CN108314680A - One kind containing aromatic compound, preparation method, pharmaceutical composition and application - Google Patents
One kind containing aromatic compound, preparation method, pharmaceutical composition and application Download PDFInfo
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- CN108314680A CN108314680A CN201710033493.2A CN201710033493A CN108314680A CN 108314680 A CN108314680 A CN 108314680A CN 201710033493 A CN201710033493 A CN 201710033493A CN 108314680 A CN108314680 A CN 108314680A
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- 0 *C(CC1)CCC1(F)F Chemical compound *C(CC1)CCC1(F)F 0.000 description 12
- NREVSGJEGOSDHG-JWGURIENSA-N C/C(/N=C)=C(\c1ccc2[N-][N+](C)(C(C3CCOCC3)c3ccccn3)c2c1)/N(C)N Chemical compound C/C(/N=C)=C(\c1ccc2[N-][N+](C)(C(C3CCOCC3)c3ccccn3)c2c1)/N(C)N NREVSGJEGOSDHG-JWGURIENSA-N 0.000 description 1
- JYSIBLXSYMTNJT-UHFFFAOYSA-N CC(C(C)=C1C)=CNC1=[O]1=CC1 Chemical compound CC(C(C)=C1C)=CNC1=[O]1=CC1 JYSIBLXSYMTNJT-UHFFFAOYSA-N 0.000 description 1
- SASAUXCMNOUPRC-UHFFFAOYSA-N CC1C(Br)=C2N=CN(C(C(CCOC)C=C)C3C=CC=CC3)C2=CC1c1c(C)nn[n]1C Chemical compound CC1C(Br)=C2N=CN(C(C(CCOC)C=C)C3C=CC=CC3)C2=CC1c1c(C)nn[n]1C SASAUXCMNOUPRC-UHFFFAOYSA-N 0.000 description 1
- VWYLATDGUBBMAQ-CNKRIOBRSA-N CC1N=C([C@H](CCC2c3cc(-c4c(C)[o]nc4C)ccc3N=C2)Cc2ccc(C)cc2)C=CC1 Chemical compound CC1N=C([C@H](CCC2c3cc(-c4c(C)[o]nc4C)ccc3N=C2)Cc2ccc(C)cc2)C=CC1 VWYLATDGUBBMAQ-CNKRIOBRSA-N 0.000 description 1
- ZANLKOHMZDJCFV-HJWRWDBZSA-N CCCCC/N=N\CC Chemical compound CCCCC/N=N\CC ZANLKOHMZDJCFV-HJWRWDBZSA-N 0.000 description 1
- VAQFWBKFRKJKFY-UHFFFAOYSA-N CCOC1=CC(B2OC(C)(C)C(C)(C)O2)=CN(C)C1=O Chemical compound CCOC1=CC(B2OC(C)(C)C(C)(C)O2)=CN(C)C1=O VAQFWBKFRKJKFY-UHFFFAOYSA-N 0.000 description 1
- VFPKZASVVCBVMG-UHFFFAOYSA-N Cc(cc1[N+]([O-])=O)cc(Br)c1N Chemical compound Cc(cc1[N+]([O-])=O)cc(Br)c1N VFPKZASVVCBVMG-UHFFFAOYSA-N 0.000 description 1
- SXLGEIGIJQYCBA-UHFFFAOYSA-N Cc1c(-c(cc2NC(C3CCOCC3)c3ccc(C)cn3)ccc2N)[n](C)nn1 Chemical compound Cc1c(-c(cc2NC(C3CCOCC3)c3ccc(C)cn3)ccc2N)[n](C)nn1 SXLGEIGIJQYCBA-UHFFFAOYSA-N 0.000 description 1
- QHQHUDDMZDPZCN-UHFFFAOYSA-N Cc1c(-c2ccc3nc[n](C(C4CCOCC4)c4ccccc4)c3c2)[n](C)nn1 Chemical compound Cc1c(-c2ccc3nc[n](C(C4CCOCC4)c4ccccc4)c3c2)[n](C)nn1 QHQHUDDMZDPZCN-UHFFFAOYSA-N 0.000 description 1
- GYRBWEWKXDMRPR-UHFFFAOYSA-N Cc1ccc(C)[n]1-c1nc(N(C)C(C2CCOCC2)c2ccccc2)cc(C(C=C2)=CN(C)C2=O)c1 Chemical compound Cc1ccc(C)[n]1-c1nc(N(C)C(C2CCOCC2)c2ccccc2)cc(C(C=C2)=CN(C)C2=O)c1 GYRBWEWKXDMRPR-UHFFFAOYSA-N 0.000 description 1
- BYFZBPUCDSALAU-HXUWFJFHSA-N Cc1ccc(C[C@H](c2ccccn2)Nc(cc(cc2)Br)c2N)cc1 Chemical compound Cc1ccc(C[C@H](c2ccccn2)Nc(cc(cc2)Br)c2N)cc1 BYFZBPUCDSALAU-HXUWFJFHSA-N 0.000 description 1
- RAQZBBDKNHBWRW-UHFFFAOYSA-N NC(C1CCOCC1)c1ccccn1 Chemical compound NC(C1CCOCC1)c1ccccn1 RAQZBBDKNHBWRW-UHFFFAOYSA-N 0.000 description 1
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- A61K31/4192—1,2,3-Triazoles
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- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses one kind containing aromatic compound, preparation method, pharmaceutical composition and application.The present invention provides a kind of compound containing aromatic ring, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its solvates as shown in Equation 1, the compound can be effectively combined the bromine structural domain of BET families BRD4, BRD3, BRD2 and BRDT, to regulate and control the transcription of downstream gene c myc target genes related to its, and then adjust the signal path in downstream, play specific function, including treatment disease such as inflammatory disease, cancer and AIDS；Which part compound has very high activity, and has preferable cell activity and metabolic stability, therefore can become the active drug for the treatment of tumour.
Description
Technical field
The present invention relates to one kind containing aromatic compound, preparation method, pharmaceutical composition and application.
Background technology
Tumour is one of the main reason for leading to human death in global range in recent years.Tumour overall cure rate is low and multiple
Hair rate is high, therefore treats tumour with important value.
The exception of epigenetic regulation is to lead to one of tumorigenic key factor.Epigenetic refers to being based on non-genomic
The variation of gene expression dose caused by sequence changes, including DNA methylation, histone modification, chromosome remodeling and non-coding RNA
Regulation and control etc., mainly by the regulation and control to genetic transcription or translation process, influence its function and characteristic.Histone is chromatinic core
The heart participates in posttranscriptional modification, includes mainly：Acetylation methylates, phosphorylation and ubiquitination.
Bromodomain is upper highly conserved albumen of evolving, and is made of 110 amino acid.It can be by identifying histone
On acetylated lysine residue, mediating proteins interaction, and then influence gene transcription regulation process.In human genome
In, 61 kinds of bromodomains are found altogether, are present in 46 kinds of different albumen.Bromodomain usually has very deep drain port
Bag, have small and close binding site be used for combine acetylated lysine.Moreover, the hydrone that pocket bottom is guarded is to patent medicine
Property has significant impact.Usually weaker (the K of combination of bromodomain and acetylated proteinDValue is in lower micromole to milli
Mole magnitude), which increases the possibilities for finding potential inhibitor.It is aobvious to the assessment of bromodomain family druggability
Show, BET (bromodomain and additional C- terminal domains) subfamily score is very high, this point found at present one
The micromolecular inhibitor with different skeleton structures is confirmed a bit.
The BET families of people include 4 members, BRD2, BRD3, BRD4 and BRDT.Each member includes two concatenated
The terminated acetylated lysine residue of histone and an additional end C- are tied for identification for bromodomain (BD1 and BD2)
Structure domain.Wherein, BRD2 can regulate and control energy balance and dyslipidemia or the lipogenetic improper regulation and control of body, inflammation water
Flat and autoimmune disease is related；The GATA1 of BRD3 combination acetylations regulates and controls red blood cell target gene；BRD4 is to there is silk point
It splits and is marked and promotes to transcribe；BRDT is only expressed in testis, extremely important to producing spermatogenic gene expression.BRD2,
BRD3 may participate in promotion transcription and extend after being combined with histone, BRD4 can combine positive transcriptional elongation factor b (P-TEFb), to
The phosphorylation and transcription output for leading to RNA polymerase increase.BRD4 and different transcription factors combine, and regulate and control the gene in downstream
Expression.The RelA of it and acetylation is combined, and leads to coreStimulation and scorching card gene transcriptional activity.BRD4 and vitamin A acid
The N-terminal region of receptor alpha is associated with, and one group of discrete gene of regulation and control is associated with p53, regulates and controls the expression of p21.BRD4 also and some
Chromatin modifies enzyme interacting, including histone methylase NSD3 and hydroxylase JMJD6.BRD4 target genes, such as c-
Myc, C-Fos, aurora B, cyclin D1 and cyclin D2, have been involved in the control of cell cycle.Data is aobvious
Show that BRD4 also takes part in DNA damage signal transduction.BRD4 participates in the regulation and control of Apolipoprotein A1 gene, to adjust high density lipoprotein level
The pathology of white level, the latter and artery sclerosis are related.
BET families are related to a variety of diseases.Chromosome translocation leads to the nucleoprotein (NUT) in BRD4 (or BRD3) and testis
The expression of fusion leads to a kind of rare cancer, NUT center line cancers (NMC).BRD4 plays the part of important angle in many neoplastic hematologic disorders
Color, including Acute Meyloid lymthoma, acute lymphoblastic leukemia, lymthoma and a variety of myeloma.In addition, BRD4 also and
A series of solid tumors are related, such as neuroblastoma, glioblastoma, lung cancer and melanoma.BRD4 also with inflammation and some
The life cycle of virus is related.
Therefore, inhibit these compounds for being combined with acetylated protein of bromodomain imply treat a series of inflammation and
The novel method of cancer.Up to the present, academia and the seminar of industrial quarters have found the BET inhibition of different chemical types
Agent, and some come into the clinical trial stage.A series of patent application for disclosing BET inhibitor at present, including
WO2011054553, WO2011054845, WO2013097052, WO2013185284, WO2014139324,
WO2014164771, WO2015100282, WO2015075665, WO2015080707, WO2015164480,
WO2015195862, WO2016050821 etc..
Invention content
The technical problems to be solved by the invention are the more novel bromine structural domain inhibitor of exploitation, to be to be related to bromine knot
Structure domain-functionalities include that the disease of BET structure domain-functionalities and indication provide more therapies, thus provide a series of and existing
Have technology it is entirely different contain aromatic compound, preparation method, pharmaceutical composition and application, which can be effectively combined
The bromine structural domain of BET families BRD4, BRD3, BRD2 and BRDT, to regulate and control turning for downstream gene c-myc target genes related to its
Record, and then the signal path in downstream is adjusted, play specific function, including treatment disease such as inflammatory disease, cancer and AIDS；Wherein
Part of compounds has very high activity, and has preferable cell activity and metabolic stability, therefore can become treatment
The active drug of tumour.
The present invention provides a kind of compound containing aromatic ring as shown in Equation 1, its pharmaceutically acceptable salt, its solid are different
Structure body, its tautomer or its solvate,
Wherein,
R1And R2It independently is methyl, substituted or unsubstituted C2-C6The alkyl (" C2-C6Alkyl " it is for example different
Propyl), substituted or unsubstituted C3-C8The naphthenic base (" C3-C8Naphthenic base " such as cyclopropyl), substitution or do not take
" one or more in hetero atom N, O and S, hetero atom number is 1~4,3~10 yuan of Heterocyclylalkyl " in generation is (described
" Heterocyclylalkyl " such as epoxy hex- 4- yls), substituted or unsubstituted C3-C8Cycloalkenyl group, it is substituted or unsubstituted that " hetero atom is
N, one or more in O and S, hetero atom number be 1~4,3~10 yuan of heterocycloalkenyl ", substituted or unsubstituted C6-C10
The aryl (" C6-C10Aryl " such as phenyl) or substituted or unsubstituted " one in hetero atom N, O and S
Kind is a variety of, and hetero atom number is 1~4,5~10 yuan of heteroaryl " (" heteroaryl " such as pyridine -2- bases)；It is described
R1And R2In all " substitutions " independently be and replaced by following one or more substituent groups, when there are multiple substituent groups,
The substituent group is identical or different：Halogen (such as fluorine or chlorine), CN, R11SO2-、R12SO2NH-、R13CONH-、R14O- and
" by one or more C1-C6Alkyl (such as methyl) " substituted or unsubstituted C6-C10Aryl (such as phenyl)；R11、R12、
R13And R14It independently is C1-C6Alkyl (such as methyl or isopropyl), C3-C8Naphthenic base (such as cyclopropyl), " hetero atom
To be one or more in N, O and S, hetero atom number is 1~4,3~7 yuan of Heterocyclylalkyl " (such as epoxy hex- 4- yls),
C3-C8Cycloalkenyl group, " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,3~7 yuan of heterocycle alkene
Base ", phenyl or " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,5~6 yuan of heteroaryl "
(such as pyridine -2- bases)；
Y is(when the Y isAnd the R1And R2When differing, in the Y
Carbon atom is asymmetric carbon atom, be S configurations carbon atom, the S configurations carbon atom of enrichment, R configurations carbon atom, enrichment R configurations
Carbon atom or racemization carbon atom；
It is finger ring B existence or non-existences；
In the absence of the ring B, (R5)mAlso it is not present, ring A is phenyl or substituted or unsubstituted " hetero atom
To be one or more in N, O and S, hetero atom number is 1~4,5~6 yuan of heteroaryl " (such as pyridyl group), X isEach R6It independently is hydrogen or C1-C6Alkyl (such as methyl)；
In the presence of the ring B, (R5)mThere is also, ring A be phenyl or it is substituted or unsubstituted " hetero atom N,
One or more in O and S, hetero atom number is 1~4,5~6 yuan of heteroaryl " (such as pyridyl group), X isThe ring B includes X and is condensed with ring A, and the ring B is " in hetero atom N, O and S
It is one or more, hetero atom number be 1~3,4~10 yuan of Heterocyclylalkyl ", C4-C10Cycloalkenyl group, " hetero atom N, O and
One or more in S, hetero atom number is 1~3,4~10 yuan of heterocycloalkenyl " (such as)、C6-C10Virtue
Base or " one or more in hetero atom N, O and S, hetero atom number is 1~4,5~10 yuan of heteroaryl " (such as pyrrole
Base, imidazole radicals, pyridyl group or indyl are coughed up, in another example imidazole radicals)；
R3For it is substituted or unsubstituted " it is one or more in hetero atom N, O and S, hetero atom number be 1~3,3~
10 yuan of heterocycloalkenyl " (such as) or substituted or unsubstituted " hetero atom
To be one or more in N, O and S, hetero atom number is 1~4,5~10 yuan of heteroaryl " (such as In another example)；The R3In all " substitutions " independently be and taken by following one or more
Replaced for base, when there are multiple substituent groups, the substituent group is identical or different：One or more hydroxyl substitutions do not take
The C in generation1-C6Alkyl (such as methyl, ethyl or isopropyl), C1-C6Alkoxy (such as methoxy or ethoxy) andEach R7And R8It independently is hydrogen or C1-C6Alkyl (such as ethyl)；
N and m independently is 0,1,2,3 or 4；
Each R4And R5It independently is amino, cyano, halogen (such as fluorine), CN, R41SO2-、R42SO2NH-、R43CONH-、
R44O-, substituted or unsubstituted C1-C6Alkyl (such as methyl or isopropyl), substituted or unsubstituted C1-C6Alkoxy
(such as methoxyl group), substituted or unsubstituted C3-C8Naphthenic base (such as cyclobutyl), substituted or unsubstituted C6-C10Virtue
Base, substituted or unsubstituted " one or more in hetero atom N, O and S, hetero atom number is 1~4,5~6 yuan of heteroaryl
Base " (such as pyrazoles -4- bases), NH2- C (=O)-(CH2)pOr R9- S (=O)2-NH-(CH2)q-；Wherein, p and q be independently
It is 0,1,2 or 3, R9For C1-C6Alkyl (such as methyl or ethyl), the R4And R5In all " substitutions " independently be by
Following one or more substituent group is replaced, and when there are multiple substituent groups, the substituent group is identical or different：Cyano, hydroxyl
Base, C1-C6Alkoxy and halogen (such as fluorine)；R41、R42、R43And R44It independently is C1-C6Alkyl (such as methyl or isopropyl
Base), C3-C8Naphthenic base (such as cyclopropyl), " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,3
~7 yuan of Heterocyclylalkyl " (such as epoxy hex- 4- yls), C3-C8Cycloalkenyl group, " it is one or more in hetero atom N, O and S,
Hetero atom number be 1~4,3~7 yuan of heterocycloalkenyl ", phenyl or " it is one or more in hetero atom N, O and S, it is miscellaneous
Atomicity is 1~4,5~6 yuan of heteroaryl " (such as pyridine -2- bases).
R1And R2In " C2-C6Alkyl " " C can independently be2-C4Alkyl ".
R1And R2In " C3-C8Naphthenic base " " C can independently be3-C6Naphthenic base ".
R1And R2In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,3~10 yuan of heterocycle
Alkyl " can independently be " it is one or more in hetero atom N, O and S, hetero atom number be 1~2,3~6 yuan of heterocycle alkane
Base ".
R1And R2In " C3-C8Cycloalkenyl group " " C can independently be3-C6Cycloalkenyl group ".
R1And R2In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,3~10 yuan of heterocycle
Alkenyl " can independently be " it is one or more in hetero atom N, O and S, hetero atom number be 1~2,3~6 yuan of heterocycle alkene
Base ".
R1And R2In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,5~10 yuan of heteroaryl
Base " is " one or more in hetero atom N, O and S, hetero atom number is 1~4,5~6 yuan of heteroaryl ".
R1And R2In it is at least one be substituted or unsubstituted C6-C10Aryl or substituted or unsubstituted " miscellaneous original
Son is one or more in N, O and S, and hetero atom number is 1~4,5~10 yuan of heteroaryl "；Alternatively, R1And R2It can be independently
For substituted or unsubstituted C6-C10Aryl or it is substituted or unsubstituted " it is one or more in hetero atom N, O and S,
Hetero atom number is 1~4,5~10 yuan of heteroaryl ".
As the R1And R2In be substituted by when being optionally substituted by halogen, the halogen can independently be fluorine, chlorine, bromine or iodine.
As the R1And R2In be substituted by by " by one or more C1-C6Alkyl " substituted or unsubstituted C6-C10
Aryl substitution when, the C1-C6Alkyl can independently be C1-C4Alkyl.
R11、R12、R13And R14In " C1-C6Alkyl " " C can independently be1-C4Alkyl ".
R11、R12、R13And R14In " C3-C8Naphthenic base " " C can independently be3-C6Naphthenic base ".
R11、R12、R13And R14In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,3~7
Member Heterocyclylalkyl " can independently be " and it is one or more in hetero atom N, O and S, hetero atom number be 1~2,3~6 yuan
Heterocyclylalkyl ".
R11、R12、R13And R14In " C3-C8Cycloalkenyl group " " C can independently be3-C6Cycloalkenyl group ".
R11、R12、R13And R14In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,3~7
Member heterocycloalkenyl " can independently be " and it is one or more in hetero atom N, O and S, hetero atom number be 1~2,3~6 yuan
Heterocycloalkenyl ".
R1And R2It can independently be
X and Y is C or N when can be different；For example, in the absence of the ring B ,-X-Y- can be In the presence of the ring B, " X can beY can be", alternatively, " X can be
Y can be”。
R6In " C1-C6Alkyl " " C can independently be1-C4Alkyl ".
In the presence of the ring B, described in ring B " one or more in hetero atom N, O and S, hetero atom number is
1~3,4~10 yuan of Heterocyclylalkyl " can independently be that " one or more in hetero atom N, O and S, hetero atom number is 1
~3,5~6 yuan of Heterocyclylalkyl ".
In the presence of the ring B, the C described in ring B4-C10Cycloalkenyl group can independently be C5-C6Cycloalkenyl group.
In the presence of the ring B, described in ring B " one or more in hetero atom N, O and S, hetero atom number is
1~3,4~10 yuan of heterocycloalkenyl " can independently be that " one or more in hetero atom N, O and S, hetero atom number is 1
~3,5~6 yuan of heterocycloalkenyl ".
In the presence of the ring B, described in ring B " one or more in hetero atom N, O and S, hetero atom number is
1~4,5~10 yuan of heteroaryl " can independently be that " one or more in hetero atom N, O and S, hetero atom number is 1~3
It is a, 5~6 yuan of heteroaryl ".
In the presence of the ring B, the ring B can be monocycle or bicyclic；The ring B can be monocycle again.
In the presence of the ring B, can be with the condensed rings formed of ring A：
R3In " it is one or more in hetero atom N, O and S, hetero atom number be 1~3,3~10 yuan of heterocycle alkene
Base " can be " one or more in hetero atom N, O and S, hetero atom number is 1~3,5~10 yuan of heterocycloalkenyl "；Again may be used
For " one or more in hetero atom N, O and S, hetero atom number is 1~3,5~6 yuan of heterocycloalkenyl ".
R3In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,5~10 yuan of heteroaryl "
It can independently be " one or more in hetero atom N, O and S, hetero atom number is 1~4,5~9 yuan of heteroaryl ".
As the R3In be substituted by by the substituted or unsubstituted C of one or more hydroxyls1-C6Alkyl substitution when, institute
The C stated1-C6Alkyl can independently be C1-C4Alkyl.
As the R3In be substituted by by C1-C6Alkoxy substitution when, the C1-C6Alkoxy can independently be
C1-C4Alkoxy.
R7And R8In C1-C6Alkyl can independently be C1-C4Alkyl.
R3Can be
R3It can be positioned at the ortho position of X, meta or para position；R3The meta position of X can be located at again.
N can be 0 or 1.
M can be 0,1 or 2；M can be 0 or 1 again.
N+m can be 1.
P can be 0 or 1.
Q can be 0 or 1.
When n is 1, R4It can be positioned at the ortho position of X, meta or para position；R4The meta position of X can be located at again.
When ring A is hexatomic ring, R3、R4With X can meta position each other, be similar to mesitylene.
R4And R5In " halogen " fluorine, chlorine, bromine or iodine can independently be.
R4And R5In " substituted or unsubstituted C1-C6Alkyl " substituted or unsubstituted C can independently be1-C4Alkane
Base.
R4And R5In " substituted or unsubstituted C3-C8Naphthenic base " substituted or unsubstituted C can independently be3-C6's
Naphthenic base.
R9In C1-C6Alkyl can independently be C1-C4Alkyl.
Work as R4And R5In be substituted by C1-C6Alkyl it is substituted when, the C1-C6Alkyl can independently be C1-C4's
Alkyl.
Work as R4And R5In be substituted by halogen it is substituted when, the halogen can independently be fluorine, chlorine, bromine or iodine.
R41、R42、R43And R44In " C1-C6Alkyl " " C can independently be1-C4Alkyl ".
R41、R42、R43And R44In " C3-C8Naphthenic base " " C can independently be3-C6Naphthenic base ".
R41、R42、R43And R44In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,3~7
Member Heterocyclylalkyl " can independently be " and it is one or more in hetero atom N, O and S, hetero atom number be 1~2,3~6 yuan
Heterocyclylalkyl ".
R41、R42、R43And R44In " C3-C8Cycloalkenyl group " " C can independently be3-C6Cycloalkenyl group ".
R41、R42、R43And R44In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,3~7
Member heterocycloalkenyl " can independently be " and it is one or more in hetero atom N, O and S, hetero atom number be 1~2,3~6 yuan
Heterocycloalkenyl ".
R4And R5Can independently be fluorine, amino, cyano, methyl, isopropyl, methoxyl group,
R4Again can be fluorine, amino, cyano,
R5Again can be methyl, methoxyl group, isopropyl,
R1And R2Substituted or unsubstituted C can independently be3-C8Naphthenic base (such as cyclopropyl), substituted or unsubstituted
" one or more in hetero atom N, O and S, hetero atom number is 1~4,3~10 yuan of Heterocyclylalkyl " (such as epoxy hex-
4- yls), substituted or unsubstituted C6-C10Aryl (such as phenyl) or substituted or unsubstituted " hetero atom N, O and S
In it is one or more, hetero atom number be 1~4,5~10 yuan of heteroaryl " (such as pyridine -2- bases)；The R1And R2In
All " substitutions " independently can be described when there are multiple substituent groups to be replaced by following one or more substituent groups
Substituent group is identical or different：" by one or more C1-C6Alkyl (such as methyl) " substituted or unsubstituted C6-C10Aryl
(such as phenyl).
Y can be
Compound 1 can beEach group determines in compound 2 and 3
Justice is the same as compound 1.
In the absence of the ring B, (R5)mAlso it is not present, ring A can be substituted or unsubstituted " hetero atom N, O and S
In it is one or more, hetero atom number is 1~4,5~6 yuan of heteroaryl " (such as pyridyl group), X isR6Can be
Hydrogen or C1-C6Alkyl (such as methyl), such as hydrogen；
In the presence of the ring B, (R5)mThere is also, ring A can be phenyl or substituted or unsubstituted " hetero atom is
N, one or more in O and S, hetero atom number is 1~4,5~6 yuan of heteroaryl " (such as pyridyl group), X is
The ring B includes X and is condensed with ring A, and the ring B is C6-C10Aryl or " one kind in hetero atom N, O and S or
A variety of, hetero atom number is 1~4,5~10 yuan of heteroaryl " (such as pyrrole radicals, imidazole radicals, pyridyl group or indyl).
R3Can be it is substituted or unsubstituted " it is one or more in hetero atom N, O and S, hetero atom number be 1~3,3
~10 yuan of heterocycloalkenyl " (such as) or substituted or unsubstituted " miscellaneous original
Son is one or more in N, O and S, and hetero atom number is 1~4,5~10 yuan of heteroaryl " (such as In another example)；R3Can be again it is substituted or unsubstituted " one kind in hetero atom N, O and S or
A variety of, hetero atom number is 1~4,5~10 yuan of heteroaryl "；The R3In all " substitutions " independently be by with next
A or multiple substituent groups are replaced, and when there are multiple substituent groups, the substituent group is identical or different：One or more hydroxyls
Substituted or unsubstituted C1-C6Alkyl (such as methyl, ethyl or isopropyl), C1-C6Alkoxy (such as methoxyl group or second
Oxygroup).
N can be 0 or 1.
M can be 0,1 or 2.
Each R4And R5Amino, cyano, halogen (such as fluorine), unsubstituted C can independently be1-C6Alkoxy (such as
Methoxyl group), it is unsubstituted " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,5~6 yuan of heteroaryl
Base " (such as pyrazoles -4- bases) or NH2- C (=O)-(CH2)p-；Wherein, 0 p.
The compound 1 can be following any compound：
6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d]
Imidazoles -4- nitriles (I-1)；
(R) -6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos
[d] imidazoles -4- nitriles；
(S) -6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos
[d] imidazoles -4- nitriles；
6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d]
Imidazole-4-carboxamide (I-2)；
(R) -6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos
[d] imidazole-4-carboxamide；
(S) -6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos
[d] imidazole-4-carboxamide；
3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -4- (1H- pyrazoles -4- bases) -1H- benzene
And [d] imidazoles -6- bases) isoxazole (I-3)；
(R) -3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -4- (1H- pyrazoles -4- bases) -
1H- benzos [d] imidazoles -6- bases) isoxazole；
(S) -3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -4- (1H- pyrazoles -4- bases) -
1H- benzos [d] imidazoles -6- bases) isoxazole；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazoles -4- nitriles (I-4)；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles -4- nitriles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles -4- nitriles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazole-4-carboxamide (I-5)；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazole-4-carboxamide；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazole-4-carboxamide；
3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) is different
Oxazole (I-6)；
(S) -3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base) isoxazole；
(R) -3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base) isoxazole；
3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first separated in 2.73min using following conditions
Base) -1H- benzos [d] imidazoles -6- bases) isoxazole：Instrument:Thar,Waters SFC-80；Chromatographic column:Daicel AD 20*
250mm,10μm；Column temperature:35℃；Mobile phase:CO containing 0.2% saturation ammonia methanol solution2/ IPA=75/25；Flow velocity:80g/
min；Back pressure:100bar；Detection wavelength:220nm；Run time:7.0min；
3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first separated in 3.38min using following conditions
Base) -1H- benzos [d] imidazoles -6- bases) isoxazole：Instrument:Thar,Waters SFC-80；Chromatographic column:Daicel AD 20*
250mm,10μm；Column temperature:35℃；Mobile phase:CO containing 0.2% saturation ammonia methanol solution2/ IPA=75/25；Flow velocity:80g/
min；Back pressure:100bar；Detection wavelength:220nm；Run time:7.0min；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazoles (I-9)；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (benzene separated in 2.52min using following conditions
Base (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles：Instrument:Thar,Waters SFC-80；Chromatographic column:
Daicell AD-H20*250mm,5μm；Column temperature:35℃；Mobile phase:CO containing 0.2% saturation ammonia methanol solution2/ methanol=
75/25；Flow velocity:70g/min；Back pressure:100bar；Detection wavelength:214nm；Run time:5min；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl separated in 3.2min using following conditions
(tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles：Instrument:Thar,Waters SFC-80；Chromatographic column:
Daicell AD-H20*250mm,5μm；Column temperature:35℃；Mobile phase:CO containing 0.2% saturation ammonia methanol solution2/ methanol=
75/25；Flow velocity:70g/min；Back pressure:100bar；Detection wavelength:214nm；Run time:5min；
3- ethyoxyl -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base) pyridine -2 (1H) -one (I-12)；
(R) -3- ethyoxyls -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] miaows
Azoles -6- bases) pyridine -2 (1H) -one；
(S) -3- ethyoxyls -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] miaows
Azoles -6- bases) pyridine -2 (1H) -one；
(R) -3,5- dimethyl -4- (1- (1- (pyridine -2- bases) -2- p-methylphenyls ethyl) -1H- benzos [d] imidazoles -6-
Base) isoxazole (I-13)；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (1- (pyridine -2- bases) -2- tolyl second
Base) -1H- benzos [d] imidazoles (I-14)；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) fluoro- 1- of -4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles (I-15)；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) the fluoro- 1- of -4- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) the fluoro- 1- of -4- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles；
1- benzhydryls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d] imidazoles (I-16)；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (1,2- diphenyl-ethyls) -1H- benzos [d] imidazoles
(I-17)；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (1,2- diphenyl-ethyls) -1H- benzos [d]
Imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (1,2- diphenyl-ethyls) -1H- benzos [d]
Imidazoles；
1- (cyclopropyl (phenyl) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d] miaow
Azoles (I-18)；
(R) -1- (cyclopropyl (phenyl) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos
[d] imidazoles；
(S) -1- (cyclopropyl (phenyl) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos
[d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- imidazos [4,5-c] pyridine；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- imidazos [4,5-c] pyridine；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- imidazos [4,5-c] pyridine；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyrroles separated in 1.03min using following conditions
Pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyridine：Instrument:Thar,Waters SFC-80；
Chromatographic column:Daicel AS-H 20*250mm,5μm；Column temperature:35℃；Mobile phase:Containing 0.2% saturation ammonia methanol solution
CO2/ methanol=60/40；Flow velocity:80g/min；Back pressure:100bar；Detection wavelength:214nm；Run time:2.5min；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyrroles separated in 1.51min using following conditions
Pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyridine：Instrument:Thar,Waters SFC-80；
Chromatographic column:Daicel AS-H 20*250mm,5μm；Column temperature:35℃；Mobile phase:Containing 0.2% saturation ammonia methanol solution
CO2/ methanol=60/40；Flow velocity:80g/min；Back pressure:100bar；Detection wavelength:214nm；Run time:2.5min；
6- (3,5- dimethyl -3H-1,2,3- triazole -4- bases) -1- phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- imidazos [4,5-c] pyridine (I-21)；
(R) -6- (3,5- dimethyl -3H-1,2,3- triazole -4- bases) -1- phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- imidazos [4,5-c] pyridine；
(S) -6- (3,5- dimethyl -3H-1,2,3- triazole -4- bases) -1- phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- imidazos [4,5-c] pyridine；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -1H- imidazos [4,5-c] pyridine (I-22)；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- imidazos [4,5-c] pyridine；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- imidazos [4,5-c] pyridine；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (pyridine -2- bases) methyl) -1H- benzos
[d] imidazoles (I-23)；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (pyridine -2- bases) methyl) -1H- benzene
And [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (pyridine -2- bases) methyl) -1H- benzene
And [d] imidazoles；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d miaows
Azoles (I-24)；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles (I-25)；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) methyl) -1H-
Benzo [d] imidazole formic acid salt (I-27)；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) first
Base) -1H- benzos [d] imidazole formic acid salt；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) first
Base) -1H- benzos [d] imidazole formic acid salt；
1- benzhydryls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indoles (I-28)；
1- methyl -2'- ((phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6 (1H) -one (I-
29)；
(R) -1- methyl -2'- ((phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6 (1H) -
Ketone；
(S) -1- methyl -2'- ((phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6 (1H) -
Ketone；
1- methyl -2'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6 (1H) -
Ketone (I-30)；
(R) -1- methyl -2'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6
(1H) -one；
(S) -1- methyl -2'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6
(1H) -one；
[3,4'- joins pyrrole to 2'- amino -1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -
Pyridine] -6 (1H) -one (I-31)；
(R) [3,4'- joins -2'- amino -1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -
Pyridine] -6 (1H) -one；
(S) [3,4'- joins -2'- amino -1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -
Pyridine] -6 (1H) -one；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (two pyridine -2- ylmethyls) -1H- benzos [d] miaow
Azoles -2 (3H) -one (I-32)；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) methyl) -2-
Methyl-1 H- benzos [d] imidazoles (I-33)；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) first
Base) -2- methyl-1 H- benzos [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) first
Base) -2- methyl-1 H- benzos [d] imidazoles；
4- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3,5- dimethyl isoxazoles (I-34)；
5- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3- methoxyl group -1- picolines -2
(1H) -one (I-35)；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (two pyridine -2- ylmethyls) -2- methoxyl group -2- first
Base -2,3- dihydro -1H- benzos [d] imidazoles (I-36)；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (2- methyl-1s-phenyl propyl) -1H- benzos [d]
Imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (2- methyl-1s-phenyl propyl) -1H- benzos
[d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (2- methyl-1s-phenyl propyl) -1H- benzos
[d] imidazoles；
3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyridine -6-
Base) isoxazole；
(R) -3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyrroles
Pyridine -6- bases) isoxazole；
(S) -3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyrroles
Pyridine -6- bases) isoxazole；
6- methyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -1,6- two
Hydrogen -7H- pyrrolo-es [2,3-c] pyridin-7-one；
(R) -6- methyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -1,
6- dihydro-7 H-pyrrolos simultaneously [2,3-c] pyridin-7-one；
(S) -6- methyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -1,
6- dihydro-7 H-pyrrolos simultaneously [2,3-c] pyridin-7-one；
3- (ethylamino-) -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -
6- yls) pyridine -2 (1H) -one；
(R) -3- (ethylamino-) -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] miaows
Azoles -6- bases) pyridine -2 (1H) -one；
(S) -3- (ethylamino-) -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] miaows
Azoles -6- bases) pyridine -2 (1H) -one；
6- (5- methoxyl group -1- methyl -6- oxo -1,6- dihydropyridine -3- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles -4- formamides；
(R) -6- (5- methoxyl group -1- methyl -6- oxo -1,6- dihydropyridine -3- bases) -1- (phenyl (tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) -1H- benzos [d] imidazoles -4- formamides；
(S) -6- (5- methoxyl group -1- methyl -6- oxo -1,6- dihydropyridine -3- bases) -1- (phenyl (tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) -1H- benzos [d] imidazoles -4- formamides；
3- methoxyl group -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base) pyridine -2 (1H) -one；
(R) -3- methoxyl groups -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] miaows
Azoles -6- bases) pyridine -2 (1H) -one；
(S) -3- methoxyl groups -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] miaows
Azoles -6- bases) pyridine -2 (1H) -one；
6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1,3- dihydros -
2H- benzos [d] imidazoles -2- ketone；
(R) -6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1,3- two
Hydrogen -2H- benzos [d] imidazoles -2- ketone；
(S) -6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1,3- two
Hydrogen -2H- benzos [d] imidazoles -2- ketone；
2- (5- (3,5- dimethyl isoxazole -4- bases) -2- oxos -3- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
2,3- dihydro -1H- benzos [d] imidazoles -1- bases) acetonitrile；
(R) -2- (5- (3,5- dimethyl isoxazole -4- bases) -2- oxos -3- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -2,3- dihydro -1H- benzos [d] imidazoles -1- bases) acetonitrile；
(S) -2- (5- (3,5- dimethyl isoxazole -4- bases) -2- oxos -3- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -2,3- dihydro -1H- benzos [d] imidazoles -1- bases) acetonitrile；
2- (5- (3,5- dimethyl isoxazole -4- bases) -2- oxos -3- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
2,3- dihydro -1H- benzos [d] imidazoles -1- bases) acetamide；
(R) -2- (5- (3,5- dimethyl isoxazole -4- bases) -2- oxos -3- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -2,3- dihydro -1H- benzos [d] imidazoles -1- bases) acetamide；
(S) -2- (5- (3,5- dimethyl isoxazole -4- bases) -2- oxos -3- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -2,3- dihydro -1H- benzos [d] imidazoles -1- bases) acetamide；
3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases)-[1,2,
4] triazole simultaneously [4,3-b] pyridazine -8- amine；
(R) -3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -
[1,2,4] triazole simultaneously [4,3-b] pyridazine -8- amine；
(S) -3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -
[1,2,4] triazole simultaneously [4,3-b] pyridazine -8- amine；
3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases)-[1,2,
4] triazole simultaneously [4,3-b] pyridazine；
(R) -3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -
[1,2,4] triazole simultaneously [4,3-b] pyridazine；
(S) -3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -
[1,2,4] triazole simultaneously [4,3-b] pyridazine；
3,8- dimethyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -
[1,2,4] triazole simultaneously [4,3-b] pyridazine；
(R) -3,8- dimethyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base)-[1,2,4] triazole simultaneously [4,3-b] pyridazine；
(S) -3,8- dimethyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base)-[1,2,4] triazole simultaneously [4,3-b] pyridazine；
6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d]
Imidazoles -4- amine；
(R) -6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos
[d] imidazoles -4- amine；
(S) -6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos
[d] imidazoles -4- amine；
4- (the fluoro- 1- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3,5- diformazans
Base isoxazole；
(R) -4- (the fluoro- 1- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3,5-
Dimethyl isoxazole；
(S) -4- (the fluoro- 1- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3,5-
Dimethyl isoxazole；
N- (6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos
[d] imidazol-4 yl) Methanesulfomide；
(R)-N- (6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H-
Benzo [d] imidazol-4 yl) Methanesulfomide；
(S)-N- (6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H-
Benzo [d] imidazol-4 yl) Methanesulfomide；
3,7- dimethyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -
[1,2,4] triazole simultaneously [4,3-b] pyridazine；
(R) -3,7- dimethyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base)-[1,2,4] triazole simultaneously [4,3-b] pyridazine；
(S) -3,7- dimethyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base)-[1,2,4] triazole simultaneously [4,3-b] pyridazine；
7- isopropyl -3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base)-[1,2,4] triazole simultaneously [4,3-b] pyridazine；
(R) -7- isopropyls -3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] miaows
Azoles -6- bases)-[1,2,4] triazole simultaneously [4,3-b] pyridazine；
(S) -7- isopropyls -3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] miaows
Azoles -6- bases)-[1,2,4] triazole simultaneously [4,3-b] pyridazine；
1- methyl -5- (4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) amino) quinoline -6- bases) pyridine -2 (1H) -one；
(R) -1- methyl -5- (4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) amino) quinoline -6- bases) pyridine -2 (1H) -one；
(S) -1- methyl -5- (4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) amino) quinoline -6- bases) pyridine -2 (1H) -one；
5- methyl -7- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -1,5- two
Hydrogen -4H- pyrrolo-es [3,2-c] pyridine -4- ketone；
(R) -5- methyl -7- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -1,
5- dihydro -4H- pyrrolo-es [3,2-c] pyridine -4- ketone；
(S) -5- methyl -7- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -1,
5- dihydro -4H- pyrrolo-es [3,2-c] pyridine -4- ketone；
1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) pyridine -2
(1H) -one；
(R) -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) pyrrole
Pyridine -2 (1H) -one；
(S) -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) pyrrole
Pyridine -2 (1H) -one；
6- (3,5- dimethyl isoxazole -4- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases) quinolin-4-amines；
(R) -6- (3,5- dimethyl isoxazole -4- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases) quinolin-4-amines；
(S) -6- (3,5- dimethyl isoxazole -4- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases) quinolin-4-amines；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) fluoro- 1H- benzene of -4-
And [d] imidazoles；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) fluoro- 2- first of -4-
Base -1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) the fluoro- 1- of -4- ((4- fluorophenyls) (pyridine -2- bases) first
Base) -2- methyl-1 H- benzos [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) the fluoro- 1- of -4- ((4- fluorophenyls) (pyridine -2- bases)
Methyl) -2- methyl-1 H- benzos [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) the fluoro- 1- of -4- ((4- fluorophenyls) (pyridine -2- bases)
Methyl) -2- methyl-1 H- benzos [d] imidazoles；
1- (bis- (2,4 difluorobenzene base) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) fluoro- 2- of -4-
Methyl-1 H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(pyridine -2- bases (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- benzos [4,5-b] pyridine；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(pyridine -2- bases (tetrahydrochysene -2H-
Pyrans -4- bases) methyl) -1H- benzos [4,5-b] pyridine；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(pyridine -2- bases (tetrahydrochysene -2H-
Pyrans -4- bases) methyl) -1H- benzos [4,5-b] pyridine；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s H-
Imidazo [4,5-b] pyridine；
1- (bis- (2,4 difluorobenzene base) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl -
1H- imidazos [4,5-b] pyridine；
1- (bis- (4- fluorophenyls) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1 H- miaows
Azoles simultaneously [4,5-b] pyridine；
1- (bis- (4- fluorophenyls) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- imidazos [4,
5-b] pyridine；
N- (1- benzhydryls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indol-3-yls) second sulphonyl
Amine；
N- (1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indoles -
3- yls) ethyl sulfonamide；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases) quinoline -
4- amine；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases)
Quinolin-4-amines；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases)
Quinolin-4-amines；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s H-
Benzo [d] imidazoles；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- trifluoromethyls -
1H- benzos [d] imidazoles；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d]
Imidazoles -2- nitriles；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- isopropyls -
1H- benzos [d] imidazoles；
4- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3,5- dimethyl isoxazoles；
5- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3- methoxyl group -1- picolines -2
(1H) -one；
1- ((2,4 difluorobenzene base) (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazoles -5-
Base) -2- methyl-1 H- benzos [d] imidazoles；
(R) -1- ((2,4 difluorobenzene base) (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazoles -
5- yls) -2- methyl-1 H- benzos [d] imidazoles；
(S) -1- ((2,4 difluorobenzene base) (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazoles -
5- yls) -2- methyl-1 H- benzos [d] imidazoles；
1- (bis- (5- fluorine pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl -
1H- benzos [d] imidazoles；
1- ((4,4- difiuorocyclohexyls) (phenyl) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2-
Methyl-1 H- benzos [d] imidazoles；
(R) -1- ((4,4- difiuorocyclohexyls) (phenyl) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazoles -5-
Base) -2- methyl-1 H- benzos [d] imidazoles；
(S) -1- ((4,4- difiuorocyclohexyls) (phenyl) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazoles -5-
Base) -2- methyl-1 H- benzos [d] imidazoles；
1- (bis- (4- chlorphenyls) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1 H- benzene
And [d] imidazoles；
1- (two (pyridine -2- bases) methyl) -6- (1- ethyl -4- methyl-1 H-1,2,3- triazole -5- bases) -1H- benzos
[d] imidazoles；
2- (tri- nitrogen of 5- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -4- methyl-1s H-1,2,3-
Azoles -1- bases) ethane -1- alcohol；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) methyl) -2-
Methyl-1 H- benzos [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) first
Base) -2- methyl-1 H- benzos [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) first
Base) -2- methyl-1 H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((5- fluorine pyridine -2- bases) (phenyl) methyl) -2-
Methyl-1 H- benzos [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((5- fluorine pyridine -2- bases) (phenyl) first
Base) -2- methyl-1 H- benzos [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((5- fluorine pyridine -2- bases) (phenyl) first
Base) -2- methyl-1 H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((5- fluorine pyridine -2- bases) (phenyl) methyl) -1H-
Benzo [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((5- fluorine pyridine -2- bases) (phenyl) first
Base) -1H- benzos [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((5- fluorine pyridine -2- bases) (phenyl) first
Base) -1H- benzos [d] imidazoles；
1- (bis- (2,4 difluorobenzene base) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl -
1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- isopropyls -1- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- isopropyls -1- (phenyl (tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) -1H- benzos [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- isopropyls -1- (phenyl (tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) -1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazoles -2- nitriles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles -2- nitriles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles -2- nitriles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazoles -2- formamides；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles -2- formamides；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles -2- formamides；
N- ((6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles -2- bases) methyl) Methanesulfomide；
(R)-N- ((6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles -2- bases) methyl) Methanesulfomide；
(S)-N- ((6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles -2- bases) methyl) Methanesulfomide；
2- cyclobutyl -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles；
(R) -2- cyclobutyl -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) -1H- benzos [d] imidazoles；
(S) -2- cyclobutyl -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) -1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -1H- benzos [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- benzos [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -1H- imidazos [4,5-b] pyridine；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- imidazos [4,5-b] pyridine；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- imidazos [4,5-b] pyridine；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- imidazos [4,5-c] pyridine；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- imidazos [4,5-c] pyridine；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- imidazos [4,5-c] pyridine；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- imidazos [4,5-c] pyridine；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- imidazos [4,5-c] pyridine；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- imidazos [4,5-c] pyridine；
N2Benzhydryl -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N2Picoline -2,6- diamines；
N2Benzhydryl -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-pyridine -2,6- diamines；
2'- amino -5- ethyoxyl -1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,
4'- bipyridyls] -6 (1H) -one；
(R) -2'- amino -5- ethyoxyls -1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -
[3,4'- bipyridyls] -6 (1H) -one；
(S) -2'- amino -5- ethyoxyls -1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -
[3,4'- bipyridyls] -6 (1H) -one；
N- (1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -6- oxo -1,6- dihydros -
[3,4'- bipyridyls] -2'- bases) Methanesulfomide；
(R)-N- (1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -6- oxos -1,6- two
Hydrogen-[3,4'- bipyridyls] -2'- bases) Methanesulfomide；
(S)-N- (1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -6- oxos -1,6- two
Hydrogen-[3,4'- bipyridyls] -2'- bases) Methanesulfomide；
N- (5- ethyoxyl-1- methyl-6'- (methyl (phenyl (tetrahydrochysene-2H- pyrans-4- bases) methyl) amine) oxo-1-6-,
6- dihydros-[3,4'- bipyridyls] -2'- bases) Methanesulfomide；
(R)-N- (5- ethyoxyl -1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -6- oxygen
Generation -1,6- dihydros-[3,4'- bipyridyls] -2'- bases) Methanesulfomide；
(S)-N- (5- ethyoxyl -1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -6- oxygen
Generation -1,6- dihydros-[3,4'- bipyridyls] -2'- bases) Methanesulfomide；
4- (3,5- dimethyl isoxazole -4- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases) picolinamide；
(R) -4- (3,5- dimethyl isoxazole -4- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases) picolinamide；
(S) -4- (3,5- dimethyl isoxazole -4- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases) picolinamide；
4- (3,5- dimethyl isoxazole -4- bases)-N- methyl-N- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -
2- amine；
(R) -4- (3,5- dimethyl isoxazole -4- bases)-N- methyl-N- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl)
Pyridine -2- amine；
(S) -4- (3,5- dimethyl isoxazole -4- bases)-N- methyl-N- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl)
Pyridine -2- amine；
N- (two (pyridine -2- bases) methyl) -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N- picolines -
2- amine；
N2(two (pyridine -2- bases) methyl) -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N2Methyl pyrrole
Pyridine -2,6- diamines；
N- (two (pyridine -2- bases) methyl) -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) pyridine -2- amine；
N2(two (pyridine -2- bases) methyl) -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) pyridine -2,6- two
Amine；
2- (3- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -5- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -5H- pyridos [4,3-b] indoles -7- bases) propane -2- alcohol；
(R) -2- (3- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -5- (phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -5H- pyridos [4,3-b] indoles -7- bases) propane -2- alcohol；
(S) -2- (3- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -5- (phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -5H- pyridos [4,3-b] indoles -7- bases) propane -2- alcohol；
3- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -5- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
5H- pyridos [4,3-b] indoles；
(R) -3- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -5- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -5H- pyridos [4,3-b] indoles；
(S) -3- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -5- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -5H- pyridos [4,3-b] indoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N, N- bis- (pyridine -2- bases) quinolin-4-amines.
The present invention also provides a kind of preparation methods containing fragrant cyclics as shown in Equation 1 comprising following steps：
The halide intermediates as shown in formula 1-A with contain R3Pinacol borate intermediate carry out Suzuki coupling reactions, obtain
Compound 1；Alternatively, the halide intermediates as shown in formula 1-A with contain R3Tin reagent intermediate, it is even to carry out Stille
Connection reaction, obtains compound 1；
Wherein, the definition of each substituent group is as previously mentioned, Z is halogen.
Wherein, the conventional anti-of the such reaction in this field can be used in the Suzuki coupling reactions or Stille coupling reactions
Condition and parameter is answered to carry out.The present invention preferably in a solvent, is reacted in the presence of palladium catalyst and alkali；Or it is aided with microwave
Radiation promotes.
Wherein, the solvent is the Conventional solvents that this field carries out Suzuki coupling reactions or Stille coupling reactions,
Including but not limited to or mixtures thereof 1,4- dioxane, acetonitrile, water.
The reaction temperature of the Suzuki coupling reactions or Stille coupling reactions is that this field carries out such reaction
Ordinary temperature, such as 60 DEG C -125 DEG C.
The palladium catalyst is the conventional catalyst that this field carries out Suzuki coupling reactions or Stille coupling reactions,
It includes but not limited to tetra-triphenylphosphine palladium, [1,1 '-bis- (diphenylphosphino) ferrocene] dichloro palladium (II).
The alkali is the conventional catalyst that this field carries out Suzuki coupling reactions or Stille coupling reactions comprising
But it is not limited to the carbonate or phosphate of sodium, potassium and caesium.
The present invention also provides above-mentioned compound 1, its pharmaceutically acceptable salt, its stereoisomer, its mutually variations
Structure body or its solvate, the application in preparing bromine structural domain inhibitor.The bromine structural domain is preferably BRD4.
The present invention also provides above-mentioned compound 1, its pharmaceutically acceptable salt, its stereoisomer, its mutually variations
Structure body or its solvate, application in medicine preparation, the drug is for preventing or treating related with bromine structural domain
Disease.The bromine structural domain is preferably BRD4.
The disease related with bromine structural domain includes but not limited to：Acoustic neurinoma, acute leukemia, acute lymphoblastic are thin
Born of the same parents' property leukaemia, acute myelocytic leukemia (monocarpotic cellularity, myeloblastic, gland cancer, angiosarcoma, astrocytoma,
Myelo-monocytic and promyelocytic leukemic cell；Preferably acute myelocytic leukemia caused by MV-4-11 cells), it is acute
T- chronic myeloid leukemias, basal-cell carcinoma, cholangiocarcinoma, carcinoma of urinary bladder, the cancer of the brain, breast cancer, bronchiolar carcinoma, cervical carcinoma, chondrosarcoma, ridge
It is rope tumor, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukaemia, slow
Property myelomatosis, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, Diffuse large B-cell lymphoma are (preferably
For B- cell lymphomas caused by SU-DHL-6 cells), bad Hypertrophic variation (dysproliferativechanges) (hair
Educate bad and metaplasia), embryonal carcinoma, carcinoma of endometrium, endotheliosarcoma, ependymoma, epithelioma, erythroleukemia, the cancer of the esophagus, it is female swash
Plain receptor positive breast, primary thrombocytosis, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, reproduction cell
Carcinoma of testis, glioma, spongioblastoma, atypical hyloma, heavy chain disease, hemangioblastoma, liver cancer, liver cell
Cancer, Hormone-refractory prostate cancer, leiomyosarcoma, leukaemia, embryonal-cell lipoma, lung cancer, lymphangioendothelial sarcoma
(lymphagioendotheliosarcoma), lymphangioendothelial sarcoma, Iymphoblastic leukemia, lymthoma (Huo Qijin and Fei Huo
Strange gold), bladder, mammary gland, colon, lung, ovary, pancreas, prostate, skin and uterus malignant tumour and hyperproliferative disorder,
T- cells or B- cell sources lymphoid malignancy, leukaemia, lymthoma, cephaloma, medulloblastoma, melanoma, meningioma,
Celiothelioma, Huppert's disease, myelomatosis, myeloma, myxosarcoma, neuroblastoma, NUT center line cancers (NMC),
Non-small cell lung cancer, oligodendroglioma, carcinoma of mouth, osteogenic sarcoma, oophoroma, cancer of pancreas, papillary adenocarcinoma, mamillary
Cancer, pinealoma, polycythemia vera, prostate cancer, the carcinoma of the rectum, clear-cell carcinoma, retinoblastoma, band muscle
Tumor, sarcoma, carcinoma of sebaceous glands, seminoma, cutaneum carcinoma, Small Cell Lung Cancer, solid tumor (cancer and sarcoma), Small Cell Lung Cancer, stomach
Cancer, squamous cell carcinoma, synovialoma, spiroma, thyroid cancer, primary macroglobulinaemia, orchioncus, uterine cancer and kidney are female
Cytoma etc..
The present invention also provides above-mentioned compound 1, its pharmaceutically acceptable salt, its stereoisomer, its mutually variations
Structure body or its solvate, application in medicine preparation, the drug is for preventing or treating pulmonary disease, inflammatory disease
Or autoimmune disease.
Pulmonary disease, inflammatory disease or the autoimmune disease include but not limited to：Addison disease, acute gout,
Ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin disease, chronic obstructive pulmonary disease (COPD), Crow
Grace disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus
Property ephritis, multiple sclerosis, myocarditis, myositis, ephritis, organ-graft refection, osteoarthritis, pancreatitis, pericarditis, nodositas
Panarteritis, pneumonitis, primary biliary cirrhosis, psoriasis, psoriasis arthropathica, rheumatoid arthritis,
Sclerotitis, sclerosing cholangitis, pyemia, systemic loupus erythematosus, high iS-One arteritis, toxic shock, thyroiditis, I
Patients with type Ⅰ DM, ulcerative colitis, uveitis, leucoderma, vasculitis and wegener granulomatosis etc..
The present invention also provides a kind of pharmaceutical composition, it includes above-mentioned compound 1, its pharmaceutically acceptable salt,
Its stereoisomer, its tautomer or its solvate, and at least one pharmaceutic adjuvant.
The selection of the pharmaceutic adjuvant is different because of administration method and action character, generally can be filler, diluent, glues
Mixture, wetting agent, disintegrant, lubricant, emulsifier or suspending agent etc..
Described compound 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its solvation
The dosage of object can be therapeutically effective amount.
The pharmaceutical composition of the present invention can by oral, injection (vein, muscle, in subcutaneous and coronary artery), it is sublingual,
Buccal, per rectum, per urethra, Via vagina, intranasal, sucking or topic route application, optimization approach is oral.
In the present invention, unless otherwise indicated, the following term occurred in description of the invention and claims has
Following meanings：
Term " stereoisomer " refers to enantiomter, diastereoisomer, epimer (epimers), introversion-
Export-oriented isomers (endo-exo isomers), atropisomer (atropisomers), position are to isomers
(regioisomers), cis--and trans-isomer etc. including all stereoisomers." stereoisomer " of this paper
" pure stereoisomers " and " enrichment stereoisomer " or " raceme " including aforementioned various stereoisomers.These solids are different
Structure body can by method of asymmetric synthesis or chiral separation method (include but not limited to thin-layer chromatography, rotary chromatography, column chromatography,
Gas-chromatography, high pressure liquid chromatography etc.) separation, purifying and enrichment, it can also be by the way that (chemistry is tied with other chipal compounds bondings
Close etc.) or at modes such as salt (physical bond etc.) carry out chiral resolution acquisition." pure stereoisomers " of this paper refer to involvedization
A kind of stereoisomer for closing object is not less than 95% relative to the mass content of other kinds of stereoisomers of the compound.Herein
" enrichment stereoisomer " refer to involved compound a kind of stereoisomer it is different relative to other kinds of solids of the compound
The mass content of structure body is not less than 50%." raceme " of this paper refers to that a kind of quality of stereoisomer of involved compound contains
Amount is equal with the mass content of other kinds of stereoisomers of the compound.
Term " condensed " refers to that two rings share two adjacent atoms.
Term " halogen " refers to fluorine, chlorine, bromine, iodine or astatine.
Term " C1~C6Alkyl " expression includes the radical of saturated aliphatic alkyl of the branch and straight chain of 1~6 carbon atom, specific
Example includes but not limited to：Methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl
(i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), 2- methyl-propyls or isobutyl group (i-Bu ,-CH2CH
(CH3)2), 1- methyl-propyls or sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tertiary butyl (t-Bu ,-C (CH3)3), n-pentyl (-
CH2CH2CH2CH2CH3), 2- amyls (- CH (CH3)CH2CH2CH3), 3- amyls (- CH (CH2CH3)2), 2- methyl -2- butyl (- C
(CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1s-butyl (- CH2CH2CH(CH3)2), 2- first
Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 4- methyl amyls (- CH2CH2CH2CH
(CH3)CH3), 3- methyl amyls (- CH2CH2CH(CH3)CH2CH3), 2- methyl amyls (- CH2CH(CH3)CH2CH2CH3), 2- oneself
Base (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3), 3,3- dimethylbutyl (- CH2CH2CH2
(CH3)2CH3), 2,2- dimethylbutyls (- CH2C(CH3)2CH2CH3), 2- methyl -2- amyls (- C (CH3)2CH2CH2CH3), 3-
Methyl -2- amyls (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyls (- CH (CH3)CH2CH(CH3)2), 3- methyl -3-
Amyl (- C (CH3)(CH2CH3)2), 2- methyl -3- amyls (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C
(CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3)。
Term " C1~C6Alkoxy " indicates the C connected by oxygen bridge1~C6Alkyl；The C1~C6The definition of alkyl is same
On.
Term " C3~C8Naphthenic base " indicate that the saturated cyclic hydrocarbon group of the carbon atom of ring can be formed comprising 3-8, and
Not comprising hetero atom.Wherein ,-CH2Group can be substituted by-C (=O)-,-C (=S)-or-C (=N)-.Suitable naphthenic base packet
It includes, but is not limited to：Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl.Depending on structure, naphthenic base can be monoradical or divalent
Group, i.e. cycloalkylidene.
Term " C3~C6Cycloalkenyl group " indicate that the unsaturated cyclic hydrocarbon group of the carbon atom of ring can be formed comprising 3-6
(comprising one or more double bonds, but at least one ring does not have armaticity), and do not include hetero atom.Wherein ,-CH2Group can
It is substituted by-C (=O)-,-C (=S)-or-C (=N)-.Suitable cycloalkenyl group includes, but is not limited to：Cyclopropanyl, cyclobutane
Base, cyclopentenyl, cyclohexenyl group.Depending on structure, cycloalkenyl group can be monoradical or bivalent group, i.e., sub- cycloalkenyl group.
Term " Heterocyclylalkyl " indicates the 3-10 members comprising 1-4 hetero atom (one or more in N, S and O)
It is saturated one or more cyclic groups (including loop coil, bridged ring and condensed ring).Heterocyclic system can be on any hetero atom or carbon atom
It is connected to and forms stable compound in main structure.Wherein ,-CH2Group can by-C (=O)-,-C (=S)-or-C (=
N)-substitute ,-S- groups can be by-S (=O)-or-S (=O)2It substitutes.For example, monocycle (1-6 carbon atom and the choosing of 3-7 membered rings
From the 1-4 hetero atom of N, S and O；When the ring is a three-membered ring, only one of which hetero atom) or 7-10 atom group
At bicyclic (4-9 carbon atom and 1-4 hetero atom) selected from N, S and O.Depending on structure, Heterocyclylalkyl can be monovalent radical
Group or bivalent group, i.e., sub- Heterocyclylalkyl.In some embodiments, the N atoms in nitrogenous heterocycle can be aoxidized, and form nitrogen oxidation
Object.In some embodiments, N atoms can be quaternized.
Term " heterocycloalkenyl " indicates the 3-10 members comprising 1-4 hetero atom (one or more in N, S and O)
Unsaturated (comprising one or more double bonds, but at least one ring does not have armaticity) one or more cyclic groups (include loop coil, bridge
Ring and condensed ring).Heterocyclic system, which can be connected on any hetero atom or carbon atom in main structure, forms stable change
Close object.Wherein ,-CH2Group can be substituted by-C (=O)-,-C (=S)-or-C (=N)-,-S- groups can by-S (=O)-or-
S (=O)2It substitutes.For example, monocycle (1-6 carbon atom and the 1-4 hetero atom selected from N, S and O of 3-7 membered rings；When described
When ring is three-membered ring, only one of which hetero atom) or 7-10 it is former it is molecular it is bicyclic (4-9 carbon atom and be selected from N, S and
The 1-4 hetero atom of O).Depending on structure, heterocycloalkenyl can be monoradical or bivalent group, i.e., sub- heterocycloalkenyl.Some realities
It applies in example, the N atoms in nitrogenous heterocycle can be aoxidized, and nitrogen oxides is formed.In some embodiments, N atoms can be quaternized.
It is appreciated that be two ring substituents in heterocycloalkenyl, and in the case of one of ring is aromatic rings, connection is to pass through non-aromatic ring
It carries out.
Term " aryl " indicates 6-14 unit monocycles or polycyclic aroma system, and at least one ring has armaticity, and does not include
Hetero atom.It is appreciated that be two ring substituents in aryl substituent, and in the case of one of ring is non-aromatic ring, connection
It is to be carried out by aromatic ring.Term " aryl " can with term " aromatic rings " exchange use, such as, but not limited to phenyl, naphthalene and
Anthryl.Depending on structure, aryl can be monoradical or bivalent group, i.e. arlydene.
Term " heteroaryl " indicates the 5-15 unit monocycles for including 1-4 hetero atom (one or more in N, S and O)
Or polycyclic aroma system, at least one ring has armaticity.Wherein, hetero-aromatic ring and aromatic ring, Bicyclic heteroaromatic rings, tricyclic hetero-aromatic ring
Or Fourth Ring heteroaromatic ring systems cyclization in the form of condensed.Heteroaryl can be connected to master on any hetero atom or carbon atom
Stable compound is formed in structure.Heteroaryl include but not limited to be 5-7 former molecular monocycle or 7-10 original
Molecular bicyclic or 10-15 former molecular tricyclic.Bicyclic with 7-10 atom can be two rings [4,5], [5,
5], [5,6] or [6,6] system, the tricyclic with 10-15 atom can be tricyclic [5,5,6], [5,7,6] or [6,5,6] body
System.Depending on structure, heteroaryl can be monoradical or bivalent group, i.e. inferior heteroaryl.Heteroaryl includes but is not limited to：2-
Furyl, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5-
Isoxazolyl, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, 4- methyl-isoxazole -5- bases, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrroles
Cough up base, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- bases, pyridazinyl (such as 3- pyridazines
Base) base, 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazolyl (such as 2- triazolyls and 5- triazoles
Base), 2- thienyls, 3- thienyls, pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2,3- oxadiazolyl, 1,2,5- oxadiazole
Base, 1,2,4- oxadiazolyl, 1,2,3-triazoles base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1,2,5- thio two
Oxazolyl, 1,3,4- thiadiazoles -2- bases, pyrazinyl, pyrazine -2- bases, 1,3,5-triazines base, benzo [d] thiazol-2-yl, imidazo
[1,5-a] pyridine -6- bases, benzimidazolyl, benzoxazolyl, quinoxalinyl, 1,8- phthalazinyl, benzofuranyl, benzene
Bithiophene base, benzothiazolyl, indoles (such as 2- indyls) base, purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolines
Quinoline), isoquinolyl (such as 1- isoquinolyls, 3- isoquinolyls or 4- isoquinolyls), tetralyl, benzopyrazoles base, acridinyl,
Benzimidazolyl, benzindole base, Ben Bing Yi oxazinyls, benzo [4,6] imidazo [1,2-a] pyridyl group, benzo [d] imidazoles
[2,1-b] thiazolyl, benzofuranyl, benzo aphthofurans base, diazosulfide base, benzothiazolyl, benzo thio-phenyl,
Benzotriazole base, benzo thiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, B-carboline base, carbazyl are adjacent
Phthalazinyl, dibenzofuran group, imidazopyridyl, Imidazothiazole base, indazolyl, indolizine base, indyl, different benzene
And thienyl, iso-dihydro-indole-group, isoquinolyl, isothiazole alkyl, isothiazolyl, naphthyridines base, decahydro indyl, the different Yin of decahydro
Diindyl base, oxazolidinedione base, oxazolidine radical, oxazole and pyridyl group, oxazolyl, Oxyranyle, embedding two pyridyl of tea, phenanthridines
Base, phenanthroline base, phenarsazine base, phenazinyl, phenothiazinyl , phenoxazine groups, phthalazinyl, pteridyl, pyridopyridine base, quinoline azoles
Quinoline base , quinoxalinyls, thio-phenyl, triazine radical, 2H- pyrrolo-es [3,4-c] pyridyl group, pyrazolo [2 ', 1 ':2,3] oxazole is simultaneously
[4,5-c] pyridyl group, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,5-c] pyridyl group, imidazo [2 ', 1 ':2,3] thiazole simultaneously [4,
5-b] pyridyl group, imidazo [2 ', 1 ':2,3] thiazole simultaneously [5,4-b] pyridyl group, pyrazolo [2 ', 1 ':2,3] thiazole simultaneously [4,5-
B] pyrazinyl, 1H- benzos [4,5] thieno [2,3-d] imidazole radicals, 1- methyl-1 H- benzos [4,5] thieno [2,3-d] imidazoles
Base, imidazo [2', 1':2,3] thiazole simultaneously [4,5-b] pyrazinyl, imidazo [2', 1':2,3] thiazole simultaneously [5,4-b] pyridyl group,
Imidazo [2', 1':2,3] thiazole simultaneously [4,5-c] pyridyl group, 1H- benzos [f] imidazo [4,5-b] [Isosorbide-5-Nitrae] sulphur azatropylidene base
Deng.In some embodiments, the N atoms in nitrogenous heterocycle are aoxidized, and form nitrogen oxides.
Term " pharmaceutically acceptable salt " is indicated by suitable non-toxic organic, inorganic acid, organic base or inorganic base
The salt formed with compound 1 retains the bioactivity of compound 1.The organic acid can be this field it is conventional can be at salt
Various organic acids, preferably methanesulfonic acid, trifluoromethanesulfonic acid, benzene methanesulfonic acid, p-methyl benzenesulfonic acid, maleic acid, fumaric acid, succinic acid,
Citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, phenylacetic acid,
It is one or more in isethionic acid, 1-naphthalene sulfonic aicd, 2- naphthalene sulfonic acids, mandelic acid and salicylic acid.The inorganic acid can be this
Field it is conventional can be preferably one or more in hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid at the various inorganic acids of salt.Described
Organic base can be this field it is conventional can be at the various organic bases of salt, preferably pyridines, imidazoles, Pyrazine, indoles, fast quinoline
It is one or more in class, tertiary amines and phenyl amines.The preferred triethylamine of tertiary amines organic base and/or N, N- diisopropyl
Ethamine.The preferred N of phenyl amines organic base, accelerine.The preferred pyridine of pyridines organic base, methyl pyrrole
It is one or more in pyridine, 4-dimethylaminopyridine and 2- methyl -5- ethylpyridines.The inorganic base can be that this field is conventional
Can be at the various inorganic bases of salt, preferred as alkali hydride, the hydroxide of alkali metal, the alkoxide of alkali metal, carbonic acid
It is one or more in potassium, sodium carbonate, lithium carbonate, cesium carbonate, saleratus and sodium bicarbonate.The alkali metal hydride is excellent
Select sodium hydride and/or hydrofining.In the preferred sodium hydroxide of hydroxide of the alkali metal, potassium hydroxide and lithium hydroxide
It is one or more.One kind in the preferred sodium methoxide of alkoxide of the alkali metal, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide
Or it is a variety of.
Term " solvate " indicates the substance that compound 1 is formed with suitable solvent.It is the preferred solvents water
Or organic solvent.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined arbitrarily each preferably to get the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that：The compound can be effectively combined BET families BRD4, BRD3, BRD2 and
The bromine structural domain of BRDT, to regulate and control the transcription of downstream gene c-myc target genes related to its, and then the signal for adjusting downstream is logical
Road plays specific function, including treatment disease such as inflammatory disease, cancer and AIDS；Which part compound has very high work
Property, and there is preferable cell activity and metabolic stability, therefore the active drug for the treatment of tumour can be become.
Specific implementation mode
Below by embodiment, the present invention will be described in detail, but is not meant to any unfavorable limitation of the present invention.
The present invention is described in detail herein, wherein its specific embodiment mode is also disclosed that, to those skilled in the art
Speech, being directed to specific embodiment of the invention progress various changes and modifications without departing from the spirit and scope of the present invention will
It is obvious.
In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or says according to commodity
Bright book selection.Raw material can obtain from commercial channels, or be prepared by methods known in the art, or according to side described herein
It is prepared by method.The structure of compound by nuclear magnetic resonance (1HNMR) or mass spectrum (MS) determines, wherein NMR, which is measured, to be used
BrukerAV-300 type Nuclear Magnetic Resonance, measurement solvent are deuterated dimethyl sulfoxide (DMSO-D6) or deuterochloroform (CDCl3), TMS
For internal standard.
Embodiment 1:6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H-
Benzo [d] imidazoles -4- nitriles
Step 1:4- methyl-N'- (phenyl tetrahydrochysene -2H- pyrans -4- bases) methylene) benzene sulfonyl hydrazide
By phenyl (tetrahydrochysene -2H- pyrans -4- bases) ketone (1.9g, 10mmol) and 4- toluenesulfonic acids (172mg, 1mmol)
It is dissolved in methanol (30mL), 4- Methyl benzenesulfonyls hydrazine (1.99g, 10.7mmol) is then added.Reaction solution is in 50 DEG C and nitrogen protection
Under be stirred overnight, be then cooled to room temperature, be further continued for stirring 10 minutes.Crude title compound (3.5g, 93%) is filtered to obtain, is white
Color solid.LCMS(ESI)[M+H]+=359.2.
Step 2:The iodo- 6- nitroanilines of the bromo- 4- of 2-
The bromo- 6- nitroanilines (5.65g, 26.0mmol) of 2- are dissolved in acetic acid (40mL), N- iodo ambers are then added
Acid imide (5.4g, 31.2mmol), reaction solution are stirred overnight at 50 DEG C, are then cooled to room temperature.It is diluted with water reaction solution, continues to stir
It mixes 10 minutes.Crude title compound (9g) is filtered to obtain, is crocus solid.LCMS(ESI)[M+H]+=344.9.
Step 3:The bromo- 5- iodobenzenes -1,2- diamines of 3-
By compound 1B (9.0g, 26.2mmol), iron powder (7.35g, 131mmol) and ammonium chloride (21.1g, 394mmol)
It is dissolved in ethyl alcohol (120mL), in tetrahydrofuran (120mL) and water (60mL), and is stirred 2 hours at 90 DEG C.Reaction solution is cooled to room
Temperature, filtering, filtrate concentration obtain crude title compound (8.01g), are brown solid, are directly used in without further purification anti-in next step
It answers.LCMS(ESI)[M+H]+=314.9.
Step 4:Iodo- 1H- benzos [d] imidazoles of the bromo- 6- of 4-
Compound 1C (8.01g, 25.6mmol) is dissolved in formic acid (15mL), and in 100 DEG C and stirred under nitrogen atmosphere 3
Hour, then concentrate.Residue is re-dissolved in dichloromethane, is washed with dilute aqueous solution of sodium bicarbonate, anhydrous sodium sulfate drying, filtering
And it concentrates.Residue isolates and purifies (methylene chloride/methanol=10/1) with flash chromatography, obtain title compound (3.83g, three
Walk yield 46%), it is Light brown solid.LCMS (ESI) [M+H] +=324.9.
Step 5:The iodo- 1- of the bromo- 6- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles
By compound 1D (1.87g, 6.0mmol), compound 1A (900mg, 2.51mmol), acetylacetone copper (89mg,
It 0.34mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (15mL) with cesium carbonate (1.11g, 3.4mmol), and in 100 DEG C and nitrogen protection
Under be stirred overnight.Filtering, filtrate concentration, residue isolate and purify (petrol ether/ethyl acetate=1/4) with flash chromatography, obtain
Title compound (437mg, 52%) is white solid.LCMS(ESI)[M+H]+=498.9.
Step 6:4- (the bromo- 1- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3,
5- dimethyl isoxazoles
By compound 1E (200mg, 0.40mmol), 3,5- dimethyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxos
Penta ring -2- bases of boron) isoxazole (108mg, 0.48mmol), sodium carbonate (217mg, 2.01mmol) and tetra-triphenylphosphine palladium (93mg,
It 0.08mmol) is dissolved in 2- methyltetrahydrofurans (6mL) and water (3mL), and is stayed overnight in 60 DEG C and stirred under nitrogen atmosphere.It crosses
Filter, filtrate are extracted with ethyl acetate.Organic phase is separated, is dried, filtered and concentrated with anhydrous sodium sulfate.Residue flash chromatography
Method isolates and purifies (petrol ether/ethyl acetate=1/4), obtains title compound (220mg), is yellow solid.LCMS(ESI)[M+
H]+=466.1.
Step 7:6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzene
And [d] imidazoles -4- nitriles
By compound 1F (92mg, 0.197mmol), zinc cyanide (48mg, 0.394mmol) and tetra-triphenylphosphine palladium (24mg,
It 0.020mmol) is dissolved in n,N-Dimethylformamide (4mL), and is stayed overnight in 100 DEG C and stirred under nitrogen atmosphere.Filtering, filtrate
It is extracted with ethyl acetate.Organic phase is separated, is dried, filtered and concentrated with anhydrous sodium sulfate.Residue is pure with preparation-HPLC separation
Change, obtain title compound (35mg, 43%), is white solid.MS(ESI):M/z=413.1 [M+1]+；1H NMR(400MHz,
DMSO-d6) δ 9.06 (s, 1H), 8.21 (d, J=1.6Hz, 1H), 7.76 (d, J=1.2Hz, 1H), 7.67 (d, J=6.8Hz,
2H), 7.38 (t, J=7.2Hz, 2H), 7.29 (t, J=7.2Hz, 1H), 5.56 (d, J=10.8Hz, 1H), 3.91-3.80 (m,
2H),3.34-3.25(m,2H),3.10-2.97(m,1H),4.49(s,2H),2.42(s,3H),2.26(s,3H),1.37-
1.18(m,4H).
Embodiment 2:6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H-
Benzo [d] imidazole-4-carboxamide
Step 1:6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzene
And [d] imidazole-4-carboxamide
Embodiment 1 (56mg, 0.140mmol) and potassium carbonate (50mg, 0.362mmol) are dissolved in dimethyl sulfoxide (DMSO) (2mL),
Then 30% aqueous hydrogen peroxide solution (0.5mL) is added.Reaction is stirred at room temperature 3 hours.Reaction is quenched with water, is used in combination
Ethyl acetate extracts, and ethyl acetate layer is separated, with water and saturated common salt water washing, dry (anhydrous sodium sulphate), filtering
And be concentrated in vacuo, residue is isolated and purified with reverse phase preparation-HPLC, and it is white to obtain title compound (8.2mg, yield 14%)
Color solid.LCMS(ESI)[M+H]+=431.2；1H NMR(400MHz,DMSO-d6) δ 9.11 (d, J=3.6Hz, 1H), 9.05
(s, 1H), 8.06 (d, J=1.6Hz, 1H), 7.86 (d, J=2.8Hz, 1H), 7.78 (d, J=1.6Hz, 1H), 7.86 (d, J=
7.2Hz, 2H), 7.37 (t, J=7.2Hz, 2H), 7.29 (t, J=7.2Hz, 1H), 5.57 (d, J=11.2Hz, 1H), 3.93-
3.79(m,2H),3.39-3.25(m,2H),3.13-2.96(m,1H),2.41(s,3H),2.24(s,3H),1.39-1.22(m,
4H).
Embodiment 3:3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -4- (1H- pyrazoles -4-
Base) -1H- benzos [d] imidazoles -6- bases) isoxazole
Step 1:3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -4- (1H- pyrazoles -4- bases) -
1H- benzos [d] imidazoles -6- bases) isoxazole
By compound 1F (112mg, 0.24mmol), 3,5- dimethyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxos
Penta ring -2- bases of boron) isoxazole (70mg, 0.36mmol), sodium carbonate (104mg, 0.96mmol) and tetra-triphenylphosphine palladium (56mg,
It 0.048mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (6mL) and water (1.5mL), microwave heating is stirred under nitrogen protection to 100 DEG C
2 hours.Reaction solution is cooled to room temperature, and filtering, filtrate is extracted with ethyl acetate again.Organic phase is dried with anhydrous sodium sulfate, and filtering is simultaneously
Concentration.Residue is isolated and purified with preparation-HPLC, obtains title compound (7.8mg, 7%), is white solid.LCMS(ESI)[M
+H]+=454.2；1H NMR(400MHz,DMSO-d6)δ12.96(s,1H),8.81(s,1H),8.61(s,1H),8.37(s,
1H), 7.66 (d, J=7.2Hz, 1H), 7.60 (s, 1H), 7.46 (s, 1H), 7.36 (t, J=7.6Hz, 2H), 7.86 (t, J=
7.6Hz, 1H), 5.45 (d, J=11.2Hz, 1H), 3.89-3.80 (m, 2H), 3.46-3.254 (m, 2H), 3.07-2.94 (m,
1H),2.41(s,3H),2.33(s,3H),1.44-1.28(m,4H).
Embodiment 4:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles -4- nitriles
Step 1:The bromo- 6- of 4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- benzos [d] imidazoles
By compound 1E (175mg, 0.25mmol), 1,4- dimethyl -5- (tri-n-butyl tin) -1H-1,2,3- triazoles
(175mg, 0.33mmol) and tetra-triphenylphosphine palladium (29mg, 0.025mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (10mL), and
110 DEG C are stayed overnight with stirred under nitrogen atmosphere.Filtering, filtrate are extracted with ethyl acetate.Organic phase is separated, it is dry with anhydrous sodium sulfate
It is dry, it filters and concentrates.Residue isolates and purifies (petrol ether/ethyl acetate=1/4) with flash chromatography, obtains title compound
(46mg, 28%) is yellow solid.LCMS(ESI)[M+H]+=466.1.
Step 2:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -1H- benzos [d] imidazoles -4- nitriles
By compound 4A (38mg, 0.081mmol), zinc cyanide (19mg, 0.163mmol) and tetra-triphenylphosphine palladium (9mg,
It 0.008mmol) is dissolved in n,N-Dimethylformamide (4mL), and is stayed overnight in 100 DEG C and stirred under nitrogen atmosphere.Filtering, filtrate
It is extracted with ethyl acetate.Organic phase is separated, is dried, filtered and concentrated with anhydrous sodium sulfate.Residue is pure with preparation-HPLC separation
Change, obtain title compound (20.4mg, 61%), is white solid.MS(ESI):M/z=413.2 [M+1]；1H NMR
(400MHz,DMSO-d6) δ 9.13 (s, 1H), 8.37 (d, J=1.2Hz, 1H), 7.90 (d, J=1.2Hz, 1H), 7.68 (d, J
=6.8Hz, 2H), 7.37 (t, J=7.2Hz, 2H), 7.29 (t, J=7.2Hz, 1H), 5.58 (d, J=11.2Hz, 1H), 3.96
(s,3H),3.89-3.80(m,2H),3.38-3.24(m,2H),3.10-2.97(m,1H),2.24(s,3H),1.36-1.19
(m,4H).
Embodiment 5:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazole-4-carboxamide
Step 1:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -1H- benzos [d] imidazole-4-carboxamide
Embodiment 4 (30mg, 0.073mmol) and potassium carbonate (50mg, 0.362mmol) are dissolved in dimethyl sulfoxide (DMSO) (2mL),
Then 30% aqueous hydrogen peroxide solution (0.5mL) is added.Reaction is stirred at room temperature 3 hours.Reaction is quenched with water, is used in combination
Ethyl acetate extracts, and ethyl acetate layer is separated, with water and saturated common salt water washing, dry (anhydrous sodium sulphate), filtering
And be concentrated in vacuo, residue is isolated and purified with reverse phase preparation-HPLC, obtains title compound (16.2mg, 52%), solid for white
Body.LCMS(ESI)[M+H]+=431.2；1H NMR(400MHz,DMSO-d6) δ 9.12 (s, 1H), 9.09 (d, J=2.8Hz,
1H), 8.23 (d, J=1.2Hz, 1H), 7.92 (d, J=3.2Hz, 1H), 7.85 (d, J=1.2Hz, 1H), 7.69 (d, J=
7.2Hz, 2H), 7.37 (t, J=7.2Hz, 2H), 7.29 (t, J=7.2Hz, 1H), 5.57 (d, J=11.6Hz, 1H), 3.95
(s,3H),3.89-3.81(m,2H),3.39-3.26(m,2H),3.10-2.97(m,1H),2.32(s,3H),1.40-1.21
(m,4H).
Embodiment 6:3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -
6- yls) isoxazole
Step 1:3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base) isoxazole
Compound 1F (170mg, 0.36mmol) is dissolved in ethyl alcohol (40mL), palladium/carbon (34mg, 10%w/w is then added
Palladium) and ammonium formate (230mg, 3.6mmol).Reaction solution is stirred overnight at 90 DEG C, is then cooled to room temperature.It is anti-with Celite pad filtering
It answers liquid, filtrate concentration, residue to be isolated and purified with preparation-HPLC, obtains title compound (70mg, 50%), be white solid.MS
(ESI):M/z=388.1 [M+1]+；1H NMR(400MHz,DMSO-d6) δ 9.04 (s, 1H), 7.87 (s, 1H), 7.73 (d, J=
8.4Hz, 1H), 7.66 (d, J=7.2Hz, 2H), 7.37 (t, J=7.6Hz, 2H), 7.30 (d, J=7.6Hz, 1H), 7.25 (d,
J=8.4Hz, 1H), 5.52 (d, J=10.8Hz, 1H), 3.88-3.80 (m, 2H), 3.38-3.25 (m, 2H), 3.05-2.94
(m,1H),2.41(s,3H),2.24(s,3H),1.40-1.27(m,4H).
Embodiment 7,8:(S) -3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos
[d] imidazoles -6- bases) isoxazole；With
(R) -3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6-
Base) isoxazole
Embodiment 6 (65mg) detaches (instrument with chiral preparation-HPLC:SFC-80；Column：AD columns), the separation ginseng of chiral column
Number：Instrument:SFC-80(Thar,Waters)；Chromatographic column:AD 20*250mm,10μm(Daicel)；Column temperature:35℃；Mobile phase:
CO2/IPA (0.2% saturation ammonia methanol solution)=75/25；Flow velocity:80g/min；Back pressure:100bar；Detection wavelength:
220nm；Run time:7.0min.Respectively obtain two configurations：Embodiment 7 (16.5mg) is white solid.RTchiral=
2.73min is R or S configurations, MS (ESI):M/z=388.1 [M+1]+；1H NMR(400MHz,DMSO-d6)δ8.78(s,
1H), 7.79 (s, 1H), 7.69 (d, J=8.4Hz, 1H), 7.65 (d, J=7.6Hz, 2H), 7.35 (t, J=7.2Hz, 2H),
7.27 (t, J=7.2Hz, 1H), 7.16 (dd, J=1.2Hz, 8.4Hz, 1H), 5.45 (d, J=11.6Hz, 1H), 3.88-3.80
(m,2H),3.31-3.26(m,2H),3.07-2.93(m,1H),2.41(s,3H),2.24(s,3H),1.38-1.18(m,4H)。
It is white solid with embodiment 8 (13.1mg).RTchiral=3.38min is the enantiomter of embodiment 7,
MS(ESI):M/z=388.1 [M+1]+；1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),7.79(s,1H),7.69(d,J
=8.4Hz, 1H), 7.65 (d, J=7.2Hz, 2H), 7.35 (t, J=7.2Hz, 2H), 7.27 (t, J=7.6Hz, 1H), 7.16
(dd, J=1.2Hz, 8.0Hz, 1H), 5.44 (d, J=11.2Hz, 1H), 3.88-3.80 (m, 2H), 3.32-3.26 (m, 2H),
3.06-2.94(m,1H),2.41(s,3H),2.24(s,3H),1.38-1.18(m,4H).
Embodiment 9:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles
Step 1:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -1H- benzos [d] imidazoles
Compound 4A (50mg, 0.107mmol) is dissolved in ethyl alcohol (20mL), palladium/carbon (25mg, 10%w/w is then added
Palladium) and ammonium formate (135mg, 1.07mmol).Reaction solution is stirred overnight at 90 DEG C, is then cooled to room temperature.It is filtered with Celite pad
Reaction solution, filtrate concentration, residue are isolated and purified with preparation-HPLC, obtain title compound (19.5mg, 47%), solid for white
Body.MS(ESI):M/z=388.2 [M+1]+；1HNMR(400MHz,DMSO-d6) δ 8.85 (s, 1H), 7.96 (d, J=1.2Hz,
1H), 7.76 (d, J=8.0Hz, 1H), 7.66 (d, J=6.8Hz, 2H), 7.36 (t, J=7.2Hz, 2H), 7.27 (t, J=
7.2Hz, 2H), 5.47 (d, J=11.2Hz, 1H), 3.94 (s, 3H), 3.87-3.79 (m, 2H), 3.38-3.24 (m, 2H),
3.08-2.95(m,1H),2.23(s,3H),1.37-1.19(m,4H).
Embodiment 10 and 11:(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H-
Pyrans -4- bases) methyl) -1H- benzos [d] imidazoles；With
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles
Embodiment 9 (65mg) detaches (instrument with chiral preparation-HPLC:SFC-80；Column：AD-H columns), the separation of chiral column
Parameter：Instrument:SFC-80(Thar,Waters)；Chromatographic column:AD-H 20*250mm,5μm(Daicell)；Column temperature:35℃；Stream
Dynamic phase:CO2/ methanol (0.2% saturation ammonia methanol solution)=75/25；Flow velocity:70g/min；Back pressure:100bar；Detect wave
It is long:214nm；Run time:5min.Respectively obtain two configurations：Embodiment 10 (16.7mg) is white solid.RTchiral=
2.52min is R or S configurations, MS (ESI):M/z=388.2 [M+1]+；1H NMR(400MHz,DMSO-d6)δ8.86(s,
1H), 7.97 (d, J=1.2Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.66 (d, J=6.8Hz, 2H), 7.36 (t, J=
7.2Hz, 2H), 7.27 (t, J=7.2Hz, 2H), 5.47 (d, J=11.6Hz, 1H), 3.94 (s, 3H), 3.87-3.79 (m,
2H),3.38-3.24(m,2H),3.08-2.95(m,1H),2.24(s,3H),1.36-1.17(m,4H).
Embodiment 11 (16.4mg) is white solid.RTchiral=3.2min is the enantiomter of embodiment 10,
MS(ESI):M/z=388.2 [M+1]+；1H NMR(400MHz,DMSO-d6) δ 8.86 (s, 1H), 7.97 (d, J=1.2Hz,
1H), 7.76 (d, J=8.0Hz, 1H), 7.66 (d, J=6.8Hz, 2H), 7.36 (t, J=7.2Hz, 2H), 7.27 (t, J=
7.2Hz, 2H), 5.47 (d, J=11.2Hz, 1H), 3.95 (s, 3H), 3.87-3.79 (m, 2H), 3.38-3.24 (m, 2H),
3.08-2.95(m,1H),2.24(s,3H),1.36-1.20(m,4H).
Embodiment 12:3- ethyoxyl -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos
[d] imidazoles -6- bases) pyridine -2 (1H) -one
Step 1:Bromo- -2 (1H) -one of 3- methoxyl groups -1- picolines of 5-
By the bromo- 2,3- dihydroxy-pyridines (4.00g, 20.83mmol) of 5-, iodomethane (7.39g, 52.08mmol) and carbonic acid
Potassium (8.64g, 62.50mmol) is dissolved in n,N-Dimethylformamide (40mL), and is stirred at room temperature 16 hours.Reaction solution mistake
Filter, filtrate concentration.Residue is isolated and purified with reverse phase flash chromatography, obtains title compound (4.30g, 95%), solid for brown
Body.MS(ESI):M/z=218.0 [M+H]+.
Step 2:Bromo- -2 (1H) -one of 3- hydroxyls -1- picolines of 5-
It is slowly added into Boron tribromide into dichloromethane (10mL) solution of compound 12A (1.09g, 5.0mmol)
(1.5g, 6.0mmol), reaction solution is stirred at room temperature overnight.Methanol (20mL) is added, reaction is quenched, concentrate, residue is with soon
Fast chromatography isolates and purifies (petrol ether/ethyl acetate=1/2), obtains title compound (860mg, 84%), is violet solid.MS
(ESI):M/z=204.1 [M+H]+.
Step 3:Bromo- -2 (1H) -one of 3- ethyoxyls -1- picolines of 5-
By compound 12B (1.05g, 5.15mmol), iodoethane (1.60g, 10.30mmol) and potassium carbonate (1.42g,
It 10.30mmol) is dissolved in n,N-Dimethylformamide (5mL), and is stirred 2 hours at 80 DEG C.Add water and acetic acid into reaction solution
Ethyl ester separates organic layer, and with saturated common salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated, residue flash chromatography
(petrol ether/ethyl acetate=1/1) is isolated and purified, title compound (750mg, 63%) is obtained, is white solid.MS(ESI):m/
Z=234.0 [M+H]+.
Step 4:3- ethyoxyl -1- methyl -5- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxos boron) pyridine -
2 (1H) -one
By compound 12C (500mg, 2.15mmol), connection boric acid pinacol ester (1.64g, 6.45mmol), three (two benzal
Benzylacetone) palladium (0) (200mg, 0.22mmol), 2- dicyclohexylphosphontetrafluoroborates -2', 4', 6'- triisopropyl -1,1'- biphenyl (210mg,
It 0.44mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (20mL) with potassium acetate (632mg, 6.45mmol), and in 70 DEG C and nitrogen protection
Under be stirred overnight.Concentration of reaction solution, residue isolate and purify (petrol ether/ethyl acetate=1/4) with flash chromatography, obtain title
Compound (450mg, 75%) is brown solid.LCMS(ESI)[M+H]+=280.1.
Step 5:5- (- 6 base of the bromo- 1- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles) -3-
Ethyoxyl -1- picolines -2 (1H) -one
By compound 1E (141mg, 0.25mmol), compound 12D (95mg, 0.34mmol), sodium carbonate (151mg,
1.4mmol) it is dissolved in 2- methyltetrahydrofurans (8mL) and water (4mL) with tetra-triphenylphosphine palladium (33mg, 0.028mmol), and
60 DEG C are stayed overnight with stirred under nitrogen atmosphere.Filtering, filtrate are extracted with ethyl acetate.Organic phase is separated, is dried with anhydrous sodium sulfate,
It filters and concentrates.Residue isolates and purifies (petrol ether/ethyl acetate=1/4) with flash chromatography, obtains title compound
(110mg, 74%) is yellow solid.LCMS(ESI)[M+H]+=522.1.
Step 6:3- ethyoxyl -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] miaows
Azoles -6- bases) pyridine -2 (1H) -one
Compound 12E (84mg, 0.16mmol) is dissolved in ethyl alcohol (20mL), palladium/carbon (84mg, 10%w/w is then added
Palladium) and ammonium formate (304mg, 4.8mmol).Reaction solution is stirred overnight at 90 DEG C, is then cooled to room temperature.It is anti-with Celite pad filtering
It answers liquid, filtrate concentration, residue to be isolated and purified with preparation-HPLC, obtains title compound (25mg, 35%), be white solid.MS
(ESI):M/z=444.2 [M+1]+；1H NMR(400MHz,DMSO-d6) δ 8.73 (s, 1H), 7.94 (d, J=1.6Hz, 1H),
7.71-7.61 (m, 4H), 7.43-7.33 (m, 3H), 7.30-7.25 (m, 1H), 7.17 (d, J=2Hz, 1H), 5.52 (d, J=
11.6Hz,1H),4.12-4.07(m,2H),3.90-3.80(m,2H),3.55(s,3H),3.32-3.24(m,2H),3.03-
2.88 (m, 1H), 1.38 (t, J=6.8Hz, 3H), 1.34-1.27-1 (m, 4H)
Embodiment 13:(R) -3,5- dimethyl -4- (1- (1- (pyridine -2- bases) -2- p-methylphenyls ethyl) -1H- benzos
[d] imidazoles -6- bases) isoxazole
Step 1:(1S, 2S, 5S, E) -2,6,6- trimethyls -3- (pyridine -2- ylmethyls imino group) bicyclic [3.1.1] heptan
Alkane -2- hydroxyls
By bicyclic [3.1.1] heptane -3- ketone of (1S, 2S, 5S) -2- hydroxyl -2,6,6- trimethyls (4.00g, 23.8mmol)
(60mL) is dissolved in toluene with pyridine -2- bases methylamine (2.63g, 23.8mmol), and the ether that boron trifluoride is then slowly added dropwise is molten
Liquid (0.24mL, 0.24mmol).Reaction solution is heated to reflux and is stirred overnight, and then concentrates.Residue is detached with flash chromatography
It purifies (petrol ether/ethyl acetate=2/1~1/1), it is colorless oil (3g, 49%) to obtain title compound.LCMS(ESI):
M/z=259.2 [M+1]+.
Step 2:(1S, 2S, 5S, E) -2,6,6- trimethyls -3- ((R) -1- (pyridine -2- bases) -2- p-methylphenyls-ethyl
Imido grpup) bicyclic [3.1.1] heptane -2- hydroxyls
At -78 DEG C, to (1S, 2S, 5S, E) -2,6,6- trimethyl -3- (pyridine -2- ylmethyls imino group) are bicyclic
N-BuLi (2.5N is slowly added dropwise in (12mL) in the tetrahydrofuran solution of [3.1.1] heptane -2- hydroxyls (1.4g, 5.43mmol)
Tetrahydrofuran solution, 13.58mmol, 5.4mL), keep this temperature stir 2 hours, then slowly be added dropwise 1- (bromomethyl) -4-
The tetrahydrofuran solution (10mL) of methylbenzene (3.5g, 19mmol), and continue stirring 2 hours at this temperature.Into reaction solution
Saturated ammonium chloride solution is added and reaction is quenched in ethyl acetate (20mL), separates organic layer, is dried with anhydrous sodium sulfate, filtering is simultaneously
Concentration, residue isolate and purify (petrol ether/ethyl acetate=4/1~2/1) with flash chromatography, and it is yellow to obtain title compound
Grease (694mg, 35%).LCMS(ESI):M/z=363.3 [M+1]+.
Step 3:(R) -1- (pyridine -2- bases) -2- p-methylphenyl ethylamines
By (1S, 2S, 5S, E) -2,6,6- trimethyls -3- ((R) -1- (pyridine -2- bases) -2- p-methylphenyls-ethylimido
Base) bicyclic [3.1.1] heptane -2- hydroxyls (650mg 1.79mmol) and hydroxylamine hydrochloride (622mg, 8.95mmol) be dissolved in acetic acid
In (0.5mL) and ethyl alcohol (10mL), and it is heated to 90 DEG C and stirs 24 hours.Reaction solution is cooled to room temperature, is neutralized with ammonium hydroxide and uses second
Acetoacetic ester extracts (50mL*2), merges organic phase and is washed with brine (25mL) and water (25mL), anhydrous sodium sulfate drying, filtering
And concentrate, it is brown oil (315mg, 85%) to obtain title compound.LCMS(ESI)[M+H]+=213.0.
Step 4:(R) the bromo- 2- nitros-N- of -5- (1- (pyridine -2- bases) -2- p-methylphenyls ethyl) aniline
By (R) -1- (pyridine -2- bases) -2- p-methylphenyls ethylamine (314mg, 1.48mmol), the fluoro- 1- nitros of the bromo- 2- of 4-
Benzene (488mg, 2.22mmol) and potassium carbonate (409mg, 2.96mmol) are dissolved in acetonitrile (10mL), and it is small to be heated to 70 DEG C of stirrings 16
When.Reaction solution is poured into water (100mL) and (50*3mL) is extracted with ethyl acetate.Merge organic phase and with brine (25mL) and
Water (25mL) washs, and anhydrous sodium sulfate is dried, filtered and concentrated, and obtains crude title compound (600mg, 98%), without further purification
It is directly used in and reacts in next step.LCMS(ESI)[M+H]+=414.0.Chiral analysis shows that it is single configuration, RTchiral=
2.12min (OJ columns).
Step 5:(R) the bromo- N1- of -5- (1- (pyridine -2- bases) -2- tolylethyls) benzene -1,2- diamines
By the bromo- 2- nitros-N- of (R) -5- (1- (pyridine -2- bases) -2- p-methylphenyls ethyl) aniline (615mg,
1.49mmol), iron powder (417mg, 7.45mmol) and ammonium chloride (160mg, 2.96mmol) are dissolved in tetrahydrofuran (10mL), ethyl alcohol
In (10mL) and water (4mL), and it is heated to 100 DEG C and stirs 2 hours.Reaction solution is cooled to room temperature and is filtered, filtrate concentration.It is remaining
Object isolates and purifies (ethyl acetate/petroleum ether=1/5) with flash chromatography, obtain title compound be yellow oil (500mg,
88%).MS(ESI):M/z=382.1 [M+1]+.
Step 6:(R) the bromo- 1- of -6- (1- (pyridine -2- bases) -2- tolylethyls) -1H- benzos [d] imidazoles
By the bromo- N1- of (R) -5- (1- (pyridine -2- bases) -2- tolylethyls) benzene -1,2- diamines (450mg, 1.18mmol)
It is heated to 100 DEG C with the mixed liquor of formic acid (5mL) and stirs 1 hour.Decompression boils off solvent, and residue is re-dissolved in ethyl acetate
(50mL), is washed with saturated sodium carbonate solution, and anhydrous sodium sulfate is dried, filtered and concentrated.Residue is detached with flash chromatography
It purifies (ethyl acetate/petroleum ether=1/4), it is white solid (350mg, 76%) to obtain title compound.LCMS(ESI)[M+H]+
=392.0.
Step 7:(R) -3,5- dimethyl -4- (1- (1- (pyridine -2- bases) -2- p-methylphenyls ethyl) -1H- benzos [d] miaows
Azoles -6- bases) isoxazole
By the bromo- 1- of (R) -6- (1- (pyridine -2- bases) -2- tolylethyls) -1H- benzos [d] imidazoles (80mg,
0.20mmol), 3,5- dimethyl -4- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron) isoxazole (67mg,
0.30mmol), [1,1 '-bis- (diphenylphosphino) ferrocene] dichloro palladium (II) (15mg, 0.02mmol) and potassium carbonate (83mg,
It 0.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (5mL) and water (1mL), and is reacted 4 hours in 100 DEG C and stirred under nitrogen atmosphere.
Reaction solution is cooled to room temperature and filters, and filtrate is re-dissolved in ethyl acetate, is washed with brine, and anhydrous sodium sulfate is dried, filtered and concentrated.
Residue isolates and purifies (ethyl acetate/petroleum ether=4/1) with flash chromatography, and obtained crude product further uses preparation-HPLC
Purifying, it is white solid (60mg, 73%) to obtain sterling title compound.MS(ESI):M/z=409.2 [M+H]+；1H NMR
(400MHz,DMSO-d6) δ 8.63 (s, 1H), 8.59 (d, J=4.0Hz, 1H), 7.77 (dt, J=8.0,1.6Hz, 1H), 7.65
(s, 1H), 7.62 (s, 1H), 7.55 (d, J=7.6Hz, 1H), 7.31 (dd, J=4.8,5.6Hz, 2H), 7.18-7.09 (m,
3H),6.99(s,1H),6.97(s,1H),6.22-6.16(m,1H),3.82-3.66(m,2H),2.35(s,3H),2.18(s,
3H),2.17(s,3H).
Embodiment 14:(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (1- (pyridine -2- bases) -2-
Tolylethyl) -1H- benzos [d] imidazoles
Step 1:(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (1- (pyridine -2- bases) -2- toluene
Base ethyl) -1H- benzos [d] imidazoles
By the bromo- 1- of (R) -6- (1- (pyridine -2- bases) -2- tolylethyls) -1H- benzos [d] imidazoles (100mg,
0.25mmol), 1,4- dimethyl -5- (tri-n-butyl tin base) -1H-1,2,3- triazoles (193mg, 0.50mmol), four triphens
Base phosphine palladium (29mg, 0.25mmol) and cuprous iodide (10mg) are dissolved in Isosorbide-5-Nitrae-dioxane (5mL), and in 125 DEG C and nitrogen
The lower stirring of protection 48 hours.Reaction solution is cooled to room temperature and filters, and filtrate is extracted with ethyl acetate.Organic phase is separated, with anhydrous sulphur
Sour sodium is dried, filtered and concentrated.Residue isolates and purifies (petrol ether/ethyl acetate=1/4) with flash chromatography, and what is obtained is thick
Product further use preparation-HPLC purifying, obtain sterling title compound (40mg, 39%), are white solid.MS(ESI):M/z=
409.2[M+H]+；1HNMR(400MHz,DMSO-d6) δ 8.72 (s, 1H), 8.60 (d, J=4.0Hz, 1H), 7.81 (s, 1H),
7.78 (dt, J=7.6,1.2Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 7.57 (d, J=7.6Hz, 1H), 7.34-7.29 (m,
1H), 7.22 (d, J=8.4Hz, 1H), 7.16 (s, 1H), 7.14 (s, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 6.25-6.19
(m,1H),3.89(s,3H),3.84-3.67(m,2H),2.18(s,3H),2.16(s,3H).
Embodiment 15:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) the fluoro- 1- of -4- (phenyl (tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) -1H- benzos [d] imidazoles
Step 1:The bromo- 3- fluorobenzene -1,2- diamines of 5-
By the fluoro- 6- nitroanilines (1.5g, 6.3mmol) of the bromo- 2- of 4-, iron powder (1.8g, 31.8mmol) and ammonium chloride
(5.1g, 96.0mmol) is dissolved in ethyl alcohol (15mL), in tetrahydrofuran (15mL) and water (5mL), and is heated to 90 DEG C of stirring 2h.Instead
It answers liquid cooling to room temperature, filters, filtrate concentration obtains crude title compound (1.69g), is directly used in without further purification anti-in next step
It answers.LCMS(ESI)[M+H]+=206.2.
Step 2:Fluoro- 1H- benzos [d] imidazoles of the bromo- 4- of 6-
Compound 15A (457mg, 2.23mmol) is dissolved in formic acid (2mL), and is heated to 100 DEG C under nitrogen protection
Stirring 3 hours.Reaction solution is cooled to room temperature, and filtering, filtrate is re-dissolved in dichloromethane, is washed with dilute sodium bicarbonate solution and salt
It washs, anhydrous sodium sulfate is dried, filtered and concentrated, and obtains crude title compound (439mg), is yellow solid.LCMS(ESI)[M+
H] +=217.0.
Step 3:The fluoro- 1- of the bromo- 4- of 6- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles
By compound 15B (323mg, 1.5mmol), compound 1A (808mg, 2.25mmol), acetylacetone copper (79mg,
0.3mmol) and cesium carbonate (975mg, 3.0mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (12mL), and is heated to 100 under nitrogen protection
It DEG C is stirred overnight.Reaction solution is cooled to room temperature and filters, filtrate concentration.Residue isolates and purifies (petroleum ether/second with flash chromatography
Acetoacetic ester=1/4), title compound (174mg, 30%) is obtained, is white solid.LCMS(ESI)[M+H]+=391.1.
Step 4:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) the fluoro- 1- of -4- (phenyl (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- benzos [d] imidazoles
By compound 15C (135mg, 0.35mmol), 1,4- dimethyl -5- (tri-n-butyl tin) -1H-1,2,3- triazoles
(267mg, 0.69mmol), tetra-triphenylphosphine palladium (40mg, 0.035mmol) and cuprous iodide (5mg) are dissolved in Isosorbide-5-Nitrae-dioxane
In (6mL), and in 125 DEG C and stirred under nitrogen atmosphere 30 hours.Filtering, filtrate are extracted with ethyl acetate.Organic phase is separated, is used
Anhydrous sodium sulfate is dried, filtered and concentrated.Residue isolates and purifies (petrol ether/ethyl acetate=1/4) with flash chromatography, obtains
Title compound (30mg, 22%) is white solid.LCMS(ESI)[M+H]+=406.2；1H NMR(400MHz,DMSO-d6)
δ 8.92 (s, 1H), 7.85 (d, J=1.2Hz, 1H), 7.67 (d, J=6.4Hz, 1H), 7.37 (t, J=8.0Hz, 2H), 7.29
(t, J=7.6Hz, 1H), 7.21 (dd, J=11.2Hz, 0.8Hz, 1H), 5.50 (d, J=11.6Hz, 1H), 3.96 (s, 3H),
3.88-3.80(m,2H),3.39-3.26(m,2H),3.10-2.97(m,1H),2.24(s,3H),1.40-1.21(m,4H).
Embodiment 16:1- benzhydryls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d] miaow
Azoles
Step 1:The bromo- 2- nitroanilines of N- benzhydryls -5-
By the fluoro- 1- nitrobenzenes (500mg, 2.27mmol) of the bromo- 2- of 4-, benzhydrylamine (500mg, 2.72mmol) and potassium carbonate
(630mg, 4.54mmol) is dissolved in n,N-Dimethylformamide (6mL), and is heated to 90 DEG C and is stirred overnight.Add into reaction solution
Water is simultaneously extracted with ethyl acetate.Organic layer is separated, is washed with brine, anhydrous sodium sulfate is dried, filtered and concentrated.Residue is with soon
Fast chromatography isolates and purifies (petrol ether/ethyl acetate=10/1), and it is yellow solid (310mg, 37%) to obtain title compound.
LCMS(ESI)[M+H]+=384.7.
Step 2:N- benzhydryl -5- bromobenzene -1,2- diamines
The bromo- 2- nitroanilines (300mg, 0.78mmol) of N- benzhydryls -5-, iron powder (870mg, 15.6mmol) and chlorination
Ammonium (830mg, 15.6mmol) is dissolved in ethyl alcohol (10mL) and water (2mL), and is heated to 80 DEG C and is stirred 2 hours.Liquid cooling will be reacted
It to room temperature and filters, filtrate is re-dissolved in ethyl acetate (50mL), and with water and salt water washing, anhydrous sodium sulfate drying is filtered and dense
Contracting.Residue isolates and purifies (petrol ether/ethyl acetate=10/1~5/1) with flash chromatography, and it is white to obtain title compound
Solid (210mg, 76%).LCMS(ESI)[M+H]+=352.0.
Step 3:Bromo- 1H- benzos [d] imidazoles of 1- benzhydryls -6-
By N- benzhydryl -5- bromobenzenes -1,2- diamines (200mg, 0.57mmol), p-methyl benzenesulfonic acid (19mg,
It 0.11mmol) is stirred at room temperature overnight with the mixed liquor of triethyl orthoformate (6mL), there is white solid product precipitation, filtered,
With petroleum ether and drying, title compound (175mg, 85%) is obtained.LCMS (ESI) [M+H] +=363.0.
Step 4:1- benzhydryls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d] imidazoles
Bromo- 1H- benzos [d] imidazoles (150mg, 0.41mmol) of 1- benzhydryls -6-, 1,4- dimethyl -5- (three normal-butyls
Tinbase) -1H-1,2,3- triazoles (320mg, 0.82mmol), tetra-triphenylphosphine palladium (46mg, 0.04mmol) and cuprous iodide
(2mg) is dissolved in Isosorbide-5-Nitrae-dioxane (6mL), and in 125 DEG C and stirred under nitrogen atmosphere 48 hours.Reaction solution is cooled to room temperature simultaneously
Filtering, filtrate are extracted with ethyl acetate.Organic phase is separated, is dried, filtered and concentrated with anhydrous sodium sulfate.The quick color of residue
Spectrometry isolates and purifies (petrol ether/ethyl acetate=10/1to 3/1), and obtained crude product further uses preparation-HPLC purifying, obtains
Sterling title compound (39.6mg, 25%) is white solid.LCMS(ESI)[M+H]+=380.2；1H NMR(400MHz,
DMSO-d6) δ 8.18 (s, 1H), 7.86-7.84 (d, J=8.4Hz, 1H), 7.44-7.29 (m, 13H), 3.83 (s, 3H), 2.09
(s,3H).
Embodiment 17:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (1,2- diphenyl-ethyls) -1H- benzene
And [d] imidazoles
Step 1:The bromo- N- of 5- (1,2- diphenyl-ethyls) -2- nitroanilines
By the fluoro- 1- nitrobenzenes (500mg, 2.27mmol) of the bromo- 2- of 4-, 1,2- diphenyl-ethyls amine (450mg, 2.27mmol)
It is dissolved in acetonitrile (10mL) with potassium carbonate (630mg, 4.54mmol), and is heated to 70 DEG C and is stirred overnight.Add water into reaction solution
And it is extracted with ethyl acetate.Organic layer is separated, is washed with brine, anhydrous sodium sulfate is dried, filtered and concentrated.Residue is with quickly
Chromatography isolates and purifies (petrol ether/ethyl acetate=8/1), and it is yellow solid (900mg, 99%) to obtain title compound.LCMS
(ESI)[M+H]+=421.0.
Step 2:The bromo- N- of 5- (1,2- diphenyl-ethyls) benzene -1,2- diamines
The bromo- N- of 5- (1,2- diphenyl-ethyls) -2- nitroanilines (900mg, 2.27mmol), iron powder (2.54g,
It 45.4mmol) is dissolved in ethyl alcohol (15mL) and water (3mL) with ammonium chloride (2.43g, 45.4mmol), and is heated to 80 DEG C of stirrings 2
Hour.Reaction solution is cooled to room temperature and is filtered, filtrate is re-dissolved in ethyl acetate (50mL), with water and salt water washing, anhydrous slufuric acid
Sodium is dried, filtered and concentrated.Residue isolates and purifies (petrol ether/ethyl acetate=10/1~8/1) with flash chromatography, must mark
Topic compound is red oil (750mg, 90%).LCMS(ESI)[M+H]+=369.0.
Step 3:The bromo- 1- of 6- (1,2- diphenyl-ethyls) -1H- benzos [d] imidazoles
By the bromo- N- of 5- (1,2- diphenyl-ethyl) benzene -1,2- diamines (375mg, 1.02mmol), p-methyl benzenesulfonic acid
The mixed liquor of (34mg, 0.20mmol) and triethyl orthoformate (6mL) is stirred at room temperature overnight, and has white solid product analysis
Go out, filters, with petroleum ether and drying, obtain title compound (250mg, 65%).LCMS (ESI) [M+H] +=377.0.
Step 4:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (1,2- diphenyl-ethyls) -1H- benzos
[d] imidazoles
By the bromo- 1- of 6- (1,2- diphenyl-ethyls) -1H- benzos [d] imidazoles (150mg, 0.4mmol), 1,4- dimethyl -5-
(tri-n-butyl tin base) -1H-1,2,3- triazoles (310mg, 0.8mmol), tetra-triphenylphosphine palladium (46mg, 0.04mmol) and iodine
Change cuprous (4mg) to be dissolved in Isosorbide-5-Nitrae-dioxane (6mL), and in 125 DEG C and stirred under nitrogen atmosphere 24 hours.Reaction solution is cooled to
Room temperature simultaneously filters, and filtrate is extracted with ethyl acetate.Organic phase is separated, is dried, filtered and concentrated with anhydrous sodium sulfate.Residue is used
Flash chromatography isolates and purifies (petrol ether/ethyl acetate=10/1to 3/1), and obtained crude product further uses preparation-HPLC pure
Change, obtain sterling title compound (32mg, 20%), is white solid.LCMS(ESI)[M+H]+=394.2；1H NMR
(400MHz,DMSO-d6) δ 8.82 (s, 1H), 7.79 (d, J=0.8Hz, 1H), 7.72-7.69 (d, J=8.4Hz, 1H),
7.60-7.58(m,2H),7.37-7.10(m,9H),6.17-6.13(m,1H),3.93-3.87(m,1H),3.87(s,3H),
3.71-3.66(m,1H),2.17(s,3H).
Embodiment 18:1- (cyclopropyl (phenyl) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H-
Benzo [d] imidazoles
Step 1:The bromo- N- of 5- (cyclopropyl (phenyl) methyl) -2- nitroanilines
By the fluoro- 1- nitrobenzenes (500mg, 2.27mmol) of the bromo- 2- of 4-, cyclopropyl (phenyl) methylamine hydrochloride (420mg,
2.27mmol) and potassium carbonate (940mg, 6.8mmol) mixes (10mL) in acetonitrile, and is heated to 70 DEG C and is stirred overnight.Concentration
Reaction solution, residue are re-dissolved in ethyl acetate, and with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.Residue is used
Flash chromatography isolates and purifies (petrol ether/ethyl acetate=8/1), and it is yellow solid (740mg, 94%) to obtain title compound.
LCMS(ESI)[M+H]+=348.1.
Step 2:The bromo- N- of 5- (cyclopropyl (phenyl) methyl) benzene -1,2- diamines
By the bromo- N- of 5- (cyclopropyl (phenyl) methyl) -2- nitroanilines (740mg, 2.13mmol), iron powder (2.38g,
It 42.6mmol) is dissolved in ethyl alcohol (15mL) and water (3mL) with ammonium chloride (2.28g, 42.6mmol), and is heated to 80 DEG C of stirrings 2
Hour.Reaction solution is cooled to room temperature and is filtered, filtrate is re-dissolved in ethyl acetate (50mL), with water and salt water washing, anhydrous slufuric acid
Sodium is dried, filtered and concentrated.Residue isolates and purifies (petrol ether/ethyl acetate=10/1~4/1) with flash chromatography, must mark
Topic compound is red oil (570mg, 84%).LCMS(ESI)[M+H]+=319.1.
Step 3:The bromo- 1- of 6- (cyclopropyl (phenyl) methyl) -1H- benzos [d] imidazoles
The bromo- N- of 5- (cyclopropyl (phenyl) methyl) benzene -1,2- diamines (300mg, 0.95mmol), p-methyl benzenesulfonic acid
The mixed liquor of (33mg, 0.19mmol) and triethyl orthoformate (6mL) is stirred at room temperature overnight, and is then concentrated, and residue is used
Flash chromatography isolates and purifies (petrol ether/ethyl acetate=10/1~1/1), and it is red oil to obtain title compound
(270mg, 87%).LCMS(ESI)[M+H]+=329.0.
Step 4:1- (cyclopropyl (phenyl) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzene
And [d] imidazoles
The bromo- 1- of 6- (cyclopropyl (phenyl) methyl) -1H- benzos [d] imidazoles (150mg, 0.46mmol), 1,4- dimethyl -
5- (tri-n-butyl tin base) -1H-1,2,3- triazoles (355mg, 0.92mmol), tetra-triphenylphosphine palladium (60mg, 0.05mmol)
It is dissolved in Isosorbide-5-Nitrae-dioxane (6mL) with cuprous iodide (5mg), and in 125 DEG C and stirred under nitrogen atmosphere 24 hours.Reaction solution
It is cooled to room temperature and filters, filtrate is extracted with ethyl acetate.Organic phase is separated, with water and salt water washing, anhydrous sodium sulfate drying, mistake
It filters and concentrates.Residue is isolated and purified with preparation-HPLC, and it is white solid (80.5mg, 51%) to obtain title compound.LCMS
(ESI)[M+H]+=344.2；1H NMR(400MHz,DMSO-d6) δ 8.81 (s, 1H), 7.81-7.79 (d, J=8.8Hz, 1H),
7.44-7.24 (m, 7H), 5.00-4.97 (d, J=10Hz, 1H), 3.81 (s, 3H), 2.08 (s, 3H), 2.04-1.97 (m,
1H),0.83-0.69(m,2H),0.61-0.44(m,2H).
Embodiment 19 and 20 6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- base (tetrahydrochysenes -
2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyridine；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- imidazos [4,5-c] pyridine；With
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- imidazos [4,5-c] pyridine
Step 1:(R, E) -2- methyl-N- (tetrahydrochysene -2H- pyrans -4- bases) methylene) propane -2- sulfonamide
By tetrahydrochysene -2H- pyrans -4- formaldehyde (1.8g, 15.8mmol), (R) -2- methylpropane -2- sulfonamide (0.9g,
It 7.4mmol) is dissolved in 1,2- dichloroethanes (180mL) with magnesium sulfate (4.7g, 39.2mmol), p-methyl benzenesulfonic acid is then added
(0.2g,0.8mmol).Reaction solution is stirred at room temperature 12 hours, is then filtered with Celite pad and is washed with dichloromethane
(100mL*3).Filtrate and cleaning solution are merged, concentration.Residue isolated and purified with flash chromatography (methylene chloride/methanol=
50:1) it is colorless oil (1.6g, 90%), to obtain title compound.LCMS(ESI)[M+H]+=218.2.
Step 2:(R) -2- methyl-N- ((R)-pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) propane -2- sulphonyl
Amine
Under -78 DEG C and nitrogen protection, to (R, E) -2- methyl-N- (tetrahydrochysene -2H- pyrans -4- bases) methylene) propane -
N-BuLi (the tetrahydrofuran of 2.5M is slowly added dropwise in (150mL) in the tetrahydrofuran solution of 2- sulfonamide (1.5g, 6.9mmol)
Solution, 5.6mL, 14.0mmol), reaction solution stirs 0.5 hour at -78 DEG C, be then slowly added dropwise again 2- bromopyridines (1.1g,
Tetrahydrofuran solution (20ml) 8.3mmol).Reaction solution continues stirring 0.5 hour at -78 DEG C, is then warmed to room temperature stirring 12
Hour.Reaction solution is poured into water and (80mL*3) is extracted with ethyl acetate.Merge organic phase, it is anhydrous with water and salt water washing
Sodium sulphate is dried, filtered and concentrated.Residue isolates and purifies (petrol ether/ethyl acetate=2 with flash chromatography:1) title, is obtained
Compound is colorless oil (1g, 67%).LCMS(ESI)[M+H]+=319.1.
Step 3:Pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methylamine
By (R) -2- methyl-N- ((R)-pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) propane -2- sulfonamide
The mixed liquor of (1g, 3.4mmol) and hydrochloric acid (4M, 20mL) is stirred at room temperature 2 hours, then concentrates, it is thick to obtain title compound
Product (600mg, 60%) are white solid, are directly used in react in next step without further purification.LCMS(ESI)[M+H]+=193.2.
Step 4:The bromo- 5- nitros-N- of 2- (pyridine 2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -4- amine
By bis- bromo- 5- nitre of (R)-pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methylamine (600mg, 3.1mmol) and 2,4-
Yl pyridines (872mg, 3.1mmol) are dissolved in tetrahydrofuran (50mL), and triethylamine (405mg, 4.0mmol), reaction solution is then added
12h is stirred at room temperature.Reaction solution is poured into water and (30mL*3) is extracted with ethyl acetate.Merge organic phase, with water and salt
Water washing, anhydrous sodium sulfate are dried, filtered and concentrated.Residue isolated and purified with flash chromatography (petrol ether/ethyl acetate=
1:1) it is white solid (440mg, 73%), to obtain title compound.Chirality-HPLC is analysis shows that the compound is two isomers
Mixture, based on one of them (92.5/7.5).LCMS(ESI)[M+H]+=393.0.
Step 5:The bromo- N of 6-4(pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -3,4- diamines
By the bromo- 5- nitros-N- of 2- (pyridine 2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -4- amine (250mg,
0.63mmol), the mixed liquor of iron powder (353mg, 6.3mmol) and acetic acid (10mL) be heated to 65 DEG C stir 0.5 hour.Reaction solution
It is cooled to room temperature and is filtered with Celite pad, filter cake is washed (20mL*3) with dichloromethane again.Merging filtrate and cleaning solution simultaneously concentrate,
Residue isolates and purifies (ethyl acetate/methanol=25 with flash chromatography:1), obtain title compound be white solid (205mg,
82%).LCMS(ESI)[M+H]+=363.1.
Step 6:The bromo- 1- of 6- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyridine
By the bromo- N of 6-4(pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -3,4- diamines (170mg,
0.47mmol) it is heated to 100 DEG C with the mixed liquor of formic acid (5mL) and stirs 2 hours.Reaction solution is poured into water and uses ethyl acetate
It extracts (15mL*3).Merge organic phase, with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.Residue is with quickly
Chromatography isolates and purifies (ethyl acetate/methanol=25:1) it is white solid (95mg, 56%), to obtain title compound.LCMS
(ESI)[M+H]+=373.0.
Step 7:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- imidazos [4,5-c] pyridine；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- imidazos [4,5-c] pyridine and
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- imidazos [4,5-c] pyridine
By the bromo- 1- of 6- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyridine
(95mg, 0.26mmol), 1,4- dimethyl -5- (tri-n-butyl tin base) -1H-1,2,3- triazoles (355mg, 0.92mmol),
Tetra-triphenylphosphine palladium (30mg, 0.03mmol) and cuprous iodide (5mg, 0.01mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (6mL), and
125 DEG C are heated under nitrogen protection to stir 25 hours.Reaction solution is cooled to room temperature and filters, and filtrate concentration, residue is re-dissolved in
Ethyl acetate, with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.Residue is isolated and purified with preparation-HPLC,
Obtain 6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- imidazos [4,5-c] pyridine (35mg, 37%), is white solid, and chiral HPLC shows it for the mixed of two isomers
Close object (46:54).
This mixture further detaches (instrument with chiral preparation-HPLC:SFC-80；Column：AS-H columns), point of chiral column
From parameter：Instrument:SFC-80(Thar,Waters)；Chromatographic column:AS-H 20*250mm,5μm(Daicel)；Column temperature:35℃；Stream
Dynamic phase:CO2/ methanol (0.2% saturation ammonia methanol solution)=60/40；Flow velocity:80g/min；Back pressure:100bar；Detect wave
It is long:214nm；Run time:2.5min.Two configurations are respectively obtained, embodiment 19 is white solid.RTchiral=1.03min,
It is R or S configurations, LCMS (ESI) [M+H]+=390.2；1H NMR(400MHz,DMSO-d6) δ 9.08-9.08 (d, J=
1.2Hz, 1H), 8.687 (s, 1H), 8.64-8.63 (m, 1H), 8.21-8.20 (d, J=0.8Hz, 1H), 7.86-7.82 (m,
1H), 7.70-7.68 (d, J=8Hz 1H), 7.37-7.34 (m, 1H), 5.75-5.72 (d, J=10.8Hz 1H), 4.12 (s,
1H),3.84-3.59(m,2H),3.41(s,3H),3.31-3.21(m,2H),3.04-2.97(m,1H),2.24(s,3H),
2.03-1.96(m,1H),1.41-1.23(m,2H),0.87-0.84(m,2H)。
It is white solid with embodiment 20.RTchiral=1.51min is the enantiomter of 19 compound of embodiment,
LCMS(ESI)[M+H]+=390.1；1H NMR(400MHz,DMSO-d6) δ 9.08-9.08 (d, J=1.2Hz, 1H), 8.687
(s, 1H), 8.64-8.63 (m, 1H), 8.21-8.20 (d, J=0.8Hz, 1H), 7.86-7.82 (m, 1H), 7.70-7.68 (d, J
=8Hz 1H), 7.37-7.34 (m, 1H), 5.75-5.72 (d, J=10.8Hz 1H), 4.12 (s, 1H), 3.84-3.59 (m,
2H),3.41(s,3H),3.31-3.21(m,2H),3.04-2.97(m,1H),2.24(s,3H),2.03-1.96(m,1H),
1.41-1.23(m,2H),0.87-0.84(m,2H)。
Embodiment 21:6- (3,5- dimethyl -3H-1,2,3- triazole -4- bases) -1- phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- imidazos [4,5-c] pyridine
Step 1:Phenyl (tetrahydrochysene -2H- pyrans -4- bases) ketoxime
By phenyl (tetrahydrochysene -2H- pyrans -4- bases) ketone (1.0g, 5.26mmol), sodium acetate (1.424g, 10.4mmol)
It is dissolved in water (6.3mL) and ethyl alcohol (21mL), and is refluxed overnight with hydroxylamine hydrochloride (0.73g, 10.5mmol).Concentration reaction
Liquid, filtering, filter cake are washed with water and dry, and obtain title compound (1.0g, 93%), are white solid, directly use without further purification
It is reacted in next step.LCMS(ESI)[M+H]+=206.
Step 2:Phenyl (tetrahydrochysene -2H- pyrans -4- bases) methylamine
Phenyl (tetrahydrochysene -2H- pyrans -4- bases) ketoxime (1.0g, 5.4mmol) is dissolved in methanol (20mL), is then added
Enter Raney nickel (30mg, 0.524mmol) and methanolic ammonia solution (7M, 10mL), reaction solution is stirred overnight at room temperature under a hydrogen atmosphere.
Filtering, filtrate concentration, obtains title compound (600mg, 58%yield), is white solid, is directly used in without further purification in next step
Reaction.LCMS(ESI)[M+H]+=192.
Step 3:The bromo- 5- nitros-N- of 2- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -4- amine
By phenyl (tetrahydrochysene -2H- pyrans -4- bases) bis- bromo- 5- nitropyridines of methylamine (200mg, 1.05mmol) and 2,4-
(441mg, 1.57mmol) is dissolved in tetrahydrofuran (10mL), triethylamine (318mg, 3.15mmol) is then added, reaction solution adds
Heat stirs 12 hours to 60 DEG C.Reaction solution is poured into water, and (30mL*3) is extracted with ethyl acetate.Merge organic phase, uses water
With salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.Residue isolates and purifies (petroleum ether/acetic acid second with flash chromatography
Ester=1/1), it is white solid (220mg, 53%) to obtain title compound.LCMS(ESI)[M+H]+=389.2.
Step 4:The bromo- N of 6-4(phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -3,4- diamines
By the bromo- 5- nitros-N- of 2- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -4- amine (181mg,
0.46mmol), iron powder (130mg, 2.3mmol) and ammonium chloride (372mg, 3.9mmol) are dissolved in ethyl alcohol (6mL) and water (3mL),
And it is heated to 90 DEG C and stirs 2 hours.Add water into reaction solution and is extracted with dichloromethane.Organic phase water and salt water washing, nothing
Aqueous sodium persulfate is dried, filtered and concentrated, and it is white solid (150mg, 90%) to obtain title compound, is directly used in down without further purification
Single step reaction.LCMS(ESI)[M+H]+=362.0,364.0.
Step 5:The bromo- 1- of 6- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyridine
By the bromo- N of 6-4(phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -3,4- diamines (136mg, 0.416mmol)
It is heated to 100 DEG C with the mixed liquor of formic acid (5mL) and is stirred overnight.Reaction solution is poured into water (10mL), ethyl acetate is used in combination
It extracts (15mL*3).Merge organic phase, with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.Residue is with quickly
Chromatography isolates and purifies, and it is white solid (ethyl acetate/methanol=25 to obtain title compound:1) it is white, to obtain title compound
Solid (141mg, 91%).LCMS(ESI)[M+H]+=372.0,374.0.
Step 6:6- (3,5- dimethyl -3H-1,2,3- triazole -4- bases) -1- phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- imidazos [4,5-c] pyridine
By the bromo- 1- of 6- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyridine (141mg,
0.38mmol), 1,4- dimethyl -5- (tri-n-butyl tin base) -1H-1,2,3- triazoles (294mg, 0.76mmol), four triphens
Base phosphine palladium (44mg, 0.038mmol) and cuprous iodide (7mg, 0.038mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (2mL), and in nitrogen
125 DEG C are heated under gas shielded to stir 25 hours.Reaction solution is cooled to room temperature and filters, and filtrate concentration, residue is re-dissolved in acetic acid
Ethyl ester, with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.Residue is isolated and purified with preparation-HPLC, must be marked
Topic compound is white solid (33.5mg, 24%).LCMS(ESI)[M+H]+=390.2；1H NMR(400MHz,DMSO-d6)δ
9.081 (d, J=0.8Hz, 1H), 9.001 (s, 1H), 8.141 (s, 1H), 7.699 (d, J=7.2Hz, 2H), 7.387 (t, J=
8Hz, 2H), 7.302 (t, J=7.6Hz, 1H), 5.567 (d, J=7.2Hz, 1H), 4.115 (s, 3H), 3.875-3.828 (m,
2H),3.316-3.282(m,2H),3.058(br,1H),2.377(s,3H),1.288(m,4H).
Embodiment 22:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H-
Pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyridine
Step 1:N- (the bromo- 4- of 6- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methylamine) pyridin-3-yl) acetamide
By the bromo- 5- nitros-N- of 2- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -4- amine (200mg,
0.51mmol) and iron powder (143mg, 2.55mmol) is dissolved in acetic acid (10mL), and is heated to 70 DEG C and stirs 2 hours.To reaction
Add water in liquid and is extracted with dichloromethane.Organic phase water and salt water washing, anhydrous sodium sulfate are dried, filtered and concentrated, and must be marked
Topic compound is white solid (155mg, 75%), is directly used in reacts in next step without further purification.LCMS(ESI)[M+H]+=
404.0,406.0.
Step 2:The bromo- 2- methyl-1s-of 6- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyrrole
Pyridine
By N- (the bromo- 4- of 6- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methylamine) pyridin-3-yl) acetamide (155mg,
0.38mmol) it is heated to 100 DEG C with the mixed liquor of acetic acid (5mL) and is stirred overnight.Reaction solution is poured into water (10mL), is used in combination
Ethyl acetate extracts (15mL*3).Merge organic phase, with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.It is remaining
Object is isolated and purified with flash chromatography, and it is white solid (ethyl acetate/methanol=25 to obtain title compound:1) title compound, is obtained
Object is white solid (55mg, 38%).LCMS(ESI)[M+H]+=386.0,388.0.
Step 3:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) -1H- imidazos [4,5-c] pyridine
By the bromo- 2- methyl-1s-of 6- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- imidazos [4,5-c] pyridine
(55mg, 0.143mmol), 1,4- dimethyl -5- (tri-n-butyl tin base) -1H-1,2,3- triazoles (110mg,
0.286mmol), tetra-triphenylphosphine palladium (17mg, 0.0143mmol) and cuprous iodide (3mg, 0.0143mmol) are dissolved in 1,4- bis-
In six ring of oxygen (2mL), and it is heated to 125 DEG C under nitrogen protection and stirs 24 hours.Reaction solution is cooled to room temperature and filters, and filtrate is dense
Contracting, residue are re-dissolved in ethyl acetate, and with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.Residue system
Standby-HPLC is isolated and purified, and it is white solid (7.5mg, 13%yield) to obtain title compound.LCMS(ESI)[M+H]+=403；1H NMR(400MHz,DMSO-d6) δ 8.9 (s, 1H), 8.015 (s, 1H), 7.684 (d, J=6.8Hz, 2H), 7.387 (t, J=
7.2Hz, 2H), 7.330 (d, J=7.2Hz, 1H), 5.464 (d, J=11.2Hz, 1H), 4.095 (s, 3H), 3.846 (dd, J=
9.2Hz,2H),3.426(m,1H),3.303(m,2H),2.785(s,3H),2.314(s,3H),1.550-1.233(m,4H)。
Embodiment 23:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (pyridine -2- bases) methyl) -
1H- benzos [d] imidazoles
Step 1:5- (the fluoro- 4- nitrobenzophenones of 3-) -1,4- dimethyl -1H-1,2,3- triazoles
By the fluoro- 1- nitrobenzenes (220mg, 1mmol) of the bromo- 2- of 4-, 1,4- dimethyl -5- (tri-n-butyl tin base) -1H-1,2,
3- triazoles (772mg, 2mmol), tetra-triphenylphosphine palladium (116mg, 0.1mmol) and cuprous iodide (19mg, 0.1mmol) are dissolved in
In Isosorbide-5-Nitrae-dioxane (2mL), and it is heated to 110 DEG C under nitrogen protection and is stirred overnight.Reaction solution is cooled to room temperature and filters, filter
Liquid concentrates, and residue is re-dissolved in ethyl acetate, and with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.Residue is used
Flash chromatography isolates and purifies (petrol ether/ethyl acetate=1/1), and it is yellow solid (213mg, 90%) to obtain title compound.
LCMS(ESI)[M+H]+=237.1.
Step 2:5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- nitros-N- (phenyl (pyridine -2- bases) first
Base) aniline
By 5- (the fluoro- 4- nitrobenzophenones of 3-) -1,4- dimethyl -1H-1,2,3- triazoles (84mg, 0.36mmol) and carbonic acid
Potassium (98mg, 0.71mmol) is dissolved in acetonitrile (10mL), and phenyl (pyridine -2- bases) methylamine (131mg, 0.71mmol) is then added,
Reaction solution is heated to 70 DEG C and is stirred overnight, and is then cooled to room temperature.Ethyl acetate is added to dilute and be washed with water, anhydrous sodium sulfate is dry
It is dry, it filters and concentrates.Residue isolates and purifies (ethanol/methylene=6/94) with flash chromatography, obtains title compound and is
Yellow solid (122mg, 86%).LCMS (ESI) [M+H] +=401.1.
Step 3:5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N1- (phenyl (pyridine -2- bases) methyl) benzene -
1,2- diamines
By 5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- nitros-N- (phenyl (pyridine -2- bases) methyl)
Aniline (110mg, 0.275mmol), iron powder (77mg, 1.375mmol) and ammonium chloride (223mg, 4.125mmol) are dissolved in ethyl alcohol
(10mL), in tetrahydrofuran (5mL) and water (2mL), reaction solution is heated to 90 DEG C and stirs 2 hours.Filtering, filtrate concentration, must mark
Crude compound (134mg) is inscribed, is brown solid, is directly used in reacts in next step without further purification.LCMS(ESI)[M+H]+=
371.1.
Step 4:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (pyridine -2- bases) methyl) -1H-
Benzo [d] imidazoles
By 5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N1- (phenyl (pyridine -2- bases) methyl) benzene -1,2-
Diamines (134mg, 0.36mmol) and p-methyl benzenesulfonic acid (6.8mg, 0.036mmol) are dissolved in triethyl orthoformate (5mL), instead
It answers liquid to be stirred at room temperature overnight, then filters.Filtrate concentrates, and residue is isolated and purified with preparation-HPLC, obtains title compound
For white solid (36.6mg, two step yields 32%).LCMS(ESI)[M+H]+=381.1；1H NMR(400MHz,DMSO-d6)δ
8.62 (d, J=4.8Hz, 1H), 8.34 (s, 1H), 7.91-7.79 (m, 1H), 7.82 (d, J=8.4Hz, 2H), 7.59 (s,
1H), 7.50 (d, J=7.2Hz, 1H), 7.42-7.27 (m, 8H), 3.86 (s, 3H), 2.13 (s, 3H)
Embodiment 24:1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -
1H- benzos [d imidazoles
Step 1:Two (pyridine -2- bases) ketoximes
By two pyridine -2- bases ketones (5g, 27mmol), hydroxylamine hydrochloride (5.63g, 81mmol) and sodium acetate (6.64g,
It 81mmol) is dissolved in ethyl alcohol (150mL), and is heated to 80 DEG C and is stirred overnight.Residue is mixed with water and is beaten by concentration of reaction solution
Slurry, there is white solid precipitation, filters, and filter cake is washed with water and dries, and obtains crude title compound (6g), directly uses without further purification
It is reacted in next step.LCMS(ESI)[M+H]+=200.1.
Step 2:Two pyridine -2- base methylamines
By two (pyridine -2- bases) ketoximes (2.4g, 12mmol), zinc powder (3.34g, 31.4mmol) and ammonium acetate
(1.86g, 24.1mmol) is dissolved in ethyl alcohol (10mL), in the mixed liquor of ammonium hydroxide (10mL) and water (10mL), and is heated to 90 DEG C and stirs
It mixes overnight.Reaction solution is cooled to room temperature and filters, filtrate concentration.Residue with alkali alumina column chromatography (ethanol/methylene=
6/94) it is yellow oil (1.7g, two step yields 76%), to obtain title compound.LCMS(ESI)[M+H]+=186.1.
Step 3:5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N- (two pyridine -2- ylmethyls) -2- nitros
Aniline
To 5- (the fluoro- 4- nitrobenzophenones of 3-) -1,4- dimethyl -1H-1,2,3- triazoles (472mg, 2mmol) and potassium carbonate
Two pyridine -2- bases methylamines (555mg, 3mmol) are added in (20mL) in the acetonitrile solution of (552mg, 4mmol), and reaction solution is heated to
70 DEG C are stirred overnight, and are then cooled to room temperature.Ethyl acetate dilute reaction solution is added and is washed with water, anhydrous sodium sulfate drying, mistake
It filters and concentrates.Residue isolates and purifies (ethanol/methylene=6/94) with flash chromatography, and it is solid for yellow to obtain title compound
Body (220mg, 27%).LCMS (ESI) [M+H] +=402.2.
Step 4:5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N1- (two pyridine -2- ylmethyls) benzene -1,2-
Diamines
By 5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N- (two pyridine -2- ylmethyls) -2- nitroanilines
(220mg, 0.548mmol), iron powder (154mg, 2.74mmol) and ammonium chloride (444mg, 8.23mmol) are dissolved in ethyl alcohol (10mL),
In tetrahydrofuran (5mL) and water (2mL), reaction solution is heated to 90 DEG C and stirs 2 hours.Filtering, filtrate concentration, obtains title compound
Crude product (186mg) is yellow solid, is directly used in reacts in next step without further purification.LCMS(ESI)[M+H]+=372.1.
Step 5:1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzene
And [d imidazoles
By 5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N1- (two pyridine -2- ylmethyls) benzene -1,2- diamines
(186mg, 0.501mmol) and p-methyl benzenesulfonic acid (9.6mg, 0.051mmol) are dissolved in trimethyl orthoformate (8mL), and in room
It is stirred overnight under temperature, then concentrates.Residue is isolated and purified with preparation-HPLC, obtain title compound be white solid (35mg,
Two step yields 27%) as white solid.LCMS (ESI) [M+H]+=382.2；1HNMR(400MHz,DMSO-d6)δ8.58
(d, J=3.6Hz, 1H), 8.50 (s, 1H), 7.89-7.80 (m, 3H), 7.71 (d, J=1.2Hz, 1H), 7.46 (s, 1H),
7.44 (s, 2H), 7.40-7.35 (m, 2H), 7.30 (dd, J=7.2Hz, 1.6Hz, 1H), 3.88 (s, 3H), 2.15 (s, 3H)
Embodiment 25:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) -1H- benzos [d] imidazoles
Step 1:5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- nitros-N- (pyridine -2- base (tetrahydrochysenes -
2H- pyrans -4- bases) methyl) aniline
By 5- (the fluoro- 4- nitrobenzenes of 3-) -1,4- dimethyl 1H-1,2,3- triazoles (70mg, 0.30mmol), pyridine -2-
Base (tetrahydrochysene -2H- pyrans -4- bases) methylamine (86.4mg, 0.45mmol) and diisopropyl ethyl amine (116.1mg, 0.90mmol)
It is dissolved in 1-Methyl-2-Pyrrolidone (2mL), and is heated to 140 DEG C and stirs 12 hours.Reaction solution is poured into water (10mL), and
It is extracted with ethyl acetate (3*10mL).Merge organic phase, with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.It is residual
Excess isolates and purifies (petrol ether/ethyl acetate=1/1) with flash chromatography, obtain title compound be yellow oil (70mg,
100%).MS(ESI):M/z=409.2 [M+1]+.
Step 2:5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N1(pyridine -2- bases (tetrahydrochysene -2H- pyrans -
4- yls) methyl) benzene -1,2- diamines
By 5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- nitros-N- (pyridine -2- bases (tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) aniline (70mg, 0.17mmol), iron powder (95.2mg, 1.7mmol) and ammonium chloride (18.2mg,
It 0.34mmol) is dissolved in the mixed liquor of tetrahydrofuran/ethanol/water (3mL/3mL/1mL), and is heated to 100 DEG C and stirs 1 hour.
Filtering, filtrate is poured into water (10mL), and (3*10mL) is extracted with ethyl acetate.Merge organic phase, with water and salt water washing, nothing
Aqueous sodium persulfate is dried, filtered and concentrated.Residue isolates and purifies (petrol ether/ethyl acetate=1/1) with flash chromatography, must mark
Topic compound is yellow oil (50mg, 71%).MS(ESI):M/z=379.3 [M+1]+.
Step 3:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -
4- yls) methyl) -1H- benzos [d] imidazoles
By 5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N1(pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) benzene -1,2- diamines (50mg, 0.13mmol) and formic acid (2mL) is mixed and heated to 100 DEG C and stirs 1 hour, then
Reaction solution is poured into water (10mL), and (3*10mL) is extracted with ethyl acetate.Merge organic phase, with water and salt water washing, nothing
Aqueous sodium persulfate is dried, filtered and concentrated.Residue is isolated and purified with preparation-HPLC, and it is white solid to obtain title compound
(20.6mg, 41%).MS(ESI):M/z=389.2 [M+1]+；1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.63-
8.62 (d, J=4Hz, 1H), 8.02 (s, 1H), 7.84-7.76 (m, 2H), 7.69-7.67 (d, J=7.6Hz, 1H), 7.34-
7.31 (m, 1H), 7.28-7.26 (m, 1H), 5.65-5.62 (d, J=10.8Hz, 1H), 3.96 (s, 3H), 3.83-3.80 (m,
1H),3.35-3.24(m,2H),3.04-2.96(m,1H),2.51(s,3H),1.40-1.31(m,2H),1.30-1.11(m,
2H).
Comparative example 1:1- benzyls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d] imidazoles
Step 1:N- benzyls -5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- nitroanilines
To 5- (the fluoro- 4- nitrobenzophenones of 3-) -1,4- dimethyl -1H-1,2,3- triazoles (118mg, 0.5mmol) and carbonic acid
Phenylmethanamine (107mg, 1mmol) is added in the acetonitrile solution (9mL) of potassium (138mg, 1mmol), reaction solution is heated to 70 DEG C and stirs
It mixes overnight.Reaction solution is cooled to room temperature and is diluted with ethyl acetate, is then washed with water, anhydrous sodium sulfate drying is filtered and dense
Contracting.Residue isolates and purifies (ethyl acetate/dichloromethane=1/9) with flash chromatography, and it is yellow solid to obtain title compound
(162mg, 100%).LCMS (ESI) [M+H] +=324.2.
Step 2:N1Benzyl -5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) benzene -1,2- diamines
By N- benzyls -5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- nitroanilines (162mg,
It 0.5mmol) is mixed with stannous chloride (948mg, 5mmol) (2mL) in ethyl acetate, and is heated to 70 DEG C and stirs 3 hours.To
Saturated sodium bicarbonate solution is added in reaction solution, reaction is quenched, is then extracted with ethyl acetate.Organic phase is separated, anhydrous slufuric acid is used
Sodium is dried, filtered and concentrated, and it is yellow solid to obtain crude title compound (189mg), is directly used in without further purification anti-in next step
It answers.LCMS(ESI)[M+H]+=294.2.
Step 3:1- benzyls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d] imidazoles
By N1Benzyl -5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) benzene -1,2- diamines (189mg,
It 0.645mmol) is dissolved in triethyl orthoformate (5mL) with p-methyl benzenesulfonic acid (12.1mg, 0.065mmol), reaction solution is 30
It is stirred overnight at DEG C, then filters.Filtrate concentrates, and residue is isolated and purified with preparation-HPLC, and it is that white is solid to obtain title compound
Body (25mg, two step yields 16%).LCMS(ESI)[M+H]+=304.2；1H NMR(400MHz,DMSO-d6)δ8.57(s,
1H), 7.80 (d, J=8.4Hz, 1H), 7.70 (s, 1H), 7.46-7.23 (m, 6H), 5.55 (s, 2H), 3.88 (s, 3H), 2.17
(s,3H).
Embodiment 27:6- (3,5- dimethyl -3H-1,2,3- triazole -4- bases) -1- ((4- fluorophenyls) (pyridine -2- bases)
Methyl) -1H- benzos [d] imidazoles
Step 1:(4- fluorophenyls) (pyridine -2- bases) ketone
At -78 DEG C, n-BuLi (hexane solution of 2.5M, 14mL, 34.76mmol) is slowly added drop-wise to 2- bromine pyrroles
In the tetrahydrofuran solution of pyridine (5.0g, 31.6mmol) (47.4mL), be then slowly added dropwise again 4- fluorobenzaldehydes (4.11g,
33.18mmol), reaction solution is slowly warmed to room temperature and stirs 1 hour.Reaction solution is spin-dried for remove solvent, residue is re-dissolved in uncle
Butanol (47.4mL) is added iodine (12.8g, 50.56mmol) and potassium carbonate (13.0g, 94.8mmol), and is heated to reflux 3 hours.
Saturated sodium bisulfite solution (50mL) is added, reaction is quenched, is extracted with ethyl acetate (50mLX3).Organic phase is separated, is washed with salt
It washs, anhydrous sodium sulfate is dried, filtered and concentrated.Residue isolates and purifies (petrol ether/ethyl acetate=1/ with flash chromatography
3) it is white solid (5.0g, 79%), to obtain title compound.LCMS(ESI)[M+H]+=202.1.
Step 2:(4- fluorophenyls) (pyridine -2- base l) ketoximes
By (4- fluorophenyls) (pyridine -2- bases) ketone (5.0g, 24.88mmol), hydroxylamine hydrochloride (3.48g, 50mmol)
It is dissolved in ethyl alcohol (100mL) and water (30mL) with sodium acetate (4.1g, 50mmol), and is heated to 90 DEG C and is stirred overnight.Concentration is anti-
Liquid is answered, residue and water are mixed with beating, there is white solid precipitation, is filtered, filter cake is washed with water and dries, and obtains title compound
(4.0g, 74%) is directly used in reacts in next step without further purification.LCMS(ESI)[M+H]+=217.1.
Step 3:(4- fluorophenyls) (pyridine -2- bases) methylamine
By (4- fluorophenyls) (pyridine -2- base l) ketoximes (4.0g, 18.5mmol), zinc powder (5.38g, 82.8mmol) and
Ammonium acetate (3.08g, 37mmol) is dissolved in ethyl alcohol (100mL), in the mixed liquor of ammonium hydroxide (55mL) and water (10mL), and is heated to 90
It DEG C is stirred overnight.Reaction solution is cooled to room temperature and filters, filtrate concentration.Residue alkali alumina column chromatography (methanol/dichloromethane
Alkane=1/15), it is yellow oil (2.0g, 54%) to obtain title compound.LCMS(ESI)[M+H]+=203.1.
Step 4:5- (3,5- dimethyl -3H-1,2,3- triazole -4- bases)-N- ((4- fluorophenyls) (pyridine -2- bases) first
Base) -2- nitroanilines
To 5- (the fluoro- 4- nitrobenzophenones of 3-) -1,4- dimethyl -1H-1,2,3- triazoles (236mg, 1mmol) and potassium carbonate
In the acetonitrile solution of (401mg, 2.91mmol) (5mL) be added (4- fluorophenyls) (pyridine -2- bases) methylamine (293mg,
1.45mmol), reaction solution is heated to 70 DEG C and is stirred overnight, and is then cooled to room temperature.Ethyl acetate dilute reaction solution is added and uses water
Washing, anhydrous sodium sulfate are dried, filtered and concentrated.Residue isolated and purified with flash chromatography (ethyl acetate/dichloromethane=
1/9) it is yellow solid (270mg, 64%), to obtain title compound.LCMS (ESI) [M+H] +=419.1.
Step 5:5- (3,5- dimethyl -3H-1,2,3- triazole -4- bases)-N1((4- fluorophenyls) (pyridine -2- bases) first
Base) benzene -1,2- diamines
By 5- (3,5- dimethyl -3H-1,2,3- triazole -4- bases)-N- ((4- fluorophenyls) (pyridine -2- bases) methyl) -
(10mL) is mixed in ethanol for 2- nitroanilines (275mg, 0.645mmol) and stannous chloride (1.46g, 6.45mmol), and is added
Heat stirs 2 hours to 90 DEG C.Saturated sodium bicarbonate solution is added into reaction solution, reaction is quenched, is then extracted with ethyl acetate.
Organic phase is separated, with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated, and residue flash chromatography detaches pure
Change (petrol ether/ethyl acetate=1/1), it is yellow solid to obtain title compound (175mg, 69%).LCMS(ESI)[M+H]+=
389.1.
Step 6:6- (3,5- dimethyl -3H-1,2,3- triazole -4- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) first
Base) -1H- benzos [d] imidazoles
By 5- (3,5- dimethyl -3H-1,2,3- triazole -4- bases)-N1((4- fluorophenyls) (pyridine -2- bases) methyl)
Benzene -1,2- diamines (175mg, 0.45mmol) and p-methyl benzenesulfonic acid (12.1mg, 0.065mmol) are dissolved in trimethyl orthoformate
In (5mL), reaction solution is stirred overnight at 30 DEG C, and water is added into reaction solution and (50mL X3) is extracted with ethyl acetate.It has separated
Machine phase, is washed with brine, and anhydrous sodium sulfate is dried, filtered and concentrated.Residue is isolated and purified with preparation-HPLC, is obtained titled
Conjunction object is white solid (41.7mg, 23%).(LCMS(ESI)[M+H]+=399.1；1H NMR(400MHz,DMSO-d6)δ
8.63 (d, J=4.0Hz, 1H), 8.37 (s, 1H), 7.90 (ddd, J=1.6Hz, 7.6Hz, 15.2Hz, 1H), 7.83 (d, J=
8.4Hz, 1H), 7.59 (s, 1H), 7.48 (J=8.0Hz, 2H), 7.42 (m, J=4.0Hz, 3H), 7.34 (s, 1H), 7.30
(dd, J=1.6Hz, 8.4Hz, 1H), 7.24 (t, J=8.8Hz, 2H), 3.87 (s, 3H), 3.02 (s, 3H)
Embodiment 28:1- benzhydryls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indoles
Step 1:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indoles
By the bromo- 1H- indoles (600mg, 3.06mmol) of 6-, 1,4- dimethyl -5- (tri-n-butyl tin base) -1H-1,2,3-
Triazole (2.36g, 6.12mmol), tetra-triphenylphosphine palladium (358mg, 0.31mmol) and cuprous iodide (60mg, 0.31mmol)
It is dissolved in Isosorbide-5-Nitrae-dioxane (8mL), and is heated to 125 DEG C under nitrogen protection and is stirred overnight.Reaction solution is cooled to room temperature and mistake
Filter, filtrate concentration, residue are re-dissolved in ethyl acetate, and with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.It is residual
Excess isolates and purifies (petrol ether/ethyl acetate=10/1~3/1) with flash chromatography, and it is yellow solid to obtain title compound
(500mg, 77%).LCMS(ESI)[M+H]+=213.1.
Step 2:1- benzhydryls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indoles
By 6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indoles (90mg, 0.42mmol) and sodium hydride
(60% oil dispersion liquid, 25mg, 0.63mmol) mixing in n,N-Dimethylformamide (10mL), and it is heated to 80 DEG C of stirrings
1 hour.Reaction solution is cooled to room temperature, and the N of diphenyl bromomethane (155mg, 0.63mmol), N- dimethyl formyls is then slowly added dropwise
Amine aqueous solution (2mL), stirring was continued at room temperature overnight for reaction solution.Reaction solution is poured into water (50mL), is extracted with ethyl acetate
(60mL×3).Merge organic phase, with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.The quick color of residue
Spectrometry isolates and purifies (petrol ether/ethyl acetate=10/1~3/1), obtains 48mg crude products, further uses preparation-HPLC separation pure
Change, it is white solid (12mg, 7%) to obtain title compound.LCMS(ESI)[M+H]+=379.1.1HNMR(400MHz,DMSO-
d6) δ 7.72 (d, J=8.4Hz, 1H), 7.52 (s, 1H), 7.41-7.34 (m, 6H), 7.23-7.18 (m, 6H), 7.12 (d, J=
8.4Hz,1H),6.59(s,1H),3.83(s,3H),2.10(s,3H).
Embodiment 29:1- methyl -2'- ((phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6
(1H) -one
Step 1:Phenyl (tetrahydrochysene -2H- pyrans -4- bases) ketoxime
By phenyl (tetrahydrochysene -2H- pyrans -4- bases) ketone (1.0g, 5.26mmol), sodium acetate (1.424g, 10.4mmol)
It is dissolved in water (6.3mL) and ethyl alcohol (21mL), and is refluxed overnight with hydroxylamine hydrochloride (0.73g, 10.5mmol).Concentration reaction
Liquid, filtering, filter cake are washed with water and dry, and obtain title compound (1.0g, 93%), are white solid, directly use without further purification
It is reacted in next step.LCMS(ESI)[M+H]+=206.
Step 2:Phenyl (tetrahydrochysene -2H- pyrans -4- bases) methylamine
Phenyl (tetrahydrochysene -2H- pyrans -4- bases) ketoxime (1.0g, 5.4mmol) is dissolved in methanol (20mL), is then added
Enter Raney Ni (30mg, 0.524mmol) and methanolic ammonia solution (7M, 10mL), reaction solution is stirred overnight at room temperature under a hydrogen atmosphere.
Filtering, filtrate concentration, obtains title compound (600mg, 58%), is white solid, is directly used in reacts in next step without further purification.
LCMS(ESI)[M+H]+=192.
Step 3:The bromo- N- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -2- amine
By phenyl (tetrahydrochysene -2H- pyrans -4- bases) methylamine (400mg, 2.08mmol), the bromo- 2 fluorine pyridines of 4- (304mg,
It 1.74mmol) is dissolved in 1-Methyl-2-Pyrrolidone (4mL), and heats with diisopropyl ethyl amine (675mg, 5.23mmol)
It is stirred overnight to 140 DEG C.Add water into reaction solution and is extracted with ethyl acetate.Organic phase is washed with brine, and anhydrous sodium sulfate is dry
It is dry, it filters and concentrates.Residue isolates and purifies (ethyl acetate/petroleum ether=1/2) with flash chromatography, obtains title compound
(140mg, 20%) is faint yellow solid.LCMS(ESI)[M+H]+=347,349.
Step 4:1- methyl -2'- ((phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6
(1H) -one
By the bromo- N- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -2- amine (70mg, 0.2mmol), 1- methyl -
5- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron) pyridine -2 (1H) -one (57mg, 0.24mmol), potassium carbonate
(55mg, 0.4mmol) and [1,1 '-bis- (diphenylphosphino) ferrocene] dichloro palladium (II) (29mg, 0.04mmol) is dissolved in 1,4-
In dioxane/water (2mL, v/v=5/1), and stayed overnight in 100 DEG C and stirred under nitrogen atmosphere.Into reaction solution plus water is used in combination
Ethyl acetate extracts, ethyl acetate washed with water and saturated common salt water washing, and dry (anhydrous sodium sulphate) is filtered and concentrated, remaining
Object is isolated and purified with preparation-HPLC, obtains title compound (35mg, 47%), is white solid.LCMS(ESI)[M+H]+=
376.1H NMR(400MHz,DMSO-d6) δ 8.15 (d, 1H), 7.87 (d, 1H, J=5.6Hz), 7.72 (dd, 1H, J=
5.6Hz), 7.37 (d, 2H, J=7.2Hz), 7.28 (t, 2H), 7.17 (d, 1H, J=7.2Hz), 7.05 (d, 1H, J=
9.2Hz), 6.65 (t, 2H), 6.47 (d, 1H, J=9.2Hz), 4.77 (s, 1H), 3.86 (dd, 2H), 3.49 (s, 3H), 3.19
(m,2H),1.88(d,1H),1.29(m,2H),1.12(m,1H).
Embodiment 30:[3,4'- joins pyrrole to 1- methyl -2'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -
Pyridine] -6 (1H) -one
Step 1:The bromo- N- methyl-N- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -2- amine
By the bromo- N- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -2- amine (70mg, 0.2mmol) and sodium hydride
(60% oil dispersion liquid, 12mg, 0.3mmol) is dissolved in n,N-Dimethylformamide (4mL), and is stirred at room temperature 30 points
Clock.Then the n,N-Dimethylformamide solution (1mL) of iodomethane (0.02mL, 0.3mmol) is slowly added in reaction solution,
And continue to be stirred at room temperature overnight.Add water into reaction solution, there is solid precipitation.It filters and dries, obtain title compound
(70mg, 97%) is faint yellow solid, is directly used in reacts in next step without further purification.LCMS(ESI)[M+H]+=361,363.
Step 2:1- methyl -2'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6
(1H) -one
By the bromo- N- methyl-N- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -2- amine (70mg,
0.194mmol), 1- methyl -5- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron) pyridine -2 (1H) -one (54mg,
0.23mmol), potassium carbonate (53mg, 0.39mmol) and [1,1 '-bis- (diphenylphosphino) ferrocene] dichloro palladium (II) (28mg,
It 0.038mmol) is dissolved in Isosorbide-5-Nitrae-dioxane/water (2mL, v/v=5/1), and is stayed overnight in 100 DEG C and stirred under nitrogen atmosphere.
Add water into reaction solution and is extracted with ethyl acetate, ethyl acetate washed with water and saturated common salt water washing, dry (anhydrous slufuric acid
Receive), it filters and concentrates, residue is isolated and purified with preparation-HPLC, obtains title compound (16mg, 21%), is yellow solid.
LCMS(ESI)[M+H]+=390.1H NMR(400MHz,DMSO-d6) δ 8.27 (d, 1H), 8.12 (d, 1H, J=5.2Hz),
7.90 (dd, 1H, J=9.6Hz), 7.41 (d, 2H, J=7.2Hz), 7.31 (t, 2H), 7.23 (d, 1H, J=7.2Hz), 6.78
(d, 1H, J=5.2Hz), 6.71 (s, 1H), 6.46 (d, 1H, J=9.6Hz), 5.86 (s, 1H), 3.84 (dd, 2H), 3.50 (s,
3H),3.29(m,2H),2.78(s,3H),1.49(d,1H),1.32(d,1H),1.20(m,2H).
Embodiment 31:5- (2- amino -6- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amino) pyridine -4-
Base) -1- picolines -2 (1H) -one
Step 1:(tetrahydrochysene -2H- pyrans -4- bases) methanol
Tetrahydrochysene -2H- pyrans -4- carboxylic acids (10.8g, 83.1mmol) are dissolved in tetrahydrofuran (100mL), are then slowly added dropwise
Borine (tetrahydrofuran solution of 1M, 83.1mL, 83.1mmol), reaction solution is stirred at room temperature overnight.It is careful into reaction solution
Methanol (20mL) is added dropwise, reaction is quenched, concentration of reaction solution obtains crude title compound (10g), is white solid, without further purification directly
It connects for reacting in next step.MS(ESI):M/z=117.1 [M+1]+
Step 2:Tetrahydrochysene -2H- pyrans -4- formaldehyde
By (tetrahydrochysene -2H- pyrans -4- bases) methanol (9.64g, 83.1mmol) and Dess-Martin oxidants (35.2g,
It 83.1mmol) is dissolved in dichloromethane (200mL), reaction solution is stirred at room temperature overnight.Filtering, filtrate concentration, obtains title compound
Object crude product (9g) is colorless oil, is directly used in reacts in next step without further purification.1H NMR(400MHz,CDCl3)δ9.65
(s,1H),4.05-3.95(m,2H),3.55-3.42(m,2H),1.96-1.56(m,5H).
Step 3:Phenyl (tetrahydrochysene -2H- pyrans -4- bases) methanol
Under -78 DEG C and nitrogen protection, to the tetrahydrofuran solution of tetrahydrochysene -2H- pyrans -4- formaldehyde (1.14g, 10mmol)
Phenyl-magnesium-chloride (tetrahydrofuran solution of 2M, 5mL, 10mmol) is slowly added dropwise in (20mL).Reaction solution was stirred at room temperature
Saturated ammonium chloride solution (10mL) and ethyl acetate (50mL) is added to quench the reaction into reaction solution in night.Several layers of, use is separated
Water and salt water washing, anhydrous sodium sulfate are dried, filtered and concentrated.Residue isolates and purifies (petroleum ether/acetic acid with flash chromatography
Ethyl ester=4/1), it is colorless oil (1g, 52%) to obtain title compound.MS(ESI):M/z=175.2 [M-17]+
Step 4:4- (bromine (phenyl) methyl) tetrahydrochysene -2H- pyrans
Tribromide is added into the dichloromethane solution of phenyl (tetrahydrochysene -2H- pyrans -4- bases) methanol (768mg, 4mmol)
Phosphine (1.08g, 4mmol), reaction solution is stirred at room temperature overnight.Reaction solution is poured into water, organic layer is separated, uses anhydrous slufuric acid
Sodium is dried, filtered and concentrated.Residue isolates and purifies (petrol ether/ethyl acetate=4/1~2/1) with flash chromatography, must mark
Topic compound is colorless oil (1g, 98%).1H NMR(400MHz,CDCl3) δ 7.41-7.24 (m, 5H), 4.65 (d, J=
9.2Hz,1H),4.10-4.01(m,1H),3.90-3.81(m,1H),3.48-3.36(m,1H),3.30-3.20(m,1H),),
3.27-3.13(m,2H),1.49-1.10(m,3H).
Step 5:The bromo- 6- of 4- (2,5- dimethyl -1H- pyrroles -1- bases) pyridine -2- amine
By 4- bromopyridine -2,6- diamines (564mg, 3mmol), n-hexane -2,5- diketone (342mg, 3mmol) and to methyl
Benzene sulfonic acid (20mg, 0.12mmol) is dissolved in toluene (20mL), and is stirred at reflux overnight by Dean-Stark devices.Concentration reaction
Liquid, residue isolate and purify (petrol ether/ethyl acetate=4/1~2/1) with flash chromatography, and it is solid for yellow to obtain title compound
Body (460mg, 58%).MS(ESI):M/z=266.0/268.1 [M+1]+
Step 6:The bromo- 6- of 4- (2,5- dimethyl -1H- pyrroles -1- bases)-N- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) pyridine -2- amine
The bromo- 6- of 4- (2,5- dimethyl -1H- pyrroles -1- bases) pyridine -2- amine (300mg, 1.12mmol) is dissolved in N, N- bis-
In methylformamide (5mL), sodium hydride (60% oil dispersion liquid, 150mg, 3.72mmol) is then added.Reaction solution is in room temperature
Lower stirring half an hour will add 4- (bromine (phenyl) methyl) tetrahydrochysene -2H- pyrans (857mg, 3.36mmol), and will be then heated to 80
It DEG C is stirred overnight.Reaction solution is cooled to room temperature, saturated ammonium chloride solution and ethyl acetate (20mL) is added.Organic layer is separated, is used
Salt water washing (30mL*3), anhydrous sodium sulfate is dried, filtered and concentrated, residue isolated and purified with flash chromatography (petroleum ether/
Ethyl acetate=4/1), it is yellow solid (100mg, 20%) to obtain title compound.MS(ESI):M/z=441.2/442.1 [M+
1]+
Step 7:The bromo- 6- of 4- (2,5- dimethyl -1H- pyrroles -1- bases)-N- methyl-N- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) pyridine -2- amine
By the bromo- 6- of 4- (2,5- dimethyl -1H- pyrroles -1- bases)-N- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyrrole
Pyridine -2- amine (80mg, 0.18mmol) is dissolved in n,N-Dimethylformamide (10mL), and is cooled to 0 DEG C, and sodium hydride is then added
(60% oil dispersion liquid, 14.5mg, 0.36mmol).Reaction solution stirs half an hour at 0 DEG C, then be added iodomethane (51mg,
0.36mmol), it is warmed to room temperature and continues stirring 2 hours.Water (20mL) and ethyl acetate (20mL) are added into reaction solution, has separated
Machine layer is washed with brine (30mL*3), and anhydrous sodium sulfate is dried, filtered and concentrated, and residue is isolated and purified with flash chromatography
(petrol ether/ethyl acetate=4/1), it is colorless oil (89mg, 87%yield) to obtain title compound.LCMS(ESI)[M+
H]+=454.1.
Step 8:5- (2- (2,5- dimethyl -1H- pyrroles -1- bases) -6- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) amino) pyridin-4-yl) -1- picolines -2 (1H) -one
By the bromo- 6- of 4- (2,5- dimethyl -1H- pyrroles -1- bases)-N- methyl-N- (phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) pyridine -2- amine (89mg, 0.19mmol), 1- methyl -5- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron)
Pyridine -2 (1H) -one (54mg, 0.23mmol), potassium carbonate (52mg, 0.38mmol) and [1,1 '-bis- (diphenylphosphinos) two cyclopentadienyl
Iron] dichloro palladium (II) (28mg, 0.038mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (6mL) and water (1mL), and is heated to 100 DEG C and is stirred
It mixes overnight.Add water into reaction solution and be extracted with ethyl acetate, separates organic layer, be washed with brine, anhydrous sodium sulfate drying, mistake
It filters and concentrates.Residue isolates and purifies (methanol/ethyl acetate=3/97) with flash chromatography, and it is solid for brown to obtain title compound
Body (104mg, 100%yield).LCMS(ESI)[M+H]+=483.3.
Step 9:5- (2- amino -6- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amino) pyridin-4-yl) -
1- picolines -2 (1H) -one
By 5- (2- (2,5- dimethyl -1H- pyrroles -1- bases) -6- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl)
Amino) pyridin-4-yl) -1- picolines -2 (1H) -one (80mg, 0.16mmol) and hydroxylamine hydrochloride (54mg, 0.83mmol)
Ethanol solution (8mL) is heated to 80 DEG C and is stirred overnight.Filtering, filtrate concentration, residue are isolated and purified with preparation-HPLC, must be marked
Topic compound is white solid (11.9mg, 18%).LCMS(ESI)[M+H]+=405.2；1HNMR(400MHz,DMSO-d6)δ
8.06 (d, J=2.4Hz, 1H), 7.68 (dd, J=9.6,2.8Hz, 1H), 7.44 (d, J=7.2Hz, 2H), 7.31 (t, J=
7.6Hz, 2H), 7.21 (d, J=7.6Hz, 1H), 6.44 (d, J=9.2Hz, 1H), 5.85 (s, 2H), 5.61 (s, 1H), 3.85
(dd, J=33.2,8.8Hz, 2H), 3.48 (s, 3H), 3.29-3.27 (m, 4H), 2.70 (s, 3H), 1.53-1.50 (m, 1H),
1.35-1.12(m,4H).
Embodiment 32:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (two pyridine -2- ylmethyls) -1H-
Benzo [d] imidazoles -2 (3H) -one
By 5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N1- (two pyridine -2- ylmethyls) benzene -1,2- diamines
(30mg, 0.081mmol), triphosgene (24mg, 0.081mmol) and triethylamine (8mg, 0.081mmol) are dissolved in dichloromethane
(3mL), and be stirred at room temperature 5 hours, then concentrate.Residue is isolated and purified with preparation-HPLC, and it is white to obtain title compound
Color solid (16mg, 50%).LCMS(ESI)[M+H]+=398.1；1HNMR(400MHz,CD3OD)δ8.56(s,1H),8.55
(s, 1H), 7.86-7.84 (m, 2H), 7.42-7.37 (m, 4H), 7.28 (d, J=8Hz, 1H), 7.11 (s, 1H), 7.08 (s,
1H),6.79(s,1H),3.80(s,3H),2.10(s,3H).
Embodiment 33:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases)
Methyl) -2- methyl-1 H- benzos [d] imidazoles
Step 1:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) first
Base) -2- methyl-1 H- benzos [d] imidazoles
By 5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N1((4- fluorophenyls) (pyridine -2- bases) methyl)
Benzene -1,2- diamines (210mg, 0.54mmol) and p-methyl benzenesulfonic acid (12.1mg, 0.065mmol) are dissolved in trimethyl orthoacetate
In (5mL), reaction solution is stirred overnight at 30 DEG C, and water is added into reaction solution and (20mL X3) is extracted with ethyl acetate.It has separated
Machine phase, is washed with brine, and anhydrous sodium sulfate is dried, filtered and concentrated.Residue is isolated and purified with preparation-HPLC, is obtained titled
Conjunction object is white solid (13.7mg, 6%).LCMS(ESI)[M+H]+=413.1；1HNMR(400MHz,DMSO-d6)δ8.60
(d, J=4.0Hz, 1H), 7.86 (t, J=6.4Hz, 15.2Hz, 1H), 7.66 (d, J=8.2Hz, 1H), 7.41 (d, J=
8.2Hz, 2H), 7.34 (s, 1H), 7.19 (m, J=8.0Hz, 15.6Hz, 5H), 6.90 (s, 1H), 3.77 (s, 3H), 2.56 (s,
3H),2.01(s,3H).
Embodiment 34:4- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) different evil of -3,5- dimethyl
Azoles
Step 1:The bromo- N- of 5- (two pyridine -2- ylmethyls) -2- nitroanilines
By the fluoro- 1- nitrobenzenes (200mg, 0.91mmol) of the bromo- 2- of 4-, two pyridine -2- bases methylamines (253mg, 1.36mmol)
It is dissolved in acetonitrile (10mL) with potassium carbonate (377mg, 2.73mmol), and is heated to 70 DEG C and is stirred overnight.Add water into reaction solution
And be extracted with ethyl acetate, it has separated several layers of, has been washed with brine, anhydrous sodium sulfate is dried, filtered and concentrated.Residue is with quickly
Chromatography isolates and purifies (petrol ether/ethyl acetate=3/1), and it is yellow solid (160mg, 80%) to obtain title compound.LCMS
(ESI)[M+H]+=385.0.
Step 2:The bromo- N of 5-1(two pyridine -2- ylmethyls) benzene -1,2- diamines
By the bromo- N- of 5- (two pyridine -2- ylmethyls) -2- nitroanilines (160mg, 0.41mmol) and stannous chloride
(788mg, 4.1mmol) (10mL) is mixed in ethanol, and is heated to 80 DEG C and is stirred 2 hours.Reaction solution filters after being cooled to room temperature,
Filtrate concentrates.Residue is re-dissolved in ethyl acetate, and with water and salt water washing, anhydrous sodium sulfate is dried, filtered and concentrated.Residue
(petrol ether/ethyl acetate=2/1~1/1) is isolated and purified with flash chromatography, it is colorless oil to obtain title compound
(96mg, 60%).LCMS(ESI)[M+H]+=355.0.
Step 3:The bromo- 1- of 6- (two pyridine -2- ylmethyls) -1H- benzos [d] imidazoles
By the bromo- N of 5-1(two pyridine -2- ylmethyls) benzene -1,2- diamines (96mg, 0.27mmol) and p-methyl benzenesulfonic acid
(5mg, 0.03mmol) is dissolved in trimethyl orthoformate (6mL), and is stirred at room temperature 2 hours, has white solid precipitation, filtering is simultaneously
With petroleum ether, title compound (38mg, 40%) is obtained after dry.LCMS (ESI) [M+H] +=365.0.
Step 4:4- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3,5- dimethyl isoxazoles
By the bromo- 1- of 6- (two pyridine -2- ylmethyls) -1H- benzos [d] imidazoles (38mg, 0.10mmol), 3,5- dimethyl -
4- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3- dioxies boron) isoxazole (47mg, 0.20mmol), potassium carbonate (43mg,
0.3mmol) and [1,1 '-bis- (diphenylphosphino) ferrocene] dichloro palladium (II) (7.5mg, 0.01mmol) is dissolved in 1,4- dioxies six
In ring (2mL) and water (0.1mL), and in 90 DEG C and stirred under nitrogen atmosphere 1 hour.Add water into reaction solution and uses ethyl acetate
Extraction, ethyl acetate washed with water and saturated common salt water washing, dry (anhydrous sodium sulphate), filter and concentrate, residue preparation-
HPLC is isolated and purified, and obtains title compound (22mg, 57%), is white solid.LCMS(ESI)[M+H]+=382.1；1HNMR
(400MHz,CD3OD) δ 8.63-8.62 (d, J=4.0Hz, 2H), 8.31 (s, 1H), 7.90-7.86 (m, 2H), 7.80-7.78
(d, J=8.0Hz, 1H), 7.45-7.39 (m, 4H), 7.37 (s, 1H), 7.27-7.25 (d, J=8Hz, 1H), 7.22 (s, 1H),
2.33(s,3H),2.16(s,3H).
Embodiment 35:5- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3- methoxyl group -1- first
Yl pyridines -2 (1H) -one
Step 1:3- methoxyl group -1- methyl -5- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxos boron) pyridine -
2 (1H) -one
By bromo- -2 (1H) -one (900mg, 4.15mmol) of 3- methoxyl groups -1- picolines of 5-, connection boric acid pinacol ester
(3.18g, 12.44mmol), three (dibenzyl subunit acetone) palladiums (379mg, 0.41mmol), 2- dicyclohexyl phosphorus -2,4,6- tri- are different
Pentylbiphenyl (395mg, 0.83mmol) and potassium acetate (813mg, 8.30mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (30mL), and
70 DEG C and stirred under nitrogen atmosphere 16 hours.Concentration of reaction solution, residue isolate and purify (ethyl acetate/stone with flash chromatography
Oily ether=7/3), title compound (757mg, 69%) is obtained, is brown solid.LCMS(ESI)[M+H]+=266.2.
Step 2:5- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3- methoxyl group -1- methyl pyrroles
Pyridine -2 (1H) -one
By the bromo- 1- of 6- (two pyridine -2- ylmethyls) -1H- benzos [d] imidazoles (38mg, 0.10mmol), 3- methoxyl groups -1-
Methyl -5- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxos boron) pyridine -2 (1H) -one (56mg, 0.20mmol),
Potassium carbonate (43mg, 0.3mmol) and [1,1 '-bis- (diphenylphosphino) ferrocene] dichloro palladium (II) (7.5mg, 0.01mmol) are molten
In Isosorbide-5-Nitrae-dioxane (2mL) and water (0.1mL), and in 90 DEG C and stirred under nitrogen atmosphere 1 hour.Add water into reaction solution
And be extracted with ethyl acetate, ethyl acetate washed with water and saturated common salt water washing, dry (anhydrous sodium sulphate) is filtered and is concentrated,
Residue is isolated and purified with preparation-HPLC, obtains title compound (9.3mg, 24%), is white solid.LCMS(ESI)[M+H]+
=424.1；1HNMR(400MHz,CD3OD) δ 8.63-8.62 (d, J=4.0Hz, 2H), 8.32 (s, 1H), 7.90-7.86 (m,
2H), 7.77-7.75 (d, J=8.0Hz, 1H), 7.68 (s, 1H), 7.53-7.52 (d, J=4.0Hz, 2H), 7.44-7.42 (m,
4H),7.28(s,1H),7.20(s,1H),3.92(s,3H),3.67(s,3H).
Embodiment 36:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (two pyridine -2- ylmethyls) -2- first
Oxygroup -2- methyl -2,3- dihydro -1H- benzos [d] imidazoles
Step 1:5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N1(two pyridine -2- ylmethyls) benzene -1,2-
Diamines
By 5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N- (two pyridine -2- ylmethyls) -2- nitroanilines
(600mg, 1.5mmol) and stannous chloride (1.42g, 7.5mmol) are dissolved in ethyl alcohol (30mL), and it is small to be heated to 80 DEG C of stirrings 3
When.Saturated sodium bicarbonate solution is added into reaction solution, reaction is quenched, is extracted with ethyl acetate.Organic phase is separated, with water and salt
Water washing, anhydrous sodium sulfate are dried, filtered and concentrated, and residue isolates and purifies (ethanol/methylene=6/ with flash chromatography
94) crude title compound (386mg, 70%), is obtained, is yellow solid.LCMS (ESI) [M+H] +=372.2.
Step 2:6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (two pyridine -2- ylmethyls) -2- methoxies
Base -2- methyl -2,3- dihydro -1H- benzos [d] imidazoles
By 5- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N1(two pyridine -2- ylmethyls) benzene -1,2- diamines
The mixed liquor of (186mg, 0.501mmol) and trimethyl orthoacetate (8mL) is heated to 80 DEG C and is stirred overnight.Concentration of reaction solution, it is residual
Excess is isolated and purified with preparation-HPLC, and it is white solid (85mg, 40%) to obtain title compound.LCMS(ESI)[M+H]+=
428.3；1HNMR(400MHz,DMSO-d6) δ 8.58 (d, J=3.6Hz, 2H), 7.74 (t, J=7.2Hz, 2H), 7.45 (d, J=
7.2Hz, 2H), 7.33-7.24 (m, 2H), 6.86-6.78 (m, 2H), 6.65 (d, J=7.6Hz, 1H), 6.37 (s, 1H), 5.84
(d, J=4.8Hz, 1H), 3.96 (s, 3H), 3.69 (s, 3H), 2.00 (s, 3H), 1.94 (s, 3H)
Following present invention effect example 1-3 is using (+)-JQ1 and ABBV-75 as positive control.
Effect example 1：BRD4 (BD1, BD2) enzyme level determination of activity to BET protein inhibitors
BRD4 (BD1, BD2) enzyme level activity of each compound in above-described embodiment is measured, concrete operations are as follows：
Experimental method：
The combination active testing of each compound and BRD4 albumen bromodomain is examined using HTRF in above-described embodiment
Survey technology, the IC of detection compound50Value.Gradient dilution is carried out to compound using DMSO.Use the Diluent in kit
Buffer dilutes the histone H 4 peptide fragment of BRD4 (BD1, BD2) albumen and Biotin labels, and prepares reaction solution.Use kit
In Detection Buffer dilute Anti-GST-TB2+Cryptate and SA-XL-665, and configure detection liquid.Take 384 holes
One piece of plate, is arranged according to plate-laying, and untested compound hole, control wells min (high concentration positive drug), control wells max are divided on plate
(DMSO), positive drug control wells.Each hole into orifice plate is separately added into the compound or DMSO solution 20nL of corresponding concentration.Continue
10 μ L of reaction solution are added in each hole into orifice plate, and 10 μ L of detection liquid are then added.After being incubated 2h at room temperature, detected with Envision
The TR-Fret patterns (λ ex=340nm, λ em1=615nm, λ em2=665nm) of instrument read fluorescence values and HTRF signal values.
Numerical value processing：Inhibiting rate=(Max-Signal)/(Max-Min) * 100%.Max：The histone of Biotin labels
The HTRF signal values that H4 peptide fragments are completely combined with albumen.Min：The histone H 4 peptide that Biotin is marked after addition high concentration positive drug
Section and the completely uncombined HTRF background values of albumen.Signal：HTRF signal values under compound respective concentration.It is dense with compound
Degree and corresponding inhibiting rate do four parameter curves, obtain the IC of respective compound50。
Table 1 is compound BRD4 bioorganism Activity Results
Table 1
Part of compounds IC listed by table 150Better than (+)-JQ1, shows stronger activity, show the compound of the present invention
Biochemical test level can effectively combine the albumen with bromodomain in vitro, therefore the compound of the present invention can become
Effective medicine of tumour.
Effect example 2：To the inhibiting effect of MV-4-11 cells
The inhibiting effect that each compound is measured the inhibiting effect of MV-4-11 cells in above-described embodiment is surveyed
Fixed, concrete operations are as follows：
Experimental method：
1st day：Cell kind plate
1. microscopically observation determines that cell state is good；
2. cell is transferred in 15mL centrifuge tubes, 1000rpm centrifuges 5min, abandons supernatant；
3. complete medium (IMDM+10%FBS) is added, blow and beat into single cell suspension, Vi-cell cell count instrument meters
Number, required cell density is adjusted to complete medium by cell suspension；
4. being seeded in 96 orifice plates, it is 15000/ hole that cell number is made per 100 μ L of hole, and blank control is added 100 μ L and trains completely
Support base；
5.37 DEG C, 5%CO2Overnight incubation.
2nd day：Dosing
1.1000 × compound plate is prepared
1.1 are made into untested compound with DMSO the working solution of 10mM.STS is made into the working solution of 2mM with DMSO.
1.2 work that A arranges 60 μ L 10mM untested compounds (or STS) of addition to the 2nd of H rows in 96 orifice plate of round bottom
40 μ L DMSO are added in liquid, 3-11 row, draw 20 μ L drug solutions to the 3rd row from the 2nd row with the volley of rifle fire, piping and druming is uniformly mixed；Again
From the 3rd row in draw 20 μ L solution to the 4th row, piping and druming be uniformly mixed, continue successively by drug carry out 3 doubling dilutions, totally 10
Concentration.1st and the 12nd 40 μ L DMSO of row supplement of 96 orifice plates.
2. intermediate plate is prepared
Sterile 96 deep-well plates of V-type bottom are taken, RPMI1640 culture mediums of the 495 μ L without FBS is added per hole, draw 1000 × chemical combination
The 5 μ L of compound (or DMSO) diluted in object plate are added in 96 orifice plate of V-type bottom of corresponding position, and fully piping and druming is uniform.
3. drug is added
3.1 take out cell plates, microscopically observation from incubator.The compound diluted in intermediate plate or DMSO is taken to add
Enter in cell plates, per 11 μ L of hole.
Cell is placed in 37 DEG C, 5%CO by 3.22In continue cultivate 72h.
5th day：CellTiter-Glo detects cell activity
1. CellTiter-Glo buffer solutions and reaction substrate are taken out from refrigerator, buffer solution is fallen after balance to room temperature
Enter in the brown bottle equipped with substrate, turning upside down makes substrate powder fully dissolve.
2. cell is observed under the microscope, cell plates are balanced to room temperature.
3. prepared CellTiter-Glo is added in 96 orifice plates, per 100 μ L of hole.
4. cell plates are placed on shaking table and shake 10min, then room temperature stands 10min.
5. sticking white sealer in orifice plate bottom, Enspire micropore board detectors detect each hole chemiluminescence signal.
6. carrying out data processing using XLfit.Inhibiting rate %=(d-c)/(d-b) × 100, wherein d are DMSO processing groups
Signal value, c is the signal value of compound processing group, and b is the letter only containing culture medium and DMSO without celliferous blank group
Number value.Data [fit=(A+ ((B-A)/(1+ ((C/x) of f (x) 205 in XLfit softwares^D))))] equation is fitted.
Table 2 is compound MV-4-11 cell experiment bioactivity results.
Table 2
Effect example 3：To the inhibiting effect of SU-DHL-6 cells
Each compound in above-described embodiment is measured the inhibiting effect of SU-DHL-6 cells, concrete operations are as follows：
Experimental method：
1st day：Cell kind plate
1. microscopically observation determines that cell state is good；
2. cell is transferred in centrifuge tube, 1000rpm centrifuges 5min, abandons supernatant；
3. complete medium (1640+10%FBS) is added, blow and beat into single cell suspension, Vi-cell cell count instrument meters
Number, required cell density is adjusted to complete medium by cell suspension；
It is 12000/ hole per 100 μ L cell numbers of hole 4. being seeded in 96 orifice plates, blank control is added 100 μ l and cultivates completely
Base；
5.37 DEG C, 5%CO2Overnight incubation.
2nd day：Dosing
1.1000 × compound plate is prepared
1.1 are made into untested compound with DMSO the working solution of 10mM.STS is made into the working solution of 2mM with DMSO.
1.2 work that A arranges 60 μ L10mM untested compounds (or STS) of addition to the 2nd of H rows in 96 orifice plate of round bottom
40 μ LDMSO are added in liquid, 3-11 row, draw 20 μ L drug solutions to the 3rd row from the 2nd row with the volley of rifle fire, piping and druming is uniformly mixed；Again
From the 3rd row in draw 20 μ L solution to the 4th row, piping and druming be uniformly mixed, continue successively by drug carry out 3 doubling dilutions, totally 10
Concentration.1st and the 12nd 40 μ LDMSO of row supplement of 96 orifice plates.
2. intermediate plate is prepared
Sterile 96 deep-well plates of V-type bottom are taken, RPMI1640 culture mediums of the 495 μ L without FBS is added per hole, draw 1000 × chemical combination
The 5 μ L of compound (or DMSO) diluted in object plate are added in 96 orifice plate of V-type bottom of corresponding position, and fully piping and druming is uniform.
3. drug is added
3.1 take out cell plates, microscopically observation from incubator.The compound diluted in intermediate plate or DMSO is taken to add
Enter in cell plates, per 11 μ L of hole.
Cell is placed in 37 DEG C, 5%CO by 3.22In continue cultivate 72h.
5th day：CellTiter-Glo detects cell activity
1. CellTiter-Glo buffer solutions and reaction substrate are taken out from refrigerator, buffer solution is fallen after balance to room temperature
Enter in the brown bottle equipped with substrate, turning upside down makes substrate powder fully dissolve.
2. cell is observed under the microscope, cell plates are balanced to room temperature.
3. prepared CellTiter-Glo is added in 96 orifice plates, per 100 μ L of hole.
4. cell plates are placed on shaking table and shake 10min, then room temperature stands 10min.
5. sticking white sealer in orifice plate bottom, Enspire micropore board detectors detect each hole chemiluminescence signal.
6. carrying out data processing using XLfit.Inhibiting rate %=(d-c)/(d-b) × 100%, wherein d are DMSO processing
The signal value of group, c are the signal value of compound processing group, and b is only containing culture medium and DMSO without celliferous blank group
Signal value.Data [fit=(A+ ((B-A)/(1+ ((C/x) of f (x) 205 in XLfit softwares^D))))] equation is fitted.
Table 3 is compound SU-DHL-6 cell experiment bioactivity results
Table 3
Claims (10)
1. a kind of compound containing aromatic ring as shown in Equation 1, its pharmaceutically acceptable salt, its stereoisomer, its mutually variation
Structure body or its solvate,
Wherein,
R1And R2It independently is substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C8Naphthenic base, substitution or
Unsubstituted " one or more in hetero atom N, O and S, hetero atom number is 1~4,3~10 yuan of Heterocyclylalkyl " takes
Generation or unsubstituted C6-C10Aryl or substituted or unsubstituted " one or more in hetero atom N, O and S, miscellaneous original
Subnumber is 1~4,5~10 yuan of heteroaryl "；The R1And R2In all " substitutions " independently be by with next or more
A substituent group is replaced, and when there are multiple substituent groups, the substituent group is identical or different：Halogen and " by one or more
A C1-C6Alkyl " substituted or unsubstituted C6-C10Aryl；
Y is
It is finger ring B existence or non-existences；
In the absence of the ring B, (R5)mAlso be not present, ring A be phenyl or it is substituted or unsubstituted " hetero atom N,
One or more in O and S, hetero atom number is 1~4,5~6 yuan of heteroaryl ", X is
Each R6It independently is hydrogen or C1-C6Alkyl；
In the presence of the ring B, (R5)mThere is also ring A is phenyl or substituted or unsubstituted " hetero atom N, O and S
In it is one or more, hetero atom number be 1~4,5~6 yuan of heteroaryl ", X is It is described
Ring B include X and condensed with ring A, the ring B is that " one or more in hetero atom N, O and S, hetero atom number is 1~3
A, 4~10 yuan of Heterocyclylalkyl ", C4-C10Cycloalkenyl group, " it is one or more in hetero atom N, O and S, hetero atom number be 1
~3,4~10 yuan of heterocycloalkenyl ", C6-C10Aryl or " one or more in hetero atom N, O and S, hetero atom
Number is 1~4,5~10 yuan of heteroaryl "；
R3For it is substituted or unsubstituted " it is one or more in hetero atom N, O and S, hetero atom number be 1~3,3~10 yuan
Heterocycloalkenyl " or it is substituted or unsubstituted " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,5~
10 yuan of heteroaryl "；The R3In all " substitutions " independently be and replaced by following one or more substituent groups, when depositing
In multiple substituent groups, the substituent group is identical or different：One or more substituted or unsubstituted C of hydroxyl1-C6Alkyl,
C1-C6Alkoxy andEach R7And R8It independently is hydrogen or C1-C6Alkyl；
N and m independently is 0,1,2,3 or 4；
Each R4And R5It independently is amino, cyano, halogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted
C3-C8Naphthenic base, it is substituted or unsubstituted " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,5~
6 yuan of heteroaryl ", NH2- C (=O)-(CH2)pOr R9- S (=O)2-NH-(CH2)q-；Wherein, p and q independently is 0,1,2
Or 3, R9For C1-C6Alkyl, the R4And R5In all " substitutions " independently be by following one or more substituent groups institute
Substitution, when there are multiple substituent groups, the substituent group is identical or different：Cyano, hydroxyl and halogen.
2. compound 1 as described in claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or
Its solvate, which is characterized in that R1And R2In " C3-C8Naphthenic base " be " C3-C6Naphthenic base "；
And/or R1And R2In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,3~10 yuan of heterocycle
Alkyl " is " one or more in hetero atom N, O and S, hetero atom number is 1~2,3~6 yuan of Heterocyclylalkyl "；
And/or R1And R2In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,5~10 yuan of heteroaryl
Base " is " one or more in hetero atom N, O and S, hetero atom number is 1~4,5~6 yuan of heteroaryl "；
And/or in the presence of the ring B, " one or more in hetero atom N, O and S, the hetero atom number described in ring B
Be 1~3,4~10 yuan of Heterocyclylalkyl " be " one or more in hetero atom N, O and S, hetero atom number is 1~3,5
~6 yuan of Heterocyclylalkyl "；
And/or in the presence of the ring B, the C described in ring B4-C10Cycloalkenyl group be C5-C6Cycloalkenyl group；
And/or in the presence of the ring B, " one or more in hetero atom N, O and S, the hetero atom number described in ring B
Be 1~3,4~10 yuan of heterocycloalkenyl " be " one or more in hetero atom N, O and S, hetero atom number is 1~3,5
~6 yuan of heterocycloalkenyl "；
And/or in the presence of the ring B, " one or more in hetero atom N, O and S, the hetero atom number described in ring B
Be 1~4,5~10 yuan of heteroaryl " be " one or more in hetero atom N, O and S, hetero atom number is 1~3,5~
6 yuan of heteroaryl "；
And/or in the presence of the ring B, the ring B is monocycle or bicyclic；
And/or R3In " it is one or more in hetero atom N, O and S, hetero atom number be 1~3,3~10 yuan of heterocycle alkene
Base " is " one or more in hetero atom N, O and S, hetero atom number is 1~3,5~10 yuan of heterocycloalkenyl "；
And/or R3In " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,5~10 yuan of heteroaryl "
For " one or more in hetero atom N, O and S, hetero atom number is 1~4,5~9 yuan of heteroaryl "；
And/or R3Positioned at the ortho position of X, meta or para position；
And/or when n is 1, R4Positioned at the ortho position of X, meta or para position；
And/or when ring A is hexatomic ring, R3、R4With X meta positions each other；
And/or R4And R5Middle C3-C8Naphthenic base be C3-C6Naphthenic base.
3. compound 1 as claimed in claim 2, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or
Its solvate, which is characterized in that R1And R2It independently is
And/or in the presence of the ring B, it is with the condensed rings formed of ring A：
And/or R3For
And/or R4And R5Independently be fluorine, amino, cyano, methyl, isopropyl,
4. compound 1 as described in claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or
Its solvate, which is characterized in that R1And R2In it is at least one be substituted or unsubstituted C6-C10Aryl or substitution or
Unsubstituted " one or more in hetero atom N, O and S, hetero atom number is 1~4,5~10 yuan of heteroaryl "；
And/or R1And R2It independently is substituted or unsubstituted C3-C8Naphthenic base, substituted or unsubstituted " hetero atom N, O
With it is one or more in S, hetero atom number be 1~4,3~10 yuan of Heterocyclylalkyl ", substituted or unsubstituted C6-C10Virtue
Base or it is substituted or unsubstituted " it is one or more in hetero atom N, O and S, hetero atom number be 1~4,5~10 yuan
Heteroaryl "；The R1And R2In all " substitutions " independently be and replaced by following one or more substituent groups, when depositing
In multiple substituent groups, the substituent group is identical or different：" by one or more C1-C6Alkyl " it is substituted or unsubstituted
C6-C10Aryl；
And/or Y is
And/or when X with Y differences be C or N；
And/or compound 1 is
And/or in the absence of the ring B, (R5)mAlso it is not present, ring A is substituted or unsubstituted " hetero atom N, O and S
In it is one or more, hetero atom number be 1~4,5~6 yuan of heteroaryl ", X isR6For hydrogen or C1-C6Alkyl；
And/or in the presence of the ring B, (R5)mThere is also, ring A be phenyl or substituted or unsubstituted " hetero atom is
N, one or more in O and S, hetero atom number is 1~4,5~6 yuan of heteroaryl ", X isThe ring B includes
X and condensed with ring A, the ring B is C6-C10Aryl or " one or more in hetero atom N, O and S, hetero atom number
It is 1~4,5~10 yuan of heteroaryl "；
And/or R3For it is substituted or unsubstituted " it is one or more in hetero atom N, O and S, hetero atom number be 1~3,3~
10 yuan of heterocycloalkenyl " or it is substituted or unsubstituted " it is one or more in hetero atom N, O and S, hetero atom number be 1~4
It is a, 5~10 yuan of heteroaryl "；The R3In all " substitutions " independently be and taken by following one or more substituent groups
In generation, when there are multiple substituent groups, the substituent group is identical or different：One or more substituted or unsubstituted C of hydroxyl1-C6
Alkyl and C1-C6Alkoxy；
And/or each R4And R5It independently is amino, cyano, halogen, unsubstituted " one kind or more in hetero atom N, O and S
Kind, hetero atom number is 1~4,5~6 yuan of heteroaryl " or NH2- C (=O)-(CH2)p-；
And/or n is 0 or 1；
And/or m is 0 or 1；
And/or n+m=1；
And/or p is 0 or 1；
And/or q is 0 or 1.
5. compound 1 as described in claim 1, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or
Its solvate, which is characterized in that the compound 1 is following any compounds：
6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -
4- nitriles；
6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -
4- carboxylic acid amides；
3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -4- (1H- pyrazoles -4- bases) -1H- benzos [d]
Imidazoles -6- bases) isoxazole；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzene
And [d] imidazoles -4- nitriles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzene
And [d] imidazole-4-carboxamide；
3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) isoxazole；
(S) -3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) is different
Oxazole；
(R) -3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) is different
Oxazole；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzene
And [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazoles；
3- ethyoxyl -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) pyrrole
Pyridine -2 (1H) -one；
(R) -3,5- dimethyl -4- (1- (1- (pyridine -2- bases) -2- p-methylphenyls ethyl) -1H- benzos [d] imidazoles -6- bases) is different
Oxazole；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (1- (pyridine -2- bases) -2- tolylethyls) -
1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) fluoro- 1- of -4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazoles；
1- benzhydryls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (1,2- diphenyl-ethyls) -1H- benzos [d] imidazoles；
1- (cyclopropyl (phenyl) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d] imidazoles；
(S) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- imidazos [4,5-c] pyridine；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- imidazos [4,5-c] pyridine；
6- (3,5- dimethyl -3H-1,2,3- triazole -4- bases) -1- phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- miaows
Azoles simultaneously [4,5-c] pyridine；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- imidazos [4,5-c] pyridine；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (pyridine -2- bases) methyl) -1H- benzos [d] miaow
Azoles；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) methyl) -1H- benzos
[d] imidazole formic acid salt；
1- benzhydryls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indoles；
1- methyl -2'- ((phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6 (1H) -one；
1- methyl -2'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6 (1H) -one；
2'- amino -1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,4'- bipyridyls] -6
(1H) -one；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (2- methyl-1s-phenyl propyl) -1H- benzos [d] imidazoles；
3,5- dimethyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- base l) methyl) -1H- imidazos [4,5-c] pyridine -6- bases)
Isoxazole；
6- methyl -4- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -1,6- dihydros -
7H- pyrrolo-es [2,3-c] pyridin-7-one；
3- (ethylamino-) -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases)
Pyridine -2 (1H) -one；
6- (5- methoxyl group -1- methyl -6- oxo -1,6- dihydropyridine -3- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles -4- formamides；
3- methoxyl group -1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) pyrrole
Pyridine -2 (1H) -one；
6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1,3- dihydro -2H- benzene
And [d] imidazoles -2- ketone；
2- (5- (3,5- dimethyl isoxazole -4- bases) -2- oxos -3- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -2,3-
Dihydro -1H- benzos [d] imidazoles -1- bases) acetonitrile；
2- (5- (3,5- dimethyl isoxazole -4- bases) -2- oxos -3- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -2,3-
Dihydro -1H- benzos [d] imidazoles -1- bases) acetamide；
3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases)-[1,2,4] three
Nitrogen azoles simultaneously [4,3-b] pyridazine -8- amine；
3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases)-[1,2,4] three
Nitrogen azoles simultaneously [4,3-b] pyridazine；
3,8- dimethyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases)-[1,2,
4] triazole simultaneously [4,3-b] pyridazine；
6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -
4- amine；
4- (the fluoro- 1- of 4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3,5- dimethyl is different
Oxazole；
N- (6- (3,5- dimethyl isoxazole -4- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] miaows
Azoles -4- bases) Methanesulfomide；
3,7- dimethyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases)-[1,2,
4] triazole simultaneously [4,3-b] pyridazine；
7- isopropyl -3- methyl -6- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -
[1,2,4] triazole simultaneously [4,3-b] pyridazine；
1- methyl -5- (4- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) amino) quinoline -6- bases) pyridine -2 (1H) -one；
5- methyl -7- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -1,5- dihydros -
4H- pyrrolo-es [3,2-c] pyridine -4- ketone；
1- methyl -5- (1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- benzos [d] imidazoles -6- bases) pyridine -2 (1H) -
Ketone；
6- (3,5- dimethyl isoxazole -4- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases) quinolin-4-amines；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) fluoro- 1H- benzos [d] of -4-
Imidazoles；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) fluoro- 2- methyl-1s H- of -4-
Benzo [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) the fluoro- 1- of -4- ((4- fluorophenyls) (pyridine -2- bases) methyl) -2-
Methyl-1 H- benzos [d] imidazoles；
1- (bis- (2,4 difluorobenzene base) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) fluoro- 2- methyl-of -4-
1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(pyridine -2- bases (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [4,5-b] pyridine；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1 H- imidazoles
And [4,5-b] pyridine；
1- (bis- (2,4 difluorobenzene base) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1 H- miaows
Azoles simultaneously [4,5-b] pyridine；
1- (bis- (4- fluorophenyls) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1 H- imidazos
[4,5-b] pyridine；
1- (bis- (4- fluorophenyls) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- imidazos [4,5-b]
Pyridine；
N- (1- benzhydryls -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indol-3-yls) ethyl sulfonamide；
N- (1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indoles -3-
Base) ethyl sulfonamide；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- indoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases) quinoline -4-
Amine；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1 H- benzos
[d] imidazoles；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- Trifluoromethyl-1s H-
Benzo [d] imidazoles；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1H- benzos [d] imidazoles -
2- nitriles；
1- (two (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- isopropyl -1H- benzene
And [d] imidazoles；
4- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3,5- dimethyl isoxazoles；
5- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] imidazoles -6- bases) -3- methoxyl group -1- picolines -2 (1H) -
Ketone；
1- ((2,4 difluorobenzene base) (pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2-
Methyl-1 H- benzos [d] imidazoles；
1- (bis- (5- fluorine pyridine -2- bases) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s H-
Benzo [d] imidazoles；
1- ((4,4- difiuorocyclohexyls) (phenyl) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- first
Base -1H- benzos [d] imidazoles；
1- (bis- (4- chlorphenyls) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1 H- benzos
[d] imidazoles；
1- (two (pyridine -2- bases) methyl) -6- (1- ethyl -4- methyl-1 H-1,2,3- triazole -5- bases) -1H- benzos [d] miaow
Azoles；
2- (5- (1- (two (pyridine -2- bases) methyl) -1H- benzos [d] i imidazoles -6- bases) -4- methyl-1 H-1,2,3- triazoles -
1- yls) ethane -1- alcohol；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((4- fluorophenyls) (pyridine -2- bases) methyl) -2- methyl -
1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((5- fluorine pyridine -2- bases) (phenyl) methyl) -2- methyl -
1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- ((5- fluorine pyridine -2- bases) (phenyl) methyl) -1H- benzos
[d] imidazoles；
1- (bis- (2,4 difluorobenzene base) methyl) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1 H- benzene
And [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- isopropyls -1- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazoles -2- nitriles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- benzos [d] imidazoles -2- formamides；
(R)-N- ((6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) first
Base) -1H- benzos [d] imidazoles -2- bases) methyl) Methanesulfomide；
(R) -2- cyclobutyl -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4-
Base) methyl) -1H- benzos [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -1H- benzos [d] imidazoles；
(R) -6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -2- methyl-1s-(phenyl (tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -1H- imidazos [4,5-b] pyridine；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -1H- miaows
Azoles simultaneously [4,5-c] pyridine；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (pyridine -2- bases (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
1H- imidazos [4,5-c] pyridine；
N2Benzhydryl -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N2Picoline -2,6- diamines；
N2Benzhydryl -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-pyridine -2,6- diamines；
(R) -2'- amino -5- ethyoxyls -1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine)-[3,
4'- bipyridyls] -6 (1H) -one；
(R)-N- (1- methyl -6'- (methyl (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) amine) -6- oxo -1,6- dihydros -
[3,4'- bipyridyls] -2'- bases) Methanesulfomide；
(R)-N- (5- ethyoxyl-1- methyl-6'- (methyl (phenyl (tetrahydrochysene-2H- pyrans-4- bases) methyl) amine) oxo-1-6-,
6- dihydros-[3,4'- bipyridyls] -2'- bases) Methanesulfomide；
4- (3,5- dimethyl isoxazole -4- bases)-N- phenyl-N- (tetrahydrochysene -2H- pyrans -4- bases) picolinamide；
4- (3,5- dimethyl isoxazole -4- bases)-N- methyl-N- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) pyridine -2-
Amine；
N- (two (pyridine -2- bases) methyl) -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N- picolines -2-
Amine；
N2(two (pyridine -2- bases) methyl) -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N2Picoline -2,
6- diamines；
N- (two (pyridine -2- bases) methyl) -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) pyridine -2- amine；
N2(two (pyridine -2- bases) methyl) -4- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) pyridine -2,6- diamines；
2- (3- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -5- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
5H- pyridos [4,3-b] indoles -7- bases) propane -2- alcohol；
With 3- (Isosorbide-5-Nitrae-dimethyl -1H-1,2,3- triazole -5- bases) -5- (phenyl (tetrahydrochysene -2H- pyrans -4- bases) methyl) -
5H- pyridos [4,3-b] indoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (two pyridine -2- ylmethyls) -1H- benzos [d] imidazoles -2
(3H) -one；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases) -1- (two pyridine -2- ylmethyls) -2- methoxyl group -2- methyl -
2,3- dihydro -1H- benzos [d] imidazoles；
6- (1,4- dimethyl -1H-1,2,3- triazole -5- bases)-N, N- bis- (pyridine -2- bases) quinolin-4-amines.
6. a kind of preparation method containing fragrant cyclics as shown in formula 1 according to any one of claims 1 to 5, packet
Include following steps：The halide intermediates as shown in formula 1-A with contain R3Pinacol borate intermediate to carry out Suzuki even
Connection reaction, obtains compound 1；Alternatively, the halide intermediates as shown in formula 1-A with contain R3Tin reagent intermediate,
Stille coupling reactions are carried out, compound 1 is obtained；
Wherein, Z is halogen, and the definition of remaining substituent group is as described in any one of Claims 1 to 5.
7. as compound 1 according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its stereoisomer, its
Tautomer or its solvate, the application in preparing bromine structural domain inhibitor.
8. as compound 1 according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its stereoisomer, its
Tautomer or its solvate, application in medicine preparation, the drug is for preventing or treating and bromine structural domain
Related disease.
9. as compound 1 according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its stereoisomer, its
Tautomer or its solvate, application in medicine preparation, the drug is for preventing or treating pulmonary disease, inflammation
Property disease or autoimmune disease.
10. a kind of pharmaceutical composition, it includes compound 1 such as according to any one of claims 1 to 5, it can pharmaceutically connect
Salt, its stereoisomer, its tautomer or its solvate received, and at least one pharmaceutic adjuvant.
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| PCT/CN2018/072872 WO2018130227A1 (en) | 2017-01-16 | 2018-01-16 | Aromatic ring-containing compound, preparation method therefor, pharmaceutical composition, and use |
| CN201880007037.3A CN110177784A (en) | 2017-01-16 | 2018-01-16 | One kind containing aromatic compound, preparation method, pharmaceutical composition and application |
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| WO2021233371A1 (en) * | 2020-05-21 | 2021-11-25 | 贝达药业股份有限公司 | Compound functioning as bromodomain protein inhibitor, and composition |
| CN114630830A (en) * | 2019-10-31 | 2022-06-14 | 治愈医药社株式会社 | Novel compound and pharmaceutical composition for preventing or treating cancer comprising the same |
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| WO2008089307A2 (en) * | 2007-01-18 | 2008-07-24 | Lexicon Pharmaceuticals, Inc. | Delta 5 desaturase inhibitors for the treatment of pain, inflammation and cancer |
| EP2858983B1 (en) * | 2012-06-11 | 2018-04-18 | UCB Biopharma SPRL | Tnf-alpha modulating benzimidazoles |
| KR20150135359A (en) * | 2013-03-14 | 2015-12-02 | 컨버진 엘엘씨 | Methods and compositions for inhibition of bromodomain-containing proteins |
| RS57733B1 (en) * | 2013-03-15 | 2018-12-31 | Plexxikon Inc | Heterocyclic compounds and uses thereof |
| TWI527811B (en) * | 2013-05-09 | 2016-04-01 | 吉李德科學股份有限公司 | Benzimidazole derivatives as bromodomain inhibitors |
| PT3010503T (en) * | 2013-06-21 | 2020-06-16 | Zenith Epigenetics Corp | Novel bicyclic bromodomain inhibitors |
| CA2930499C (en) * | 2013-12-09 | 2021-11-23 | Ucb Biopharma Sprl | Imidazopyridine derivatives as modulators of tnf activity |
| US9321762B2 (en) * | 2013-12-11 | 2016-04-26 | Development Center For Biotechnology | Quinazoline compounds, method for preparing the same and use thereof |
| AU2015318233B2 (en) * | 2014-09-15 | 2020-03-12 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
| CA2966452A1 (en) * | 2014-12-17 | 2016-06-23 | Samuel David Brown | Substituted bicyclic compounds as bromodomain inhibitors |
| AR104259A1 (en) * | 2015-04-15 | 2017-07-05 | Celgene Quanticel Res Inc | BROMODOMINUM INHIBITORS |
| CN115806550A (en) * | 2015-11-25 | 2023-03-17 | 康威基内有限公司 | Bicyclic BET bromodomain inhibitors and uses thereof |
| WO2017106630A1 (en) * | 2015-12-18 | 2017-06-22 | The General Hospital Corporation | Polyacetal polymers, conjugates, particles and uses thereof |
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| CN114630830A (en) * | 2019-10-31 | 2022-06-14 | 治愈医药社株式会社 | Novel compound and pharmaceutical composition for preventing or treating cancer comprising the same |
| WO2021233371A1 (en) * | 2020-05-21 | 2021-11-25 | 贝达药业股份有限公司 | Compound functioning as bromodomain protein inhibitor, and composition |
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