CN109705071B - HDAC inhibitors and methods of making and using the same - Google Patents

HDAC inhibitors and methods of making and using the same Download PDF

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CN109705071B
CN109705071B CN201811247197.3A CN201811247197A CN109705071B CN 109705071 B CN109705071 B CN 109705071B CN 201811247197 A CN201811247197 A CN 201811247197A CN 109705071 B CN109705071 B CN 109705071B
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membered aromatic
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CN109705071A (en
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李进
吴波
张登友
尚巳耘
楚洪柱
王稚京
吕开智
梁秋香
农云宏
陈伟
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Hitgen Inc
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Abstract

The invention discloses a compound shown as a formula (I). The invention also relates to a composition comprisingPharmaceutical compositions containing a compound of formula (I) and the use of the compound in the manufacture of a medicament for the inhibition of HDAC. The compounds of the present invention or pharmaceutical compositions thereof may be used to treat cell proliferative disorders, autoimmune disorders, inflammation, neurodegenerative disorders or viral disorders.

Description

HDAC inhibitors and methods of making and using the same
Technical Field
The present invention relates to HDAC inhibitors, methods of making and uses thereof.
Background
Tumor refers to a new organism formed by clonal abnormal hyperplasia caused by the loss of normal regulation and control of local tissue cells on the gene level under the action of various tumorigenic factors. 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.
Histone acetylation plays a central role in transcriptional regulation in eukaryotic cells. Its action 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, increased histone acetylation levels are associated with increased gene transcription activity, while too low acetylation levels are associated with suppressed gene expression. 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 will lead to growth inhibition and apoptosis in many cancer cells. Therefore, HDACs have become the newest and most popular target in the current field of antineoplastic drug development.
HDAC inhibitors have the function of interfering with histone deacetylase. There are generally two broad categories: NAD + -dependent enzymes and Zn2+ -dependent enzymes. Zn2+ -dependent proteases include HDACs I (including HDACs 1,2, 3 and 8), II (including HDACs 4,5, 6, 7, 9 and 11), IV (including HDAC 11) subfamily; NAD + -dependent enzymes are mainly of the HDACs subgroup III. The mechanism of action of HDAC inhibitors is to modulate gene expression in the treatment of cancer by inhibiting HDAC, blocking the repression of gene expression due to dysfunction of HDAC recruitment, and altering chromatin structure by altering the degree of acetylation of histones. 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.
Five HDAC inhibitors are currently on the market. SAHA marketed in 2006, with a Pan-HDAC as an active target; FK-288 marketed in 2011 has the action targets of HDAC1 and HDAC 2; PXD101 marketed in 2014 has the action targets of HDAC1 and HDAC 2; the effect targets of the cidam amine marketed in 2015 are HDAC1, HDAC2, HDAC3 and HDAC 10; LBH589 marketed in 2015, the target of action is HDAC (MOLT-4 cells). The five HDAC inhibitors have certain problems in the aspects of anti-cancer activity, toxic and side effects, subtype selectivity and the like, and the action targets of the five HDAC inhibitors are free from HDAC 6.
Therefore, there is an urgent need for a novel compound having histone deacetylase inhibitory activity.
Disclosure of Invention
In order to solve the above problems, the present invention provides a compound represented by formula (I), or a crystalline form thereof, or a hydrate thereof, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0001840794250000021
wherein n is 0-10;
L1represents none or C1～C10Alkylene or C1～C10Alkenyl of (a);
y is N or CR2Wherein R is2Selected from hydrogen, halogen, hydroxy, amino, trifluoromethyl, cyano, C1～C10Alkyl or C1～C10Alkoxy group of (a);
x is O, S or NR3(ii) a Wherein R is3Selected from hydrogen, C1～C10Alkyl or C1～C10Acyl group of (4);
R1is hydrogen, C1～C10Alkyl of (C)3～C10Cycloalkane or heterocycloalkane of (a);
the ring A represents a 3-to 10-membered cycloalkane, a 3-to 10-membered heterocycloalkane, a 5-to 10-membered aryl or a 5-to 10-membered arylThe heteroaryl group of (a); wherein the A ring may be further substituted by 0 to 5R4Substituted, wherein each R4Are respectively and independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, - (CH)2)qR5、–(CH2)qOR5、–(CH2)qOCOR5、–(CH2)qNR5R6、–(CH2)qNR5COR6、–(CH2)qCOR5、–(CH2)qCOOR5、–(CH2)qCONR5R6Q is 0-10;
R5、R6are respectively selected from hydrogen and C1～C10The alkyl group, the cycloalkane having 5 to 10 ring members, the heterocycloalkane having 5 to 10 ring members, the aryl group having 5 to 10 ring members or the heteroaryl group having 5 to 10 ring members, wherein R is5、R6May be further substituted by R7Substitution;
R7selected from halogen, hydroxy, amino, C1～C10Alkyl of (C)1～C10Alkoxy group of (C)1～C10Alkylamino of (a) - (CH)2)rOR8(ii) a Wherein r is 0-10; .
R8Selected from hydrogen, C1～C10Alkyl group of (1).
Further, the compounds have a structure as shown in formula (Ia) or formula (Ib):
Figure BDA0001840794250000022
Figure BDA0001840794250000031
further, the compound of formula (Ia) has the structure shown in formula (Ia-1):
Figure BDA0001840794250000032
wherein L is1Indicates that is not, C1～C5Alkylene or
Figure BDA0001840794250000033
Wherein m is 0-3;
R1represents hydrogen, C1～C5Alkyl groups of (a);
R2represents hydrogen, halogen, trifluoromethyl, trifluoromethoxy, - (CH)2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、–(CH2)qCOR5Q is 0 to 5;
R5、R6are respectively selected from hydrogen and C1～C5The alkyl group of (A), a 5-10 membered cycloalkane, a 5-10 membered heterocycloalkane, a 5-10 membered aryl group or a 5-10 membered heteroaryl group; wherein R is5、R6May be further substituted by R7Substitution;
R7selected from halogen, hydroxy, amino, C1～C5Alkyl of (C)1～C5Alkoxy group of (C)1～C5Alkylamino group of (I)
(CH2)rOR8(ii) a Wherein r is 0 to 5; .
R8Selected from hydrogen, C1～C5Alkyl groups of (a);
ring A represents a phenyl group, a 5-membered aromatic heterocycle, a 6-membered aromatic heterocycle, or a 10-membered aromatic heterocycle.
Further, the compound of formula (Ia) has the structure shown in formula (Ia-2):
Figure BDA0001840794250000034
wherein R is1Represents hydrogen, halogen; ring A represents a phenyl group, a 5-membered aromatic heterocycle, or a 6-membered aromatic heterocycle.
Further, the compound of formula (Ia) has the structure shown in formula (Ia-3):
Figure BDA0001840794250000035
wherein n is 0,1, 2, 3; x represents hydrogen or halogen;
R1represents hydrogen, C1～C5Alkyl, 6-membered aryl or heteroaryl of (a);
R3represents hydrogen, C1～C5Alkyl groups of (a);
R2represents hydrogen, halogen, trifluoromethyl, methoxy, - (CH)2)qR5、–(CH2)qNR5R6、–(CH2)qCOR5Q is 0 to 5;
R5、R6are respectively selected from hydrogen and C1～C5The alkyl, 5-6 membered cycloalkane, 5-6 membered heterocycloalkane, 5-6 membered aromatic heterocycle, phenyl;
the ring A represents a phenyl group, a cyclohexane group, a 5-6 membered heterocyclic alkane group, a 5-6 membered aromatic heterocyclic ring or a 10 membered aromatic heterocyclic ring.
Further, the compound of formula (Ia) has the structure shown in formula (Ia-4):
Figure BDA0001840794250000041
wherein X represents O, S, N; the ring A represents a phenyl group, a 5-to 6-membered aromatic heterocycle or a 10-membered aromatic heterocycle.
Further, the formula (Ia) is one of the following compounds:
Figure BDA0001840794250000042
Figure BDA0001840794250000051
Figure BDA0001840794250000061
further, the compound of formula (Ib) has a structure as shown in formula (Ib-1):
Figure BDA0001840794250000062
wherein L is1Indicates that is not, C1～C5Alkylene or
Figure BDA0001840794250000063
Wherein m is 0-3; r1Represents hydrogen, C1～C5Alkyl groups of (a);
R2represents hydrogen, halogen, trifluoromethyl, trifluoromethoxy, - (CH)2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、–(CH2)qCOR5Q is 0 to 5;
R5、R6are respectively selected from hydrogen and C1～C5The alkyl group of (1), 5-10 membered cycloalkane, 5-10 membered heterocyclic alkane, 5-10 membered aryl or 5-10 membered heteroaryl; wherein R is5、R6May be further substituted by R7Substitution;
R7selected from halogen, hydroxy, amino, C1～C5Alkyl of (C)1～C5Alkoxy group of (C)1～C5Alkylamino of (a) - (CH)2)rOR8(ii) a Wherein r is 0 to 5;
R8selected from hydrogen, C1～C5Alkyl groups of (a);
the ring A represents a phenyl group, a 5-to 6-membered aromatic heterocycle or a 10-membered aromatic heterocycle.
Further, the compound of formula (Ib) has a structure as shown in formula (Ib-2):
Figure BDA0001840794250000071
wherein R is1Represents hydrogen, halogen; ring A represents a phenyl group, a 5-membered aromatic heterocycle, or a 6-membered aromatic heterocycle.
Further, the compound of formula (Ib) has a structure as shown in formula (Ib-3):
Figure BDA0001840794250000072
wherein n is 0,1, 2, 3; x represents hydrogen or halogen;
R1represents hydrogen, C1～C5Alkyl, 6-membered aryl or heteroaryl of (a);
R3represents hydrogen, C1～C5Alkyl groups of (a);
R2represents hydrogen, halogen, trifluoromethyl, methoxy, - (CH)2)qR5、–(CH2)qNR5R6、–(CH2)qCOR5Q is 0 to 5;
R5、R6are respectively selected from hydrogen and C1～C5The alkyl, 5-6 membered cycloalkane, 5-6 membered heterocycloalkane, 5-6 membered aromatic heterocycle, phenyl;
the ring A represents a phenyl group, a cyclohexane group, a 5-6 membered heterocyclic alkane group, a 5-6 membered aromatic heterocyclic ring or a 10 membered aromatic heterocyclic ring.
Further, the compound of formula (Ib) has a structure as shown in formula (Ib-4):
Figure BDA0001840794250000073
wherein X represents O, S, N; the ring A represents a phenyl group, a 5-to 6-membered aromatic heterocycle or a 10-membered aromatic heterocycle.
Further, the formula (ib) is one of the following compounds:
Figure BDA0001840794250000081
Figure BDA0001840794250000091
the invention also provides application of the compound, or a crystal form, a hydrate, an optical isomer, a solvate or a pharmaceutically acceptable salt thereof in preparation of HDAC inhibitor medicines.
Further, the medicament is a medicament for treating a cell proliferative disease, an autoimmune disease, inflammation, a neurodegenerative disease, or a viral disease.
Further, the cell proliferative disease is cancer.
Further, the cancer includes colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, thyroid cancer.
Further, the HDAC is HDAC 6.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound of any one of claims 1 to 12, or a crystal form, a hydrate, an optical isomer, a solvate or a pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Further, the preparation is an oral preparation, a transdermal absorption preparation or an injection preparation.
The invention also provides application of the pharmaceutical composition in preparing HDAC inhibitor medicines.
Further, the medicament is a medicament for treating a cell proliferative disease, an autoimmune disease, inflammation, a neurodegenerative disease, or a viral disease.
Further, the cell proliferative disease is cancer.
Further, the cancer includes colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, thyroid cancer.
Further, the HDAC is HDAC 6.
In some embodiments, in the compounds of formula (I), n is 0,1, 2, or 3, L1Is none, C1～C3Alkylene or
Figure BDA0001840794250000101
Y is N or CR2，R2Selected from hydrogen, halogen, hydroxy, amino, trifluoromethyl, cyano, C1～C3Alkyl or C1～C3X is O, S or NR3，R3Selected from hydrogen, C1～C3Alkyl or C1～C3Acyl group of (A), R1Is hydrogen, C1～C3Alkyl of (C)3～C6The cyclic alkane or 3-6 membered heterocyclic alkane, ring A is 3-10 membered cyclic alkane, 3-10 membered heterocyclic alkane, 5-10 membered aryl or 5-10 membered heteroaryl, wherein ring A can be further substituted with 1-3R4Substituted, wherein each R4Are respectively and independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, - (CH)2)qR5、–(CH2)qOR5、–(CH2)qOCOR5、–(CH2)qNR5R6、–(CH2)qNR5COR6、–(CH2)qCOR5、–(CH2)qCOOR5、–(CH2)qCONR5R6Q is 0,1, 2 or 3, R5、R6Are respectively selected from hydrogen and C1～C3The alkyl group, the cycloalkane having 5 to 6 members, the heterocycloalkane having 5 to 6 members, the aryl group having 5 to 6 members or the heteroaryl group having 5 to 6 members of the formula (I) in which R is5、R6May be further substituted by R7Substituted, R7Selected from halogen, hydroxy, amino, C1～C3Alkyl of (C)1～C3Alkoxy group of (C)1～C3Alkylamino of (a) - (CH)2)rOR8R is 0,1, 2 or 3, R8Selected from hydrogen, C1～C10Alkyl group of (1).
In some embodiments, in the compounds of formula (I), n is 0 and L1Is absent or
Figure BDA0001840794250000102
Y is N or CR2，R2Selected from hydrogen, halogen, trifluoromethyl, cyano, methyl, ethyl or methoxy, X is O, S or NR3，R3Selected from hydrogen, methyl, ethyl, formyl or acetyl, R1Is hydrogen, methyl or ethyl, the ring A is 5-6 membered cycloalkane, 5-6 membered heterocycloalkane, 5-6 membered aryl, 9-10 membered aryl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, wherein the ring A may be further substituted with 1-3R4Substituted, wherein each R4Are respectively independently selected from halogen, cyano, trifluoromethyl, trifluoromethoxy, - (CH)2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、–(CH2)qCOR5、–(CH2)qCOOR5、–(CH2)qCONR5R6Q is 0,1, 2 or 3, R5、R6Are respectively selected from hydrogen and C1～C3The alkyl group, the cycloalkane having 5 to 6 members, the heterocycloalkane having 5 to 6 members, the aryl group having 5 to 6 members or the heteroaryl group having 5 to 6 members of the formula (I) in which R is5、R6May be further substituted by R7Substituted, R7Selected from halogen, hydroxy, amino, C1～C3Alkyl of (C)1～C3Alkoxy group of (C)1～C3Alkylamino of (a) - (CH)2)rOR8R is 0,1, 2 or 3, R8Selected from hydrogen, C1～C10Alkyl group of (1).
In some embodiments, in the compounds of formula (I), ring A is
Figure BDA0001840794250000103
Figure BDA0001840794250000104
Figure BDA0001840794250000111
In some embodiments, in the compounds of formula (Ia-1), L1Means none or
Figure BDA0001840794250000112
R1Is hydrogen, methyl or ethyl, ring A is phenyl, 5-membered nitrogen-containing aromatic heterocycle, 6-membered nitrogen-containing aromatic heterocycle or 10-membered nitrogen-containing aromatic heterocycle, R is2Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, - (CH)2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、–(CH2)qCOR5Q is 0,1, 2 or 3, R5、R6Are respectively selected from hydrogen and C1～C3The alkyl group, the cycloalkane having 5 to 6 members, the heterocycloalkane having 5 to 6 members, the aryl group having 5 to 6 members or the heteroaryl group having 5 to 6 members of the formula (I) in which R is5、R6May be further substituted by R7Substituted, R7Selected from halogen, hydroxy, amino, C1～C3Alkyl of (C)1～C3Alkoxy group of (C)1～C3Alkylamino of (a) - (CH)2)rOR8Wherein R is 0,1, 2 or 3, R8Selected from hydrogen, C1～C3Alkyl groups of (a);
in some embodiments, in the compounds of formula (Ib-1), L1Means none or
Figure BDA0001840794250000113
R1Is hydrogen, methyl or ethyl, ring A is phenyl, 5-membered nitrogen-containing aromatic heterocycle, 6-membered nitrogen-containing aromatic heterocycle or 10-membered nitrogen-containing aromatic heterocycle, R is2Is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, - (CH)2)qR5、–(CH2)qOR5、–(CH2)qNR5R6、–(CH2)qCOR5Q is 0,1, 2 or 3, R5、R6Are respectively selected from hydrogen and C1～C3The alkyl group, the cycloalkane having 5 to 6 members, the heterocycloalkane having 5 to 6 members, the aryl group having 5 to 6 members or the heteroaryl group having 5 to 6 members of the formula (I) in which R is5、R6May be further substituted by R7Substituted, R7Selected from halogen, hydroxy, amino, C1～C3Alkyl of (C)1～C3Alkoxy group of (C)1～C3Alkylamino of (a) - (CH)2)rOR8Wherein R is 0,1, 2 or 3, R8Selected from hydrogen, C1～C3Alkyl groups of (a);
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 values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix Ca～CbAlkyl indicates any alkyl group containing "a" to "b" carbon atoms, including straight chain and branched chain alkyl groups. Thus, for example, C1～C4The alkyl group means a straight-chain alkyl group and a branched-chain alkyl group having 1 to 4 carbon atoms.
In the present invention, Ca～CbAlkoxy radical, Ca～CbAlkylamino radical, Ca～CbAcyl and the like each means a group formed by linking an alkyl group having "a" to "b" carbon atoms with a corresponding oxygen atom, amino group, acyl group or the like.
In the present invention, halogen means fluorine atom, chlorine atom, bromine atom, and iodine atom.
The term "cycloalkyl" or "cycloalkane" as used herein refers to a saturated or non-aromatic unsaturated ring formed of all carbon atoms.
The term "heterocycle", heterocycloalkane "and" heterocycloalkyl "as used herein refer to a saturated or non-aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom.
The term "aryl" and "aromatic ring" as used herein refer to an aromatic unsaturated ring formed of all carbon atoms.
The term "heteroaryl" as used herein refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom.
"alkylene" in the present invention refers to a hydrocarbon group bonded to two atoms, respectively;
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 term "salt" refers 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 salts (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 that can be incorporated into compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e., 2H,3H, 13C, 14C, 15N, 17O, 18O, 35S. 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.
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.
The compound of the invention has the activities of inducing differentiation, immunoregulation, blocking cell cycle and promoting apoptosis and good HDAC6 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 compounds of the present invention have HDAC inhibitory activity and are useful for the treatment of diseases associated with abnormal HDAC activity.
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.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift () at 10-6The units of (ppm) are given. NMR was measured using (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
LC-MS was measured using Shimadzu LC-MS 2020 (ESI).
HPLC was performed using Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
Reversed phase preparative chromatography Gilson GX-281 reversed phase preparative chromatography was used.
The thin layer chromatography silica gel plate is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials for the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Enduragi chemistry, Chengdulong chemistry, Shaoshi chemistry technology, and Bailingwei technology.
In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is room temperature, unless otherwise specified.
In the examples, M is mole per liter, unless otherwise specified.
The room temperature is an optimum reaction temperature, and is usually 20 ℃ to 30 ℃.
The overnight is typically 12. + -. 1 hours.
EXAMPLE 1 Synthesis of Compounds of the invention
General synthetic scheme 1
Figure BDA0001840794250000141
(1.1) Synthesis of intermediate 3 a:
Figure BDA0001840794250000142
4-bromo-2-fluorobenzaldehyde (100g,493mmol) and methyl 2-hydroxyacetate (102g,1.13mol) were dissolved in DMF (1.0L), sodium hydrogen (59.2g,1.48mol, 60%) was added at 0 deg.C, after stirring for 1 hour, ice water (2.0L) was added, ethyl acetate (1.0L) was extracted 4 times, and the organic layers were combined and washed 1 time with saturated sodium chloride solution. The solvent was distilled off under reduced pressure, and purification was performed by column chromatography to give intermediate 3a (22.0g,86.3mmol, 18% yield).
(1.2) Synthesis of intermediate 3 b:
starting from 5-bromo-2-fluorobenzaldehyde and methyl 2-hydroxyacetate, intermediate 3b was obtained according to the synthesis method for intermediate 3a (yield 42%).
(1.3) Synthesis of intermediate 3 c:
starting from 4-bromo-2-fluorobenzaldehyde and methyl 2-mercaptoacetate, intermediate 3c was obtained according to the synthesis of intermediate 3a (94% yield).
(1.4) Synthesis of intermediate 3 d:
starting from 5-bromo-2-fluorobenzaldehyde and methyl 2-mercaptoacetate, intermediate 3d was obtained according to the synthesis of intermediate 3a (87% yield).
(2.1) Synthesis of intermediate 4 a:
Figure BDA0001840794250000143
intermediate 3a (38.20g,151mmol) was dissolved in toluene (300mL) and benzylmercaptan (24.50g,197.00 mmol) was added
mmol), DIPEA (39.50g,306.00mmol,53.2mL), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (8.90g,15.40mmol) and tris (dibenzylideneacetone) dipalladium (6.89g,7.53mmol), and reacted at reflux overnight. After the reaction, water (500mL) was added, and the mixture was extracted 2 times with ethyl acetate (300mL), and the organic layers were combined and the solvent was evaporated under reduced pressure. Purification by column chromatography gave intermediate 4a (27.00g,86.4mmol, 57% yield).
(2.2) Synthesis of intermediate 4 b:
the intermediate 4b was obtained according to the synthesis method of the intermediate 4a using the intermediate 3b as a starting material (yield 91%).
(2.3) Synthesis of intermediate 4 c:
intermediate 4c was obtained according to the method for synthesizing intermediate 4a using intermediate 3c as a starting material (yield 89%).
(2.4) Synthesis of intermediate 4 d:
intermediate 4d was obtained according to the synthesis method of intermediate 4a starting from intermediate 3d (yield 76%).
(3.1) Synthesis of intermediate 6a 1:
Figure BDA0001840794250000151
intermediate 4a (600mg,2.01mmol) was dissolved in acetic acid (15.0mL) and water (5.00mL) and N-chlorosuccinimide (1.07g,8.00mmol) was added portionwise. After stirring the reaction for 2 hours, water (20.0mL) was added. Ethyl acetate (30.0mL) was extracted 2 times, and the organic layers were combined and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride (10.0 mL). Pyridine (470mg,6.00mmol) was added thereto, and the reaction was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and purification was performed by column chromatography to give intermediate 6a1(410mg,1.25mmol, yield 62%).
(3.2) synthesizing an intermediate 6a 2-6 a 60:
according to the synthesis method of the intermediate 6a1, the intermediate 6a 2-6 a60 is obtained.
Figure BDA0001840794250000152
Figure BDA0001840794250000161
Figure BDA0001840794250000171
Figure BDA0001840794250000181
Figure BDA0001840794250000191
Figure BDA0001840794250000201
Figure BDA0001840794250000211
1. Synthesis of Compound 1
Figure BDA0001840794250000212
Intermediate 6a1(3.70g,11.20mmol) was dissolved in dichloromethane (15.0mL) and methanol (15.0mL), and after adding aqueous hydroxylamine (22.2mL,336.00mmol, 50%) and sodium hydroxide (1.34g,33.5mmol), the reaction was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and purified by preparative HPLC to give the final product (3.20g,9.15mmol, 82% yield).1H NMR(400MHz,DMSO-d6)10.94(brs,2H),9.46(s,1H),8.00–7.96(m,1H),7.93(d,J＝8.4Hz,1H),7.71(dd,J＝8.4,1.6Hz,1H),7.58–7.53(m,1H),7.26–7.19(m,2H),7.15–7.09(m,2H),7.05–6.99(m,1H)；MS(ESI)m/z 333(M+1)+。
2. Synthesis of Compounds 2 to 60
The intermediates 6a 2-6 a60 are used as raw materials, and the following examples 2-60 are obtained according to the synthesis method of the compound 1.
Figure BDA0001840794250000221
Figure BDA0001840794250000231
Figure BDA0001840794250000241
Figure BDA0001840794250000251
Figure BDA0001840794250000261
Figure BDA0001840794250000271
Figure BDA0001840794250000281
3. Synthesis of Compound 61
(3.1) Synthesis of intermediate 61a
Figure BDA0001840794250000282
Intermediate 6a1(500mg,1.51mmol) was dissolved in methanol (4.00mL) and water (4.00mL), and after adding sodium hydroxide (181mg,4.53mmol), the reaction was stirred at room temperature for 3 hours. The aqueous layer was washed with ethyl acetate 2 times, adjusted to pH 2 with 1N hydrochloric acid, and extracted with ethyl acetate 2 times. Several layers were combined and the solvent was distilled off under reduced pressure to give crude intermediate 61a (500 mg).
(3.2) Synthesis of intermediate 61b
Figure BDA0001840794250000291
Intermediate 61a (500mg,1.58mmol) was dissolved in chloroform (10.0mL), oxalyl chloride (401mg,3.16mmol) was added at 0 deg.C, and the reaction was stirred at room temperature for 3.5 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in tetrahydrofuran (4.92mL) and acetonitrile (5.0 mL). Trimethylsilylated diazomethane cyclohexane solution (1.60mL,3.20mmol,2.0M) was added at 0 deg.C and the reaction stirred for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in dioxane (5.37mL) and water (5.37mL), followed by addition of silver carbonate (158mg, 948. mu. mol) and stirring at 60 ℃ for 2 hours. After the reaction, the mixture was cooled, extracted with ethyl acetate 2 times, the organic layers were combined, washed with a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (10.0mL), and trimethylsilylated diazomethane cyclohexane solution (2.60mL,5.21mmol,2.0M) was added, stirred for 30 minutes and quenched with a few drops of acetic acid. The diluted solution was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and purification by column chromatography gave intermediate 61b (160mg, 463. mu. mol, yield 29%).
(3.3) Synthesis of Compound 61
Figure BDA0001840794250000293
Intermediate 61b (160mg, 463. mu. mol) was dissolved in methylene chloride (3.00mL) and methanol (3.00mL), and an aqueous hydroxylamine solution (306mg,9.27mmol) and sodium hydroxide (55.6mg,1.39mmol) were added thereto and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and purified by MPLC to give the final product (30.0mg, 83.2. mu. mol, 18% yield).1H NMR(400MHz,DMSO–D6-d6)10.69(brs,2H),9.02(s,1H),7.86(s,1H),7.72(d,J＝8.4Hz,1H),7.60(dd,J＝8.4,1.6Hz,1H),7.22-7.20(m,2H),7.09-7.07(m,2H),6.98(t,J＝7.2Hz,1H),6.82(s,1H),3.61(s,2H)；MS(ESI)m/z 347(M+1)+。
4. Synthesis of Compounds 62 and 63
(4.1) Synthesis of intermediate 62a
Figure BDA0001840794250000292
Intermediate 6a1(2.90g,8.75mmol) was dissolved in dry tetrahydrofuran (25.0mL) and lithium aluminum hydride (365mg,9.63mmol) was added portionwise at 0 ℃. After stirring the reaction for 1 hour, sodium sulfate decahydrate (3.00g) was added. The solvent was distilled off under reduced pressure to give crude intermediate 62a (1.90 g).
(4.2) Synthesis of intermediate 62b
Figure BDA0001840794250000301
Intermediate 62a (1.90g,6.26mmol) was dissolved in dichloromethane (30.0mL), dess-martin oxidant (3.72g,8.77mmol) was added and the reaction stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, followed by column chromatography purification to give intermediate 62b (1.20g,3.98mmol, yield 64%).
(4.3) Synthesis of intermediate 46c
Figure BDA0001840794250000302
Sodium hydride (143mg,5.97mmol) was dissolved in tetrahydrofuran (20.0mL), and methyl 2- (dimethoxyphosphoryl) acetate (1.34g,5.97mmol) was added thereto at 0 ℃ and the reaction was stirred for 1 hour. A solution of intermediate 62b (1.20g,3.98mmol) in tetrahydrofuran (20.0mL) was then added slowly and the reaction stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, followed by column chromatography purification to give intermediate 62c (1.20g,3.10mmol, yield 78%).
(4.4) Synthesis of Compound 62
Figure BDA0001840794250000303
Intermediate 62c (600mg,1.62mmol) was dissolved in dichloromethane (10.0mL) and methanol (10.0mL) and aqueous hydroxylamine (1.61g,48.6 mm) was addedol) and sodium hydroxide (194mg,4.86mmol) and stirred at room temperature for 2 hours. The pH was adjusted to acidity with 1N hydrochloric acid, and the solvent was distilled off under reduced pressure and purified by column chromatography to give the final product (490mg,1.34mmol, yield 83%).1H NMR(400MHz,DMSO-d6)10.99(s,1H),10.29(s,1H),9.25(s,1H),7.93(s,1H),7.83(d,J＝8.4Hz,1H),7.65(dd,J＝8.4,1.6Hz,1H),7.47(d,J＝15.6Hz,1H),7.31(s,1H),7.23(dd,J＝8.4,7.2Hz,2H),7.14–7.09(m,2H),7.05–6.99(m,1H),6.61(d,J＝15.6Hz,1H)；MS(ESI)m/z 359(M+1)+。
(4.5) Synthesis of Compound 63
Figure BDA0001840794250000304
The compound of example 62 (173mg, 483. mu. mol) was dissolved in methanol (10.0mL), palladium on carbon (49.8mg, 410. mu. mol) was added, and the reaction was stirred at room temperature under hydrogen for 2 hours. The solvent was distilled off under reduced pressure, followed by column chromatography to give the final product (120mg, 333. mu. mol, yield 69%).1H NMR(400MHz,DMSO-d6)10.49(s,1H),10.18(s,1H),8.78(s,1H),7.90–7.84(m,1H),7.70(d,J＝8.4Hz,1H),7.60(dd,J＝8.4,1.6Hz,1H),7.23–7.19(m,2H),7.13–7.07(m,2H),7.02–6.98(m,1H),6.71(d,J＝0.8Hz,1H),3.04(t,J＝7.2Hz,2H),2.41(t,J＝7.2Hz,2H)；MS(ESI)m/z 361(M+1)+。
EXAMPLE 2 Synthesis of Compounds of the invention
General synthetic scheme 2:
Figure BDA0001840794250000311
(1.1) Synthesis of intermediate 9a
Figure BDA0001840794250000312
5-Bromobenzo [ d ] thiazole (2.57g,12.0mmol) was dissolved in dry tetrahydrofuran (75.0mL), and lithium hexamethyldisilazide (17.0mL) was added dropwise at-78 ℃ and the reaction was continued with stirring at-78 ℃ for 30 minutes. Ethyl cyanoformate (1.80g,18.2mmol) was added dropwise and the reaction was stirred at-78 ℃ for 30 minutes. After completion of the reaction, saturated ammonium chloride solution (50.0mL) was added, quenched and warmed to room temperature. Ethyl acetate (30mL) was extracted 3 times, the organic layers were combined, the solvent was distilled off under reduced pressure, and purification was performed by column chromatography to give intermediate 9a (660mg,2.31mmol, yield 19%).
(1.2) Synthesis of intermediate 9b
Starting from 6-bromobenzo [ d ] thiazole and ethyl cyanoformate, intermediate 9a was synthesized to give intermediate 9b (28% yield).
(1.3) Synthesis of intermediate 9c
Starting from 5-bromobenzo [ d ] oxazole and ethyl cyanoformate, intermediate 9a was synthesized to give intermediate 9c (25% yield).
(2.1) Synthesis of intermediate 10a
Figure BDA0001840794250000321
Intermediate 9a (660mg,2.31mmol), benzylthiol (3434mg,2.77mmol), DIPEA (894mg,6.92mmol,1.21mL), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (267mg, 461. mu. mol) and tris (dibenzylideneacetone) dipalladium (211mg, 231. mu. mol) were dissolved in toluene (10.0mL) and reacted under reflux under nitrogen for 5 hours. After cooling to room temperature, ethyl acetate (250mL) and water (250mL) were added and the insoluble material was removed by filtration. Ethyl acetate (250mL) was added and the mixture was washed successively with water, 0.2N hydrochloric acid, a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and then, purification was performed by column chromatography to give intermediate 10a (530mg,1.61mmol, yield 70%).
(2.2) Synthesis of intermediate 10b
Intermediate 10b was obtained according to the synthesis method of intermediate 10a using intermediate 9b as a starting material (yield 82%).
(2.3) Synthesis of intermediate 10c
Intermediate 10c was obtained according to the method for synthesizing intermediate 10a using intermediate 9c as a starting material (yield 71%).
(2.4) Synthesis of intermediate 11a1
Figure BDA0001840794250000323
Intermediate 10a (530mg,1.61mmol) was dissolved in acetic acid (9.0mL) and water (3.0mL), N-chlorosuccinimide (859mg,6.44mmol) was added at 0 ℃ and the reaction was stirred at 0 ℃ for 2 hours. After the solvent was distilled off under reduced pressure, ethyl acetate and water were added to separate an organic layer, which was then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (10.0mL), and aniline (164mg,1.76mmol) and pyridine (11.9g,150mmol,12.1mL) were added and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, dichloromethane and water were added to separate an organic layer, anhydrous magnesium sulfate was added to dry, and the solvent was distilled off under reduced pressure and purified by column chromatography to obtain intermediate 11a (480mg,1.38mmol, yield 86%).
(2.5) Synthesis of intermediates 11a 2-11 a7
The intermediates 11a 2-11 a7 are obtained by using the following raw materials in the following table according to the synthesis method of the intermediate 11a 1.
Figure BDA0001840794250000322
Figure BDA0001840794250000331
1. Synthesis of Compound 64
Figure BDA0001840794250000332
Intermediate 11a (480mg,1.32mmol) was dissolved in methylene chloride (5.00mL) and methanol (5.00mL), and an aqueous hydroxylamine solution (875mg,26.5mmol) and sodium hydroxide (159mg,3.97mmol) were added to stir the reaction at room temperature for 3 hours. The solvent was evaporated under reduced pressure and purified by MPLC to give the final product (364mg,1.04mmol, 79% yield).1H NMR(400MHz,DMSO–d6)12.08(s,1H),10.46(s,1H),9.61(s,1H),8.42(d,J＝8.4Hz,1H),8.34(d,J＝2.0Hz,1H),7.90(dd,J＝8.4,2.0Hz,1H),7.30–7.19(m,2H),7.18–7.10(m,2H),7.06-7.01(m,1H)；MS(ESI)m/z 350(M+1)+。
2. Synthesis of Compounds 65 to 70
Taking the intermediates 11a 2-11 a7 as raw materials, and obtaining the compounds 65-70 in the following table according to the synthesis method of the compound 64.
Figure BDA0001840794250000333
Figure BDA0001840794250000341
Example 3 preparation of a Compound of the invention
General synthetic scheme 3:
Figure BDA0001840794250000342
(1.1) Synthesis of intermediate 14a
Starting from methyl 5-bromo-1H-indole-2-carboxylate, the procedure for the synthesis of intermediate 4a gave intermediate 14a (60% yield).
(1.2) Synthesis of intermediate 14b
Starting from methyl 6-bromo-1H-indole-2-carboxylate, the procedure for the synthesis of intermediate 4a gave intermediate 14b (72% yield).
(1.3) Synthesis of intermediate 14c
Starting from ethyl 5-bromo-1-methyl-1H-indole-2-carboxylate, the procedure for the synthesis of intermediate 4a gave intermediate 14c (71% yield).
(1.4) Synthesis of intermediates 15a 2-15 a24
The intermediates 15a 1-15 a24 are obtained from the raw materials in the following table according to the synthesis method of the intermediate 6a 1.
Figure BDA0001840794250000351
Figure BDA0001840794250000361
Figure BDA0001840794250000371
1. Synthesis of Compound 71
Figure BDA0001840794250000381
Intermediate 15a1(480mg,1.28mmol) was dissolved in ethanol (10.0mL), 10% palladium on carbon (330mg,2.74mmol) and ammonium formate (806mg,12.80mmol) were added, and the reaction was stirred at reflux for 2 hours. After completion of the reaction, the solvent was filtered and evaporated under reduced pressure, and the residue was dissolved in methylene chloride (3.0mL) and methanol (3.0mL), and sodium hydroxide (150mg,3.84mmol) and an aqueous hydroxylamine solution (1.32g,40.0mmol) were added and stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and purified by MPLC to obtain a final product (123mg, 351. mu. mol, yield 29%).1H NMR(400MHz,DMSO-d6)12.17(s,1H),10.18(s,1H),9.25(s,1H),8.09(s,1H),7.59–7.47(m,2H),7.17(t,J＝7.6Hz,2H),7.10–7.04(m,3H),6.95(t,J＝7.2Hz,1H)；MS(ESI)m/z 332(M+1)+。
2. Synthesis of Compounds 72 to 94
Taking the intermediates 15a 2-15 a24 as raw materials, and obtaining the compounds 72-94 in the following table according to the synthesis method of the compound 71.
Figure BDA0001840794250000382
Figure BDA0001840794250000391
Figure BDA0001840794250000401
Figure BDA0001840794250000411
3. Synthesis of Compound 95
Figure BDA0001840794250000412
Intermediate 15a1(210mg, 554. mu. mol) was dissolved in dichloromethane (3.00mL) and methanol (3.00mL), and sodium hydroxide (66.5mg,1.66mmol) and aqueous hydroxylamine (366mg,11.1mmol) were added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and purified by preparative HPLC to give the final product (62.0mg, 166.3. mu. mol, yield 30%).1H NMR(400MHz,DMSO–d6)12.43(s,1H),10.99(s,1H),10.19(s,1H),9.41(s,1H),7.96(s,1H),7.62(d,J＝8.8Hz,1H),7.54(d,J＝8.8Hz,1H),7.19(t,J＝7.6Hz,2H),7.08(d,J＝8.0Hz,2H),6.98(t,J＝7.6s Hz,1H)；MS(ESI)m/z 366(M+1)+
4. Synthesis of Compounds 96 to 97
Taking the intermediates 15a8 and 15a18 as raw materials, and obtaining compounds 96-97 in the following table according to the synthesis method of the compound 79.
Figure BDA0001840794250000421
Example 4 Synthesis of Compounds of the invention
General synthetic scheme 4
Figure BDA0001840794250000422
(1.1) Synthesis of intermediate 18a
Figure BDA0001840794250000423
Ethyl 1H-indole-2-carboxylate (1.89g,9.99mmol) was dissolved in acetonitrile (200mL), and 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt (4.24g,12.0mmol) was added thereto, followed by stirring at room temperature for 24 hours. The solvent was distilled off under reduced pressure, followed by column chromatography to give intermediate 18a (470mg,2.27mmol, yield 22.71%).
(1.2) Synthesis of intermediate 19a
Figure BDA0001840794250000431
Intermediate 18a (470mg,2.27mmol) was dissolved in tetrahydrofuran (10.0mL), and trifluoroacetic acid (259mg,2.27mmol, 320. mu.L) and N-bromosuccinimide were added to stir the reaction at room temperature for 16 hours. The solvent was distilled off under reduced pressure, followed by column chromatography purification to give intermediate 19a (640mg,2.24mmol, yield 99%).
(1.3) Synthesis of intermediate 20a
Intermediate 20a was obtained according to the method for synthesizing intermediate 4a starting from intermediate 19a (yield 82%).
(1.4) Synthesis of intermediates 21a1 and 21a2
The starting materials in the table below, following the synthesis of intermediate 6a1, gave intermediates 21a1 and 21a 2.
Figure BDA0001840794250000432
1. Synthesis of Compounds 82 and 83
Starting from intermediates 21a1 and 21a2, the synthesis of compound 79 gave compounds 82 and 83 in the table below.
Figure BDA0001840794250000433
2. Synthesis of Compound 100
(1) Synthesis of intermediate 100a
Figure BDA0001840794250000434
Methyl 2,2, 2-trichloroacetimidate (6.60g,37.4mmol) was added to acetic acid (50.0mL), and a solution of 4-bromobenzene-1, 2-diamine (7.00g,37.4mmol) in acetic acid (50.0mL) was slowly added dropwise at 0 deg.C, followed by stirring at room temperature overnight. After the reaction, water was added, extraction was performed with ethyl acetate 2 times, the organic layers were combined, washed with water and saturated sodium chloride solution, respectively, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol (100mL) and then the reaction was stirred at 80 ℃ for 5 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to dissolve the solvent, followed by washing with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in this order, and drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by column chromatography purification to give intermediate 100a (3.00g,11.8mmol, yield 26%).
(2) Synthesis of intermediate 100b
Figure BDA0001840794250000441
The intermediate 100a was used as a starting material, and the synthesis method of the intermediate 4a was followed to obtain the intermediate 100b (yield 76%).
(3) Synthesis of intermediate 100c
Figure BDA0001840794250000442
The synthesis of intermediate 6a1 was performed according to the procedure for the synthesis of intermediate 6a1, starting from intermediate 100b, to give intermediate 100c (62% yield).
(4) Synthesis of Compound 100
Figure BDA0001840794250000443
The synthesis of compound 79 was performed using intermediate 100c as the starting material to give compound 84 (43% yield).1H NMR(400MHz,DMSO-d6)13.75(s,1H),11.91(s,1H),10.32(s,1H),9.42(s,1H),8.10–7.62(m,3H),7.25–6.95(m,5H)；MS(ESI)m/z 333(M+1)+。
The following test examples specifically illustrate the advantageous effects of the present invention:
test example 1 HDAC1 and HDAC6 enzymatic detection method
The HDAC inhibitory activity of the compounds of the present invention was measured using a homogeneous time-resolved fluorescence (HTRF) method.
Enzyme buffer (50mM Tris-HCl pH 8.0,137mM NaCl,2.7mM KCl,1mM MgCl)20.01% Tween20) to make up solutions of the compounds at different concentrations. A detection mixture of Streptavidin XL-665(Cisbio Bioassays #610SAXLA) and anti-H3K9me0-Eu (K) (Cisbio Bioassays #61KB0KAE) was formulated using detection buffer (Cisbio Bioassays #62 SDBRDD).
mu.L of the compound solution was added to the reaction plate, and 2. mu.L of the HDAC solution (terminal HDAC 1: 30 ng/plate; HDAC 6: 70 ng/plate) was added and incubated at room temperature for 10 minutes. mu.L of Histone H3(1-21) lysine 9 acylated biotinylated peptide (Anaspec # AS-64361) was added and incubated at 37 ℃ for 60 minutes after application. 10 μ L of the assay mixture was added, incubated at room temperature for 1 hour, and the fluorescent signal was read using a multifunctional microplate reader (Envision 2104). Determining the inhibitory effect of the compound from the data obtained and plotting it against the compound concentration to obtain a concentration response curve, fitting the IC to a four parameter model50The value is obtained.
The compounds prepared in the previous examples were tested for HDAC1 and HDAC6 enzymatic activity according to the methods described above, the results of which are shown in Table 1, wherein the IC of each compound was determined50Classified as per the description.
TABLE 1 inhibitory Activity of Compounds on HDAC1 and HDAC6
Figure BDA0001840794250000451
Figure BDA0001840794250000461
Figure BDA0001840794250000471
Note: and "+" indicates IC50Is more than 500nM and less than 10 μ M; "+ +" denotes IC50Greater than 100nM and less than 500 nM; "+ + + +" denotes IC50Less than 100 nM. ND data is in detection analysis.
Test results show that the compound has good deacetylase inhibitory activity and can be effectively used for treating diseases with abnormal histone deacetylase activity.
Test example 2 cell growth inhibition assay
HCT-116 cells were seeded in 12-well plates in logarithmic growth phase. After the cells adhered overnight, the compounds were added to treat the cells for 24 hours, respectively. Cells were harvested and lysed in SDS lysate on ice bath. And (3) performing SDS-PAGE electrophoresis on the cell lysate, and transferring the protein to a PVDF membrane by using a wet transfer system. After 5% skim milk blocking solution prepared in TBST solution (100mM Tris-HCl pH 7.2-7.4, 0.9% NaCl, 0.2% Tween-20) was added, the shaker was blocked for 60 minutes at room temperature. The membrane was placed in primary antibody diluted in antibody diluent (5% skim milk) overnight at 4 ℃. Three washes with TBST solution at room temperature for 10 minutes each. A secondary antibody labeled with a near infrared label was added thereto, and the mixture was gently shaken on a shaker at room temperature for 1 hour. And washing the solution with TBST for three times, and acquiring a fluorescence signal value in an Odyssey CLx near-infrared two-color fluorescence imaging system. Determining the inhibitory effect of the compound from the data obtained and plotting it against the compound concentration to obtain a concentration response curve, fitting the EC according to a four parameter model50The value is obtained.
The compounds prepared in the preceding examples were tested for inhibition of cell growth as described above and the results are shown in Table 2, where the EC for each compound was determined50Classified as per the description.
TABLE 2 inhibitory Activity of Compounds on HCT-116 cells
Examples Activity of Examples Activity of Examples Activity of Examples Activity of
1 +++ 2 ++ 3 ++ 4 +++
5 +++ 6 ++ 7 ++ 8 +++
9 +++ 10 ++ 11 ++ 12 +++
13 +++ 14 ++ 15 +++ 16 +++
17 +++ 18 +++ 19 +++ 20 +++
21 +++ 22 ++ 23 ++ 24 +++
25 +++ 26 +++ 27 +++ 28 +++
29 +++ 30 ++ 31 ++ 32 ++
33 ++ 34 ++ 35 ++ 36 +++
37 ++ 38 ++ 39 ++ 40 ++
41 +++ 42 ++ 43 ++ 44 +++
45 ++ 46 +++ 47 ++ 48 ++
49 ++ 50 ++ 51 ++ 52 ++
53 ++ 54 ++ 55 ++ 56 ++
57 ++ 58 ++ 59 ++ 60 ++
61 +++ 62 +++ 63 +++ 64 ++
65 ++ 66 ++ 67 ++ 68 +
69 + 70 + 71 + 72 ++
73 + 74 + 75 + 76 ++
77 ++ 78 ++ 79 ++ 80 ++
81 ++ 82 ++ 83 ++ 84 ++
85 ++ 86 ++ 87 + 88 ++
89 ++ 90 + 91 ++ 92 ++
93 + 94 + 95 ++ 96 ++
97 ++ 98 ++ 99 ++ 100 ++
Note: "+" indicates EC50Greater than 50 μ M; "+ +" indicates EC50More than 10 μ M and less than 50 μ M; (ii) a "+ + + +" denotes EC5010 μ M smaller; ND data is in detection analysis.
The test result shows that the compound has good inhibitory activity on HCT-116 cells.
In conclusion, the novel compound shown in the formula I shows good deacetylase inhibitory activity, provides a new medicinal possibility for clinically treating diseases related to abnormal histone deacetylase activity, and has good application prospect.

Claims (24)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
Figure FDA0002626316310000011
wherein n is 0,1, 2, 3;
L1indicates that is not, C1～C5Alkylene or
Figure FDA0002626316310000012
Wherein m is 0-3;
y is N or CR2Wherein R is2Selected from hydrogen, halogen;
x is O, S or NR3(ii) a Wherein R is3Selected from hydrogen, C1～C5Alkyl groups of (a);
R1is hydrogen, C1～C5Alkyl, 6-membered aryl or heteroaryl of (a);
ring A represents phenyl, cyclohexane, 5-6 membered heterocyclic alkane, 5-6 membered aromatic heterocycle or 10 membered aromatic heterocycle; wherein the A ring may be substituted by 0 to 5R4Substituted, wherein each R4Are respectively independently selected from halogen, trifluoromethyl, trifluoromethoxy, - (CH)2)qR5、–(CH2)qOR5、–(CH2)qNR5 R6、–(CH2)q COR5Q is 0 to 5;
R5、R6are respectively selected from hydrogen and C1～C5The alkyl group, the cycloalkane having 5 to 10 ring members, the heterocycloalkane having 5 to 10 ring members, the aryl group having 5 to 10 ring members or the heteroaryl group having 5 to 10 ring members, wherein R is5、R6May be further substituted by R7Substitution;
R7selected from halogen, hydroxy, amino, C1～C5Alkyl of (C)1～C5Alkoxy group of (C)1～C5Alkylamino of (a) - (CH)2)rOR8(ii) a Wherein r is 0 to 5;
R8selected from hydrogen, C1～C5Alkyl group of (1).
2. The compound of claim 1, wherein: the compound of formula (I) has a structure as shown in formula (Ia) or formula (Ib):
Figure FDA0002626316310000013
3. the compound of claim 2, wherein: the compound of formula (Ia) has a structure as shown in formula (Ia-1):
Figure FDA0002626316310000021
wherein L is1Indicates that is not, C1～C5Alkylene or
Figure FDA0002626316310000022
Wherein m is 0-3;
R1represents hydrogen, C1～C5Alkyl groups of (a);
R2represents hydrogen, halogen, trifluoromethyl, trifluoromethoxy, - (CH)2)qR5、–(CH2)qOR5、–(CH2)qNR5 R6、–(CH2)qCOR5Q is 0 to 5;
R5、R6are respectively selected from hydrogen and C1～C5The alkyl group, the cycloalkane having 5 to 10 ring members, the heterocycloalkane having 5 to 10 ring members, the aryl group having 5 to 10 ring members or the heteroaryl group having 5 to 10 ring members, wherein R is5、R6May be further substituted by R7Substitution;
R7selected from halogen, hydroxy, amino, C1～C5Alkyl of (C)1～C5Alkoxy group of (C)1～C5Alkylamino of (a) - (CH)2)rOR8(ii) a Wherein r is 0 to 5;
R8selected from hydrogen, C1～C5Alkyl groups of (a);
ring A represents a phenyl group, a 5-membered aromatic heterocycle, a 6-membered aromatic heterocycle, or a 10-membered aromatic heterocycle.
4. The compound of claim 2, wherein: the compound of formula (Ia) has a structure as shown in formula (Ia-2):
Figure FDA0002626316310000023
wherein R is1Represents hydrogen, halogen; ring A represents a phenyl group, a 5-membered aromatic heterocycle, or a 6-membered aromatic heterocycle.
5. The compound of claim 2, wherein: the compound of formula (Ia) has a structure as shown in formula (Ia-3):
Figure FDA0002626316310000024
wherein n is 0,1, 2, 3; x represents hydrogen or halogen;
R1represents hydrogen, C1～C5Alkyl, 6-membered aryl or heteroaryl of (a);
R3represents hydrogen, C1～C5Alkyl groups of (a);
R2represents hydrogen, halogen, trifluoromethyl, methoxy, - (CH)2)qR5、–(CH2)qNR5 R6、–(CH2)q COR5Q is 0 to 5;
R5、R6are respectively selected from hydrogen and C1～C5The alkyl, 5-6 membered cycloalkane, 5-6 membered heterocycloalkane, 5-6 membered aromatic heterocycle, phenyl;
the ring A represents a phenyl group, a cyclohexane group, a 5-6 membered heterocyclic alkane group, a 5-6 membered aromatic heterocyclic ring or a 10 membered aromatic heterocyclic ring.
6. The compound of claim 2, wherein: the compound of formula (Ia) has a structure as shown in formula (Ia-4):
Figure FDA0002626316310000031
wherein X represents O, S, N; the ring A represents a phenyl group, a 5-to 6-membered aromatic heterocycle or a 10-membered aromatic heterocycle.
7. The compound of claim 2, wherein: the formula (Ia) is one of the following compounds:
Figure FDA0002626316310000032
Figure FDA0002626316310000041
Figure FDA0002626316310000051
8. the compound of claim 2, wherein: the compound of formula (Ib) has a structure as shown in formula (Ib-1):
Figure FDA0002626316310000052
wherein L is1Indicates that is not, C1～C5Alkylene or
Figure FDA0002626316310000053
Wherein m is 0-3;
R1represents hydrogen, C1～C5Alkyl groups of (a);
R2represents hydrogen, halogen, trifluoromethyl, trifluoromethoxy, - (CH)2)qR5、–(CH2)qOR5、–(CH2)qNR5 R6、–(CH2)qCOR5Q is 0 to 5;
R5、R6are respectively selected from hydrogen and C1～C5Alkyl of (3), 5-10 membered cycloalkane, 5-10 membered heterocycloalkane, 5-10 membered aryl or 5-10 membered arylA 10 membered heteroaryl; wherein R is5、R6May be further substituted by R7Substitution;
R7selected from halogen, hydroxy, amino, C1～C5Alkyl of (C)1～C5Alkoxy group of (C)1～C5Alkylamino of (a) - (CH)2)rOR8(ii) a Wherein r is 0 to 5;
R8selected from hydrogen, C1～C5Alkyl groups of (a);
the ring A represents a phenyl group, a 5-to 6-membered aromatic heterocycle or a 10-membered aromatic heterocycle.
9. The compound of claim 2, wherein: the compound of formula (Ib) has a structure as shown in formula (Ib-2):
Figure FDA0002626316310000061
wherein R is1Represents hydrogen, halogen; ring A represents a phenyl group, a 5-membered aromatic heterocycle, or a 6-membered aromatic heterocycle.
10. The compound of claim 2, wherein: the compound of formula (Ib) has a structure as shown in formula (Ib-3):
Figure FDA0002626316310000062
wherein n is 0,1, 2, 3; x represents hydrogen or halogen;
R1represents hydrogen, C1～C5Alkyl, 6-membered aryl or heteroaryl of (a);
R3represents hydrogen, C1～C5Alkyl groups of (a);
R2represents hydrogen, halogen, trifluoromethyl, methoxy, - (CH)2)qR5、–(CH2)qNR5 R6、–(CH2)q COR5Q is 0 to 5;
R5、R6are respectively selected from hydrogen and C1～C5The alkyl, 5-6 membered cycloalkane, 5-6 membered heterocycloalkane, 5-6 membered aromatic heterocycle, phenyl;
the ring A represents a phenyl group, a cyclohexane group, a 5-6 membered heterocyclic alkane group, a 5-6 membered aromatic heterocyclic ring or a 10 membered aromatic heterocyclic ring.
11. The compound of claim 2, wherein: the compound of formula (Ib) has a structure as shown in formula (Ib-4):
Figure FDA0002626316310000071
wherein X represents O, S; the ring A represents a phenyl group, a 5-to 6-membered aromatic heterocycle or a 10-membered aromatic heterocycle.
12. The compound of claim 2, wherein: the formula (Ib) is one of the following compounds:
Figure FDA0002626316310000072
Figure FDA0002626316310000081
13. use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the HDAC inhibitor class.
14. Use according to claim 13, characterized in that: the medicament is a medicament for treating a cell proliferative disease, an autoimmune disease, an inflammation, a neurodegenerative disease, or a viral disease.
15. Use according to claim 14, characterized in that: the cell proliferative disease is cancer.
16. Use according to claim 15, characterized in that: the cancer comprises colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer and thyroid cancer.
17. Use according to any one of claims 13 to 16, characterized in that: the HDAC is HDAC 6.
18. A pharmaceutical composition characterized by: the compound or the pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable auxiliary materials.
19. The composition as claimed in claim 18, wherein: the preparation is an oral preparation, a transdermal absorption preparation or an injection preparation.
20. Use of a pharmaceutical composition according to claim 18 or 19 in the manufacture of a medicament for an HDAC inhibitor.
21. Use according to claim 20, characterized in that: the medicament is a medicament for treating 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 cell proliferative disease is cancer.
23. Use according to claim 22, characterized in that: the cancer comprises colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer and thyroid cancer.
24. Use according to any one of claims 20 to 23, characterized in that: the HDAC is HDAC 6.
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