CN105732459A - Pyrrole amide compounds, preparation method and applications thereof - Google Patents

Pyrrole amide compounds, preparation method and applications thereof Download PDF

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CN105732459A
CN105732459A CN201511003591.9A CN201511003591A CN105732459A CN 105732459 A CN105732459 A CN 105732459A CN 201511003591 A CN201511003591 A CN 201511003591A CN 105732459 A CN105732459 A CN 105732459A
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李进
李雪明
窦登峰
万金桥
高剑
穆云
李才奎
潘飞
钟国庆
胡晓
刘绍军
吕鹏
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Chengdu Pioneer Drug Development Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • 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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links

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  • Pyrrole Compounds (AREA)

Abstract

The invention discloses pyrrole amide compounds represented by the formula (I) or pharmaceutically acceptable salts/crystal forms/hydrates/solvates thereof; in the formula (I), R1 represents a hydrogen atom, a hydroxyl group, a cyano group, a halogen atom, or a carboxyl group; R2 and R3 represent a hydrogen atom, a hydroxyl group, a cyano group, a halogen atom, a carboxyl group, or a C1-C6 alkyl group, R2 and R3 can be the same or different; R4 represents a hydroxyl group, a mercapto group, an amino substituted phenyl group, or an epoxy ketone group. The novel compounds represented by the formula (I) have a good activity on inhibiting histone deacetylase, can be used to prevent and/or treat diseases caused by abnormal activity of histone deacetylase, at the same time have an good activity on inhibiting different liver cancer cells, and can be applied to clinic.

Description

Pyrrole amide compound and preparation method and application thereof
Technical Field
The invention relates to a pyrrole amide compound and a preparation method and application thereof, in particular to a pyrrole amide compound with histone deacetylase inhibitory activity and a preparation method and application thereof.
Background
Inactivation of genes that control cell growth in the body is one of the hallmarks of tumorigenesis. Epigenetic mechanisms that cause gene inactivation mainly include DNA methylation, histone acetylation, and modifications of other components in chromatin higher order structures, which alter chromatin conformation, resulting in changes in gene transcription regulation, and dysregulation of gene transcription causing cell proliferation disorders, resulting in tumor production.
Over 40 years ago, Allfrey et al recognized that histone acetylation and eukaryotic gene transcription regulation are closely related (AllfreyVG, FaulknerR, MirskyAE. Acetylationand methylation of histones and theirposphile solorenectorestriolationnofRNAsyntesis [ J]Procnatl acadsiiusa, 1964, 51: 786-794). Histone acetylation plays a central role in transcriptional regulation in eukaryotic cells. Acetylation of histones occurs at the-amino group of the N-terminally evolutionarily conserved lysine residue, with modifications at H3 and H4 more prevalent than H2A and H2B, and the more important acetylation site being Lys at H39And Lys14And Lys at H45，Lys8，Lys12And Lys16. Acetylation of HAT to the N-terminus of HistoneLysine amino acetylation is carried out, positive charges on the amino groups are eliminated, negative charges carried by DNA molecules are beneficial to unfolding of DNA conformation, the structure of nucleosomes becomes relaxed, the contact of transcription factors and cooperative transcription activators with the DNA molecules is facilitated, and histone acetylation can activate the transcription expression of specific genes. In contrast, deacetylation of histones is detrimental to the expression of specific genes (e.g.Rb, p21, p 27). Acetylation and deacetylation of histones into a switch for specific gene expression (Thiagalingams, Chengkh, Leehj, et. histonedeacetylases: uniqueplaylinhashiphenylhiconinechistocode [ J].AnnNYAcadSci，2003，983：84-100)。
Histone acetylation is regulated by a pair of functionally antagonistic proteases Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs). In normal cells, the pair of enzymes is in a state of dynamic equilibrium. In general, an increased acetylation level of histones is associated with an increased transcriptional activity of the gene, whereas an excessively low acetylation level is associated with an inhibited expression of the gene (ForsbergEC, BresenickEH. Histoneacetyl genes and promoters: long-random acetylationpatternwhichmanninworld [ J ]. Bioessays, 2001, 23 (9): 820-. Studies have found that HDACs are overexpressed and recruited by transcription factors, leading to abnormal suppression of specific genes, leading to tumors and other diseases; inhibition of HDAC activity, in turn, causes growth inhibition and apoptosis in many cancer cells (SomechR, Izralis, JSimon A. histonedeacetylaseeinhibitors-anetotpolytreatearcancer [ J ]. cancer treatRev, 2004, 30 (5): 461-472). Therefore, HDACs have become the newest and most popular target in the current field of antineoplastic drug development.
HDAC inhibitors, which inhibit HDAC enzymatic activity, act by inhibiting HDAC, blocking the inhibition of gene expression due to dysfunction of HDAC recruitment, and modifying chromatin structure by altering histone acetylation, thereby modulating gene expression to treat cancer. It has obvious curative effect on treating blood system tumor and solid tumor by inducing growth arrest, differentiation or apoptosis of tumor cell. HDAC inhibitors are tumor specific and cytotoxic to proliferating and quiescent variant cells, whereas normal cells are more than 10-fold tolerant to them and do not cause growth arrest and apoptosis in normal cells. Moreover, the clinical dosage of the HDAC inhibitor is far lower than the maximum tolerance of human bodies, and the toxicity to the organisms is lower. The development and utilization of HDAC inhibitors have become a new hotspot in tumor therapy.
Currently, HDAC inhibitors that have been investigated and developed can be divided into five major classes: (1) hydroxamic acid compounds, the functional group being hydroxamic acid, representatives being TSA, SAHA (CurtiniML, Garland RB, Heymanhr, eta1.succinimideHydroxamic acid bacteriostatic polyamide in the histones section of enzyme [ J ]. bioorgMedChemLett, 2002, 12 (20): 2919) -2923), LAQ824(Atadjap, HsuM, KwonP, eta1. Moleculard cellular mineral for the same-hydroxamic acid fluoride in the Novartis Found L, 2004, 259: 249-266); (2) cyclic tetrapeptides containing 2-amino-8-oxo-9, 10-epoxydecanoyl group or not containing the group, such as FK-228; (3) benzamide compound, representative MS-275, has entered clinical studies; (4) short chain fatty acids such as butyric acid and phenylbutyric acid; (5) other classes of HDAC inhibitors do not have the structural features of common HDACs, but all contain some or all of the structural subunits required for inhibiting HDAC activity.
For example, chinese patent CN103420917A discloses a benzamide compound containing a fused ring structure, as shown in formula a, which has histone deacetylase inhibitory activity and is applied to the treatment of malignant tumor and diseases related to differentiation and proliferation; chinese patent CN103288728A discloses a naphthamide derivative, shown as formula B, which can effectively treat partial diseases caused by abnormal regulation of protein kinase; chinese patent CN103539695A discloses a substituted diphenyl ether histone deacetylase inhibitor, which is shown in formula C; chinese patent CN103467359A discloses a cinnamamide histone deacetylase inhibitor containing indole, which is shown in formula D; chinese patent CN102659630A discloses hydroxamic acid compounds represented by formula E.
Chinese patent CN102786458A discloses a pyrrole carboxamide derivative represented by formula F, which is used as an anti-malignant tumor drug, in particular, for preparing drugs for treating breast cancer, lung cancer and gastric cancer.
R1，R2，R3，R4Comprises the following steps: C1-C6 straight or branched chain alkyl, C3-C6 cycloalkyl;
R5，R6simultaneously or separately: hydrogen, C1-C6 alkyl; hydroxyl, halogen, C1-C4 alkoxy, and nitrate substituted C1-C6 alkyl.
At present, SAHA developed by Merck is a histone deacetylase inhibitor which is already on the market, is only limited to the treatment of T cell lymphoma of skin, and has no obvious curative effect on other cancers. Other developed HDAC inhibitors also have certain problems in the aspects of anticancer activity, toxic and side effects, subtype selectivity, and the like. Therefore, the development of a novel compound having histone deacetylase inhibitory activity is of great social and economic significance.
Disclosure of Invention
The invention aims to provide a pyrrole amide compound.
The invention provides a pyrrole amide compound shown in formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof:
wherein,
R1selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R4selected from hydroxyl, sulfhydryl, amino substituted phenyl or epoxy ketone groups.
Further, in the above-mentioned case,
R1selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butylamido, isobutylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanamido, n-alaninamidoAcyl, isoalanyl, n-butylacyl, isobutylyl, tert-butylacyl, pentylyl, hexylyl, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted phenyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R4selected from hydroxy, mercapto or amino substituted phenyl.
Further, the compound shown in the formula I is:
the invention also provides a preparation method of the pyrrole amide compound shown in the formula I,
when R is4When the hydroxyl is adopted, the synthetic route is as follows:
wherein, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; Fmoc-Cl represents fluorenylmethoxycarbonyl chloride; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; DCM represents dichloromethane;
R1selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5is halogen;
the method comprises the following steps:
a. stirring a mixed solvent of a compound IM-1a, lithium hydroxide and an ether solvent/water at the temperature of 20-30 ℃ for reaction for 1-6 h, removing the organic solvent, adding water for dilution, adjusting the pH value to 3-6, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-1a to the lithium hydroxide is 1: 1-10; the mass-volume ratio of the compound IM-1a to the mixed solvent is 1: 7-20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
b. b, dissolving the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a in a halohydrocarbon solvent at the temperature of 0-5 ℃, adding trifluoroacetic acid, and stirring and reacting at the temperature of 20-30 ℃ for 2-12H to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 a;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 5-20 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 2-10 g/ml;
c. b, stirring the compound IM-2a obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at the temperature of 20-30 ℃ for reaction for 12-16 h, adding water for dilution, adjusting the pH value to 1-3, extracting the ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-3 a;
the molar ratio of the compound IM-2a to the sodium carbonate to the fluorenyloxycarbonyl chloride is 1: 1-5: 0.9 to 1.5; the mass-volume ratio of the compound IM-2a to the mixed solvent is 1: 10-25 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
d. c, stirring and reacting the compound IM-3a obtained in the step c, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 12 to 16 hours, adding water for dilution, extracting an ester solvent, combining organic phases, drying, filtering and concentrating the organic phase to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 a;
the molar ratio of the compound IM-3a, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1-2: 1-2: 2-4; the mass-volume ratio of the compound IM-3a to the halocarbon solvent is 1: 9-20 g/ml;
e. d, stirring the compound IM-4a obtained in the step d, piperidine and a nitrogen-containing solvent at 25-30 ℃ for reaction for 4-6 h, adding water for dilution, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM-5 a;
the mass-to-volume ratio of the compound IM-4a to piperidine is 1: 1-4 g/ml; the mass-volume ratio of the compound IM-4a to the nitrogen-containing solvent is 1: 5-20 g/ml;
f. e, stirring and reacting the compound IM-5a, triethylamine, the compound IM-6a and a halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 1 to 10 hours, and removing the solvent to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 a;
the mol ratio of the compound IM-5a to the triethylamine to the compound IM-6a is 1: 1-5: 1-2; the mass-volume ratio of the compound IM-5a to the halocarbon solvent is 1: 50-100 g/ml;
g. dissolving the compound TM-1a obtained in the step f in a halohydrocarbon solvent at the temperature of 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at the temperature of 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound shown in a formula I;
the mass-volume ratio of the compound TM-1a to the halocarbon solvent is 1: 50-100 g/ml; the mass-volume ratio of the compound TM-1a to trifluoroacetic acid is 1: 10-50 g/ml.
Further, in the above-mentioned case,
a. stirring a mixed solvent of the compound IM-1a, lithium hydroxide and an ether solvent/water at 25 ℃ for 2 hours, removing the organic solvent, adding water for dilution, adjusting the pH to be 5, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-1a to the lithium hydroxide is 1: 4.5-5; the mass-volume ratio of the compound IM-1a to the mixed solvent is 1: 10-12 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 2: 1;
b. b, dissolving the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, and stirring and reacting at 25 ℃ for 2 hours to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 a;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 10 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 4-5 g/ml;
c. b, stirring the compound IM-2a obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at 25 ℃ for 12-16 h, adding water for dilution, adjusting the pH value to be 1, extracting by using an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-3 a;
the molar ratio of the compound IM-2a to the sodium carbonate to the fluorenyloxycarbonyl chloride is 1: 3: 1; the mass-volume ratio of the compound IM-2a to the mixed solvent is 1: 20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 5: 3;
d. c, stirring the compound IM-3a obtained in the step c, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at 25 ℃ for 12-16H, adding water for dilution, extracting an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 a;
the molar ratio of the compound IM-3a, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1.1: 1.2: 3; the mass-volume ratio of the compound IM-3a to the halocarbon solvent is 1: 9-10 g/ml;
e. d, stirring the compound IM-4a obtained in the step d, piperidine and a nitrogen-containing solvent at 25 ℃ for reaction for 4-6 h, adding water for dilution, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM-5 a;
the mass-to-volume ratio of the compound IM-4a to piperidine is 1: 2 g/ml; the mass-volume ratio of the compound IM-4a to the nitrogen-containing solvent is 1: 10 g/ml;
f. e, stirring the compound IM-5a, triethylamine, the compound IM-6a and a halohydrocarbon solvent in the step e at 25 ℃ for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 a;
the mol ratio of the compound IM-5a to the triethylamine to the compound IM-6a is 1: 1.4: 1 to 1.2; the mass-volume ratio of the compound IM-5a to the halocarbon solvent is 1: 80 g/ml;
g. dissolving the compound TM-1a obtained in the step f in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound shown in a formula I;
the mass-volume ratio of the compound TM-1a to the halocarbon solvent is 1: 60-65 g/ml; the mass-volume ratio of the compound TM-1a to trifluoroacetic acid is 1: 25 g/ml.
Further, in the above-mentioned case,
R1selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butylamido, isobutylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isoalanyl, n-butylamido, isobutylamino, tert-butylamido, pentylamino, hexylamino, Czocyclo, butylamino, pentanoylamino, hexanoylamino, N-butylamido, tert3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted phenyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Nitrogen ofHeterocycloalkenyl, C4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5selected from fluorine, chlorine, bromine or iodine.
Further, in step f, the compound IM-6a is:
further, in the steps a to g, the ether solvent is one or more selected from tetrahydrofuran, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvent is selected from one or more than two of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvent is selected from one or more of ethyl acetate and ethyl formate; the nitrogen-containing solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide, acetonitrile and pyridine.
The invention also provides another preparation method of the pyrrole amide compound shown in the formula I,
when R is4When the hydroxyl is adopted, the synthetic route is as follows:
wherein,
R1selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5、R6are each halogen;
the method comprises the following steps:
i. stirring a mixed solvent of a compound IM-5b, a compound IM-6b, sodium bicarbonate and an ether solvent/water at 25-30 ℃ for reaction for 1-10 h, removing the solvent, adding water, extracting with an ester solvent, combining organic phases, washing with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-7 b;
the molar ratio of the compound IM-5b to the compound IM-6b to the sodium bicarbonate is 1: 1-2: 1-5; the mass-volume ratio of the compound IM-5b to the mixed solvent of the ether solvent/water is 1: 20-100 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-5: 1;
ii. I, stirring and reacting a compound IM-7b obtained in the step i, a compound IM-8b, sodium carbonate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and a mixed solvent of an ether solvent/water at 50-100 ℃ under the protection of inert gas for 1-10 h, removing the solvent, adding water and a halohydrocarbon solvent for extraction, combining organic phases, washing the organic phases with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 b;
the mol ratio of the compound IM-7b to the compound IM-8b to the sodium carbonate is 1: 1-2: 1-5; the mass ratio of the compound IM-7b to [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is 1: 0.05 to 0.2; the mass-volume ratio of the compound IM-7b to the mixed solvent of the ether solvent/water is 1: 20-100 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-10: 1;
iii, dissolving the compound TM-1b in the step II in an alcohol solvent, adding hydrochloric acid, stirring and reacting at 25-30 ℃ for 1-10 h, and then separating and purifying to obtain the compound shown in the formula I;
the mass-volume ratio of the compound TM-1b to the alcohol solvent is 1: 18-100 g/ml; the mass-volume ratio of the compound TM-1b to hydrochloric acid is 1: 3-20 g/ml; the concentration range of the hydrochloric acid is 0.5N-2N.
Further, in the above-mentioned case,
i. stirring a compound IM-5b, a compound IM-6b, sodium bicarbonate and a mixed solvent of an ether solvent/water at 25 ℃ for 2 hours, removing the solvent, adding water, extracting with an ester solvent, combining organic phases, washing with saturated saline water, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-7 b;
the molar ratio of the compound IM-5b to the compound IM-6b to the sodium bicarbonate is 1: 1: 2-3; the mass-volume ratio of the compound IM-5b to the mixed solvent of the ether solvent/water is 1: 20-40 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
ii. I, stirring and reacting a mixed solvent of the compound IM-7b, the compound IM-8b, sodium carbonate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and an ether solvent/water at 80 ℃ for 2 hours under the protection of inert gas, removing the solvent, adding water, extracting a halohydrocarbon solvent, combining organic phases, washing with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 b;
the mol ratio of the compound IM-7b to the compound IM-8b to the sodium carbonate is 1: 1: 2-3; the mass ratio of the compound IM-7b to [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is 1: 0.08 to 0.12; the mass-volume ratio of the compound IM-7b to the mixed solvent of the ether solvent/water is 1: 20-40 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 4-6: 1;
iii, dissolving the compound TM-1b in the step II in an alcohol solvent, adding hydrochloric acid, stirring at 25 ℃ for reaction for 2 hours, and then separating and purifying to obtain a compound shown in the formula I;
the mass-volume ratio of the compound TM-1b to the alcohol solvent is 1: 18-40 g/ml; the mass-volume ratio of the compound TM-1b to hydrochloric acid is 1: 3-10 g/ml; the concentration range of the hydrochloric acid is 0.5N-2N.
Further, in the above-mentioned case,
R1selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butylamido, isobutylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isoalanyl, n-butylamido, isobutylamino, tert-butylamido, pentylamino, hexylamino, Czocyclo, butylamino, pentanoylamino, hexanoylamino, N-butylamido, tert3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted benzenesA group;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5、R6selected from fluorine, chlorine, bromine or iodine.
Further, in the above-mentioned case,
in step i, the compound IM-6b is:
in step ii, said compound IM-8b is:
further, in the steps i to iii, the ether solvent is one or more selected from tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvent is selected from one or more than two of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvent is selected from one or more of ethyl acetate and ethyl formate; the alcohol solvent is selected from one or more of methanol, ethanol, n-propanol and isopropanol.
The invention also provides another preparation method of the pyrrole amide compound shown in the formula I,
when R is4When the phenyl is substituted by amino, the synthetic route is as follows:
wherein, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; LiOH represents lithium hydroxide;
R1selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl (III)、C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5selected from halogens;
the method comprises the following steps:
dissolving a compound IM-1c in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, and stirring and reacting at 20-30 ℃ for 2-12 h to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 c;
the mass-to-volume ratio of the compound IM-1c to the halocarbon solvent is 1: 5-20 g/ml; the mass-to-volume ratio of the compound IM-1c to trifluoroacetic acid is 1: 2-10 g/ml;
secondly, stirring and reacting the compound IM-2c, the compound IM-3c, triethylamine and a halohydrocarbon solvent obtained in the step I at the temperature of between 25 and 30 ℃ for 1 to 10 hours, and concentrating to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 c;
the mol ratio of the compound IM-2c to the compound IM-3c to triethylamine is 1: 1-2: 1-5; the mass-volume ratio of the compound IM-2c to the halocarbon solvent is 1: 50-100 g/ml;
thirdly, stirring the compound IM-4c obtained in the step II, lithium hydroxide and mixed solvent of ether solvent/water at the temperature of between 20 and 30 ℃ for reaction for 2 to 16 hours to obtain reaction liquid; separating and purifying to obtain a compound IM-5 c;
the molar ratio of the compound IM-4c to the lithium hydroxide is 1: 1-10; the mass-volume ratio of the compound IM-4c to the mixed solvent is 1: 55-60 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-5: 1;
fourthly, stirring and reacting the compound IM-5c, the 1, 2-diaminobenzene, the 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, the N, N-diisopropylethylamine and the halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 12 to 16 hours to obtain reaction liquid; separating and purifying to obtain a compound shown as a formula I;
the molar ratio of the compound IM-5c, 1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 0.8-2: 0.8-2: 1.5 to 4; the mass-to-volume ratio of the compound IM-5c to the halocarbon solvent is 1: 40-100 g/ml.
Further, in the above-mentioned case,
dissolving a compound IM-1c in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, and stirring and reacting at 25 ℃ for 2 hours to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 c;
the mass-to-volume ratio of the compound IM-1c to the halocarbon solvent is 1: 20 g/ml; the mass-to-volume ratio of the compound IM-1c to trifluoroacetic acid is 1: 8 g/ml;
secondly, stirring the compound IM-2c, the compound IM-3c, triethylamine and a halohydrocarbon solvent obtained in the step I at 25 ℃ for 2 hours, and concentrating to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 c;
the mol ratio of the compound IM-2c to the compound IM-3c to triethylamine is 1: 1.1-1.2: 2.5-3; the mass-volume ratio of the compound IM-2c to the halocarbon solvent is 1: 65-70 g/ml;
thirdly, stirring the compound IM-4c obtained in the second step, lithium hydroxide and mixed solvent of ether solvent/water at 25 ℃ for 2-16 h to obtain reaction liquid; separating and purifying to obtain a compound IM-5 c;
the molar ratio of the compound IM-4c to the lithium hydroxide is 1: 4.5; the mass-volume ratio of the compound IM-4c to the mixed solvent is 1: 55-60 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 3: 1;
fourthly, stirring and reacting the compound IM-5c, the 1, 2-diaminobenzene, the 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, the N, N-diisopropylethylamine and the halohydrocarbon solvent at 25 ℃ for 12 to 16 hours to obtain reaction liquid; separating and purifying to obtain a compound shown as a formula I;
the molar ratio of the compound IM-5c, 1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 0.8-1.2: 0.8-1.2: 1.5-2; the mass-to-volume ratio of the compound IM-5c to the halocarbon solvent is 1: 40-45 g/ml.
Further, in the above-mentioned case,
R1selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butylamido, isobutylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isoalanyl, n-butylamido, isobutylamino, tert-butylamido, pentylamino, hexylamino, Czocyclo, butylamino, pentanoylamino, hexanoylamino, N-butylamido, tert3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted phenyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, ammoniaPhenylpropyl, aminobutylalkyl, aminopentyl, aminohexylalkyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamide, t-butylamido, pentanamido, hexanamido, methionyl, ethanamido, n-alaninyl, isoalanyl, n-butylamido, isobutylyl, t-butylamido, pentylyl, hexylyl, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5selected from fluorine, chlorine, bromine or iodine.
Further, in step two, the compound IM-3c is:
further, in the first to fourth steps, the halocarbon solvent is selected from any one or more than two of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ether solvent is one or more selected from tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether.
The invention also provides application of the pyrrole amide compound or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof in preparation of histone deacetylase inhibitor medicines.
The histone deacetylase inhibitor medicament is a medicament for preventing and/or treating diseases caused by abnormal histone deacetylase activity.
Further, the disease is any one or more of a cell proliferative disease, an autoimmune disease, an inflammation, a neurodegenerative disease, or a viral disease.
Still further, the disease is cancer.
The invention also provides a pharmaceutical composition for inhibiting the activity of histone deacetylase, which is a preparation prepared by taking the pyrrole amide compound or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
Further, the preparation comprises an oral administration preparation, a sublingual administration preparation, a buccal administration preparation, a transdermal absorption preparation or an injection preparation.
The novel compound shown in the formula I shows good deacetylase inhibitory activity, and has the potential of preventing and/or treating diseases caused by abnormal histone deacetylase activity; meanwhile, the novel compound has good inhibitory activity on different liver cancer cells, and has a prospect of clinical application. The following compounds 1-11 with good deacetylase inhibitory activity are prepared in the invention, and are shown in table 1:
TABLE 1 Compounds 1 to 11 prepared according to the invention
Histone deacetylase plays an important role in the physiological and pathological processes of gene transcription regulation, signal transduction, growth and development, differentiation apoptosis, metabolic diseases, tumors and the like. If the activity of histone deacetylase is abnormal, a series of diseases with abnormal histone deacetylase activity can be caused. Including cell proliferative disorders, autoimmune disorders, inflammation, neurodegenerative disorders, viral disorders (for example, a review of the disorders in world patent WO2011011186 where HDAC6 inhibitors are useful).
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix, e.g., the prefix (Ca-b) alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1-4 alkyl refers to an alkyl group containing 1-4 carbon atoms.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
In certain embodiments of the present invention, the invention includes isotopically-labeled compounds, which are intended to be identical to those recited herein, but wherein one or more atoms are replaced by another atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Isotopes which may be incorporated into compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e.2H,3H、13C、14C、15N、17O、18O、35And S. Compounds of formula (I) and stereoisomers thereof, and pharmaceutically acceptable salts of the compounds, stereoisomers, containing the aforementioned isotopes and/or other atomic isotopes are included within the scope of the invention.
The key intermediates and compounds in the present invention are isolated and purified by means of isolation and purification methods commonly used in organic chemistry and examples of such methods include filtration, extraction, drying, spin-drying and various types of chromatography. Alternatively, the intermediate may be subjected to the next reaction without purification.
In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The pharmaceutically acceptable auxiliary material of the invention refers to a substance contained in a dosage form except for an active ingredient.
The pharmaceutically acceptable auxiliary components have certain physiological activity, but the addition of the components does not change the dominant position of the pharmaceutical composition in the disease treatment process, but only plays auxiliary effects, and the auxiliary effects are only the utilization of the known activity of the components and are auxiliary treatment modes which are commonly used in the field of medicine. If the auxiliary components are used in combination with the pharmaceutical composition of the present invention, the protection scope of the present invention should still be included.
The compound of the invention has the activities of inducing differentiation, immunoregulation, blocking cell cycle and promoting apoptosis and good HDAC subtype selectivity, aims to have better curative effect on various cancers, and simultaneously overcomes the toxic and side effects of the existing HDAC inhibitor, such as anemia, ischemic stroke, deep venous thrombosis, thrombocytopenia, emesis and the like.
The compound of the present invention has HDAC inhibitory activity, and can be used for treating diseases associated with abnormal HDAC activity, particularly liver cancer.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
In the invention, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; Fmoc-Cl represents fluorenyloxycarbonyl chloride; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; DCM stands for dichloromethane.
EXAMPLE 1 preparation of N-hydroxy-1- (4 '-methoxy- [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide preparation of 1,2, 5-dihydro-1H-pyrrole-3-carboxylic acid
Dissolving ethyl N-t-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylate (8.5g,36 mmol; manufacturer: Shaoshima technologies, Ltd.) in a mixed solution of 60mL tetrahydrofuran and 30mL water, adding lithium hydroxide (4.2g,176mmol), reacting at 25 ℃ with stirring for 2 hours, and removing the organic solvent in vacuo to obtain a residue; diluting the residue with an appropriate amount of water, adjusting the pH to 5 with 1N hydrochloric acid, precipitating a solid, and filtering to obtain a solid; the solid was washed with water and dried to give N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid (7.0g, 93% yield) as a white solid.
MS(ESI)m/z214(M+1)+。
Under an ice bath, dissolving N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid (7g,36mmol) in 70mL of dichloromethane solution, then dropwise adding 30mL of trifluoroacetic acid, stirring, slowly raising the temperature to 25 ℃, and continuing to stir for 2H to obtain a reaction solution; the reaction was concentrated to give 2, 5-dihydro-1H-pyrrole-3-carboxylic acid (4.0g, 99% yield) as a yellow oil.
MS(ESI)m/z114(M+1)+。
2. Preparation of N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid
2, 5-dihydro-1H-pyrrole-3-carboxylic acid (4.0g,35.4mmol) was dissolved in 50mL of tetrahydrofuran and 30mL of water, followed by addition of sodium carbonate (11.2g,106mmol) and fluorenyloxycarbonyl chloride (9.2g,35.4 mmol; manufacturer: Afahesa (China) chemical Co., Ltd.), and reaction with stirring at 25 ℃ overnight; after the reaction, 200mL of water was added to dilute the reaction mixture, the pH was adjusted to 1 with 2N hydrochloric acid, ethyl acetate was used for extraction, the organic phases were combined, dried and concentrated in vacuo to give N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid as a white solid (11.0g, 92% yield).
MS(ESI)m/z336(M+1)+。
3. Preparation of N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide
Dissolving N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid (11.0g, 32.8mmol) in 100mL of dichloromethane, sequentially adding O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (4.2g,36mmol), HATU (15g,39.4mmol) and DIEA (12.8g,98.4 mmol; manufacturer: Bailingwei Technology Co., Ltd.), and stirring at 25 ℃ for reacting overnight to obtain a reaction solution; adding 50mL of water into the reaction solution for dilution, extracting with ethyl acetate (50mLx2), combining ethyl acetate phases, drying, filtering and concentrating the ethyl acetate phases to obtain a crude product; the crude product was purified by column chromatography to give N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide as a white solid (12g, 48% yield).
MS(ESI)m/z435(M+1)+。
4. Preparation of 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide
Dissolving N-fluorenyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -formamide (10g, 23mmol) in 100mL of DMF, adding 20mL of piperidine, stirring at 25 ℃ for reacting for 4 hours, then adding 800mL of water for diluting, extracting with ethyl acetate, and combining organic phases; the organic phase was dried, filtered and concentrated to give 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide as a white solid (4.5g, 92% yield).
MS(ESI)m/z213(M+1)+。
5. Preparation of 1- ((4-benzonitrile) sulfonyl) -N-hydroxy-2, 5-dihydro-1H-pyrrole-3-carboxamide
Dissolving 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -formamide (100mg,0.5mmol) and triethylamine (66mg,0.7mmol) in dichloromethane (8mL), adding 4 '-methoxy- [1,1' -biphenyl ] -4-sulfonyl chloride (113mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.) to the reaction solution at 25 ℃, stirring for 2 hours at 25 ℃, and concentrating to remove the solvent to obtain a crude product; and purifying the crude product by column chromatography to obtain N- ((tetrahydro-2H-pyran-2-yl) oxy) -1- (4 '-methoxy- [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-formamide as a white solid.
Dissolving N- ((tetrahydro-2H-pyran-2-yl) oxy) -1- (4 '-methoxy- [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-formamide (80mg,0.3mmol) in 5mL of dichloromethane solution under ice bath, then dropwise adding 2mL of trifluoroacetic acid, stirring, slowly raising to 25 ℃, continuing stirring for reaction for 2H, and concentrating to remove the solvent to obtain a crude product; the crude product was purified by preparative high performance liquid chromatography to give N-hydroxy-1- (4 '-methoxy- [1,1' -biphenyl ] -4-sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide as a white solid (29mg, 7% yield).
MS(ESI)m/z375(M+1)+。
1HNMR(400MHz,DMSO-d6)10.81(brs,1H),9.05(brs,1H),7.90-7.85(m,4H),7.73-7.71(m,2H),7.08-7.06(m,2H),6.34(s,1H),4.20(s,4H),3.82(s,3H)。
Example 2 preparation of N-hydroxy-1- ((4- (4-fluorophenyl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (4-fluorophenyl) benzenesulfonyl chloride (162mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), white solid N-hydroxy-1- ((4- (4-fluorophenyl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide (32mg, 18% yield) was prepared according to the similar procedure in example 1.
MS(ESI)m/z363(M+1)+。
1HNMR(400Hz,DMSO-D6)＝10.83(s,1H),9.02(s,1H),7.94-7.89(m,4H),7.84-7.80(m,2H),7.38-7.33(m,2H),6.35(s,1H),4.22(s,4H)。
Example 3 preparation of N-hydroxy-1- ((4- (4-tert-butylphenyl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (4-tert-butylphenyl) benzenesulfonyl chloride (184mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), a white solid, N-hydroxy-1- ((4- (4-tert-butylphenyl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide (23mg, 12% yield) was prepared according to the similar procedure in example 1.
MS(ESI)m/z401(M+1)+。
1HNMR(400Hz,DMSO-D6)＝10.83(s,1H),9.03(s,1H),7.92-7.87(m,4H),7.77(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,2H),6.35(s,1H),4.22(s,4H)。
Example 4 preparation of N-hydroxy-1- ((4- (4-morpholin-N-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (100mg,0.5mmol) and 4- (4-morpholine-N-phenyl) benzenesulfonyl chloride (202mg,0.6 mmol; manufacturer: Bailingwei science and technology Co., Ltd.), a white solid, N-hydroxy-1- ((4- (4-morpholine-N-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide (45mg, 21% yield) was prepared according to the similar procedure as in example 1.
MS(ESI)m/z430(M+1)+。
1HNMR(400Hz,DMSO-D6)＝10.83(s,1H),9.03(s,1H),7.87-7.82(m,4H),7.66(d,J＝8.4Hz,2H),7.05(d,J＝8.4Hz,2H),6.35(s,1H),4.18(s,4H),3.76-3.74(m,4H),3.51-3.50(m,4H)。
EXAMPLE 5 preparation of N-hydroxy-1- (((3-methyl-4-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
Preparation of N-hydroxy-1- (((3-methyl-4-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide (33mg, 18% yield) was prepared as a white solid in analogy to the procedure in example 1, starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (100mg,0.5mmol) and (3-methyl-4-phenyl) benzenesulfonyl chloride (177mg,0.6 mmol; manufacturer: Bailingwei technologies, Ltd.).
MS(ESI)m/z359(M+1)+。
1HNMR(400Hz,DMSO-D6)＝10.85(s,1H),9.04(s,1H),7.78(s,1H),7.72-7.70(m,1H),7.50-7.39(m,6H),6.37(s,1H),4.23(s,4H),2.33(s,3H)。
EXAMPLE 6 preparation of N-hydroxy-1- (((3-methyl-4-p-fluorophenyl) phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide
Preparation of N-hydroxy-1- (((3-methyl-4-phenyl) sulfonyl) 2, 5-dihydro-1H-pyrrole-3-carboxamide (29mg, 15% yield) was prepared as a white solid in analogy to the procedure in example 1, starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (100mg,0.5mmol) and (3-methyl-4-p-fluorophenyl) benzenesulfonyl chloride (177mg,0.6 mmol; manufacturer: Bailingwei Techno Co., Ltd.).
MS(ESI)m/z377(M+1)+。
1HNMR(400Hz,DMSO-D6)＝10.85(s,1H),9.04(s,1H),7.78(s,1H),7.71-7.69(m,1H),7.48-7.45(m,3H),7.33-7.29(d,J＝8.0Hz,2H),6.37(s,1H),4.23(s,4H),2.32(s,3H)。
Example 7 preparation of N-hydroxy-1- ((3 '- (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide
1. Preparation of 1- ((4-bromophenyl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide
2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (2.1g,10mmol) was dissolved in a mixed solution of 50mL tetrahydrofuran and 50mL water, followed by the addition of p-bromobenzenesulfonyl chloride (2.6g,10 mmol). Sodium bicarbonate (2.6g,30mmol) was added thereto and the solution was stirred at room temperature for 1 hour. After the reaction was completed, the organic solvent was removed in vacuo, the residue was diluted with an appropriate amount of water and extracted 2 times with ethyl acetate, which was dried and concentrated to give 1- ((4-bromophenyl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide as a white solid (3.8g, 88.2% yield).
MS(ESI)m/z431(M+1)+。
1HNMR(400MHz,CD3OD)＝11.38(br,1H),7.86(d,J＝4.0Hz,2H),7.84(d,J＝4.0Hz,2H),6.42(s,1H),4.82(s,1H),4.21-4.19(m,4H),4.03-4.01(m,1H),3.49(s,1H),1.62(s,3H),1.50(s,3H).
2. Preparation of N-hydroxy-1- ((3 '- (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide
Dissolving 1- ((4-bromophenyl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (431mg,1.0mmol) in 10mL of dioxane and 2mL of water, adding sodium carbonate (212mg,2 mmol) and 1- ((3 '- (4-methylpiperazin-1-yl) -phenylboronic acid pinacol ester (302mg,1.0mmol, manufacturer: Bailingwei Techno Co., Ltd.), adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (50mg), replacing the solution with nitrogen gas three times, heating to 80 ℃ for 2 hours, removing the organic solvent in vacuo after the reaction is finished, adding 20mL of water for dilution, extracting with dichloromethane 3 times, the combined organic phases were dried and concentrated in vacuo to give a crude product which was purified by chromatography to give N-hydroxy-1- ((3 '- (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide as a white solid (250.00mg, 47.5% yield).
MS(ESI)m/z527(M+1)+。
3. Preparation of N-hydroxy-1- ((3 '- (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide
N-hydroxy-1- ((3 '- (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (250mg, 0.48mmol) was dissolved in 5mL of methanol, and 1NHCl solution (1.0mL) was added dropwise to the solution, the mixture was stirred at room temperature for 2 hours, and after the reaction was completed, filtration was performed to obtain N-hydroxy-1- ((3 '- (4-methylpiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide (46mg, yield 13.3%).
MS(ESI)m/z443(M+1)+。
1HNMR(400Hz,DMSO-D6)＝10.98(br,1H),7.95-7.88(m,4H),7.42-7.38(t,J＝8.0Hz1H),7.32(s,1H),7.23-7.21(d,J＝8.0Hz,1H),7.09-7.07(m,1H),6.36(s,1H),4.21(s,4H),3.98-3.93(m,,2H),3.50-3.43(m,2H),3,22-3.148(m,4H),2.81(s,3H)。
Example 8 preparation of N-hydroxy-1- ((4 '- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (300mg,1.41mmol) and 1- ((4 ' - (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) phenylboronic acid pinacol ester (321mg,1.0mmol, manufacturer: Bailingwei science Co., Ltd.) according to the procedure described in example 7, a white solid, N-hydroxy-1- ((4 ' - (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide hydrochloride (22mg, yield 6.6%).
MS(ESI)m/z440(M+1)+。
1HNMR(400Hz,DMSO-D6)＝10.86(s,1H),10.84-10.72(br,1H),9.01(s,1H),7.98-7.96(d,J＝8.8Hz,2H),7.92-7.90(d,J＝8.4Hz,2H),7.81-7.79(d,J＝8.4Hz,2H),7.65-7.63(d,J＝8.8Hz,2H)6.37(s,1H),6.32(s,1H),4.23(s,4H),4.02-3.82(br,2H),3.75-3.52(br,2H),2.86(s,5H)。
Example 9 preparation of N-hydroxy-1- ((4 '- (1-methylpiperidin-4-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide
Starting from 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxy) -carboxamide (300mg,1.4mmol) and pinacol ester of 1- ((4 ' - (1-methylpiperidin-4-yl) methyl) phenylboronic acid (321mg,1.0mmol, manufacturer: Bailingwei science and technology Co., Ltd.), white solid N-hydroxy-1- ((4 ' - (1-methylpiperidin-4-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide (24mg, 10.3% yield) was obtained according to the similar procedure as in example 7.
MS(ESI)m/z442(M+1)+。
1HNMR(400Hz,DMSO-D6)＝10.82(br,1H),7.91-7.90(d,J＝2.8Hz,4H),7.75.7.73(d,J＝8.4Hz2H),7.40-7.38(d,J＝8.4Hz,2H),6.36(s,1H),4.22(s,4H),3.20-3.02(m,2H),2.90-2.84(m,1H),2.75(s,3H),2.20-1.95(m,4H)。
Example 10 preparation of N-hydroxy-1- ((4 '- (4-methyl-2-oxopiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide
With 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (300mg,1.4mmol) and pinacol ester of 1- ((4' - (4-methyl-2-oxopiperazin-1-yl) phenylboronic acid (321mg,1.0mmol, manufacturer: welengi science and technology limited) as a raw material, a white solid, N-hydroxy-1- ((4 '- (4-methyl-2-oxopiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide hydrochloride (32mg, 10.6% yield) was prepared according to a similar procedure as in example 7.
MS(ESI)m/z457(M+1)+。
1HNMR(400Hz,DMSO-D6)＝11.82-11.70(br,1H),10.86(s,1H),9.10-8.92(br,1H),9.01(s,1H),7.97-7.91(m,4H),7.85-7.83(m,2H),7.52-7.49(m,2H),6.36(s,1H),4.23(s,4H),4.02(s,2H),3.70-3.45(m,2H),3.43-3.41(m,2H),2.91(s,3H)。
Example 11 preparation of N-hydroxy-1- ((4 '- (4-methyl-3-oxopiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide
With 2, 5-dihydro-1H-pyrrole-3- (tetrahydropyran-2-oxo) -carboxamide (300mg,1.4mmol) and pinacol ester of 1- ((4' - (4-methyl-3-oxopiperazin-1-yl) phenylboronic acid (321mg,1.0mmol, manufacturer: welengi science and technology limited) as a raw material, a white solid, N-hydroxy-1- ((4 '- (4-methyl-3-oxopiperazin-1-yl) - [1,1' -biphenyl ] -4-yl) sulfonyl) -2, 5-dihydro-1H-pyrrole-3-carboxamide hydrochloride (38mg, 11.5% yield) was prepared according to a similar procedure as in example 7.
MS(ESI)m/z457(M+1)+。
1HNMR(400Hz,DMSO-D6)＝10.84(s,1H),10.61-10.53(br,1H),9.0(s,1H),7.90-7.84(m,4H),7.71-7.69(d,J＝9.2Hz,2H),7.15-7.13(d,J＝8.8Hz,2H),6.36(s,1H),4.21(s,4H),3.98-3.95(d,J＝12.4Hz,2H),3.58-3.55(d,J＝11.6Hz,2H),3.21-3.08(m,6H),1.31-1.27(t,J＝7.2Hz,3H)。
To illustrate the advantageous effects of the present invention, the present invention provides the following test examples:
test example 1 biological Activity assay
The HDA inhibitory activity of the compounds of the invention was tested in a substrate deacetylation assay.
A: detection of the enzyme activity of deacetylase 6 (#50076, BPSBioscience):
HDAC6 deacetylates the substrate, activates the substrate, can be acted on by a subsequently added developing solution and releases a fluorescent group, and the size of the fluorescent signal reflects the activity of HDAC 6. The method of detecting IC50 of this enzyme is disclosed in Chupingxu, Elisabettas Soragini ImprovedHistoneDeacetylase III therapeutics for the NeudegenerergieveDisearediedFriedreich' sAtaxia: AnewSynthetic route. The total reaction (100. mu.L/well) contained 0.35 ng/. mu.L of HDAC6, 20. mu.M substrate and varying concentrations of compound. After incubation at 37 ℃ for 30 minutes, the fluorescence signal was measured, and the inhibition of the compound was determined from the data obtained and plotted against the compound concentration to obtain a concentration response curve, and the IC50 values were fitted according to a four parameter model.
B: deacetylase 3 enzyme activity assay (#50003, BPSBioscience):
HDAC3 deacetylates the substrate, activates the substrate, is acted on by the chromogenic solution and releases a fluorophore, the magnitude of the fluorescence signal of which reflects the activity of HDAC 3. The method of detecting IC50 of this enzyme is disclosed in Chupingxu, Elisabettas Soragini ImprovedHistoneDeacetylase III therapeutics for the NeudegenerergieveDisearediedFriedreich' sAtaxia: AnewSynthetic route. The total reaction (100. mu.L/well) contained 0.16 ng/. mu.L of HDAC3, 10. mu.M of substrate and varying concentrations of compound. The fluorescence signal was detected on-line at Ex/Em ═ 360/460. The inhibition of the compound was determined from the data obtained and plotted against compound concentration to obtain a concentration response curve, and IC50 values were fitted according to a four parameter model.
The enzymatic activity of deacetylase 6 (i.e., HDAC6) was assayed for compounds 1-11 prepared in the examples as described above and the results are shown in table 2, where the IC50 for each compound was determined according to the instructions and is shown in table 2:
"+" indicates that the IC50 assay for HDAC6 was greater than 500 nM;
"+ + +" indicates that IC50 for HDAC6 was less than 300nM and greater than 100 nM;
"+ + + + +" indicates that IC50 for HDAC6 was less than 100nM
The enzymatic activity of deacetylase 3 (i.e., HDAC3) was assayed for compounds 1-11 prepared in the examples as described above and the results are shown in table 2, where the IC50 for each compound was determined according to the instructions and is shown in table 2:
"+" indicates that the IC50 assay for HDAC3 was greater than 1000 nM;
"+ + +" indicates that IC50 for HDAC3 was greater than 100nM and less than 1000 nM;
"+ + + + +" indicates that the IC50 for HDAC3 was less than 100 nM.
TABLE 2 inhibitory Activity of Compounds 1 to 11 of the present invention on HDAC6& HDAC3
Test results show that the compounds 1-11 have good deacetylase inhibitory activity and have the potential of preventing and/or treating diseases caused by abnormal histone deacetylase activity.
Test example 2 cell assay-cell growth inhibition assay
Materials and reagents
HepG2 cell line, Hep3B cell line, Huh7 cell line and Li7 cell line were purchased from Shanghai Life sciences institute of Chinese academy of sciences; DMEM high-glucose medium and MEM medium were purchased from Hyclone; fetal bovine serum was purchased from Gibco; trypsin was purchased from invitrogen shanghai; the CCK-8 kit is purchased from Biyuntian Biotechnology institute (beyond time); the other consumables such as cell culture dishes were purchased from corning china (corning china).
Cell preparation prior to Compound action
Digesting HepG2 cells, Hep3B cells, Huh7 cells and Li7 cells in logarithmic growth phase by trypsin, taking uniform cell suspension, counting, adjusting the cell density to 1500 cells/hole by using a culture medium containing 10% serum, re-inoculating the cells in a 96-hole cell culture plate, culturing the cells in a volume of 200 mu L at 37 ℃ and 5% CO2Culturing in an incubator; the culture was carried out for 24 hours and used for the experiment.
Action of the Compound
The cells cultured for 24 hours were taken out from the incubator, the culture solution in the well plate was aspirated, 200. mu.L of a compound solution prepared with a medium containing 10% fetal bovine serum was added to each well, each concentration was 5 in parallel, DMSO was set as a negative control, and the cells were cultured at 37 ℃ for 72 hours in 5% CO2 to carry out CCK-8 assay.
CCK-8 detection
Serum-free culture medium and CCK-8 solution are taken to prepare CCK-8 working solution according to the proportion of 10:1 (the process needs to be protected from light).
The cells cultured for 72 hours were removed from the incubator, the culture medium was aspirated from the well plate, and 120. mu. LCCK-8 working solution was added to each well, and 120. mu. LCCK-8 working solution was added to the cell-free well plate as a blank, and the cell-free well plate was incubated at 37 ℃ in a 5% CO2 incubator for 1 hour (this process required protection from light).
The plates were removed from the incubator and 100. mu.L of solution was pipetted into each well of a new 96-well plate and the absorbance read at 450nm (the process required protection from light).
Data processing:
tx: absorbance of the compound measured 72 hours after the compound was exposed to CCK-8
C: the absorbance of the negative control wells measured by CCK-8 after 72 hours of incubation
B: absorbance measured in blank control well, CCK-8
The compounds 1 to 11 prepared in the examples were run in the above assay and the results are shown in table 3, where the highest IC50 of one or more runs of each compound determined is classified by description, in table 3:
"+" indicates that the compound had an IC50 assay of greater than 10 μ M in cancer cells;
"+ +" indicates that the IC50 assay of the compound in cancer cells was less than 10. mu.M;
TABLE 3 inhibitory Activity of Compounds 1 to 11 of the present invention on different hepatocarcinoma cells
Compound (I) HepG2 Huh-7 Li-7 Hep3B
1 + + + +
2 ++ ++ + ++
3 + + + +
4 ++ ++ ++ ++
5 + + ++ ++
6 + + + +
7 ++ ++ ++ ++
8 ++ ++ ++ ++
9 ++ ++ ++ ++
10 ++ + + +
11 ++ + + +
Test results show that the compounds 1-11 have good inhibitory activity on different liver cancer cells (HepG2, Huh-7, Li-7 and Hep3B) and have a prospect of clinical application.
In conclusion, the novel compound shown in the formula I shows good deacetylase inhibitory activity, and has the potential of preventing and/or treating diseases caused by abnormal histone deacetylase activity; meanwhile, the novel compound has good inhibitory activity on different liver cancer cells, and has a prospect of clinical application.

Claims (24)

1. A pyrrole amide compound shown as a formula I or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof:
wherein,
R1selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R4selected from hydroxyl, sulfhydryl, amino substituted phenyl or epoxy ketone groups.
2. The pyrrole amide compound or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof according to claim 1, wherein:
R1selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butylamido, isobutylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isoalanyl, n-butylamido, isobutylamino, tert-butylamido, pentylamino, hexylamino, Czocyclo, butylamino, pentanoylamino, hexanoylamino, N-butylamido, tert3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted phenyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R4selected from hydroxy, mercapto or amino substituted phenyl.
3. The pyrrole amide compound or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof according to claim 1 or 2, wherein: the compound shown in the formula I is:
4. a preparation method of pyrrole amide compounds shown in formula I is characterized in that:
when R is4When the hydroxyl is adopted, the synthetic route is as follows:
wherein, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; Fmoc-Cl represents fluorenylmethoxycarbonyl chloride; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; DCM represents dichloromethane;
R1selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5is halogen;
the method comprises the following steps:
a. stirring a mixed solvent of a compound IM-1a, lithium hydroxide and an ether solvent/water at the temperature of 20-30 ℃ for reaction for 1-6 h, removing the organic solvent, adding water for dilution, adjusting the pH value to 3-6, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-1a to the lithium hydroxide is 1: 1-10; the mass-volume ratio of the compound IM-1a to the mixed solvent is 1: 7-20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
b. b, dissolving the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a in a halohydrocarbon solvent at the temperature of 0-5 ℃, adding trifluoroacetic acid, and stirring and reacting at the temperature of 20-30 ℃ for 2-12H to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 a;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 5-20 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 2-10 g/ml;
c. b, stirring the compound IM-2a obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at the temperature of 20-30 ℃ for reaction for 12-16 h, adding water for dilution, adjusting the pH value to 1-3, extracting the ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-3 a;
the molar ratio of the compound IM-2a to the sodium carbonate to the fluorenyloxycarbonyl chloride is 1: 1-5: 0.9 to 1.5; the mass-volume ratio of the compound IM-2a to the mixed solvent is 1: 10-25 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
d. c, stirring and reacting the compound IM-3a obtained in the step c, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 12 to 16 hours, adding water for dilution, extracting an ester solvent, combining organic phases, drying, filtering and concentrating the organic phase to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 a;
the molar ratio of the compound IM-3a, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1-2: 1-2: 2-4; the mass-volume ratio of the compound IM-3a to the halocarbon solvent is 1: 9-20 g/ml;
e. d, stirring the compound IM-4a obtained in the step d, piperidine and a nitrogen-containing solvent at 25-30 ℃ for reaction for 4-6 h, adding water for dilution, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM-5 a;
the mass-to-volume ratio of the compound IM-4a to piperidine is 1: 1-4 g/ml; the mass-volume ratio of the compound IM-4a to the nitrogen-containing solvent is 1: 5-20 g/ml;
f. e, stirring and reacting the compound IM-5a, triethylamine, the compound IM-6a and a halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 1 to 10 hours, and removing the solvent to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 a;
the mol ratio of the compound IM-5a to the triethylamine to the compound IM-6a is 1: 1-5: 1-2; the mass-volume ratio of the compound IM-5a to the halocarbon solvent is 1: 50-100 g/ml;
g. dissolving the compound TM-1a obtained in the step f in a halohydrocarbon solvent at the temperature of 0-5 ℃, adding trifluoroacetic acid, stirring and reacting at the temperature of 25-30 ℃ for 1-12 h, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound shown in a formula I;
the mass-volume ratio of the compound TM-1a to the halocarbon solvent is 1: 50-100 g/ml; the mass-volume ratio of the compound TM-1a to trifluoroacetic acid is 1: 10-50 g/ml.
5. The method of claim 4, wherein:
a. stirring a mixed solvent of the compound IM-1a, lithium hydroxide and an ether solvent/water at 25 ℃ for 2 hours, removing the organic solvent, adding water for dilution, adjusting the pH to be 5, precipitating a solid, and filtering to obtain a solid; washing and drying the solid to obtain N-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid;
the molar ratio of the compound IM-1a to the lithium hydroxide is 1: 4.5-5; the mass-volume ratio of the compound IM-1a to the mixed solvent is 1: 10-12 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 2: 1;
b. b, dissolving the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-formic acid obtained in the step a in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, and stirring and reacting at 25 ℃ for 2 hours to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 a;
the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the halohydrocarbon solvent is 1: 10 g/ml; the mass volume ratio of the N-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-carboxylic acid to the trifluoroacetic acid is 1: 4-5 g/ml;
c. b, stirring the compound IM-2a obtained in the step b, sodium carbonate, fluorenyloxycarbonyl chloride and a mixed solvent of an ether solvent and water at 25 ℃ for 12-16 h, adding water for dilution, adjusting the pH value to be 1, extracting by using an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a compound IM-3 a;
the molar ratio of the compound IM-2a to the sodium carbonate to the fluorenyloxycarbonyl chloride is 1: 3: 1; the mass-volume ratio of the compound IM-2a to the mixed solvent is 1: 20 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 5: 3;
d. c, stirring the compound IM-3a obtained in the step c, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine and a halohydrocarbon solvent at 25 ℃ for 12-16H, adding water for dilution, extracting an ester solvent, combining organic phases, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 a;
the molar ratio of the compound IM-3a, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 1.1: 1.2: 3; the mass-volume ratio of the compound IM-3a to the halocarbon solvent is 1: 9-10 g/ml;
e. d, stirring the compound IM-4a obtained in the step d, piperidine and a nitrogen-containing solvent at 25 ℃ for reaction for 4-6 h, adding water for dilution, extracting by using an ester solvent, combining organic phases, and drying, filtering and concentrating the organic phases to obtain a compound IM-5 a;
the mass-to-volume ratio of the compound IM-4a to piperidine is 1: 2 g/ml; the mass-volume ratio of the compound IM-4a to the nitrogen-containing solvent is 1: 10 g/ml;
f. e, stirring the compound IM-5a, triethylamine, the compound IM-6a and a halohydrocarbon solvent in the step e at 25 ℃ for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 a;
the mol ratio of the compound IM-5a to the triethylamine to the compound IM-6a is 1: 1.4: 1 to 1.2; the mass-volume ratio of the compound IM-5a to the halocarbon solvent is 1: 80 g/ml;
g. dissolving the compound TM-1a obtained in the step f in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, stirring at 25 ℃ for reacting for 2 hours, and removing the solvent to obtain a crude product; purifying the crude product by preparative high performance liquid chromatography to obtain a compound shown in a formula I;
the mass-volume ratio of the compound TM-1a to the halocarbon solvent is 1: 60-65 g/ml; the mass-volume ratio of the compound TM-1a to trifluoroacetic acid is 1: 25 g/ml.
6. The production method according to claim 4 or 5, characterized in that:
R1selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butylamido, isobutylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isoalanyl, n-butylamido, isobutylamino, tert-butylamido, pentylamino, hexylamino, Czocyclo, butylamino, pentanoylamino, hexanoylamino, N-butylamido, tert3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted phenyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5selected from fluorine, chlorine, bromine or iodine.
7. The method of claim 6, wherein: in step f, the compound IM-6a is:
8. the production method according to claim 4 or 5, characterized in that: in the steps a to g, the ether solvent is selected from one or more than two of tetrahydrofuran, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvent is selected from one or more than two of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvent is selected from one or more of ethyl acetate and ethyl formate; the nitrogen-containing solvent is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide, acetonitrile and pyridine.
9. A preparation method of pyrrole amide compounds shown in formula I is characterized in that:
when R is4When the hydroxyl is adopted, the synthetic route is as follows:
wherein,
R1selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5、R6are each halogen;
the method comprises the following steps:
i. stirring a mixed solvent of a compound IM-5b, a compound IM-6b, sodium bicarbonate and an ether solvent/water at 25-30 ℃ for reaction for 1-10 h, removing the solvent, adding water, extracting with an ester solvent, combining organic phases, washing with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-7 b;
the molar ratio of the compound IM-5b to the compound IM-6b to the sodium bicarbonate is 1: 1-2: 1-5; the mass-volume ratio of the compound IM-5b to the mixed solvent of the ether solvent/water is 1: 20-100 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-5: 1;
ii. I, stirring and reacting a compound IM-7b obtained in the step i, a compound IM-8b, sodium carbonate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and a mixed solvent of an ether solvent/water at 50-100 ℃ under the protection of inert gas for 1-10 h, removing the solvent, adding water and a halohydrocarbon solvent for extraction, combining organic phases, washing the organic phases with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 b;
the mol ratio of the compound IM-7b to the compound IM-8b to the sodium carbonate is 1: 1-2: 1-5; the mass ratio of the compound IM-7b to [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is 1: 0.05 to 0.2; the mass-volume ratio of the compound IM-7b to the mixed solvent of the ether solvent/water is 1: 20-100 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-10: 1;
iii, dissolving the compound TM-1b in the step II in an alcohol solvent, adding hydrochloric acid, stirring and reacting at 25-30 ℃ for 1-10 h, and then separating and purifying to obtain the compound shown in the formula I;
the mass-volume ratio of the compound TM-1b to the alcohol solvent is 1: 18-100 g/ml; the mass-volume ratio of the compound TM-1b to hydrochloric acid is 1: 3-20 g/ml; the concentration range of the hydrochloric acid is 0.5N-2N.
10. The method of claim 9, wherein:
i. stirring a compound IM-5b, a compound IM-6b, sodium bicarbonate and a mixed solvent of an ether solvent/water at 25 ℃ for 2 hours, removing the solvent, adding water, extracting with an ester solvent, combining organic phases, washing with saturated saline water, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-7 b;
the molar ratio of the compound IM-5b to the compound IM-6b to the sodium bicarbonate is 1: 1: 2-3; the mass-volume ratio of the compound IM-5b to the mixed solvent of the ether solvent/water is 1: 20-40 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-2: 1;
ii. I, stirring and reacting a mixed solvent of the compound IM-7b, the compound IM-8b, sodium carbonate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and an ether solvent/water at 80 ℃ for 2 hours under the protection of inert gas, removing the solvent, adding water, extracting a halohydrocarbon solvent, combining organic phases, washing with saturated saline solution, drying, filtering and concentrating the organic phases to obtain a crude product; purifying the crude product by column chromatography to obtain a compound TM-1 b;
the mol ratio of the compound IM-7b to the compound IM-8b to the sodium carbonate is 1: 1: 2-3; the mass ratio of the compound IM-7b to [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is 1: 0.08 to 0.12; the mass-volume ratio of the compound IM-7b to the mixed solvent of the ether solvent/water is 1: 20-40 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 4-6: 1;
iii, dissolving the compound TM-1b in the step II in an alcohol solvent, adding hydrochloric acid, stirring at 25 ℃ for reaction for 2 hours, and then separating and purifying to obtain a compound shown in the formula I;
the mass-volume ratio of the compound TM-1b to the alcohol solvent is 1: 18-40 g/ml; the mass-volume ratio of the compound TM-1b to hydrochloric acid is 1: 3-10 g/ml; the concentration range of the hydrochloric acid is 0.5N-2N.
11. The production method according to claim 9 or 10, characterized in that:
R1selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butylamido, isobutylamino, tert-butyrylamino, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isoalanyl, n-butylamido, isobutylamino, tert-butylamido, pentylamino, hexylamino, Czocyclo, butylamino, pentanoylamino, hexanoylamino, N-butylamido, tert3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted phenyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5、R6selected from fluorine, chlorine, bromine or iodine.
12. The method of claim 11, wherein:
in step i, the compound IM-6b is:
in step ii, said compound IM-8b is:
13. the production method according to claim 9 or 10, characterized in that: in the steps i to iii, the ether solvent is selected from one or more of tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether; the halocarbon solvent is selected from one or more than two of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ester solvent is selected from one or more of ethyl acetate and ethyl formate; the alcohol solvent is selected from one or more of methanol, ethanol, n-propanol and isopropanol.
14. A preparation method of pyrrole amide compounds shown in formula I is characterized in that:
when R is4When the phenyl is substituted by amino, the synthetic route is as follows:
wherein, Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; HATU stands for 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; DIEA represents N, N-diisopropylethylamine; LiOH represents lithium hydroxide;
R1selected from hydrogen, hydroxy, cyano, halogen, carboxy, C1～C6Alkyl of (C)1～C6Alkoxy group of (C)2～C6Amide group of (1), C1～C6Aminoalkyl of (C)2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6The heterocycloalkenyl, phenoxy, phenyl or substituted phenyl of (a);
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, halogen, carboxyl and C1～C6Alkyl of (C)1～C6Alkoxy group of (C)1～C6Aminoalkyl of (C)2～C6Amide group of (1), C2～C6Aminoacyl, C3～C6Heterocyclic group of (A), C3～C6Heterocycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, or substituted piperazinyl of (a);
R5selected from halogens;
the method comprises the following steps:
dissolving a compound IM-1c in a halohydrocarbon solvent at 0-5 ℃, adding trifluoroacetic acid, and stirring and reacting at 20-30 ℃ for 2-12 h to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 c;
the mass-to-volume ratio of the compound IM-1c to the halocarbon solvent is 1: 5-20 g/ml; the mass-to-volume ratio of the compound IM-1c to trifluoroacetic acid is 1: 2-10 g/ml;
secondly, stirring and reacting the compound IM-2c, the compound IM-3c, triethylamine and a halohydrocarbon solvent obtained in the step I at the temperature of between 25 and 30 ℃ for 1 to 10 hours, and concentrating to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 c;
the mol ratio of the compound IM-2c to the compound IM-3c to triethylamine is 1: 1-2: 1-5; the mass-volume ratio of the compound IM-2c to the halocarbon solvent is 1: 50-100 g/ml;
thirdly, stirring the compound IM-4c obtained in the step II, lithium hydroxide and mixed solvent of ether solvent/water at the temperature of between 20 and 30 ℃ for reaction for 2 to 16 hours to obtain reaction liquid; separating and purifying to obtain a compound IM-5 c;
the molar ratio of the compound IM-4c to the lithium hydroxide is 1: 1-10; the mass-volume ratio of the compound IM-4c to the mixed solvent is 1: 55-60 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 1-5: 1;
fourthly, stirring and reacting the compound IM-5c, the 1, 2-diaminobenzene, the 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, the N, N-diisopropylethylamine and the halohydrocarbon solvent at the temperature of between 25 and 30 ℃ for 12 to 16 hours to obtain reaction liquid; separating and purifying to obtain a compound shown as a formula I;
the molar ratio of the compound IM-5c, 1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 0.8-2: 0.8-2: 1.5 to 4; the mass-to-volume ratio of the compound IM-5c to the halocarbon solvent is 1: 40-100 g/ml.
15. The method of claim 14, wherein:
dissolving a compound IM-1c in a halohydrocarbon solvent at 0 ℃, adding trifluoroacetic acid, and stirring and reacting at 25 ℃ for 2 hours to obtain a reaction solution; concentrating the reaction solution to obtain a yellow oily substance, namely a compound IM-2 c;
the mass-to-volume ratio of the compound IM-1c to the halocarbon solvent is 1: 20 g/ml; the mass-to-volume ratio of the compound IM-1c to trifluoroacetic acid is 1: 8 g/ml;
secondly, stirring the compound IM-2c, the compound IM-3c, triethylamine and a halohydrocarbon solvent obtained in the step I at 25 ℃ for 2 hours, and concentrating to obtain a crude product; purifying the crude product by column chromatography to obtain a compound IM-4 c;
the mol ratio of the compound IM-2c to the compound IM-3c to triethylamine is 1: 1.1-1.2: 2.5-3; the mass-volume ratio of the compound IM-2c to the halocarbon solvent is 1: 65-70 g/ml;
thirdly, stirring the compound IM-4c obtained in the second step, lithium hydroxide and mixed solvent of ether solvent/water at 25 ℃ for 2-16 h to obtain reaction liquid; separating and purifying to obtain a compound IM-5 c;
the molar ratio of the compound IM-4c to the lithium hydroxide is 1: 4.5; the mass-volume ratio of the compound IM-4c to the mixed solvent is 1: 55-60 g/ml; in the mixed solvent, the volume ratio of the ether solvent to water is 3: 1;
fourthly, stirring and reacting the compound IM-5c, the 1, 2-diaminobenzene, the 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, the N, N-diisopropylethylamine and the halohydrocarbon solvent at 25 ℃ for 12 to 16 hours to obtain reaction liquid; separating and purifying to obtain a compound shown as a formula I;
the molar ratio of the compound IM-5c, 1, 2-diaminobenzene, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1: 0.8-1.2: 0.8-1.2: 1.5-2; the mass-to-volume ratio of the compound IM-5c to the halocarbon solvent is 1: 40-45 g/ml.
16. The production method according to claim 14 or 15, characterized in that:
R1selected from the group consisting of hydrogen, hydroxy, cyano, fluoro, chloro, bromo, carboxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropylamido, n-butyramido, iso-butyramido, tert-butyramido, pentanamido, hexanamido, methionyl, ethanamido, n-alaninyl, isopropylaminoAcyl, n-butylacyl, isobutylyl, tert-butylacyl, pentylyl, hexylyl, C3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl or substituted phenyl;
R2、R3independently or simultaneously selected from hydrogen, hydroxyl, cyano, fluorine, chlorine, bromine, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, carboxamido, acetylamino, n-propionamido, isopropionamido, n-butylamido, isobutylamino, tert-butylamido, pentanamido, hexanamido, methionyl, ethanyl, n-alaninyl, isopropylamino, n-butylamido, isobutylamino, tert-butylamino, pentylamino, hexylamino, Czocyclo-butyrylamino, pentanoylamino, hexanoylamino, carbamyl, alanyl, butyryl, pentanoyl, hexanoyl3Nitrogen heterocyclic group of, C4Nitrogen heterocyclic group of, C5Nitrogen heterocyclic group of, C6Nitrogen heterocyclic group of, C3Azacycloalkenyl of4Azacycloalkenyl of5Azacycloalkenyl of6Azacycloalkenyl, phenoxy, phenyl, substituted phenyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butanepiperazinyl, pentylpiperazinyl or hexylpiperazinyl;
R5selected from fluorine, chlorine, bromine or iodine.
17. The method of manufacturing according to claim 16, wherein: in the second step, the compound IM-3c is:
18. the production method according to claim 9 or 10, characterized in that: in the first to fourth steps, the halocarbon solvent is selected from any one or more than two of dichloromethane, chloroethane, dichloroethane, trichloromethane and carbon tetrachloride; the ether solvent is one or more selected from tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, isopropyl ether and butyl ether.
19. Use of the pyrrole amide compound or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof according to any one of claims 1 to 3 in preparation of histone deacetylase inhibitor drugs.
20. Use according to claim 19, characterized in that: the histone deacetylase inhibitor medicament is a medicament for preventing and/or treating diseases caused by abnormal histone deacetylase activity.
21. Use according to claim 20, characterized in that: the disease is any one or more of a cell proliferative disease, an autoimmune disease, an inflammation, a neurodegenerative disease, or a viral disease.
22. Use according to claim 21, characterized in that: the disease is cancer.
23. A pharmaceutical composition for inhibiting histone deacetylase activity, comprising: the preparation is prepared by taking the pyrrole amide compounds or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
24. The pharmaceutical composition of claim 23, wherein: the preparation comprises an oral administration preparation, a sublingual administration preparation, a buccal administration preparation, a transdermal absorption preparation or an injection preparation.
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