl and methyl substituted with 1-3 fluorines;

R₈selected from H, D, oxygen, hydroxy, optionally substituted C_1-4Alkyl, optionally substituted C_1-6Alkanoyl, optionally substituted C_3-6Cycloalkyl, optionally substituted 3-6 membered heterocyclic group containing oxygen or nitrogen as heteroatom, optionally substituted C_3-6Cycloalkylmethylene, optionally substituted benzyl, and optionally substituted pyridylmethylene; for R₈In the case of (A) preferred substituents are one or more, for example 1-3, substituents independently selected from-OH, halogen (e.g. F, Cl, Br and I), CN and C_1-6Alkoxy (e.g. C)_1-2Alkoxy) groups.

The compound of claim 1, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

R₁selected from:

Y₁selected from the group consisting of CR₄' and N; wherein R is₄' is selected from H, D and hydroxy;

R₄selected from optionally substituted phenyl, optionally substituted pyridyl and optionally substituted benzyl for R₄Preferably, the substituents are one or more substituents independently selected from F, Cl, C_1-2Alkyl, C substituted by 1-3 fluoro_1-2Alkyl and-CN groups;

R₉selected from the group consisting of fluoro, chloro, carboxy, methyl, methoxy, fluoromethyl and fluoromethoxy, and m is R₉M is 0, 1 or 2;

R₂selected from methyl, ethyl, -CHF₂、-CH₂F and-CF₃；

R₃and R₃' each is independently selected from H, D, methyl, and ethyl, and R₃And R₃' at least one is not H;

X₁is N;

X₂is CR_6bOr N;

X₃is CR_6c；

X₄Is NR₈Or O;

R_6band R_6cEach independently selected from H and F;

R₈selected from H, D, oxygen, hydroxyl, methyl, ethyl, propyl such as isopropyl, hydroxyethyl, acetyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, furyl, pyranyl, tetrahydropyranyl, cyclopropanemethylene, benzyl and pyridylmethylene for R₈Preferably, the substituents are one or more substituents independently selected from halogen (e.g., F, Cl, Br and I), CN and C_1-6Alkoxy groups such as methoxy groups.

A compound according to the preceding claim, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof,

R₁selected from:

Y₁selected from the group consisting of CR₄' and N; wherein R is₄' is selected from H, D, hydroxy, F, Cl, cyano, methyl, ethyl, methyl substituted with 1-3 fluorines, and ethyl substituted with 1-3 fluorines;

R₄selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted C_3-4Cycloalkyl, optionally substituted benzyl, optionally substituted pyridylmethylene and optionally substituted C_3-4A cycloalkylmethylene group; for R₄Preferably, the substituents are one or more substituents independently selected from halogen, C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkyl, halo C_1-4Alkoxy, methanesulfonyl, and-CN;

Y₂selected from C, O and N; n represents 1 or 2, and R₅Each independently selected from H and optionally substituted C_1-3An alkyl group;

ring a is selected from an optionally substituted benzene ring, an optionally substituted pyridine, an optionally substituted pyrrole, an optionally substituted furan, and an optionally substituted thiophene;

ring B is selected from optionally substituted benzene rings, and optionally substituted pyridines;

for the case of substitution in the a and B rings, it is preferred that the substituents are one or more, for example one or two, independently selected from the following groups: halogen, carboxyl, C_1-8Alkyl, halo C_1-8Alkyl, -C₁-C₆alkyl-OH, C_1-8Alkylthio, cyano, -C (O) NR_aR_b、-OR_dUnsubstituted or 1-3C_1-3Alkyl-substituted 5-to 10-membered heterocyclyl C_1-3Alkylene radical, C_1-3Alkylene radical NR_aR_bUnsubstituted or 1-3C_1-3Alkyl-substituted 5-10 membered heteroarylcarbonyl, -NR_aR_b、-S(O)₂C_1-6Alkyl, -S (O) C_1-6Alkyl, -N (R)_a)S(O)₂R_b、-N(R_a)C(O)R_band-C (O) OC_1-8Alkyl radical, wherein R_aAnd R_bEach independently selected from hydrogen and C_1-8Alkyl, halo C_1-8Alkyl and C_3-8Cycloalkyl, or R_aAnd R_bTogether form an optionally substituted C_1-4Alkyl substituted C_3-8A heterocyclic group; r_dIs H, C_6-10Aryl radical, C_1-8Alkyl, halo C_1-8Alkyl, -NR_aR_bSubstituted C_1-8Alkyl, hydroxy substituted C_1-8Alkyl or C_1-3Alkoxy-substituted C_1-8An alkyl group;

R₇and R₇' independently from each other selected from H, D, CN, C_1-3Alkyl and halo C_1-3An alkyl group;

R₂selected from H, D, C_1-2Alkyl, C substituted by one or more deuterium_1-3Alkyl, C substituted by 1-3 fluoro_1-2An alkyl group;

R₃and R₃' each is independently selected from H, D and optionally substituted C_1-6Alkyl (e.g. C)_1-3Alkyl), preferably each independently selected from H, D, methyl and ethyl, and R₃And R₃' at least one is not H;

X₁selected from the group consisting of CR_6aAnd N;

X₂selected from the group consisting of CR_6bAnd N;

X₃selected from the group consisting of CR_6cAnd N, and X₁、X₂And X₃At most two are N;

X₄selected from NR₈And O;

R_6a、R_6band CR_6cEach independently selected from H, D, F, Cl, methyl and methyl substituted with 1-3 fluorines;

R₈selected from H, D, oxygen, hydroxy, optionally substituted C_1-4Alkyl, optionally substituted C_1-6Alkanoyl, optionally substituted C_3-6Cycloalkyl, optionally substituted 3-6 membered heterocyclic group containing oxygen or nitrogen as heteroatom, optionally substituted C_3-6Cycloalkylmethylene, optionally substituted benzyl, and optionally substituted pyridylmethylene; for R₈In the case of (A) preferred substituents are one or more, for example 1-3, substituents independently selected from-OH, halogen (e.g. F, Cl, Br and I), CN, C_1-6Alkyl and C_1-6Alkoxy (e.g. C)_1-2Alkoxy) groups.

A compound according to the preceding claim, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof,

R₁selected from:

Y₁selected from the group consisting of CR₄' and N; wherein R is₄' is selected from H, D, hydroxy, F, Cl, cyano, methyl, ethyl, methyl substituted with 1-3 fluorines, and ethyl substituted with 1-3 fluorines;

R₄selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted C_3-4Cycloalkyl, optionally substituted benzyl, optionally substituted pyridylmethylene and optionally substituted C_3-4A cycloalkylmethylene group; for R₄Preferably, the substituents are one or more substituents independently selected from halogen, C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkyl, halo C_1-4Alkoxy, methanesulfonyl, and-CN;

Y₂selected from C, O and N; n represents 1 or 2, and R₅Each independently selected from H and optionally substituted C_1-3An alkyl group;

ring a is selected from an optionally substituted benzene ring, an optionally substituted pyridine, an optionally substituted pyrrole, an optionally substituted furan, and an optionally substituted thiophene;

ring B is selected from optionally substituted benzene rings, and optionally substituted pyridines;

for the case of substitution in the a and B rings, it is preferred that the substituents are one or more, for example one or two, independently selected from the following groups: halogen, carboxyl, C_1-8Alkyl, halo C_1-8Alkyl, -C₁-C₆alkyl-OH, cyano, -C (O) NR_aR_b、-OR_dUnsubstituted or 1-3C_1-3Alkyl-substituted 5-to 10-membered heterocyclyl C_1-3Alkylene radical, C_1-3Alkylene radical NR_aR_bUnsubstituted or 1-3C_1-3Alkyl-substituted 5-10 membered heteroarylcarbonyl, -NR_aR_b、-S(O)₂C_1-6Alkyl, -S (O) C_1-6Alkyl, -N (R)_a)S(O)₂R_b、-N(R_a)C(O)R_band-C (O) OC_1-8Alkyl radical, wherein R_aAnd R_bEach independently selected from hydrogen and C_1-8Alkyl, halo C_1-8An alkyl group; r_dIs H, C_6-10Aryl radical, C_1-8Alkyl, halo C_1-8Alkyl, -NR_aR_bSubstituted C_1-8Alkyl, hydroxy substituted C_1-8Alkyl or C_1-3Alkoxy-substituted C_1-8An alkyl group;

R₇and R₇' independently from each other selected from H, D, CN, C_1-3Alkyl and halo C_1-3An alkyl group;

R₂selected from H, D, C_1-2Alkyl, C substituted by one or more deuterium_1-3Alkyl, C substituted by 1-3 fluoro_1-2An alkyl group;

R₃and R₃' each is independently selected from H, D and optionally substituted C_1-6Alkyl (e.g. C)_1-3Alkyl), preferably each independently selected from H, D, methyl and ethyl, and R₃And R₃' at least one is not H;

X₁selected from the group consisting of CR_6aAnd N;

X₂selected from the group consisting of CR_6bAnd N;

X₃selected from the group consisting of CR_6cAnd N, and X₁、X₂And X₃At most two are N;

X₄selected from NR₈And O;

R_6a、R_6band CR_6cEach independently selected from H, D, F, Cl, methyl and methyl substituted with 1-3 fluorines;

R₈selected from H, D, oxygen, hydroxy, optionally substituted C_1-4Alkyl, optionally substituted C_1-6Alkanoyl, optionally substituted C_3-6Cycloalkyl, optionally substituted 3-6 membered heterocyclic group containing oxygen or nitrogen as heteroatom, optionally substituted C_3-6Cycloalkylmethylene, optionally substituted benzyl, and optionally substituted pyridylmethylene;for R₈In the case of (A) preferred substituents are one or more, for example 1-3, substituents independently selected from-OH, halogen (e.g. F, Cl, Br and I), CN, C_1-6Alkyl and C_1-6Alkoxy (e.g. C)_1-2Alkoxy) groups.

A compound according to the preceding claim, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein:

formula (I) is:

preferably, R₃And R₃' each is independently selected from H, D, and optionally substituted C_1-6Alkyl (e.g. C)_1-3Alkyl), and R₃And R₃At least one of is not H;

preferably, R₃And R₃' each is independently selected from H, D, and C optionally substituted with one, two or more halogens (e.g., F, Cl, Br, and I)_1-3Alkyl (e.g., methyl, ethyl), and R₃And R₃At least one of is not H;

further preferably, R₃Is methyl or ethyl, and R₃' is H; more preferably, R₃Is methyl, and R₃' is H.

A compound selected from the examples or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a compound of any one of claims 1-13, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

Use of a compound according to any one of claims 1 to 13, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of diseases associated with bromodomain protein mediation or a product for use as a bromodomain protein inhibitor.

Use according to claim 15, wherein diseases associated with bromodomain protein mediation include cancers such as hematological malignancies, midline cancers, inflammatory diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, radiation intoxication, acute rejection of transplanted organs or multiple organ dysfunction syndrome and alzheimer's disease.

A method of non-therapeutically inhibiting the activity of a bromodomain protein, the method comprising contacting an effective amount of a compound of any one of claims 1-13, or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, with the bromodomain protein, thereby inhibiting the bromodomain protein.