CN114685382B - Quinazoline-4-amine derivative with HDACs inhibitory activity, and preparation method and application thereof - Google Patents

Quinazoline-4-amine derivative with HDACs inhibitory activity, and preparation method and application thereof Download PDF

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CN114685382B
CN114685382B CN202210391023.4A CN202210391023A CN114685382B CN 114685382 B CN114685382 B CN 114685382B CN 202210391023 A CN202210391023 A CN 202210391023A CN 114685382 B CN114685382 B CN 114685382B
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amino
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quinazolin
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CN114685382A (en
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张阳
李学东
贾庆忠
刘新岗
贺殿
朱峰
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Zhejiang University ZJU
Lanzhou University
Hebei Medical University
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Lanzhou University
Hebei Medical University
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    • C07—ORGANIC CHEMISTRY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to quinazoline-4-amine derivatives with HDACs inhibitory activity, and a preparation method and application thereof. The invention designs and synthesizes a series of small molecule inhibitors targeting HDACs, which can inhibit the enzymatic functions of HDAC and show the therapeutic potential of cancers such as melanoma, non-small cell lung cancer, breast cancer and the like; the small molecule has remarkable anti-tumor cell proliferation activity, has the effect equivalent to or better than that of SAHA, can be used for preparing anti-tumor drugs, and has wide application prospect.

Description

Quinazoline-4-amine derivative with HDACs inhibitory activity, and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to quinazoline-4-amine derivatives with HDACs inhibitory activity, and a preparation method and application thereof.
Background
The epigenetic change caused by epigenetic regulator or protein dysfunction can cause the occurrence and development of various diseases such as cancer, inflammation, infection, neurodegenerative diseases and the like, and the small molecular medicine can effectively treat the diseases caused by the dysfunction through the targeted dynamic reversible epigenetic modification process. The most widely studied of epigenetic modifications is the acetylation and deacetylation of histones, mainly catalyzed by histone acetyltransferases (histone acetyltransferases, HATs) and histone deacetylases (histone deacetylases, HDACs), affecting the tissue morphology and gene expression of chromatin, critical to cell homeostasis.
Histone Deacetylase (HDAC) is involved in important life processes such as deacetylation and protein ubiquitination, and plays an important role in regulating gene transcription and protein functions. To date, 18 HDAC subtypes have been identified and are classified into 4 classes based on their homology to yeast proteins: class I (HDAC 1, 2,3 and 8), class II (IIa: HDAC4, 5, 7, 9; IIb: 6 and 10), class III (SIRT 1-7), class IV (HDAC 11), wherein Class I, II and IV are metal zinc ions (Zn) 2 + ) Dependent enzyme, class III is NAD + A dependent enzyme.
The biological dysfunction of HDACs is closely related to the occurrence and development of various tumors, and thus HDACs have attracted a great deal of attention as important targets for tumor treatment. At present, various research results show that the expression level of p21 and other genes can be improved to induce apoptosis and inhibit proliferation of tumor cells by changing the acetylation status of various cell proteins. To date, vorinostat (SAHA), romidepsin (FK-228),Belinostat (PXD-101) and panobinostat (LBH-589) have been FDA approved for the treatment of lymphomas (CL), cutaneous T-cell lymphomas (CTCL), peripheral T-cell lymphomas (PTCL), multiple Myeloma (MM) and the like, further demonstrating Zn 2+ The dependent enzyme can become an effective target for treating tumors. In view of the foregoing, there is a strong need in the art to develop novel backbone-targeted small molecule inhibitors of HDACs and for the treatment of related diseases.
Disclosure of Invention
The invention aims at designing, synthesizing and verifying a series of small molecule inhibitors targeting HDACs, and shows great potential for treating cancers such as melanoma, non-small cell lung cancer, breast cancer and the like by inhibiting the enzymatic functions of HDAC. The method specifically comprises the following steps:
in a first aspect, the present invention provides a compound of formula (I) or formula (ii), or a pharmaceutically acceptable salt, hydrate, deuterate, prodrug thereof;
wherein A is 1 、A 2 、A 3 、A 4 Each independently selected from CR' or N; r' is selected from H, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxycarbonyl, substituted or unsubstituted C 1 -C 6 Amido, substituted or unsubstituted C 1 -C 10 An alkyl group;
r is selected from H, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxycarbonyl, substituted or unsubstituted C 1 -C 6 Amido, substituted or unsubstituted C 1 -C 10 An alkyl group;
m is selected from CR', NH, O or S; r' is selected from H, halogen, carbonyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxycarbonyl, substituted or unsubstituted C 1 -C 6 Amido, substituted or unsubstituted C 1 -C 10 An alkyl group;
y selection (CH) 2 ) n Substituted or unsubstituted C 6-14 Aryl, C 5-14 Aryl radicals, C 7-12 Aralkyl, C 6-12 An aralkyl group; n is greater than or equal to 0;
x is selected from substituted or unsubstituted C 6 -C 12 Aryl or heteroaryl, substituted or unsubstituted 3-12 membered alicyclic or heterocyclic group;
by substituted is meant that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogen atom, carbonyl group, carboxyl group, hydroxyl group, amino group, nitro group, cyano group, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 Amido, substituted or unsubstituted C 1 -C 10 Alkyl, substituted or unsubstituted C 6 -C 10 Aryl or five-or six-membered heteroaryl, preferably C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 1 -C 6 An alkylamino group; wherein said substituted or unsubstituted C 1 -C 10 Alkyl, substituted or unsubstituted C 6 -C 10 The substituents of the aryl or five-or six-membered heteroaryl groups are selected from the group consisting of: halogen atom, carbonyl group, hydroxyl group, carboxyl group, C 1 -C 6 Alkoxycarbonyl, amino, C 1 -C 6 Amido, nitro, cyano, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 6 -C 10 Aryl or five-or six-membered heteroaryl, preferably halogen atoms, C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or phenyl.
Preferably, the structural formula of the compound is shown as a formula (III):
preferably, M is NH and X is a substituted or unsubstituted phenyl group.
Preferably, the substituted phenyl is selected from alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, haloalkyl substituted phenyl.
Preferably, the substituted phenyl is selected from the group consisting of C 1-4 Alkyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl.
Preferably, the substituted phenyl is 4-methyl substituted phenyl, 4-ethyl substituted phenyl, 4-isopropyl substituted phenyl, 4-tert-butyl substituted phenyl, 4-methoxy substituted phenyl, 4-halogen substituted phenyl, 4-trifluoromethyl substituted phenyl, 3-methyl substituted phenyl, 3-trifluoromethyl substituted phenyl, 2, 3-dimethyl substituted phenyl, 2, 4-difluoro substituted phenyl, 4-bromo-3-fluoro substituted phenyl, 2,4, 6-trimethyl substituted phenyl.
Preferably, the structural formula of the compound is shown as a formula (IV) or a formula (V):
preferably, the structural formula of the compound is shown in any one of formulas (VI) - (VIII):
the compounds of the present invention include: n-hydroxy-4- (2-oxo-2- ((4- (phenylamino) quinazolin-6-yl) amino) ethyl) benzamide, N-hydroxy-4- (2-oxo-2- ((4- (p-tolylamino) quinazolin-6-yl) amino) ethyl) benzamide, 4- (2- ((4- ((4-ethylphenyl) amino) quinazolin-6-yl) amino) -2-oxyethyl) -N-hydroxybenzoamide, N-hydroxy-4- (2- ((4- ((4-isopropylphenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) benzamide, 4- (2- ((4- ((4- (tert-butyl) phenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide, N-hydroxy-4- (2- ((4-methoxyphenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) benzamide, 4- (2- ((4- ((2, 3-dimethylphenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide, 4- (2- ((4- ((2, 4, 6-trimethylphenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide, N-hydroxy-4- (2-oxo-2- ((4- (m-tolyl) amino) quinazolin-6-yl) amino) ethyl) benzamide, 4- (2- ((4- ((4-fluorophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide, 4- (2- ((4- ((4-chlorophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide, 4- (2- ((4-bromophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide, N-hydroxy-4- (2- ((4- ((4-iodophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) benzamide, N-hydroxy-4- (2-oxo-2- ((4- ((4- (trifluoromethyl) phenyl) amino) quinazolin-6-yl) amino) ethyl) benzamide, N-hydroxy-4- (2-oxo-2- ((4- ((3- (trifluoromethyl) phenyl) amino) quinazolin-6-yl) amino) ethyl) benzamide, 4- (2- ((4- ((2, 4-difluorophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide, 4- (2- ((4- ((4-bromo-3-fluorophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide.
In a second aspect, the invention provides the use of a compound according to the first aspect, or a pharmaceutically acceptable salt, hydrate, deuterate, prodrug thereof, in the preparation of an HDAC inhibitor medicament.
In a second aspect, the invention provides the use of a compound according to the first aspect, or a pharmaceutically acceptable salt, hydrate, deuterate or prodrug thereof, for the preparation of a medicament for the treatment of a tumor, autoimmune disease, inflammation or Alzheimer's disease.
Preferably, the tumor comprises melanoma, lung cancer, breast cancer, gastric cancer.
The invention provides any pharmaceutically acceptable dosage form prepared by adding pharmaceutically acceptable salt auxiliary materials into any compound.
Preferably, the dosage form comprises a tablet, an injection, a granule, a suspension.
The beneficial effects of the invention are as follows: the invention provides a quinazoline-4-amine derivative, which has HDAC inhibitory activity, wherein most of the compounds can inhibit HDAC6 and/or HDAC1 with high intensity and display remarkable anti-tumor cell proliferation activity; other partial compounds exhibit excellent HDAC6 selectivity while inhibiting HDAC6 at high intensity; pharmacodynamic experiments show that the compound disclosed by the invention can be used as a therapeutic drug for tumors, autoimmune diseases, inflammations or Alzheimer's disease.
Detailed Description
Taking compounds 1-17 (scheme I) and compounds 18-20 (scheme II) as examples, the preparation method of the compound of the invention is as follows:
it should be noted that the following specific examples are included for illustrative purposes and should not be construed as limiting the scope of the present invention. Further, it is understood that various changes and modifications may be made by those skilled in the art after reading the description of the invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
The synthetic route for compound 1 is shown in scheme I:
in route I: a is formamide, ammonium formate, 120 ℃;
b is: sulfoxide chloride, refluxing;
c is as follows: aniline, isopropanol, reflux;
d is: stannous chloride, methanol, reflux, N 2 Protecting;
and e is as follows: 1) Sulfoxide chloride, refluxing; 2) Methanol; 3) Lithium hydroxide, THF/H 2 O/MeOH，rt；
f is: EDCI (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride), HOBt (1-hydroxybenzotriazole), DIPEA (N, N-diisopropylethylamine), 80 ℃;
g is: i) NH (NH) 2 OH·HCl，NaOH，MeOH，rt；ii)NaOH，MeOH，rt。
Other quinazolin-4-amine derivatives (compounds 2-17) were prepared in a similar manner to the synthesis of example 1 using the corresponding starting materials, as shown in scheme II:
in route II: f is: EDCI (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride), HOBt (1-hydroxybenzotriazole), DIPEA (N, N-diisopropylethylamine), 80 ℃;
g is: i) NH (NH) 2 OH·HCl，NaOH，MeOH，rt；ii)NaOH，MeOH，rt。
Example 1 Synthesis of N-hydroxy-4- (2-oxo-2- ((4- (phenylamino) quinazolin-6-yl) amino) ethyl) benzamide (1)
The first step: to a 1000mL three-necked flask was added 2-amino-5 nitrobenzoic acid (50 g), formamide (123.6 g) and ammonium formate (20 g), the reaction mixture was warmed to 120℃and stirred for 15h, TLC was monitored to completion of the reaction, the reaction mixture was cooled to room temperature, poured into 1000mL water and stirred for 0.5h at room temperature, suction filtration was performed, the filter cake was rinsed with water, and after rotary evaporation at 50℃about 36g of yellow solid was obtained, the yield was about 70%.
And a second step of: in a 100mL single port flask, compound 22 (36 g) of scheme I, thionyl chloride (200 mL), DMF (2 mL) was added, the reaction was heated to reflux for 4h, the reaction cooled to room temperature, excess thionyl chloride was removed by rotary evaporation under reduced pressure, and dried twice with DCM to give 22g of compound 23 of scheme I (a tan viscous solid) as about 22g, yield: 56%. (used directly in the next step without purification).
And a third step of: a500 mL flask was charged with compound 23 (8.0 g) in scheme I and isopropanol (200 mL) was added and stirred to dissolve, then aniline (22.5 g) was added dropwise at room temperature, the reaction was heated to reflux after completion of the addition, the reaction was allowed to cool to room temperature for 2h, suction filtration was performed, and the filter cake was rinsed with isopropanol to give 6.6g of compound 24 (yellow solid) in scheme I, yield: 65%.
Fourth step: a500 mL flask was charged with compound 24 (6.6 g) in scheme I and MeOH (200 mL), stirred, stannous chloride (22.5 g) was added at room temperature, nitrogen blanket, heated to reflux for 3h, the reaction cooled to room temperature, methanol was removed by rotary evaporation, water was added to adjust pH=8 with 1mol/L sodium hydroxide, the solution was separated, the aqueous phase was extracted with EA (200 mL. Times.4), the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, dried under reduced pressure, and PE was used: ea=20: 1, pulping for 30min, suction filtering, rotary steaming at 45 ℃ and drying to obtain about 4.3g of compound 25 (yellow solid) in the route I, and the yield: 74%.
Fifth step: 4-carboxymethylbenzoic acid (compound 26 in scheme I) was added to a 500mL flask, thionyl chloride was added and heated to reflux, stirred for 2 hours, thionyl chloride was removed by rotary evaporation, absolute methanol was added to the residue, and the reaction was carried out at room temperature for 3 hours, and excess methanol was removed by rotary evaporation. The crude intermediate obtained was added to a 500mL flask, THF/H was added 2 O/EtOH (6/6/1, 65 mL) was added after the starting material had dissolved, lithium hydroxide (2.75 g) was added, the reaction mixture was stirred and warmed to 60℃and reacted for 8h, concentrated under reduced pressure, and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was adjusted to ph=5-6 with 2.5N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure, and the crude product was purified by flash column chromatography to give compound 27 in scheme i (white solid) about 1.17g, yield: 60%.
Sixth step: in a 100mL flask, the intermediate (compound 27 in scheme I) (1.0 g), EDCI (1.2 g), HOBt (0.84 g), DIPEA (1.8 mL), was added, and stirred at room temperature for 30min, the intermediate (compound 25 in scheme I) (1.45 g) was added to the reaction solution, the temperature was raised to 80℃and reacted for 16h, and TLC detection found that no intermediate (compound 27 in scheme I) remained, and the reaction was stopped. After cooling to room temperature, the mixture was cooled to room temperature,100mL of water was added, extraction was performed with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography (developing solvent: CH) 2 Cl 2 : meoh=80: 1) Purification gave compound 28 in scheme i in about 1.0g, 50% yield.
Seventh step: naOH powder (10.0 eq) was added to NH at 0deg.C 2 In a methanol solution of OH HCl (hydroxylamine hydrochloride) for 30min at room temperature, the mixture was filtered, the filtrate was added to a methanol solution (0.1M) of compound 28 (1.0 g) in scheme I, naOH powder (4.0 eq) was additionally added to the reaction solution at 0℃and the mixture was stirred at room temperature overnight, TLC detection found that no compound 28 in scheme I remained, and the reaction was complete. Adding 40mL of water into the reaction solution, adjusting the pH to be 6-7 by using 1M HCl, stirring for 30min at room temperature, carrying out suction filtration, decompressing and spin-drying a filter cake at 50 ℃ to obtain a gray solid, adding the gray solid into a methanol solution, heating to reflux and stirring for 20min, pulping, and filtering to obtain about 0.52g of white pure product solid compound 1, wherein the yield is: 52%. 1 H NMR(600MHz,DMSO-d 6 )δ11.21(s,1H),10.62(s,1H),9.79(s,1H),9.03(s,1H),8.71(s,1H),8.50(s,1H),7.93–7.85(m,1H),7.80–7.69(m,5H),7.46(d,J＝7.8Hz,2H),7.37(t,J＝7.7Hz,2H),7.11(t,J＝7.3Hz,1H),3.81(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.3,164.6,162.8,158.0,153.8,147.1,139.9,139.5,137.1,131.7,129.8,128.8,127.5,127.4,124.0,122.9,115.9,112.6,43.4.MS(ESI):412.3(M-H) - .
Other quinazolin-4-amine derivatives (2-17) were prepared in a similar manner to the synthesis of example 1 using the corresponding starting materials.
Example 2 Synthesis of N-hydroxy-4- (2-oxo-2- ((4- (p-tolylamino) quinazolin-6-yl) amino) ethyl) benzamide (2)
The preparation was carried out in a similar manner to example 1, except that in the third step, the corresponding intermediate 23 and p-methylaniline were used as starting materials.
1 H NMR(600MHz,DMSO-d 6 )δ10.82(d,J＝20.0Hz,2H),9.81(s,1H),8.83(d,J＝5.9Hz,1H),8.48(s,1H),7.96(d,J＝7.7Hz,3H),7.73(t,J＝9.2Hz,4H),7.47(dd,J＝12.2,7.9Hz,2H),7.18(dd,J＝8.6,2.8Hz,2H),3.88(s,2H),2.30(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ169.4,169.3,158.0,153.8,146.9,139.5,137.4,137.3,133.0,131.7,130.2,129.8,129.4,129.3,128.7,127.4,127.1,122.9,115.9,112.6,43.6,21.0.MS(ESI):426.3(M-H) - .
Example 3 4 Synthesis of- (2- ((4- ((4-ethylphenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide (3)
The preparation was carried out in a similar manner to example 1, except that in the third step, starting from the corresponding intermediate 23 and p-ethylaniline, the procedure was followed in example 1.
1 H NMR(600MHz,DMSO-d 6 )δ11.52(s,1H),11.22(d,J＝17.3Hz,2H),9.03(d,J＝2.2Hz,1H),8.81(s,1H),8.11(dd,J＝9.0,2.1Hz,1H),7.98(d,J＝9.0Hz,1H),7.80–7.63(m,2H),7.56–7.50(m,2H),7.50–7.45(m,2H),7.33–7.28(m,2H),2.65(q,J＝7.6Hz,2H),1.21(t,J＝7.6Hz,3H). 13 C NMR(151MHz,DMSO-d 6 )δ169.8,164.5,160.0,149.9,142.9,139.5,139.3,135.2,134.9,131.7,129.9,129.8,128.5,127.4,125.4,120.9,114.4,113.3,43.3,28.3,16.1.MS(ESI):442.4(M+H) + .
Example 4 Synthesis of N-hydroxy-4- (2- ((4- ((4-isopropylphenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) benzamide (4)
The preparation was carried out in a similar manner to example 1, except that in the third step, the corresponding intermediate 23 and p-isopropylaniline were used as starting materials.
1 H NMR(600MHz,DMSO-d 6 )δ11.55(s,1H),11.21(d,J＝15.0Hz,2H),9.03(d,J＝2.1Hz,1H),8.82(s,1H),8.12(ddd,J＝9.0,2.3,1.1Hz,1H),7.99(dt,J＝9.0,1.6Hz,1H),7.82–7.63(m,2H),7.55–7.50(m,2H),7.50–7.46(m,2H),7.39–7.27(m,2H),3.87(s,2H),2.94(p,J＝6.9Hz,1H),1.24(d,J＝6.9Hz,6H). 13 C NMR(151MHz,DMSO-d 6 )δ169.8,164.5,160.0,149.8,147.5,139.5,139.3,135.0,134.9,131.7,129.9,129.8,127.4,127.0,125.4,125.2,120.8,114.3,113.2,49.1,43.3,33.6,24.3.MS(ESI):456.3(M+H) + .
Example 54 Synthesis of- (2- ((4- ((4- (tert-butyl) phenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide (5)
The preparation was carried out in a similar manner to example 1, except that in the third step, starting from the corresponding intermediate 23 and p-tert-butylaniline, the procedure was followed in example 1.
1 H NMR(600MHz,DMSO-d 6 )δ11.22(s,1H),10.80(s,1H),9.75(s,1H),9.04(s,1H),8.70(s,1H),8.46(s,1H),7.92(d,J＝8.8Hz,1H),7.74(d,J＝8.1Hz,3H),7.68(d,J＝8.2Hz,2H),7.47(d,J＝7.8Hz,2H),7.38(d,J＝8.2Hz,2H),3.82(s,2H),1.30(s,9H). 13 C NMR(151MHz,DMSO-d 6 )δ169.4,158.1,153.8,147.0,146.4,137.2,137.1,129.8,128.7,127.4,125.5,122.8,115.9,112.6,43.4,31.7.MS(ESI):470.8(M+H) + .
Example 6 Synthesis of N-hydroxy-4- (2- ((4- ((4-methoxyphenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) benzamide (6)
The preparation was carried out in a similar manner to example 1, except that in the third step, the corresponding intermediate 23 and p-methoxyaniline were used as starting materials.
1 H NMR(600MHz,DMSO-d 6 )δ10.60(s,1H),9.74(s,1H),8.68(s,1H),8.43(s,1H),8.01–7.55(m,6H),7.42(s,2H),6.94(d,J＝6.4Hz,2H),3.76(s,5H). 13 C NMR(151MHz,DMSO-d 6 )δ169.4,158.1,156.1,153.9,146.9,137.0,132.7,129.6,128.7,127.2,124.8,115.8,114.0,55.7,43.4.MS(ESI):442.0(M-H) - .
Example 74 Synthesis of- (2- ((4- ((2, 3-dimethylphenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide (7)
The preparation was carried out in a similar manner to example 1, except that in the third step, starting from the corresponding intermediate 23 and 2, 3-dimethylaniline, the procedure was followed in example 1.
1 H NMR(600MHz,DMSO-d 6 )δ11.20(s,1H),10.55(s,1H),9.69(s,1H),9.04(s,1H),8.78–8.59(m,1H),8.30(s,1H),7.98–7.66(m,4H),7.46(d,J＝7.9Hz,2H),7.19–7.00(m,3H),3.79(s,2H),2.29(s,3H),2.01(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ169.2,164.5,159.3,154.3,146.9,139.5,137.9,137.5,136.9,134.1,131.7,129.7,128.7,128.1,127.4,127.2,125.9,125.8,115.4,112.8,43.4,20.6,14.9.MS(ESI):442.2(M+H) + .
Example 84 Synthesis of- (2- ((4- ((2, 4, 6-trimethylphenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide (8)
The preparation was carried out in a similar manner to example 1, except that in the third step, starting from the corresponding intermediate 23 and 2,4, 6-trimethylaniline, the procedure was followed as in example 1.
1 H NMR(600MHz,DMSO-d 6 )δ11.19(s,1H),10.51(s,1H),9.41(s,1H),9.02(s,1H),8.66–8.63(m,1H),8.25(s,1H),7.83(dd,J＝9.0,2.2Hz,1H),7.73(t,J＝9.1Hz,3H),7.45(d,J＝7.9Hz,2H),6.94(s,2H),3.79(s,2H),2.27(s,3H),2.06(s,6H). 13 C NMR(151MHz,DMSO-d 6 )δ169.2,164.6,159.1,154.5,146.9,139.5,136.7,136.0,134.2,131.7,129.7,129.0,128.9,128.7,127.4,127.3,115.2,112.8,43.3,21.0,18.4.MS(ESI):454.4(M-H) - .
Example 9 Synthesis of N-hydroxy-4- (2-oxo-2- ((4- (m-tolylamino) quinazolin-6-yl) amino) ethyl) benzamide (9)
The preparation was carried out in a similar manner to example 1, except that in the third step, the corresponding intermediate 23 and 3-methylaniline were used as starting materials.
1 H NMR(600MHz,DMSO-d 6 )δ11.51(s,1H),11.22(d,J＝18.9Hz,2H),9.04(d,J＝2.1Hz,1H),8.84(s,1H),8.12(dt,J＝9.0,2.1Hz,1H),7.99(dd,J＝9.0,1.5Hz,1H),7.74(d,J＝8.1Hz,2H),7.48(d,J＝8.0Hz,2H),7.43(d,J＝8.2Hz,2H),7.36(t,J＝7.5Hz,1H),7.15(d,J＝7.5Hz,1H),3.87(s,2H),2.35(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ169.8,164.5,160.0,149.9,139.5,139.3,138.6,137.2,135.3,131.7,129.9,129.8,129.1,127.8,127.4,125.9,122.6,121.0,114.4,113.2,43.3,21.5.MS(ESI):428.8(M+H) + .
Example 10 Synthesis of 4- (2- ((4- ((4-fluorophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide (10)
The preparation was carried out in a similar manner to example 1, except that in the third step, the corresponding intermediate 23 and p-fluoroaniline were used as starting materials.
1 H NMR(600MHz,DMSO-d 6 )δ11.55(s,1H),11.22(d,J＝16.1Hz,2H),9.04(d,J＝2.1Hz,1H),8.84(s,1H),8.11(dd,J＝9.1,2.1Hz,1H),7.99(d,J＝9.0Hz,1H),7.74(d,J＝8.0Hz,2H),7.66(dd,J＝8.9,5.0Hz,2H),7.47(d,J＝8.0Hz,2H),7.32(t,J＝8.8Hz,2H),3.87(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.8,164.5,161.5,160.1,159.9,150.0,139.5,139.3,135.5,133.6,131.7,129.9,129.8,127.7,127.6,127.4,121.1,116.1,115.9,114.4,113.1,43.3.MS(ESI):432.9(M+H) + .
Example 11 Synthesis of 4- (2- ((4- ((4-chlorophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide (11)
The preparation was carried out in a similar manner to example 1, except that in the third step, the corresponding intermediate 23 and p-chloroaniline were used as starting materials.
1 H NMR(600MHz,DMSO-d 6 )δ11.23(s,1H),10.90(s,1H),9.90(s,1H),9.02(s,1H),8.74(d,J＝2.2Hz,1H),8.52(s,1H),7.94(dd,J＝9.0,2.1Hz,1H),7.89–7.81(m,2H),7.75(dd,J＝17.5,8.4Hz,3H),7.47(d,J＝8.0Hz,2H),7.45–7.37(m,2H),3.83(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.42,157.84,153.54,147.08,138.94,137.37,129.78,128.80,128.68,127.46,127.38,124.27,115.91,112.4,43.3.MS(ESI):446.0(M-H) - .
Example 12 Synthesis of 4- (2- ((4- ((4-bromophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide (12)
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The preparation was carried out in a similar manner to example 1, except that in the third step, starting from the corresponding intermediate 23 and p-bromoaniline, the procedure was followed as in example 1.
1 H NMR(600MHz,DMSO-d 6 )δ12.89(s,1H),10.59(s,1H),9.89(s,1H),8.71(s,1H),8.54(s,1H),8.00–7.74(m,6H),7.53(dd,J＝21.1,8.2Hz,4H),3.84(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.2,167.7,157.8,153.6,147.1,141.3,139.3,137.2,131.6,130.0,129.84,129.75,129.0,127.6,124.6,123.8,115.9,115.6,112.4,43.5.MS(ESI):492.0(M+H) + .
Example 13 Synthesis of N-hydroxy-4- (2- ((4- ((4-iodophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) benzamide (13)
The preparation was carried out in a similar manner to example 1, except that in the third step, the corresponding intermediate 23 and p-iodoaniline were used as starting materials.
1 H NMR(600MHz,DMSO-d 6 )δ11.49(s,1H),11.19(d,J＝36.5Hz,2H),9.03(d,J＝2.1Hz,1H),8.86(s,1H),8.11(dt,J＝9.2,2.4Hz,1H),7.99(dd,J＝9.0,2.3Hz,1H),7.87–7.78(m,2H),7.74(d,J＝8.0Hz,2H),7.54–7.37(m,4H),3.87(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.8,159.9,150.0,139.5,139.3,137.9,137.3,131.7,129.9,129.8,127.4,121.3,114.6,113.1,92.0,43.3.MS(ESI):538.3(M-H) - .
Example 14 Synthesis of N-hydroxy-4- (2-oxo-2- ((4- ((4- (trifluoromethyl) phenyl) amino) quinazolin-6-yl) amino) ethyl) benzamide (14)
The preparation was carried out in a similar manner to example 1, except that in the third step, the corresponding intermediate 23 and p-trifluoromethylaniline were used as starting materials.
1 H NMR(600MHz,DMSO-d 6 )δ11.85–11.57(m,1H),11.28(s,2H),9.09(d,J＝2.1Hz,1H),8.92(s,1H),8.17(dd,J＝9.1,2.1Hz,1H),8.05(d,J＝9.0Hz,1H),7.94(d,J＝8.3Hz,2H),7.85(d,J＝8.5Hz,2H),7.75(dd,J＝8.2,2.0Hz,2H),7.49(d,J＝8.2Hz,2H),3.89(s,2H). 13 CNMR(151MHz,DMSO-d 6 )δ169.9,164.5,160.2,149.9,141.2,139.6,139.3,135.9,131.7,130.1,129.8,127.4,126.9,126.6,126.4,126.32,126.30,126.27,125.6,123.7,121.4,114.7,113.0,43.3.MS(ESI):480.1(M-H) - .
Example 15 Synthesis of N-hydroxy-4- (2-oxo-2- ((4- ((3- (trifluoromethyl) phenyl) amino) quinazolin-6-yl) amino) ethyl) benzamide (15)
The preparation was carried out in a similar manner to example 1, except that in the third step, starting from the corresponding intermediate 23 and 3-trifluoromethylaniline, the procedure was followed in example 1.
1 H NMR(600MHz,DMSO-d 6 )δ11.20(s,1H),10.61(s,1H),10.05(s,1H),9.02(s,1H),8.76(d,J＝2.2Hz,1H),8.59(s,1H),8.25(d,J＝2.3Hz,1H),8.23–8.14(m,1H),7.89(dd,J＝9.0,2.2Hz,1H),7.81(d,J＝8.9Hz,1H),7.74(d,J＝7.9Hz,2H),7.61(t,J＝8.0Hz,1H),7.45(dd,J＝15.6,7.8Hz,3H),3.81(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.4,164.6,157.8,153.5,147.2,140.8,139.4,137.4,131.7,130.0,129.8,129.7,129.5,129.0,127.7,127.4,126.2,125.6,123.8,120.0,118.6,118.6,115.9,112.2,43.4.MS(ESI):480.4(M-H) - .
Example 16 Synthesis of 4- (2- ((4- ((2, 4-difluorophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide (16)
The preparation was carried out in a similar manner to example 1, except that in the third step, starting from the corresponding intermediate 23 and 2, 4-difluoroaniline, the procedure was followed as in example 1.
1 H NMR(600MHz,DMSO-d 6 )δ11.51(s,1H),11.19(d,J＝34.2Hz,2H),9.05(q,J＝2.5Hz,1H),8.82(d,J＝4.3Hz,1H),8.10(ddd,J＝11.3,8.9,4.2Hz,1H),8.06–7.95(m,1H),7.74(d,J＝7.9Hz,2H),7.57(dt,J＝9.9,7.6Hz,1H),7.47(dd,J＝7.8,2.5Hz,2H),7.23(td,J＝8.6,2.8Hz,1H),3.87(d,J＝4.3Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.9,164.5,150.4,139.5,139.3,131.7,130.4,130.0,129.8,127.4,114.1,112.7,112.4,112.2,105.5,105.3,105.2,43.3.MS(ESI):450.4(M+H) + .
EXAMPLE 17 Synthesis of 4- (2- ((4- ((4-bromo-3-fluorophenyl) amino) quinazolin-6-yl) amino) -2-oxoethyl) -N-hydroxybenzoamide (17)
The preparation was carried out in a similar manner to example 1, except that in the third step, starting from the corresponding intermediate 23 and 4-bromo-3-fluoroaniline, the procedure was followed in example 1.
1 H NMR(600MHz,DMSO-d 6 )δ11.57(s,1H),11.22(s,2H),9.05(d,J＝2.1Hz,1H),8.93(s,1H),8.14(dd,J＝9.1,2.1Hz,1H),8.03(d,J＝9.0Hz,1H),7.88–7.78(m,2H),7.74(d,J＝8.0Hz,2H),7.53(dd,J＝8.7,2.3Hz,1H),7.48(d,J＝8.1Hz,2H),3.88(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.9,164.5,160.0,159.1,157.4,150.0,139.6,139.2,138.7,138.6,135.9,133.7,131.7,130.1,129.8,127.4,122.5,122.5,121.4,114.7,113.6,113.4,112.9,105.4,105.3,43.3.MS(ESI):510.1(M+H) + .
EXAMPLE 18 Synthesis of N-hydroxy-4- (2-oxo-2- (quinolin-6-ylamino) ethyl) benzamide (18)
The first step: in a 100mL flask, compound 27 (1.0 g) in scheme II, EDCI (1.2 g), HOBt (0.84 g), DIPEA (1.8 mL), was added, and the reaction mixture was stirred at room temperature for 30min, compound 29 (891 mg) in scheme II was added, the temperature was raised to 80℃and reacted for 16h, and the TLC detection found that Compound 27 remained, and the reaction was stopped. After cooling to room temperature, 100mL of water, acetic acid, was addedEthyl ester extraction (40 mL. Times.3) of the aqueous phase, combining the organic phases, drying over anhydrous sodium sulfate, column chromatography (developing solvent: CH) 2 Cl 2 Meoh=80:1) to afford compound 30 in scheme ii about 890mg in 54% yield.
And a second step of: naOH powder (10 eq) was added to NH at 0deg.C 2 In methanol solution of OH HCl (hydroxylamine hydrochloride), stirring at room temperature for 30min, filtering the mixture, adding the filtrate to methanol solution (0.1M) of Hawhat 30, adding NaOH powder (4.0 eq) to the reaction solution additionally at 0deg.C and stirring the mixture at room temperature overnight, TLC detection found no compound 30 remained, and the reaction was completed. Adding 40mL of water into the reaction solution, adjusting the pH to be 6-7 by using 1M HCl, stirring for 30min at room temperature, carrying out suction filtration, decompressing and spin-drying a filter cake at 50 ℃ to obtain a gray solid, adding the gray solid into a methanol solution, heating to reflux and stirring for 20min, pulping, and filtering to obtain a white pure product solid compound 18 of about 450mg, wherein the yield is: 51%. 1 H NMR(600MHz,DMSO-d 6 )δ11.20(s,1H),10.55(s,1H),9.03(s,1H),8.78(dd,J＝4.1,1.7Hz,1H),8.37(d,J＝2.4Hz,1H),8.30–8.20(m,1H),7.98(d,J＝9.0Hz,1H),7.82(dd,J＝9.2,2.4Hz,1H),7.74(d,J＝7.9Hz,2H),7.53–7.37(m,3H),3.79(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.6,164.6,149.5,145.2,139.5,137.5,136.0,131.7,130.0,129.7,128.8,127.4,123.7,122.3,115.5,43.6.MS(ESI):320.2(M-H) - .
EXAMPLE 19 Synthesis of N-hydroxy-4- (2-oxo-2- (quinoxalin-6-ylamino) ethyl) benzamide (19)
Compound 19 is prepared according to reference example 18, substituting only 6-aminoquinoline with 6-aminoquinoxaline.
1 H NMR(600MHz,DMSO-d 6 )δ11.04(s,1H),8.87(d,J＝1.8Hz,1H),8.81(d,J＝1.8Hz,1H),8.54(d,J＝2.2Hz,1H),8.06–7.98(m,1H),7.77–7.65(m,5H),7.46(d,J＝7.9Hz,2H),3.85(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ170.1,167.8,167.4,146.4,144.4,143.5,140.9,139.6,132.2,132.1,132.0,131.9,130.0,129.7,129.2,129.1,124.2,115.9,46.5.MS(ESI):321.6(M-H) - .
EXAMPLE 20 Synthesis of N-hydroxy-4- (2- (naphthalen-2-ylamino) -2-oxoethyl) benzamide (20)
Compound 20 was prepared according to reference example 18 substituting only 6-aminoquinoline with 2-aminonaphthalene.
1 H NMR(600MHz,DMSO-d 6 )δ11.19(s,1H),10.53(d,J＝3.6Hz,1H),8.30(d,J＝2.1Hz,1H),7.84(dd,J＝18.2,8.5Hz,2H),7.79(d,J＝8.2Hz,1H),7.76–7.70(m,2H),7.63(dt,J＝8.8,1.9Hz,1H),7.51–7.43(m,3H),7.39(ddd,J＝8.1,6.7,1.2Hz,1H),3.79(s,2H). 13 C NMR(151MHz,DMSO-d 6 )δ169.5,164.6,139.7,137.2,133.9,131.6,130.2,129.7,128.8,127.9,127.8,127.4,126.9,125.1,120.4,115.7,60.2,43.6.MS(ESI):319.5(M-H) - .
HDAC6 and HDAC1 enzyme inhibitory Activity of the Compounds of example 21
In this example, the HDAC1 and HDAC6 enzyme inhibitory activities of the present compounds and Tubastatin a were evaluated using a fluorescence-based HDAC activity assay using the commonly used tool compound Tubastatin a as a positive control. Measuring fluorescence value at excitation wavelength of 365nm and emission wavelength of 450nm by using a multifunctional enzyme-labeled instrument, calculating inhibition rate, and IC 50 Values were obtained by fitting software GraphPad Prism 5.01. Other compounds of the present invention have similar beneficial effects to those listed below, but this should not be construed as the compounds of the present invention having only the following beneficial effects.
The test steps for the HDAC1/6 enzyme inhibition activity are: a DMSO solution of the test compound was prepared, a series of concentration gradients of the target compound (5. Mu.L/well) and enzyme (5. Mu.L/well) were added to HDAC6 buffer (40. Mu.L/well, 5. Mu. L Fluorogenic HDAC6 substate 3 (200. Mu.M) +5. Mu.L BSA (1 mg/mL) +30. Mu. L HDAC Assay Buffer), pre-incubated at 37℃for 30min, then undiluted 2 XHDAC developer 50. Mu.L was added to each well, and the plates were incubated at room temperature for 15min. Using SpectraMax i3 measures fluorescence intensity at excitation and emission wavelengths of 365 and 450nm, respectively. 3 independent experiments were performed for each group, and IC for the HDAC6 enzyme inhibition activity of each compound was obtained by fitting GraphPad Prism 5.01 50 Values (table 1); the procedure for testing the HDAC1 enzyme inhibitory activity was similar to that of the HDAC6 enzyme inhibitory activity.
Inhibitory Activity of Compounds of Table 1 on the enzymes HDAC1 and HDAC6
As can be seen from the data in table 1, the listed compounds all exhibited significant HDAC1 and HDAC6 enzyme inhibitory activity, and the inhibitory activity was comparable to or better than that of tubstatin a. And the compounds 13, 17 and the like synthesized by the invention have certain selective inhibition activity on HDAC 6.
Antitumor cell proliferation Activity of the Compounds of example 22
In this example, tubastatin A and SAHA were used as positive controls, and CCK-8 was used to evaluate the antiproliferative activity of the compounds of the present invention and Tubastatin A against melanoma cell line A375, lung cancer cell line A549, breast cancer cell line MCF-7, MDA-MB-231, and gastric cancer cell line SGC-7901. Other compounds of the present invention have similar antiproliferative effects as the compounds listed below, but should not be construed to be limited to the compounds of the present invention having only the following beneficial effects.
The test steps of the anti-tumor cell proliferation activity are as follows: digestion and collection of tumor cells in logarithmic growth phase at 10 5 Cell density of each mL was inoculated into 96-well plates, 100. Mu.L of each well was added, and the plates were placed in an incubator (37 ℃,5% CO) 2 ) After about 24 hours the medium was aspirated and the cells were treated with different concentrations of compound solution, respectively. After 48h of action, 10. Mu.L of CCK-8 was added to each well of the plate, and the plate was placed in an incubator (37 ℃,5% CO) 2 ) The culture is continued for 1-3h. Finally, measuring the absorbance (OD) value at the wavelength of 450nm by adopting a multifunctional enzyme-labeled instrument, calculating the inhibition rate and IC 50 Values were fit by GraphPad Prism 5.01 software. The results are shown in Table2.
Antitumor cell proliferation Activity of the compounds of Table 2
From the data in table 2, it can be seen that the compounds of the present invention exhibit a significant anti-tumor cell proliferation activity, which is comparable to or better than that of tubostatin a.
In conclusion, the compound prepared by the invention has good application prospect.

Claims (5)

1. A compound of formula (I) or (iii), or a pharmaceutically acceptable salt thereof;
wherein the compound of formula (I) is selected from:
the compound of formula (iii) is selected from:
2. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structural formula of formula (iv) or formula (v):
3. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structural formula (vi) or (viii):
4. the use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of an HDAC inhibitor medicament.
5. An HDAC inhibitor medicament in any pharmaceutically acceptable dosage form made from a compound according to any one of claims 1 to 3 in combination with pharmaceutically acceptable excipients.
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