CN109111426B - Fused bicyclic heteroaryl or aryl compound and application thereof - Google Patents

Fused bicyclic heteroaryl or aryl compound and application thereof Download PDF

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CN109111426B
CN109111426B CN201710486439.3A CN201710486439A CN109111426B CN 109111426 B CN109111426 B CN 109111426B CN 201710486439 A CN201710486439 A CN 201710486439A CN 109111426 B CN109111426 B CN 109111426B
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amino
alkyl
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CN109111426A (en
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罗成
姚志艺
郑明月
谢轶谦
张元元
邢婧
乔刚
梅良和
蒋昊
蒋华良
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Suzhou Suplead Life Sciences Co ltd
Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention provides a compound shown as the following general formula (I), or pharmaceutically acceptable salts, isomers, racemates, crystal hydrates, solvates or mixtures thereof, a pharmaceutical composition containing the compound, and application of the compound in preparing a medicament for treating BRD 4-related diseases.

Description

Fused bicyclic heteroaryl or aryl compound and application thereof
Technical Field
The invention belongs to the technical field of medicines. In particular to a fused bicyclic heteroaryl or aryl compound or pharmaceutically acceptable salt thereof, or isomer, racemate, crystal hydrate, solvate or mixture thereof, a pharmaceutical composition containing the same, and application thereof in preparing medicaments for treating BRD 4-related diseases.
Background
In recent years, bromine-containing structural protein 4 (BRD4) is found to be closely related to heart failure, and BRD4 inhibitors relieve the symptoms of myocardial cell hypertrophy by reducing the expression of excessive hypertrophy genes, which provides a new direction for developing medicaments for treating heart failure. In addition, BRD4 has been identified as a target for a variety of cancers (including NUT-midline carcinoma, multiple myeloma, acute lymphoid leukemia, etc.) by a major mechanism that, in midline carcinoma, chromosomal translocation leads to the formation of BRD4 protein fused with NUT, causing the cells to develop dysdifferentiation and malignant proliferation, thereby causing the development of the associated cancer. In c-myc dependent tumors, BRD4 recognizes acetylated lysines on histones, initiating transcription of downstream c-myc, leading to related cancers.
Cardiac hypertrophy, which includes primary myocardial hypertrophy and compensatory myocardial hypertrophy to resist high load caused by other factors (such as hypertension, etc.), is a major cause of heart failure. The patient has symptoms of edema, incapability of lying down and the like, and the life quality is seriously influenced. Heart failure often occurs in the middle-aged and elderly people, but in recent years, many young people have symptoms of heart failure due to high pressure on life. The current treatment is to increase myocardial contractility using cardiotonic drugs, but such drugs have problems of narrow therapeutic window or poor selectivity, and neglect the treatment of hypertrophic cardiomyocytes. 8-hydroxyquinoline can be used as a new treatment for heart failure by inhibiting BRD4, relieving myocardial hypertrophy and reducing heart load by being matched with other medicines.
NUT-midline carcinoma (NUT-midline carcinoma) is a rare, highly invasive and high mortality malignancy, occurring well in children, young adults, and usually less than a year from the discovery to death. The pathogenesis is that the fusion of testicular nuclear protein (NUT) and BRD4 protein is caused by chromosome ectopy, so that BRD4 loses a PID structural domain combined with a transcription factor and cannot activate transcription, cell differentiation cannot be completed, and further the cancer is evolved. NUT-midline carcinoma currently has no specific effective drug, which poses a serious threat to the patient's life.
In addition, BRD4 has been identified as a target for many cancers associated with c-myc overexpression, including acute lymphoblastic leukemia, mixed lineage leukemia, multiple myeloma, Burkitt's lymphoma, hepatocellular carcinoma, triple negative breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, neuroblastoma, etc., and there are currently no specific therapeutic guidelines or current drugs that are highly toxic and relapse. Therefore, development of anticancer drugs having a new parent nucleus structure is required.
Disclosure of Invention
An object of the present invention is to provide a fused bicyclic heteroaryl or aryl compound, or a pharmaceutically acceptable salt, isomer, racemate, crystalline hydrate, solvate or mixture thereof.
It is still another object of the present invention to provide a pharmaceutical composition comprising the fused bicyclic heteroaryl or aryl compound, or a pharmaceutically acceptable salt, isomer, racemate, crystalline hydrate, solvate or mixture thereof, as an effective ingredient, and a pharmaceutically acceptable carrier.
It is still another object of the present invention to provide a use of the fused bicyclic heteroaryl or aryl compound, or a pharmaceutically acceptable salt, isomer, racemate, crystal hydrate, solvate or mixture thereof for the manufacture of a medicament for treating BRD 4-related diseases. The compounds target bromodomain protein (BRD4), and can be used for preventing or treating cardiovascular diseases or tumors.
It is a further object of the present invention to provide the use of the fused bicyclic heteroaryl or aryl compound, or a pharmaceutically acceptable salt, isomer, racemate, crystal hydrate, solvate or mixture thereof for the treatment of BRD 4-related diseases.
The inventor finds that a compound with a structure shown as a general formula (I) has the effect of inhibiting the activity of BRD4 and can be used for preparing a medicament for treating or preventing mammal diseases related to BRD4 through long-term and intensive research. Based on the above findings, the inventors have completed the present invention.
According to one aspect of the present invention, there is provided a compound represented by the general formula (I), or a pharmaceutically acceptable salt, isomer, racemate, crystalline hydrate, solvate or mixture thereof:
Figure BDA0001330584580000021
wherein the content of the first and second substances,
w is N, O or S, W is,
x is C or N;
Figure BDA0001330584580000022
is an aromatic heterocycle;
when W is O or S, R1Is absent;
when W is N, R1Is absent or R1Selected from H, C1-C10 alkyl, C1-C10 alkoxy, preferably R1Is absent or R1Selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy or propoxy;
R2selected from:
H；
an oxo group;
unsubstituted or hydroxy-substituted C1-C10An alkyl group;
C1-C10an alkoxy group;
halogen;
a nitro group;
a cyano group;
C1-C10an acyl group;
C1-C10alkoxy radical C1-C10An alkanoyl group;
a sulfonic acid group;
substituted or unsubstituted 5-to 8-membered aryl, wherein the substituents in the substituted 5-to 8-membered aryl are selected from the group consisting of halogen, oxo, amino, hydroxy, C1-C10Alkyl or C1-C10One or more (preferably one to three) of alkoxy groups;
substituted or unsubstituted 3-to 8-membered cycloalkyl, wherein the substituents in the substituted 3-to 8-membered cycloalkyl are selected from the group consisting of halogen, amino, hydroxy, C1-C10Alkyl or C1-C10One or more (preferably one to three) of alkoxy groups;
substituted or unsubstituted amino, wherein the substituents in the substituted amino are selected from one or more of the following groups: halogen, C1-C10Alkyl radical, C1-C10Alkanoyl radical, C1-C10Alkoxy, hydroxy, C1-C10Alkylsulfonyl radicals, unsubstituted or selected from C1-C10Alkoxy radical, C1-C105-to 8-membered aryl substituted by one or more (preferably one to three) groups selected from alkyl, halogen, amino, hydroxy, nitro or oxo, unsubstituted or substituted by C1-C10Alkoxy radical, C1-C105-to 8-membered aryl C substituted with one or more (preferably one to three) of alkyl, halogen, amino, hydroxy, nitro or oxo groups1-C10Alkyl, unsubstituted or selected from C1-C10Alkoxy radical, C1-C105-to 8-membered heteroaryl, unsubstituted or substituted by one or more (preferably one to three) groups selected from alkyl, halogen, amino, hydroxy, nitro or oxo1-C10Alkoxy radical, C1-C105-to 8-membered heteroaryl C substituted with one or more (preferably one to three) of alkyl, halogen, amino, hydroxy, nitro or oxo groups1-C10An alkyl group;
substituted or unsubstituted 5-to 8-membered heteroaryl, wherein the substituents in the substituted 5-to 8-membered heteroaryl are selected from halogen, amino, hydroxy, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups;
substituted or unsubstituted 5 to 8 membered heteroaryl C1-C10Alkyl, wherein, substituted 5 to 8 membered heteroaryl C1-C10The substituent in the alkyl is selected from halogen, amino, hydroxyl, nitro, cyano and C1-C10Alkyl or C1-C10One or more of alkoxy groups;
substituted or unsubstituted 5-to 8-membered aryl, wherein the substituents in the substituted 5-to 8-membered aryl are selected from halogen, amino, hydroxy, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups;
substituted or unsubstituted 5 to 8 membered aryl C1-C10Alkyl, wherein, substituted 5-to 8-membered aryl C1-C10The substituent in the alkyl is selected from halogen, amino, hydroxyl, nitro, cyano and C1-C10Alkyl or C1-C10One or more of alkoxy groups;
substituted or unsubstituted 5 to 8 membered aryl C2-C10Alkenyl, wherein, substituted 5-to 8-membered aryl C2-C10The substituent in the alkenyl group is selected from halogen, oxo, amino, hydroxyl, nitro, cyano, C1-C10Alkyl or C1-C10One or more (preferably one to three) of alkoxy groups;
Figure BDA0001330584580000031
wherein Y is O, S or NH,
R9comprises the following steps: h; a hydroxyl group; an amino group; c1-C10An alkylamino group; substituted or unsubstituted C1-C10Alkyl, wherein, substituted C1-C10The substituent in the alkyl is selected from amino, hydroxyl, sulfydryl or C1-C10One to three of alkylthio groups; substituted or unsubstituted C1-C10Alkoxy, in which there is substituted C1-C10The substituent in the alkoxy is selected from amino, hydroxyl, sulfydryl or C1-C10An alkylthio group; substituted or unsubstituted 5-to 8-membered heteroaryl, wherein the substituents in the substituted 5-to 8-membered heteroaryl are selected from halogen, amino, hydroxy, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups; substituted or unsubstituted 5 to 8 membered heteroaryl C1-C10Alkyl, wherein, substituted 5 to 8 membered heteroaryl C1-C10The substituent in the alkyl is selected from halogen, amino, hydroxyl, nitro, cyano and C1-C10Alkyl or C1-C10One or more of alkoxy groups; substituted or unsubstituted 5-to 8-membered aryl, wherein the substituents in the substituted 5-to 8-membered aryl are selected from halogen, amino, hydroxy, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups; substituted or unsubstituted 5 to 8 membered aryl C1-C10Alkyl, wherein, substituted 5-to 8-membered aryl C1-C10The substituent in the alkyl is selected from halogen, amino, hydroxyl, nitro, cyano and C1-C10Alkyl or C1-C10One or more of alkoxy groups; substituted or unsubstituted 5 to 8 membered aryl C2-C10Alkenyl, wherein, substituted 5-to 8-membered aryl C2-C10The substituents in the alkenyl radical being selected fromFrom halogen, amino, hydroxy, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups;
preferably, R2Selected from: oxo, H, methyl, ethyl, propyl, butyl, fluoro, chloro, bromo, iodo, formyl (-CHO), acetyl, propionyl, butyryl, -SO3H. Methoxy formyl group, ethoxy formyl group, butoxy formyl group, propoxy formyl group, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, hydroxybutyl group, phenyl group, amino group, carboxamide group, acetamide group, propionamido group, butyrylamino group, methylamino group, dimethylamino group, ethylamino group, methylethylamino group, propylamino group, butylamino group, methylsulfonylamino group, ethylsulfonamide group, propylsulfonamide group, butylsulfonamide group, substituted amino group,
Figure BDA0001330584580000041
or R1、R2And together with the atoms to which they are attached form an imidazole ring;
R3selected from: h; a nitro group; an amino group; a hydroxyl group; c1-C10An alkyl group; c1-C10An alkoxy group; hydroxy radical C1-C10An alkyl group; amino group C1-C10An alkyl group; amino group C1-C10An acyl group; substituted or unsubstituted 5 to 8 membered heteroaryl (preferably 5 to 6 membered heteroaryl), wherein the substituents in the substituted 5 to 8 membered heteroaryl (preferably 5 to 6 membered heteroaryl) are selected from halogen, amino, hydroxy, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups; substituted or unsubstituted 5-to 8-membered aryl, wherein the substituents in the substituted 5-to 8-membered aryl are selected from the group consisting of halogen, amino, hydroxy, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups;
preferably, R3Selected from H, nitro, amino, hydroxymethyl, hydroxyethyl, hydroxypropyl, aminomethyl, aminoethyl, aminopropylAn aminobutyl group,
Figure BDA0001330584580000042
Carbamoyl, aminoacetyl or aminobutyryl;
R4selected from: h; an oxo group; c1-C10An alkyl group; c1-C10An alkoxy group; substituted or unsubstituted 5 to 8 membered heteroaryl (preferably 5 to 6 membered heteroaryl), wherein the substituents in the substituted 5 to 8 membered heteroaryl (preferably 5 to 6 membered heteroaryl) are selected from halogen, amino, hydroxy, oxo, nitro, cyano, C1-C10Alkyl or C1-C10One or more (preferably one, two or three) of alkoxy groups; substituted or unsubstituted 5 to 8 membered heteroaryl C1-C10Alkyl (preferably 5-to 6-membered heteroaryl C)1-C10Alkyl), wherein, substituted 5 to 8 membered heteroaryl C1-C10Alkyl (preferably 5-to 6-membered heteroaryl C)1-C10Alkyl) is selected from the group consisting of halogen, amino, hydroxy, oxo, nitro, cyano, C1-C10Alkyl or C1-C10One or more (preferably one, two or three) of alkoxy groups; substituted or unsubstituted 5-to 8-membered aryl, wherein the substituents in the substituted 5-to 8-membered aryl are selected from the group consisting of halogen, amino, hydroxy, oxo, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups; a substituted or unsubstituted 3 to 8-membered saturated heterocyclic group, wherein the substituent in the substituted 3 to 8-membered saturated heterocyclic group is selected from the group consisting of halogen, amino, hydroxy, oxo, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups; hydroxy radical C1-C10An alkoxy group; c1-C10Alkoxy radical C1-C10An alkoxy group; a substituted or unsubstituted 3 to 8-membered saturated heterocyclyloxy group, wherein the substituents in the substituted 3 to 8-membered saturated heterocyclyloxy group are selected from halogen, amino, hydroxy, oxo, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups; substituted or unsubstituted amino group or substituted or unsubstituted amino group C1-C10Alkyl, wherein, substituted amino or substituted amino C1-C10The substituents in the alkyl group are selected from halogen, amino, hydroxy C1-C10Alkyl, oxo, nitro, cyano, C1-C10Alkyl radical, C1-C10Alkoxy, substituted or unsubstituted 3 to 8 membered cycloalkyl, substituted or unsubstituted 5 to 8 membered heteroaryl (preferably 5 to 6 membered heteroaryl), substituted or unsubstituted 5 to 8 membered heteroaryl C1-C10Alkyl (preferably 5-to 6-membered heteroaryl C)1-C10Alkyl radicals),
Figure BDA0001330584580000051
Figure BDA0001330584580000052
Wherein, substituted 3-to 8-membered cycloalkyl, substituted 5-to 8-membered heteroaryl (preferably 5-to 6-membered heteroaryl), and substituted 5-to 8-membered heteroaryl C1-C10Alkyl (preferably 5-to 6-membered heteroaryl C)1-C10Alkyl) is selected from the group consisting of halogen, amino, hydroxy, oxo, nitro, cyano, C1-C10Alkyl or C1-C10One or more of alkoxy groups;
preferably, R4Selected from H, oxo (═ O),
Figure BDA0001330584580000053
Figure BDA0001330584580000054
R5To R8Are each the same or different and are each independently selected from:
H；
halogen;
a hydroxyl group;
a nitro group;
a mercapto group;
C1-C10an alkylthio group;
a trifluoromethyl group;
a trifluoroethyl group;
a cyano group;
a substituted or unsubstituted 3-to 8-membered saturated heterocyclic group, wherein the substituent in the substituted 3-to 8-membered saturated heterocyclic group is selected from the group consisting of amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, or halogen;
substituted or unsubstituted 5-to 8-membered aryl, wherein the substituents in the substituted 5-to 8-membered aryl are selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, or halogen;
substituted or unsubstituted 5-to 8-membered heteroaryl (preferably 5-to 6-membered heteroaryl), wherein the substituents in the substituted 5-to 8-membered heteroaryl (preferably 5-to 6-membered heteroaryl) are selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, or halogen;
-NR10R12；
-NCOR13；
substituted or unsubstituted C1-C10Alkyl, wherein, substituted C1-C10Substituents in the alkyl group are selected from: a hydroxyl group; a nitro group; a cyano group; an amino group; a trifluoromethyl group; a trifluoroethyl group; a mercapto group; c1-C10An alkoxy group; c1-C10An alkylamino group; c1-C10An alkylamino amide group;an amino amide group; -NR10R12；
Figure BDA0001330584580000061
Figure BDA0001330584580000062
Figure BDA0001330584580000063
Unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, tert-butoxycarbonyl substituted tetrahydropyrrolyl, aminosulfonyl, halogen and C1-C105-to 8-membered heteroaryl substituted with one or more substituents in alkoxyformyl; unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, tert-butoxycarbonyl substituted tetrahydropyrrolyl, aminosulfonyl, halogen and C1-C10A 5-to 8-membered aryl group substituted with one or more substituents in an alkoxyformyl group;
amino group C1-C10An acyl group;
C1-C10alkylamino radical C1-C10An acyl group;
-OCOR14；
substituted or unsubstituted C1-C10Alkoxy, in which there is substituted C1-C10The substituent in the alkoxy is selected from hydroxyl, amino and C1-C10One or more of alkoxy, cyano, trifluoromethyl, trifluoroethyl, mercapto, a 3-to 8-membered saturated heterocyclyl, and halogen;
substituted or unsubstituted3-to 8-membered cycloalkyl, wherein the substituents in the substituted 3-to 8-membered cycloalkyl are selected from the group consisting of hydroxy, amino, C1-C10Alkoxy radical, C1-C10One or more of alkyl, hydroxy, cyano, trifluoromethyl, trifluoroethyl, mercapto, and halogen;
-OR15,R15selected from substituted or unsubstituted 3-to 8-membered cycloalkyl or substituted or unsubstituted 3-to 8-membered saturated heterocyclic group, wherein the substituent in the substituted 3-to 8-membered cycloalkyl or substituted 3-to 8-membered saturated heterocyclic group is selected from hydroxy, amino, C1-C10Alkoxy radical, C1-C10One or more of alkyl, cyano, trifluoromethyl, trifluoroethyl, mercapto, halogen; substituted or unsubstituted 3 to 8 membered cycloalkyl C1-C10Alkyl, wherein, substituted 3 to 8 membered cycloalkyl C1-C10The substituents in the alkyl group are selected from hydroxy, amino, C1-C10Alkoxy radical, C1-C10One or more of alkyl, hydroxy, cyano, trifluoromethyl, trifluoroethyl, mercapto, and halogen;
substituted or unsubstituted 3-to 8-membered saturated heterocyclyl C1-C10Alkyl, wherein, substituted 3 to 8-membered saturated heterocyclic group C1-C10The substituents in the alkyl group are selected from hydroxy, amino, C1-C10Alkoxy radical, C1-C10One or more of alkyl, hydroxy, cyano, trifluoromethyl, trifluoroethyl, mercapto, and halogen;
preferably, R5To R8Are each the same or different and are each independently selected from: h; fluorine; chlorine; bromine; iodine; a hydroxyl group; an amino group; a nitro group; a methyl group; an ethyl group; propyl; a butyl group; a methoxy group; an ethoxy group; a propoxy group; butoxy group; c1-C10An alkyl group; c1-C10An alkoxy group;
Figure BDA0001330584580000064
methoxybenzene; ethoxybenzene; propoxybenzene;
Figure BDA0001330584580000065
Figure BDA0001330584580000066
-NHMe；
Figure BDA0001330584580000067
Figure BDA0001330584580000071
R10and R12The same or different, each independently selected from H; a hydroxyl group; a nitro group; a cyano group; a trifluoromethyl group; a trifluoroethyl group; a mercapto group; hydroxy radical C1-C10An alkyl group; c1-C10An alkyl group; c1-C10An alkoxy group; c1-C10Alkoxy radical C1-C10An alkyl group; c1-C10Alkylamino radical C1-C10An alkyl group; unsubstituted or selected from C1-C10Alkyl substituted
Figure BDA0001330584580000072
Quilt
Figure BDA0001330584580000073
Substituted C1-C10An alkyl group; unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, halogen and C1-C105-to 8-membered heteroaryl substituted with one or more substituents in alkoxyformyl; unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, halogen and C1-C10Alkoxy formyl radical5-to 8-membered heteroaryl C substituted with one or more substituents of (1)1-C10An alkyl group; unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, halogen and C1-C105-to 8-membered aryl C substituted with one or more substituents of alkoxyformyl1-C10An alkyl group; or unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, aminosulfonyl, halogen and C1-C10A 5-to 8-membered aryl group substituted with one or more substituents in an alkoxyformyl group;
wherein R is11Represents one or more substituents and is each independently selected from H, halogen, hydroxy, oxo, nitro, amino, tert-butyloxycarbonyl, C1-C10Alkyl radical, C1-C10Alkoxy, trifluoromethyl, tert-butoxycarbonyl substituted tetrahydropyrrolyl or aminosulfonyl;
R13is selected from H; a hydroxyl group; a nitro group; a cyano group; a trifluoromethyl group; a trifluoroethyl group; a mercapto group; hydroxy radical C1-C10An alkyl group; c1-C10An alkyl group; c1-C10An alkoxy group; c1-C10Alkoxy radical C1-C10An alkyl group; c1-C10Alkylamino radical C1-C10An alkyl group; c2-C10An alkenyl group; unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, halogen and C1-C105-to 8-membered heteroaryl substituted with one or more substituents in alkoxyformyl; unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, halogen and C1-C105-to 8-membered heteroaryl C substituted with one or more substituents in alkoxyformyl1-C10An alkyl group; unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, halogen and C1-C105-to 8-membered heteroaryl C substituted with one or more substituents in alkoxyformyl2-C10An alkenyl group; unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, halogen and C1-C105-to 8-membered aryl C substituted with one or more substituents of alkoxyformyl1-C10An alkyl group; unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, halogen and C1-C10A 5-to 8-membered aryl group substituted with one or more substituents in an alkoxyformyl group; or unsubstituted or selected from amino, amino C1-C10Alkyl, amino C1-C10Alkoxy, hydroxy, nitro, cyanoRadical, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10Alkoxy, halogen and C1-C105-to 8-membered aryl C substituted with one or more substituents of alkoxyformyl2-C10An alkenyl group;
R14is selected from C1-C10Alkyl radical, C1-C10Alkoxy, or by a radical selected from amino, amino C1-C10Alkoxy, hydroxy, nitro, cyano, trifluoromethyl, trifluoroethyl, mercapto, hydroxy C1-C10Alkyl radical, C1-C10Alkyl radical, C1-C10C substituted by one or more substituents selected from alkoxy, t-butoxycarbonyl-substituted tetrahydropyrrolyl, aminosulfonyl and halogen1-C10An alkyl group.
Preferably, the compound represented by the general formula (I) has a structure selected from the group consisting of those represented by the general formulae (I-1) to (I-5):
Figure BDA0001330584580000081
wherein R is1To R8The substituents are as defined above.
Still further preferably, the compound has the structure:
Figure BDA0001330584580000082
Figure BDA0001330584580000091
Figure BDA0001330584580000101
Figure BDA0001330584580000111
Figure BDA0001330584580000121
Figure BDA0001330584580000131
definition of terms
Wherein, in the present specification,
halogen means fluorine, chlorine, bromine or iodine;
C1-C10alkyl means a straight or linear alkyl group having 1 to 10 carbon atoms, preferably, C1-C6Alkyl radical, C1-C10Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, octyl;
C1-C10alkoxy means a straight or branched chain alkoxy group having 1 to 10 carbon atoms, preferably, C1-C6Alkoxy radical, C1-C10Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, pentoxy, octoxy;
C2-C10alkenyl means a straight-chain or branched alkenyl group having 2 to 10 carbon atoms and having at least one carbon-carbon double bond, preferably, C2-C6An alkenyl group; c2-C10Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, octenyl;
C1-C10acyl means a straight or branched chain acyl group having 1 to 10 carbon atoms and a terminal group of carbonyl, preferably, C1-C6Acyl radical, C1-C10Examples of acyl groups include, but are not limited to, formyl, acetylPropionyl, butyryl, valeryl, octanoyl;
the 3-to 8-membered cycloalkyl group is a 3-to 8-membered saturated cycloalkyl group, and examples thereof include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane;
in the present invention, the heterocyclic group includes a 3-to 8-membered saturated heterocyclic group (preferably a 3-to 8-membered, 5-membered, 6-membered saturated heterocyclic group) which is a 3-to 8-membered saturated heterocyclic group containing one or more heteroatoms (including 1,2,3 or 4) selected from N, O and S, examples of which include, but are not limited to, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, tetrahydropyrazolyl, tetrahydroimidazolyl, tetrahydrobitriazolyl, tetrahydro 1,2, 4-triazolyl, tetrahydro 1,2, 5-triazolyl, tetrahydro 1,3, 4-triazolyl, tetrahydro 1,2,3, 4-tetrazolyl, tetrahydro 1,2,3, 5-tetrazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, tetrahydroisothiazolyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, hexahydropyridazinyl, hexahydropyrimidyl, Morpholinyl, hexahydropyrazinyl, piperidinyl, hexahydrotriazinyl, tetrahydrooxazinyl;
examples of 5-to 8-membered aryl groups include, but are not limited to, benzene;
in the present invention, heteroaryl includes 5 to 8-membered heteroaryl (preferably 5 to 6-membered heteroaryl), which is 5 to 8-membered heteroaryl (preferably 5 to 6-membered heteroaryl) containing one or more heteroatoms (including 1,2,3 or 4) selected from N, O and S, examples of which include, but are not limited to, furyl, thienyl, pyrazolyl, imidazolyl, bitriazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, 1,2,3, 4-tetrazolyl, 1,2,3, 5-tetrazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyranyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl.
In the present invention, one or more may include 1,2,3 or 4.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound represented by the general formula (I), or a pharmaceutically acceptable salt, isomer, racemate, crystalline hydrate, solvate or mixture thereof, as an active ingredient, and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers refer to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0001330584580000141
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
Because the compound has excellent inhibitory activity on BRD4, the compound and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating, preventing and relieving diseases related to BRD 4. According to the prior art, the compounds of the invention are useful for the treatment of the following diseases: cardiovascular diseases and cancer, etc.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 5 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
According to a further aspect of the present invention, there is provided a use of a compound represented by the general formula (I), or a pharmaceutically acceptable salt or isomer, racemate, crystal hydrate, solvate thereof, for the manufacture of a medicament for the treatment of BRD 4-related diseases.
The BRD 4-related diseases include, but are not limited to, heart failure, cardiovascular disease, NUT-midline cancer, acute lympholeukemia, mixed lineage leukemia, multiple myeloma, Burkitt's lymphoma, hepatocellular carcinoma, triple negative breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, neuroblastoma, lymphoma, kidney tumor, retinoblastoma, osteosarcoma and chondrosarcoma, posterior fossa medulloblastoma, nasopharyngeal carcinoma, thyroid papillary carcinoma, thymoma, pulmonioma, pancreatoma, islet cell tumor of pancreas, ileocecal carcinoma or mesothelioma, and the like, wherein the heart failure includes myocardial hypertrophy disease and myocardial hypertrophy disease.
Still another object of the present invention is to provide a use of the compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or an isomer, a racemate, a crystalline hydrate, a solvate, or a mixture thereof, for treating BRD 4-related diseases, comprising administering a therapeutically effective amount of the compound represented by the general formula (I), or a pharmaceutically acceptable salt, isomer, racemate, crystalline hydrate, solvate, or a mixture thereof.
In the present invention, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.
In the present invention, the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The precise effective amount for a subject will depend upon the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation and can be determined by a clinician.
Unless otherwise specified, all occurrences of a compound in the present invention are intended to include all possible optical isomers, such as a single chiral compound, or a mixture of various chiral compounds (i.e., a racemate). In all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
As used herein, the term "compounds of the invention" refers to compounds of formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
The NMR spectra were recorded on a Bruker AMX-400, Gemini-300 or AMX-600 NMR spectrometer with the chemical shift delta in ppm. All solvents were analytical grade reagents. The color is developed by methods of iodine, ultraviolet fluorescence and the like. The organic solvent was distilled off under reduced pressure in a rotary evaporator. The starting reactants used in the present invention are not specifically described and are all commercially available.
It should be noted that in the following examples, the conventional post-treatment method is: after the reaction is completed, adding proper amounts of organic solvent and water into the reaction solution, separating organic phase and aqueous phase, combining organic phase, and using NaSO4Drying, filtering, rotary steaming under reduced pressure to obtain crude product, and separating and purifying by column chromatography to obtain final product.
Preparation examples:
example 1: preparation of Compound 1 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000171
Step (i) Compound a (500mg,1eq) was dissolved in 5mL of dichloromethane, imidazole (182mg, 1.2eq) and DIEA (483mg, 1.5eq) were added, and the reaction was refluxed overnight. After the TLC detection reaction, the solvent column chromatography was evaporated to dryness to obtain compound b (compound 1) (271 mg).
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.78(dd,J＝7.5,1.4Hz,1H),7.65(dd,J＝7.5,1.4Hz,1H),7.53(td,J＝7.5,1.5Hz,1H),7.46(d,J＝7.5Hz,1H),7.32(td,J＝7.5,1.5Hz,1H),7.14(d,J＝7.5Hz,1H),6.92(s,1H).
Example 2: preparation of Compound 2 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000172
Step (i) Compound a (500mg,1eq) was dissolved in 5mL of dichloromethane, imidazole (115mg, 1.2eq) and DIEA (305mg, 1.5eq) were added, and the reaction was refluxed overnight. After the TLC detection reaction, the solvent column chromatography was evaporated to dryness to obtain compound b (157 mg).
Step (ii) Compound b (157mg, 1eq) was dissolved in THF (5mL), TBAF (132mg, 1.1eq) was added, and the reaction was heated to 50 ℃ for 1h and checked by TLC for completion. The solvent was evaporated to dryness, and the residue was slurried with methanol and water and filtered to give compound c (compound 2) (35 mg).
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.46(d,J＝15.0Hz,1H),7.36(t,J＝14.9Hz,1H),7.25–7.08(m,3H),6.91(s,1H),5.03(s,1H).
The synthesis methods of the compounds shown in the following table were the same as the preparation methods of compound 1 or compound 2, except that the substrate a was different.
Figure BDA0001330584580000173
Figure BDA0001330584580000181
Figure BDA0001330584580000191
Figure BDA0001330584580000201
Example 3: preparation of Compound 3 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000202
Step (i) Compound a (500mg,1eq) was dissolved in 10mL of 1, 4-dioxane solution, isoxazole-4-boronic acid (239mg, 1.5eq) and potassium carbonate (390mg, 2eq) were added, nitrogen gas was replaced, palladium tetratriphenylphosphine (81mg, 0.05eq) was added, and the mixture was refluxed for 6 hours. After the TLC detection reaction, the solvent was evaporated to dryness and the column chromatography was carried out to obtain compound b (259 mg).
Step (ii) Compound b (259mg) was dissolved in THF (10mL), TBAF (217mg, 1.1eq) was added, the reaction was heated to 50 ℃ for 1h, and the reaction was complete by TLC. The solvent was evaporated to dryness, and the residue was slurried with methanol and water and filtered to give compound c (compound 3) (63 mg).
1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.36(t,J＝14.9Hz,1H),7.21(dd,J＝15.0,3.1Hz,1H),7.12(dd,J＝14.7,3.2Hz,1H),6.69(s,1H),5.04(s,1H).
Example 4: preparation of Compound 39 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000211
Step (i): compound a (500mg,1eq) was dissolved in 10mL of 1, 4-dioxane, imidazole (161mg, 1.2eq) and cesium carbonate (962mg, 1.5eq) were added, nitrogen was replaced, Pd2(dba)3(90mg, 0.05eq) and Xantphos (114mg, 0.1eq) were added, and the mixture was reacted at 110 ℃ for 12 hours. After the reaction, the solvent was evaporated to dryness and column chromatography was carried out to obtain compound b (230 mg).
Step (ii): compound b (230mg, 1eq) was dissolved in 5mL of dichloromethane, and boron tribromide (716mg, 3eq) was added dropwise under ice-bath, and the reaction was carried out for 8 hours after completion of dropwise addition. After the TLC detection reaction, the mixture is poured into ice water, extracted by dichloromethane, washed by saturated sodium bicarbonate, dried and evaporated to dryness, and subjected to column chromatography to obtain a compound c (a compound 4) (33 mg).
1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),8.09(s,1H),7.88(d,J＝15.0Hz,2H),7.44(d,J＝15.0Hz,2H),7.30–7.23(m,2H),7.15(s,2H),7.01(d,J＝15.0Hz,2H),6.49(s,1H),6.44(s,1H),5.07(s,2H).
The following table shows the same method for producing the compound as that of the compound 39, except that the compound a was different.
Figure BDA0001330584580000212
Figure BDA0001330584580000221
Example 5: preparation of Compound 49 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000222
Step (i): compound a (500mg,1eq), imidazole (115mg, 1.2eq) and cesium carbonate (690mg, 1.5eq) were dissolved in 15mL of toluene, and after nitrogen gas was replaced, palladium acetate (15.8mg, 0.05eq) and BINAP (88mg, 0.1eq) were added, followed by reflux reaction for 24 hours. After the reaction, the solvent was evaporated to dryness and column chromatography was performed to obtain the objective compound b (157 mg).
Step (ii) Compound b (157mg, 1eq) was dissolved in THF (6mL), TBAF (132mg, 1.1eq) was added and heated to 50 ℃ for 1h, and the reaction was checked by TLC to completion. The solvent was evaporated to dryness, and the residue was slurried with methanol and water and filtered to give compound c (compound 49) (35 mg).
1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),9.26(s,1H),7.74(d,J＝15.0Hz,2H),7.27(d,J＝15.0Hz,2H),7.19–7.06(m,6H),6.86(d,J＝15.0Hz,2H),4.14(s,2H).
The following table shows the same method for preparing the compound as compound 49, except that compound a was different.
Figure BDA0001330584580000223
Figure BDA0001330584580000231
Example 6: preparation of Compound 60 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000232
In step (i), compound a (1g, 1eq) was dissolved in 10mL of a 33% hydrobromic acid acetic acid solution in ice bath, and after dropwise addition of bromine (844mg, 1.1eq), the reaction was carried out overnight at room temperature. After the reaction, the mixture is poured into ice water, washed by saturated sodium bicarbonate/saturated sodium bisulfite, extracted by ethyl acetate, and the organic layer is dried, evaporated and subjected to column chromatography to obtain a target compound b (193 mg).
Step (ii) Compound b (193mg, 1eq) was dissolved in 5mL of dichloromethane and imidazole (55mg, 1.2eq) and DIEA (174mg, 2eq) were added to reflux for 24 h. After the reaction, the solvent was evaporated to dryness and column chromatography was performed to obtain the objective compound c (131 mg).
Step (iii) Compound c (131mg, 1eq) was dissolved in 5mL of dichloromethane, and boron tribromide (359mg, 3eq) was added under ice-bath and reacted for 6h in ice-bath. After the reaction, the mixture was poured into ice water, washed with saturated sodium bicarbonate, extracted with ethyl acetate, and the organic layer was dried, evaporated to dryness, and subjected to column chromatography to obtain the objective compound d (compound 60) (25 mg).
1H NMR(400MHz,DMSO-d6)δ8.93(s,2H),8.12(s,1H),7.45(dd,J＝15.0,0.6Hz,1H),7.12(dd,J＝15.0,0.6Hz,1H),7.05(dd,J＝15.9,2.9Hz,1H),6.82(dd,J＝15.9,2.9Hz,1H),4.25(s,1H).
Example 7: preparation of Compound 63 (see scheme for reaction)
Figure BDA0001330584580000241
In step (i), compound a (1g, 1eq) was dissolved in 10mL of a 33% hydrobromic acid acetic acid solution in ice bath, and after dropwise addition of bromine (844mg, 1.1eq), the reaction was carried out overnight at room temperature. After the reaction, the mixture is poured into ice water, washed by saturated sodium bicarbonate/saturated sodium bisulfite, extracted by ethyl acetate, and the organic layer is dried, evaporated and subjected to column chromatography to obtain a target compound b (193 mg).
In step (ii), compound b (193mg, 1eq), 3, 5-dimethylisoxazole-4-boronic acid (142mg, 1.4eq) and potassium carbonate (186mg, 2eq) were dissolved in 8mL of a 1, 4-dioxane solution, and after replacement of nitrogen gas, palladium tetratriphenylphosphine (39mg, 0.05eq) was added to the solution, followed by reaction at 110 ℃ for 12 hours. After the reaction, the solvent was evaporated to dryness and column chromatography was performed to give the objective compound c (119 mg).
Step (iii) Compound c (119mg, 1eq) was dissolved in 5mL of dichloromethane, and boron tribromide (295mg, 3eq) was added to the solution in ice bath to react for 3h in ice bath. After the reaction, the mixture was poured into ice water, washed with saturated sodium bicarbonate, extracted with ethyl acetate, and the organic layer was dried, evaporated to dryness, and subjected to column chromatography to obtain the objective compound d (compound 63) (45 mg).
1H NMR(400MHz,DMSO-d6)δ8.78(s,2H),7.05(dd,J＝16.0,3.0Hz,1H),6.82(dd,J＝15.9,2.9Hz,1H),4.79(s,1H),2.59(s,3H),2.43(s,3H).
The following table shows the same method for the preparation of the compound as compound 63, except that the substrate a was different.
Figure BDA0001330584580000242
Figure BDA0001330584580000251
Example 8: preparation of Compound 81 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000252
Step (i): dissolving the compound a (1.5g, 1.0eq) and imidazole (1.2eq) in DMF (10mL), adding sodium hydride (1.2eq) in batches in an ice-water bath, slowly raising the temperature to room temperature after the addition is finished, and reacting overnight until the reaction is complete. Quenching with water, extracting with EA twice, washing the organic phase with saturated saline solution 4 times, drying, concentrating, and purifying by column chromatography to obtain compound b (1.02 mg).
Step (ii): compound b (500mg, 1.0eq) and p-methoxybenzylamine (4.0eq) were dissolved in DMSO (5mL) and heated to 95 ℃ for reaction overnight. The reaction was complete by TLC. Cooling, adding water for quenching, extracting twice with EA, combining the EA phases, washing 3 times with saturated saline, drying, concentrating, and purifying by column chromatography to obtain compound c (477 mg).
Step (iii): dissolving the compound c (477mg, 1.0eq) in 33% HBr in HOAc solution, heating at 95 ℃, extracting with EA to obtain saturated sodium bicarbonate, washing, drying, and evaporating to obtain crude product, and performing column chromatography to obtain compound d (compound 81) (213 mg).
1H NMR(400MHz,DMSO-d6)δ8.47(dd,J＝14.9,3.0Hz,1H),8.10(d,J＝15.0Hz,1H),7.38(t,J＝14.9Hz,1H),7.27(dd,J＝15.0,0.6Hz,1H),7.15(s,1H),7.08(dd,J＝15.0,2.9Hz,1H),6.64(s,1H),1.97(s,2H).
The following table shows the preparation of the compounds and the preparation of compound 81, except for the substrate a.
Figure BDA0001330584580000261
Figure BDA0001330584580000271
Example 9: preparation of Compound 99 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000272
Step (i): dissolving the compound a (1.2g, 1.0eq) and imidazole (1.2eq) in DMF (10mL), adding sodium hydride (1.2eq) in batches in an ice-water bath, slowly raising the temperature to room temperature after the addition is finished, and reacting overnight until the reaction is complete. Quenched with water, extracted twice with EA, and the organic phase washed 4 times with saturated brine, dried, concentrated, and purified by column chromatography to give compound b (674 mg).
Step (ii): compound b (674mg, 1.0eq) and p-methoxybenzylamine (4.0eq) were dissolved in DMSO (5mL) and heated to 95 ℃ overnight. The reaction was complete by TLC. Cooling, adding water for quenching, extracting twice with EA, combining EA phases, washing 3 times with saturated saline, drying, concentrating, and purifying by column chromatography to obtain compound c (650 mg).
Step (iii): dissolving the compound c (500mg, 1.0eq) in 33% HBr in HOAc solution, heating at 95 ℃, extracting with EA to obtain saturated sodium bicarbonate, washing, drying, and evaporating to obtain crude product, and performing column chromatography to obtain compound d (compound 99) (330 mg).
1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.06(s,1H),7.63(s,1H),7.21(s,1H),6.89(d,J＝10.6Hz,2H),6.62(s,2H),6.52(d,J＝10.0Hz,1H).
Example 10: preparation of Compound 100 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000281
Step (i): compound a (145mg, 1.0eq) was dissolved in THF (5mL), TBAF (1.1eq) was added, the mixture was heated to 50 ℃ for 1h, and the reaction was complete by TLC. And (3) post-treatment: concentration, the residue slurried with methanol and water and filtered to give b (compound 100) as an off-white solid (35 mg).
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.75(s,1H),8.30(s,1H),8.10(s,1H),7.67(s,1H),7.37(d,J＝6.3Hz,1H),7.25(s,1H),7.17(d,J＝10.4Hz,1H),7.06(s,1H),2.18(s,3H).
The following table shows the same method for producing the compound 99 or the compound 100, except that the substrates were different.
Figure BDA0001330584580000282
Figure BDA0001330584580000291
Figure BDA0001330584580000301
Figure BDA0001330584580000311
Figure BDA0001330584580000321
Figure BDA0001330584580000331
Figure BDA0001330584580000341
Figure BDA0001330584580000351
Example 11: preparation of Compound 204 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000361
Step (i): compound a (237mg,1eq.), 2-aminoimidazole (100mg,2eq.), Pd2(dba)3(50mg,0.1eq.), Xphos (51mg,0.2eq.) and potassium carbonate (240mg,3eq.) were dissolved in t-butanol (10mL), refluxed at 90 ℃ for 7h, TLC monitored for completion of the reaction of the starting materials, and subjected to solvent column chromatography by evaporation to obtain the target product b (147 mg).
Step (ii): compound b (116mg,1eq.) and tetrabutylammonium fluoride (70mg,1eq.) in THF (10mL) were stirred at 50 ℃ for 4h to complete the reaction, and Pre-HPLC isolated to give the desired product c (compound 204) (20 mg).
1H NMR(400MHz,cd3od)δ8.56(s,1H),7.90(s,1H),7.53(d,J＝30.0Hz,2H),7.29(d,J＝15.0Hz,2H),2.32(s,3H).
The following table shows the same method for the preparation of the compounds as the compound 204, except that the substrates were different.
Figure BDA0001330584580000362
Figure BDA0001330584580000371
Example 12: preparation of Compound 178 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000372
Step (i): compound a (240mg,1eq.),3, 5-dimethylisoxazole-4-boronic acid (110mg,1.5eq.), Pd2(dba)3(46mg,0.1eq.), Xphos (47mg,0.2eq.) and potassium carbonate (210mg,3eq.) were dissolved in t-butanol (10mL), refluxed at 90 ℃ for 7h and monitored by TLC for completion of the starting material reaction. Column chromatography to obtain target product b (170 mg).
Step (ii): the compound b (170mg,0.32mmol), TBAF (79mg,0.3mmol) in 5mL THF,50 ℃ stirring for 3h after the raw materials completely react, removing the solvent, adding ammonium chloride saturated solution, stirring for 1h, filtering, washing with water, EA slurry, filtering and drying to obtain yellow solid c (compound 178)45 mg.
1H NMR(400MHz,MeOD)δ8.21(s,1H),7.38(t,J＝8.0Hz,1H),7.15(d,J＝6.8Hz,1H),7.04(d,J＝9.2Hz,1H),2.34(s,3H),2.28(s,3H),2.16(s,3H).
The following table shows the preparation of the compounds in the same manner as compound 178, except that the substrates were different.
Figure BDA0001330584580000373
Example 13: preparation of Compound 226 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000374
Step (i): compound a (1g, 1eq) was dissolved in 10mL of DMF solution, imidazole (275mg, 1.5eq) was added, and after nitrogen substitution, cuprous iodide (154mg, 0.3eq) and N, N-dimethylethanolamine (144mg, 0.6eq) were added and reacted at 150 ℃ for 6 hours. After the reaction, water quenching, ethyl acetate extraction, drying the organic layer to dryness and column chromatography to obtain the target compound b (476 mg).
Step (ii): compound b (476mg, 1eq) was dissolved in 10mL of methanol, and 10% palladium on carbon (50mg) was added to replace hydrogen and reacted for 3 hours. After the reaction, the reaction mixture was filtered through celite, and the filtrate was evaporated to dryness and subjected to column chromatography to obtain the objective compound c (319 mg).
Step (iii): compound c (319mg, 1eq) was dissolved in 10mL of ethanol/water (v: v ═ 1: 1), and potassium carbonate (4eq) was added to the solution to conduct a reflux reaction for 12 hours. After the reaction, dichloromethane was extracted, and the organic layer was dried to dryness and column chromatography was performed to give the objective compound d (compound 226) (97 mg).
The following table shows the preparation of the compounds, except for the reaction substrates, and the preparation of compound 226.
Figure BDA0001330584580000381
Example 14: preparation of Compound 236 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000391
Step (i) Compound a (378mg, 1eq) was dissolved in 10mL of 1, 4-dioxane solution, isoxazole-4-boronic acid (239mg, 1.5eq) and potassium carbonate (390mg, 2eq) were added, nitrogen gas was replaced, palladium tetratriphenylphosphine (81mg, 0.05eq) was added, and the mixture was refluxed for 6 hours. After the TLC detection reaction, the solvent was evaporated to dryness and the column chromatography was carried out to obtain compound b (259 mg).
Step (ii) Compound b (259mg) was dissolved in methanolic hydrochloric acid and heated to 50 ℃ for 1h, and the reaction was complete by TLC. The extract was washed with saturated sodium bicarbonate, extracted with ethyl acetate, and the organic layer was dried to dryness and subjected to column chromatography to give compound c (compound 236) (159 mg).
1H NMR(400MHz,DMSO-d6)δ8.95(dd,J＝7.4,1.5Hz,1H),8.09(dd,J＝7.5,1.4Hz,1H),8.04(s,1H),7.69(d,J＝7.5Hz,1H),7.36(t,J＝7.5Hz,1H),6.94(d,J＝7.5Hz,1H),6.78(s,1H).
Example 15: preparation of Compound 237 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000392
Step (i) imidazole (343mg, 3eq) was dissolved in anhydrous DMF (10ml) and 60% NaH (168mg,2.5eq) was added and stirred at room temperature for 5 min. Then, Compound a (500mg,1eq) was added and stirred at room temperature for 1 h. The reaction solution was slowly poured into ice water, extracted with EA, the organic phase was washed 4 times with water, washed with brine, dried and concentrated to give crude product b which was used directly in the next step.
In step (ii), Compound b (200mg) was dissolved in 10mL of a methanol solution of hydrochloric acid, and the reaction was completed at 50 ℃ for 1 hour. Washing with saturated sodium bicarbonate solution, extracting with ethyl acetate, drying the organic layer, evaporating, and performing column chromatography to obtain target compound c (compound 237) (96 mg).
1H NMR(400MHz,DMSO-d6)δ8.88(dd,J＝15.0,2.9Hz,1H),8.54(dd,J＝15.0,2.9Hz,1H),7.74(s,1H),7.60(t,J＝15.0Hz,1H),7.38(d,J＝15.0Hz,1H),7.09(dd,J＝23.3,7.9Hz,2H),6.86(d,J＝15.0Hz,1H),6.54(s,1H),5.57(s,2H).
The following table shows the same method for preparing the compound as the compound 237 except that the reaction substrates were different.
Figure BDA0001330584580000393
Figure BDA0001330584580000401
Figure BDA0001330584580000411
Example 16: preparation of Compound 255 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000412
Step (i): compound a (500mg,1eq) was dissolved in 16mL of 1, 4-dioxane solution, 2-chlorothiazole (286mg, 1.2eq) and sodium tert-butoxide (383mg, 2eq) were added, nitrogen was replaced, Pd2(dba)3(92mg, 0.05eq) and BINAP (125mg, 0.1eq) were added, and reaction was carried out at 110 ℃ for 12 hours. After the reaction, the solvent was evaporated to dryness and column chromatography was carried out to obtain compound b (258 mg).
Step (ii): compound b (258mg, 1eq) was dissolved in 10mL of a 33% hydrobromic acid acetic acid solution and reacted at 90 ℃ for 5 hours. After the reaction, the reaction mixture was quenched with saturated sodium bicarbonate, and the organic layer was extracted with ethyl acetate, dried, evaporated to dryness, and subjected to column chromatography to obtain the objective compound c (compound 255) (55 mg).
1H NMR(400MHz,DMSO-d6)δ9.01–8.86(m,2H),8.19(dd,J＝15.0,2.9Hz,1H),7.91(d,J＝15.0Hz,1H),7.34(d,J＝15.0Hz,1H),7.21(d,J＝15.0Hz,1H),6.75(dd,J＝39.7,15.0Hz,2H),6.59(s,1H).
The following table shows the same preparation method of the compound as that of the compound 255 except that the reaction substrates were different.
Figure BDA0001330584580000421
Figure BDA0001330584580000431
Example 17: preparation of Compound 181 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000432
Step (i) imidazole (0.36g, 3eq) was dissolved in anhydrous DMF (10ml) and 60% NaH (2.5eq) was added and stirred at room temperature for 5 min. Then, the raw material a is added, and the mixture is stirred for 1 hour at room temperature. The reaction solution was slowly poured into ice water, extracted with EA, the organic phase was washed 4 times with water, washed with brine, dried and concentrated to give crude product b which was used directly in the next step.
In step (ii), crude product b was dissolved in ethanol (10 ml)/water (10ml), and K was weighed2CO3(4eq), the reaction was refluxed at 80 ℃ overnight. And cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water, extracting with DCM, washing an organic phase with water, washing with brine, drying, concentrating, and purifying and separating a crude product by column chromatography to obtain a target product c of 250 mg.
Step (iii): feed c (250mg) was dissolved in saturated HCl (g)/MeOH (10ml) and stirred at room temperature for 3 h. The precipitated solid was filtered, and the residue was dissolved in 10mL of an ammonia-methanol solution, stirred for 30min, and the solvent was evaporated to dryness to give a solid, which was washed with water/methanol to give the desired compound d (compound 181) (92 mg).
1HNMR(400MHz,CD3OD)δ9.16(s,1H),8.17(s,1H),7.52-7.80(m,2H),7.40-7.49(m,2H),7.25-7.27(d,J＝8.0Hz,1H),6.04(s,2H).
The preparation methods of the compounds 182-201 shown in the following table are the same as the preparation method of the compound 181, except that the substrates a are different.
Figure BDA0001330584580000433
Figure BDA0001330584580000441
Figure BDA0001330584580000451
Example 18: preparation of Compound 186 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000452
Step (i): acetylacetone (4.0eq) was dissolved in DMF (10ml), 60% NaH (2.5eq) was added at-10 ℃ and stirred at room temperature for 10min, raw material (400mg) was added and the reaction was stirred at room temperature for 1 h-TLC showed little reaction, warmed to 55 ℃ and stirred for 1 h-TLC showed complete reaction, the reaction solution was poured slowly into ice water, EA extracted, the organic phase washed with water, brine washed, dried, concentrated to give crude product, which was used directly in the next step.
Step (ii): dissolving the crude product of the previous step in ethanol (20ml), adding hydroxylamine hydrochloride (2.0eq) at room temperature, reacting at 80 ℃ under reflux for 1 hour, TLC shows that a new spot is generated, pouring the reaction solution into ice water, EA extracting, washing an organic phase, washing with brine, drying, concentrating, and carrying out column chromatography on the crude product to obtain a target product (300 mg);
step (iii): the starting material (300mg) was dissolved in saturated HCl (g)/MeOH solution (20ml), the reaction mixture was stirred at room temperature for 1 hour, then warmed to 8 ℃ for reaction for 2 hours, TLC showed substantial completion of the reaction, the reaction mixture was poured into ice water, the pH was adjusted to slightly alkaline with saturated sodium bicarbonate, the solid precipitated was filtered by suction, washed with water and ether for 3 times, and dried to give product d (compound 186) (200 mg).
1HNMR(CD3OD)7.87(br,1H)，7.57-7.59(br,1H),7.40-7.42(br,1H),7.11-7.12(br,1H),4.20(s,2H),2.31(s,3H),2.18(s,3H),2.11(s,3H).
Example 19: preparation of Compound 221 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000453
Step (i): dissolving the compound a (500mg, 1.0eq) and imidazole (2eq) in DMF (10mL), adding sodium hydride (2.2eq) in batches in an ice-water bath, slowly raising the temperature to room temperature after the addition is finished, and reacting overnight until the reaction is complete. Quenching with water, extracting with EA twice, washing the organic phase with saturated saline solution 4 times, drying, concentrating, and purifying by column chromatography to obtain compound b (325 mg).
Step (ii): dissolving the compound b (300mg, 1.0eq) in 1, 4-dioxane hydrochloric acid solution, reacting at room temperature for 2 hours, filtering after the reaction is finished, washing filter residue with saturated sodium bicarbonate solution, filtering again, and washing filter residue with methanol/water to obtain a compound c (compound 221) (170 mg).
1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.08(s,1H),8.53(s,1H),8.24(s,2H),7.80(s,1H),7.53(t,J＝8.1Hz,1H),7.26(ddd,J＝10.7,9.3,3.5Hz,3H),7.20(s,1H).
The preparation methods of the compounds 222-225 and 221 shown in the following table are the same as the preparation method of the compound 221, except that the substrates a are different.
Figure BDA0001330584580000461
Example 20: preparation of Compound 284 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000462
Step (i): compound a (140mg,1.0eq) was dissolved in ethanol, 40% chloroacetaldehyde (2.0eq) and sodium bicarbonate (2.5eq) were added, and the reaction was heated to reflux for 30 min. TLC showed complete reaction, the reaction was directly concentrated and purified by column chromatography to give compound b (120 mg).
Step (ii): compound b (120mg,1.0eq) was dispersed in methanol hydrochloride solution (20mL) and stirred at room temperature overnight. After the reaction, the mixture was concentrated, dissolved in water, adjusted to weak alkaline with an aqueous solution of sodium hydrogencarbonate, and a solid was precipitated, filtered, and the filter cake was dried to obtain compound c (compound 284) (80 mg).
1HNMR(400MHz,DMSO-d6)br,1H),8.98(s,1H),7.85(s,1H),7.48-7.53(m,2H),7.37(t,J＝8.0Hz,1H),7.23-7.28(m,2H),7.08(s,1H),6.97(s,1H),5.59(s,2H).
The compounds shown in the following table were prepared in the same manner as compound 284, except that the reaction substrate a was different.
Figure BDA0001330584580000471
Figure BDA0001330584580000481
Example 21: preparation of Compound 283 (see scheme shown in the following reaction scheme)
Figure BDA0001330584580000482
Step (i): compound a (230mg,1.0eq) was dissolved in 2mL of anhydrous tetrahydrofuran at-78 deg.C, added dropwise to 6mL of anhydrous tetrahydrofuran over lithium aluminum hydride (84mg, 3eq), and reacted for 2 h. TLC shows that the reaction is finished, saturated ammonium chloride solution is quenched, and the organic layer is extracted by ethyl acetate, dried, evaporated and subjected to column chromatography to obtain compound b (compound 283) (47 mg).
1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.33(d,J＝15.0Hz,1H),7.94(dd,J＝15.0,3.1Hz,1H),7.73(s,1H),7.64(t,J＝15.0Hz,1H),7.27(dd,J＝15.0,0.6Hz,1H),7.15(s,1H),6.75(dd,J＝14.9,3.0Hz,1H),5.33(s,1H),4.95(s,2H),3.26(s,1H).
Compound in vitro BRD4 inhibitory Activity assay
Molecular level experiments:
a prokaryotic expression system is constructed to express and purify BRD4 protein containing a BD1 structural domain, a screening platform is established by utilizing an amplified chemiluminescence affinity homogeneous detection (ALPHA) technology, the 5-position, 8-position, 12-position and 16-position acetylation modified H4 polypeptide is used as a substrate, the screening platform targeting the BRD4_ BD1 structural domain is successfully established, and the inhibitory activity of the compound is screened and verified. Specifically, 2.5. mu.l of the compound was incubated with 2.5. mu.l of BRD4_ BD1 protein for 10min in 20. mu.l of alpha Screen reaction at room temperature, and 5. mu.l of acetylated H was added4And (3) polypeptide incubation is carried out for 10min, 10 mul of mixed solution of donor microbeads and acceptor microbeads is added, incubation is carried out for 60min, and data are read by an Envision microplate reader.
Cell level experiments:
two AML leukemia cell strains MV4.11 and THP1 are cell models, and IC of the compound on inhibition of cell proliferation of the two strains is examined50.. 10% fetal bovine serum was added using 1640 medium. After cell counting, the cells were seeded at 104/100 ul per well in 96-well plates, while compound treatment was given, with a concentration gradient starting at 100 μ M, diluted in a two-fold gradient. Changes in cell proliferation were detected by the alrma blue method 72 hours after administration. The cell viability was plotted on the ordinate against the drug concentration and the IC of the compound on the inhibition of proliferation of both cell lines was calculated50. The cell survival rate (%) calculation method was: the survival rate (%) (administration well OD-blank well OD)/(control well OD-blank well OD) × 100. The results show that the compound effectively inhibits the proliferation of leukemia cells.
TABLE 1 determination of BRD4 inhibition Activity (IC)50Means +++<0.1 μ M; , + ++ represents 0.1-1. mu.M; , + represents 1-10. mu.M; + represents>10 mu M; -indicates no activity)
Figure BDA0001330584580000491
Figure BDA0001330584580000501
Figure BDA0001330584580000511
It should be noted that the above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the technical solutions of the present invention, and any equivalent replacement or modification should be considered to be included in the scope of the present invention.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (8)

1. A compound of formula (I-4), or a pharmaceutically acceptable salt thereof, or a mixture thereof:
Figure FDA0003295179220000011
wherein the content of the first and second substances,
R2selected from:
substituted or unsubstituted amino, wherein the substituents in the substituted amino are selected from one or more of the following groups: c1-C10Alkyl radical, C1-C10Alkylsulfonyl radicals, by C1-C10Alkoxy-substituted 5-to 8-membered aryl C1-C10An alkyl group;
alternatively, the substituted amino group may also be substituted with
Figure FDA0003295179220000012
It is shown that,
wherein Y is O, S or NH,
R9comprises the following steps: an amino group; c1-C10An alkylamino group; substituted or unsubstituted C1-C10An alkyl group, wherein,substituted C1-C10The substituents in the alkyl group being selected from amino, hydroxy or C1-C10One to three of alkylthio groups; unsubstituted C1-C10An alkoxy group;
R3is H;
R4selected from:
Figure FDA0003295179220000013
R5to R7Are each the same or different and are each independently selected from:
H；
halogen;
a hydroxyl group;
a nitro group;
a mercapto group;
a trifluoromethyl group;
a trifluoroethyl group;
a cyano group;
an unsubstituted 3-to 8-membered saturated heterocyclic group;
a substituted or unsubstituted 5-to 8-membered aryl group, wherein the substituents in the substituted 5-to 8-membered aryl group are selected from C1-C10An alkoxy group;
a substituted or unsubstituted 5-to 8-membered heteroaryl group, wherein the substituent in the substituted 5-to 8-membered heteroaryl group is C1-C10An alkyl group;
-NR10R12wherein R is10And R12The same or different, each independently selected from H; c1-C10An alkyl group; c1-C10Alkoxy radical C1-C10An alkyl group; c1-C10Alkylamino radical C1-C10An alkyl group;
substituted or unsubstituted C1-C10Alkyl, wherein, substituted C1-C10Substituents in the alkyl group are selected from: a hydroxyl group; an amino group; a trifluoromethyl group; a trifluoroethyl group; c1-C10An alkylamino amide group;
Figure FDA0003295179220000021
amino group C1-C10An acyl group;
substituted or unsubstituted C1-C10Alkoxy, in which there is substituted C1-C10The substituent in the alkoxy is selected from hydroxyl, amino and C1-C10One or more of alkoxy, 3-to 8-membered saturated heterocyclyl;
-OR15,R15a substituent selected from a substituted or unsubstituted 3-to 8-membered cycloalkyl group or a substituted or unsubstituted 3-to 8-membered saturated heterocyclic group, wherein the substituent in the substituted 3-to 8-membered cycloalkyl group or the substituted 3-to 8-membered saturated heterocyclic group is a hydroxyl group;
R8is a hydroxyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a mixture thereof,
R2selected from: amino group, carboxamide group, acetamide group, propionamido group, butyrylamino group, methylamino group, dimethylamino group, ethylamino group, methylethylamino group, propylamino group, butylamino group, methylsulfonylamino group, ethylsulfonamido group, propylsulfonamido group, butylsulfonamido group, a salt thereof, a hydrate thereof, a pharmaceutical composition comprising the same, and a pharmaceutical composition comprising the same,
Figure FDA0003295179220000022
Figure FDA0003295179220000023
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a mixture thereof,
R5to R7Are each the same or different and are each independently selected from: h; fluorine; chlorine; bromine; iodine; a hydroxyl group; an amino group; a nitro group; a methyl group; an ethyl group; propyl; a butyl group; a methoxy group; an ethoxy group; a propoxy group; butoxy group;
Figure FDA0003295179220000024
methoxybenzene; ethoxybenzene; propoxybenzene;
Figure FDA0003295179220000025
Figure FDA0003295179220000026
4. a compound, or a pharmaceutically acceptable salt thereof, or a mixture thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003295179220000027
Figure FDA0003295179220000031
Figure FDA0003295179220000041
5. a pharmaceutical composition comprising a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a mixture thereof, as an active ingredient, and a pharmaceutically acceptable carrier.
6. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a pharmaceutical composition according to claim 5, in the manufacture of a medicament for the treatment of a disease associated with BRD 4.
7. The use of claim 6, wherein the BRD 4-associated disease is selected from heart failure, cardiovascular disease, NUT-midline cancer, multiple myeloma, Burkitt's lymphoma, hepatocellular carcinoma, triple negative breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, and neuroblastoma, lymphoma, renal tumors, retinoblastoma, osteosarcoma and chondrosarcoma, posterior fossa medulloblastoma, nasopharyngeal carcinoma, thyroid papillary carcinoma, thymoma, pulmonioma, pancreatoblastoma, islet cell tumor of pancreas, ileocecal carcinoid or mesothelioma.
8. Use according to claim 7, wherein the heart failure is selected from the group consisting of myocardial hypertrophy diseases and cardiomyocyte hypertrophy diseases.
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