CN116874468A - Synthesis and application of small molecular compound with 2-pyridine substituted formamide structure - Google Patents

Synthesis and application of small molecular compound with 2-pyridine substituted formamide structure Download PDF

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CN116874468A
CN116874468A CN202310717218.8A CN202310717218A CN116874468A CN 116874468 A CN116874468 A CN 116874468A CN 202310717218 A CN202310717218 A CN 202310717218A CN 116874468 A CN116874468 A CN 116874468A
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王增涛
黄佳藤
庞荔丹
万屏南
刘华
王甜甜
何梦妮
牛祥
王婕
韩小瑞
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Jiangxi University of Traditional Chinese Medicine
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    • 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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • 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
    • A61P9/12—Antihypertensives

Abstract

The invention relates to a small molecule inhibitor of ASK1 kinase, in particular to synthesis and application of a small molecule compound with a 2-pyridine substituted formamide structure, a pharmaceutical composition thereof and application of the small molecule inhibitor in preparation of ASK1 small molecule inhibitor or in preparation of medicines for preventing and/or treating diseases related to ASK1, especially liver diseases, lung diseases, tumors, cardiovascular diseases, kidney diseases and metabolic diseases.

Description

Synthesis and application of small molecular compound with 2-pyridine substituted formamide structure
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to synthesis and application of a small molecular compound with a 2-pyridine substituted formamide structure, a pharmaceutical composition thereof and application of the pharmaceutical composition in medicines for preventing or treating diseases or symptoms mediated by apoptosis signal regulating kinase I (ASKl, also called MAP3K5, MAPKKK5 and MEKK 5), in particular to liver diseases, lung diseases, cardiovascular diseases, kidney diseases and metabolic diseases.
Background
ASK1 kinase, collectively known as apoptosis signal-regulating kinase I (Apoptosis Signal Regulating Kinase 1), belongs to the MAP3K family of members, and is located upstream of Jun N-terminal kinase (JNK) and p 38. A large number of experiments prove that ASK1 plays an important role in stress response of mammalian cells and induction of apoptosis-related diseases.
ASK1 kinase inhibitors have potential therapeutic prospects for the treatment of common liver diseases such as non-alcoholic fatty liver, non-alcoholic steatohepatitis, chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, liver ischemia-reperfusion injury, primary biliary cirrhosis, diabetes-related liver diseases, and the like. Biological and medical related studies have also shown that ASK1 kinase inhibitors have therapeutic efficacy in the treatment of pulmonary diseases (e.g. pulmonary arterial hypertension, pulmonary fibrosis). In addition, inhibition of ASK1 kinase also has the potential to treat kidney diseases (glomerulonephritis, diabetic nephropathy, hypertensive nephropathy) and tumors. Inhibiting ASK1 kinase activity has significant therapeutic effects in a diabetic mouse model; the ASK1 small molecule inhibitor GS-444217 can be used for reducing the parameter index of diabetes. ASK1 is thus a potential target for the treatment of the above diseases, and the development of novel ASK1 inhibitors is of great importance for alleviating and even curing these diseases.
At present, some ASK1 inhibitors reported in the literature have the potential problems of low activity at the molecular level, poor target selectivity, insignificant animal drug effect dose-effect relationship, poor drug properties of compounds and the like. In addition, some compounds have potential problems with chemical stability and metabolic stability in vivo. Some ASK1 kinase small molecule inhibitors have strong water solubility, the in vivo exposure of animals is low after the animals take the drugs orally, and the corresponding drugs have poor pharmacokinetic properties in the animals, so that the in vivo efficacy of the compounds needs to be improved.
Thus, there remains a need in the art to develop a better performing small molecule inhibitor of ASK1 kinase.
Disclosure of Invention
The invention aims to provide a small molecule inhibitor of ASK1 kinase with a novel structure.
The invention also aims to provide a synthesis method and application of the compound.
In a first aspect, the invention provides a small molecule compound having a 2-pyridine substituted carboxamide structure according to formula (I), or an enantiomer, racemate or mixture thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
r1 represents halogen, deuterium atom, cyano, hydroxy, amino, nitro, oxo, alkyl, substituted or unsubstituted 5-12 membered heteroaromatic ring containing N, O or S atoms, substituted or unsubstituted 5-13 membered saturated heterocyclic ring containing N, O or S atoms, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl ethynyl, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkylcarbonylamino, substituted or unsubstituted C1-C4 alkoxycarbonylamino, substituted or unsubstituted C1-C4 sulfonyl, substituted or unsubstituted C1-C4 alkyl-S-, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C1-C4 alkylcarbonyl, or a combination thereof;
a quinoline ring representing a different N-atom position or a 6-membered heterocyclic ring containing two nitrogen atoms;
x represents N, CH or c=o;
a, b represent the position of an amide substitution on the N-containing heterocycle.
R2 represents H or methyl;
r3 represents a substituted or unsubstituted 5-6 membered heteroaromatic ring containing 1-4 heteroatoms N, O or S, one or more hydrogen atoms of said substituent being replaced by a group selected from the group consisting of: halogen, deuterium atom, cyano, hydroxy, amino, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy; wherein one or more hydrogen atoms on the corresponding substituent group in said substituent group is substituted with a group selected from the group consisting of: hydroxy, amino, carboxy.
Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof. The compound is specifically selected from one of the following structural formulas:
the invention also provides an ASK1 inhibitor comprising said compound, or an enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt, crystalline hydrate or solvate thereof.
The invention also provides a pharmaceutical composition comprising: (A) A therapeutically effective amount of one or more of the compounds, and enantiomers, diastereomers, racemates, and mixtures thereof, and pharmaceutically acceptable salts, crystalline hydrates, and solvates thereof; and (B) a pharmaceutically acceptable carrier.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant selected from one of binders, fillers, diluents, disintegrants, suspensions, suspending agents, sustained release agents or control agents, lyoprotectants, coating agents, enteric materials, lubricants, glidants, anti-adherents, sweeteners, flavors, plasticizers, opacifiers, solubilizers, humectants, solvents, tonicity modifiers, colorants, pigments, surfactants, emulsifiers, water-soluble matrices, liposoluble matrices, porogens, gels, preservatives, buffers, chelating agents, and antioxidants, or a combination thereof.
The use of the pharmaceutical composition of the invention for the manufacture of a medicament for the prevention or treatment of an apoptosis signal-regulating kinase1 (ASK 1) -mediated disease or condition is provided.
The invention also provides application of the compound in preparing a medicament for treating diseases related to the activity or expression quantity of ASK1 kinase.
Preferably, the disease related to the activity or expression amount of ASK1 kinase is selected from one of liver disease, lung disease, cardiovascular disease, kidney disease, metabolic disease and tumor disease.
Preferably, the liver disease is selected from one of non-alcoholic fatty liver, non-alcoholic steatohepatitis, chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, liver ischemia-reperfusion injury, primary biliary cirrhosis, and diabetes-related liver disease;
the pulmonary disease is pulmonary arterial hypertension or pulmonary fibrosis;
the cardiovascular disease is heart failure;
the kidney disease is selected from one of glomerulonephritis, diabetic nephropathy and hypertensive nephropathy;
the metabolic disease is type II diabetes or type I diabetes;
the tumor disease is selected from one of liver cancer, lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, cervical cancer, ovarian cancer, bladder cancer and pancreatic cancer.
The invention also provides a synthesis method of the compound, which comprises the following synthesis routes:
preferably, I-1 in the synthetic route is prepared by a one-step reaction, the first step is specifically: the amine S1 is mixed with the corresponding acid chloride S2 in a suitable solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, methylene chloride, or N, N-dimethylformamide, and the like. Adding base (triethylamine, diisopropylethylamine, N-methylmorpholine, etc.), and reacting at room temperature, suitable low temperature (-10deg.C to 0deg.C) or suitable elevated temperature (40-50deg.C, for example) to obtain final product I-1; the second step is to dissolve I-1 in DMF, add NaH and methyl iodide, stir and react at room temperature, low temperature or elevated temperature to prepare the final product I-2.
Description of the embodiments
Definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. Although the terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
As used herein, the terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
As used herein, the term "hydrogen" refers to protium (H), deuterium (D), tritium (T).
As used herein, the term "alkyl" is defined as an off-line or branched saturated aliphatic hydrocarbon. C (C) 1-12 Alkyl means having 1 to 12, for example 1 to 6 carbon atoms (C 1-6 Alkyl) or 1 to 4 carbon atoms (C 1-4 Alkyl). For example, as used herein, the term "C 1-6 Alkyl "means an off-line or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is selected fromSubstituted with 1 or more (such as 1 to 3) suitable substituents, such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CH) 2 F、CHF 2 、CF 3 、CCl 3 、C 2 F 5 、C 2 Cl 5 、CH 2 CF 3 、CH 2 Cl or-CH 2 CH 2 CF 3 Etc.). The term "C 1-4 Alkyl "refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).
As used herein, the term "alkenyl" means an offline or branched monovalent hydrocarbon group containing one or more double bonds and having 2 to 6 carbon atoms ("C 2-6 Alkenyl "). The alkenyl group is, for example, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the present invention contain alkenyl groups, the compounds may exist in pure E (ipsilateral (entgegen)) form, pure Z (ipsilateral (zusammen)) form or as a mixture thereof in any proportion.
As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, for example having 2,3, 4,5 or 6 carbon atoms, for example ethynyl or propynyl.
As used herein, the term "cycloalkyl" refers to a saturated monocyclic or multicyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1:1:]amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalyl, etc.), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 Cycloalkyl "refers to a saturated, mono-or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally substituted with 1 or more (such as 1 to 3) suitableFor example methyl-substituted cyclopropyl.
As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monovalent monocyclic or bicyclic radical having 2,3, 4,5, 6, 7, 8, or 9 carbon atoms in the ring or one or more (e.g., one, two, three, or four) heteroatom-containing groups selected from C (=o), O, S, S (=o), S (=o) 2, and NRa, wherein Ra represents a hydrogen atom
As used herein, the term "5-12 membered heteroaryl ring" refers to a monocyclic aromatic group of ring members, and at least 1 (e.g., 1,2,3, or 4) heteroatoms selected from N, O, S are saturated in the ring members, e.g., a "5-6 membered heteroaryl group", a 5-membered heteroaryl group, a 6-membered heteroaryl group, and the like. Specific examples thereof include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl and the like.
As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.
As used herein, the term "substitution" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, unless otherwise indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
The invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are useful in the context of the compounds of the inventionAlso, except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Isotopes suitable for inclusion in the compounds of the invention (e.g. deuterium 2 H) Tritium @ 3 H) Isotopes of carbon (e.g.) 11 C、 13 C, C is a metal alloy 14 C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g 36 Cl); isotopes of fluorine (e.g 18 F) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of iodine (e.g 123 I, I 125 I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g 13 N is N 15 N); isotopes of oxygen (e.g 15 O、 17 O and O 18 O); isotopes of phosphorus (e.g 32 P) is as follows; isotopes of sulfur (e.g 35 S). Certain isotopically-labeled compounds of the present invention (e.g., for incorporation of radioisotopes) are useful in pharmaceutical and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium @, a process for preparing same 3 H) Carbon-14% 14 C) Particularly useful for this purpose because of (1) incorporation and ease of detection. Using positron-emitting isotopes (e.g 11 C、 18 F、 15 O and O 13 N) substitution can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g., D 2 O, acetone-d 6 Or DMSO-d 6 。
Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts, examples include aspartate, gluconate, lactate, palmitate, hydrochloride and other like salts.
Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, sodium salts, calcium salts, potassium salts, choline salts, and other like salts.
The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-compound proportions.
The term "about" means within + -10%, preferably within + -5%, more preferably within + -2% of the stated value.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by mass unless otherwise indicated.
Experimental example 1: synthesis of Compounds
Synthetic intermediate 01:6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (12-4-41)
Step one: methyl 6-aminopicolinate (500 mg,3.289 mmol) was dissolved in 25mL of methanol and hydrazine hydrate (318.75. Mu.L, 6.578 mmol) was slowly added dropwise under argon, the temperature was raised to 75℃and refluxed for 3h. After the reaction was completed, the reaction mixture was cooled to room temperature, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Crude title compound 475mg (12-3-41) was obtained as a white solid in 95% yield.
Step two: 6-amino-pyridine formylhydrazine (470 mg,3.125 mmol) was dissolved in 30mL of toluene, and N, N-dimethylformamide dimethyl acetal (104.74. Mu.L, 9.375 mmol) and isopropylamine (157.5. Mu.L, 21.875 mmol) were added. Cooled to 0deg.C and acetic acid (45.1 μl,9.375 mmol) was added dropwise. In argon atmosphere, the temperature is increased to 95 ℃ and reflux is carried out for 10 hours, the temperature is reduced to room temperature, the mixture is concentrated by a rotary evaporator and then dissolved in 10mL of purified water, and the reaction is continued for 10 hours at 85 ℃. After the reaction, 20mL of diethyl ether was added to wash and 20mL of dichloro was addedMethane washing, drying over anhydrous sodium sulfate, rotary evaporation concentration, column chromatography purification (petroleum ether/ethyl acetate=20/1), 243.485mg white solid (12-4-41) of the target compound pure product, yield 51.26%. 1 H NMR(400MHz,DMSO-d 6 ):δ8.78(s,1H),7.52(dd,J＝8.1,7.6Hz,1H),7.23–7.13(m,1H),6.58–6.47(m,1H),δ5.53(dt,J＝13.5,6.7Hz,1H).,1.43(d,J＝6.7Hz,6H).
Final product 1: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) isoquinoline-4-carboxamide (1, 12-168-41)
Intermediate 01 (12-4-41, 70.2mg, 0.348 mmol) and isoquinoline-4-carboxylic acid (50 mg,0.289 mmol) were dissolved in 5mL of dichloromethane, cooled to 0deg.C and triethylamine (280 μL,2.02 mmol) and 1-propylphosphoric anhydride (688 μL,2.310 mmol) were added. And (3) in an argon environment, raising the temperature to 40 ℃ and refluxing for 7 hours. After the reaction was completed, 20mL of saturated aqueous sodium bicarbonate solution was added for washing, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by column chromatography (dichloromethane/methanol=80/1) to give the title compound as a white solid 10mg (1, 12-168-41) in 25.8% yield. 1 H NMR(400MHz,CD 3 OD):δ9.48–9.32(m,1H),8.79(dd,J＝15.6,3.6Hz,1H),8.44(t,J＝8.9Hz,1H),8.23(tt,J＝17.0,8.6Hz,1H),7.94(dt,J＝15.3,7.7Hz,1H),7.88–7.75(m,1H),7.60–7.55(m,1H),7.21(dd,J＝12.9,6.8Hz,1H),6.66(d,J＝8.4Hz,1H),5.51(dt,J＝13.5,6.7Hz,1H),1.52(t,J＝4.8Hz,6H)。
End product 2: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-4-carboxamide (2, 12-161-41)
Intermediate 01 (12-4-41, 70.2mg, 0.348 mmol) and quinoline-4-carboxylic acid (50 mg,0.289 mmol) were dissolved in 5mL of dichloromethane, cooled to 0deg.C, and triethylamine (280 μL,2.02 mmol) and 1-propylphosphoric anhydride (688 μL,2.310 mmol) were added. In argon atmosphere, the temperature is raised to 40 ℃ and returnedStream 7h. After the completion of the reaction, 20mL of saturated aqueous sodium bicarbonate solution was added for washing, dried over anhydrous sodium sulfate, concentrated by spin-drying, and purified by column chromatography (dichloromethane/methanol=80/1) to give 54.1mg (2, 12-161-41) of the objective compound as a white solid in 52.3% yield. 1 H NMR(400MHz,CD 3 OD):δ9.01(d,J＝4.4Hz,1H),8.80(s,1H),8.45(d,J＝8.3Hz,1H),8.26(d,J＝8.4Hz,1H),8.15(d,J＝8.5Hz,1H),8.09(t,J＝8.0Hz,1H),7.94(d,J＝7.7Hz,1H),7.87(t,J＝7.7Hz,1H),7.78–7.73(m,1H),7.71(d,J＝7.3Hz,1H),5.76(dt,J＝13.5,6.8Hz,1H),1.48(d,J＝6.7Hz,6H)。
End product 3: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) isoquinoline-1-carboxamide (3, 12-68-41)
Isoquinoline-1-carboxylic acid (50 mg,0.289 mmol) was dissolved in 5mL of dichloromethane and carbodiimide hydrochloride (55.4 mg,0.289 mmol) and N-hydroxysuccinimide (34.1 mg,0.289 mmol) were added. Intermediate 01 (12-4-41, 59mg,0.289 mmol) was added under argon, and the temperature was raised to 40℃and refluxed for 7h. After the completion of the reaction, 20mL of saturated aqueous sodium bicarbonate solution was added for washing, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by column chromatography (dichloromethane/methanol=80/1) to give 24.5mg (3, 12-68-41) of the title compound as a white solid in 23.7% yield. 1 H NMR(400MHz,CDCl 3 ):δ10.73(s,1H),9.61(dd,J＝
6.7,3.0Hz,1H),8.52(t,J＝5.4Hz,2H),7.99(s,1H),7.93–7.81(m,3H),7.75–
7.67(m,2H),5.73(s,1H),1.56(s,6H)。
End product 4: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoxaline-2-carboxamide (4, 12-13-42)
Quinoxaline-2-carboxylic acid (81.78 mg,0.47 mmol) was dissolved in 6mL of dichloromethane and 0.06mL of N, N-dimethylformamide was addedDimethyl acetal. Cooled to 0 ℃, oxalyl chloride (80 μl,0.93 mmol) was added dropwise under argon atmosphere, and stirred at room temperature for 2h. After the completion of the acid chloride preparation, the reaction solvent and excess oxalyl chloride were removed by spin-drying, a dichloromethane solution (6 mL) of intermediate 01 (12-4-41, 62.93mg,0.31 mmol) was added, and triethylamine (85.8. Mu.L, 0.62 mmol) was further added dropwise, followed by stirring at room temperature for 1h. After the completion of the reaction, 20mL of saturated aqueous sodium bicarbonate solution was added for washing, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by column chromatography (dichloromethane/methanol=80/1) to give 21.42mg (4, 12-13-42) of the objective compound as a white solid in 42.84% yield. 1 H NMR(400MHz,CDCl 3 ):δ9.72(s,1H),8.45(d,J＝8.2Hz,1H),8.39(s,1H),8.18(d,J＝8.1Hz,1H),8.13(d,J＝7.7Hz,1H),8.00(d,J＝7.6Hz,1H),7.88(dd,J＝16.2,8.9Hz,3H),7.20(s,1H),5.53(dt,J＝13.3,6.7Hz,1H),1.58(d,J＝6.7Hz,6H)。
Final product 5: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-1, 4-dihydroquinazoline-2-carboxamide (5, 12-163-41)
4-oxo-1, 4-dihydroquinazoline-2-carboxylic acid (40 mg,0.210 mmol) and intermediate 01 (12-4-41, 51.2mg,0.252 mmol) were dissolved in 5mL of dichloromethane, cooled to 0deg.C, and triethylamine (206. Mu.L, 1.472 mmol) and 1-propylphosphoric anhydride (500. Mu.L, 1.682 mmol) were added. And (3) in an argon environment, raising the temperature to 40 ℃ and refluxing for 7 hours. After the completion of the reaction, 20mL of saturated aqueous sodium hydrogencarbonate solution was added for washing, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by column chromatography (dichloromethane/methanol=80/1) to give the title compound 32mg (5, 12-163-41) as a white solid in 40.5% yield. 1 H NMR(400MHz,CD 3 OD)δ8.86(s,1H),8.43(d,J＝8.3Hz,1H),8.31(d,J＝7.9Hz,1H),8.08(t,J＝8.0Hz,1H),7.98–7.89(m,3H),7.66(dd,J＝9.8,4.2Hz,1H),5.69–5.62(m,1H),1.63(s,3H),1.62(s,3H).
End product 6: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (6, 12-70-41)
Quinoline-2-carboxylic acid (50 mg,0.289 mmol) was dissolved in 5mL of dichloromethane and carbodiimide hydrochloride (55.4 mg,0.289 mmol) and N-hydroxysuccinimide (34.1 mg,0.289 mmol) were added. Intermediate 01 (12-4-41, 59mg,0.289 mmol) was added under argon, the temperature was raised to 40 ℃ and refluxed for 7h, after the reaction was completed, 20mL of saturated aqueous sodium bicarbonate solution was added for washing, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by reverse phase silica gel column (dichloromethane/methanol=80/1) to give the title compound as a white solid 27.5mg (6, 12-70-41) in 26.57% yield. . 1 H NMR(400MHz,CDCl3)δ8.49(d,J＝8.2Hz,2H),8.36(s,3H),8.11(d,J＝8.4Hz,1H),7.90(t,J＝10.2Hz,3H),7.63(t,J＝7.5Hz,1H),5.23(s,1H),1.63(s,6H)。
End product 7: 8-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (7, 21-25-41)
8-bromoquinoline-2-carboxylic acid (50 mg,0.2 mmol), intermediate 01 (12-4-41, 40.3mg,0.2 mmol) was added to a 50mL eggplant-type flask, and 5mL of anhydrous dichloromethane was added. Cooled to 0deg.C, triethylamine (140.5 mg,1.4 mmol) was added, followed by slow addition of T3P (50% ethyl acetate, 504.9mg,0.8 mmol) and stirring overnight at room temperature. After the reaction was completed, it was diluted with methylene chloride, washed with water and sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by normal phase silica gel column. 35.7mg (7, 21-25-41) of the title compound was obtained in 40.9% yield. 1 H NMR(400MHz,CDCl 3 ):δ10.86(s,1H),8.45(d,J＝8.2Hz,1H),8.37(dt,J＝12.8,6.4Hz,3H),8.11–8.03(m,2H),7.88(d,J＝24.2Hz,2H),7.48(t,J＝7.8Hz,1H),5.81–5.67(m,1H),1.59(d,J＝6.8Hz,6H).
End product 8: 7-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (8, 21-26-41)
7-bromoquinoline-2-carboxylic acid (50 mg,0.2 mmol), intermediate 01 (12-4-41, 40.3mg,0.2 mmol) was added to a 50mL eggplant-type flask, and 5mL of anhydrous dichloromethane was added. Cooled to 0deg.C, triethylamine (140.5 mg,1.4 mmol) was added, followed by slow addition of T3P (50% ethyl acetate, 504.9mg,0.8 mmol) and stirring overnight at room temperature. After the reaction was completed, it was diluted with methylene chloride, washed with water and sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by normal phase silica gel column. 48.3mg (8, 21-26-41) of the title compound was obtained in 55.2% yield. 1 H NMR(400MHz,CDCl 3 ):δ10.51(s,1H),8.46(d,J＝8.2Hz,1H),8.37(d,J＝8.4Hz,2H),8.32(d,J＝8.6Hz,1H),8.29(s,1H),8.00(d,J＝7.6Hz,1H),7.89(t,J＝8.0Hz,1H),7.76(d,J＝8.7Hz,1H),7.70(dd,J＝8.7,1.7Hz,1H),5.62–5.47(m,1H),1.60(d,J＝6.7Hz,6H)。
End product 9: 6-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (9, 21-18-41)
6-bromoquinoline-2-carboxylic acid (50 mg,0.2 mmol), intermediate 01 (12-4-41, 40.3mg,0.2 mmol) was added to a 50mL eggplant-type flask, and 5mL of anhydrous dichloromethane was added. Cooled to 0deg.C, triethylamine (140.5 mg,1.4 mmol) was added, followed by slow addition of T3P (50% ethyl acetate, 504.9mg,0.8 mmol) and stirring overnight at room temperature. After the reaction was completed, it was diluted with methylene chloride, washed with water and sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by normal phase silica gel column. 48.5mg (9, 21-18-41) of the title compound was obtained in 55.5% yield. 1 H NMR(400MHz,CDCl 3 ):δ10.55(s,1H),8.46(d,J＝8.2Hz,1H),8.37(d,J＝8.5Hz,1H),8.26(d,J＝8.5Hz,1H),8.05(d,J＝1.5Hz,1H),7.98(dd,J＝8.0,5.7Hz,2H),7.89(d,J＝15.9Hz,1H),7.85–7.81(m,1H),5.54(dt,J＝13.4,6.7Hz,1H),1.59(d,J＝6.7Hz,6H)。
End product 10: 5-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (10, 21-19-41)
5-bromoquinoline-2-carboxylic acid (50 mg,0.2 mmol), intermediate 01 (12-4-41, 40.3mg,0.2 mmol) was added to a 50mL eggplant-type flask, and 5mL of anhydrous dichloromethane was added. Cooled to 0deg.C, triethylamine (140.5 mg,1.4 mmol) was added, followed by slow addition of T3P (50% ethyl acetate, 504.9mg,0.8 mmol) and stirring overnight at room temperature. After the reaction was completed, it was diluted with methylene chloride, washed with water and sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by normal phase silica gel column. 56.2mg (10, 21-19-41) of the title compound was obtained in 64.3% yield. 1 H NMR(400MHz,CDCl3):δ10.57(s,1H),8.73(d,J＝8.7Hz,1H),8.45(d,J＝3.0Hz,1H),8.35(s,1H),8.08(d,J＝8.5Hz,1H),7.98(s,1H),7.91–7.87(m,1H),7.63(t,J＝8.0Hz,1H),5.61–5.42(m,1H),1.59(d,J＝6.7Hz,6H)。
End product 11: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -8- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) quinoline-2-carboxamide (11, 21-59-36)
8-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (07, 21-25-41, 40mg,0.09 mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine (22.5 mg,0.1 mmol), sodium carbonate (48.5 mg,0.45 mmol), tetraphenylphosphine palladium (10.6 mg,0.009 mmol) were added to a 50mL eggplant flask, and 2mL of 1, 2-dimethoxyethane and water were added, each, and reacted at 80℃for 2 hours. Concentrating by a rotary evaporator, and purifying by a normal phase silica gel column. 42mg (11, 21-59-36) of the target compound was produced in 100% yield. 1 H NMR(400MHz,CDCl 3 ):δ10.38(s,1H),8.42(d,J＝8.2Hz,1H),8.33(d,J＝6.1Hz,3H),7.90(t,J＝7.9Hz,1H),7.80(dd,J＝11.6,7.8Hz,2H),7.64(d,J＝6.5Hz,1H),7.56(t,J＝7.6Hz,1H),5.92(s,1H),5.34–5.24(m,1H),3.30(s,2H),2.92–2.86(m,4H),2.45(s,3H),1.50(d,J＝6.7Hz,6H).
End product 12: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) quinoline-2-carboxamide (12, 21-36-36)
7-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (08, 21-26-41, 30mg,0.07 mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine (16.8 mg,0.075 mmol), sodium carbonate (72.7 mg,0.69 mmol), tetrakis triphenylphosphine palladium (7.9 mg,0.0073 mmol) were added to a 50mL eggplant flask and 1, 2-dimethoxyethane and water were added to each 2mL and reacted at 80℃for 2H. Concentrating by a rotary evaporator, and purifying by a normal phase silica gel column. 40.1mg (12, 21-36-36) of the title compound was obtained in 100% yield. 1 H NMR(400MHz,CDCl 3 ):δ10.61(s,1H),8.45(dd,J＝8.2,0.9Hz,1H),8.34(s,1H),8.29(s,2H),8.01(d,J＝1.4Hz,1H),7.95(d,J＝7.0Hz,1H),7.88(t,J＝7.9Hz,1H),7.80(d,J＝8.6Hz,1H),7.72(dd,J＝8.6,1.8Hz,1H),6.29(t,J＝3.5Hz,1H),5.59–5.47(m,1H),3.25(d,J＝2.6Hz,2H),2.79(s,2H),2.76(d,J＝2.2Hz,2H),2.46(s,3H),1.58(d,J＝6.7Hz,6H)。
End product 13: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) quinoline-2-carboxamide (13, 21-45-36)
6-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (09, 21-18-41, 40mg,0.09 mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine (22.5 mg,0.1 mmol), sodium carbonate (48.5 mg,0.45 mmol), tetrakis triphenylphosphine palladium (10.6 mg,0.009 mmol) were added to a 50mL eggplant-type flask, 1, 2-dimethoxyethane andthe reaction was carried out with 2mL of water at 80℃for 2h. Concentrating by a rotary evaporator, and purifying by a normal phase silica gel column. 33.6mg (13, 21-45-36) of the target compound was obtained in 82.3% yield. 1 H NMR(400MHz,CDCl 3 ):δ10.62(s,1H),8.45(d,J＝7.5Hz,1H),8.33(s,1H),8.30(d,J＝4.7Hz,1H),8.01(d,J＝8.9Hz,1H),7.96(d,J＝6.9Hz,1H),7.89–7.85(m,2H),7.76(d,J＝1.8Hz,1H),6.29(t,J＝3.5Hz,1H),5.62–5.50(m,1H),3.17(d,J＝3.0Hz,2H),2.71(d,J＝3.8Hz,4H),2.40(s,3H),1.58(d,J＝6.7Hz,6H)。
End product 14: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) quinoline-2-carboxamide (14, 21-46-36)
5-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (10, 21-19-41, 40mg,0.09 mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine (22.5 mg,0.1 mmol), sodium carbonate (48.5 mg,0.45 mmol), tetraphenylphosphine palladium (10.6 mg,0.009 mmol) were added to a 50mL eggplant flask, and 2mL of 1, 2-dimethoxyethane and water were added, each, and reacted at 80℃for 2 hours. Concentrating by a rotary evaporator, and purifying by a normal phase silica gel column. 20.6mg (14, 21-46-36) of the title compound was obtained in 50.5% yield. 1 H NMR(400MHz,CDCl 3 ):δ10.65(s,1H),8.58(d,J＝8.8Hz,1H),8.47–8.43(m,1H),8.33(s,1H),8.30(d,J＝8.7Hz,1H),7.98(d,J＝3.1Hz,1H),7.88(t,J＝7.9Hz,1H),7.70(dd,J＝8.5,7.1Hz,1H),7.43(dd,J＝7.1,1.0Hz,1H),5.76–5.72(m,1H),5.62–5.49(m,1H),3.21(d,J＝2.8Hz,2H),2.77(t,J＝5.6Hz,2H),2.57(d,J＝1.8Hz,2H),2.46(s,3H),1.59(d,J＝6.7Hz,6H)。
End product 15: n- (6- (4-cyclopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (15, 24-57-31)
Step one: by reacting 6-aminopyrazoleMethyl picolinate (250 mg,1.6 mmol) was added to a 100mL eggplant-type flask, hydrazine hydrate (3 mL) was added, argon was purged, and the mixture was stirred at 120℃under reflux for 1h. After the reaction was completed, the mixture was concentrated by a rotary evaporator, and the solid was dried. Crude white solid, 250.8mg, was obtained in 100% yield. The crude product obtained was put into a 100mL eggplant-type flask, dissolved in toluene, 1-dimethoxy-N, N-dimethylamine (573.7 mg,4.8 mmol) and cyclopropylamine (635.4 mg,11.2 mmol) were added, cooled to 0℃and glacial acetic acid (289.2 mg,4.8 mmol) was added under argon atmosphere, and refluxed at 95℃for 20 hours. Concentrating by rotary evaporator, drying by rotary evaporator, adding appropriate amount of water, concentrating again by rotary evaporator, dissolving the concentrated residue with 10 times of water, and stirring overnight at 85deg.C. After the reaction was completed, the aqueous layer was left by extraction with diethyl ether twice, the aqueous layer was extracted three times with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column. 163mg (22-55-33) of the title compound were obtained as a white solid in 50.7% yield. 1 H NMR(400MHz,CDCl 3 ):δ8.14(s,1H),7.53(t,J＝8.0Hz,1H),7.46(d,J＝7.2Hz,1H),6.58(d,J＝8.0Hz,1H),3.86(m,1H),1.05(q,J＝6.8Hz,2H),0.89–0.82(m,2H)； 13 C NMR(101MHz,DMSO-d 6 ):δ163.43,158.62,147.84,143.63,138.10,111.22,109.80,25.86,6.05；ESI-HRMS(m/z)[M+H] + ，C 10 H 11 N 5 Calculated values: 202.1014, found: 202.1093.
step two: quinoline-2-carboxylic acid (30 mg,0.17 mmol), (6- (4-cyclopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (35 mg,0.17 mmol) was added to a 50mL eggplant-type flask, 3mL of anhydrous pyridine was added under argon protection, phosphorus oxychloride (106.1 mg,0.7 mmol) was slowly added, stirring at room temperature was continued for 2H after completion of the reaction, quenched with water, extracted three times with ethyl acetate, the ethyl acetate layer was dried with anhydrous sodium sulfate, concentrated with an organic solvent rotary evaporator, and purified by silica gel column chromatography, 47mg (15, 24-57-31) of the title compound was obtained as a white partial powder solid in 76.3% yield. 1 H NMR(400MHz,CDCl 3 ):δ10.75(s,1H),8.55(dd,J＝8.0,0.8Hz,1H),8.41(s,2H),8.31(s,1H),8.17(d,J＝8.4Hz,1H),7.99(dd,J＝7.6,0.8Hz,1H),7.95(t,J＝8.0Hz,2H),7.82(m,1H),7.68(m,1H),4.02–3.92(m,1H),1.24(m,2H),1.01(m,2H)；ESI-HRMS(m/z)[M+Na] + ，C 20 H 16 N 6 O, calculated: 379.1386, found: 3791286.
end product 16: n- (6- (1-cyclobutyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (16, 24-61-34)
Step one: methyl 6-aminopicolinate (250 mg,1.6 mmol) was added to a 100mL eggplant-type flask, hydrazine hydrate (3 mL) was added, and the mixture was stirred under reflux at 120℃for 1h under argon atmosphere. After the reaction was completed, the mixture was concentrated by a rotary evaporator, and the solid was dried. Crude white solid, 250.8mg, was obtained in 100% yield. The crude product obtained was put into a 100mL eggplant-type flask, dissolved in toluene, 1-dimethoxy-N, N-dimethylamine (573.7 mg,4.8 mmol) and cyclobutylamine (800 mg,11.2 mmol) were added, cooled to 0℃and glacial acetic acid (289.2 mg,4.8 mmol) was added under argon atmosphere and refluxed at 95℃for 20 hours. Concentrating by rotary evaporator, drying by rotary evaporator, adding appropriate amount of water, concentrating again by rotary evaporator, dissolving the concentrated residue with 10 times of water, and stirring overnight at 85deg.C. After the reaction was completed, the aqueous layer was left by extraction with diethyl ether twice, the aqueous layer was extracted three times with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column. 224mg (21-149-37) of the title compound was obtained as a yellow solid in 65.1% yield. 1 H NMR(400MHz,CDCl 3 ):δ8.36(s,1H),7.57–7.52(m,1H),7.49(dd,J＝7.6,0.8Hz,1H),6.58(dd,J＝7.6,0.8Hz,1H),5.53–5.41(m,1H),2.60–2.51(m,2H),2.32–2.28(m,2H),1.88–1.78(m,2H)； 13 C NMR(101MHz,DMSO-d 6 ):δ159.18,151.04,145.34,143.62,138.06,111.19,108.53,49.64,30.79,14.34；ESI-HRMS(m/z)[M+Na] + calcd for C 11 H 13 N 5 ,238.1171,found 238.1061.
Step two: quinoline-2-carboxylic acid (30 mg,0.17 mmol), 6- (4-cyclobutyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (37 mg,0.17 mmol) was added to a 50mL eggplant-type flask, and 3mL of anhydrous pyridine was added. Phosphorus oxychloride (106.1 mg,0.7 mmol) was added slowly under argon and stirred at room temperature for 2h. After the reaction was completed, the mixture was quenched with water and extracted three times with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. Concentrating the organic solvent by a rotary evaporator, and purifying by silica gel column chromatography. 47mg (16, 24-61-34) of the title compound was obtained as a white solid in 74.9% yield. 1H NMR (400 MHz, CDCl 3): delta 10.40 (s, 1H), 9.80 (s, 1H), 8.51 (d, J=8.0 Hz, 2H), 8.28-8.23 (m, 1H), 8.21-8.16 (m, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.99-7.89 (m, 3H), 5.53 (m, 1H), 2.76-2.64 (m, 2H), 2.48-2.37 (m, 2H), 2.05-1.98 (m, 2H); ESI-HRMS (M/z) [ M+H ] +calcd for C21H18N6O,371.1542, found371.1628.
End product 17N- (6- (1-cyclopentyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (17, 24-58-31)
Step one: methyl 5-aminonicotinate (550 mg,3.6 mmol) was added to a 100mL eggplant-type flask, and 15mL of anhydrous methanol was added. Hydrazine hydrate (326.5 mg,6.5 mmol) was added again and the mixture was stirred at 65℃under reflux overnight under argon. After the reaction was completed, the mixture was concentrated by a rotary evaporator, and the solid was dried. Crude white solid, 550.8mg, was obtained in 100% yield. The crude product obtained was put into a 100mL eggplant-type flask, dissolved in toluene, 1-dimethoxy-N, N-dimethylamine (1629.8 mg,8.9 mmol) and cyclopentylamine (1627 mg,19.1 mmol) were added, cooled to 0℃and glacial acetic acid (491.4 mg,8.9 mmol) was added under argon atmosphere, and refluxed at 95℃for 20 hours. Concentrating by rotary evaporator, drying by rotary evaporator, adding appropriate amount of water, concentrating again by rotary evaporator, dissolving the concentrated residue with 10 times of water, and stirring overnight at 85deg.C. After the reaction was completed, the aqueous layer was left by extraction with diethyl ether twice, the aqueous layer was extracted three times with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column. 110mg (23-143-36) of the title compound was obtained as a white solid in 17.6% yield. 1 H NMR(400MHz,CDCl 3 )δ8.28(s,1H),7.59–7.50(m,2H),6.58(dd,J＝8.0,1.2Hz,1H),5.63–5.50(m,1H),2.30–2.18(m,2H),1.92–1.69(m,6H)； 13 C NMR(101MHz,CDCl 3 ):δ157.70,152.11,145.85,142.26,138.86,114.79,109.37,57.62,33.98,24.03.ESI-HRMS(m/z)[M+H] + calcd for C 12 H 15 N 5 ,230.1327,found 230.1408.
Step two: quinoline-2-carboxylic acid (22.7 mg,0.13 mmol), 6- (4-cyclopentyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (30 mg,0.13 mmol) was added to a 50mL eggplant-type flask, and 3mL of anhydrous pyridine was added. Phosphorus oxychloride (80.4 mg,0.5 mmol) was slowly added under argon and stirred at room temperature for 2h. After the reaction was completed, the mixture was quenched with water and extracted three times with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. Concentrating the organic solvent by a rotary evaporator, and purifying by silica gel column chromatography. 48mg (17, 24-58-31) of the title compound was obtained as a white solid in 96.4% yield. 1 H NMR(400MHz,CDCl 3 )δ10.75(s,1H),8.52(dd,J＝8.4,0.8Hz,1H),8.43(s,1H),8.41(s,1H),8.13(d,J＝8.4Hz,1H),8.04(dd,J＝7.6,0.8Hz,1H),7.99–7.92(m,2H),7.84(m,1H),7.69(m,1H),5.71–5.58(m,1H),2.41(m,2H),2.02–1.88(m,6H)；ESI-HRMS(m/z)[M+Na] + calcd for C 22 H 20 N 6 O,407.1699,found 407.1606.
End product 18 (S) -8-bromo-N- (6- (4- (1-hydroxy-prop-2-yl) -4H-1.24-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (18, 21-159-42)
Step one: 6-aminopyridine hydrazide (500 mg,3.3 mmol) was added to a 100mL eggplant-type flask, dissolved in acetonitrile, cooled to 15℃and 1, 1-dimethoxy-N, N-dimethylamine (1.57 g,13.2 mmol) was added thereto, and the mixture was stirred at 90℃under argon atmosphere for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, added (R) -2-aminopropanol (1.24 g,16.4 mmol), cooled again to 15℃and glacial acetic acid (394.7 mg,6.6 mmol) was added thereto under argon atmosphere, and the reaction mixture was stirred at 90℃overnight. After the reaction is finished, the mixture is concentrated by a rotary evaporator, and the normal phase silica gel column is purified. Target compound 575.1mg (21-130-39) yield 79.5%. 1 H NMR(400MHz,DMSO-d6):δ8.68(s,1H),7.51(t,J＝8.0Hz,1H),7.17(d,J＝7.2Hz,1H),6.51(d,J＝8.0Hz,1H),6.17(s,2H),5.47–5.35(m,1H),3.65–3.59(m,2H),1.42(d,J＝6.8Hz,3H)； 13 C NMR(101MHz,DMSO-d 6 ):δ159.17,151.33,145.84,143.32,138.17,111.68,108.56,64.37,45.29,17.71；ESI-HRMS(m/z)[M+H] + calcd for C 10 H 13 N 5 O,220.1120,found 220.1195.
Step two: 8-bromoquinoline-2-carboxylic acid (62.1 mg,0.25 mmol) was added to a 50mL eggplant-type flask, and 4mL of anhydrous toluene was added. Thionyl chloride (39.1 mg,0.33 mmol) was slowly added dropwise and refluxed at 80℃for 2h. After the reaction, concentrating and drying by a rotary evaporator. The residue was dissolved in anhydrous toluene, and (S) -2- (3- (6-aminopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) propan-1-ol (30 mg,0.14 mmol) and DIPEA (35.4 mg,0.27 mmol) were added and refluxed at 80℃for 2 hours. After the reaction, the mixture was concentrated by a rotary evaporator, the residue was diluted with methylene chloride, the saturated aqueous sodium hydrogencarbonate solution was washed, the organic layer was dried over anhydrous sodium sulfate, and the mixture was concentrated by a rotary evaporator, and purified by silica gel column chromatography. 12mg (18, 21-159-42) of the title compound was obtained as a white pale yellow solid in 19.0% yield. 1 H NMR(400MHz,CD 3 OD):δ9.63(s,1H),8.65(t,J＝8.4Hz,2H),8.44(d,J＝8.4Hz,1H),8.26(dd,J＝7.6,1.2Hz,1H),8.20–8.13(m,1H),8.09(dd,J＝8.4,1.2Hz,1H),8.00(d,J＝7.2Hz,1H),7.67–7.63(m,1H),5.88–5.77(m,1H),4.09(dd,J＝12.0,3.6Hz,1H),3.96(dd,J＝12.0,5.6Hz,1H),1.74(d,J＝7.2Hz,3H)；ESI-HRMS(m/z)[M+H] + calcd for C 20 H 17 BrN 6 O 2 ,453.0596,found453.0659.
End product 19 (R) -8-bromo-N- (6- (4- (1-hydroxy-prop-2-yl) -4H-1.24-triazol-3-yl) pyridin-2-yl) quinoline-2-carboxamide (19, 21-155-36)
Step one: 6-aminopyridine hydrazide (100 mg,0.66 mmol) was added to a 100mL eggplant-type flask, dissolved in acetonitrile, cooled to 15℃and 1, 1-dimethoxy-N, N-dimethylamine (313.2 mg,2.6 mmol) was added thereto, and the mixture was stirred at 90℃under argon atmosphere for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, added with (S) -2-aminopropanol (247.9 mg,3.3 mmol), cooled again to 15℃and added with glacial acetic acid (78.9 mg,1.3 mmol) under argon atmosphereThe reaction was stirred overnight at 90 ℃. After the reaction is finished, the mixture is concentrated by a rotary evaporator, and the normal phase silica gel column is purified. 38mg (20-141-42) of the target compound was obtained in 26.4% yield. 1 H NMR(400MHz,DMSO-d6):δ8.68(s,1H),7.55–7.48(m,1H),7.17(d,J＝7.2Hz,1H),6.51(dd,J＝8.4,0.8Hz,1H),6.16(d,J＝5.2Hz,1H),5.46–5.36(m,1H),3.70–3.54(m,2H),1.42(d,J＝6.8Hz,3H)； 13 C NMR(101MHz,DMSO-d 6 ):δ159.12,151.31,145.89,143.29,138.12,111.63,108.48,64.39,53.28,17.71；ESI-HRMS(m/z)[M+H] + calcd for C 10 H 13 N 5 O,220.1120,found 220.1183.
Step two: 8-bromoquinoline-2-carboxylic acid (30 mg,0.12 mmol), (R) -2- (3- (6-aminopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) propan-1-ol (26.1 mg,0.12 mmol) was added to a 50mL eggplant-type flask, and 3mL of anhydrous pyridine was added. Phosphorus oxychloride (73.0 mg,0.5 mmol) was slowly added under argon and stirred at room temperature for 2h. After the reaction was completed, the mixture was quenched with water and extracted three times with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. Concentrating the organic solvent by a rotary evaporator, and purifying by silica gel column chromatography. Target compound 6.2mg (19, 21-155-36), white solid, yield 11.4%. 1 H NMR(400MHz,DMSO-d 6 ):δ10.38(s,1H),9.11(s,1H),8.58(d,J＝8.8Hz,1H),8.25(dd,J＝7.6,1.2Hz,1H),8.11(dd,J＝8.0,1.2Hz,1H),8.02(dd,J＝8.0,1.2Hz,1H),7.96(d,J＝8.4Hz,1H),7.82–7.73(m,2H),7.67–7.61(m,1H),6.24–6.15(m,1H),4.68(m,2H),1.68(d,J＝7.2Hz,3H).
End product 20: n- (6- (1-isopropyl-1H-pyrazol-5-yl) pyridin-2-yl) quinoline-2-carboxamide (20, 21-127-36)
Step one: 6-bromopyridin-2-amine (100 mg,0.58 mmol) was put into a 100mL eggplant-type flask, and 1-isopropyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaboro-2-yl) -1H-pyrazole (279 mg,1.16 mmol), xphos-Pd-G was added 2 (45.4 mg,0.058 mmol) and sodium carbonate (612.68 mg,5.78 mmol) were finally dissolved in 1, 4-dioxane and water (5:1), and the reaction was stirred at 100℃for 2h. Reaction completionAfter that, water was added for dilution, the aqueous layer was extracted three times with methylene chloride, the methylene chloride layer was collected, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by normal phase silica gel column. 60mg (14-163-41) of the target compound was obtained in a yield of 51.3%. 1 H NMR(400MHz,CDCl 3 ):δ7.53(d,J＝1.6Hz,1H),7.50(dd,J＝8.4,7.6Hz,1H),6.87(dd,J＝7.2,0.8Hz,1H),6.48(dd,J＝8.4,0.8Hz,1H),6.43(d,J＝2.0Hz,1H),5.32(m,1H),4.59(s,2H),1.50(d,J＝6.4Hz,6H)； 13 C NMR(101MHz,CDCl 3 ):δ157.99,148.66,141.03,138.48,138.18,113.91,107.56,106.26,50.79,22.89；ESI-HRMS(m/z)[M+H] + calcd for C 11 H 14 N 4 ,203.1218,found 203.1297.
Step two: quinoline-2-carboxylic acid (25.7 mg,0.15 mmol), 6- (1-isopropyl-1H-pyrazol-5-yl) pyridin-2-amine (30 mg,0.15 mmol) were added to a 50mL eggplant-type flask, and 3mL of anhydrous pyridine was added. Phosphorus oxychloride (91.03 mg,0.59 mmol) was added slowly under argon and stirred at room temperature for 2h. After the reaction, acidifying with 2M hydrochloric acid solution until solid is separated out, filtering the separated solid with a Buchner funnel, washing with clear water, and finally drying. 54mg (20, 21-127-36) of the title compound was obtained as a pale yellow solid in 75.6% yield. 1 H NMR(400MHz,CDCl 3 ):δ10.80(s,1H),8.46(dd,J＝8.4,0.8Hz,1H),8.41(s,2H),8.19(d,J＝8.8Hz,1H),7.93(dd,J＝8.4,0.8Hz,1H),7.90–7.81(m,2H),7.72–7.65(m,1H),7.60(d,J＝2.0Hz,1H),7.34(dd,J＝7.6,0.8Hz,1H),6.54(d,J＝2.0Hz,1H),5.36(m,1H),1.61(d,J＝6.8Hz,6H)；ESI-HRMS(m/z)[M+H] + calcd for C 21 H 19 N 5 O,358.1590,found 358.1699.
End product 21 (R) -N- (6- (1- (1-hydroxy-prop-2-yl) -1H-pyrazol-5-yl) pyridin-2-yl) quinoline-2-carboxamide (21, 21-174-39)
Step one: 6-aminopyridine hydrazide (100 mg,0.66 mmol) was added to a 100mL eggplant-type flask, dissolved in acetonitrile, cooled to 15℃and 1, 1-dimethoxy-N, N-dimethylamine (313.2 mg,2.6 mmol) was added, and argon was used as a sourceThe reaction is carried out for 4 hours at 90 ℃ with stirring. After the reaction was completed, the reaction mixture was cooled to room temperature, added (S) -2-aminopropanol (247.9 mg,3.3 mmol), cooled again to 15℃and glacial acetic acid (78.9 mg,1.3 mmol) was added thereto under argon atmosphere, and the reaction mixture was stirred at 90℃overnight. After the reaction is finished, the mixture is concentrated by a rotary evaporator, and the normal phase silica gel column is purified. 38mg (20-141-42) of the target compound was obtained in 26.4% yield. 1 H NMR(400MHz,DMSO-d6):δ8.68(s,1H),7.55–7.48(m,1H),7.17(d,J＝7.2Hz,1H),6.51(dd,J＝8.4,0.8Hz,1H),6.16(d,J＝5.2Hz,1H),5.46–5.36(m,1H),3.70–3.54(m,2H),1.42(d,J＝6.8Hz,3H)； 13 C NMR(101MHz,DMSO-d 6 ):δ159.12,151.31,145.89,143.29,138.12,111.63,108.48,64.39,53.28,17.71；ESI-HRMS(m/z)[M+H] + calcd for C 10 H 13 N 5 O,220.1120,found 220.1183.
Step two: quinoline-2-carboxylic acid (30 mg,0.17 mmol) was dissolved in 5mL of dichloromethane, and carbodiimide hydrochloride (33.2 mg,0.17 mmol) and N-hydroxysuccinimide (33.2 mg,0.17 mmol) were added. (R) -2- (3- (6-aminopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) propan-1-ol (38.0 mg,0.17 mmol) was added under argon and the temperature was raised to 40℃and refluxed overnight. After the completion of the reaction, 20mL of a saturated aqueous sodium hydrogencarbonate solution was added for washing, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by column chromatography to give 19.9mg (21, 21-174-39) of the title compound as a white solid in 31.3% yield. 1 H NMR(400MHz,DMSO-d6):δ8.94(s,1H),8.47(d,J＝8.4Hz,1H),8.08(d,J＝8.4Hz,1H),8.04(d,J＝7.6Hz,1H),7.87–7.80(m,2H),7.75–7.68(m,1H),7.40–7.34(m,1H),7.10(d,J＝6.8Hz,1H),6.42(d,J＝7.6Hz,1H),6.06–5.96(m,1H),4.66(m,2H),1.60(d,J＝7.2Hz,3H)；ESI-HRMS(m/z)[M+H] + calcd for C 20 H 18 N 6 O 2 ,375.1491,found 375.1565.
End product 22 (S) -N- (6- (1- (1-hydroxy-prop-2-yl) -1H-pyrazol-5-yl) pyridin-2-yl) quinoline-2-carboxamide (22, 22-92-40)
Step one: to 6-aminopyridine hydrazides(500 mg,3.3 mmol) was put into a 100mL eggplant-type flask, dissolved in acetonitrile, cooled to 15℃and 1, 1-dimethoxy-N, N-dimethylamine (1.57 g,13.2 mmol) was added thereto, and the mixture was stirred at 90℃for 4 hours under argon atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, added (R) -2-aminopropanol (1.24 g,16.4 mmol), cooled again to 15℃and glacial acetic acid (394.7 mg,6.6 mmol) was added thereto under argon atmosphere, and the reaction mixture was stirred at 90℃overnight. After the reaction is finished, the mixture is concentrated by a rotary evaporator, and the normal phase silica gel column is purified. Target compound 575.1mg (21-130-39) yield 79.5%. 1 H NMR(400MHz,DMSO-d6):δ8.68(s,1H),7.51(t,J＝8.0Hz,1H),7.17(d,J＝7.2Hz,1H),6.51(d,J＝8.0Hz,1H),6.17(s,2H),5.47–5.35(m,1H),3.65–3.59(m,2H),1.42(d,J＝6.8Hz,3H)； 13 C NMR(101MHz,DMSO-d 6 ):δ159.17,151.33,145.84,143.32,138.17,111.68,108.56,64.37,45.29,17.71；ESI-HRMS(m/z)[M+H] + calcd for C 10 H 13 N 5 O,220.1120,found 220.1195.
Step two: quinoline-2-carboxylic acid (70.9 mg,0.41 mmol) was charged into a 50mL eggplant-type flask, and 4mL of anhydrous toluene was added. Thionyl chloride (65 mg,0.55 mmol) was slowly added dropwise and refluxed at 80℃for 2h. After the reaction, concentrating and drying by a rotary evaporator. The residue was dissolved in anhydrous toluene, and (S) -2- (3- (6-aminopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) propan-1-ol (50 mg,0.23 mmol) and DIPEA (59 mg,0.46 mmol) were added and refluxed at 80℃for 2 hours. After the reaction, the mixture was concentrated by a rotary evaporator, the residue was diluted with methylene chloride, the saturated aqueous sodium hydrogencarbonate solution was washed, the organic layer was dried over anhydrous sodium sulfate, and the mixture was concentrated by a rotary evaporator, and purified by silica gel column chromatography. 23mg (22, 22-92-40) of the title compound was obtained as a pale yellow solid in 26.7% yield. 1 H NMR(400MHz,DMSO-d6):δ10.78(s,1H),8.80(s,1H),8.64(d,J＝8.4Hz,1H),8.31(d,J＝8.4Hz,1H),8.25(d,J＝8.8Hz,1H),8.18(d,J＝8.4Hz,1H),8.10(d,J＝8.0Hz,1H),8.06(t,J＝8.0Hz,1H),7.88(m,2H),7.74(t,J＝8.0Hz,1H),5.39(m,1H),3.74–3.65(m,2H),1.50(d,J＝7.2Hz,3H)；ESI-HRMS(m/z)[M+H] + calcd for C 20 H 18 N 6 O 2 ,375.1491,found 375.1553.
The following compounds can be synthesized by selecting the corresponding raw materials:
TABLE 1
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Experimental example 2: ADP Glo kinase assay screening method of ASK 1: ADP-GLO luminescence kinase assay, which detects the formation of ADP in the kinase reaction, which is converted to ATP, which is then converted to light by Ultra-GLO luciferase.
Instrument: a multifunctional enzyme-labeled instrument (2104Multilabel Reader,PerkinElmer,USA); biochemical incubator, available from Biochemical incubator company; ultrasonic nanoliter liquid handling systems were purchased from Echo corporation.
Materials: ADP-GloTM kit (Promega USA); ASK1 kinase, available from Eurofins company. Principle of: after the kinase reaction, the remaining ATP is completely consumed by the ADP-Glo reagent, then ADP is converted to ATP, and the energy of ATP is transferred to luciferin, so that the Ultra-Glo (TM) luciferase is converted to light, and the luminescence signal is positively correlated with the kinase activity. ADP-GloTM allows detection of the activity of any ADP-producing enzyme without the need for antibody involvement and radiolabeling.
Sample treatment: the samples were dissolved in DMSO and stored at low temperature, and the concentration of DMSO in the final system was controlled within a range that did not affect the ADP-GloTM reagent.
ASK1 and HTRF kinase buffer solution for substrate (1X Kinase buffer,25mM MgCl) 2 4mM DTT,20mM HEPES,PH7.5,0.01%Triton x-100) are diluted. Transfer 40 μl of compound from the source plate to a new 384 well plate as an intermediate plate and transfer 50nl of compound to the assay plate by Echo. ASK1 solution was prepared in 1 Xkinase buffer at a concentration 2 times the final concentration of each reagent, 2.5. Mu.L of kinase solution was added to each well of the assay plate, and the solution was stimulated at 1XThe substrate solutions of MBP substrate and ATP were prepared in enzyme reaction buffer at a concentration 4 times the final concentration, the concentration of each reagent required in the assay. To each well of the assay plate 2.5 μl substrate solution was added to start the reaction, the plate was shaken, incubated at 37 ℃ for 60 minutes, 5 μl ADP-Glo reagent was added, incubated at 37 ℃ for 180 minutes, then 10 μl kinase detection reagent was added, equilibrated at room temperature for 30 minutes, ADP was converted to ATP and luciferase and luciferin were introduced to examine ATP. Data on Envision is collected. The RLU values were converted to percent inhibition values, and the data was fit in XLFit excel loader version 5.4.0.8 to obtain IC 50 Values, the formula used is: y=bottom+ (top-bottom)/(1+ (IC) 50 X), slope.
TABLE 2
(in the table, represent IC) 50 >2001nM; * 501-2000nM; * Represents IC 50 50-500nM; * Represents:,:<50nM, representing<20nM)。

Claims (8)

1. A small molecule compound having a 2-pyridine substituted carboxamide structure, or an enantiomer, racemate or mixture thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: the structural general formula of the compound is shown as formula (I):
，
wherein, the liquid crystal display device comprises a liquid crystal display device,
r1 represents halogen, deuterium atom, cyano, hydroxy, amino, nitro, oxo, alkyl, substituted or unsubstituted 5-12 membered heteroaromatic ring containing N, O or S atoms, substituted or unsubstituted 5-13 membered saturated heterocyclic ring containing N, O or S atoms, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkyl ethynyl, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkylcarbonylamino, substituted or unsubstituted C1-C4 alkoxycarbonylamino, substituted or unsubstituted C1-C4 sulfonyl, substituted or unsubstituted C1-C4 alkyl-S-, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C1-C4 alkylcarbonyl, or a combination thereof;
a quinoline ring representing a different N-atom position or a 6-membered heterocyclic ring containing two nitrogen atoms;
x represents N, CH or c=o;
a, b represent the position of an amide substitution on the N-containing heterocycle;
r2 represents H or methyl;
r3 represents a substituted or unsubstituted 5-6 membered heteroaromatic ring containing 1-4 heteroatoms N, O or S, one or more hydrogen atoms of said substituent being replaced by a group selected from the group consisting of: halogen, deuterium atom, cyano, hydroxy, amino, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy; wherein one or more hydrogen atoms on the corresponding substituent group in said substituent group is substituted with a group selected from the group consisting of: hydroxy, amino, carboxy.
2. A small molecule compound having a 2-pyridine substituted carboxamide structure, or an enantiomer, racemate or mixture thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: the compound is specifically selected from one of the following structural formulas:
。
3. an ASK1 inhibitor characterized in that: the inhibitor comprises a compound according to any one of claims 1 or 2, or an enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt, crystalline hydrate, or solvate thereof.
4. A pharmaceutical composition characterized by: comprising the following steps: (A) A therapeutically effective amount of a compound of claim 1 or 2, and one or more of enantiomers, diastereomers, racemates, and mixtures thereof, and pharmaceutically acceptable salts, crystalline hydrates, and solvates thereof; and (B) a pharmaceutically acceptable carrier.
5. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of a disease associated with ASK1 kinase activity or expression level.
6. The use according to claim 5, characterized in that: the disease related to the activity or expression amount of ASK1 kinase is selected from one of liver disease, lung disease, cardiovascular disease, kidney disease, metabolic disease and tumor disease.
7. A method of synthesizing a compound according to claim 1 or 2, characterized in that: the synthetic route is as follows:
。
8. the method for synthesizing a compound according to claim 7, wherein: i-1 in the synthetic route is prepared through one-step reaction, and the first step specifically comprises the following steps: mixing amine S1 and corresponding acyl chloride S2 in a solvent, adding alkali, and reacting at room temperature, low temperature or elevated temperature to obtain a final product I-1; the second step is to dissolve I-1 in DMF, add NaH and methyl iodide, stir and react at room temperature, low temperature or elevated temperature to prepare the final product I-2.
CN202310717218.8A 2022-12-24 2023-06-16 Synthesis and application of small molecular compound with 2-pyridine substituted formamide structure Pending CN116874468A (en)

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