CN108929312A - Novel benzheterocycle with CDK or HDAC inhibitory activity joins pyrimidine inhibitors - Google Patents
Novel benzheterocycle with CDK or HDAC inhibitory activity joins pyrimidine inhibitors Download PDFInfo
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- CN108929312A CN108929312A CN201710363239.9A CN201710363239A CN108929312A CN 108929312 A CN108929312 A CN 108929312A CN 201710363239 A CN201710363239 A CN 201710363239A CN 108929312 A CN108929312 A CN 108929312A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
There is the present invention the novel benzheterocycle of CDK or HDAC inhibitory activity to join pyrimidine inhibitors, be related to the new new type heterocycle derivative with formula (I) and its salt including officinal salt, wherein R1、R2、R3、R4、R5It is defined with X, Z, L herein.The compound of the present invention is CDK or hdac inhibitor, can be used for treating the disease and disorder mediated by CDK or HDAC, such as cancer including lymphoma mantle cell, sarcolipoma, non-small cell lung cancer, melanoma, the squamous cell cancer of the esophagus and breast cancer etc..The invention further relates to the pharmaceutical compositions comprising the compound of the present invention.The invention further relates to use the compound of the present invention or pharmaceutical composition comprising the compound of the present invention treats associated disorder.
Description
Technical field
The present invention relates to new type heterocycle derivative and its pharmaceutical composition, especially as the new of CDK or hdac inhibitor
Type Hete rocyclic derivatives and its pharmaceutical composition.The invention further relates to these compounds and composition in treatment hyperproliferative disorders
Such as the purposes in cancer.
Background technique
The life of cell starts from the cell cycle, and the normal operation of cell cycle depends on fine regulatory mechanism.It has been found that
Cell cycle protein dependent kinase(cyclin-dependent kinase, CDK)It is the core of cell cycle regulating.CDKs
Family is broadly divided into two classes:CDK1-4,6 control cell cycles, regulating cell enters G1 in conjunction with corresponding cyclin
Phase, to influence the synthesis of cell DNA;CDK5,7-9 control cell transcription, the study found that the diseases such as cancer occur, development with
The regulation of cell cycle is extremely related, and it is not normal to have more than CDK and corresponding Cyclin expression in 90% cancer.Due to the cell cycle
Caused by molecular mechanism out of control often passes through the inappropriate activation of CDK, therefore, CDK is that the disease treatments such as tumour are great latent
The target spot of power.
In tumour cell, the enhancing that the overexpression of HDAC causes deacetylation to act on, by restoring histone positive electricity
Lotus makes loose nucleosome become very close to increase the gravitation between DNA and histone, is unfavorable for some tumour suppressions
The expression of gene processed.The advanced activation and HDAC of CDK over-expresses while promoting the proliferation of tumour cell.Target CDK's
The inhibitor for targeting HDAC simultaneously can more efficiently inhibit the excessive proliferated cells such as tumour.
Therefore, while the inhibitor that targets CDK and HDAC has better drug effect, can reduce drug resistance and poison is secondary makees
With.
Summary of the invention
The compound of the present invention is CDK or hdac inhibitor, can be used for treating by the CDK or HDAC disease mediated and disorderly
It is random, such as cancer including lymphoma mantle cell, sarcolipoma, non-small cell lung cancer, melanoma, the squamous cell cancer of the esophagus and mammary gland
Cancer.Pharmaceutical composition the invention further relates to the compound of the present invention is used or comprising the compound of the present invention has to treat with it
The disorder of pass.
The present invention relates to the new benzopyrroles with formula (I) to join pyrimidine cycle compound and its salt including officinal salt:
Wherein:
R1Selected from H,、、、、、、
、、, alkyl, alkenyl, alkynyl, heterocycle, aryl, hetero-aromatic ring, wherein R7And R8It is hydrogen respectively
Base, alkyl, naphthenic base, heteroatomic ring alkyl, aryl or hetero-aromatic ring;
R2It is C1-8Alkyl;Optionally C is selected from by one1-8The C that the substituent group of alkyl, halogen atom and OH replaces4-7Cycloalkanes
Base;Optionally C is selected from by one1-8Alkyl, C (CH3)2The phenyl that the substituent group of CN, halogen atom and OH replace;Optionally by one
A cyclopropyl or C1-8Alkyl-substituted piperidyl;Optionally by a cyclopropyl or C1-8Alkyl-substituted THP trtrahydropyranyl;Or
Two rings [2.2.1] heptane base, wherein halogen atom includes F, Cl, Br, I;
R3And R4It is hydrogen atom or fluorine atom, wherein R3And R4At least one is fluorine atom;
R5Selected from substituted or unsubstituted aryl, substituted or unsubstituted pyridyl group, substituted or unsubstituted pyrimidine radicals, replace or
Unsubstituted pyridine oxide base, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrrole radicals, substituted or unsubstituted pyrrole
Oxazolyl, substituted or unsubstituted imidazole radicals, indyl substituted or unsubstituted, isoindolyl substituted or unsubstituted replace or do not take
For furyl, thiazolyl substituted or unsubstituted, Qu generation or non-substituted oxazole quinoline base, thienyl substituted or unsubstituted;
R6 It is selected from、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、Wherein n=
1 ~ 9, A, D are each independently selected from valence link, O, NH, NR11、C(O)、C(O)NH、NHC(O)、CH2 、CH2C(O)NH、CH2NHC (O) or
S(O)1~2, R9、R10H, OH, C can be independently selected from1-C8Alkane ,-(CH2)t(C1-C10Alkane) ,-(CH2)t(C3-C10Miscellaneous alkane
Hydrocarbon) ,-(CH2)t(C3-C10) cycloalkane) ,-(CH2)t(C6-C10The miscellaneous alkane of ring), wherein t represents number 0-6, and all alkane can
Selection is replaced by one or more F, Cl or Br;
L is valence link, O, NH, C (O), C (O) NH, NHC (O), CH2 、CH2C(O)NH、CH2NHC(O) 、CH2 S(O)1~2Or S
(O)1~2;
X and Z are each independently selected from CH, N, when Z selects N, R1For unsubstituted.
Benzopyrrole of the present invention connection pyrimidine cycle compound can according to conventional medicine preparation technique and pharmaceutical carrier or
Excipient (such as pharmaceutically acceptable carrier and excipient) is mixed to form pharmaceutical preparation.The benzopyrrole can be joined phonetic
Phenazine ring Compound Compound is blended in any commonly employed peroral dosage form as active constituent, the peroral dosage form include tablet,
Capsule and liquid preparation (such as elixir and suspension), wherein including the object of colorant, corrigent, stabilizer and taste masking
Matter.For mixing peroral dosage form, benzopyrrole connection pyrimidine cycle compound as active constituent can with it is various commonly
Tablet material (such as starch, calcium carbonate, lactose, sucrose and Dicalcium Phosphate) mixing is to help tabletting and is packed into capsule.It can incite somebody to action
The benzopyrrole joins pyrimidine cycle compound pharmaceutically acceptable sterile liquid carrier such as sterile water, sterile organic solvent
Or both mixture in dissolve or be suspended.Liquid-carrier can be the carrier of suitable injection, such as physiological saline, the third two
Alcohol or Aqueous Solutions of Polyethylene Glycol.In other cases, the active constituent of micronization can also be dispersed in starch or carboxymethyl
In the aqueous solution of sodium cellulosate or it is dispersed in oily (such as peanut oil) appropriate and is made.Liquid pharmaceutical formulation (refers to sterile molten
Liquid or suspension) it can be used for intravenous injection, intramuscular injection, intraperitoneal injection or subcutaneous injection.
The present invention also provides a kind of pharmaceutical composition, which includes at least one sheet as active constituent
Invent the benzopyrrole connection pyrimidine cycle compound.In addition to this, described pharmaceutical composition can also include one or more nothings
The pharmaceutically acceptable carrier or excipient of machine or organic, solid or liquid.Term " pharmaceutically acceptable ", which refers to, works as
When being administered to animal such as mammal (such as mankind) it is physiologically tolerable and will not usually generate allergy or it is similar not
The additive or composition of good reaction (such as dizziness etc.).Pharmaceutical carrier and excipient can include but is not limited to diluent, example
Such as lactose, glucose, mannose and/or glycerol;Lubricant;Polyethylene glycol;Adhesive, for example, aluminum magnesium silicate, starch, gelatin,
Methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone;Also, it if necessary, further include disintegrating agent,
Such as starch, agar, alginic acid or its salt such as sodium alginate;And/or adsorbent, colorant, preservative, stabilizer, corrigent
And sweetener.
Specific embodiment
It is further described to various aspects of the present invention with feature below.
Abbreviation used herein is usually well-known to those skilled in the art, or can be easy according to rudimentary knowledge
In understanding.
The starting material employed in the preparation of the compounds of this invention be it is known, can be prepared according to known method
Or it is commercially available.
The invention further relates to new intermediate and/or starting materials.It is particularly preferably identical as those of being mentioned in embodiment
Or similar reaction condition and new intermediate.
Intermediate and final product can be post-processed according to conventional methods and/or be purified, and the conventional method includes
Adjust pH, extraction, filtering, drying, concentration, chromatography, grinding, crystallization etc..
In addition, the compounds of this invention can also pass through the accommodation of various methods known in the art or methods described herein
It is prepared by method.
The following example is only used for illustrating the present invention, and does not limit the invention in any way.
(((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-) is phonetic by 4- by 1 N-1- of embodiment
Pyridine -2- base) amino) phenyl) and-N- 8- oxyammonia oxo octanoic acid amide preparation
8- ((4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) phenyl) amino) -8- oxo octanoic acid methyl esters (400 mg, 0.71 mmoL), aqueous hydroxylamine solution (50%,
4 mL), 20 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, residue column chromatographic purifying obtains
305 mg, yield=76%.1H NMR (400 MHz, DMSO-d 6): δ 10.35 (s, 1H), 9.80 (s, 1H),
9.70 (s, 1H), 8.69 (s, 1H), 8.60 (d, J = 3.9 Hz, 1H), 8.26 (s, 1H), 7.67 (dd,J = 19.3, 10.3 Hz, 3H), 7.55 (d, J = 8.5 Hz, 2H), 4.91 – 4.76 (m, 1H), 2.64
(s, 3H), 2.28 (t, J = 7.4 Hz, 2H), 1.95 (t, J = 7.3 Hz, 2H), 1.66 – 1.45 (m,
12H), 1.28 (d, J = 7.4 Hz, 2H)。
(((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-) is phonetic by 4- by 2 N-1- of embodiment
Pyridine -2- base) amino) phenyl) and-N- 7- oxyammonia oxo-heptanoic acid amide preparation
8- ((4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) phenyl) amino) -7- oxo-heptanoic acid methyl esters (200 mg, 0.36 mmoL), aqueous hydroxylamine solution
(50%, 2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent, residue column chromatography are removed
Purify to obtain 140 mg, yield=70%.1H NMR (400 MHz, DMSO-d 6): δ 10.35 (s, 1H), 9.80 (s,
1H), 9.70 (s, 1H), 8.69 (s, 1H), 8.60 (d, J = 3.9 Hz, 1H), 8.26 (s, 1H), 7.67
(dd, J = 19.3, 10.3 Hz, 3H), 7.55 (d, J = 8.5 Hz, 2H), 4.92 – 4.78 (m, 1H),
2.64 (s, 3H), 2.28 (t, J = 7.4 Hz, 2H), 1.95 (t, J = 7.3 Hz, 2H), 1.67 – 1.46
(m, 10H), 1.31-1.23 (m, 2H)。
(((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-) is phonetic by 4- by 3 N-1- of embodiment
Pyridine -2- base) amino) phenyl) and-N- 9- oxyammonia oxo n-nonanoic acid amide preparation
8- ((4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) phenyl) amino) -9- oxo methyl pelargonate (200 mg, 0.35 mmoL), aqueous hydroxylamine solution(50,
2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, residue column chromatographic purifying obtains
124 mg, yield=62%.1H NMR (400 MHz, DMSO-d 6): δ10.36 (s, 1H), 9.81 (s, 1H), 9.69
(s, 1H), 8.69 (s, 1H), 8.59 (d, J = 3.9 Hz, 1H), 8.26 (s, 1H), 7.67 (dd, J =
20.5, 10.3 Hz, 3H), 7.55 (d, J = 8.5 Hz, 2H), 4.90 – 4.74 (m, 1H), 2.64 (s,
3H), 2.28 (t, J = 7.4 Hz, 2H), 1.94 (t, J = 7.3 Hz, 2H), 1.62 (d, J = 6.8 Hz,
6H), 1.50-1.47 (s, 2H), 1.39 – 1.11 (m, 8H)。
4 N-1- of embodiment (5-((the fluoro- 4- of 5- (fluoro- 1- isopropyl-2- methyl-1 H- benzo [d] imidazoles-6- base of 4-)
Pyrimidine -2-base) amino) pyridine -2- base) and-N-8- oxyammonia oxo octanoic acid amide preparation
8- ((5-((the fluoro- 4- of 5- (fluoro- 1- isopropyl-2- methyl-1 H- benzo [d] imidazoles-of 4- are added in 50 mL single port bottles
6- yl) pyrimidine -2-base) amino) pyridine pyridine -2- base) amino) -8- oxo octanoic acid methyl esters (200 mg, 0.35 mmoL), hydroxyl
Amine aqueous solution (50%, 2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, it is remaining
Object column chromatographic purifying obtains 148mg, yield=74%.1H NMR (400 MHz, DMSO-d 6): δ10.35 (d, J = 4.8 Hz,
1H), 9.85 (s, 1H), 8.69 (s, 0H), 8.63 (dd, J = 7.5, 3.2 Hz, 1H), 8.19 (dd, J
= 12.0, 2.0 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.67 – 7.61 (m, 1H), 4.87-4.81
(m, 1H), 2.64 (s, 2H), 2.36 (t, J = 7.4 Hz, 1H), 1.94 (t, J = 7.4 Hz, 1H),
1.61 (d, J = 6.8 Hz, 4H), 1.49 (t, J = 6.9 Hz, 1H), 1.29-1.25 (m, 2H)。
(((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-) is phonetic by 3- by 5 N-1- of embodiment
Pyridine -2- base) amino) phenyl) and-N-8- oxyammonia oxo octanoic acid amide preparation
8- ((3- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) phenyl) amino)-8-oxo octanoic acid methyl esters (200 mg, 0.35 mmoL), aqueous hydroxylamine solution
(50%, 2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent, residue column chromatography are removed
Purify to obtain 142 mg, yield=71%.1H NMR (400 MHz, DMSO-d 6): δ10.35 (s, 1H), 9.85 (s, 1H),
9.76 (s, 1H), 8.72 – 8.50 (m, 2H), 7.97 (s, 1H), 7.75 – 7.68 (m, 1H), 7.51
(d, J = 7.0 Hz, 1H), 7.20 (d, J = 7.3 Hz, 2H), 4.86-4.80 (m, 1H), 2.63 (s,
3H), 2.29 (t, J = 7.4 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.60 (d, J = 6.8 Hz,
6H), 1.48 (t, J = 7.1 Hz, 2H), 1.31 – 1.21 (m, 4H)。
6 4- of embodiment ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-) pyrimidine -2-
Base) amino)-N- (8- (hydroxyl amino) -8- oxo butyl) benzamide preparation
8- (4- ((the fluoro- 4- of 5- (the fluoro- 1- isopropyl -2- methyl-1 H of 4--benzo [d] imidazoles -6- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) benzamido) methyl caprylate (200 mg, 0.346 mmoL), aqueous hydroxylamine solution (50%, 2
ML), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, residue column chromatographic purifying obtains
100 mg, yield=50%.1H NMR (400 MHz, DMSO-d 6): δ10.36 (s, 1H), 10.07 (s, 1H),
8.70 – 8.57 (m, 2H), 8.27 (d, J = 32.6 Hz, 2H), 8.00 – 7.77 (m, 4H), 7.66 (d,J = 11.9 Hz, 1H), 4.89 – 4.74 (m, 1H), 3.24 (d, J = 6.6 Hz, 2H), 2.64 (s,
3H), 1.94 (t, J = 7.3 Hz, 2H), 1.62 (d, J = 6.5 Hz, 6H), 1.51 (s, 2H), 1.26
(d, J = 17.8 Hz, 8H)。
(((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-) is phonetic by 4- by 7 N-1- of embodiment
Pyridine -2- base) amino) benzyl) and-N-8- oxyammonia oxo octanoic acid amide preparation
8- ((4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) benzyl) amine) -8- oxo octanoic acid methyl esters (200 mg, 0.346 mmoL), aqueous hydroxylamine solution (50%,
2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, residue column chromatographic purifying obtains
134 mg, yield=67%.1H NMR (400 MHz, DMSO-d 6): δ10.36 (s, 1H), 9.76 (s, 1H), 8.70
(s, 1H), 8.60 (d, J = 3.8 Hz, 1H), 8.25 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H),
7.64 (d, J = 12.1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H), 4.92-4.75 (m, 1H), 4.22
(d, J = 5.4 Hz, 2H), 2.64 (s, 3H), 2.12 (t, J = 7.4 Hz, 2H), 1.93 (t, J = 7.3
Hz, 2H), 1.61 (s, 4H), 1.54 – 1.42 (m, 4H), 1.27-1.19 (m, 4H)。
Embodiment 8 4-((the fluoro- 4- of 5- (fluoro- 1- isopropyl-2- methyl-1 H- benzo [d] imidazoles-6- base of 4-) pyrimidine-
2- yl) amino)-N- (6- (hydroxyl amino) -6- oxo-hexyl) benzamide preparation
6- (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) benzamido) methyl caproate (200 mg, 0.36 mmoL), aqueous hydroxylamine solution (50%, 2
ML), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, residue column chromatographic purifying obtains
132 mg, yield=66%.1H NMR (400 MHz, DMSO-d 6): δ10.37 (s, 1H), 10.07 (s, 1H),
8.75 – 8.60 (m, 2H), 8.27 (d, J = 34.8 Hz, 2H), 7.94 – 7.77 (m, 4H), 7.66 (d,J = 12.0 Hz, 1H), 4.85 (q, J = 6.8 Hz, 1H), 3.29 – 3.04 (m, 3H), 2.64 (s,
3H), 1.95 (d, J = 7.5 Hz, 2H), 1.62 (d, J = 6.7 Hz, 6H), 1.52 (d, J = 7.4 Hz,
4H), 1.29 (d, J = 7.4 Hz, 2H)。
(((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-) is phonetic by 4- by 9 N-1- of embodiment
Pyridine-2- base) amino) phenyl) and-N-6-oxyammonia oxo hexanoic acid amide preparation
6- ((4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) phenyl) amino) -6- oxo methyl caproate (200 mg, 0.37 mmoL), aqueous hydroxylamine solution
(50%, 2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent, residue column chromatography are removed
Purify to obtain 122 mg, yield=61%.1H NMR (400 MHz, DMSO-d 6): δ10.40 (s, 1H), 9.75 (d, J =
49.2 Hz, 2H), 8.65 (d, J = 53.7 Hz, 2H), 8.26 (s, 1H), 7.77 – 7.36 (m, 5H),
4.84 (s, 1H), 2.63 (s, 3H), , 2.30 (s, 2H) 1.99 (s, 2H), 1.59 (d, J = 25.7
Hz, 10H)。
10 N-1- of embodiment (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-)
Pyrimidine -2-base) amino) benzyl) and-N-5- oxyammonia oxopentanoic acid amide preparation
5- ((4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) benzyl) amino) -5- oxopentanoic (200 mg, 0.37 mmoL), aqueous hydroxylamine solution
(50%, 2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent, residue column chromatography are removed
Purify to obtain 116 mg, yield=58%.1H NMR (400 MHz, DMSO-d 6): δ9.78 (s, 1H), 8.63 (d, J =
3.9 Hz, 1H), 8.38 – 8.12 (m, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 13.1
Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 4.92 – 4.69 (m, 1H), 4.23 (d, J = 5.8 Hz,
2H), 2.65 (s, 3H), 2.15 (t, J = 7.5 Hz, 2H), 1.98 (t, J = 7.5 Hz, 2H), 1.76
(t, J = 7.5 Hz, 2H), 1.63 (d, J = 6.8 Hz, 6H)。
11 N-1- of embodiment (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-)
Pyrimidine -2-base) amino) benzyl) and-N-6- oxyammonia oxo hexanoic acid amide preparation
6- ((4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) benzyl) amino) -6- oxo methyl caproate (200 mg, 0.36 mmoL), aqueous hydroxylamine solution
(50%, 2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent, residue column chromatography are removed
Purify to obtain 146 mg, yield=73%.1H NMR (400 MHz, DMSO-d 6): δ10.37 (s, 1H), 9.78 (s,
1H), 8.70 (s, 1H), 8.63 (d, J = 3.9 Hz, 1H), 8.32 – 8.16 (m, 2H), 7.80 – 7.70
(m, 2H), 7.66 (dd, J = 11.9, 1.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 4.85 (q,J = 6.9 Hz, 1H), 4.23 (d, J = 5.8 Hz, 2H), 2.65 (s, 3H), 2.14 (t, J = 4.8 Hz,
2H), 2.00 – 1.88 (m, 2H), 1.63 (d, J = 6.9 Hz, 6H), 1.54 – 1.48 (m, 4H)。
12 N-1- of embodiment (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-)
Pyrimidine -2-base) amino) benzyl) and-N-7- oxyammonia oxo-heptanoic acid amide preparation
7- ((4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) benzyl) amine) -7- oxo-heptanoic acid methyl esters (200 mg, 0.346 mmoL), aqueous hydroxylamine solution (50%,
2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, residue column chromatographic purifying obtains
140 mg, yield=70%.1H NMR (400 MHz, DMSO-d 6): δ10.35 (s, 1H), 9.77 (s, 1H), 8.68
(s, 1H), 8.63 (d, J = 3.9 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H), 7.74 (d, J = 8.6
Hz, 2H), 7.66 (dd, J = 11.9, 1.2 Hz, 1H), 7.25 – 7.12 (m, 2H), 4.91 – 4.78
(m, 1H), 4.22 (d, J = 5.8 Hz, 2H), 2.65 (s, 3H), 2.12 (t, J = 7.5 Hz, 2H),
1.94 (t, J = 7.4 Hz, 2H), 1.63 (d, J = 6.9 Hz, 6H), 1.51 (dt, J = 10.4, 7.5
Hz, 4H), 1.24 (ddt, J = 9.0, 6.9, 3.6 Hz, 2H)。
13 N-1- of embodiment (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-)
Pyrimidine -2-base) amino) benzyl) and-N-9- oxyammonia oxo n-nonanoic acid amide preparation
9- ((4- ((the fluoro- 4- of 5- is added in 50 mL single port bottles(The fluoro- 1- isopropyl -2- methyl-1 H of 4--benzo [d] imidazoles -
6- base)Pyrimidine -2-base) amino) benzyl) amino) -9- oxo methyl pelargonate (200 mg, 0.34 mmoL), aqueous hydroxylamine solution
(50%, 2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent, residue column chromatography are removed
Purify to obtain 134 mg, yield=67%.1H NMR (400 MHz, DMSO-d 6): δ10.33 (s, 1H), 9.76 (s,
1H), 8.67 (s, 1H), 8.63 (d, J = 3.9 Hz, 1H), 8.25 (d, J = 1.4 Hz, 2H), 7.74
(d, J = 8.5 Hz, 2H), 7.68 – 7.62 (m, 1H), 7.18 (d, J = 8.3 Hz, 2H), 4.87-4.82
(m, 1H), 4.21 (d, J = 5.8 Hz, 2H), 2.64 (s, 3H), 2.12 (t, J = 7.4 Hz, 2H),
1.92 (t, J = 7.3 Hz, 2H), 1.62 (d, J = 6.8 Hz, 6H), 1.49 (dt, J = 20.3, 6.9
Hz, 4H), 1.24 (s, 6H)。
14 4- of embodiment (2- (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-)
Pyrimidine -2-base) amino) phenyl) acetylamino)-N- hydroxybutyrate amide preparation
4- (2- (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles-of 4- is added in 50 mL single port bottles
6- yl) pyrimidine -2-base) amino) phenyl) acetylamino) methyl butyrate (200 mg, 0.37 mmoL), aqueous hydroxylamine solution (50%,
2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, residue column chromatographic purifying obtains
138 mg, yield=69%.1H NMR (400 MHz, DMSO-d 6): δ10.37 (s, 1H), 9.74 (s, 1H), 8.71
(s, 1H), 8.62 (d, J = 3.9 Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.77 – 7.57
(m, 2H), 7.19 (d, J = 8.4 Hz, 2H), 4.94 – 4.76 (m, 1H), 3.35 (s, 2H), 3.03
(q, J = 6.7 Hz, 2H), 2.64 (s, 3H), 1.96 (t, J = 7.5 Hz, 2H), 1.63 (d, J = 6.8
Hz, 8H)。
15 5- of embodiment (2- (4 ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-)
Pyrimidine -2-base) amino) phenyl) acetylamino)-N- hydroxyvaleramide preparation
5- (2- (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles-of 4- is added in 50 mL single port bottles
6- yl) pyrimidine -2-base) amino) phenyl) acetylamino) methyl valerate (200 mg, 0.36 mmoL), aqueous hydroxylamine solution (50%,
2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, residue column chromatographic purifying obtains
156 mg, yield=78%.1H NMR (400 MHz, DMSO-d 6): δ 10.35 (d, J = 1.7 Hz, 1H), 9.73
(s, 1H), 8.68 (d, J = 1.7 Hz, 1H), 8.62 (d, J = 3.9 Hz, 1H), 8.26 (s, 1H),
8.01 (s, 1H), 7.68 (dd, J = 18.8, 10.2 Hz, 3H), 7.18 (d, J = 8.4 Hz, 2H),
4.87-4.83 (m, 1H), 3.34 (s, 2H), 3.02 (d, J = 6.4 Hz, 2H), 2.64 (s, 3H), 1.94
(t, J = 7.2 Hz, 2H), 1.62 (d, J = 6.9 Hz, 6H), 1.49 (t, J = 7.7 Hz, 2H), 1.37
(t, J = 7.6 Hz, 2H)。
16 6- of embodiment (2- (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-)
Pyrimidine -2-base) amino) phenyl) acetylamino)-N- hydroxyl hexanamide preparation
6- (2- (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles-of 4- is added in 50 mL single port bottles
6- yl) pyrimidine -2-base) amino) phenyl) acetylamino) methyl caproate (200 mg, 0.35 mmoL), aqueous hydroxylamine solution (50%,
2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, residue column chromatographic purifying obtains
110 mg, yield=55%.1H NMR (400 MHz, DMSO-d 6): δ10.34 (s, 1H), 9.73 (s, 1H), 8.67
(s, 1H), 8.62 (d, J = 4.0 Hz, 1H), 8.25 (s, 1H), 7.98 (q, J = 5.4 Hz, 1H),
7.75 – 7.59 (m, 3H), 7.18 (d, J = 8.2 Hz, 2H), 4.86-4.81 (m, J = 7.0 Hz, 1H),
3.34 (d, J = 1.8 Hz, 2H), 3.02-2.99 (m, 2H), 2.64 (s, 3H), 1.92 (q, J = 8.7,
8.0 Hz, 2H), 1.60 (dd, J = 16.4, 7.0 Hz, 6H), 1.47 (q, J = 7.6 Hz, 2H), 1.38
(q, J = 7.4 Hz, 2H), 1.27 – 1.17 (m, 2H)。
17 7- of embodiment (2- (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-)
Pyrimidine -2-base) amino) phenyl) acetylamino)-N- hydroxyl heptamide preparation
7- (2- (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles-of 4- is added in 50 mL single port bottles
6- yl) pyrimidine -2-base) amino) phenyl) acetylamino) methyl heptanoate (200 mg, 0.346 mmoL), aqueous hydroxylamine solution
(50%, 2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent, residue column chromatography are removed
Purify to obtain 154 mg, yield=77%.1H NMR (400 MHz, DMSO-d 6): δ 10.34 (d, J = 1.7 Hz, 0H),
9.74 (s, 0H), 8.68 (d, J = 1.7 Hz, 0H), 8.63 (d, J = 3.9 Hz, 0H), 8.26 (d, J
= 1.3 Hz, 0H), 7.98 (t, J = 5.6 Hz, 0H), 7.73 – 7.63 (m, 1H), 7.22 – 7.16 (m,
1H), 4.88-4.82 (m, 1H), 3.35 (s, 1H), 3.02 (q, J = 6.6 Hz, 1H), 2.65 (s, 1H),
1.91 (d, J = 7.4 Hz, 1H), 1.63 (d, J = 6.9 Hz, 3H), 1.47 (t, J = 7.0 Hz, 1H),
1.38 (t, J = 6.5 Hz, 1H), 1.23 (d, J = 5.9 Hz, 2H)。
18 8- of embodiment (2- (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-)
Pyrimidine -2-base) amino) phenyl) acetylamino)-N- hydroxy capryloyl amine preparation
8- (2- (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles-of 4- is added in 50 mL single port bottles
6- yl) pyrimidine -2-base) amino) phenyl) acetylamino) methyl caprylate (200 mg, 0.34 mmoL), aqueous hydroxylamine solution (50%,
2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent is removed, residue column chromatographic purifying obtains
146 mg, yield=73%.1H NMR (400 MHz, DMSO-d 6): δ10.33 (s, 1H), 9.74 (s, 1H), 8.67
(s, 1H), 8.62 (d, J = 3.9 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H), 7.98 (t, J = 5.6
Hz, 1H), 7.73 – 7.59 (m, 3H), 7.19 (d, J = 8.4 Hz, 2H), 5.00-4.63 (m, 1H),
3.34(s, 2H), 3.03 (d, J = 6.3 Hz, 2H), 2.65 (s, 3H), 1.92 (t, J = 7.3 Hz,
2H), 1.63 (d, J = 6.9 Hz, 6H), 1.46 (t, J = 7.0 Hz, 2H), 1.38 (dd, J = 8.7,
4.8 Hz, 2H), 1.23 (s, 6H)。
19 N-1- of embodiment (4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- base of 4-)
Pyrimidine -2-base) amino) phenyl) and-N-5- oxyammonia oxopentanoic acid amide preparation
5- ((4- ((the fluoro- 4- of 5- (fluoro- 1- isopropyl -2- methyl-1 H- benzo [d] imidazoles -6- of 4- is added in 50 mL single port bottles
Base) pyrimidine -2-base) amino) phenyl) amino) -5- oxopentanoic (200 mg, 0.38 mmoL), aqueous hydroxylamine solution
(50%, 2 mL), 10 mL of methanol, 80 DEG C are heated to reflux, and reaction is overnight.After reaction, solvent, residue column chromatography are removed
Purify to obtain 114 mg, yield=57%.1H NMR (400 MHz, DMSO-d 6) δ 9.83 (s, 1H), 9.69 (s, 1H),
8.60 (d, J = 3.9 Hz, 1H), 8.27 (d, J = 1.3 Hz, 1H), 7.71 (d, J = 9.0 Hz, 2H),
7.65 (dd, J = 11.9, 1.2 Hz, 1H), 7.55 (d, J = 9.0 Hz, 2H), 4.85 (p, J = 6.9
Hz, 1H), 3.60 (s, 3H), 2.64 (s, 3H), 2.36 (dt, J = 14.3, 7.4 Hz, 4H), 1.85
(p, J = 7.4 Hz, 2H), 1.63 (d, J = 6.9 Hz, 6H)。
Biological characteristis.
HDAC1 enzyme assay.
The biological activity of vitro detection compound HDAC1 enzyme is carried out in 384 orifice plates.In experiment, overall length is used
HDAC1 albumen, under the concentration of Km, in the polypeptide A c-peptide-AMC of fluorescent marker(Ac:Acetyl group, AMC:7- amino -4-
Methylcoumarin)Middle hatching.It reacts in Tris-based measurement buffer, then makees in deacetylate enzyme and trypsase
Under, substrate discharges fluorogen 7- amino -4- methylcoumarin, carries out fluorescence detection using multiple labeling micropore board detector
(355nm excitation, 460nm transmitting).Data carry out the linear analysis of fluorescence at any time.Software carries out data processing calculating
IC50 value.
Experimental material:HDAC1 (BPS Bioscience, USA, Cat. No. 50051);384-well plate
(from Perkin Elmer, Cat. No. 6007279)。
Experimental method:Prepare 1x test buffer (Tris buffer) first;The inhibitor that will be dissolved in DMSO, four
Times serial dilution is added in porous plate;Prepare enzyme solutions:Prepare enzyme solutions in 1x test buffer;Prepare substrate solution:
The peptide substrate of trypsase and acetyl group modification is added in 1x test buffer;The enzyme solutions of 15 μ L are added to porous
In plate;Incubation at room temperature 15 minutes;10 μ L substrate solutions are added in each hole, reaction starts;Incubation at room temperature 60 minutes.?
On Synergy MX instrument, read plate under 355nm excitation and 460nm launch wavelength.Data are carried out using following equation in Excel
Processing calculates inhibiting rate (1) formula (1):Inhibiting rate %=(maximum value-reading)/(maximum value-minimum value) * 100 uses
Software GraphPad Prism V5.0 and formula(2)Processing data obtain IC50 value (2), formula (2): Y=Bottom +
(Top-Bottom)/(1+10^ ((LogIC50-X) * area threshold)).Y is inhibiting rate %, and X is compound concentration.
CDK enzyme assay.
Inhibitory activity using Caliper Mobility Shift Assay method test compound to CDK enzyme, the skill
The basic concept of Capillary Electrophoresis is applied in microfluidic environment by art, and it is real to detect zymetology in the case where being added without and stopping reagent
It tests.Substrate for experiment is the polypeptide with fluorescent marker, and in the reaction system under the action of enzyme, substrate is changed into product,
Corresponding variation also has occurred in the charge of its band, and Mobility-Shift Assay is electrically charged using substrate and product
Difference separates the two, and is detected respectively.
Experimental material:CDK4/CycD3 (Carna, Cat.No 04-105, Lot. No 10CBS-0429 C, GST-
CDK4(1-303end)/GSTCycD3(1-292end)); Peptide FAM-P8 (GL Biochem, Cat. No.
112396, Lot. No. P100804-XZ112396); ATP (Sigma, Cat. No. A7699-1G, CAS No.
987-65-5); DMSO (Sigma, Cat. No. D2650, Lot. No. 474382);EDTA (Sigma, Cat.
No. E5134, CAS No. 60-00-4); 96-well plate (Corning, Cat. No. 3365, Lot. No.
22008026); 384-well plate (Corning, Cat. No. 3573, Lot. No. 12608008)。
Experimental method:Measure the apparent Km of ATP on Mobility Shift, be added in 384 microwell plates 5 holes μ L/ 2 ×
Enzyme & peptide mixed liquor.2 × ATP solution of 5 hole μ L/ three times gradient dilutions, starting reaction is added.Room temperature centrifugation
5 hole uL/ 3 × stop buffer are added after being put into 23 °C of incubator reaction 60min in 1min(100 mM HEPES, pH
7.5;0.015% Brij-35;0.2% Coating Reagent #3;50 mM EDTA)Reaction is terminated, Caliper EZ is placed in
It is detected on Reader I;4 times of gradient dilutions are carried out in 5 μM of concentration to compound in 96 microwell plates, 100 μ L are added,
100%DMSO, without kinase control group, takes 10 μ L compounds to be added to a 96 new hole microwell plates, adds as no compound
90μL, 1×kinase base buffer (20 mM HEPES, pH 7.5 ; 0.01% Triton X-100; 10 mM
MgCl2;2 mM DTT), which is placed on shaking table 10 minutes to mix compound;Every hole takes 5 μ L mixed liquors to be added
Into 384 hole microwell plates.Each 10 μ L, 2.5 × enzyme solution of Kong Zhongjia of 384 hole microwell plates.It is incubated for 10 minutes at room temperature
Add 10 μ L in each Kong Zhongzai again afterwards, 2.5 × polypeptide solution (FAM-labeled is added in 1 × kinase base buffer
Peptide and ATP).Kinase reaction, specified time stop, and are incubated for 30 DEG C.25 μ L stop buffer are added to terminate reaction.It sets
It is detected on Caliper EZ Reader I.
Table 1 is inhibition effect of the compound to HDAC1 kinases
Table 2 is inhibition effect of the compound to CDK4 kinases
Table 1
Table 2
Claims (10)
- Formula 1. (I) compound or pharmaceutically acceptable salt thereofWherein:R1Selected from H,、、、、、、、、, alkyl, alkenyl, alkynyl, heterocycle, aryl, hetero-aromatic ring, wherein R7 And R8It is hydrogen-based, alkyl, naphthenic base, heteroatomic ring alkyl, aryl or hetero-aromatic ring respectively;R2It is C1-8Alkyl;Optionally C is selected from by one1-8The C that the substituent group of alkyl, halogen atom and OH replaces4-7Naphthenic base; Optionally C is selected from by one1-8Alkyl, C (CH3)2The phenyl that the substituent group of CN, halogen atom and OH replace;Optionally by a ring Propyl or C1-8Alkyl-substituted piperidyl;Optionally by a cyclopropyl or C1-8Alkyl-substituted THP trtrahydropyranyl;Or two ring [2.2.1] heptane base, wherein halogen atom includes F, Cl, Br, I;R3And R4It is hydrogen atom or fluorine atom, wherein R3And R4At least one is fluorine atom;R5Selected from substituted or unsubstituted aryl, substituted or unsubstituted pyridyl group, substituted or unsubstituted pyrimidine radicals, replace or Unsubstituted pyridine oxide base, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrrole radicals, substituted or unsubstituted pyrrole Oxazolyl, substituted or unsubstituted imidazole radicals, indyl substituted or unsubstituted, furyl substituted or unsubstituted are substituted or unsubstituted Thiazolyl, Qu generation or non-substituted oxazole quinoline base, thienyl substituted or unsubstituted;R6 It is selected from、、、 、、、、、、、、、、、、、、、、、、、、、、、、、、、、Wherein n=1 ~ 9, A, D are each independently selected from valence link, O, NH, NR11、C(O)、C(O)NH、NHC(O)、CH2 、CH2C(O)NH、CH2NHC (O) or S (O)1~2, R9、R10H, OH, C can be independently selected from1-C8Alkane ,-(CH2)t(C1-C10Alkane) ,-(CH2)t(C3-C10Miscellaneous alkane Hydrocarbon) ,-(CH2)t(C3-C10) cycloalkane) ,-(CH2)t(C6-C10The miscellaneous alkane of ring), wherein t represents number 0-6, and all alkane can Selection is replaced by one or more F, Cl or Br;R6 Valence link, O, NH, NR are each independently selected from selected from wherein n=1 ~ 9, A, D11、C(O)、C(O)NH、NHC(O)、CH2 、 CH2C(O)NH、CH2NHC (O) or S (O)1~2, R9、R10H, OH, C can be independently selected from1-C8Alkane ,-(CH2)t(C1-C10Alkane Hydrocarbon) ,-(CH2)t(C3-C10Miscellaneous alkane) ,-(CH2)t(C3-C10) cycloalkane) ,-(CH2)t(C6-C10The miscellaneous alkane of ring), wherein t is represented Digital 0-6, all alkane may be selected to be replaced by one or more F, Cl or Br;L is valence link, O, NH, C (O), C (O) NH, NHC (O), CH2 、CH2C(O)NH、CH2NHC(O) 、CH2 S(O)1~2Or S (O)1~2;X and Z are each independently selected from CH, N, when Z selects N, R1For unsubstituted.
- 2. formula (I) compound according to claim 1, R1Selected from methyl;R2Selected from isopropyl;R3Selected from F;R4Selected from F;R5 It is selected from、、、、、、、、; R6 It is selected from、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、Wherein n=1 ~ 9, A, D are each independently selected from valence link, O, NH, NR11、CO、C(O)NH、NHC(O)、CH2 、CH2C(O)NH、CH2NHC (O) or S (O)1~2, R9、R10H, OH, C can be independently selected from1-C8Alkane;L is valence link, O, NH, C (O), CH2 、C(O)NH、NHC (O)、CH2C(O)NH、CH2NHC(O)、CH2 S(O)1~2Or S (O)1~2;X and Z are each independently selected from CH, N, when Z selects N, R1For Unsubstituted.
- 3. the method for treating disease relevant to CDK or HDAC inhibiting effect, obstacle or syndrome, the method includes giving to need Want its individual application according to claim 1 the compound of -2 any one or its prodrug or comprising Formulas I compound or its The pharmaceutical composition of prodrug and pharmaceutically acceptable excipient.
- 4. the treatment method as described in claim 3, wherein the disease, obstacle or syndrome are excessively increased in individual Growing property, it is selected from cancer and inflammation, wherein individual is the animal for including people.
- 5. inhibiting the method for cyclin dependent kinase (for example, CDK4), the method includes the kinases and according to power Benefit requires the compound contact of the inhibition kinases of 1 to 2 any one.
- 6. the method for regulating cell process (for example, cell division), by using according to claim 1 to 2 it is any The activity for the kinases that one compound inhibits cyclin to rely on.
- 7. according to claim 1 to 2 any one compound, for morbid state as described herein prevention or control It treats.
- 8. according to claim 1 to 2 any one compound be used for medicine preparation purposes, wherein the drug be use In any one or more purposes defined herein.
- 9. pharmaceutical composition, the compound or pharmaceutically acceptable salt thereof comprising any one of the claims and include pharmaceutical load Body or excipient.
- 10. the method for the treatment of cancer in the patient for needing its treatment, this method includes that a effective amount of the claims are any The compound or pharmaceutically acceptable salt thereof of item.
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