CN113493407A - Pyridine compound and preparation method and pharmaceutical application thereof - Google Patents

Pyridine compound and preparation method and pharmaceutical application thereof Download PDF

Info

Publication number
CN113493407A
CN113493407A CN202010258425.8A CN202010258425A CN113493407A CN 113493407 A CN113493407 A CN 113493407A CN 202010258425 A CN202010258425 A CN 202010258425A CN 113493407 A CN113493407 A CN 113493407A
Authority
CN
China
Prior art keywords
compound
substituted
unsubstituted
nmr
group
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
CN202010258425.8A
Other languages
Chinese (zh)
Inventor
肖志艳
景连栋
张浩超
杨亚军
杨颖�
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.)
Institute of Materia Medica of CAMS
Original Assignee
Institute of Materia Medica of CAMS
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 Institute of Materia Medica of CAMS filed Critical Institute of Materia Medica of CAMS
Priority to CN202010258425.8A priority Critical patent/CN113493407A/en
Publication of CN113493407A publication Critical patent/CN113493407A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/61—Halogen atoms or nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • 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
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of medicines, and discloses a novel pyridine compound, and a preparation method and a medicinal application thereof. Particularly discloses a novel pyridine compound shown as a compound in a formula (I), pharmaceutically acceptable salts thereof, a preparation method of the compound, application of the compound in preparing CDK8 inhibitors, a pharmaceutical preparation containing the compound and application of the compound in preparing medicaments for preventing and treating tumor-related diseases.

Description

Pyridine compound and preparation method and pharmaceutical application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to novel pyridine compounds shown in a general formula (I) and pharmaceutically acceptable salts thereof; pharmaceutical compositions of the compounds, a preparation method of the compounds, application of the compounds in preparing cyclin-dependent kinase 8(CDK8) inhibitors, and application of the compounds in preparing medicaments for preventing or treating CDK8 related diseases.
Background
Malignant tumor has become one of the major diseases seriously threatening human health, and the antitumor drug plays a great role in the clinical treatment process. However, as the living habits, diet, environment and other factors of people change, the incidence and pathogenesis of malignant tumors also change significantly. Meanwhile, long-term use of a certain drug causes drug resistance of tumor cells. Therefore, the demand for antitumor drugs with novel structures and new routes of action is increasing, and the research and development of such drugs is urgent.
Cyclin-dependent kinase 8(CDK8) is an important component of mediator complexes, and plays a key role in the functioning of mediator complexes after binding with cyclin c to form dimers. CDK8 is involved in multiple regulatory pathways, has high expression in many cancer samples, and is considered as a potential target for treating malignant tumors such as colorectal cancer, breast cancer, gastric cancer, ovarian cancer, melanoma and the like.
At present, CDK8 kinase small-molecule inhibitors have been reported, but no drug has been successfully marketed due to the existence of various problems such as unstable pharmacokinetic properties and poor selectivity. In view of the above, the inventors of the present application intend to provide a novel, safe and effective small molecule antitumor drug with molecular targeting.
Disclosure of Invention
The invention aims to provide a novel pyridine compound shown as a formula (I), a preparation method thereof, a pharmaceutical composition and application thereof in preparing CDK8 inhibitors and preventing or treating diseases related to hyperuricemia.
In order to solve the technical problem, the invention adopts the following technical scheme:
the first aspect of the technical scheme of the invention provides a novel pyridine compound represented by the following general formula (I) and pharmaceutically acceptable salts thereof,
Figure BDA0002438339260000021
wherein,
Figure BDA0002438339260000022
selected from double or single bonds; r1Selected from the group consisting of halogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted indazolyl; the substituent is a mono-substituent group or a multi-substituent group, and each substituent is independently selected from halogen, -NH2、-OH、C1-C3Alkyl radical, C1-C3Alkoxy, morpholinyl, N-methylpiperazinyl, trifluoromethyl, cyano, nitro; r2Is selected from-NH2、-OH、-NHNH2、C1-C3Alkoxy radical, C1-C3Alkylamino, morpholinyl, N-methylpiperazinyl, - (CH)2)nCOOH，n＝1,2,3、-CHR3COOH，R3Selected from hydrogen, C1-C6Alkyl radical, C1-C3A hydroxyalkyl group.
Preferred compounds are compounds of formula (IA) and pharmaceutically acceptable salts thereof,
Figure BDA0002438339260000023
wherein R is1Selected from the group consisting of halogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted indazolyl; the substituent is a mono-substituent group or a multi-substituent group, and each substituent is independently selected from halogen, -NH2、-OH、C1-C3Alkyl radical, C1-C3Alkoxy, morpholinyl, N-methylpiperazinyl, trifluoromethyl, cyano, nitro; r2Is selected from-NH2、-OH、-NHNH2、C1-C3Alkoxy radical, C1-C3Alkylamino, morpholinyl, N-methylpiperazinyl, - (CH)2)nCOOH，n＝1,2,3、-CHR3COOH，R3Selected from hydrogen, C1-C6Alkyl radical, C1-C3A hydroxyalkyl group.
Preferred compounds are those described by general formula (IB) and pharmaceutically acceptable salts thereof,
Figure BDA0002438339260000031
wherein R is1Selected from the group consisting of halogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted indazolyl; the substituent is a mono-substituent group or a multi-substituent group, and each substituent is independently selected from halogen, -NH2、-OH、C1-C3Alkyl radical, C1-C3Alkoxy, morpholinyl, N-methylpiperazinyl, trifluoromethyl, cyano, nitro; r2Is selected from-NH2、-OH、-NHNH2、C1-C3Alkoxy radical, C1-C3Alkylamino, morpholinyl, N-methylpiperazinyl, - (CH)2)nCOOH，n＝1,2,3、-CHR3COOH，R3Selected from hydrogen, C1-C6Alkyl radical, C1-C3A hydroxyalkyl group.
More preferred compounds are the following compounds and their pharmaceutically acceptable salts, wherein the compounds are selected from the group consisting of:
Figure BDA0002438339260000032
Figure BDA0002438339260000041
Figure BDA0002438339260000051
in a second aspect of the present invention, there is provided a method for synthesizing the compound of the first aspect, comprising the steps of:
the compound of the general formula (I) is obtained by taking 3-bromoisonicotinal as a starting material:
Figure BDA0002438339260000061
Figure BDA0002438339260000062
R1and R2The definition of (2) is as described in the first aspect of the present invention.
In a third aspect of the technical solution of the present invention, a pharmaceutical composition is provided, wherein the pharmaceutical composition contains an effective dose of any one of the novel pyridines of the first aspect of the present invention and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient. The medicine composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various particle delivery systems.
For the preparation of medicaments, the compounds of the general formula (I) are mixed in a known manner with suitable pharmaceutical carrier substances, fragrances, flavors and colors in a known manner and are tableted or coated, or are suspended or dissolved in water or oil with other additional substances.
The compounds of the invention may be administered orally or parenterally. The oral preparation can be tablet, capsule, and coating agent, and the parenteral preparation can be injection and suppository. These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, coatings are the customary auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils, such as corn oil, peanut oil, olive oil, etc. The formulations containing the compounds of the present invention may also contain other adjuvants such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, coloring agents, and the like.
In a fourth aspect the present invention provides the use of a compound according to the first aspect of the invention and pharmaceutically acceptable salts thereof in the preparation of an inhibitor of CDK 8.
The fourth aspect of the technical scheme of the invention also provides an application of the novel pyridine compound and the pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating diseases related to CDK 8. The CDK8 related diseases are selected from tumors and immune related diseases. The tumor comprises rectal cancer, breast cancer, gastric cancer, ovarian cancer and melanoma.
Pharmacological studies have shown that the compounds of general formula (I) according to the invention have an activity of inhibiting CDK8, thus achieving therapeutic objectives.
The beneficial technical effects are as follows:
CDK8 inhibitor has inhibitory effect on various tumor strains, and can be used for treating malignant tumors such as rectal cancer, breast cancer, gastric cancer, ovarian cancer and melanoma. Poor specificity of action is one of the major challenges facing the current study of CDK8 inhibitors. The compound has the characteristics and advantages of specifically inhibiting CDK8, and is expected to provide a novel, safe and effective CDK8 inhibitor as a small-molecule antitumor drug.
Drawings
FIG. 1. Selective inhibition of CDK8 by Compounds (Single concentration inhibition of kinase by the Compound of interest (10. mu.M)).
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS) or High Resolution Mass Spectrometry (HRMS). The NMR shifts (δ) are given in parts per million (ppm). The column chromatography generally uses 200-300 mesh silica gel as a carrier. NMR was measured using INOVA-300 and CDCl as the solvent3、DMSO-d6And Acetone-d6The internal standard is TMS and the chemical shifts are given in ppm. MS was measured using an Agilent LC/MSD TOF LC/MS spectrometer.
Example 1: preparation of Compound 1
Figure BDA0002438339260000081
(1) Synthesis of ethyl (E) -3- (3-bromopyridin-4-yl) acrylate
Sodium hydride (content: 60%, 520mg) was weighed into a dry round-bottomed flask, 5mL of anhydrous tetrahydrofuran was added, triethyl phosphonoate (2.912g, 13mmol) dissolved in 20mL of anhydrous tetrahydrofuran was slowly added dropwise under ice bath, and the reaction was stirred for 1 hour under ice bath. 3-bromo-4-formylpyridine (1.86g, 10mmol) diluted with 25mL of tetrahydrofuran was further added dropwise to the above reaction system, and the reaction was stirred at room temperature for about 3 hours after the addition. After completion of the reaction, the solvent was distilled off, extracted with ethyl acetate and saturated brine, and the organic layers were combined and concentrated to give a pale yellow oil, which was subjected to silica gel column chromatography (petroleum ether: ethyl acetate 20: 1) to give a white solid (1.8g, yield 70%).
(2) Synthesis of (E) -3- (3-bromopyridin-4-yl) acrylamide
(E) Ethyl (3-bromopyridin-4-yl) acrylate (77mg, 0.3mmol) was dissolved in 2mL of 7M NH3The mixture was stirred at room temperature for 24 hours, and 2mL of NH was added thereto3The methanol solution of (1). After completion of the reaction, the solvent was distilled off, and purified by silica gel column chromatography to give a white solid (38mg, yield 50%).1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.56(d,J＝5.2Hz,1H),7.75(s,1H),7.64(d,J＝5.2Hz,1H),7.55(d,J＝15.6Hz,1H),7.40(s,1H),6.83(d,J＝15.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ165.31,152.25,148.87,141.79,134.55,129.45,121.62,121.62；HR-ESI-MS:m/z＝226.9824[M+H]+,calcd for C8H8BrN2O:226.9815.
Example 2: preparation of Compound 2
Figure BDA0002438339260000082
(1) Synthesis of ethyl (E) -3- (3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) acrylate
(E) -ethyl 3- (3-bromopyridin-4-yl) acrylate (512mg, 2mmol), p-piperazinylaniline (420mg, 2.2mmol), X-phos (95mg, 0.2mmol), Pd2(dba)3(92mg, 0.1mmol), sodium tert-butoxide (269mg, 2.8mmol) was placed in a round bottom flask and 10mL of toluene was added. The reaction system was purged with nitrogen for 5min and then heated to reflux under nitrogen for about 8 h. After the reaction, the temperature was lowered to room temperature, the solvent was distilled off, extraction was performed with saturated brine and ethyl acetate, and organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a solid (366mg, yield 50%).
(2) Synthesis of (E) -3- (3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) acrylamide
(E) Ethyl (3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridin-4-yl) acrylate (110mg, 0.3mmol) was dissolved in 2mL of 7M NH3The mixture was stirred at room temperature for 24 hours, and 2mL of NH was added thereto3The methanol solution of (1). After completion of the reaction, the solvent was distilled off, and purified by silica gel column chromatography to give a white solid (45mg, yield 45%).1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.16(d,J＝5.2Hz,1H),7.94(s,1H),7.61(s,1H),7.55(d,J＝16.0Hz,1H),7.46(d,J＝5.2Hz,1H),7.21(s,1H),7.02(t,J＝8.0Hz,1H),6.71(d,J＝16.0Hz,1H),6.43-6.47(m,2H),6.27(dd,J＝8.0,1.2Hz,1H),3.05(t,J＝4.8Hz,4H),2.42(t,J＝4.8Hz,4H),2.20(s,3H)；13C NMR(100MHz,DMSO-d6)δ166.21,151.99,144.93,143.72,142.65,137.66,133.42,133.16,129.51,125.93,120.10,107.89,107.23,103.82,54.54,54.54,47.97,47.97,45.66；HR-ESI-MS:m/z＝338.1970[M+H]+,calcd for C19H24N5O:338.1975.
Example 3: preparation of Compound 3
Figure BDA0002438339260000091
(1) Synthesis of ethyl (E) -3- (3- ((4-fluorophenyl) amino) pyridin-4-yl) acrylate
(E) -ethyl 3- (3-bromopyridin-4-yl) acrylate (512mg, 2mmol), p-fluoroaniline (244mg, 2.2mmol), X-phos (95mg, 0.2mmol), Pd2(dba)3(92mg, 0.1mmol), sodium tert-butoxide (269mg, 2.8mmol) was placed in a round bottom flask and 10mL of toluene was added. The reaction system was purged with nitrogen for 5min and then heated to reflux under nitrogen for about 8 h. After the reaction, the temperature was lowered to room temperature, the solvent was distilled off, extraction was performed with saturated brine and ethyl acetate, and organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a solid (300mg, yield 50%).
(2) Synthesis of (E) -3- (3- ((4-fluorophenyl) amino) pyridin-4-yl) acrylamide
(E) Ethyl (3- ((4-fluorophenyl) amino) pyridin-4-yl) acrylate (86mg, 0.3mmol) was dissolved in 2mL of 7M NH3The mixture was stirred at room temperature for 24 hours, and 2mL of NH was added thereto3The methanol solution of (1). After completion of the reaction, the solvent was distilled off, and purified by silica gel column chromatography to give a white solid (38mg, yield 45%).1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.17(d,J＝4.8Hz,1H),8.05(s,1H),7.61(s,1H),7.56(d,J＝15.6Hz,1H),7.46(d,J＝5.2Hz,1H),7.21(s,1H),7.03-7.08(m,2H),6.90-6.96(m,2H),6.72(d,J＝15.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ166.17,142.85,142.65,140.55,140.54,137.91,133.03,132.95,126.12,120.18,118.44,118.37,115.87,115.65；HR-ESI-MS:m/z＝258.1036[M+H]+,calcd for C14H13FN3O:258.1037.
Example 4: preparation of Compound 4
Figure BDA0002438339260000101
(1) Synthesis of ethyl (E) -3- (3- (4-fluorophenyl) pyridin-4-yl) acrylate
(E) Ethyl 3- (3-bromopyridin-4-yl) acrylate (1024mg, 4mmol), (4-fluorophenyl) boronic acid (616mg, 4.4mmol), Na2CO3(1272mg，12mmol)，(PPh3)2PdCl2(140mg, 0.2mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio: 1: 0.2), and purged with nitrogen for 5 min. The reaction was then heated to reflux overnight under nitrogen with an oil bath. After the reaction, the solvent was distilled off, the mixture was extracted with saturated brine and ethyl acetate, and the organic layers were combined and concentrated to obtain a crude solid product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate 10: 1 elution) to give a white solid (564mg, 52% yield).
(2) Synthesis of (E) -3- (3- (4-fluorophenyl) pyridin-4-yl) acrylic acid
(E) Ethyl-3- (3- (4-fluorophenyl) pyridin-4-yl) acrylate (678mg, 2.5mmol) was dissolved in 10mL of ethanol and neutralized, then 7.5mL of a 1N aqueous NaOH solution (7.5mmol) was added to the system, and the reaction was stirred at room temperature for about 2 hours. After the reaction was completed, the organic solvent was distilled off, about 5mL of distilled water was added to the residue, the residue was completely dissolved, part of impurities was removed by extraction with ethyl acetate, an aqueous layer was separated, 1N HCl aqueous solution was added thereto, and the pH was adjusted to weak acidity. Upon completion of the adjustment, a large amount of white solid precipitated, which was filtered and washed with distilled water, and dried to give the product as a white solid (528mg, yield 87%).
(3) Synthesis of (E) -3- (3- (4-fluorophenyl) pyridin-4-yl) acryloyl-3-methoxyazetidine
(E) Weighing (122mg, 0.5mmol), 3-methoxyazetidine hydrochloride (52mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.5mmol) as (3- (4-fluorophenyl) pyridin-4-yl) acrylic acid,dissolved in 5mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a white solid product (94mg, yield 60%).1H NMR(400MHz,CDCl3)δ8.60(d,J＝5.2Hz,1H),8.59(s,1H),7.56(d,J＝15.6Hz,1H),7.46(d,J＝5.2Hz 1H),7.29-7.32(m,1H),7.27-7.29(m,1H),7.14-7.20(m,2H),6.51(d,J＝16.0Hz,1H),4.36-4.40(m,1H),4.22-4.27(m,2H),4.09-4.11(m,1H),3.94-3.99(m,1H),3.33(s,3H)；13C NMR(100MHz,DMSO-d6)δ164.14,150.66,148.78,139.69,135.30,135.18,132.52,132.49,131.88,131.79,122.57,120.47,115.69,115.47,68.41,56.81,55.39,54.66；HR-ESI-MS:m/z＝313.1346[M+H]+,calcd for C18H18FN2O2:313.1347.
Example 5: preparation of Compound 5
Figure BDA0002438339260000121
(E) -3- (3- (4-fluorophenyl) pyridin-4-yl) acrylic acid is reacted with N-methylpiperazine to obtain the compound, and the synthetic method and operation are the same as those of the compound 4.1H NMR(400MHz,CDCl3)δ8.59(d,J＝5.2Hz,1H),8.57(s,1H),7.54(d,J＝15.6Hz,1H),7.46-7.48(m,1H),7.26-7.32(m,2H),7.13-7.18(m,2H),6.91(d,J＝15.6Hz,1H),3.70(s,2H),3.58(s,2H),2.41(t,J＝15.6Hz,4H),2.31(s,3H)；13C NMR(100MHz,DMSO-d6)δ163.48,150.67,148.70,139.88,136.65,135.14,132.61,132.58,131.89,131.81,123.47,120.44,115.67,115.45,55.02,54.25,45.54,44.92,41.57；HR-ESI-MS:m/z＝326.1658[M+H]+,calcd for C19H21FN3O:326.1663.
Example 6: preparation of Compound 6
Figure BDA0002438339260000122
(1) Synthesis of ethyl (E) -3- (3- (3, 4-dimethoxyphenyl) pyridin-4-yl) acrylate
(E) Ethyl 3- (3-bromopyridin-4-yl) acrylate (1024mg, 4mmol), 3, 4-dimethoxyphenylboronic acid (800mg, 4.4mmol), Na2CO3(1272mg，12mmol)，(PPh3)2PdCl2(140mg, 0.2mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio: 1: 0.2), and purged with nitrogen for 5 min. The reaction was then heated to reflux overnight under nitrogen with an oil bath. After the reaction, the solvent was distilled off, the mixture was extracted with saturated brine and ethyl acetate, and the organic layers were combined and concentrated to obtain a crude solid product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate 10: 1 elution) to give a white solid (677mg, 54% yield).
(2) Synthesis of (E) -3- (3- (3, 4-dimethoxyphenyl) pyridin-4-yl) acrylic acid
(E) Ethyl-3- (3- (3, 4-dimethoxyphenyl) pyridin-4-yl) acrylate (783mg, 2.5mmol) was dissolved in 10mL of ethanol and neutralized, then 7.5mL of 1N aqueous NaOH solution (7.5mmol) was added to the system, and the reaction was stirred at room temperature for about 2 h. After the reaction was completed, the organic solvent was distilled off, about 5mL of distilled water was added to the residue, the residue was completely dissolved, part of impurities was removed by extraction with ethyl acetate, an aqueous layer was separated, 1N HCl aqueous solution was added thereto, and the pH was adjusted to weak acidity. Upon completion of the adjustment, a large amount of white solid precipitated, which was filtered and washed with distilled water, and dried to give the product as a white solid (628mg, 89% yield).
(3) Synthesis of (E) -3- (3- (3, 4-dimethoxyphenyl) pyridin-4-yl) acryloyl-3-methoxyazetidine
(E) The (E) -3- (3- (3, 4-dimethoxyphenyl) pyridine-4-yl) acrylic acid reacts with 3-methoxy azetidine hydrochloride, and the synthesis method and the operation are the same as the compound 4.1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.57(d,J＝5.2Hz,1H),7.65(d,J＝15.6Hz,1H),7.46(d,J＝5.2Hz,1H),6.96(d,J＝8.0Hz,1H),6.83-6.87(m,2H),6.52(d,J＝15.6Hz,1H),4.37-4.41(m,1H),4.24-4.27(m,2H),4.10-4.13(m,1H),3.96-4.00(m,1H),3.93(s,3H),3.90(s,3H),3.33(s,3H)；13C NMR(100MHz,DMSO-d6)δ164.32,150.74,148.80,148.64,148.17,139.48,136.10,135.96,128.39,122.31,121.89,120.38,113.40,111.77,68.42,56.81,55.58,55.55,55.39,54.66；HR-ESI-MS:m/z＝355.1651[M+H]+,calcd for C20H23N2O4:355.1652.
Example 7: preparation of Compound 7
Figure BDA0002438339260000131
(E) -ethyl 3- (3-bromopyridin-4-yl) acrylate (1024mg, 4mmol), 2-naphthaleneboronic acid (757mg, 4.4mmol), Na2CO3(1272mg，12mmol)，(PPh3)2PdCl2(140mg, 0.2mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio: 1: 0.2), and purged with nitrogen for 5 min. The reaction was then heated to reflux overnight under nitrogen with an oil bath. After the reaction, the solvent was distilled off, the mixture was extracted with saturated brine and ethyl acetate, and the organic layers were combined and concentrated to obtain a crude solid product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate 10: 1 elution) to give a white solid (800mg, 53% yield).1H NMR(500MHz,DMSO-d6)δ8.74(s,1H),8.68(d,J＝4.4Hz,1H),8.08(d,J＝6.8Hz,1H),8.05–8.00(m,2H),7.98(s,1H),7.94(d,J＝4.4Hz,1H),7.63–7.61(m,2H),7.52(d,J＝12.8Hz,1H),7.52(dd,J＝6.8,1.6Hz,1H),6.90(d,J＝12.8Hz,1H),4.14(q,J＝5.6Hz,2H),1.19(t,J＝5.6Hz,3H)；13C NMR(125MHz,DMSO-d6)δ165.62,151.05,149.00,139.95,138.87,136.43,133.48,132.81,132.36,128.99,128.21,128.20,127.71,127.67,126.91,126.88,123.42,120.49,60.49,14.10；HR-ESI-MS:m/z＝304.13345[M+H]+,calcd for C20H18O2N:304.13375.
Example 8: preparation of Compound 8
Figure BDA0002438339260000141
(E) -3- (3- (naphthalen-2-yl) pyridin-4-yl) acrylic acidEthyl ester (758mg, 2.5mmol), dissolved in 5mL ethanol and 5mL tetrahydrofuran, was added to the system 7.5mL 1N aqueous NaOH (7.5mmol) and the reaction stirred at room temperature for about 2 h. After the reaction was completed, the organic solvent was distilled off, about 5mL of distilled water was added to the residue, the residue was completely dissolved, part of impurities was removed by extraction with ethyl acetate, an aqueous layer was separated, 1N HCl aqueous solution was added thereto, and the pH was adjusted to weak acidity. Upon completion of the adjustment, a large amount of white solid precipitated, which was filtered and washed with distilled water, and dried to obtain a white solid (600mg, yield 87%).1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),8.71(s,1H),8.67(d,J＝5.2Hz,1H),8.08(d,J＝8.4Hz,1H),8.00-8.04(m,2H),7.97(s,1H),7.92(d,J＝5.2Hz,1H),7.59-7.64(m,2H),7.52(dd,J＝8.4,1.6Hz,1H),7.46(d,J＝16.0Hz,1H),6.79(d,J＝15.6Hz,1H)；13C NMR(100MHz,DMSO-d6)δ166.82,150.92,148.91,139.29,139.06,136.29,133.52,132.74,132.27,128.83,128.11,128.11,127.62,127.58,126.78,126.77,124.53,120.36；HR-ESI-MS:m/z＝276.1019[M+H]+,calcd for C18H14O2N:276.1019.
Example 9: preparation of Compound 9
Figure BDA0002438339260000151
(E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) acrylic acid and methanol, and the synthesis method and operation thereof are the same as those of the compound 4.1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.67(d,J＝5.2Hz,1H),8.06(d,J＝8.0Hz,1H),7.98-8.02(m,2H),7.95(s,1H),7.91(d,J＝5.2Hz,1H),7.59-7.61(m,2H),7.55-7.44(m,2H),6.87(d,J＝16.0Hz,1H),3.65(s,3H)；13C NMR(100MHz,DMSO-d6)δ165.96,150.98,148.93,139.95,138.80,136.35,133.42,132.74,132.29,128.86,128.14,128.12,127.62,127.56,126.82,126.79,123.10,120.44,51.75；HR-ESI-MS:m/z＝290.1173[M+H]+,calcd for C19H16NO2:290.1176.
Example 10: preparation of Compound 10
Figure BDA0002438339260000152
(E) The (E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) ethyl acrylate NH3 in methanol, and the synthesis method and operation are the same as those of the compound 1.1H NMR(400MHz,Acetone-d6)δ8.69(s,1H),8.63(d,J＝5.2Hz,1H),8.05(d,J＝8.4Hz,1H),7.98-8.03(m,2H),7.94(d,J＝1.6Hz,1H),7.69(d,J＝5.2Hz,1H),7.57-7.61(m,2H),7.55(d,J＝15.2Hz,1H),7.53(dd,J＝8.4,2.0Hz,1H),7.07(s,1H),6.91(d,J＝16.0Hz,1H),6.47(s,1H)；13C NMR(100MHz,DMSO-d6)δ166.16,151.40,149.41,140.44,136.68,135.37,134.22,133.25,132.75,129.18,128.59,128.54,128.09,128.09,127.93,127.19,127.19,120.35；HR-ESI-MS:m/z＝275.1178[M+H]+,calcd for C18H15N2O:275.1179.
Example 11: preparation of Compound 11
Figure BDA0002438339260000161
(E) The (E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) acrylic acid is obtained by reacting with methylamine hydrochloride, and the synthesis method and the operation are the same as those of the compound 4.1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.63(d,J＝5.2Hz,1H),7.93(d,J＝8.8Hz,1H),7.87-7.92(m,2H),7.81(s,1H),7.59(s,1H),7.52-7.57(m,2H),7.49(d,J＝5.2Hz,1H),7.43(dd,J＝8.4,2.0Hz,1H),6.47(d,J＝15.6Hz,1H),5.62(s,1H),2.88(d,J＝4.8Hz,3H)；13C NMR(100MHz,DMSO-d6)δ164.41,150.09,148.08,140.94,136.41,133.92,133.44,132.73,132.31,128.75,128.11,128.09,127.68,127.61,127.54,126.79,126.74,120.23,25.66；HR-ESI-MS:m/z＝289.1334[M+H]+,calcd for C19H17N2O:289.1335.
Example 12: preparation of Compound 12
Figure BDA0002438339260000162
(E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) acrylic acid and cyclopropylamine, and the synthesis method and operation thereof are the same as those of compound 4.1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.62(d,J＝5.3Hz,1H),7.95(s,1H),7.89(dt,J＝6.9,3.8Hz,2H),7.81(s,1H),7.60(d,J＝15.7Hz,1H),7.55(m,2H),7.50(d,J＝5.3Hz,1H),7.42(dd,J＝8.4,1.7Hz,1H),6.44(d,J＝15.7Hz,1H),5.74(s,1H),2.82-2.76(m,1H),0.80(dt,J＝6.9,5.5Hz,2H),0.56-0.51(m,2H)；13C NMR(125MHz,DMSO-d6)δ165.09,150.98,149.00,140.00,136.25,134.22,133.78,132.81,132.32,128.75,128.18,128.12,127.69,127.68,127.02,126.80,126.78,119.83,22.58,5.87,5.87；HR-ESI-MS:m/z＝315.15018[M+H]+,calcd for C21H19ON2:315.14919.
Example 13: preparation of Compound 13
Figure BDA0002438339260000171
(E) -3- (3- (naphthalen-2-yl) pyridin-4-yl) acrylic acid (138mg, 0.5mmol), methyl 3-amino-alanine (84mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol) dissolved in 10mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a white solid product (110mg, yield 61%). The white solid (110mg, 0.5mmol) was dissolved in absolute ethanol, 2ml of a 1M aqueous NaOH solution was added dropwise, and the reaction was stirred at room temperature for about 2 hours. After the reaction, the reaction solution was evaporated to dryness under reduced pressure, dissolved in distilled water, washed with ethyl acetate, the aqueous phase was adjusted to pH 5 with 1M HCl aqueous solution, a white solid precipitated, and filtered to obtain a white solid (85mg, yield 82%).1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.70(d,J＝5.3Hz,1H),8.38(t,J＝5.6Hz,1H),8.07(d,J＝8.5Hz,1H),8.02(td,J＝6.9,4.4Hz,2H),7.96(s,1H),7.74(d,J＝5.3Hz,1H),7.65-7.59(m,2H),7.50(dd,J＝8.4,1.7Hz,1H),7.34(d,J＝15.7Hz,1H),6.91(d,J＝15.7Hz,1H),3.33(q,J＝6.6Hz,2H),2.42(t,J＝6.7Hz,2H)；13C NMR(125MHz,DMSO-d6)δ172.91,164.02,150.17,148.13,140.91,136.56,134.19,133.48,132.79,132.37,128.83,128.20,128.17,127.70,127.66,127.64,126.88,126.83,120.20,35.03,33.69；HR-ESI-MS:m/z＝347.13937[M+H]+,calcd for C21H19O3N2:347.13902.
Example 14: preparation of Compound 14
Figure BDA0002438339260000172
(E) -3- (3- (naphthalen-2-yl) pyridin-4-yl) acrylic acid (138mg, 0.5mmol), L-valine ethyl ester hydrochloride (109mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol), dissolved in 10mL of dichloromethane, stirred at room temperature for about 6 h. After the reaction is finished, the reaction liquid is respectively washed by saturated sodium carbonate solution, 0.5N hydrochloric acid solution and saturated saline solution, an organic layer is concentrated to obtain a crude product, and the crude product is subjected to silica gel column chromatography to obtain a light yellow oily substance. The pale yellow oil (116mg, 0.3mmol) was dissolved in absolute ethanol, 2ml of a 1M aqueous NaOH solution was added dropwise, and the reaction was stirred at room temperature for about 2 hours. After the reaction, the reaction solution was evaporated to dryness under reduced pressure, dissolved in distilled water, washed with ethyl acetate, the aqueous phase was adjusted to pH 5 with 1M HCl aqueous solution, a white solid precipitated, and filtered to obtain a white solid (110mg, 73% yield).1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.68(s,1H),8.38(d,J＝8.5Hz,1H),8.06(d,J＝8.6Hz,1H),8.01(ddd,J＝9.6,4.7,3.3Hz,2H),7.95(d,J＝1.7Hz,1H),7.68(d,J＝5.3Hz,1H),7.63-7.59(m,2H),7.50(dd,J＝8.4,1.8Hz,1H),7.35(d,J＝15.8Hz,1H),7.12(d,J＝15.7Hz,1H),4.21(dd,J＝8.5,5.6Hz,1H),2.13–2.04(m,1H),0.89(t,J＝6.9Hz,6H)；13C NMR(100MHz,DMSO-d6)δ172.66,164.12,150.89,148.87,139.74,136.21,134.67,133.61,132.65,132.17,128.61,128.00,127.97,127.52,127.52,126.71,126.63,126.63,119.51,57.25,29.81,19.01,17.85；HR-ESI-MS:m/z＝375.17050[M+H]+,calcd for C23H23O3N2:375.17032.
Example 15: preparation of Compound 15
Figure BDA0002438339260000181
(E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) acrylic acid and dimethylamine hydrochloride, and the synthesis method and operation are the same as those of the compound 4.1H NMR(400MHz,Acetone-d6)δ8.68(s,1H),8.62(d,J＝5.2Hz,1H),8.04(d,J＝8.4Hz,1H),7.97-8.02(m,2H),7.94(d,J＝1.6Hz,1H),7.83(d,J＝5.2Hz,1H),7.57-7.61(m,2H),7.55(d,J＝15.2Hz,1H),7.52(dd,J＝8.4,2.0Hz,1H),7.36(d,J＝15.4Hz,1H),3.18(s,3H),2.91(s,3H)；13C NMR(100MHz,DMSO-d6)δ164.66,150.82,148.70,140.02,136.38,136.33,133.78,132.69,132.19,128.69,128.04,128.00,127.59,127.56,126.70,126.66,123.72,120.44,36.82,35.28；HR-ESI-MS:m/z＝303.1491[M+H]+,calcd for C20H19N2O:303.1492.
Example 16: preparation of Compound 16
Figure BDA0002438339260000191
(E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) acrylic acid and 3-methoxy azetidine hydrochloride, and the synthesis method and the operation are the same as those of the compound 4.1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.64(d,J＝5.2Hz,1H),7.93(d,J＝8.4Hz,1H),7.86-7.92(m,2H),7.80(d,J＝1.2Hz,1H),7.59(d,J＝15.6Hz,1H),7.51-7.56(m,2H),7.50(d,J＝5.2Hz,1H),7.42(dd,J＝8.4,1.6Hz,1H),6.49(d,J＝15.6Hz,1H),4.26-4.30(m,1H),4.16-4.25(m,2H),3.99-4.02(m,1H),3.93(m,1H),3.28(s,3H)；13C NMR(100MHz,DMSO-d6)δ164.17,150.76,148.70,139.83,136.26,135.43,133.68,132.72,132.26,128.72,128.08,128.07,127.60,127.58,126.75,126.73,122.51,120.46,68.39,56.82,55.37,54.65；HR-ESI-MS:m/z＝345.1597[M+H]+,calcd for C22H21N2O2:345.1598.
Example 17: preparation of Compound 17
Figure BDA0002438339260000192
(E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) acrylic acid and morpholine, and the synthesis method and operation are the same as those of compound 4.1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.64(d,J＝5.2Hz,1H),7.94(d,J＝8.4Hz,1H),7.86-7.91(m,2H),7.81(d,J＝1.2Hz,1H),7.60(d,J＝15.6Hz,1H),7.53-7.57(m,2H),7.51(d,J＝5.2Hz,1H),7.43(dd,J＝8.4,2.0Hz,1H),6.81(d,J＝15.6Hz,1H),3.65(s,4H),3.57(s,2H),3.42(s,2H)；13C NMR(100MHz,DMSO-d6)δ163.65,150.85,148.72,139.93,136.99,136.2,133.80,132.73,132.23,128.71,128.08,128.05,127.64,127.60,126.71,126.71,123.11,120.41,66.30,66.01,45.57,42.05；HR-ESI-MS:m/z＝345.1598[M+H]+,calcd for C22H21N2O2:345.1598.
Example 18: preparation of Compound 18
Figure BDA0002438339260000201
(E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) acrylic acid and N-methyl piperazine, and the synthesis method and operation are the same as those of the compound 4.1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.64(d,J＝5.2Hz,1H),7.94(d,J＝8.6Hz,1H),7.91-7.87(m,2H),7.81(s,1H),7.56-7.53(m,3H),7.52(d,J＝5.2Hz,1H),7.43(dd,J＝8.3,1.7Hz,1H),6.87(d,J＝15.6Hz,1H),3.67(s,2H),3.48(s,2H),2.35(d,J＝27.7Hz,4H),2.29(s,3H)；13C NMR(125MHz,DMSO-d6)δ163.39,150.75,148.62,139.84,136.74,136.10,133.72,132.63,132.13,128.61,127.99,127.96,127.56,127.51,126.62,126.62,123.26,120.34,54.91,54.13,45.44,44.80,41.44；HR-ESI-MS:m/z＝358.19046[M+H]+,calcd for C23H24ON3:358.19139.
Example 19: preparation of Compound 19
Figure BDA0002438339260000202
(E) The (E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) acrylic acid is obtained by reacting with L-proline methyl ester hydrochloride, and the synthetic method and the operation are the same as those of the compound 4.1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝5.2Hz,2H),8.08-7.80(m,6H),7.60(dd,J＝7.2,2.4Hz,2H),7.49(d,J＝10.0Hz,1H),7.42-7.34(m,1H),7.29-7.04(m,1H),4.96-4.21(m,1H),3.75(m,2H),2.20-2.11(m,1H),2.00-1.76(m,3H)；13C NMR(100MHz,DMSO-d6)δ172.53,162.65,150.45,148.46,139.69,136.21,135.96,133.58,132.51,132.03,128.30,127.71,127.71,127.23,127.14,126.30,126.30,124.49,120.16,58.42,46.34,28.37,23.92；HR-ESI-MS:m/z＝373.15472[M+H]+,calcd for C23H21O3N2:373.15467.
Example 20: preparation of Compound 20
Figure BDA0002438339260000211
(E) -ethyl 3- (3-bromopyridin-4-yl) acrylate (1228mg, 4.8mmol), 1-methyloxazole-5-boronic acid (845mg, 4.8mmol), Na2CO3(2035mg，19.2mmol)，(PPh3)2PdCl2(168mg, 0.24mmol) was dissolved in a mixed solution of toluene, ethanol and water (volume ratio: 1: 0.2), and the mixed system was purged with nitrogen 5 times. The reaction was then heated under reflux in an oil bath under nitrogen for 12 h. After the reaction is finished, the solvent is evaporated, ethyl acetate is added, the mixture is washed by distilled water, and the organic layers are combined and concentrated to obtain a solid crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 2: 1 elution) to give a white solid (870mg, yield 59%).1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.63(d,J＝5.2Hz,1H),8.15(s,1H),7.89(d,J＝5.2Hz,1H),7.79(d,J＝8.7Hz,1H),7.78(d,J＝0.8Hz,1H),7.49(d,J＝16.0Hz,1H),7.39(dd,J＝8.6,1.6Hz,1H),6.86(d,J＝16.0Hz,1H),4.17-4.12(q,7.2Hz,2H),4.12(s,3H),1.20(t,J＝7.1Hz,3H).HR-ESI-MS:m/z＝308.13956[M+H]+,calcd for C18H18O2N3:308.13935.
Example 21: preparation of Compound 21
Figure BDA0002438339260000212
(E) Ethyl (3- (1-methyl-1H-indazol-5-yl) pyridin-4-yl) acrylate (615mg, 2.0mmol) was dissolved in 20ml of absolute ethanol, 3ml of a 1M aqueous NaOH solution was added dropwise thereto, and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off, and the mixture was dissolved in distilled water, washed with ethyl acetate, and the pH of the aqueous layer was adjusted to about 5 with 1M aqueous HCl to precipitate a pale yellow solid (470mg, 84% yield).1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.61(d,J＝5.2Hz,1H),8.14(d,J＝0.9Hz,1H),7.84(d,J＝5.2Hz,1H),7.80-7.77(m,1H),7.77-7.76(m,1H),7.41-7.38(m,1H),7.37-7.35(m,1H),6.77-6.72(m,1H),4.11(s,3H)；13C NMR(125MHz,DMSO-d6)δ167.01,150.99,148.37,139.22,138.96,138.62,136.59,132.70,128.11,127.90,125.14,123.51,121.87,120.16,109.83,35.41；HR-ESI-MS:m/z＝280.10889[M+H]+,calcd for C16H14O2N3:280.10805.
Example 22: preparation of Compound 22
Figure BDA0002438339260000221
(E) -3- (3- (1-methyl-1H-indazol-5-yl) pyridin-4-yl) acrylic acid (140mg, 0.5mmol), methylamine hydrochloride (40.5mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol) dissolved in 10mL dichloromethane and stirred at room temperature for about 6H. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (100mg, yield 68%).1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.61(d,J＝0.8Hz,1H),8.18,(d,J＝4.4Hz,1H),8.13(d,J＝0.9Hz,1H),7.78(dt,J＝8.6,0.9Hz,1H),7.75(dd,J＝1.6,0.8Hz,1H),7.64(d,J＝5.3Hz,1H),7.36(dd,J＝8.6,1.6Hz,1H),7.28(d,J＝15.7Hz,1H),6.78(d,J＝15.7Hz,1H),4.11(s,3H),2.66(d,J＝4.4Hz,3H)；13C NMR(125MHz,DMSO-d6)δ164.45,150.98,148.40,139.89,138.94,136.47,134.28,132.69,128.24,127.90,126.74,123.50,121.77,119.73,109.80,35.41,25.56；HR-ESI-MS:m/z＝293.13940[M+H]+,calcd for C17H17ON4:293.13969.
Example 23: preparation of Compound 23
Figure BDA0002438339260000231
(E) -3- (3- (1-methyl-1H-indazol-5-yl) pyridin-4-yl) acrylic acid (140mg, 0.5mmol), morpholine (52mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol) dissolved in 10mL dichloromethane and the reaction stirred at room temperature for about 6H. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (110mg, yield 63%).1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.62(s,1H),8.14(d,J＝0.9Hz,1H),7.98(d,J＝5.3Hz,1H),7.78(dt,J＝8.7,0.9Hz,1H),7.76(dd,J＝1.6,0.8Hz,1H),7.47(d,J＝15.4Hz,1H),7.40-7.35(m,2H),4.11(s,3H),3.74-3.67(m,2H),3.59(dd,J＝8.1,4.0Hz,4H),3.52-3.46(m,2H)；13C NMR(100MHz,DMSO-d6)δ163.57,150.75,147.98,140.08,138.95,137.08,136.63,132.68,128.22,127.93,123.50,122.80,121.82,120.35,109.80,66.22,65.95,45.48,41.96,35.41；HR-ESI-MS:m/z＝349.16483[M+H]+,calcd for C20H21O2N4:349.16590.
Example 24: preparation of Compound 24
Figure BDA0002438339260000232
(E) -3- (3- (1-methyl-1H-indazol-6-yl) pyridin-4-yl) acrylic acid (140mg, 0.5mmol), methylamine hydrochloride (40.5mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol) dissolved in 10mL dichloromethane and stirred at room temperature for about 6H. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (105mg, yield 70%).1H NMR(400MHz,DMSO-d6)δ8.66-8.64(m,2H),8.65(d,J＝0.7Hz,1H),8.14(d,J＝0.9Hz,1H),7.86(dd,J＝8.3,0.8Hz,1H),7.71(q,J＝0.9Hz,1H),7.68-7.65(m,1H),7.29(d,J＝15.8Hz,1H),7.06(dd,J＝8.3,1.4Hz,1H),6.78(d,J＝15.8Hz,1H),4.08(s,3H),2.65(d,J＝4.7Hz,3H)；13C NMR(125MHz,DMSO-d6)δ164.40,150.84,148.80,139.93,139.51,136.47,134.06,134.01,132.33,126.93,122.77,122.53,120.68,119.62,110.54,35.34,25.56；HR-ESI-MS:m/z＝293.13937[M+H]+,calcd for C17H17ON4:293.13969.
Example 25: preparation of Compound 25
Figure BDA0002438339260000241
(E) -3- (3- (1-methyl-1H-indazol-6-yl) pyridin-4-yl) acrylic acid (140mg, 0.5mmol), morpholine (52mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol) dissolved in 10mL dichloromethane and the reaction stirred at room temperature for about 6H. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (160mg, yield 92%).1H NMR(400MHz,DMSO-d6)δ8.67-8.65(m,2H),8.14(d,J＝0.9Hz,1H),7.99(d,J＝5.3Hz,1H),7.87(dd,J＝8.3,0.8Hz,1H),7.71(d,J＝1.1Hz,1H),7.47(d,J＝15.4Hz,1H),7.37(d,J＝15.4Hz,1H),7.07(dd,J＝8.3,1.4Hz,1H),4.08(s,3H),3.72-3.66(m,2H),3.61-3.54(m,4H),3.52-3.46(m,2H)；13C NMR(125MHz,DMSO-d6)δ163.57,150.81,148.60,139.87,139.49,136.94,136.54,134.05,132.33,122.90,122.76,122.56,120.69,120.18,110.61,66.22,65.93,45.47,41.95,35.34；HR-ESI-MS:m/z＝349.16684[M+H]+,calcd for C20H21O2N4:349.16590.
Example 26: preparation of Compound 26
Figure BDA0002438339260000251
(E) -ethyl 3- (3-bromopyridin-4-yl) acrylate (1228mg, 4.8mmol), indole-5-boronic acid (773mg, 4.8mmol), Na2CO3(2035mg，19.2mmol)，(PPh3)2PdCl2(168mg, 0.24mmol) was dissolved in a mixed solution of toluene, ethanol and water (volume ratio: 1: 0.2), and the mixed system was purged with nitrogen 5 times. The reaction was then heated under reflux in an oil bath under nitrogen for 12 h. After the reaction is finished, the solvent is evaporated, ethyl acetate is added, the mixture is washed by distilled water, and the organic layers are combined and concentrated to obtain a solid crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 2: 1 elution) to give a white solid (700mg, 50% yield).1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.64(s,1H),8.59(d,J＝5.2Hz,1H),7.86(d,J＝5.2Hz,1H),7.56(d,J＝16.0Hz,1H),7.54(s,1H),7.53(d,J＝4.4Hz,1H),7.46(t,J＝2.8Hz,1H),7.06(dd,J＝8.4,1.6Hz,1H),6.84(d,J＝16.0Hz,1H),6.53-6.51(m,1H),4.14(q,J＝7.2Hz,2H),1.20(t,J＝7.2Hz,3H).HR-ESI-MS:m/z＝293.12799[M+H]+,calcd for C18H17O2N2:293.12845.
Example 27: preparation of Compound 27
Figure BDA0002438339260000252
(E) Ethyl (585mg, 2.0mmol) 3- (3- (1H-indol-5-yl) pyridin-4-yl) acrylate was dissolved in 20ml absolute ethanol and 6ml of 1M aqueous NaOH solution was added dropwise theretoStirring for 10 h. After the reaction, the solvent was distilled off, and the mixture was dissolved in distilled water, washed with ethyl acetate, and the pH of the aqueous layer was adjusted to about 5 with 1M aqueous HCl to precipitate a pale yellow solid (225mg, 85% yield).1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),8.45(s,1H),8.44(d,J＝5.2Hz,1H)7.81(d,J＝5.6Hz,1H),7.50(d,J＝5.6Hz,1H),7.48(s,1H),7.42(t,J＝2.4Hz,1H),7.05(d,J＝9.2Hz,1H),7.02(s,1H),6.73(d,J＝16.0Hz,1H),6.52(s,1H)；13C NMR(125MHz,DMSO-d6)δ169.69,151.51,148.21,142.53,137.88,136.29,135.98,131.38,128.34,128.13,126.87,123.59,121.80,120.24,111.98,101.98；HR-ESI-MS:m/z＝265.09689[M+H]+,calcd for C16H13O2N2:265.09715.
Example 28: preparation of Compound 28
Figure BDA0002438339260000261
(E) -3- (3- (1H-indol-5-yl) pyridin-4-yl) acrylic acid (140mg, 0.5mmol), methylamine hydrochloride (40.5mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol) dissolved in 10mL dichloromethane and stirred at room temperature for about 6H. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (80mg, yield 58%).1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),8.59(s,1H),8.57(d,J＝5.2Hz,1H),8.17(q,J＝4.8Hz,1H),7.61(d,J＝5.2Hz,1H),7.53-7.51(m,2H),7.45(t,J＝2.8Hz,1H),7.36(d,J＝15.6Hz,1H),7.04(dd,J＝8.4,1.6Hz,1H),6.77(d,J＝15.6Hz,1H),6.51-6.50(m,1H),2.66(d,J＝4.8Hz,3H)；13C NMR(125MHz,DMSO-d6)δ164.58,151.02,147.74,139.67,137.70,135.34,134.77,127.65,126.61,126.35,126.18,122.83,121.23,119.56,111.40,101.32,25.56；HR-ESI-MS:m/z＝278.12817[M+H]+,calcd for C17H16ON3:278.12879.
Example 29: preparation of Compound 29
Figure BDA0002438339260000262
(E) -3- (3- (1H-indol-5-yl) pyridin-4-yl) acrylic acid (132mg, 0.5mmol), morpholine (52mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol), dissolved in 10mL dichloromethane, stirred at room temperature for about 6H. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (100mg, yield 60%).1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.67(s,1H),8.64(d,J＝5.2Hz,1H),8.05(d,J＝5.2Hz,1H),7.54(s,1H),7.53-7.52(m,1H),7.48-7.45(m,3H),7.06(dd,J＝8.4,1.6Hz,1H),6.52-6.51(m,1H),3.71-3.70(m,2H),3.62-3.55(m,4H),3.50-3.49(m,2H)；13C NMR(125MHz,DMSO-d6)δ163.54,149.52,146.01,141.28,138.29,137.17,135.43,127.65,126.50,126.12,123.10,122.81,121.37,120.83,111.48,101.35,66.22,65.93,45.48,41.96；HR-ESI-MS:m/z＝334.15463[M+H]+,calcd for C20H20O2N3:334.15500.
Example 30: preparation of Compound 30
Figure BDA0002438339260000271
(E) -ethyl 3- (3-bromopyridin-4-yl) acrylate (1228mg, 4.8mmol), indole-6-boronic acid pinacol ester (1215mg, 5.0mmol), Na2CO3(2035mg，19.2mmol)，(PPh3)2PdCl2(168mg, 0.24mmol) was dissolved in a mixed solution of toluene, ethanol and water (volume ratio: 1: 0.2), and the mixed system was purged with nitrogen 5 times. The reaction was then heated under reflux in an oil bath under nitrogen for 12 h. After the reaction is finished, the solvent is evaporated, ethyl acetate is added, the mixture is washed by distilled water, and the organic layers are combined and concentrated to obtain a solid crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate 2: 1 wash)Dear) to give a white solid (1000mg, 71% yield).1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.66(s,1H),8.60(d,J＝5.2Hz,1H),7.87(d,J＝5.2Hz,1H),7.68(d,J＝8.0Hz,1H),7.57(d,J＝16.0Hz,1H),7.46(t,J＝2.4Hz,1H),7.38(s,1H),6.98(dd,J＝8.0,1.6Hz,1H),6.85(d,J＝16.0Hz,1H),6.53(t,J＝2.4Hz,1H),4.14(q,J＝7.2Hz,2H),1.20(t,J＝7.2Hz,3H)；HR-ESI-MS:m/z＝293.12872[M+H]+,calcd for C18H17O2N2:293.12845.
Example 31: preparation of Compound 31
Figure BDA0002438339260000281
(E) Ethyl (585mg, 2.0mmol) 3- (3- (1H-indol-6-yl) pyridin-4-yl) acrylate was dissolved in 20ml absolute ethanol, 4ml of a 1M aqueous NaOH solution was added dropwise thereto, and the mixture was stirred at room temperature for 6 hours. After the reaction, the solvent was distilled off, and the mixture was dissolved in distilled water, washed with ethyl acetate, and the pH of the aqueous layer was adjusted to about 5 with 1M aqueous HCl to precipitate a pale yellow solid (423mg, yield 80%).1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.47(s,1H),8.46(d,J＝5.2Hz,1H),7.64(d,J＝1.6Hz,1H),7.62(d,J＝5.2Hz,1H),7.41(t,J＝2.4Hz,1H),7.33(s,1H),7.07,(dd,J＝15.6,1.2Hz,1H),6.95(dd,J＝8.0,1.6Hz,1H),6.56(dd,J＝15.6,1.2Hz,1H),6.49(t,J＝2.4Hz,1H)；13C NMR(125MHz,DMSO-d6)δ169.07,150.65,147.58,141.71,136.89,135.69,135.47,130.71,129.35,126.98,126.18,120.73,119.80,119.55,112.54,100.83；HR-ESI-MS:m/z＝265.09796[M+H]+,calcd for C16H13O2N2:265.09715.
Example 32: preparation of Compound 32
Figure BDA0002438339260000282
(E) -3- (3- (1H-indol-6-yl) pyridin-4-yl) acrylic acid (140mg, 0.5mmol), methylamine hydrochloride (40.5mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129 m)g, 1.0mmol), dissolved in 10mL of dichloromethane and the reaction stirred at room temperature for about 6 h. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (78mg, yield 57%).1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),8.61(s,1H),8.58(d,J＝5.2Hz,1H),8.18(q,J＝4.4Hz,1H),7.66(d,J＝8.4Hz,1H),7.62(d,J＝5.2Hz,1H),7.45(m,1H),7.38(d,J＝15.6Hz,1H),7.36-7.35(m,1H),6.97(dd,J＝8.4,1.6Hz,1H),6.78(d,J＝15.6Hz,1H),6.52-6.51(m,1H),2.67(d,J＝4.4Hz,3H)；13C NMR(125MHz,DMSO-d6)δ164.56,150.97,147.94,139.64,137.42,135.67,134.81,128.60,127.24,126.50,126.27,120.77,120.03,119.67,112.66,100.93,25.57；HR-ESI-MS:m/z＝278.12878[M+H]+,calcd for C17H16ON3:278.12879.
Example 33: preparation of Compound 33
Figure BDA0002438339260000291
(E) -3- (3- (1H-indol-6-yl) pyridin-4-yl) acrylic acid (132mg, 0.5mmol), morpholine (52mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol), dissolved in 10mL dichloromethane, stirred at room temperature for about 6H. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (50mg, yield 30%).1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.60(s,1H),8.54(s,1H),7.70(d,J＝8.0Hz,1H),7.64(d,J＝15.6Hz,1H),7.52(d,J＝5.2Hz,1H),7.33(s,1H),7.29-7.27(m,1H),7.05(d,J＝8.0Hz,1H),6.83(d,J＝15.6Hz,1H),6.59(s,1H),3.71-3.62(m,4H),3.64-3.59(m,2H),3.50-3.44(m,2H)；13C NMR(125MHz,CDCl3)δ164.75,151.19,147.62,141.21,139.18,138.24,135.82,129.72,127.76,125.55,122.41,121.75,120.94,120.79,112.47,102.50,66.74,66.66,46.26,42.39；HR-ESI-MS:m/z＝334.15472[M+H]+,calcd for C20H20O2N3:334.15500.
Example 34: preparation of Compound 34
Figure BDA0002438339260000292
(E) -ethyl 3- (3-bromopyridin-4-yl) acrylate (1228mg, 4.8mmol), 1-methylindole-5-boronic acid (962mg, 5.5mmol), Na2CO3(2035mg，19.2mmol)，(PPh3)2PdCl2(168mg, 0.24mmol) was dissolved in a mixed solution of toluene, ethanol and water (volume ratio: 1: 0.2), and the mixed system was purged with nitrogen 5 times. The reaction was then heated under reflux in an oil bath under nitrogen for 12 h. After the reaction is finished, the solvent is evaporated, ethyl acetate is added, the mixture is washed by distilled water, and the organic layers are combined and concentrated to obtain a solid crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 2: 1 elution) to give a white solid (1000mg, 71% yield).1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.59(d,J＝5.2Hz,1H),7.86(d,J＝5.2Hz,1H),7.59(d,J＝8.4Hz,1H),7.55(d,J＝1.6Hz,1H),7.54(d,J＝16.0Hz,1H),7.44(d,J＝3.2,0.8Hz,1H),7.12(dd,J＝8.4,1.6Hz,1H),6.84(d,J＝16.0Hz,1H),6.51(dd,J＝3.2,0.8Hz,1H),4.14(q,J＝7.2Hz,2H),3.86(s,3H),1.20(t,J＝7.2Hz,3H)；HR-ESI-MS:m/z＝307.14426[M+H]+,calcd for C19H19O2N2:307.14410.
Example 35: preparation of Compound 35
Figure BDA0002438339260000301
(E) Ethyl (3- (1-methyl-1H-indol-5-yl) pyridin-4-yl) acrylate (613mg, 2.0mmol) was dissolved in 20ml of anhydrous ethanol, 4ml of a 1M aqueous NaOH solution was added dropwise thereto, and the mixture was stirred at room temperature for 6 hours. After the reaction, the solvent was distilled off, and the mixture was dissolved in distilled water, washed with ethyl acetate, and the pH of the aqueous layer was adjusted to about 5 with 1M aqueous HCl to precipitate a pale yellow solid (334mg, yield 60)％)。1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.57(d,J＝5.2Hz,1H),7.81(d,J＝5.2Hz,1H),7.58(d,J＝8.4Hz,1H),7.53(d,J＝1.2Hz,1H),7.44(d,J＝16.0Hz,1H),7.43(d,J＝3.2Hz,1H),7.11(d,J＝8.4,Hz,1H),6.72(d,J＝16.0Hz,1H),6.51(dd,J＝3.2,1.2Hz,1H),3.86(s,3H)；13C NMR(125MHz,DMSO-d6)δ167.08,151.06,147.85,138.98,137.65,135.87,130.68,128.04,126.63,122.90,122.90,121.53,121.53,120.03,109.81,100.60,32.51；HR-ESI-MS:m/z＝279.11383[M+H]+,calcd for C17H15O2N2:279.11280.
Example 36: preparation of Compound 36
Figure BDA0002438339260000311
(E) -3- (3- (1-methyl-1H-indol-5-yl) pyridin-4-yl) acrylic acid (139mg, 0.5mmol), methylamine hydrochloride (40.5mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol) dissolved in 10mL of dichloromethane and stirred at room temperature for about 6H. After the reaction, the reaction solution was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated saline solution, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a pale yellow solid (130mg, yield 90%).1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.62(d,J＝5.2Hz,1H),8.20(q,J＝4.4Hz,1H),7.70(d,J＝5.2Hz,1H),7.58(d,J＝8.4Hz,1H),7.54(d,J＝2.0Hz,1H),7.44(d,J＝3.2Hz,1H),7.35(d,J＝15.6Hz,1H),7.11(dd,J＝8.4,2.0Hz,1H),6.81(d,J＝15.6Hz,1H),6.51(dd,J＝2.8,0.8Hz,1H),3.86(s,3H),2.67(d,J＝4.4Hz,3H)；13C NMR(125MHz,DMSO-d6)δ164.44,149.85,146.66,141.01,137.93,135.92,134.40,130.71,128.01,126.98,126.32,122.86,121.54,120.12,109.84,100.63,32.51,25.58；HR-ESI-MS:m/z＝292.14410[M+H]+,calcd for C18H18ON3:292.14444.
Example 37: preparation of Compound 37
Figure BDA0002438339260000312
(E) -3- (3- (1-methyl-1H-indol-5-yl) pyridin-4-yl) acrylic acid (139mg, 0.5mmol), morpholine (52mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol) dissolved in 10mL of dichloromethane and stirred at room temperature for about 6H. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (110mg, yield 63%).1H NMR(400MHz,CDCl3)δ8.70(s,1H),8.62(d,J＝4.8Hz,1H),7.60(d,J＝15.6Hz,1H),7.56-7.54(m,2H),7.40(d,J＝8.4Hz,1H),7.14-7.12(m,2H),6.85(d,J＝15.6Hz,1H),6.52(dd,J＝3.2,0.8Hz,1H),3.84(s,3H),3.69-3.64(m,4H),3.64-3.60(m,2H),3.52-3.48(m,2H)；13C NMR(125MHz,CDCl3)δ164.68,151.09,147.31,141.81,139.05,138.78,136.41,129.97,128.64,126.96,123.46,122.48,122.14,120.86,109.52,101.38,66.7,66.69,46.28,42.38,33.00；HR-ESI-MS:m/z＝348.16931[M+H]+,calcd for C21H22O2N3:348.17065.
Example 38: preparation of Compound 38
Figure BDA0002438339260000321
(E) -3- (3- (quinolin-6-yl) pyridin-4-yl) acrylic acid (138mg, 0.5mmol), methylamine hydrochloride (40.5mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol), dissolved in 10mL of dichloromethane, and the reaction stirred at room temperature for about 6 h. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (80mg, yield 55%).1H NMR(400MHz,DMSO-d6)δ8.99(dd,J＝4.4,1.6Hz,1H),8.69(s,1H),8.68(d,J＝5.2Hz,1H),8.45(dd,J＝8.4,1.2Hz,1H),8.20(q,J＝4.8Hz,1H),8.14(d,J＝8.8Hz,1H),8.03(d,J＝1.6Hz,1H),7.74(dd,J＝8.8,2.0Hz,1H),7.69(d,J＝5.2Hz,1H),7.62(dd,J＝8.4,4.4Hz,1H),7.30(d,J＝16.0Hz,1H),6.81(d,J＝16.0Hz,1H),2.65(d,J＝4.8Hz,3H)；13C NMR(125MHz,DMSO-d6)δ164.34,151.17,150.80,149.10,146.93,139.96,136.22,135.43,134.28,133.83,131.10,129.01,128.92,127.64,127.31,122.04,119.86,25.57；HR-ESI-MS:m/z＝290.12762[M+H]+,calcd for C18H16ON3:290.12879.
Example 39: preparation of Compound 39
Figure BDA0002438339260000331
(E) -3- (3- (quinolin-6-yl) pyridin-4-yl) acrylic acid (138mg, 0.5mmol), morpholine (52mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol), dissolved in 10mL of dichloromethane, and the reaction stirred at room temperature for about 6 h. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (80mg, yield 46%).1H NMR(400MHz,DMSO-d6)δ8.99(dd,J＝4.4,2.0Hz,1H),8.70(s,1H),8.69(d,J＝5.2Hz,1H),8.44(dd,J＝8.8,2.0Hz,1H),8.15(d,J＝8.4Hz,1H),8.03(s,1H),8.03(d,J＝8.4Hz,1H),7.75(dd,J＝8.8,2.0Hz,1H),7.63(dd,J＝8.4,4.4Hz,1H),7.50(d,J＝15.6Hz,1H),7.39(d,J＝15.6Hz,1H),3.72-3.69(m,2H),3.61-3.55(m,4H),3.51-3.47(m,2H)；13C NMR(125MHz,DMSO-d6)δ163.48,151.19,150.77,148.89,146.90,139.87,136.69,136.20,135.52,134.31,131.14,129.00,128.96,127.61,123.21,122.06,120.35,66.21,65.92,45.47,41.96；HR-ESI-MS:m/z＝346.15396[M+H]+,calcd for C21H20O2N3:346.15500.
Example 40: preparation of Compound 40
Figure BDA0002438339260000332
(E) -3- (3- (quinolin-7-yl)) Pyridin-4-yl) acrylic acid (138mg, 0.5mmol), methylamine hydrochloride (40.5mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol) were dissolved in 10mL of dichloromethane and the reaction stirred at room temperature for about 6 h. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (90mg, yield 62%).1H NMR(400MHz,DMSO-d6)δ8.99(dd,J＝4.0,1.6Hz,1H),8.71(s,1H),8.69(d,J＝5.2Hz,1H),8.50-8.46(m,1H),8.21(q,J＝5.2Hz,1H),8.14(d,J＝8.4Hz,1H),8.01-7.99(m,1H),7.70(d,J＝5.2Hz,1H),7.64-7.61(m,2H),7.32(d,J＝15.6Hz,1H),6.81(d,J＝15.6Hz,1H),2.66(d,J＝4.4Hz,3H)；13C NMR(125MHz,DMSO-d6)δ164.35,151.27,150.73,149.15,147.24,139.98,137.27,135.86,135.35,133.95,129.57,128.39,128.12,127.33,127.20,122.00,119.98,25.57；HR-ESI-MS:m/z＝290.12878[M+H]+,calcd for C18H16ON3:290.12879.
Example 41: preparation of Compound 41
Figure BDA0002438339260000341
(E) -3- (3- (quinolin-7-yl) pyridin-4-yl) acrylic acid (138mg, 0.5mmol), morpholine (52mg, 0.6mmol), HATU (228mg, 0.6mmol), DIEA (129mg, 1.0mmol), dissolved in 10mL of dichloromethane, and the reaction stirred at room temperature for about 6 h. After the reaction, the reaction mixture was washed with a saturated sodium carbonate solution, a 0.5N hydrochloric acid solution and a saturated brine, respectively, and the organic layer was concentrated to give a crude product, which was subjected to silica gel column chromatography to give a pale yellow solid (112mg, yield 65%).1H NMR(400MHz,DMSO-d6)δ8.99(dd,J＝4.4,1.6Hz,1H),8.71(d,J＝0.8Hz,1H),8.69(dd,J＝5.2,0.8Hz,1H),8.50-8.46(m,1H),8.14(d,J＝8.4Hz,1H),8.02(d,J＝5.2Hz,1H),8.00-7.99(m,1H),7.63(dd,J＝8.4,3.2Hz,1H),7.62(d,J＝8.4Hz,1H),7.50(d,J＝15.6Hz,1H),7.42(d,J＝15.6Hz,1H),3.75-3.67(m,2H),3.63-3.53(m,4H),3.52-3.45(m,2H)；13C NMR(125MHz,DMSO-d6)δ163.47,151.30,150.70,148.94,147.20,139.87,137.31,136.76,135.87,135.44,129.62,128.40,128.17,127.17,123.24,122.01,120.45,66.21,65.91,45.47,41.96；HR-ESI-MS:m/z＝346.15503[M+H]+,calcd for C21H20O2N3:346.15500.
Example 42: preparation of Compound 42
Figure BDA0002438339260000351
(1) (E) -3- (3- (1H-indazol-5-yl) pyridin-4-yl) acrylic acid ethyl ester
(E) -ethyl 3- (3-bromopyridin-4-yl) acrylate (1228mg, 4.8mmol), 1H-indole-5-boronic acid pinacol ester (1342mg, 5.5mmol), Na2CO3(2035mg，19.2mmol)，(PPh3)2PdCl2(168mg, 0.24mmol) was dissolved in a mixed solution of toluene, ethanol and water (volume ratio: 1: 0.2), and the mixed system was purged with nitrogen 5 times. The reaction was then heated under reflux in an oil bath under nitrogen for 12 h. After the reaction is finished, the solvent is evaporated, ethyl acetate is added, the mixture is washed by distilled water, and the organic layers are combined and concentrated to obtain a solid crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 2: 1 elution) to give a white solid (1014mg, 72% yield).
(2) (E) -3- (3- (1H-indazol-5-yl) pyridin-4-yl) acrylic acid
(E) Ethyl (3- (1H-indazol-5-yl) pyridin-4-yl) acrylate (586mg, 2.0mmol) was dissolved in 20ml of absolute ethanol, 4ml of a 1M aqueous NaOH solution was added dropwise thereto, and the mixture was stirred at room temperature for 6 hours. After the reaction, the solvent was distilled off, and the mixture was dissolved in distilled water, washed with ethyl acetate, and the pH of the aqueous layer was adjusted to about 5 with 1M aqueous HCl to precipitate a pale yellow solid (329mg, 62% yield).
(3) (E) -3- (3- (1H-indazol-5-yl) pyridin-4-yl) acryloyl-3-methoxycyclobutylamine
(E) -3- (3- (1H-indazol-5-yl) pyridin-4-yl) acrylic acid and 3-methoxycyclobutylamine hydrochloride by the same procedure and operation as for compound 4.1H NMR(400MHz,CDCl3)δ10.92(s,1H),8.66(s,1H),8.62(d,J＝5.2Hz,1H),8.07(d,J＝1.2Hz,1H),7.68(d,J＝16.0Hz,1H),7.67-7.68(m,1H),7.51(d,J＝5.6Hz,1H),7.46-7.49(m,1H),7.28(d,J＝1.6Hz,1H),6.57(d,J＝15.6Hz,1H),4.36-4.42(m,1H),4.20-4.31(m,2H),4.06-4.16(m,1H),3.95-4.00(m,1H),3.32(s,3H)；13C NMR(100MHz,DMSO-d6)δ164.25,151.05,148.29,139.71,139.37,136.81,135.75,133.80,128.21,127.95,122.98,122.10,121.71,120.37,110.37,68.40,56.81,55.38,54.65；HR-ESI-MS:m/z＝335.1503[M+H]+,calcd for C19H19O2N4:335.1503.
Example 43: preparation of Compound 43
Figure BDA0002438339260000361
(1) Synthesis of ethyl 3- (3- (naphthalen-2-yl) pyridin-4-yl) propionate
(E) Ethyl-3- (3- (naphthalen-2-yl) pyridin-4-yl) acrylate (464mg, 1.53mmol) was dissolved in 5mL of ethanol, Pd/C (44mg, 10%) was added, and the atmosphere in the flask was replaced three times with a balloon of hydrogen at normal pressure, followed by stirring at room temperature for about 3 h. After the reaction, the palladium-carbon was filtered off with celite, the filter cake was washed with methanol several times, the filtrate was concentrated under reduced pressure, and the column chromatography was performed on normal phase column to obtain a white solid (443mg, 95% yield).
(2) Synthesis of 3- (3- (naphthalen-2-yl) pyridin-4-yl) propionic acid
Ethyl 3- (3- (naphthalen-2-yl) pyridin-4-yl) propionate (610mg, 2.0mmol) was dissolved in 20ml of anhydrous ethanol, 4ml of a 1M aqueous NaOH solution was added dropwise thereto, and the mixture was stirred at room temperature for 6 hours. After the reaction, the solvent was distilled off, and the mixture was dissolved in distilled water, washed with ethyl acetate, and the pH of the aqueous layer was adjusted to about 5 with 1M aqueous HCl to precipitate a pale yellow solid (338mg, 61% yield).1H NMR(400MHz,DMSO-d6)δ12.21(br s,1H),8.52(d,J＝5.2Hz,1H),8.46(s,1H),8.03(d,J＝8.4Hz,1H),8.01-7.98(m,2H),7.94(s,1H),7.58(q,J＝3.2Hz,2H),7.55(d,J＝8.4Hz,1H),7.43(d,J＝4.8Hz,1H),2.87(t,J＝8.0Hz,2H),2.47(t,J＝8.0Hz,2H)；13C NMR(125MHz,DMSO-d6)δ173.37,149.82,148.61,147.11,137.04,134.91,132.86,132.16,128.05,128.05,127.94,127.63,127.33,126.55,126.46,123.54,33.27,27.09；HR-ESI-MS:m/z＝278.11853[M+H]+,calcd for C18H16O2N:278.11756.
Example 44: preparation of Compound 44
Figure BDA0002438339260000362
(E) The (E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) methyl acrylate is obtained by reduction reaction, and the synthesis method and the operation are the same as those of the compound 43.1H NMR(400MHz,DMSO-d6)δ8.53(d,J＝5.2Hz,1H),8.46(s,1H),8.03(d,J＝8.4Hz,1H),8.01-7.98(m,2H),7.93(s,1H),7.58(d,J＝8.8Hz,1H),7.58(d,J＝2.8Hz,1H),7.55(dd,J＝8.4,1.6Hz,1H),7.43(d,J＝5.2Hz,1H),3.49(s,3H),2.90(t,J＝8.0Hz,2H),2.58(t,J＝8.0Hz,2H)；13C NMR(125MHz,DMSO-d6)δ172.14,149.74,148.52,146.60,136.91,134.70,132.73,132.03,127.95,127.92,127.83,127.50,127.20,126.44,126.36,123.39,51.27,32.76,26.75；HR-ESI-MS:m/z＝292.13425[M+H]+,calcd for C19H18O2N:292.13321.
Example 45: preparation of Compound 45
Figure BDA0002438339260000371
(E) The (E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) acryloyl methylamine is obtained by reduction reaction, and the synthesis method and the operation are the same as those of the compound 43.1H NMR(500MHz,DMSO-d6)δ8.52(d,J＝4.0Hz,1H),8.45(s,1H),8.02(d,J＝6.8Hz,1H),8.01-7.97(m,2H),7.93(d,J＝0.8Hz,1H),7.74(d,J＝4.0Hz,1H),7.58(d,J＝6.8Hz,1H),7.58(dd,J＝2.4,0.8Hz,1H),7.54(dd,J＝6.8,1.6Hz,1H),7.38(d,J＝4.0Hz,1H),2.85(t,J＝6.4Hz,2H),2.49(d,J＝4.0Hz,3H),2.31(t,J＝6.4Hz,2H)；HR-ESI-MS:m/z＝291.15018[M+H]+,calcd for C19H19ON2:291.14919.
Example 46: preparation of Compound 46
Figure BDA0002438339260000372
(E) The (E) -3- (3- (naphthalene-2-yl) pyridine-4-yl) acryloyl morpholine is obtained by reduction reaction, and the synthesis method and operation are the same as those of the compound 43.1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝5.2Hz,1H),8.45(s,1H),8.03(d,J＝8.4Hz,1H),8.00(d,J＝10.8Hz,1H),8.00(d,J＝3.2Hz,1H),7.94(d,J＝0.8Hz,1H),7.54(d,J＝10.8Hz,1H),7.54(d,J＝3.2,0.8Hz,1H),7.55(dd,J＝8.4,1.6Hz,1H),7.46(d,J＝5.2Hz,1H),3.43(t,J＝4.8Hz,2H),3.34-3.30(m,4H),3.19(t,J＝4.8Hz,2H),2.88-2.81(m,2H),2.57-2.51(m,2H)；13C NMR(125MHz,DMSO-d6)δ169.54,149.74,148.58,147.68,137.07,134.98,132.85,132.14,128.10,128.03,127.95,127.63,127.46,126.59,126.49,123.86,65.99,65.90,45.15,41.39,32.21,27.39；HR-ESI-MS:m/z＝347.17636[M+H]+,calcd for C22H23O2N2:347.17540.
Example 47: preparation of Compound 47
Figure BDA0002438339260000381
(E) Ethyl-3- (3- (naphthalen-2-yl) pyridin-4-yl) acrylate (30mg, 0.1mmol), hydrazine hydrate (25mg, 5mmol) were dissolved in 5mL ethanol and the reaction was heated to reflux for about 4 h. After completion of the reaction, the solvent was distilled off, and washed with a small amount of ethyl acetate to give a white flocculent solid (15mg, yield 51%).1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.50(d,J＝5.2Hz,1H),8.44(s,1H),8.01(d,J＝8.8Hz,1H),7.96-7.99(m,2H),7.91(d,J＝1.2Hz,1H),7.55-7.59(m,2H),7.53(dd,J＝8.4,1.6Hz,1H),7.37(d,J＝4.8Hz,1H),4.09(s,2H),2.82-2.86(m,2H),2.25-2.29(m,2H)；13C NMR(100MHz,DMSO-d6)δ170.20,149.80,148.52,147.38,136.96,134.84,132.82,132.13,128.05,128.02,127.87,127.57,127.36,126.49,126.40,123.46,33.10,27.57；HR-ESI-MS:m/z＝292.1444[M+H]+,calcd for C18H18ON3:292.1444.
Pharmacological experiments:
example 1: in vitro kinase inhibitory Activity assay
Compounds were diluted 100-fold in DMSO solution and buffered (50mM HEPES pH 7.5, 0.01% BRIJ-35, 10mM MgCl)21mM EGTA), the mixture of kinase and antibody and Tracer were mixed, shaken for 30s, and then incubated at room temperature for 60 min. Subsequently, the emulsion Ratio (ER, AF647 emulsion (665nm) to Europium emulsion (615 nm)) was read on a microplate reader and analyzed. IC (integrated circuit)50In the test, compounds were diluted in 3-fold gradients for a total of 10 concentrations tested. Blank control was set in the test and positive control was sorafenib as reference. The results are given as a percentage of "the difference between the ER of the blank and the ER of the test sample" and "the difference between the ER of the blank and the ER of the positive control", a larger percentage indicating better binding of the compound to the kinase. Table 1 is the results of the in vitro inhibitory activity of CDK8 kinase of the compounds of the present invention.
TABLE 1
Figure BDA0002438339260000391
Figure BDA0002438339260000401
ND Not Determined.
Example 2: in vitro kinase Selective Activity assay
The present invention selects 13 representative effective inhibitors to selectively test 12 kinases. 4 of them are CDK subtypes, including CDK2, CDK6, CDK7 and CDK 9; the other 8 are Aurora a, BRAF, EGFR, FGFR1, FLT3, JAK1, PDGFRA and GSK 3A. The kinase selectivity of 13 selected compounds of the invention was determined at a concentration of 10 μ M. As shown in table 2 and figure 1, 13 compounds according to the invention all showed selective inhibition of CDK 8.
TABLE 2 inhibition of 13 kinases by 13 compounds of the invention
Figure BDA0002438339260000411
Cyclin dependent kinase (Cyclin dependent kinase); BRAF sarcoma viral oncogene homolog B1 of filtration virus (v-raf murine sarcococcal oncogene homolog B1); aurora A Aurora kinase A (Aurora kinase A); EGFR, epidermal growth factor receptor (epidermal growth factor receptor); PDGFR alpha Platelet-derived growth factor receptor alpha (Platelet-derived growth factor receptor alpha); JAK1 Janus kinase 1(Janus kinase 1); FGFR1 Fibroblast Growth Factor Receptor 1(Fibroblast Growth Factor Receptor-1); GSK3 α glycogen synthase kinase 3 α (glycogen synthase kinase 3 α); FLT3 FMS-like tyrosine kinase 3(Fms-like tyrosine kinase).
Example 3: in vitro anti-tumor cell activity assay
The invention adopts an SRB method to carry out cytotoxic activity test on 31 compounds with better molecular level activity, and cell tumor strains are selected to be A549, MDA-MB-231, KB-VIN and MCF-7 respectively, and the test results are shown in Table 2. First, the trypsin-treated cell suspension was added to a 96-well plate at a cell density of 4000-11000 cells/well. Then, a diluted compound solution was added, mixed with the cells, and after three days of incubation, the adhered cells were fixed with 10% trichloroacetic acid after ice-bath and stained with 0.04% sulforhodamine b (sulforhodamine b). The absorbance value at 515nm was measured using a microplate reader (ELx800, BioTek). IC (integrated circuit)50Values were obtained by averaging the results of three independent experiments.
TABLE 2
Figure BDA0002438339260000421

Claims (10)

1. A pyridine compound represented by the following general formula (I) and a pharmaceutically acceptable salt thereof,
Figure FDA0002438339250000011
wherein,
Figure FDA0002438339250000012
selected from double or single bonds;
R1selected from the group consisting of halogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted indazolyl; the substituent is a mono-substituent group or a multi-substituent group, and each substituent is independently selected from halogen, -NH2、-OH、C1-C3Alkyl radical, C1-C3Alkoxy, morpholinyl, N-methylpiperazinyl, trifluoromethyl, cyano, nitro;
R2is selected from-NH2、-OH、-NHNH2、C1-C3Alkoxy radical, C1-C3Alkylamino, morpholinyl, N-methylpiperazinyl, - (CH)2)nCOOH，n＝1,2,3、-CHR3COOH，R3Selected from hydrogen, C1-C6Alkyl radical, C1-C3A hydroxyalkyl group.
2. The compound of claim 1, wherein the compound is a compound of formula (IA) or a physiologically acceptable salt thereof,
Figure FDA0002438339250000013
wherein,
R1selected from the group consisting of halogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted indazolyl; the substituent is a mono-substituent group or a multi-substituent group,each independently selected from halogen, -NH2、-OH、C1-C3Alkyl radical, C1-C3Alkoxy, morpholinyl, N-methylpiperazinyl, trifluoromethyl, cyano, nitro;
R2is selected from-NH2、-OH、-NHNH2、C1-C3Alkoxy radical, C1-C3Alkylamino, morpholinyl, N-methylpiperazinyl, - (CH)2)nCOOH，n＝1,2,3、-CHR3COOH，R3Selected from hydrogen, C1-C6Alkyl radical, C1-C3A hydroxyalkyl group.
3. The compound of claim 1, wherein the compound is a compound of the formula (IB) and physiologically acceptable salts thereof,
Figure FDA0002438339250000021
wherein,
R1selected from the group consisting of halogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted indazolyl; the substituent is a mono-substituent group or a multi-substituent group, and each substituent is independently selected from halogen, -NH2、-OH、C1-C3Alkyl radical, C1-C3Alkoxy, morpholinyl, N-methylpiperazinyl, trifluoromethyl, cyano, nitro;
R2is selected from-NH2、-OH、-NHNH2、C1-C3Alkoxy radical, C1-C3Alkylamino, morpholinyl, N-methylpiperazinyl, - (CH)2)nCOOH，n＝1,2,3、-CHR3COOH，R3Selected from hydrogen, C1-C6Alkyl radical, C1-C3A hydroxyalkyl group.
4. A compound having the structure and pharmaceutically acceptable salts thereof, wherein the compound is selected from the group consisting of:
Figure FDA0002438339250000022
Figure FDA0002438339250000031
Figure FDA0002438339250000041
Figure FDA0002438339250000051
5. a process for the preparation of a compound according to any one of claims 1 to 4, comprising the steps of:
the compound of the general formula (I) is obtained by taking 3-bromoisonicotinal as a starting material:
Figure FDA0002438339250000052
Figure FDA0002438339250000053
R1and R2As defined in any one of claims 1 to 4.
6. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier therefor.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, injections, sustained release formulations, controlled release formulations, and various microparticle delivery systems.
8. Use of a compound according to any one of claims 1 to 4 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention and/or treatment of a CDK8 related disorder.
9. The use according to claim 8 wherein said CDK8 related disorder is selected from the group consisting of tumors and immune related disorders.
10. The use according to claim 9, wherein said tumor comprises rectal cancer, breast cancer, gastric cancer, ovarian cancer, melanoma.
CN202010258425.8A 2020-04-03 2020-04-03 Pyridine compound and preparation method and pharmaceutical application thereof Pending CN113493407A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010258425.8A CN113493407A (en) 2020-04-03 2020-04-03 Pyridine compound and preparation method and pharmaceutical application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010258425.8A CN113493407A (en) 2020-04-03 2020-04-03 Pyridine compound and preparation method and pharmaceutical application thereof

Publications (1)

Publication Number Publication Date
CN113493407A true CN113493407A (en) 2021-10-12

Family

ID=77995108

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010258425.8A Pending CN113493407A (en) 2020-04-03 2020-04-03 Pyridine compound and preparation method and pharmaceutical application thereof

Country Status (1)

Country Link
CN (1) CN113493407A (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105439946A (en) * 2014-08-13 2016-03-30 上海页岩科技有限公司 Carboxylic acid compound and preparation method and use thereof
CN106456599A (en) * 2013-12-12 2017-02-22 比皮艾思药物研发有限公司 Sulfamate derivative compounds for use in treating or alleviating pain
CN106507667A (en) * 2013-12-12 2017-03-15 比皮艾思药物研发有限公司 For preventing or treating the sulfamate derivatives of epilepsy
US20170273962A1 (en) * 2012-06-20 2017-09-28 Cocrystal Discovery, Inc. Inhibitors of Hepatitis C Virus Polymerase
CN107531660A (en) * 2015-03-13 2018-01-02 福马治疗股份有限公司 α cinnamide compounds and composition as HDAC8 inhibitor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170273962A1 (en) * 2012-06-20 2017-09-28 Cocrystal Discovery, Inc. Inhibitors of Hepatitis C Virus Polymerase
CN106456599A (en) * 2013-12-12 2017-02-22 比皮艾思药物研发有限公司 Sulfamate derivative compounds for use in treating or alleviating pain
CN106507667A (en) * 2013-12-12 2017-03-15 比皮艾思药物研发有限公司 For preventing or treating the sulfamate derivatives of epilepsy
CN105439946A (en) * 2014-08-13 2016-03-30 上海页岩科技有限公司 Carboxylic acid compound and preparation method and use thereof
CN107531660A (en) * 2015-03-13 2018-01-02 福马治疗股份有限公司 α cinnamide compounds and composition as HDAC8 inhibitor

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GUNTER KARIG, 等: "C−H Activation and Palladium Migration within Biaryls under Heck Reaction Conditions", 《ORG. LETT.》, vol. 4, no. 18, pages 3115 - 3118 *
GUNTER KARIG, 等: "Directed Deprotonation-Transmetallation of 4-Bromopyridine: Flexible Routes to Substituted Pyridines", 《SYNLETT》, vol. 5, pages 808 *
府莹: "CAS-登记号", 《STN-REGISTRY》 *

Similar Documents

Publication Publication Date Title
CN111170998B (en) Pyrimidine or pyridine compound, preparation method and medical application thereof
CN106883213B (en) Dual inhibitor of EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase)
JP7320823B2 (en) Use of pteridinone derivatives as EGFR inhibitors
CN110256421A (en) KRAS-G12C inhibitor
TWI527800B (en) 1-(arylmethyl)quinazoline-2,4(1h,3h)-diones as parp inhibitors and the use thereof
CN114057771B (en) Macrocyclic compounds, their preparation and use
KR20190099209A (en) 8,9-dihydroimidazole [1,2-a] pyrimido [5,4-e] pyrimidine-5 (6H) -ketone compounds
CN113788824A (en) Pyridine compound
JP7251841B2 (en) Aromatic ring-bonded dioxino-quinazoline or dioxino-quinoline compounds, compositions and uses thereof
AU2007331722A1 (en) Epothilone analogues modified at positions C12-C13 as anticancer drugs
CN115322158A (en) As KRAS G12C Substituted quinazoline compounds of protein inhibitor
CN107151233A (en) Pyridine derivatives containing hydrazone and application thereof
CN113773305A (en) Aminopyrimidine derivative and application thereof as EGFR tyrosine kinase inhibitor
CA3130471C (en) Pan-raf kinase inhibitor and use thereof
CN113087709A (en) Pyrrolopyrimidine derivatives, and preparation method and application thereof
CN111875583B (en) Triazole derivative and preparation method and application thereof
CN113493407A (en) Pyridine compound and preparation method and pharmaceutical application thereof
CN113166148A (en) Heterocyclic compounds as CDK-HDAC dual pathway inhibitors
CN116969944A (en) Ethylamino-substituted tricyclic heterocyclic compounds and compositions, formulations and uses thereof
CN112759564B (en) Diaryl urea compound and its prepn and medicinal use
CN108069938A (en) 2,4- disubstituted pyridines and its preparation method and application
CN114181160A (en) 2, 4-dianilinopyrimidine-containing hydrazide derivative and preparation method and application thereof
CN112442105A (en) Novel pyrimido [4,5-d ] pyrimidin-2-one derivatives as protein kinase inhibitors
CN113831325A (en) Novel indole derivatives, and preparation method and application thereof
CN113880814A (en) Pyrimidinamine compound 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