CN112920115A - Quinoline-4-formamide skeleton derivative and application thereof - Google Patents

Quinoline-4-formamide skeleton derivative and application thereof Download PDF

Info

Publication number
CN112920115A
CN112920115A CN201911234907.3A CN201911234907A CN112920115A CN 112920115 A CN112920115 A CN 112920115A CN 201911234907 A CN201911234907 A CN 201911234907A CN 112920115 A CN112920115 A CN 112920115A
Authority
CN
China
Prior art keywords
compound
substituted
dmso
nmr
calcd
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201911234907.3A
Other languages
Chinese (zh)
Inventor
杨胜勇
李琳丽
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan University
Original Assignee
Sichuan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan University filed Critical Sichuan University
Priority to CN201911234907.3A priority Critical patent/CN112920115A/en
Publication of CN112920115A publication Critical patent/CN112920115A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a quinoline-4-formamide skeleton derivative and application thereof, belonging to the field of chemical medicine. The invention provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof. The invention also provides a preparation method and application of the compound. Biological experiments show that the compounds have good exciting effect on SIRT6 at the in vitro molecular level, have good selectivity for families, and can obviously improve pathological changes related to SIRT 6; particularly shows good anticancer activity in vivo and in vitro, especially pancreatic cancer activity, provides a new choice for the development and application of anticancer drugs, and has good application prospect.
Figure DDA0002304622250000011

Description

Quinoline-4-formamide skeleton derivative and application thereof
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a quinoline-4-formamide skeleton derivative and application thereof.
Background
Epigenetics is the most popular in the field of life sciences. Epigenetic regulation of gene expression mainly involves aspects such as DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation. Among them, histone acetylation modification was first discovered to be related to gene transcription regulation, and is closely related to the occurrence of many diseases, which is a hot spot of current research. Enzymes involved in deacetylation include, in addition to classical class I and class II Histone deacetylases HDAC (HDAC), class III HDAC, Sir2(Silent information regulator 2, Sirtuin 2) -related enzymes (Sir2-related enzymes, Sirtuin). Class III histone deacetylases (Class III HDACs), commonly known as longevity proteins (Sirtuins, SIRTs), are a highly conserved Class of proteins with homology to Sir2 in Saccharomyces cerevisiae. There are 7 recognized members of the human Sirtuin family: SIRT 1-SIRT 7. The Sirtuin family of proteins has diverse subcellular localization, with SIRT1, SIRT6 and SIRT7 located primarily in the nucleus, SIRT3, SIRT4 and SIRT5 located in the mitochondria, and SIRT2 distributed primarily in the cytoplasm, with the subcellular localization of these proteins also being dependent on cell type, state and intermolecular interactions, among others, such as SIRT1 and SIRT2, which can shuttle between and interact with proteins in the nucleus and cytoplasm. They perform a number of post-translational modifications of proteins in different subcellular systems to perform different functions and actions.
SIRT6, a major member of the highly conserved NAD + -dependent deacetylase family, is involved in the regulation of many physiological processes, such as the cell cycle, metabolism, stress response and aging process in prokaryotes and eukaryotes, and has a variety of catalytic functions, including Deacetylation (deacylation) 2, Mono ADP-ribosylation (Mono adenosine diphosphate glycosylation) 3, and deacylation (De-fat-acylation), among others. SIRT6 is closely related to the occurrence and progression of various diseases, such as cardiovascular diseases, chronic obstructive pulmonary diseases, diabetes, bone related diseases, retinopathy, liver diseases, etc. Today, due to its important role in tumorigenesis and development, especially in key regulation of cancer cell metabolism, the intensified concept of targeted therapy and the accelerated development of drug development, SIRT6 as a new target has triggered the development of new regulators.
Chromatin remodeling proteins are often deregulated in human cancers, but little is known about how they control tumorigenesis. For example, in the Cell-published article (Cell 2016,165,1401-1415.), the authors have discovered an epigenetic program mediated by the NAD + -dependent histone deacetylase Sirtuin 6(SIRT6), which is critical in the inhibition of Pancreatic Ductal Adenocarcinoma (PDAC), one of the most lethal malignancies. PDAC progression and metastasis are accelerated by up-regulating the negative regulator Lin28b of let-7microRNA after SIRT6 inactivation. The SIRT6 deletion resulted in high histone acetylation of the Lin28b promoter, Myc recruitment, and significant induction of Lin28b and downstream let-7 target genes HMGA2, IGF2BP1, and IGF2BP 3. This appearance program defined different subsets of poor prognosis, accounting for 30% -40% of human PDACs, characterized by reduced SIRT6 expression and an accurate dependence on Lin28b of tumor growth. Thus, SIRT6 was identified as an important PDAC tumor suppressor and the Lin28b pathway was uncovered as a potential therapeutic target in a molecularly defined subset of PDACs. Therefore, the development of a SIRT6 agonist with high activity and selectivity is very necessary.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a SIRT6 agonist with high activity and high selectivity.
The technical scheme adopted by the invention for solving the technical problems is to provide a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0002304622230000021
wherein R is1Selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstitutedCycloalkyl, substituted or unsubstituted heterocycloalkyl;
the R is1The substituent in the substituted aryl or substituted heteroaryl is selected from alkoxy, aryloxy, substituted or unsubstituted alkyl, hydroxyl, nitro, ester group and halogen, wherein the substituent of the substituted alkyl is halogen or cycloalkyl, and the cycloalkyl contains 0-3N heteroatoms;
the R is1Wherein the substituent of the substituted alkyl, substituted cycloalkyl or substituted bridged cycloalkyl is selected from aryl, heteroaryl, ester, hydroxy;
R2selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkyl, cycloalkyl;
the R is2Wherein the substituents in the substituted aryl or substituted heteroaryl are selected from alkoxy, alkyl or halogen.
Preferably, in the above-mentioned compound, R1The compound is selected from substituted or unsubstituted 6-10-membered aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-6-membered cycloalkyl and substituted or unsubstituted bridged cycloalkyl, wherein hetero atoms in the heteroaryl are N, O or S, and the number of the hetero atoms is 1-2.
Preferably, in the compound mentioned above, R is1The substituent in the substituted 6-to 10-membered aryl or substituted 5-to 10-membered heteroaryl is selected from C1-C6 alkoxy, 6-to 10-membered aryloxy, substituted or unsubstituted C1-C6 alkyl, hydroxyl, nitro, ester group and halogen, the substituent of the substituted alkyl is F or 5-to 6-membered cycloalkyl, and the cycloalkyl contains 1-2N heteroatoms;
the R is1Wherein the substituent of the substituted C1-C6 alkyl, the substituted 5-6 membered cycloalkyl or the substituted bridged cycloalkyl is selected from 6-10 membered aryl, 5-10 membered heteroaryl, ester group and hydroxyl.
Preferably, in the above-mentioned compound, R2Selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 5-6 membered cycloalkyl, wherein the heteroatom in the heteroaryl is N, OOr S, the number of heteroatoms is 1-2; the cycloalkyl contains 0-2 heteroatoms, and the heteroatoms are N, O or S.
Preferably, in the compound mentioned above, R is2The substituent in the substituted 6-10-membered aryl and the substituted 5-10-membered heteroaryl is selected from C1-C6 alkoxy, C1-C6 alkyl or halogen.
Further preferably, in the above compound, R1Selected from:
Figure BDA0002304622230000031
Figure BDA0002304622230000032
further preferably, in the above compound, R2Selected from:
Figure BDA0002304622230000033
Figure BDA0002304622230000034
most preferably, the compound is selected from the group consisting of:
Figure BDA0002304622230000041
Figure BDA0002304622230000051
SIRT6 is closely related to the occurrence and development of various diseases, such as neurodegenerative diseases (Cell Reports 2017,18, 3052-3062.), diabetes (Cell 2010,140,280-293.), cardiovascular diseases (Nature Medicine 2012,18,1643.), and cancers (such as liver cancer and pancreatic cancer), and the like. Through biological experiments, the quinoline-4-formamide skeleton derivative provided by the invention has excellent agonistic activity on SIRT6, so that the invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing SIRT6 agonist.
Furthermore, the invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing anti-cancer drugs.
Preferably, the invention also provides the application of the compound or the pharmaceutically acceptable salt thereof in preparing anti-pancreatic cancer drugs.
The invention also provides a preparation method of the quinoline-4-formamide skeleton derivative, and a specific synthetic route is as follows.
Figure BDA0002304622230000061
Routes Synthesis of Compounds 5 and 5a-n
Figure BDA0002304622230000062
Synthetic route to Compounds 8a-p
Figure BDA0002304622230000071
Route Synthesis of the three Compounds 12a-u
Definition of terms:
the compounds and derivatives provided by 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.
The term "alkyl" is a radical of a straight or branched chain saturated hydrocarbon group. Examples of C1-C6 alkyl include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6).
The term "alkoxy" refers to the group-OR OR-O (CH)2)nO-, wherein R is an alkyl group as defined above, and n is an integer of not less than 1. CExamples of 1-C6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1, 2-dimethylbutoxy.
The term "aryl" refers to a group of a 4n +2 aromatic ring system that does not contain heteroatoms in the aromatic ring system; "heteroaryl" refers to a group of a 4n +2 aromatic ring system containing heteroatoms in the aromatic ring system, wherein the heteroatoms are selected from nitrogen, oxygen and/or sulfur.
The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group, with or without heteroatoms, which may be a single ring structure or two or more rings, wherein the heteroatoms are selected from phosphorus, sulfur, oxygen and/or nitrogen.
The invention has the beneficial effects that:
the invention provides a quinoline-4-formamide skeleton derivative with a novel structure. Biological experiments show that the compound, especially the compound 12q, has good exciting effect on SIRT6 on the level of in vitro molecules, has good family selectivity, and can obviously improve the pathological changes related to SIRT 6; particularly shows good anticancer activity in vivo and in vitro, especially pancreatic cancer activity, provides a new choice for the development and application of anticancer drugs, and has good application prospect.
Drawings
FIG. 1 is a molecular level activity plot of Compound 12q in example 1: a is the activity profile of compound 12q and compound MDL-800 on SIRT6 deacetylation; b is the activity diagram of compound 12q and compound MDL-800 on Demyristoylation of SIRT 6; c is the ITC binding curve for SIRT6 and compound 12 q.
FIG. 2 is a molecular level activity plot of Compound 12q in example 1: a is a graph of the change in thermodynamic stability of compound 12q when combined with SIRT 6; b is the SPR binding curves and the fitted steady state assessment curves for SIRT6 and 12 q.
FIG. 3 is a graph of in vitro anti-proliferative activity of compound 12q and MDL-800 in example 3 on pancreatic cancer cells: a is a graph of the MTT test result of compound 12 q; b is an MTT experimental result graph of MDL-800; c is a clone formation experiment result chart of the compound 12q and MDL-800; d is the EDU test result chart of the compound 12q and MDL-800.
FIG. 4 is a graph showing the results of the cell migration experiment and Western Blot experiment in example 3: a is a graph of the ability of compound 12q and MDL-800 to inhibit pancreatic cancer cell migration; b is a Western blot experiment result chart of the compound 12q and the MDL-800.
FIG. 5 is a graph of the in vivo anti-tumor effect of Compound 12q in example 4: a is a tumor volume map; b is a tumor volume quantitative analysis chart; and C is a staining image of the tumor tissue section.
Detailed Description
The quinoline-4-carboxamide skeleton derivatives and their uses according to the present invention are further illustrated by the following examples, which should not be construed as limiting the scope of the above-described subject matter of the present invention to the following examples, but which fall within the scope of the present invention to which the technology based on the above-described contents thereof can be put.
The specific partial synthesis method is as follows:
preparation of Compound 2- (3, 4-Dimethoxyphenyl) quinoline-4-carboxylic acid (3)
Figure BDA0002304622230000081
Intermediate compound 3
Into a 100mL round-bottomed flask was added, with stirring, a solution of isatin (1.47g,20.0mmol), 3, 4-dimethyloxyacetophenone (2.16g,24.0mmol) and KOH (1.68g,60mmol) in ethanol (35 mL). The resulting mixture was heated to reflux at 85 ℃ for 24 h. After completion of the reaction, the solvent was removed under reduced pressure, and the mixture was dissolved in water and washed twice with ethyl acetate. The aqueous layer was concentrated and adjusted to pH 2 with concentrated HCl to give a yellow solid. The solid was filtered, washed with water to neutrality, dried, and purified by flash column chromatography on silica gel eluting with a mixed solution of ethyl acetate and petroleum ether to give 2- (3, 4-dimethoxyphenyl) quinoline-4-carboxylic acid intermediate as a yellow solid in 76% yield and 95% purity by HPLC.1H NMR (400MHz,DMSO-d6)δ13.95(s,1H),8.59(dd,J＝8.5,1.3Hz,1H),8.43(s,1H),8.17-8.09(m, 1H),7.91(d,J＝2.1Hz,1H),7.87(dd,J＝8.4,2.1Hz,1H),7.83(ddd,J＝8.4,6.8,1.5Hz,1H), 7.66(ddd,J＝8.3,6.8,1.3Hz,1H),7.14(d,J＝8.4Hz,1H),3.92(s,3H),3.86(s,3H).13C NMR (101MHz,DMSO)δ168.23,155.98,151.18,149.59,148.76,138.06,131.00,130.54,130.03, 127.74,125.80,123.56,120.78,119.20,112.24,110.69,56.11,56.08.MS m/z(ESI):310.11 [M+H]+.
Preparation of Compound 2- (thien-2-yl) quinolinone-4-carboxylic acid (7a)
Figure BDA0002304622230000091
Intermediate compound 7a
The specific synthesis method comprises the step of reacting compound 3 to obtain a light yellow solid compound 7a, wherein the reaction yield is 70%, and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ14.03(s,1H),8.58(dd,J＝8.7,1.3Hz,1H),8.42(s, 1H),8.10(dd,J＝3.7,1.2Hz,1H),8.05(dt,J＝8.2,1.0Hz,1H),7.82(ddd,J＝8.4,6.9,1.4Hz, 1H),7.79(dd,J＝5.0,1.1Hz,1H),7.66(ddd,J＝8.4,6.9,1.3Hz,1H),7.25(dd,J＝5.0,3.7Hz, 1H).13C NMR(101MHz,DMSO)δ167.92,152.13,148.57,144.40,138.17,130.87,130.67, 129.53,129.19,128.23,127.89,125.95,123.79,118.54.MS m/z(ESI):256.05[M+H]+.
Preparation of Compound 2- (5-Methylthiophen-2-yl) quinoline-4-carboxylic acid (7b)
Figure BDA0002304622230000092
Intermediate compound 7b
The specific synthesis method comprises the step of reacting compound 3 to obtain a light yellow solid compound 7b, wherein the reaction yield is 75%, and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ13.92(s,1H),8.56(dd,J＝8.5,1.3Hz,1H),8.34(s, 1H),8.00(dd,J＝8.5,1.2Hz,1H),7.88(d,J＝3.7Hz,1H),7.80(ddd,J＝8.4,6.9,1.4Hz,1H), 7.64(ddd,J＝8.3,6.9,1.3Hz,1H),6.94(dd,J＝3.6,1.2Hz,1H),2.53(br s,3H).13C NMR(101 MHz,DMSO)δ167.94,152.21,148.58,144.57,141.96,137.93,130.78,129.41,128.39,127.66, 127.62,125.91,123.59,118.21,15.86.MS m/z(ESI):270.06[M+H]+.
Preparation of Compound 2- (4-methoxyphenyl) quinolinone-4-carboxylic acid (7c)
Figure BDA0002304622230000101
Intermediate compound 7c
The specific synthesis method comprises the step of reacting compound 3 to obtain a white solid compound 7c, wherein the reaction yield is 69% and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ13.94(s,1H),8.62(d,J＝8.5Hz,1H),8.42(s,1H), 8.28(d,J＝8.4Hz,2H),8.13(d,J＝8.4Hz,1H),7.83(t,J＝7.7Hz,1H),7.67(t,J＝7.7Hz,1H), 7.13(d,J＝8.5Hz,2H),3.86(s,3H).13C NMR(101MHz,DMSO)δ168.15,161.39,155.92, 148.87,137.92,130.81,130.55,130.02,129.16,127.74,125.82,123.56,119.14,114.83,55.80.MS m/z(ESI):280.10[M+H]+.
Preparation of Compound 2- (oxa-4-yl) quinolinone-4-carboxylic acid (7d)
Figure BDA0002304622230000102
Intermediate compound 7d
The specific synthesis method comprises the step of reacting compound 3 to obtain a colorless oily compound 7d, wherein the reaction yield is 55%, and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ8.62(dd,J＝8.6,1.3Hz,1H),8.04(dd,J＝8.4,1.2 Hz,1H),7.85(s,1H),7.79(ddd,J＝8.4,6.9,1.5Hz,1H),7.64(ddd,J＝8.3,6.8,1.3Hz,1H),4.00 (dt,J＝11.2,3.3Hz,2H),3.50(ddd,J＝11.4,8.5,5.7Hz,2H),3.26-3.14(m,1H),1.91-1.86(m, 4H).13C NMR(101MHz,DMSO)δ168.31,164.76,148.48,130.08,129.68,127.48,125.93, 123.74,121.11,67.50,43.31,32.13.MS m/z(ESI):258.11[M+H]+.
Preparation of Compound 2- (Furan-2-yl) quinoline-4-carboxylic acid (7e)
Figure BDA0002304622230000103
Intermediate compound 7e
The specific synthesis method comprises the step of reacting compound 3 to obtain a light yellow solid compound 7e, wherein the reaction yield is 70%, and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ14.02(s,1H),8.65(dd,J＝8.6,1.3Hz,1H),8.31(s, 1H),8.09(dd,J＝8.5,1.2Hz,1H),8.00-7.97(m,1H),7.84(ddd,J＝8.4,6.8,1.4Hz,1H),7.68 (ddd,J＝8.4,6.9,1.3Hz,1H),7.46(dd,J＝3.4,0.7Hz,1H),6.76(dd,J＝3.5,1.7Hz,1H).13C NMR(101MHz,DMSO)δ167.76,152.89,148.83,148.53,145.89,137.74,130.85,129.78,128.05, 125.99,123.78,118.43,113.23,111.76.MS m/z(ESI):240.01[M+H]+.
Preparation of Compound 2- (5-Methylfuran-2-yl) quinoline-4-carboxylic acid (7f)
Figure BDA0002304622230000111
Intermediate compound 7f
The specific synthesis method uses compound 3, and the reaction treatment is carried out to obtain a light yellow solid compound 7f, the reaction yield is 66%, and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.27(d,J＝2.2Hz,1H),8.20(d,J＝ 8.3Hz,1H),8.16(s,1H),8.08(d,J＝8.4Hz,1H),7.91-7.79(m,2H),7.73(dd,J＝8.5,2.3Hz,1H), 7.64(dd,J＝8.4,6.9Hz,1H),7.36(d,J＝3.3Hz,1H),6.41(d,J＝3.2Hz,1H),2.46(s,3H).13C NMR(101MHz,DMSO)δ167.83,155.21,151.41,148.87,148.53,137.59,130.74,129.64,127.70, 125.96,123.57,118.27,113.06,109.64,14.09.MS m/z(ESI):254.08[M+H]+.
Preparation of Compound 2-cyclopentylquinoline-4-carboxylic acid (7g)
Figure BDA0002304622230000112
Intermediate Compound 7g
The specific synthesis method was carried out using compound 3, and the reaction treatment yielded 7g of a colorless oily compound, the reaction yield was 61%, and the HPLC purity was 96%.1H NMR(400MHz,DMSO-d6)δ13.79(s,1H),8.61(dd,J＝8.5,1.3Hz,1H),8.02 (dd,J＝8.5,1.2Hz,1H),7.84(s,1H),7.78(ddd,J＝8.3,6.8,1.4Hz,1H),7.64(ddd,J＝8.3,6.8, 1.3Hz,1H),3.44(p,J＝8.2Hz,1H),2.17-2.03(m,2H),1.95-1.77(m,4H),1.70(tt,J＝6.8,3.7Hz, 2H).13C NMR(101MHz,DMSO)δ168.15,165.75,148.43,136.90,130.07,129.63,127.42, 125.75,123.55,121.89,47.99,33.17,26.00.MS m/z(ESI):242.12[M+H]+.
Preparation of Compound 2-Cyclohexylquinoline-4-carboxylic acid (7h)
Figure BDA0002304622230000113
Intermediate compound 7h
The specific synthesis method comprises the step of reacting compound 3 to obtain a colorless oily compound for 7 hours, wherein the reaction yield is 55%, and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ13.84(s,1H),8.63(dd,J＝8.5,1.4Hz,1H),8.03 (dd,J＝8.5,1.2Hz,1H),7.84(s,1H),7.78(ddd,J＝8.4,6.8,1.5Hz,1H),7.64(ddd,J＝8.4,6.9, 1.4Hz,1H),2.94(tt,J＝11.8,3.4Hz,1H),1.99-1.90(m,2H),1.84(dt,J＝12.7,3.4Hz,2H), 1.78-1.70(m,1H),1.64(qd,J＝12.5,3.2Hz,2H),1.43(qt,J＝12.4,3.2Hz,2H),1.31(tt,J＝12.6, 3.2Hz,1H).13C NMR(101MHz,DMSO)δ168.20,166.33,148.52,137.12,130.00,129.66, 127.40,125.78,123.64,121.29,46.57,32.48,26.39,26.01.MS m/z(ESI):256.13[M+H]+.
Preparation of Compound 2- (3-fluoro-4-methoxyphenyl) quinoline-4-carboxylic acid (7i)
Figure BDA0002304622230000121
Intermediate compound 7i
Specific synthetic methods assimilatingCompound 3 was reacted to give compound 7i as a white solid in 67% reaction yield and 96% HPLC purity.1H NMR(400MHz,DMSO-d6)δ13.98(s,1H),8.61(dd,J＝8.6,1.3Hz,1H),8.45(s, 1H),8.23-8.11(m,3H),7.84(ddd,J＝8.4,6.9,1.4Hz,1H),7.69(ddd,J＝8.3,6.8,1.3Hz,1H), 7.34(t,J＝8.7Hz,1H),3.95(s,3H).13C NMR(101MHz,DMSO)δ168.08,154.77,153.50, 151.07,148.71,138.23,131.37,130.68,130.09,128.06,125.81,124.32,124.29,123.72,119.05, 114.41,56.64.MS m/z(ESI):298.08[M+H]+.
Preparation of the Compound 2- (2-ethoxypyridin-3-yl) quinoline-4-carboxylic acid (7j)
Figure BDA0002304622230000122
Intermediate compound 7j
The specific synthesis method comprises the step of reacting compound 3 to obtain a gray solid compound 7j, wherein the reaction yield is 55%, and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ13.80(s,1H),8.74(dd,J＝8.6,1.4Hz,1H),8.62(s, 1H),8.40(dd,J＝7.4,2.0Hz,1H),8.33(dd,J＝4.9,2.0Hz,1H),8.16(dd,J＝8.4,1.2Hz,1H), 7.86(ddd,J＝8.4,6.8,1.5Hz,1H),7.74(ddd,J＝8.3,6.9,1.3Hz,1H),7.22(dd,J＝7.5,4.9Hz, 1H),4.49(q,J＝7.0Hz,2H),1.38(t,J＝7.0Hz,3H).13C NMR(101MHz,DMSO)δ168.05, 160.95,154.51,148.93,148.63,140.26,136.41,130.43,130.18,128.45,125.87,123.94,123.71, 122.06,118.07,62.24,14.90.MS m/z(ESI):295.11[M+H]+.
Preparation of Compound 2- (pyrazin-2-yl) quinoline-4-carboxylic acid (7k)
Figure BDA0002304622230000123
Intermediate compound 7k
The specific synthesis method comprises the step of reacting compound 3 to obtain gray solid compound 7k, wherein the reaction yield is 45%, and the HPLC purity is 94%.1H NMR(400MHz,DMSO-d6)δ14.03(s,1H),9.77(d,J＝1.5Hz,1H),8.90(s,1H), 8.85(dd,J＝2.5,1.5Hz,1H),8.82(d,J＝2.5Hz,1H),8.81-8.77(m,1H),8.30-8.23(m,1H),7.93 (ddd,J＝8.4,6.8,1.4Hz,1H),7.80(ddd,J＝8.4,6.9,1.3Hz,1H).MS m/z(ESI):252.07[M+H]+Preparation of the Compound 2- (pyridin-3-yl) quinoline-4-carboxylic acid (7l)
Figure BDA0002304622230000131
Intermediate Compound 7l
The specific synthesis method was carried out with compound 3, and the reaction treatment yielded 7l of a colorless oily compound, the reaction yield was 43%, and the HPLC purity was 93%.1H NMR(400MHz,DMSO-d6)δ9.47(d,J＝2.3Hz,1H),8.73(dd,J＝4.8,1.6Hz, 1H),8.66(dt,J＝7.9,1.8Hz,2H),8.52(s,1H),8.21(dd,J＝8.5,1.2Hz,1H),7.89(ddd,J＝8.4, 6.8,1.4Hz,1H),7.75(ddd,J＝8.4,6.8,1.3Hz,1H),7.61(ddd,J＝8.0,4.8,0.9Hz,1H).MS m/z (ESI):251.08[M+H]+.
Preparation of the Compound 2- (2H-1, 3-benzodioxol-5-yl) quinolinone-4-carboxylic acid (7m)
Figure BDA0002304622230000132
Intermediate compound 7m
The specific synthesis method comprises the step of reacting compound 3 to obtain a white solid compound 7m, wherein the reaction yield is 72% and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ8.60(dd,J＝8.5,1.3Hz,1H),8.39(s,1H),8.12 (dd,J＝8.5,1.2Hz,1H),7.90-7.79(m,3H),7.67(ddd,J＝8.3,6.8,1.4Hz,1H),7.10(d,J＝8.1Hz, 1H),6.14(s,2H).13C NMR(101MHz,DMSO)δ168.17,155.66,149.48,148.71,148.68,138.28, 132.73,130.59,130.05,127.85,125.83,123.66,122.30,119.22,109.06,107.51,102.04.MS m/z (ESI):294.05[M+H]+.
Preparation of Compound 2- (benzofuran-2-yl) quinoline-4-carboxylic acid (7n)
Figure BDA0002304622230000133
Intermediate compound 7n
The specific synthesis method comprises the step of reacting compound 3 to obtain a yellow solid compound 7n, wherein the reaction yield is 69% and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ14.10(s,1H),8.71(dd,J＝8.6,1.3Hz,1H),8.51(s, 1H),8.19(dd,J＝8.5,1.1Hz,1H),7.94(d,J＝0.9Hz,1H),7.89(ddd,J＝8.4,6.8,1.5Hz,1H), 7.83-7.77(m,2H),7.74(ddd,J＝8.3,6.9,1.3Hz,1H),7.46(ddd,J＝8.5,7.2,1.3Hz,1H),7.35(td, J＝7.5,0.9Hz,1H).13C NMR(101MHz,DMSO)δ167.73,155.47,154.47,148.94,148.44, 138.09,131.03,130.03,128.75,128.64,126.60,126.10,124.32,124.12,122.67,119.16,112.17, 107.61.MS m/z(ESI):290.08[M+H]+.
Preparation of the Compound 2- (2, 3-dihydro-1, 4-benzodioxin-6-yl) quinoline-4-carboxylic acid (7o)
Figure BDA0002304622230000141
Intermediate compound 7o
The specific synthesis method uses compound 3, and the reaction treatment can obtain white solid compound 7o, the reaction yield is 69%, and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ8.61(dd,J＝8.5,1.3Hz,1H),8.37(s,1H),8.12 (dd,J＝8.5,1.2Hz,1H),7.88-7.76(m,3H),7.67(ddd,J＝8.4,6.9,1.3Hz,1H),7.04(d,J＝8.3Hz, 1H),4.34(br s,4H).13C NMR(101MHz,DMSO)δ168.14,155.58,148.78,145.81,144.26, 138.10,131.69,130.57,130.07,127.83,125.81,123.64,120.91,119.10,117.98,116.23,64.86, 64.57.MS m/z(ESI):308.09[M+H]+.
Preparation of the Compound 2- (7-methoxy-1-benzofuran-2-yl) quinoline-4-carboxylic acid (7p)
Figure BDA0002304622230000142
Intermediate compound 7p
The specific synthesis method comprises the step of reacting compound 3 to obtain a white solid compound 7p, wherein the reaction yield is 65%, and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ8.72(dd,J＝8.6,1.3Hz,1H),8.48(s,1H),8.19 (dd,J＝8.6,1.2Hz,1H),7.90(s,1H),7.89(ddd,J＝8.4,6.8,1.4Hz,1H),7.74(ddd,J＝8.4,6.9, 1.3Hz,1H),7.35(dd,J＝7.8,1.0Hz,1H),7.27(t,J＝7.8Hz,1H),7.07(dd,J＝7.9,1.0Hz,1H), 4.03(s,3H).13C NMR(101MHz,DMSO)δ167.70,154.44,148.95,148.42,145.70,144.71, 138.03,131.05,130.29,130.03,128.66,126.11,124.91,124.33,119.09,114.53,108.62,107.83, 56.27.MS m/z(ESI):320.09[M+H]+.
Preparation of the compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (3, 4-dimethoxyphenyl) quinolinone-4-carboxamide (5)
Figure BDA0002304622230000143
Target Compound 5
In a 25mL round-bottom flask, intermediate compound 3(155mg,0.5mmol) was dissolved in 6mL of phosphorus oxychloride, and the temperature was raised to 107 ℃ for 4h-5h reaction. TLC monitoring, after the reaction was completed, the reaction solution was spin-dried. The resultant acid chloride compound was dissolved in anhydrous DMF, and 3-amino-4-chlorotrifluoromethane (117mg,0.6mmol) and DMAP (12.2mg,0.1 mmol) were added to the solution to react overnight at normal temperature under a nitrogen atmosphere. TLC monitoring, after the reaction is finished, adding water to dilute the reaction solution, extracting with ethyl acetate, washing with saturated NaCl aqueous solution for three times, drying with anhydrous Na2SO4, spin-drying, and passing through a column by using a mixed solvent of ethyl acetate and petroleum ether to obtain a target product 5, namely N- [ 2-chloro-5- (trifluoromethyl) phenyl]-2- (3, 4-dimethoxyphenyl) quinolinone-4-carboxamide in 79.1% yield and 95% HPLC purity. Mp 209.7-210.6 ℃.1H NMR(400MHz, DMSO-d6)δ10.84(s,1H),8.41(s,1H),8.30(d,J＝2.2Hz,1H),8.26(d,J＝8.2Hz,1H),8.15(d, J＝8.4Hz,1H),7.97(d,J＝1.8Hz,1H),7.94(dd,J＝8.4,2.5Hz,1H),7.88-7.81(m,2H),7.71 (dd,J＝7.6,2.1Hz,1H),7.65(t,J＝7.7Hz,1H),7.17(d,J＝8.5Hz,1H),3.94(s,3H),3.87(s, 3H).13C NMR(101MHz,DMSO)δ166.61,155.93,151.22,149.59,142.52,136.08,133.56, 131.46,131.22,130.68,129.88,128.84,128.51,127.45,125.57,125.13,124.57,123.38,122.76, 120.90,117.39,112.24,110.83,56.19,56.11.HRMS m/z(ESI)calcd for C25H19ClF3N2O3[M+H]+ 487.1031 found:487.1027,calcd for C25H18ClF3N2O3Na[M+Na]+509.0850 found:509.0859.
Preparation of the Compound 2- (3, 4-Dimethoxyphenyl) -N- (naphthalen-1-yl) quinolinone-4-carboxamide (5a)
Figure BDA0002304622230000151
Target Compound 5a
The specific synthesis method comprises the step of reacting compound 5 to obtain an off-white solid compound 5a, wherein the reaction yield is 73%, and the HPLC purity is 95%. Mp 226.9-228.6 ℃.1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.50(s,1H), 8.26(d,J＝8.2Hz,1H),8.22-8.16(m,2H),8.02-8.01(m,3H),7.93(dd,J＝12.5,7.8Hz,2H),7.84 (t,J＝7.5Hz,1H),7.69-7.56(m,4H),7.17(d,J＝7.1Hz,1H),3.95(s,3H),3.87(s,3H).13C NMR (101MHz,DMSO)δ166.91,153.09,151.19,149.59,148.38,143.38,134.29,133.54,131.39, 130.61,129.94,128.89,128.63,127.40,126.81,126.67,126.63,126.06,125.59,123.66,123.61, 123.60,121.05,117.17,112.24,110.97,56.21,56.12.HRMS m/z(ESI)calcd for C28H23N2O3 [M+H]+435.1703 found:435.1714,calcd for C28H22N2O3Na[M+Na]+457.1523 found 457.1532 preparation of Compound 2- (3, 4-Dimethoxyphenyl) -N- (naphthalen-2-yl) quinolone-4-carboxamide (5b)
Figure BDA0002304622230000152
Target Compound 5b
The specific synthesis method comprises the step of reacting compound 5 to obtain an off-white solid compound 5b, wherein the reaction yield is 71%, and the HPLC purity is 95%. Mp 215.9-216.4 ℃.1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.60(d,J＝2.1 Hz,1H),8.41(s,1H),8.17(t,J＝8.3Hz,2H),8.00-7.89(m,5H),7.85-7.80(m,2H),7.64(t,J＝8.2 Hz,1H),7.53(t,J＝7.0Hz,1H),7.46(t,J＝7.1Hz,1H),7.15(d,J＝8.8Hz,1H),3.93(s,3H), 3.86(s,3H).13C NMR(101MHz,DMSO)δ166.18,156.07,151.16,149.56,148.34,143.38, 136.97,133.83,131.25,130.66,129.93,128.94,128.02,128.01,127.99,127.41,127.04,125.51, 125.48,123.41,120.97,120.91,116.96,116.82,112.21,110.90,56.19,56.09.HRMS m/z(ESI) calcd for C28H23N2O3[M+H]+435.1703 found:435.1718,calcd for C28H22N2O3Na[M+Na]+ 457.1523 found:457.1548.
Preparation of the Compound methyl (2S, 3S) -3- [2- (3, 4-dimethoxyphenyl) quinolin-4-amido ] bicyclo [2.2.2] octane-2-carboxylate (5c)
Figure BDA0002304622230000161
Target Compound 5c
The specific synthesis method comprises the step of reacting compound 5 to obtain a white solid compound 5c, wherein the reaction yield is 68%, and the HPLC purity is 95%. Mp 185.9-187.2 ℃.1H NMR(400MHz,DMSO-d6)δ8.85(d,J＝7.0Hz,1H),8.09 (d,J＝8.4Hz,1H),8.06(s,1H),8.03(d,J＝7.6Hz,1H),7.93(d,J＝2.0Hz,1H),7.88(dd,J＝8.4, 2.0Hz,1H),7.81-7.76(m,1H),7.62-7.58(m,1H),7.14(d,J＝8.5Hz,1H),4.50(t,J＝6.7Hz,1H), 3.91(s,3H),3.85(s,3H),3.68(s,3H),2.66(d,J＝6.5Hz,1H),1.93-1.90(m,2H),1.82-1.75(m, 1H),1.67-1.57(m,3H),1.54-1.39(m,4H).13C NMR(101MHz,DMSO)δ174.71,166.92,155.91, 151.11,149.54,148.20,143.87,131.31,130.49,129.80,127.12,125.49,123.62,120.88,116.58, 112.20,110.82,53.16,53.09,52.22,50.15,48.54,29.47,28.45,25.67,24.26,21.21,19.49.HRMS m/z(ESI)calcd for C28H31N2O5[M+H]+475.2227 found:475.2240,calcd for C28H30N2O5Na [M+Na]+497.2047 found:497.2059.
Preparation of the compound 2- (3, 4-dimethoxyphenyl) -N- [ (1R, 3S, 5R, 7S) -3-hydroxyadamantan-1-yl ] quinoline-4-carboxamide (5d)
Figure BDA0002304622230000162
Target Compound 5d
The specific synthesis method comprises the step of reacting compound 5 to obtain a white solid compound 5d, wherein the reaction yield is 66% and the HPLC purity is 95%. Mp 167.3-168.5 ℃.1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.08(d,J＝8.4 Hz,1H),8.01(d,J＝8.7Hz,1H),7.99(s,1H),7.92(d,J＝1.5Hz,1H),7.88(dd,J＝8.3,1.9Hz, 1H),7.77(t,J＝7.6Hz,1H),7.60(t,J＝6.8Hz,1H),7.12(d,J＝8.5Hz,1H),4.56(s,1H),3.91(s, 3H),3.85(s,3H),2.21(br s,2H),2.06-1.98(m,6H),1.65-1.48(m,6H).13C NMR(101MHz, DMSO)δ166.82,155.95,151.05,149.51,148.18,144.69,144.68,131.44,129.75,127.00,125.49, 123.66,120.91,116.12,112.14,110.85,67.83,56.19,56.08,55.07,55.08,49.38,44.72,44.71, 40.72,35.37,30.62,30.61.HRMS m/z(ESI)calcd for C28H31N2O4[M+H]+459.2278 found: 459.2295,calcd for C28H30N2O4Na[M+Na]+481.2098 found:481.2123.
Preparation of the compound N- [3, 5-bis (trifluoromethyl) phenyl ] -2- (3, 4-dimethoxyphenyl) quinoline-4-carboxamide (5e)
Figure BDA0002304622230000171
Target Compound 5e
The specific synthesis method comprises reacting compound 5 to obtain off-white solid compound 5e, and reactingThe yield was 69% and the HPLC purity was 96%. Mp 215.1-216.5 ℃.1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),8.59-8.50(m, 2H),8.46(s,1H),8.18(dd,J＝15.6,8.4Hz,2H),7.98-7.95(m,2H),7.91(s,1H),7.88-7.81(m, 1H),7.65(t,J＝7.6Hz,1H),7.16(d,J＝8.5Hz,1H),3.93(s,3H),3.87(s,3H).13C NMR(101 MHz,DMSO)δ166.74,156.00,151.27,149.59,148.35,142.22,141.19,131.50,131.17,131.06, 130.82,129.93,127.60,125.47,125.06,123.03,122.34,120.96,120.28,120.26,117.48,117.24, 112.23,110.85,56.20,56.10.HRMS m/z(ESI)calcd for C26H19F6N2O3[M+H]+521.1294 found: 521.1286,calcd for C26H18F6N2O3Na[M+Na]+543.1114 found:543.1125.
Preparation of the Compound 2- (3, 4-Dimethoxyphenyl) -N- (3-methoxyphenyl) quinoline-4-carboxamide (5f)
Figure BDA0002304622230000172
Target Compound 5f
The specific synthesis method comprises the step of reacting compound 5 to obtain a white solid compound 5f, wherein the reaction yield is 65% and the HPLC purity is 95%. Mp 171.6-172.9 ℃.1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.33(s,1H), 8.12(dd,J＝11.6,8.5Hz,2H),7.98-7.95(m,2H),7.84-7.80(m,1H),7.67-7.59(m,1H),7.56-7.52 (m,1H),7.39(d,J＝8.2Hz,1H),7.31(d,J＝6.5Hz,1H),7.15(d,J＝8.5Hz,1H),6.76(dd,J＝ 11.6,6.5Hz,1H),3.93(s,3H),3.86(s,3H),3.78(s,3H).13C NMR(101MHz,DMSO)δ165.95, 160.03,156.03,151.15,149.55,148.30,143.43,140.52,131.24,130.63,130.11,129.90,127.38, 125.46,123.33,120.94,116.85,112.70,112.22,110.88,110.05,106.24,56.19,56.09,55.56.HRMS m/z(ESI)calcd for C25H23N2O4[M+H]+415.1652 found:415.1654,calcd for C25H22N2O4Na [M+Na]+437.1472 found:437.1482.
Preparation of the compound 2- (3, 4-dimethoxyphenyl) -N- (3-fluorophenyl) quinoline-4-carboxamide (5g)
Figure BDA0002304622230000181
Target Compound 5g
The specific synthesis method comprises reacting compound 5 to obtain white solid compound 5g, with reaction yield of 63% and HPLC purity of 95%. Mp 203.9-205.6 ℃.1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),8.37(s,1H), 8.17-8.08(m,2H),8.01-7.95(m,2H),7.86-7.79(m,2H),7.64(ddd,J＝8.2,6.8,1.3Hz,1H), 7.59-7.54(m,1H),7.50-7.42(m,1H),7.15(d,J＝9.0Hz,1H),7.01(td,J＝8.4,2.6Hz,1H),3.93 (s,3H),3.86(s,3H).13C NMR(101MHz,DMSO)δ166.19,156.02,151.18,149.56,148.30, 143.06,131.17,131.05,130.95,130.70,129.92,127.47,125.41,123.23,120.95,116.95,116.23, 116.20,112.22,110.88,56.19,56.10.HRMS m/z(ESI)calcd for C24H20FN2O3[M+H]+403.1452 found:403.1460,calcd for C24H19FN2O3Na[M+Na]+425.1272 found:525.1276.
Preparation of the Compound 2- (3, 4-Dimethoxyphenyl) -N- (4-ethoxyphenyl) quinoline-4-carboxamide (5h)
Figure BDA0002304622230000182
Compound of interest 5h
The specific synthesis method comprises the step of reacting compound 5 to obtain a white solid compound 5h, wherein the reaction yield is 60% and the HPLC purity is 95%. Mp 169.3-170.1 ℃.1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.32(s,1H), 8.16-8.10(m,2H),7.97(d,J＝6.9Hz,2H),7.81(ddd,J＝8.3,6.9,1.4Hz,1H),7.77-7.71(m,2H), 7.62(ddd,J＝8.3,6.8,1.2Hz,1H),7.18-7.11(m,1H),6.97(d,J＝9.0Hz,2H),4.03(q,J＝6.9Hz, 2H),3.93(s,3H),3.86(s,3H),1.34(t,J＝6.9Hz,3H).13C NMR(101MHz,DMSO)δ165.43, 156.03,155.54,151.13,149.55,148.31,143.61,132.41,131.28,130.58,129.87,127.30,125.57, 123.46,121.96,116.83,114.94,112.21,110.88,63.64,56.18,56.09,15.16.HRMS m/z(ESI)calcd for C26H25N2O4[M+H]+429.1809 found:429.1813,calcd for C26H24N2O4Na[M+Na]+451.1628 found:451.1633.
Preparation of the compound 2- (3, 4-dimethoxyphenyl) -N- (4-fluoro-2-nitrophenyl) quinoline-4-carboxamide (5i)
Figure BDA0002304622230000183
Target Compound 5i
The specific synthesis method comprises the step of reacting compound 5 to obtain a light yellow solid compound 5i, wherein the reaction yield is 45%, and the HPLC purity is 95%. Mp 203.9-205.3 ℃.1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),8.35(s,1H), 8.23(dd,J＝8.4,1.4Hz,1H),8.19-8.13(m,1H),8.04(dd,J＝8.5,2.9Hz,1H),7.97(d,J＝2.1Hz, 1H),7.92(dd,J＝8.4,2.1Hz,1H),7.88-7.72(m,3H),7.67(ddd,J＝8.2,6.8,1.3Hz,1H),7.18(d, J＝8.5Hz,1H),3.94(s,3H),3.87(s,3H).13C NMR(101MHz,DMSO)δ166.08,160.31,157.86, 155.94,151.28,149.62,148.40,144.55,141.85,131.08,130.85,129.95,127.55,125.40,123.32, 121.79,121.57,120.87,117.23,113.09,112.28,110.80,56.18,56.13.HRMS m/z(ESI)calcd for C24H19FN3O5[M+H]+448.1303 found:448.1309,calcd for C24H18FN3O5Na[M+Na]+470.1123 found:470.1134.
Preparation of the compound N- [ 2-chloro-4- (trifluoromethyl) phenyl ] -2- (3, 4-dimethoxyphenyl) quinoline-4-carboxamide (5j)
Figure BDA0002304622230000191
Target Compound 5j
The specific synthesis method comprises the step of reacting compound 5 to obtain a white solid compound 5j, wherein the reaction yield is 70%, and the HPLC purity is 95%. Mp 186.8-187.5 ℃.1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.38(s,1H), 8.22(dd,J＝8.4,1.3Hz,1H),8.15(d,J＝8.4Hz,2H),8.04(d,J＝2.1Hz,1H),7.99-7.92(m,2H), 7.90-7.81(m,2H),7.66(ddd,J＝8.2,6.9,1.3Hz,1H),7.17(d,J＝8.4Hz,1H),3.93(s,3H),3.87 (s,3H).13C NMR(101MHz,DMSO)δ166.47,155.95,151.23,149.60,148.33,142.33,138.85, 131.20,130.71,129.93,129.31,128.53,127.50,127.34,127.30,125.44,125.18,123.35,120.94, 117.35,112.25,110.85,56.18,56.11.HRMS m/z(ESI)calcd for C25H19ClF3N2O3[M+H]+ 487.1031 found:487.1037,calcd for C25H18ClF3N2O3Na[M+Na]+509.0850 found:509.0862.
Preparation of the Compound 2- (3, 4-Dimethoxyphenyl) -N- [4- (trifluoromethyl) phenyl ] quinoline-4-carboxamide (5k)
Figure BDA0002304622230000192
Target Compound 5k
The specific synthesis method comprises the step of reacting compound 5 to obtain a white solid compound 5k, wherein the reaction yield is 67%, and the HPLC purity is 95%. Mp 211.3-212.6 ℃.1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.40(s,1H), 8.19-8.09(m,2H),8.05(d,J＝8.5Hz,2H),7.98(dq,J＝4.5,2.1Hz,2H),7.88-7.76(m,3H),7.64 (ddd,J＝8.2,6.9,1.3Hz,1H),7.15(d,J＝9.0Hz,1H),3.92(s,3H),3.86(s,3H).13C NMR(101 MHz,DMSO)δ166.44,156.02,151.19,149.56,148.30,142.90,131.14,130.73,129.94,127.52, 126.66,126.62,125.35,124.75,123.18,120.96,120.39,117.03,112.23,110.88,56.19,56.10. HRMS m/z(ESI)calcd for C25H20F3N2O3[M+H]+453.1421 found:453.1423,calcd for C25H19F3N2O3Na[M+Na]+475.1240 found:475.1252.
Preparation of the compound N- (4-tert-butylphenyl) -2- (3, 4-dimethoxyphenyl) quinoline-4-carboxamide (5l)
Figure BDA0002304622230000201
Target Compound 5l
The specific synthesis method comprises reacting compound 5 to obtain white solid compound 5l with reaction yield of 61% and HPLC purity of 95%. Mp 228.4-229.3 ℃.1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.31(s,1H), 8.17-8.08(m,2H),7.96(d,J＝7.3Hz,2H),7.82(ddd,J＝8.4,6.9,1.4Hz,1H),7.75(d,J＝8.7Hz, 1H),7.62(ddd,J＝8.1,6.8,1.3Hz,1H),7.42(d,J＝8.7Hz,2H),7.14(d,J＝8.9Hz,1H),3.92(s, 3H),3.86(s,3H),1.30(s,9H).13C NMR(101MHz,DMSO)δ165.72,156.01,151.14,149.55, 148.31,146.98,143.54,136.82,131.26,130.60,129.89,127.33,125.88,125.51,123.43,120.91, 120.20,116.85,112.22,110.88,56.18,56.09,34.60,31.68.HRMS m/z(ESI)calcd for C28H29N2O3 [M+H]+441.2173 found:441.2180,calcd for C28H28N2O3Na[M+Na]+463.1992 found 463.1995 preparation of Compound 2- (3, 4-dimethoxyphenyl) -N- (2,4, 6-trimethylphenyl) quinoline-4-carboxamide (5m)
Figure BDA0002304622230000202
Target Compound 5m
The specific synthesis method comprises the step of reacting compound 5 to obtain an off-white solid compound 5m, wherein the reaction yield is 59%, and the HPLC purity is 95%. Mp 222.8-223.9 ℃.1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.26(d,J＝6.7 Hz,2H),8.15(d,J＝8.4Hz,1H),7.97(s,1H),7.91(d,J＝8.4Hz,1H),7.83(t,J＝7.7Hz,1H), 7.66(t,J＝7.7Hz,1H),7.18(d,J＝8.4Hz,1H),6.99(s,2H),3.93(s,3H),3.87(s,3H),2.33(s, 6H),2.28(s,3H).13C NMR(101MHz,DMSO)δ165.90,156.06,151.19,149.61,148.44,143.32, 136.49,135.57,132.30,131.38,130.65,129.94,128.99,127.40,125.60,123.67,120.95,116.95, 112.30,110.91,56.17,56.12,21.03,18.74.HRMS m/z(ESI)calcd for C27H27N2O3[M+H]+ 427.2016 found:427.2021,calcd for C27H26N2O3Na[M+Na]+449.1836 found:449.1845.
Preparation of the compound N- (2, 4-di-tert-butyl-5-hydroxyphenyl) -2- (3, 4-dimethoxyphenyl) quinoline-4-carboxamide (5N)
Figure BDA0002304622230000211
Target Compound 5n
The specific synthesis method comprises the step of reacting compound 5 to obtain a white solid compound 5n, wherein the reaction yield is 58% and the HPLC purity is 95%. Mp 254.1-255.5 ℃.1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),9.33(s,1H), 8.27(dd,J＝8.4,1.4Hz,1H),8.16(d,J＝8.1Hz,2H),7.92(d,J＝2.1Hz,1H),7.88-7.81(m,2H), 7.67(ddd,J＝8.3,6.8,1.3Hz,1H),7.25(s,1H),7.20(d,J＝8.5Hz,1H),6.79(s,1H),3.93(s,3H), 3.87(s,3H),1.40(br s,18H).13C NMR(101MHz,DMSO)δ166.85,155.92,154.26,151.21, 149.64,148.53,143.08,136.66,134.40,133.67,131.35,130.67,130.01,127.31,125.53,125.01, 123.64,120.68,119.41,116.66,112.39,110.74,56.14,56.10,34.92,31.66,29.82.HRMS m/z(ESI) calcd for C32H37N2O4[M+H]+513.2748 found:513.2754,calcd for C32H36N2O4Na[M+Na]+ 535.2567 found:535.2565.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- [ 2-chloro-5- (trifluoromethyl) phenyl ] quinolone-4-carboxamide (8N)
Figure BDA0002304622230000212
Target Compound 8n
In a 25mL round bottom flask, intermediate compound 7(144.5 mg)0.5mmol) is dissolved in 6mL of phosphorus oxychloride, and the temperature is raised to 107 ℃ for reaction for 4h-5 h. TLC monitoring, after the reaction was completed, the reaction solution was spin-dried. The resultant acid chloride compound was dissolved in anhydrous DMF, and 3-amino-4-chlorotrifluoromethane (4,117mg,0.6mmol) and DMAP (12.2mg,0.1 mmol) were added to the solution, followed by reaction under nitrogen protection at room temperature overnight. TLC monitoring, after the reaction is completed, water is added to dilute the reaction solution, ethyl acetate is used for extraction, saturated NaCl aqueous solution is used for washing three times, and anhydrous Na2SO4Drying, spin-drying, and purifying with mixed solvent of ethyl acetate and petroleum ether to obtain target product 8N, i.e. 2- (1-benzofuran-2-yl) -N- [ 2-chloro-5- (trifluoromethyl) phenyl]Quinolone-4-carboxamide, reaction yield 55.2%, HPLC purity 96%. Mp 245.1-246.9 ℃.1H NMR(400MHz, DMSO-d6)δ10.94(s,1H),8.46(s,1H),8.32(s,1H),8.29(d,J＝8.4Hz,1H),8.21(d,J＝8.40Hz, 1H),7.95(s,1H),7.93-7.88(m,2H),7.82(dd,J＝7.7Hz,1.1Hz,1H),7.78(d,J＝8.3Hz,1H), 7.77-7.72(m,2H),7.49-7.45(m,1H),7,36(t,J＝9.5Hz,1H).13C NMR(101MHz,DMSO)δ 166.12,155.50,154.87,148.40,148.35,142.81,135.77,133.68,131.50,131.31,129.91,128.92, 128.75,128.60,128.44,126.69,125.80,125.33,124.85,124.81,123.96,122.74,117.05,112.15, 107.08.HRMS m/z(ESI)calcd for C25H15ClF3N2O2[M+H]+467.0769 found:467.0782,calcd for C25H14ClF3N2O2Na[M+Na]+489.0583 found:489.0616.
Preparation of the Compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (thien-2-yl) quinoline-4-carboxamide (8a)
Figure BDA0002304622230000221
Target Compound 8a
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 8a, the reaction yield is 51%, and the HPLC purity is 96%. Mp 252.2-253.6 ℃.1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.39(s,1H), 8.28(d,J＝1.2Hz,1H),8.21(d,J＝6.9Hz,1H),8.08(dd,J＝11.5,5.7Hz,2H),7.89-7.79(m,3H), 7.73(dd,J＝8.5,2.2Hz,1H),7.68-7.64(m,1H),7.28(dd,J＝4.9,3.7Hz,1H).13C NMR(101 MHz,DMSO)δ166.27,152.09,148.11,144.62,142.67,135.79,133.53,131.52,131.06,130.71, 129.39,129.14,128.87,128.55,128.21,127.66,125.66,125.07,124.74,123.57,116.63.HRMS m/z(ESI)calcd for C21H13ClF3N2OS[M+H]+433.0384 found:433.0391,calcd for C21H12ClF3N2OSNa[M+Na]+455.0203 found:455.0217.
Preparation of the Compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (5-methylthiophen-2-yl) quinolone-4-carboxamide (8b)
Figure BDA0002304622230000222
Target Compound 8b
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 8b, with the reaction yield of 46% and the HPLC purity of 96%. Mp 216.1-217.9 ℃.1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.31(s,1H), 8.27(s,1H),8.20(d,J＝8.1Hz,1H),8.02(d,J＝8.4Hz,1H),7.88(t,J＝6.9Hz,2H),7.83-7.78 (m,1H),7.72(dd,J＝8.4,1.5Hz,1H),7.63(t,J＝8.1Hz,1H),6.97(dd,J＝3.6,1.0Hz,1H),2.54 (s,3H).13C NMR(101MHz,DMSO)δ166.33,152.17,148.13,144.58,142.52,142.22,135.90, 131.49,130.93,129.27,128.87,128.54,128.38,127.59,127.37,125.66,125.45,125.03,124.69, 123.40,116.25,15.89.HRMS m/z(ESI)calcd for C22H15ClF3N2OS[M+H]+447.0540 found: 447.0541,calcd for C22H14ClF3N2OSNa[M+Na]+469.0360 found:469.0440.
Preparation of the Compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (4-methoxyphenyl) quinoline-4-carboxamide (8c)
Figure BDA0002304622230000231
Target Compound 8c
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 8c, the reaction yield is 56%, and the HPLC purity is 96%. Mp 205.7-207.1 ℃.1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.39(s,1H), 8.33(d,J＝8.8Hz,2H),8.28(d,J＝1.2Hz,1H),8.25(d,J＝8.0Hz,1H),8.14(d,J＝8.3Hz,1H), 7.89-7.82(m,2H),7.73(dd,J＝8.4,1.6Hz,1H),7.68-7.64(m,1H),7.16(d,J＝8.9Hz,2H),3.87 (s,3H).13C NMR(101MHz,DMSO)δ166.54,161.42,155.90,148.39,142.37,135.85,133.72, 131.48,131.01,130.75,129.86,129.25,128.87,128.55,127.49,125.54,125.32,125.28,124.79, 124.76,123.30,117.26,114.83,55.84.HRMS m/z(ESI)calcd for C24H17ClF3N2O2[M+H]+ 457.0925 found:457.0951,calcd for C24H16ClF3N2O2Na[M+Na]+479.0745 found:479.0740.
Preparation of the Compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (tetrahydropyran-4-yl) quinolone-4-carboxamide (8d)
Figure BDA0002304622230000232
Target Compound 8d
The specific synthesis method uses compound 8n, and the oily semisolid compound 8d is obtained by reaction treatment, the reaction yield is 27%, and the HPLC purity is 96%. Mp 169.4-168.5 ℃.1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.23(t,J ＝3.8Hz,2H),8.06(d,J＝8.4Hz,1H),7.87-7.79(m,3H),7.72(dd,J＝8.3,1.2Hz,1H),7.65(t,J ＝8.0Hz,1H),4.04(t,J＝3.0Hz,1H),4.01(t,J＝2.3Hz,1H),3.56-3.50(m,2H),3.26-3.19(m, 1H),2.01-1.91(m,4H).13C NMR(101MHz,DMSO)δ166.54,164.72,147.98,142.08,135.82, 133.75,131.46,130.37,129.57,128.89,128.56,127.36,125.55,125.28,124.78,123.36,119.04, 67.51,67.51,43.64,32.15,32.15.HRMS m/z(ESI)calcd for C22H19ClF3N2O2[M+H]+435.1082 found:435.1068,calcd for C22H18ClF3N2O2Na[M+Na]+457.0901 found:457.0890.
Preparation of the compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (furan-2-yl) quinoline-4-carboxamide (8e)
Figure BDA0002304622230000233
Target Compound 8e
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 8e, the reaction yield is 49%, and the HPLC purity is 96%. Mp 189.9-190.5 ℃.1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.29-8.23(m, 3H),8.10(d,J＝8.3Hz,1H),8.00(d,J＝1.0Hz,1H),7.88-7.83(m,2H),7.73(dd,J＝8.9,2.0Hz, 1H),7.69-7.65(m,1H),7.46(d,J＝3.3Hz,1H),6.79(dd,J＝5.5,1.8Hz,1H).13C NMR(101 MHz,DMSO)δ166.21,153.10,148.46,148.30,145.89,142.62,135.76,133.67,131.48,131.08, 129.62,128.90.128.58,127.78,125.73,125.31,124.78,123.46,116.23,113.25,111.82.HRMS m/z(ESI)calcd for C21H13ClF3N2O2[M+H]+417.0612 found:417.0589,calcd for C21H12ClF3N2O2Na[M+Na]+439.0432 found:439.0428.
Preparation of the compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (5-methylfuran-2-yl) quinoline-4-carboxamide (8f)
Figure BDA0002304622230000241
Target Compound 8f
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 8f, the reaction yield is 55%, and the HPLC purity is 96%. Mp 208.9-209.9 ℃.1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.27(s,1H), 8.21(d,J＝8.2Hz,1H),8.16(s,1H),8.08(d,J＝8.4Hz,1H),7.88-7.80(m,2H),7.72(d,J＝8.8 Hz,1H),7.64(t,J＝7.4Hz,1H),7.36(d,J＝3.2Hz,1H),6.40(d,J＝2.6Hz,1H),2.45(s,3H). 13C NMR(101MHz,DMSO)δ166.27,155.19,151.63,148.45,148.33,142.49,135.79,133.65, 131.47,130.96,129.50,128.89,128.57,127.43,125.68,125.23,124.78,123.25,116.05,113.21, 109.64,14.14.HRMS m/z(ESI)calcd for C22H15ClF3N2O2[M+H]+431.0769 found:431.0791, calcd for C22H14ClF3N2O2Na[M+Na]+453.0588 found:455.0627.
Preparation of the Compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-cyclopentylquinoline-4-carboxamide (8g)
Figure BDA0002304622230000242
Target Compound 8g
The specific synthesis method is to use the compound 8n, and the reaction treatment can obtain 8g of colorless oily semisolid compound, the reaction yield is 23%, and the HPLC purity is 96%. Mp 187.9-189.6 ℃.1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.25(s, 1H),8.21(d,J＝8.4Hz,1H),8.14(s,1H),8.08-8.01(m,1H),7.90-7.85(m,1H),7.79(ddd,J＝8.3, 6.8,1.4Hz,1H),7.75-7.70(m,1H),7.64(ddd,J＝8.2,6.9,1.3Hz,1H),3.01-2.88(m,2H), 2.70-2.55(m,3H),2.11-1.91(m,3H),0.84(q,J＝5.3,4.4Hz,1H).HRMS m/z(ESI)calcd for C22H19ClF3N2O[M+H]+419.1133 found:419.0959,calcd for C22H18ClF3N2ONa[M+Na]+ 441.0952 found:441.0790.
Preparation of the Compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2-cyclohexylquinoline-4-carboxamide (8h)
Figure BDA0002304622230000251
Target Compound 8h
The specific synthesis method is to use the compound 8n to react to obtain a colorless oily semisolid compound 8h, wherein the reaction yield is 25 percent, and the HPLC purity is 96 percent. Mp 126.6-128.3 ℃.1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.23-8.21 (m,2H),8.04(d,J＝8.4Hz,1H),7.86(d,J＝8.4Hz,1H),7.81-7.70(m,3H),7.63(t,J＝7.30Hz, 1H),2.95(t,J＝11.6Hz,1H),1.99(d,J＝11.9Hz,2H),1.86(d,J＝12.8Hz,2H),1.77-1.65(m, 3H),1.49-1.40(m,2H),1.34(d,J＝12.4Hz,1H).13C NMR(101MHz,DMSO)δ166.63,166.30, 148.00,141.90,135.90,133.78,131.44,130.23,129.51,128.88,128.56,127.14,125.51,125.43, 125.29,124.72,123.29,122.72,119.08,46.87,32.52,26.43,26.09.HRMS m/z(ESI)calcd for C23H21ClF3N2O[M+H]+433.1289 found:433.1251,calcd for C23H20ClF3N2ONa[M+Na]+ 455.1108 found:455.1088.
Preparation of the Compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (3-fluoro-4-methoxyphenyl) quinolinone-4-carboxamide (8i)
Figure BDA0002304622230000252
Target Compound 8i
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 8i, the reaction yield is 48%, and the HPLC purity is 96%. Mp 205.1-205.9 ℃.1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.44(s,1H), 8.28-8.15(m,5H),7.89-7.83(m,2H),7.73(dd,J＝8.3,1.3Hz,1H),7.68(t,J＝8.0Hz,1H),7.39 (t,J＝8.6Hz,1H),3.96(s,3H).13C NMR(101MHz,DMSO)δ166.42,154.70,153.51,151.08, 149.35,148.20,142.57,135.86,133.66,131.50,130.88,129.95,128.88,128.55,127.81,125.56, 125.22,124.81,124.38,123.50,117.26,114.99,114.49,56.68.HRMS m/z(ESI)calcd for C24H16ClF4N2O2[M+H]+475.0831 found:475.0845,calcd for C24H15ClF4N2O2Na[M+Na]+ 497.0650 found:497.0658.
Preparation of the Compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (2-ethoxypyridin-3-yl) quinolinone-4-carboxamide (8j)
Figure BDA0002304622230000261
Target Compound 8j
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 8j, the reaction yield is 28%, and the HPLC purity is 96%. Mp 163.6-165.4 ℃.1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.43-8.40(m, 2H),8.34(dd,J＝4.9,1.9Hz,1H),8.31(s,1H),8.24(s,1H),8.18(d,J＝8.4Hz,1H),7.90-7.86(m, 2H),7.73(t,J＝7.2Hz,2H),7.23(dd,J＝7.4,4.9Hz,1H),4.51(q,J＝8.6Hz,2H),1.39(t,J＝7.0 Hz,3H).13C NMR(101MHz,DMSO)δ160.95,154.46,148.65,148.42,145.02,140.41,135.73, 133.68,131.51,130.80,129.98,126.13,125.66,125.09,124.87,123.49,122.68,122.66,122.18, 120.97,118.09,116.20,62.30,14.91.HRMS m/z(ESI)calcd for C24H18ClF3N3O2[M+H]+ 472.1034 found:472.1032,calcd for C24H17ClF3N3O2Na[M+Na]+494.0854 found:494.0868.
Preparation of the compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (pyrazin-2-yl) quinolinone-4-carboxamide (8k)
Figure BDA0002304622230000262
Target Compound 8k
The specific synthesis method uses compound 8n, and the reaction treatment can obtain gray solid compound 8k, the reaction yield is 29%, and the HPLC purity is 96%. Mp 222.7-223.9 ℃.1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),9.81(d,J＝1.9 Hz,1H),8.88-8.84(m,2H),8.77(s,1H),8.35(d,J＝8.1Hz,1H),8.30-8.27(m,2H),7.94(t,J＝ 7.2Hz,1H),7.88(d,J＝8.4Hz,1H),7.80(t,J＝7.3Hz,1H),7.73(d,J＝7.7Hz,1H).13C NMR (101MHz,DMSO)δ166.25,153.90,150.11,148.06,146.19,144.65,143.48,143.18,135.75, 133.83,131.45,131.31,130.36,129.10,128.95,128.62,125.92,125.52,124.91,124.74,117.14. HRMS m/z(ESI)calcd for C21H13ClF3N4O[M+H]+429.0724 found:429.0715,calcd for C21H12ClF3N4ONa[M+Na]+451.0544 found:451.0543.
Preparation of the Compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (pyridin-3-yl) quinolinone-4-carboxamide (8l)
Figure BDA0002304622230000263
Target Compound 8l
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 8l, the reaction yield is 28%, and the HPLC purity is 96%. Mp 251.3-252.4 ℃.1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),9.53(s,1H), 8.75(d,J＝3.8Hz,1H),8.70(d,J＝7.9Hz,1H),8.54(s,1H),8.31(t,J＝6.5Hz,2H),8.22(d,J＝ 8.3Hz,1H),7.92-7.87(m,2H),7.74(t,J＝7.5Hz,2H),7.64(q,J＝7.7,4.8Hz,1H).13C NMR (101MHz,DMSO)δ166.29,154.20,151.19,148.93,148.42,142.87,135.91,135.12,134.06, 133.67,131.49,131.07,130.16,128.88,128.56,128.38,125.67,125.17,124.75,124.46,123.86, 117.80.HRMS m/z(ESI)calcd for C22H14ClF3N3O[M+H]+428.0772 found:428.0764,calcd for C22H13ClF3N3ONa[M+Na]+450.0591 found:450.0600.
Preparation of the Compound 2- (2H-1, 3-benzodioxol-5-yl) -N- [ 2-chloro-5- (trifluoromethyl) phenyl ] quinolone-4-carboxamide (8m)
Figure BDA0002304622230000271
Target Compound 8m
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 8m, the reaction yield is 56%, and the HPLC purity is 96%. Mp 196.5-197.7 ℃.1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.39(s,1H), 8.27-8.24(m,2H),8.14(d,J＝8.4Hz,1H),7.94-7.92(m,2H),7.85(dd,J＝17.9,7.8Hz,2H),7.73 (dd,J＝8.3,1.3Hz,1H),7.66(t,J＝8.1Hz,1H),7.14(d,J＝8.6Hz,1H),6.15(s,2H).13C NMR (101MHz,DMSO)δ166.46,155.61,149.51,148.68,148.28,142.37,135.88,133.73,132.91, 131.48,130.77,129.92,128.88,128.55,127.63,125.54,125.32,124.74,123.43,122.38,117.47, 109.09,107.58,102.09.HRMS m/z(ESI)calcd for C24H15ClF3N2O3[M+H]+471.0718 found: 471.0711,calcd for C24H14ClF3N2O3Na[M+Na]+493.0537 found:493.0538.
Preparation of the compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (2, 3-dihydro-1, 4-benzodioxin-6-yl) quinolone-4-carboxamide (8o)
Figure BDA0002304622230000272
Target Compound 8o
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 80, the reaction yield is 55%, and the HPLC purity is 96%. Mp 201.7-203.2 ℃.1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.38(s,1H), 8.26(t,J＝7.9Hz,2H),8.13(d,J＝8.4Hz,1H),7.90-7.81(m,4H),7.73(dd,J＝8.5,1.7Hz,1H), 7.66(t,J＝7.6Hz,1H),7.07(d,J＝8.4Hz,1H),4.34(s,4H).13C NMR(101MHz,DMSO)δ 166.47,155.56,148.34,145.82,144.25,142.30,135.90,133.77,131.89,131.45,130.73,129.92, 128.88,128.55,127.56,125.54,124.74,123.41,122.75,120.99,117.97,117.34,116.39,64.88, 64.60.HRMS m/z(ESI)calcd for C25H17ClF3N2O3[M+H]+485.0874 found:485.0866,calcd for C25H16ClF3N2O3Na[M+Na]+507.0694 found:507.0700.
Preparation of the compound N- [ 2-chloro-5- (trifluoromethyl) phenyl ] -2- (7-methoxy-1-benzofuran-2-yl) quinolinone-4-carboxamide (8p)
Figure BDA0002304622230000281
Target Compound 8p
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 8p, the reaction yield is 41%, and the HPLC purity is 96%. Mp 254.6-255.9 ℃.1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.43(s,1H), 8.31(t,J＝8.8Hz,2H),8.21(d,J＝8.4Hz,1H),7.95-7.87(m,3H),7.76-7.71(m,2H),7.37(d,J＝ 7.3Hz,1H),7.27(t,J＝7.9Hz,1H),7.07(d,J＝7.6Hz,1H),4.02(s,3H).13C NMR(101MHz, DMSO)δ166.12,154.68,148.39,148.32,145.73,144.76,142,87,135.90,133.58,131.47,131.29, 130.29,129.89,128.58,128.41,125.81,125.31,124.95,124.74,123.97,122.75,116.99,114.56, 108.71,108.05,56.29.HRMS m/z(ESI)calcd for C26H17ClF3N2O3[M+H]+497.0874 found: 497.0833,calcd for C26H16ClF3N2O3Na[M+Na]+519.0694 found:519.0660.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (pyridin-3-yl) quinolinone-4-carboxamide (12a)
Figure BDA0002304622230000282
Target Compound 12a
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12a, the reaction yield is 32%, and the HPLC purity is 96%. Mp 270.7-271.9 ℃.1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.97(d,J＝2.3 Hz,1H),8.42-8.40(m,2H),8.28(d,J＝8.2Hz,1H),8.20(d,J＝8.8Hz,2H),7.98(s,1H),7.90(t, J＝7.2Hz,1H),7.80(dd,J＝14.7,7.7Hz,2H),7.71(t,J＝7.8Hz,1H),7.52-7.44(m,2H),7.36(t, J＝7.4Hz,1H).13C NMR(101MHz,DMSO)δ165.86,155.50,154.61,148.43,145.65,143.01, 142.11,135.91,131.33,129.95,128.73,128.47,127.56,126.71,125.73,124.26,124.17,123.81, 122.73,116.90,112.18,108.00.HRMS m/z(ESI)calcd for C23H16N3O2[M+H]+366.1237 found: 366.1242,calcd for C23H15N3O2Na[M+Na]+388.1056 found:388.1080.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (pyridin-4-yl) quinolinone-4-carboxamide (12b)
Figure BDA0002304622230000291
Target Compound 12b
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12b, the reaction yield is 30%, and the HPLC purity is 96%. Mp 263.9-264.6 ℃.1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),8.57(d,J＝5.3 Hz,2H),8.40(d,J＝5.7Hz,1H),8.14-8.24(m,2H),7.98(s,1H),7.92(dd,J＝14.3,7.2Hz,1H), 7.85-7.76(m,4H),7.72(t,J＝8.0Hz,1H),7.46(t,J＝7.5Hz,1H),7.36(t,J＝7.4Hz,1H).13C NMR(101MHz,DMSO)δ166.40,155.51,154.57,151.06,148.39,145.88,142.79,131.36,129.98, 128.72,128.55,126.72,125.59,124.17,123.66,122.73,116.92,114.51,114.44,112.18,108.06. HRMS m/z(ESI)calcd for C23H16N3O2[M+H]+366.1237 found:366.1240,calcd for C23H15N3O2Na[M+Na]+388.1056 found:388.1066.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (1-methylpiperidin-4-yl) quinoline-4-carboxamide (12c)
Figure BDA0002304622230000292
Target Compound 12c
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12c, the reaction yield is 29%, and the HPLC purity is 96%. Mp 242.4-246.3 ℃.1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝7.4Hz,1H), 8.23-8.09(m,3H),7.97-7.85(m,2H),7.80(dd,J＝14.4,8.0Hz,2H),7.70(t,J＝7.7Hz,1H),7.47 (t,J＝7.8Hz,1H),7.36(t,J＝7.5Hz,1H),4.17(d,J＝10.1Hz,1H),3.39(d,J＝12.2Hz,2H), 3.09(d,J＝12.3Hz,2H),2.74(s,3H),2.25-2.08(m,2H),1.82(q,J＝6.2Hz,2H).13C NMR(101 MHz,DMSO)δ166.38,155.45,154.68,148.35,148.32,143.78,131.17,129.84,128.74,128.16, 126.64,125.81,124.17,124.07,122.70,116.31,112.15,107.69,53.05,44.74,43.71,29.53.HRMS m/z(ESI)calcd for C24H24N3O2[M+H]+386.1863 found:386.1864,calcd for C24H23N3O2Na [M+Na]+408.1682 found:408.1740.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (5-bromo-4-fluoro-2-methylphenyl) quinolinone-4-carboxamide (12d)
Figure BDA0002304622230000301
Target Compound 12d
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12d, the reaction yield is 25%, and the HPLC purity is 96%.1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.42(s,1H),8.29-8.18(m,2H), 8.00-7.97(m,1H),7.90(t,J＝7.0Hz,1H),7.80(dd,J＝16.4,7.9Hz,1H),7.73(t,J＝8.1Hz,1H), 7.73(t,J＝8.1Hz,1H),7.67(s,1H),7.49-7.30(m,2H),7.10(d,J＝9.6Hz,1H),7.05(d,J＝6.6 Hz,1H),2.14(s,3H).HRMS m/z(ESI)calcd for C25H17BrFN2O2[M+H]+475.0452 found: 475.0499,calcd for C25H16BrFN2O2Na[M+Na]+497.0271 found:497.0323.
Preparation of the Compound methyl (2S, 3S) -3- [2- (1-benzofuran-2-yl) quinolon-4-amido ] bicyclo [2.2.2] octane-2-carboxylate (12e)
Figure BDA0002304622230000302
Target Compound 12e
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12e, the reaction yield is 44%, and the HPLC purity is 96%. Mp 201.3-202.8 ℃.1H NMR(400MHz,DMSO-d6)δ8.97(d,J＝6.7Hz,1H),8.15 (d,J＝8.4Hz,1H),8.12(s,1H),8.07(d,J＝8.2Hz,1H),7.94(s,1H),7.86(t,J＝7.4Hz,1H), 7.79(t,J＝8.4Hz,2H),7.69(t,J＝7.4Hz,1H),7.46(t,J＝7.5Hz,1H),7.35(t,J＝7.3Hz,1H), 4.54(t,J＝6.9Hz,1H),3.71(s,3H),2.68(d,J＝5.6Hz,1H),1.94(d,J＝10.9Hz,2H),1.81(t,J＝ 11.7Hz,1H),1.68-1.39(m,7H).13C NMR(101MHz,DMSO)δ174.68,166.44,155.46,154.71, 148.31,144.16,131.09,129.82,128.76,128.09,126.58,125.73,124.20,124.12,122.67,116.20, 112.16,107.73,52.26,50.21,48.53,29.56,28.43,25.67,24.28,21.23,19.52.HRMS m/z(ESI) calcd for C28H27N2O4[M+H]+455.1965 found:455.1983,calcd for C28H26N2O4Na[M+Na]+ 477.1785 found:477.1803.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- [ (1R, 3S, 5R, 7S) -3-hydroxyadamantan-1-yl ] quinolone-4-carboxamide (12f)
Figure BDA0002304622230000311
Target Compound 12f
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12f, the reaction yield is 41%, and the HPLC purity is 96%. Mp 262.5-263.8 deg.C.1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.13(d,J＝8.5 Hz,1H),8.05(d,J＝8.2Hz,2H),7.93(s,1H),7.84(t,J＝7.5Hz,1H),7.80(t,J＝7.4Hz,2H), 7.69(t,J＝7.5Hz,1H),7.45(t,J＝7.7Hz,1H),7.35(t,J＝7.5Hz,1H),4.59(s,1H),2.23(s,2H), 2.07-2.05(m,6H),1.65-1.48(m,6H).13C NMR(101MHz,DMSO)δ166.35,155.43,154.80, 148.30,144.91,130.97,129.76,128.78,127.98,126.54,125.70,124.22,124.11,122.64,115.89, 112.16,107.57,67.83,55.16,49.36,44.70,35.35,30.63.HRMS m/z(ESI)calcd for C28H27N2O3 [M+H]+439.2016 found:439.2039,calcd for C28H26N2O3Na[M+Na]+461.1836 found:461.1871.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- [3, 5-bis (trifluoromethyl) phenyl ] quinolone-4-carboxamide (12g)
Figure BDA0002304622230000312
Target Compound 12g
The specific synthesis method comprises the step of reacting compound 8n to obtain 12g of a white solid compound, wherein the reaction yield is 26% and the HPLC purity is 96%. Mp 271.2-272.9 ℃.1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.51(d,J＝17.0 Hz,3H),8.25(dt,J＝21.1,8.0Hz,2H),8.04-7.89(m,3H),7.80(dd,J＝18.1,7.9Hz,2H),7.73(t, J＝7.7Hz,1H),7.53-7.44(m,1H),7.36(t,J＝7.5Hz,1H).13C NMR(101MHz,DMSO)δ166.17, 155.52,154.56,148.47,148.39,142.35,141.06,131.42,131.19,129.96,128.71,128.57,126.74, 125.79,124.18,122.75,120.42,117.08,112.16,108.02.HRMS m/z(ESI)calcd for C26H15F6N2O2 [M+H]+501.1032 found:501.1031,calcd for C26H14F6N2O2Na[M+Na]+523.0852 found: 523.0868.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (2,4, 6-trimethylphenyl) quinolinone-4-carboxamide (12h)
Figure BDA0002304622230000313
Compound of interest 12h
The specific synthesis method comprises the step of reacting compound 8n to obtain a white solid compound 12h, wherein the reaction yield is 21% and the HPLC purity is 96%. Mp 266.8-268.1 ℃.1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.30(s,1H), 8.25(dd,J＝8.4,1.3Hz,1H),8.20(d,J＝8.4Hz,1H),7.99(d,J＝0.9Hz,1H),7.90(ddd,J＝8.4, 6.9,1.4Hz,1H),7.85-7.78(m,2H),7.74(ddd,J＝8.3,6.9,1.2Hz,1H),7.50-7.44(m,1H), 7.40-7.33(m,1H),7.00(s,2H),2.34(s,6H),2.29(s,3H).13C NMR(101MHz,DMSO)δ165.53, 155.51,154.64,148.46,148.36,143.89,136.55,135.50,132.20,131.27,129.96,129.02,128.77, 128.37,126.66,125.75,124.21,124.17,122.71,116.38,112.22,107.91,21.03,18.76.HRMS m/z (ESI)calcd for C27H23N2O2[M+H]+407.1754 found:407.1760,calcd for C27H22N2O2Na[M+Na]+ 429.1573 found:429.1572.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (3-methoxyphenyl) quinolinone-4-carboxamide (12i)
Figure BDA0002304622230000321
Target Compound 12i
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12i, the reaction yield is 42%, and the HPLC purity is 96%. Mp 245.1-246.3 ℃.1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.36(s,1H), 8.23-8.14(m,2H),7.98(s,1H),7.93-7.86(m,1H),7.80(dd,J＝12.4,8.0Hz,2H),7.71(t,J＝7.6 Hz,1H),7.54(t,J＝2.2Hz,1H),7.46(t,J＝7.7Hz,1H),7.43-7.30(m,3H),6.78(dd,J＝8.2,2.5 Hz,1H),3.79(s,3H).13C NMR(101MHz,DMSO)δ165.43,160.06,155.49,154.66,148.41, 143.57,140.39,131.24,130.16,129.93,128.75,128.37,126.66,125.73,124.15,123.92,122.70, 116.71,112.75,112.18,110.20,107.94,106.31,55.58.HRMS m/z(ESI)calcd for C25H19N2O3 [M+H]+395.1390 found:395.1404,calcd for C25H18N2O3Na[M+Na]+417.1210 found:417.1212.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (3-bromophenyl) quinolone-4-carboxamide (12j)
Figure BDA0002304622230000322
Target Compound 12j
The specific synthesis method comprises the step of reacting compound 8n to obtain a white solid compound 12j, wherein the reaction yield is 21%, and the HPLC purity is 96%. Mp 287.1-288.2 ℃.1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.39(s,1H), 8.18(t,J＝7.6Hz,3H),7.98(s,1H),7.90(ddd,J＝8.3,6.8,1.4Hz,1H),7.84-7.69(m,4H),7.46(t, J＝8.4Hz,1H),7.41-7.33(m,3H).13C NMR(101MHz,DMSO)δ165.64,155.50,154.61,148.41, 143.13,140.75,131.37,131.32,129.94,128.73,128.46,127.37,126.70,125.71,124.16,123.81, 122.89,122.72,122.09,119.32,116.83,112.18,108.00.HRMS m/z(ESI)calcd for C24H16BrN2O2 [M+H]+443.0309 found:443.0393,calcd for C24H15BrN2O2Na[M+Na]+465.0209 found: 465.0213.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (3-fluorophenyl) quinolone-4-carboxamide (12k)
Figure BDA0002304622230000331
Target Compound 12k
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12k, the reaction yield is 20%, and the HPLC purity is 96%. Mp 295.3-296.9 ℃.1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.38(s,1H), 8.18(dd,J＝14.9,8.3Hz,2H),8.05-7.66(m,6H),7.62-7.30(m,4H),7.03(t,J＝8.6Hz,1H).13C NMR(101MHz,DMSO)δ165.66,155.50,154.61,148.41,143.20,131.32,129.95,128.73,128.46, 126.69,125.68,124.16,123.81,122.72,116.80,116.30,116.28,112.18,108.00.HRMS m/z(ESI) calcd for C24H16FN2O2[M+H]+383.1190 found:383.1194,calcd for C24H15FN2O2Na[M+Na]+ 405.1010 found:405.1017.
Preparation of the compound 2- (1-benzofuran-2-yl) -N- (4-tert-butylphenyl) quinolinone-4-carboxamide (12l)
Figure BDA0002304622230000332
Target Compound 12l
The specific synthesis method comprises the step of reacting compound 8n to obtain 12l of a white solid compound, wherein the reaction yield is 19% and the HPLC purity is 96%. Mp 247.6-248.8 ℃.1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.34(s,1H), 8.23-8.13(m,2H),7.97(br s,1H),7.89(ddd,J＝8.4,6.8,1.4Hz,1H),7.83-7.73(m,4H),7.70 (ddd,J＝8.2,6.9,1.3Hz,1H),7.49-7.41(m,3H),7.35(t,J＝8.4Hz,1H),1.31(s,9H).13C NMR (101MHz,DMSO)δ165.21,155.48,154.68,148.42,148.40,147.12,143.74,136.68,131.21, 129.91,128.75,128.31,126.64,125.94,125.76,124.14,124.01,122.70,120.29,116.65,112.16, 107.88,34.62,31.68.HRMS m/z(ESI)calcd for C28H25N2O2[M+H]+421.1911 found:421.1923, calcd for C28H24N2O2Na[M+Na]+443.1730 found:443.1721.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- [ 2-chloro-4- (trifluoromethyl) phenyl ] quinolone-4-carboxamide (12m)
Figure BDA0002304622230000341
Target Compound 12m
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12m, the reaction yield is 44%, and the HPLC purity is 96%. Mp 249.1-249.9 deg.C.1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.44(s,1H), 8.22(tdd,J＝21.0,12.5,6.0Hz,3H),8.06(d,J＝2.2Hz,1H),7.98-7.69(m,6H),7.49(dt,J＝15.0, 7.6Hz,1H),7.36(t,J＝7.4Hz,1H).HRMS m/z(ESI)calcd for C25H15ClF3N2O2[M+H]+ 467.0769 found:467.0774,calcd for C25H14ClF3N2O2Na[M+Na]+489.0588 found:489.0929.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- [4- (trifluoromethyl) phenyl ] quinolone-4-carboxamide (12N)
Figure BDA0002304622230000342
Target Compound 12n
The specific synthesis method comprises the steps of using a compound 8n, and carrying out reaction treatment to obtain a white solid compound 12n, wherein the reaction yield is 35%, and the HPLC purity is 96%. Mp 294.8-296.1 ℃.1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.42(s,1H), 8.19(dd,J＝16.9,8.4Hz,2H),8.05(d,J＝8.4Hz,2H),7.99(s,1H),7.90(ddd,J＝8.4,6.8,1.5 Hz,1H),7.82-7.77(m,4H),7.72(ddd,J＝8.3,6.9,1.3Hz,1H),7.49-7.44(m,1H),7.36(t,J＝7.5 Hz,1H).13C NMR(101MHz,DMSO)δ165.91,155.51,154.61,148.42,143.06,142.77,131.32, 129.97,128.73,128.48,126.69,126.65,126.15,125.64,124.90,124.58,124.15,123.78,123.46, 122.72,120.49,116.88,112.17,108.01.HRMS m/z(ESI)calcd for C25H16F3N2O2[M+H]+ 433.1158 found:433.1166,calcd for C25H15F3N2O2Na[M+Na]+455.0978 found:455.0982.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (2, 4-di-tert-butyl-5-hydroxyphenyl) quinolone-4-carboxamide (12o)
Figure BDA0002304622230000343
Target Compound 12o
The specific synthesis method is to synthesize the compound 8n,the reaction treatment gave compound 12o as a white solid in 19% yield and 96% HPLC purity. Mp 285.9-286.9 ℃.1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.35(s,1H), 8.32-8.15(m,3H),7.96-7.88(m,2H),7.86-7.70(m,3H),7.47(ddd,J＝8.4,7.2,1.4Hz,1H), 7.40-7.33(m,1H),7.26(s,1H),6.81(s,1H),1.40(d,J＝4.0Hz,18H).HRMS m/z(ESI)calcd for C32H33N2O3[M+H]+493.2486 found:493.2488,calcd for C32H32N2O3Na[M+Na]+515.2305 found: 515.2313.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (naphthalen-1-yl) quinolinone-4-carboxamide (12p)
Figure BDA0002304622230000351
Target Compound 12p
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12p, the reaction yield is 38%, and the HPLC purity is 96%. Mp 286.9-288.3 ℃.1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.52(s,1H), 8.30(d,J＝8.4Hz,1H),8.21(s,2H),8.03(t,J＝4.3Hz,2H),7.92(br s,3H),7.82(t,J＝9.6Hz, 2H),7.74(t,J＝7.1Hz,1H),7.65-7.57(m,3H),7.47(t,J＝7.3Hz,1H),7.36(t,J＝7.0Hz,1H). HRMS m/z(ESI)calcd for C28H19N2O2[M+H]+415.1441 found:415.1451,calcd for C28H18N2O2Na[M+Na]+437.1260 found:437.1272.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (benzhydryl) quinolone-4-carboxamide (12q)
Figure BDA0002304622230000352
Target Compound 12q
The specific synthesis method comprises reacting compound 8n to obtain white solid compound 12q with high yield53.9% with an HPLC purity of 96%. Mp 248.5-249.3 ℃.1H NMR(400MHz,DMSO-d6)δ9.92(d,J＝8.6Hz,1H), 8.18(s,1H),8.16(d,J＝8.5Hz,1H),7.98(d,J＝8.3Hz,1H),7.95(s,1H),7.87-7.83(m,1H), 7.79(t,J＝9.1Hz,2H),7.65-7.61(m,1H),7.49-7.28(m,12H),6.54(d,J＝8.6Hz,1H).13C NMR (101MHz,DMSO)δ166.31,155.45,154.68,148.29,143.65,142.49,131.09,129.87,129.00, 128.75,128.11,127.91,127.67,126.59,125.61,124.24,124.13,122.68,116.44,112.19,107.83, 57.21.HRMS m/z(ESI)calcd for C31H23N2O3[M+H]+455.1573 found:455.1768,calcd for C31H22N2O2Na[M+Na]+477.1573 found:477.1593.
Preparation of the Compound methyl 2- [2- (1-benzofuran-2-yl) quinolon-4-amido ] -5-nitrobenzoate (12r)
Figure BDA0002304622230000361
Target Compound 12r
The specific synthesis method uses compound 8n, and the reaction treatment can obtain light yellow solid compound 12r, the reaction yield is 19%, and the HPLC purity is 96%. Mp 237.8-239.3 ℃.1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.69(d,J ＝2.8Hz,1H),8.60(dd,J＝9.1,2.8Hz,1H),8.52-8.48(m,2H),8.32(d,J＝8.4Hz,1H),8.22(d,J ＝8.5Hz,1H),7.96-7.90(m,2H),7.83-7.73(m,3H),7.49-7.44(m,1H),7.36(t,J＝7.1Hz,1H), 3.91(s,3H).HRMS m/z(ESI)calcd for C26H18N3O6[M+H]+468.1190 found:468.1195,calcd for C26H17N3O6Na[M+Na]+490.1010 found:490.1033.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- [ phenyl (pyridin-2-yl) methyl ] quinolinone-4-carboxamide (12s)
Figure BDA0002304622230000362
Target Compound 12s
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12s, the reaction yield is 33%, and the HPLC purity is 96%. Mp 222.5-223.4 ℃.1H NMR(400MHz,DMSO-d6)δ9.87(d,J＝8.2Hz,1H), 8.66-8.55(m,1H),8.19(s,1H),8.18-8.13(m,1H),8.06(d,J＝8.1Hz,1H),7.94(s,1H),7.85(t,J ＝7.7Hz,2H),7.79(t,J＝8.3Hz,2H),7.64(t,J＝7.6Hz,1H),7.58(d,J＝7.9Hz,1H),7.50(d,J ＝7.4Hz,2H),7.45(t,J＝7.2Hz,1H),7.41-7.27(m,5H),6.55(d,J＝8.2Hz,1H).13C NMR(101 MHz,DMSO)δ166.50,160.75,155.45,154.72,149.55,148.30,148.27,143.66,141.50,137.60, 131.05,129.82,128.96,128.75,128.20,128.05,127.84,126.57,125.79,124.28,124.12,123.02, 122.66,122.23,116.54,112.18,107.74,59.08.HRMS m/z(ESI)calcd for C30H22N3O2[M+H]+ 456.1707 found:456.1714,calcd for C30H21N3O2Na[M+Na]+478.1526 found:478.1530.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- {4- [ (4-methylpiperazin-1-yl) methyl ] -3- (trifluoromethyl) phenyl } quinolone-4-carboxamide (12t)
Figure BDA0002304622230000363
Target Compound 12t
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12t, the reaction yield is 39%, and the HPLC purity is 96%. Mp 214.9-215.8 ℃.1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.41(s,1H), 8.28(d,J＝1.8Hz,1H),8.20(dd,J＝8.4,1.3Hz,2H),8.04(dd,J＝8.4,1.6Hz,1H),7.97(d,J＝ 1.4Hz,1H),7.90(t,J＝7.1Hz,1H),7.83-7.76(m,3H),7.71(t,J＝8.1Hz,1H),7.49-7.44(m,1H), 7.36(t,J＝7.5Hz,1H),3.61(s,3H),2.42-2.38(m,8H),2.19(s,3H).13C NMR(101MHz,DMSO) δ165.69,155.50,154.62,148.44,148.39,143.03,138.26,133.21,131.98,131.30,129.94,128.73, 128.44,128.26,127.96,126.69,125.74,124.16,123.83,122.72,117.53,116.88,112.16,107.95, 57.91,55.14,53.07,46.08.HRMS m/z(ESI)calcd for C31H28F3N4O2[M+H]+545.2159 found: 545.2188,calcd for C31H27F3N4O2Na[M+Na]+567.1978 found:567.2033.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (4-phenoxyphenyl) quinolinone-4-carboxamide (12u)
Figure BDA0002304622230000371
Target Compound 12u
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12u, the reaction yield is 38%, and the HPLC purity is 96%. Mp 264.5-265.8 deg.C.1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.37(s,1H), 8.20(dd,J＝8.2,3.5Hz,2H),7.98(s,1H),7.91-7.86(m,3H),7.80(dd,J＝12.8,8.0Hz,2H), 7.73-7.69(m,1H),7.48-7.33(m,4H),7.16-7.10(m,3H),7.03(d,J＝7.8Hz,2H).13C NMR(101 MHz,DMSO)δ165.21,157.73,155.49,154.67,153.03,148.43,148.41,143.55,135.09,131.24, 130.49,129.93,128.75,128.35,126.66,125.77,124.15,123.98,123.59,122.71,122.25,120.00, 118.47,116.77,112.17,107.93.HRMS m/z(ESI)calcd for C30H21N2O3[M+H]+457.1547 found: 457.1548,calcd for C30H20N2O3Na[M+Na]+479.1366 found:479.1370.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (3, 4-dichlorophenyl) quinolone-4-carboxamide (12v)
Figure BDA0002304622230000372
Target Compound 12v
The specific synthesis method comprises reacting compound 8n to obtain white solid compound 12v with reaction yield of 37% and 96% HPLC purity. Mp>290℃.1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.40(s,1H),8.28-8.14 (m,3H),8.01-7.95(m,1H),7.90(ddd,J＝8.4,6.8,1.5Hz,1H),7.84-7.67(m,5H),7.46(ddd,J＝8.4,7.2,1.4Hz,1H),7.41-7.33(m,1H).13C NMR(101MHz,DMSO)δ165.71,155.50,154.58, 148.42,148.39,142.88,139.25,131.60,131.36,131.32,129.96,128.72,128.50,126.71,126.27, 125.69,124.17,123.74,122.73,121.81,120.60,116.88,112.18,108.02.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (2, 3-dichlorophenyl) quinoline-4-carboxamide (12w)
Figure BDA0002304622230000381
Target Compound 12w
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12w, the reaction yield is 37%, and the HPLC purity is 96%. Mp>290℃.1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.39(s,1H),8.27(d,J ＝8.3Hz,1H),8.20(d,J＝8.4Hz,1H),7.96(s,1H),7.91(ddd,J＝8.4,6.9,1.4Hz,1H),7.81(dd, J＝12.8,8.1Hz,3H),7.74(ddd,J＝8.2,6.9,1.3Hz,1H),7.65(dd,J＝8.1,1.5Hz,1H),7.55-7.44 (m,2H),7.39-7.33(m,1H).
Preparation of the compound 2- (1-benzofuran-2-yl) -N- (3-chloro-2-methylphenyl) quinoline-4-carboxamide (12X)
Figure BDA0002304622230000382
Target Compound 12x
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12x, the reaction yield is 36%, and the HPLC purity is 96%. Mp>290℃.1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.41(s,1H),8.22 (dd,J＝13.7,8.4Hz,2H),7.99(s,1H),7.90(ddd,J＝8.4,6.8,1.4Hz,1H),7.81(dd,J＝13.5,8.0 Hz,2H),7.73(ddd,J＝8.2,6.8,1.3Hz,1H),7.59(d,J＝7.8Hz,1H),7.51-7.41(m,2H),7.35(q,J ＝8.1Hz,2H),2.40(s,3H).13C NMR(101MHz,DMSO)δ165.85,155.50,154.67,148.42,148.39, 143.35,137.68,134.43,132.09,131.27,129.95,128.75,128.41,127.55,126.68,126.03,125.74, 124.17,124.08,122.72,116.79,112.19,107.93,15.91.
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (2, 5-dimethylphenyl) quinoline-4-carboxamide (12y)
Figure BDA0002304622230000383
Target Compound 12y
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12y, the reaction yield is 19%, and the HPLC purity is 96%. Mp>290℃.1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.36(s,1H), 8.27-8.16(m,2H),7.98(d,J＝1.0Hz,1H),7.90(ddd,J＝8.4,6.8,1.4Hz,1H),7.81(dd,J＝12.2, 8.0Hz,2H),7.73(ddd,J＝8.2,6.9,1.3Hz,1H),7.47(ddd,J＝8.3,7.2,1.3Hz,1H),7.44-7.40(m, 1H),7.40-7.32(m,1H),7.21(d,J＝7.7Hz,1H),7.05(dd,J＝7.7,1.8Hz,1H),2.35(s,3H),2.32 (s,3H).
Preparation of the Compound 2- (1-benzofuran-2-yl) -N- (4-ethoxyphenyl) quinoline-4-carboxamide (12z)
Figure BDA0002304622230000391
Target Compound 12z
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12z, the reaction yield is 36%, and the HPLC purity is 96%. Mp>290℃.1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.34(s,1H),8.18(t,J ＝7.6Hz,2H),7.98(s,1H),7.93-7.85(m,1H),7.79(dd,J＝12.2,8.1Hz,2H),7.74-7.68(m,3H), 7.46(t,J＝7.9Hz,1H),7.35(t,J＝7.5Hz,1H),6.98(d,J＝8.9Hz,2H),4.04(q,J＝6.9Hz,2H), 1.35(t,J＝7.0Hz,3H).
Preparation of the compound 2- (1-benzofuran-2-yl) -N- [ (3, 4-dichlorophenyl) methyl ] quinoline-4-carboxamide (12aa)
Figure BDA0002304622230000392
Target Compound 12aa
The specific synthesis method uses compound 8n, and the reaction treatment can obtain white solid compound 12aa, the reaction yield is 49%, and the HPLC purity is 96%. Mp 229.8-231.2 ℃.1H NMR(400MHz,DMSO-d6)δ9.52(t,J＝6.0Hz,1H), 8.23(s,1H),8.20-8.12(m,2H),7.94(s,1H),7.87(ddd,J＝8.3,6.8,1.4Hz,1H),7.79(dd,J＝13.6, 8.0Hz,2H),7.74-7.64(m,3H),7.51-7.41(m,2H),7.35(t,J＝7.5Hz,1H),4.61(d,J＝6.0Hz, 2H).13C NMR(101MHz,DMSO)δ166.98,155.46,154.66,148.43,148.35,143.17,140.68, 131.46,131.15,130.06,129.88,128.74,128.36,128.19,126.62,125.79,124.14,124.11,122.69, 116.56,112.15,107.77,42.27.
Preparation of the compound 2- (1-benzofuran-2-yl) -N- [ (4-methylphenyl) methyl ] quinoline-4-carboxamide (12ab)
Figure BDA0002304622230000401
Target Compound 12ab
The specific synthesis method comprises the step of reacting compound 8n to obtain a white solid compound 12ab, wherein the reaction yield is 58% and the HPLC purity is 96%. Mp 235.8-236.9 ℃.1H NMR(400MHz,DMSO-d6)δ9.41(t,J＝6.0Hz,1H), 8.18(s,1H),8.16(dt,J＝8.2,1.6Hz,2H),7.92(d,J＝0.9Hz,1H),7.86(ddd,J＝8.5,6.8,1.4Hz, 1H),7.83-7.74(m,2H),7.68(ddd,J＝8.2,6.9,1.3Hz,1H),7.45(ddd,J＝8.4,7.2,1.4Hz,1H), 7.37-7.32(m,3H),7.22(s,1H),7.20(s,1H),4.57(d,J＝5.9Hz,2H),2.32(s,3H).13C NMR(101 MHz,DMSO)δ166.75,155.45,154.70,148.41,148.33,143.64,136.57,136.40,131.10,129.84, 129.49,128.75,128.12,127.96,126.59,125.88,124.19,124.13,122.67,116.40,112.16,107.67, 43.01,21.19.
Preparation of the compound 2- (1-benzofuran-2-yl) -N- [ (4-fluorophenyl) methyl ] quinoline-4-carboxamide (12ac)
Figure BDA0002304622230000402
Target Compound 12ac
The specific synthesis method comprises the step of reacting compound 8n to obtain a white solid compound 12ac, wherein the reaction yield is 53%, and the HPLC purity is 96%. Mp 225.6-226.7 ℃.1H NMR(400MHz,DMSO-d6)δ9.50(t,J＝5.9Hz,1H), 8.21(s,1H),8.16(dd,J＝8.3,1.3Hz,2H),7.93(d,J＝1.0Hz,1H),7.86(ddd,J＝8.2,6.8,1.4Hz, 1H),7.83-7.74(m,2H),7.68(ddd,J＝8.2,6.9,1.2Hz,1H),7.53-7.42(m,3H),7.35(td,J＝7.5, 1.0Hz,1H),7.23(t,J＝8.9Hz,2H),4.60(d,J＝5.8Hz,2H).13C NMR(101MHz,DMSO)δ 166.82,162.99,160.58,155.45,154.68,148.41,148.33,143.43,135.68,131.11,130.04,129.96, 129.85,128.74,128.14,126.60,125.86,124.16,122.68,116.49,115.77,115.56,112.16,107.75, 42.56.
Pharmacodynamics experimental part
Example 1 enzyme Activity agonism assay of Compounds
The aim of this experiment was to test the agonistic activity of compounds on deacetylase in vitro. In the experiment, a fluorescence intensity detection method is adopted to carry out in-vitro activity excitation test on SIRT 6. MDL-800 is a reference molecule (or referred to as a positive control). Test Compounds for Deacetylase agonistic Activity EC50(half-agonist concentration or the rate of activation of the test compound at 20. mu.M concentration on the SIRT6 activity). EC (EC)50Values can be calculated from the rate of activation of deacetylase activity by the test compound at a range of different concentrations.
1.1 Experimental materials
Human SIRT6 enzyme (constructed in Escherichia coli M15[ pREP4] with vector pQEEHL.1), Buffer solution of modified Buffer, 100% DMSO (dimethyl sulfoxide), NAD (nicotinamide adenine dinucleotide), acetylated polypeptide substrate, trypsin and enzyme marker (Synergy MX), CM5 sensor chip, Biacore X100 instrument (GE Healthcare), RT-PCR detection system (BIO-RAD CFX96), and MicroCalitC 200 instrument, which are all provided by national emphasis laboratory of biotherapy of Sichuan university.
All tested 2-substituted quinoline-4-formamide skeleton derivatives and the positive compound MDL-800 are synthesized by the method. 12q and MDL-800 have the structural formulae:
Figure BDA0002304622230000411
in vitro experiments, 10mM stock solution is prepared from 100% DMSO, and is stored in a refrigerator at-20 ℃ in the dark for later use, and is diluted to the required concentration by using complete culture solution at the time of use.
1.2 test methods
1.2.1 expression and purification of proteins
The N-terminal his-tagged human SIRT6 construct was expressed in E.coli M15[ pREP4] using the vector pQEEHL.1. Proteins were expressed and purified according to the prior art (reference You, w.; Rotili, d.; Li, t.m.; Kambach, c.; Meleshin, m.; Schutkowski, m.; Chua, k.f.; Mai, a.; Steegborn, c.structural basis of simple 6 activation by synthetic small molecules, angelwaind chemical International Edition 2017,56, 1007.). The purified SIRT6 protein was stored in buffer at-80 ℃.
1.2.2 in vitro test Compounds for agonist Activity on SIRT6
SIRT6 was deacetylated and the internal recombinant SIRT6 was held with assay buffer at 37 ℃ for 15 min in a black half-volume 96-well plate. Substrate S5(Ac-RYQK (Ac) -AMC) was added to the mixture. Then NAD was added, the reaction was started and incubated at 37 ℃ for 120 minutes. Next, a developer solution containing trypsin, nicotinamide was added and incubated at room temperature for 30 minutes, and fluorescence at excitation and emission wavelengths of 380 and 440nm was measured using Bio-Tek (Bio-Tek), respectively. For SIRT6 degranulation, internal recombinant SIRT6 was placed in a black half-volume 96-well plate with a mixture of buffer and dithiothreitol for 20 minutes at 37 ℃. The mixture contained MAcALPK (MyrK) -AMC peptide and NAD was added. The reaction was started and incubated at 37 ℃ for 120 min. Next, a developer solution containing trypsin, nicotinamide, was added and incubated at 37 ℃ for 120 minutes, and fluorescence was measured using Bio-Tek (Bio, excitation and emission wavelengths 380 and 440nm, respectively). Experimental data were fitted to GraphPad Prism to obtain inhibition or activity values using the following equation: inhibition [ (% max-signal)/(max-min) [ (% activity) ] - [ (% max-min) [ (% activity) ].
1.2.3 Surface Plasmon Resonance (SPR) measurement
Binding based on the SPR technique was determined by Biacore X100 instrument (GE Healthcare) at room temperature. First, SIRT6 protein was immobilized on a CM5 sensor chip in sodium acetate by standard amide coupling procedures; then, contacting the activated surface with a protein solution; the chip was equilibrated with PBS buffer for 4 hours; the compound was injected serially diluted for 60 seconds and then the buffer flow for 120 seconds. Determination of K for test Compounds by BIA evaluation software (GE Healthcare)DThe value is obtained.
1.2.4 Differential Scanning Fluorometric (DSF) determination
The DSF experiments were performed on the RT-PCR detection system (BIO-RAD CFX 96). SYPRO orange was monitored using a filter with FRET at 492 nm. ROX at a wavelength of 610nm is excited for emission. Each reaction solution containing SIRT6 protein buffer, SYPRO orange, test compound was heated from 25 ℃ to 95 ℃. The fluorescence intensity was recorded every 1 ℃/min and plotted as a function of temperature. The transition curve (T) is calculated by fitting the Boltzmann equation to the sigmoid curve in the Graph Pad Prismm) The inflection point of (c).
1.2.5 Isothermal Titration Calorimetry (ITC) determination
Isothermal titration calorimetry experiments were performed in a MicroCal iTC200 instrument at 25 ℃. The protein was injected into the reaction cell containing the activator for titration. Thermodynamic binding parameters were extracted by nonlinear regression analysis in combination with isotherms (MicroCal Origin software). The single point binding model was applied to generate enthalpy changes, reaction entropy changes, stoichiometry and equilibrium dissociation constants (Kd).
1.3 results of the excitation kinetic energy test of the Compound
1.3.1 results of testing the excitation powers of all the compounds
The activation capacity test of all compounds was carried out by fluorescence test method Fluor De Lys (FDL) with myristoyl peptide substrate (Ac-EALPKK (Myr) -AMC) (reference 1, Young, W.; Rotili, D.; Li, T.M.; Kambach, C.; Meleshin, M.; Schutkowski, M.; Chua, K.F.; Mai, A.; Steegborn, C.structural basis of simple 6 activation by synthetic method, C.structural basis 1011; 2, Huang, Z.; Zoo, J.; Deng, W.; chemistry, J.; Song, K.; Zhang, Z.; Zong, C.S. 11; U.S. Pat. No. 14, U.S. 7, U.S. 11; U.S. 11, U.S. Pat. No. 25).
Table 1 agonistic Activity of Compounds 5-5 d, 5 f-5 n on SIRT6
Figure BDA0002304622230000421
Figure BDA0002304622230000422
Figure BDA0002304622230000431
TABLE 2 agonistic Activity of Compounds 8 a-8 p on SIRT6
Figure BDA0002304622230000432
Figure BDA0002304622230000433
Figure BDA0002304622230000441
TABLE 3 agonistic Activity of Compounds 12 a-12 ac on SIRT6
Figure RE-GDA0002425460900000442
Figure RE-GDA0002425460900000443
Figure BDA0002304622230000451
1.3.2 molecular level Activity of Compound 12q
To further determine the agonistic activity of compound 12q on SIRT6, the present study employed orthogonal assays, including Fluorescence (FDL) method, Differential Scanning Fluorescence (DSF) method, Surface Plasmon Resonance (SPR) method, and Isothermal Titration Calorimetry (ITC) of different substrate peptides. Among them, the Fluorescence (FDL) method uses two substrates, Ac-RYQK (Ac) -AMC) and Ac-EALPKK (Myr) -AMC, for verification.
In an enzyme catalysis experiment, the compound 12q can obviously enhance the deacetylation and long-chain myristoylation activities of SIRT6, and the EC thereof1.5The values were 0.58. mu.M and 0.65. mu.M, respectively (see FIGS. 1A and B). In DSF experiments, compound 12q has an increased cleavage temperature (Δ T) for SIRT6 proteinm) Is 1.01 deg.C (FIG. 2A). SPR experiments show that the dissociation rate constant (K) of the compoundD) The value was 0.99. mu.M (FIG. 2B).
EXAMPLE 2 in vitro enzyme level Selective assay of Compound 12q against the same family
The aim of this experiment was to test the agonistic activity of compound 12q on SIRT1, SIRT2 and SIRT3 and other HDAC families in vitro. Test Compounds for Deacetylase agonistic Activity EC50(median agonist concentration). EC (EC)50Values can be calculated from the agonism of the test compound at a range of different concentrations for the deacetylase activity.
2.1 materials of the experiment
Human SIRT1 enzyme (BPS Biotechnology Limited, cat # 50012), human SIRT2 enzyme (BPS Biotechnology Limited, cat # 50013), human SIRT3 enzyme (Cayman, cat # 10011194), Tris-Buffer modified (Tris-labeled Buffer), 100% DMSO (dimethyl sulfoxide), NAD (nicotinamide adenine dinucleotide), acetylated polypeptide substrate, trypsin, and microplate reader (Synergy MX), provided by Shanghai Ruizi chemical Limited (China).
The compound of claim 12q was synthesized in this patent. In vitro experiments, 10mM stock solution is prepared from 100% DMSO, and is stored in a refrigerator at-20 ℃ in the dark for later use, and the stock solution is diluted to the required concentration by using complete culture solution when in use.
2.2 test methods
Mixing human SIRT1, SIRT2 and SIRT3 with test buffer solution, adding small molecule compounds dissolved in 100% DMSO at different concentrations, shaking, and mixing. The mixture was then incubated at room temperature for 15 minutes. The reaction is then driven by the addition of a substrate comprising NAD and acetylated polypeptide. After 240 minutes of incubation at room temperature, the trypsin solution was added and incubation continued for 90 minutes at room temperature. Then using a microplate reader at the excitation wavelength (. lamda.)ex) Is 360nm, and has an emission wavelength (lambda)em) The fluorescence intensity was measured at 460 nm. The calculation is made by the following formula:
Figure BDA0002304622230000461
Figure BDA0002304622230000462
wherein Y is the inhibition rate, X is the concentration of the compound, Max is the negative control Signal value (no inhibition at all), Min is the positive control Signal value (complete inhibition), Signal is the Signal value of the corresponding well, Inh% is the percentage of inhibition, IC in the formula50Is the concentration of the compound corresponding to an inhibition ratio of 50% (expressed in molar concentration M, and calculated as LogIC in the formula so as to match the X unit)50) In the formula 2, Bottom is the concentration minimum, Top is the concentration maximum, and Hill Slope meansThe absolute value of the maximum slope of the curve (i.e., the midpoint of the curve).
2.3 test results
The results in table 4 show that compound 12q can strongly activate SIRT 6. The results of the activity tests showed that compound 12q had little activity (IC) targeting SIRT2, SIRT3, and other HDAC families50>200 μ M), had a weak agonistic effect on SIRT 1.
TABLE 4 Selectivity of Compound 12q for the same family
Target IC50μM Target IC50μM
SIRT1 171.20 HDAC5 >200
SIRT2 >200 HDAC6 >200
SIRT3 >200 HDAC7 >200
SIRT6 0.58(EC1.5)a HDAC8 >200
HDAC1 >200 HDAC9 >200
HDAC2 >200 HDAC10 >200
HDAC3 >200 HDAC11 >200
HDAC4 >200
Note:athe selectivity test for compound 12q was tested by FDL experiments with acetylated substrate (Ac-RYQK (Ac) -AMC)).
EXAMPLE 3 in vitro Activity of Compound 12q on human pancreatic cancer cell lines PANC-1 and BxPC-3 cells
The objective of this experiment was to test the level of anti-malignant cell proliferation properties of compound 12q on cells in vitro. Human pancreatic cancer PANC-1 cells and BxPC-3 cells cultured in a laboratory are added with drugs and treated for a certain time, and then the cells are detected by an MTT (tetramethylazozolium) colorimetric method, cell clone formation, an EDU incorporation test, a cell migration test, a cell cycle and apoptosis test and a Western Blot method.
3.1 Experimental materials
Figure BDA0002304622230000471
Figure BDA0002304622230000481
3.2 Experimental methods
3.2.1 cell lines and culture
Human pancreatic cancer cell lines BxPC-3, PANC-1, AspC-1 and MIAPaCa-2 were purchased from American Type Culture Collection (ATCC, Rockville, Md., USA). It was cultured in DMEM supplemented with 10% FBS (Gibco, Eggenstein, Germany), 100 units/mL penicillin (Sigma-Aldrich) and streptomycin (Sigma) and with humidified 5% CO2The atmosphere was maintained in an incubator at 37 ℃.
3.2.2 MTT method
Various human pancreatic cancer cells were seeded in triplicate in 96-well plates (26003000,6300 and 2200 cells/well for human BxPC-3, PANC-1, AsPC-1, MIAPaCa-2 cells), treated with 12q (at concentrations of 50,16.67, 5.56,1.85,0.62,0.21,0.07, 0.02. mu.M, respectively) at the indicated concentrations for 72 hours, and assayed for cell viability (Sigma-Aldrich, St.Louis, MO) using MTT (3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide). IC calculation by Graph Pad Prism software50The value is obtained.
3.2.3 cloning formation
Cells were seeded at 750,500,20000 and 500 density per well in 6-well plates for BxPC-3, PANC-1, AsPC-1 and MIAPaCa-2. After 24 hours, 12q (10, 5,2.5 μ M each) was added at various concentrations, and after 14 to 18 days of incubation, the cells were fixed with paraformaldehyde and stained with crystal violet. Colonies with >50 cells were counted under an inverted microscope.
3.2.4 EDU incorporation test
The cells were seeded in a 96-well plate at 4X 103 to 1X 105 cells per well and subjected to a desired drug treatment or other stimulation treatment. Prepare a2 × EdU working solution: stock solution of 10mM was diluted with complete medium to the appropriate working concentration. 2 XEdU working solution was preheated, and an equal volume of medium was added to bring the concentration to 1X. Cells were incubated under appropriate conditions for an appropriate time. After incubation was complete, medium was removed and 50 μ L of 4% neutral paraformaldehyde was added to the slide of each well and after incubation at room temperature for 15-30 minutes, the fixative was removed. Mu.l of 2mg/ml glycine solution was added to each well and incubated at room temperature for 5 minutes to neutralize the remaining fixative. Cells were washed 2 times with 0.1ml of 3% BSAin PBS wash per well. The wash solution was removed and 0.1ml of 0.5% Triton X-100 in PBS was added to each well and incubated for 20 minutes at room temperature. 1 XClick-iT EdU reaction buffer was prepared. A5 Xbatch of Click-iT EdU reaction additive stock solution was prepared. A1 XClick-iT EdU buffer addition was prepared. A Click-iT reaction mixture was prepared. The penetration enhancing solution was removed, and the wells were washed 2 times with 0.1mL of 3% BSAin PBS per well, and the wash solution was removed. Add 0.1mL of Click-iT reaction mixture to each well and shake the plate briefly to ensure that the reaction mixture can cover the cells uniformly. Incubate for 30min at room temperature in the dark. The reaction mixture was removed and washed 2 times with 0.1mL 3% BSAin PBS per well and the wash removed. For nuclear staining, DNA counterstaining can be performed. If no special requirement exists, the photo analysis can be carried out. Wash each well 1 time with 0.1mL PBS and remove the wash. Dilution of Hoechst33342 (component F) stock 1 with PBS: 2000 to 1 Xhoechst 33342 solution, final concentration 5. mu.g/mL. 0.1mL of 1 × Hoechst33342 solution is added to each well, and the mixture is incubated for 15-30min at room temperature in the dark. The Hoechst33342 solution was removed. Wash solution was removed by washing each well 2 times at 0.1 mLPBS. And finally, imaging and analyzing.
3.2.5 cell migration assay
BxPC-3, PANC-1, AspC-1 or MIAPaCa-2 cells were seeded in 12-well plates at 37 ℃ with 5% CO2And allow them to grow into a monolayer of junctions. The center of the cell monolayer was scraped with a sterile 200 μ M pipette tip to create a denuded zone (gap) of constant width. Subsequently, the cell debris was washed with steroid PBS and the cells were exposed to various concentrations of 12q ( concentrations 10,5,2.5 μ M, respectively) or theirAnd (3) other reagents. At 37 ℃ 5% CO2After 24 hours of incubation, images were taken by an Olympus inverted microscope. Migrated cells were quantified by manual counting and percent inhibition was expressed using 100% untreated wells.
3.2.6 Western Blot
BxPC-3 and PANC-1 were incubated in medium containing 12q or other reagents at various concentrations for 72 hours, whole cell lysates were extracted with RIPA buffer, supplemented with protease inhibitor cocktail and PMSF. Protein concentration was determined using BCA protein assay kit. Protein extracts were separated by SDS-PAGE on polyacrylamide Tris-glycine gels and transferred to PVDF membranes (Millipore). PVDF membrane containing skimmed milk powder and TBS moderate temperature oscillation for 2 hours. Then washed and incubated with TBS-T and specific antibodies including anti-SIRT 6, anti-histone H3 (acetyl K9), anti-histone H3 (acetyl K18), anti-histone H3 (acetyl K56), anti-histone H3, anti-Lin 28b, anti-Myc, anti-IGF 2BP3, anti-HMGA 2, anti-beta-actin at 4 ℃ for 10 hours. The antibody was diluted in blocking buffer. Blots were combined with corresponding horseradish peroxidase-linked secondary antibodies in blocking buffer at 1: incubation was performed at 10000 dilution for 1 hour. Protein expression was detected by exposure to horseradish peroxidase substrate.
3.2.7 pharmacokinetic Studies
Sprague-Dawley rats 6-8 weeks old are taken as experimental subjects, 12q is dissolved in a mixed solution of DMSO, Solutol and normal saline, the pH of a prepared administration solution is adjusted to 7, and PO or IV administration is performed. After dosing, time points 0.083 h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h or 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10 h and 24h, blood samples for PO or IV were collected from each animal by cardiac puncture and plasma concentrations were determined using LC-MS/MS analysis. The non-compartmental pharmacokinetic parameters were fitted using DAS software (Enterprise, version 2.0, physical pharmaceutical Professional Committee of China).
3.3 results of the experiment
MTT experiment shows that 12q pairs of pancreatic cancer cells PANC-1, BxPC-3, MIAPaCa-2 and AsPC-1IC of50The values were 4.13. mu.M, 8.27. mu.M, 7.10. mu.M and 9.66. mu.M, respectively (see FIG. 3A). In the clonogenic experiment and the EdU experiment, 12q showed a better ability to inhibit pancreatic cancer cell proliferation (see fig. 3C and 3D). In the scoring experiment, 12q showed a better ability to inhibit pancreatic cancer cell migration (see fig. 4A). In Western blot experiments, compound 12q could dose-dependently decrease the levels of Lin28B and c-Myc, resulting in increased expression of downstream proteins IGF2BP3 and HMGA2 (see FIG. 4B).
Pharmacokinetic (PK) profile in male Sprague-Dawley rats showed a concentration-time curve AUC(0-∞)Area of 755.57h ng/mL, maximum blood concentration (C)max) 98.45ng/mL, half life (T)1/2) Was 7.52h (see Table 5).
TABLE 5 results of 12q pharmacokinetic studies of Compound
Pharmacokinetic parameters 10mg/kg for oral administrationa 2mg/kg intravenous injectiona
Clearance CL (L/h/kg) — 0.6±0.08
Steady state apparent distribution volume Vss (L/kg) — 1112.8±322.84
Half life T1/2(h) 7.52±1.44 9.06±0.21
Time to peak Tmax(h) 2.00±0.00 0.08±0.00
Peak concentration of drug Cmax(ng/mL) 98.45±3.62 5123.70±905.5
Area under the time curve AUC(0-t)(h·ng/mL) 704.67±80.47 3326.13±476.4
Area under the time curve AUC(0-∞)(h·ng/mL) 755.57±80.74 3381.49±468.48
Bioavailability F (%) 4.24±0.48 —
aRepresents ± SD, and n is 3.
EXAMPLE 4 in vivo model of Compound 12q in human pancreatic cancer cell line PANC-1 cells
The objective of this experiment was to measure the level of compound 12q against malignancy in an in vivo model. The experiment adopts human pancreatic cancer PANC-1 cells cultured in a laboratory, after culturing for a certain time, the cells are inoculated on a nude mouse, the tumor volume is measured while drug administration is carried out, after the drug administration for a certain time, the nude mouse is dissected, and subsequent detection of other levels is carried out.
4.1 Experimental methods
To establish the PANC-1 xenograft model, PANC-1 cell suspension was injected subcutaneously into the right flank region of 6-week-old female nude mice. After tumors grew to volume, mice were randomized into 4 groups and given different doses of compound. The compound was dissolved in a mixed solution of DMSO, castor oil, ethanol and distilled water. Tumor volume was monitored every 3 days using calipers. Tumor Volume (TV) was calculated using the following formula: length x width of TV2×0.5。
4.2 results of the experiment
In the mouse subcutaneous tumor PANC-1 transplantation model, 12q dose-dependently inhibited tumor growth at a dose of 150mg/kg, with an inhibition rate of 90.25% (see FIGS. 5A and 5B). The PANC-1 tumor tissue immunohistochemical experiment result shows that 12q can effectively inhibit the protein level of Lin28b and C-Myc and obviously reduce the tumor cell proliferation (ki-67 positive cells) compared with the control group (see fig. 5C).

Claims (10)

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0002304622220000011
wherein R is1Selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted endocycloalkyl;
the R is1The substituent in the substituted aryl or substituted heteroaryl is selected from alkoxy, aryloxy, substituted or unsubstituted alkyl, hydroxyl, nitro, ester group and halogen, wherein the substituent of the substituted alkyl is halogen or cycloalkyl, and the cycloalkyl contains 0-3N heteroatoms;
the R is1Wherein the substituent of the substituted alkyl, substituted cycloalkyl or substituted bridged cycloalkyl is selected from aryl, heteroaryl, ester group, hydroxy;
R2selected from substituted or unsubstituted aryl, substituted or unsubstitutedHeteroaryl, alkyl, cycloalkyl;
the R is2Wherein the substituents in the substituted aryl or substituted heteroaryl are selected from alkoxy, alkyl or halogen.
2. The compound of claim 1, wherein:
R1the compound is selected from substituted or unsubstituted 6-10-membered aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-6-membered cycloalkyl and substituted or unsubstituted bridged cycloalkyl, wherein hetero atoms in the heteroaryl are N, O or S, and the number of the hetero atoms is 1-2.
3. The compound of claim 2, wherein:
the R is1The substituent in the substituted 6-to 10-membered aryl or substituted 5-to 10-membered heteroaryl is selected from C1-C6 alkoxy, 6-to 10-membered aryloxy, substituted or unsubstituted C1-C6 alkyl, hydroxyl, nitro, ester group and halogen, the substituent of the substituted alkyl is F or 5-to 6-membered cycloalkyl, and the cycloalkyl contains 1-2N heteroatoms;
the R is1Wherein the substituent of the substituted C1-C6 alkyl, the substituted 5-6 membered cycloalkyl or the substituted bridged cycloalkyl is selected from 6-10 membered aryl, 5-10 membered heteroaryl, ester group and hydroxyl.
4. A compound according to any one of claims 1 to 3, wherein:
R2the aryl group is selected from substituted or unsubstituted 6-10-membered aryl, substituted or unsubstituted 5-10-membered heteroaryl and 5-6-membered cycloalkyl, wherein the heteroatom in the heteroaryl group is N, O or S, and the number of the heteroatoms is 1-2; the cycloalkyl contains 0-2 heteroatoms, and the heteroatoms are N, O or S.
5. The compound of claim 4, wherein:
the R is2A medium substituted 6-to 10-membered aryl group, a substituted 5-to 10-membered hetero groupThe substituent in the aryl is selected from C1-C6 alkoxy, C1-C6 alkyl or halogen.
6. A compound according to any one of claims 1 to 5, wherein: r1Selected from:
Figure FDA0002304622220000021
Figure FDA0002304622220000022
7. a compound according to any one of claims 1 to 6, wherein: r2Selected from:
Figure FDA0002304622220000023
Figure FDA0002304622220000024
8. a compound according to any one of claims 1 to 7, wherein: the compound is selected from:
Figure FDA0002304622220000025
Figure FDA0002304622220000031
Figure FDA0002304622220000041
9. use of a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the preparation of a SIRT6 agonist.
10. Use of a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the manufacture of an anti-cancer medicament; preferably, the cancer is pancreatic cancer.
CN201911234907.3A 2019-12-05 2019-12-05 Quinoline-4-formamide skeleton derivative and application thereof Pending CN112920115A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201911234907.3A CN112920115A (en) 2019-12-05 2019-12-05 Quinoline-4-formamide skeleton derivative and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911234907.3A CN112920115A (en) 2019-12-05 2019-12-05 Quinoline-4-formamide skeleton derivative and application thereof

Publications (1)

Publication Number Publication Date
CN112920115A true CN112920115A (en) 2021-06-08

Family

ID=76162201

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911234907.3A Pending CN112920115A (en) 2019-12-05 2019-12-05 Quinoline-4-formamide skeleton derivative and application thereof

Country Status (1)

Country Link
CN (1) CN112920115A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113416181A (en) * 2021-08-02 2021-09-21 四川大学 Quinazoline derivative and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080293081A1 (en) * 2005-03-03 2008-11-27 Sirtris Pharmaceuticals, Inc. Fluorescence Polarization Assays for Acetyltransferase/Deacetylase Activity
US20090069301A1 (en) * 2005-03-03 2009-03-12 Sirtris Pharmaceuticals, Inc. Acridine and Quinoline Derivatives as Sirtuin Modulators

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080293081A1 (en) * 2005-03-03 2008-11-27 Sirtris Pharmaceuticals, Inc. Fluorescence Polarization Assays for Acetyltransferase/Deacetylase Activity
US20090069301A1 (en) * 2005-03-03 2009-03-12 Sirtris Pharmaceuticals, Inc. Acridine and Quinoline Derivatives as Sirtuin Modulators

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
ACS: "RN：326870-59-1", 《STN REGISTRY数据库》 *
ACS: "RN：332157-49-0", 《STN REGISTRY数据库》 *
ACS: "RN：352689-04-4", 《STN REGISTRY数据库》 *
ACS: "RN：352701-43-0", 《STN REGISTRY数据库》 *
ACS: "RN：353474-91-6", 《STN REGISTRY数据库》 *
ACS: "RN：353785-47-4", 《STN REGISTRY数据库》 *
ACS: "RN：389078-42-6", 《STN REGISTRY数据库》 *
ACS: "RN：389078-63-1", 《STN REGISTRY数据库》 *
ACS: "RN：389079-96-3", 《STN REGISTRY数据库》 *
ACS: "RN：461032-43-9", 《STN REGISTRY数据库》 *
ACS: "RN：541526-03-8", 《STN REGISTRY数据库》 *
ACS: "RN：545347-95-3", 《STN REGISTRY数据库》 *
ACS: "RN：546074-55-9", 《STN REGISTRY数据库》 *
ACS: "RN：954772-69-1", 《STN REGISTRY数据库》 *
XIULI CHEN，等: "Discovery of Potent Small-Molecule SIRT6 Activators: Structure−Activity Relationship and Anti-Pancreatic Ductal Adenocarcinoma Activity", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113416181A (en) * 2021-08-02 2021-09-21 四川大学 Quinazoline derivative and application thereof
CN113416181B (en) * 2021-08-02 2022-05-03 四川大学 Quinazoline derivative and application thereof

Similar Documents

Publication Publication Date Title
RU2497809C2 (en) Naphthalene carboxamide derivatives as protein kinase and histone deacetylase inhibitors, methods for preparing and using them
PT1389110E (en) Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
Shi et al. Quinoxalinone (Part II). Discovery of (Z)-3-(2-(pyridin-4-yl) vinyl) quinoxalinone derivates as potent VEGFR-2 kinase inhibitors
MX2010011224A (en) Quinoline derivatives as axl kinase inhibitors.
CN113354651B (en) Pyrazolo [1,5-a ] quinazoline derivative and application thereof in preparation of medicines
US20100298358A1 (en) Naphthamide Derivatives As Multi-Target Protein Kinase Inhibitors and Histone Deacetylase Inhibitors
EA032434B1 (en) Use of isoquinolones for preparing drugs, isoquinolones and method for synthesising same
EP3272742B1 (en) Histone deacetylase inhibitor, and preparation method and use thereof
JP2015511942A (en) 2-Arylbenzofuran-7-carboxamide-based compound, production method and use thereof
CN107056755A (en) Five-ring heterocycles amide-type WNT pathway inhibitors
Potenza et al. Structure-based screening for the discovery of 1, 2, 4-oxadiazoles as promising hits for the development of new anti-inflammatory agents interfering with eicosanoid biosynthesis pathways
Li et al. Imidazole-fused benzothiadiazole-based red-emissive fluorescence probe for lysosomal pH imaging in living cells
Alves Avelar et al. Design and Synthesis of Novel Anti‐Plasmodial Histone Deacetylase Inhibitors Containing an Alkoxyamide Connecting Unit
Routholla et al. Design, synthesis and binding mode of interaction of novel small molecule o-hydroxy benzamides as HDAC3-selective inhibitors with promising antitumor effects in 4T1-Luc breast cancer xenograft model
Hui et al. Discovery of 2-(4-acrylamidophenyl)-quinoline-4-carboxylic acid derivatives as potent SIRT3 inhibitors
Mesiti et al. Mapping chromone-3-phenylcarboxamide pharmacophore: quid est veritas?
CN103848795B (en) A kind of 1,2,5-diazole-2-oxide Antibiotic FR 901228 and its preparation method and application
Zhao et al. Discovery of ARS-1620 analogs as KRas G12C inhibitors with high in vivo antitumor activity
CN112920115A (en) Quinoline-4-formamide skeleton derivative and application thereof
CN112920176B (en) Bifunctional compound capable of inducing PRC2 protein complex core subunit degradation, pharmaceutical composition and application
Capes et al. Quinol derivatives as potential trypanocidal agents
Beus et al. SAHAquines, novel hybrids based on SAHA and primaquine motifs, as potential cytostatic and antiplasmodial agents
CN106831747A (en) The N- alkylamide WNT pathway inhibitors of five-ring heterocycles substitution
CN111961043A (en) Acetazolamide derivative, preparation method thereof and application thereof in preparation of drugs for treating coronary heart disease
CN109563046A (en) 6 inhibitor of histone deacetylase enzyme and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20210608