WO2021218992A1 - Substituted pyrrolidine compound and use thereof in medicine - Google Patents

Substituted pyrrolidine compound and use thereof in medicine Download PDF

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WO2021218992A1
WO2021218992A1 PCT/CN2021/090489 CN2021090489W WO2021218992A1 WO 2021218992 A1 WO2021218992 A1 WO 2021218992A1 CN 2021090489 W CN2021090489 W CN 2021090489W WO 2021218992 A1 WO2021218992 A1 WO 2021218992A1
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alkyl
methyl
group
ethyl
isopropyl
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PCT/CN2021/090489
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French (fr)
Chinese (zh)
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刘兵
余天柱
张仕国
张英俊
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东莞市东阳光新药研发有限公司
广东东阳光药业有限公司
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Publication of WO2021218992A1 publication Critical patent/WO2021218992A1/en

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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Definitions

  • the invention belongs to the field of medicine, and specifically relates to a class of substituted pyrrolidine compounds, pharmaceutical compositions containing the compounds, and uses and methods of use thereof.
  • the compounds of the present invention are PDE4 inhibitors, which are used to treat PDE4-related diseases, such as atopic dermatitis (AD), psoriasis or chronic obstructive pulmonary disease (COPD).
  • AD atopic dermatitis
  • COPD chronic obstructive pulmonary disease
  • Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are two important second messengers in cells, which are mainly involved in energy metabolism, memory and immunity by activating protein kinase A (PKA) and protein kinase G (PKG) pathways.
  • PKA protein kinase A
  • PKG protein kinase G
  • PDE phosphodiesterase
  • PDEs can specifically use 3,5-cyclic nucleotides as substrates to catalyze the hydrolysis of cGMP and cAMP in cells into corresponding inactive 5-nucleotides, thereby affecting various metabolic functions of organisms. Therefore, inhibiting PDEs is a very effective way to cause many cell activities, which can affect the activation of inflammatory cells and immune cells and the contraction response of smooth muscle cells.
  • PDEs Phosphodiesterases
  • PDE4 Phosphodiesterases
  • PDE7 and PDE8 mainly specifically hydrolyze cAMP
  • PDE5, PDE6 and PDE9 specifically hydrolyze cGMP
  • PDE1, PDE2, PDE3, PDE10 and PDE11 are It works on both cAMP and cGMP.
  • PDE4 is mainly distributed in various inflammatory cells. Its tissue distribution shows that it is closely related to the central nervous system and immune system. Its inhibitors can be used to treat various diseases, including allergic and inflammatory diseases, diabetes, and central nervous system diseases. And pain.
  • PDE4 inhibitors exert anti-inflammatory effects mainly through the following ways: (1) inhibit the activity of a variety of inflammatory mediators; (2) inhibit the up-regulation and expression of cell adhesion factors; (3) inhibit the activation of white blood cells; (4) induce Apoptosis; (5) Induces the production of inhibitory cytokines (such as interleukin-6); (6) Induces the release of catecholamines and endogenous hormones.
  • the first-generation PDE4 inhibitors mainly include theophylline, Rolipram and Piclamilast, etc.
  • Rolipram has certain effects on neurological diseases, such as Parkinson’s disease, depression and anxiety. Therapeutic effect.
  • the first-generation PDE4 inhibitors have limited clinical application due to severe nausea, vomiting and other side effects;
  • the second-generation PDE4 inhibitors include Roflumilast and Cilomilast, among which Roflumilast is used in the treatment of COPD and has certain therapeutic effects on other inflammatory diseases, such as ulcerative colitis and Crohn's disease.
  • the third-generation PDE4 inhibitor, Apremilast has been used in the treatment of autoimmune diseases such as psoriasis, and has fewer side effects and is easier for patients to tolerate.
  • WO/2000/064260 discloses that the PDE4 inhibitor Ro 20-1724 1% cream is effective in treating psoriasis.
  • WO 2000/009504 discloses another PDE4 inhibitor CP-80633 (0.5% ointment), which significantly improves the clinical scoring of atopic dermatitis (erythema, induration and exfoliation).
  • CP-80633 0.5% ointment
  • the present invention provides a class of compounds with type 4 phosphodiesterase (Phosphodiesterase-4, PDE4) inhibitory activity for the preparation of prevention, treatment or alleviation of PDE4 related respiratory diseases, allergies, inflammations, central nervous system diseases or non- Insulin-dependent diabetes drugs, such as chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or respiratory tract Inflammation; among which bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis, bronchiolitis obliterans, allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid Arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, anky
  • the present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds or compositions to treat the above-mentioned diseases in mammals, especially humans.
  • the present invention relates to a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of the compound represented by formula (I), Pharmaceutically acceptable salts or their prodrugs,
  • X is CH or N
  • Ring A is a C 6-10 aryl group or a heteroaryl group composed of 5-10 atoms
  • R 1 is hydrogen, deuterium, -OR a or -NR c R d ;
  • R 2 is a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyl group-C 1-4 alkyl group, a heterocyclic group composed of 5-7 atoms Cyclic group or (heterocyclic group consisting of 5-7 atoms) -C 1-4 alkyl; or
  • R a and R 2 which together form a 5-7 atom heterocyclic group of atoms, said heterocyclic group consisting of 5-7 atoms optionally substituted selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl substituents;
  • R a is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclic group composed of 5-10 atoms, C 6- 10 aryl groups or heteroaryl groups composed of 5-10 atoms, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 5- 10-atom heterocyclic group, C 6-10 aryl group and 5-10 atom heteroaryl group are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 5-10 atoms Substituted by the substituent of the cyclic group;
  • the N atoms together form a heterocyclic group consisting of 4-7 atoms; wherein said R e , R
  • Each R h is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy or C 1 -4 alkoxy;
  • n is independently 0, 1, 2, 3, or 4;
  • n and p are each independently 0, 1, 2, or 3.
  • the A ring is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazole Base, indolyl, isoindolyl,
  • R a is hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 hetero atoms Cyclic group, phenyl group or heteroaryl group consisting of 5-6 atoms, wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-6 cycloalkyl group,
  • the heterocyclic group composed of 5-6 atoms, the phenyl group and the heteroaryl group composed of 5-6 atoms are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or heterocyclic group consisting of 5-6 atoms The substituents are substituted.
  • R 2 is methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 ,- CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl,- CHCl 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, piperazinyl, piperidinyl, morpholinyl , Thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, t
  • R 2 and R a and its connected atoms together form 1,3-dioxole, 1,3-dioxene, 2,3-dihydro-1,4,2-dioxazine Alkene or 1,5,3-dioxazepine
  • the 1,3-dioxolene, 1,3-dioxolene, 2,3-dihydro-1, 4,2-Dioxazineene or 1,5,3-dioxazepine is independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF
  • R a is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl , 2-propynyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thio Morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, Thiazolyl or
  • R e and R f together with the N atom to which they are connected form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
  • R e , R f , azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently optionally substituted by 1, 2, 3 or 4 substituted with a R h; wherein each R h is as defined in the present invention.
  • each R h is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy , Sec-butoxy or tert-butoxy;
  • the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (II) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
  • the present invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (III) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
  • the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate Acid salt, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate Acid salt, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethane Sulfonate or their combination.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I), (II) or (III) of the present invention or its stereoisomers, geometric isomers, tautomers, Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs, and at least one of pharmaceutically acceptable excipients, carriers, adjuvants, adjuvants, and vehicles Or a combination of them;
  • the pharmaceutical composition further comprises other additional therapeutic agents, wherein the additional therapeutic agents are: sodium pyruvate, doxofylline, tetomilast, telukast, theophylline, formoterol, salami Terrol, fluticasone propionate, rolipram, piramistrol, cilomilast, indacaterol, odacaterol, midistein, citradin, salbutamol, camoxirol , Budesonide, beclomethasone dipropionate, flunisolide, rofluronide, ciclesonide, ipratropium bromide, oxitropium bromide, tiotropium bromide, glycopyrrolate bromide, Wudi Ammonium bromide, vilanterol, aclidinium bromide, Benralizumab, Tralokinumab, revatatropate, crenzaboron, fluocinolone acetate, desoxymethasone,
  • the present invention relates to the use of a compound represented by formula (I), (II) or (III) or a pharmaceutical composition thereof in the preparation of a medicine for the prevention, treatment or alleviation of type 4 phosphodiester Enzyme-related diseases.
  • the present invention relates to the use of a compound represented by formula (I), (II) or (III) or a pharmaceutical composition thereof in the preparation of a medicine.
  • the disease related to type 4 phosphodiesterase is respiratory Disease, allergy, inflammation, central nervous system disease or non-insulin dependent diabetes.
  • the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute Respiratory distress syndrome or inflammation of the respiratory tract; among which bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis.
  • the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing Spondylitis, rheumatoid arthritis or psoriatic arthritis.
  • the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I), (II) or (III).
  • any embodiment of any aspect of the present invention can be combined with other embodiments as long as they do not appear contradictory.
  • any technical feature can be applied to the technical feature in other embodiments, as long as they do not conflict.
  • subject used in the present invention refers to an animal. Typically the animal is a mammal.
  • the subject also refers to primates (such as humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • stereoisomers refers to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rottamers), geometric (cis/trans) isomers, atropisomers, and the like.
  • chiral refers to a molecule that can not overlap with its mirror image; and “achiral” refers to a molecule that can overlap with its mirror image.
  • enantiomers refers to two isomers of a compound that cannot overlap but are mirror images of each other.
  • diastereomers refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory, and the compound with the prefix (+) or d is dextrorotatory of.
  • a specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (for example, carbon, etc.) of the compound disclosed in the present invention may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration form exist.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compound of the present invention can be one of the possible isomers or a mixture of them, such as racemates and diastereomer mixtures (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may have an E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may have a cis or trans configuration.
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • racemate of any final product or intermediate obtained can be resolved into optical enantiomers by a method familiar to those skilled in the art using known methods, for example, by performing diastereomeric salts of the obtained diastereomers. Separate.
  • the racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • a class of compounds such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different substitutions.
  • C 1 -C 6 alkyl or “C 1-6 alkyl” specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl. base.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition for the variable lists such as “alkyl” or “aryl”
  • the “alkyl” or “aryl” respectively represents the link The alkylene group or arylene group.
  • alkyl or “alkyl group” used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally Ground is substituted with one or more substituents described in this invention. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2
  • alkylene refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in another embodiment, the alkylene group The group contains 1-3 carbon atoms; in yet another embodiment, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), isopropylidene (-CH(CH 3 ) CH 2 -) and so on.
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp 2 double bond, wherein the alkenyl group Groups can be optionally substituted with one or more substituents described in the present invention, including the positioning of "cis” and “tans", or the positioning of "E” and "Z".
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted by one or more substituents described in the present invention.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), etc. .
  • Carboxy whether used alone or in combination with other terms, such as “carboxyalkyl”, means -CO 2 H or -COOH.
  • deuterium means a single deuterium atom.
  • one deuterium atom replaces a hydrogen atom in a methyl group to form a mono-deuterated methyl group (-CDH 2 )
  • two deuterium atoms replace two hydrogen atoms in a methyl group to form a double-deuterated methyl group (- CD 2 H)
  • three deuterium atoms to replace the three hydrogen atoms in the methyl group to form a tri-deuterated methyl group (-CD 3 ).
  • unsaturated means that the group contains one or more degrees of unsaturation.
  • heteroatom refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or on the nitrogen atom in the heterocyclic ring
  • the form in which hydrogen is substituted for example, N (like the N in 3,4-dihydro-2H-pyrrolyl), NH (like the NH in the pyrrolidinyl group) or NR (like the N-substituted pyrrolidinyl group NR).
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-but Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-(
  • haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted with one or more halogen atoms. Examples of this include, but are not limited to, -CH 2 F, -CHF 2 ,- CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , -OCHF 2 , -OCF 3 and so on.
  • alkylamino means that the -NH 2 group is substituted with one or two alkyl groups, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkylamino group contains 1-12 carbon atoms. In one embodiment, the alkylamino group contains 1 to 6 carbon atoms; in another embodiment, the alkylamino group contains 1 to 4 carbon atoms; in another embodiment, the alkylamino group contains 1 -3 carbon atoms. Examples of the alkylamino group include, but are not limited to: methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, and the like. The alkylamino group may be optionally substituted with one or more substituents described in this invention.
  • each of j and k is independently any non-zero natural number, and k>j; the "j-k” includes j, k and any natural number in between.
  • the number of ring-forming atoms in a molecule is j-k, and the atoms include carbon atoms and/or O, N, S, P and other heteroatoms.
  • cycloalkyl refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. In one embodiment, the cycloalkyl group contains 3-12 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in another embodiment, the cycloalkyl group contains 3-6 carbon atoms. carbon atom.
  • the cycloalkyl group may be independently optionally substituted with one or more substituents described in the present invention.
  • cycloalkyl-alkyl or “cycloalkyl-alkylene” are used interchangeably, and both refer to the alkyl group being substituted by one or more cycloalkyl groups, where the alkyl group and the ring Alkyl groups have the meanings described in the present invention. Examples of such include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, Cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, etc.
  • heterocyclic group and “heterocyclic ring” are used interchangeably herein, and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms, wherein monocyclic, bicyclic or tricyclic ring
  • the ring does not contain an aromatic ring, and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • heterocyclic groups include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, imidazolinyl , Imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, 1,3-dioxolyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl , 1,1-Dio
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • heterocyclyl-alkyl or “heterocyclyl-alkylene” can be used interchangeably, and both refer to an alkyl group substituted by a heterocyclyl group; wherein the heterocyclyl group and the alkyl group have the same characteristics as described in the present invention. meaning.
  • heterocyclyl group and the alkyl group have the same characteristics as described in the present invention. meaning.
  • Such examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydropyran-4-ylmethyl, oxetan-3-ylmethyl, Pyrrolidin-2-ylmethyl, morpholin-4-ylmethyl, etc.
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring composed of 3-7 atoms, and has one or more attachment points connected to the rest of the molecule.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.
  • aryl-alkyl or “aryl-alkylene” can be used interchangeably, and both refer to an alkyl group substituted by one or more aryl groups, wherein the aryl and alkyl groups have the meaning described in the present invention. Meaning.
  • the arylalkyl group refers to a "lower arylalkyl” group, that is, the aryl group is connected to a C1-6 alkyl or alkylene group.
  • the arylalkyl group refers to a "phenylalkyl group" containing a C 1-4 alkyl group. Specific examples thereof include diphenylmethyl, benzyl, and phenethyl.
  • the aryl group on the aryl-alkyl group or aryl-alkylene group may be further substituted with the substituents described in the present invention.
  • heteroaryl means a monocyclic, bicyclic and tricyclic ring system containing 5-15 ring atoms, 5-12 ring atoms, or 5-10 ring atoms, or 5-7 ring atoms, of which at least one The ring system is aromatic, and at least one ring system contains one or more heteroatoms, each of which contains a ring composed of 5-7 atoms, and has one or more attachment points connected to the rest of the molecule.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring", “aromatic heterocyclic ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • the 5-10 atom heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, N, or B.
  • the 11-15 atom heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, N, or B.
  • heteroaryl groups include, but are not limited to, furyl (e.g. 2-furyl, 3-furyl), imidazolyl (e.g. N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl), isoxazolyl (e.g. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5 -Oxazolyl), pyrrolyl (e.g. N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g.
  • furyl e.g. 2-furyl, 3-furyl
  • imidazolyl e.g. N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl
  • isoxazolyl e.g. 3-isoxazoly
  • heteroaryl-alkyl or “heteroaryl-alkylene” are used interchangeably and both refer to the alkyl group being substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups Having the meaning of the present invention, such examples include, but are not limited to, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4ylmethyl, pyrimidin-2-ylmethyl, pyrazole-5yl Methyl, pyrazol-4-ylmethyl, imidazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl, etc.
  • the ring system formed by attaching a substituent to the central ring by drawing a bond represents that the substituent can be substituted at any substitutable position on the ring.
  • the formula c represents that the substituent R can be mono-substituted or multi-substituted at any position on the C ring that may be substituted, as shown in formula c1 to formula c19.
  • a linking bond is connected to the ring system (as shown in formula d), which means that the linking bond can be connected to the rest of the molecule at any linkable position on the ring system.
  • the formula d represents that any possible connection position on the ring can be connected to the rest of the molecule, as shown in formula d1 to formula d5.
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) or formula (II) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissues.
  • the prodrug compounds of the present invention can be esters. In the existing invention, esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known to us in the field, as described in the literature: SMBerge et al., J. Pharmaceutical Sciences, 66:1-19, 1977.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or through other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3 -Phenylpropylprop
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • the "hydrate” in the present invention refers to an association formed by the solvent molecule being water.
  • one compound molecule of the present invention may be combined with one water molecule, such as a monohydrate; in other embodiments, one compound molecule of the present invention may be combined with more than one water molecule, such as dihydrate In other embodiments, one compound molecule of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrate of the present invention retains the bioavailability of the compound in its non-hydrated form.
  • nitrogen oxide means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), in which, for example, in an inert solvent, such as methylene chloride, the amine compound is combined with
  • carrier includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (such as antibacterial agents, antifungal agents), isotonic agents, salts, drug stabilizers, binders, excipients Forming agents, dispersing agents, lubricants, sweetening agents, flavoring agents, coloring agents, or combinations thereof, these carriers are known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990 , pp. 1289-1329). Except for the incompatibility of any conventional carrier with the active ingredient, its use in therapeutic or pharmaceutical compositions is encompassed.
  • the term “treating" any disease or condition in some embodiments refers to ameliorating the disease or condition (ie slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treatment” refers to regulating the disease or condition physically (for example, stabilizing the perceptible symptoms) or physiologically (for example, stabilizing the parameters of the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • the term "therapeutically effective dose” or “therapeutically effective dose” refers to a biological or medical response (such as reducing or inhibiting enzyme or protein activity, or improving symptoms, alleviating symptoms, slowing or delaying disease The amount of the compound of the present invention for the development, or prevention of diseases, etc.).
  • the term "therapeutically effective amount” refers to an amount effective for the following conditions when administering the compound of the present invention to an individual: (1) at least partially alleviating, inhibiting, preventing and/or ameliorating (i) related to PDE4, or (ii) related to PDE4 activity, or (iii) disorders or diseases characterized by abnormal activity of PDE4; or (2) reducing or inhibiting the activity of PDE4; or (3) reducing or inhibiting PDE4 expression.
  • the term "therapeutically effective amount” refers to the ability to at least partially reduce or inhibit the activity of PDE4 when administered to cells, or organs, or non-cellular biological substances, or media; or at least partially reduce or inhibit the activity of PDE4 The effective amount of the compound of the invention expressed by PDE4.
  • administering and “administering” a compound as used in the present invention should be understood as providing a compound of the present invention or a prodrug of a compound of the present invention to an individual in need thereof. It should be recognized that those skilled in the art can treat patients currently suffering from this disorder or preventively treat patients suffering from this disorder by using an effective amount of the compound of the present invention.
  • composition refers to a product containing a prescribed amount of prescribed ingredients, and any product directly or indirectly produced by a combination of prescribed amounts of prescribed ingredients.
  • the meaning of this term in relation to pharmaceutical compositions includes products containing active ingredients (single or multiple) and inert ingredients (single or multiple) constituting the carrier, as well as products composed of any two or more ingredients mixed, compounded or aggregated , Or any product produced directly or indirectly by the decomposition of one or more components, or by other types of reactions or interactions of one or more components. Therefore, the pharmaceutical composition of the present invention includes any composition prepared by mixing the compound of the present invention with a pharmaceutically acceptable carrier.
  • the compounds disclosed in the present invention can also be obtained in the form of their hydrates or in the form of containing their solvents (for example, ethanol, DMSO, etc.), and used for their crystallization.
  • their solvents for example, ethanol, DMSO, etc.
  • the compounds disclosed in the present invention can form solvates inherently or by design with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include solvated and unsolvated forms.
  • any structural formula given in the present invention is also intended to represent the non-isotopically enriched form and the isotopically enriched form of these compounds.
  • the isotope-enriched compound has the structure described by the general formula given in the present invention, except that one or more atoms are replaced by atoms having the selected atomic weight or mass number.
  • Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes such as 3 H, 14 C and 18 F are present, or non-radioactive isotopes such as 2 H and 13 C.
  • isotopically enriched compounds can be used for metabolism studies (using 14 C), reaction kinetics studies (using, for example, 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or including drugs or Single-photon emission computed tomography (SPECT), which measures the distribution of substrate tissue, may be used in radiotherapy of patients.
  • 18 F-enriched compounds are particularly ideal for PET or SPECT research.
  • the isotope-enriched compound represented by formula (I) or formula (II) can be replaced by a suitable isotope labeling reagent using conventional techniques familiar to those skilled in the art or as described in the examples and preparation processes of the present invention. Label the reagent to prepare.
  • isotopes particularly deuterium (ie, 2 H or D)
  • deuterium in the present invention is regarded as a substituent of the compound represented by formula (I) or formula (II).
  • the isotope enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium.
  • isotopic enrichment factor refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope.
  • the compound has at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), for each designated deuterium atom, At least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping) Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factor.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D 2 O, acetone-d 6 , DMSO-d 6 .
  • the present invention relates to new pyrrolidine compounds and methods for treating atopic dermatitis or chronic obstructive pulmonary disease.
  • the compound of the present invention or the pharmaceutical composition containing the compound is used as a PDE4 inhibitor, and has a good therapeutic effect on atopic dermatitis or chronic obstructive pulmonary disease.
  • the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts or their prodrugs:
  • X is CH or N.
  • the A ring is a C 6-10 aryl group or a 5-10 atom heteroaryl group.
  • R 1 is hydrogen, deuterium, -OR a, or -NR c R d ; wherein, R a , R c, and Rd have the meanings described in the present invention.
  • R 2 is C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, 5- Heterocyclic group consisting of 7 atoms or (heterocyclic group consisting of 5-7 atoms)-C 1-4 alkyl; or
  • R a and R 2 which together form a 5-7 atom heterocyclic group of atoms, said heterocyclic group consisting of 5-7 atoms optionally substituted selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl substituents.
  • R a is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hetero atoms 5-10 Cyclic group, C 6-10 aryl group or heteroaryl group composed of 5-10 atoms, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, heterocyclic groups composed of 5-10 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-10 atoms are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 5- A 10-atom heterocyclic group is substituted by a substituent.
  • each of R g , R j and R h has the meaning described in the present invention.
  • each R h is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 Haloalkoxy or C 1-4 alkoxy.
  • each n is independently 0, 1, 2, 3, or 4.
  • m and p are each independently 0, 1, 2, or 3.
  • the A ring is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazinyl Azolyl, indolyl, isoindolyl,
  • R a is hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 atoms Heterocyclic group, phenyl group or heteroaryl group consisting of 5-6 atoms, wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-6 cycloalkyl group , 5-6 atom heterocyclic group, phenyl group and 5-6 atom heteroaryl group are each independently optionally selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or a heterocyclic ring composed of 5-6 atoms Substituents of the group are substituted.
  • R 2 is methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, piperazinyl, piperidinyl, morpholine Group, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl
  • R 2 forms 1,3-dioxole together with R a and the atom to which it is connected 1,3-dioxene, 2,3-dihydro-1,4,2-dioxazine or 1,5,3-dioxazepine, the 1,3- Dioxole, 1,3-dioxene, 2,3-dihydro-1,4,2-dioxazine or 1,5,3-dioxazepine independent
  • deuterium F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Group, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF 3 or -CF 2 CH
  • R a is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl Base, 2-propynyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, sulfur Morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl , Thiazolyl or
  • each of R e and R f has the meaning described in the present invention.
  • R e and R f together with the N atom to which they are connected form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
  • R e , R f , azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently optionally substituted by 1, 2, 3 or 4 Replaced by R h;
  • each of R h , R g and R j has the meaning described in the present invention.
  • each R h is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy Group, sec-butoxy or tert-butoxy.
  • the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (II) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
  • the present invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (III) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
  • the present invention relates to a compound, which is a compound represented by formula (IV) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (IV) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
  • the present invention relates to a compound, which is a compound represented by formula (V) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (V) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
  • the present invention relates to a compound, which is a compound represented by formula (VI) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (VI) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
  • the present invention relates to a compound that is a compound represented by formula (VII) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (VII) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
  • the present invention includes, but is by no means limited to, compounds having one of the following structures or stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolism of compounds having one of the following structures Products, pharmaceutically acceptable salts or their prodrugs:
  • the pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, and maleic acid.
  • Salt succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucose Alkate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methane Sulfonate, ethanesulfonate, trifluoromethanesulfonate, or a combination thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I), (II), (III), (IV), (V) or (VI) disclosed in the present invention .
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, adjuvant, vehicle, or any combination thereof.
  • the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, telukast , Theophylline, Formoterol, Salmeterol, Fluticasone Propionate, Rolipram, Piramister, Cilomilast, Indacaterol, Odaterol, Midistein, Qi Circulation , Salbutamol, carmoxirol, budesonide, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, rofluonide, ciclesonide, ipratropium bromide Ammonium, oxotropium bromide, tiotropium bromide, glycopyrrolate, umeclidinium bromide, vilanterol, aclidinium bromide, Benralizumab, Tralokinumab, rev
  • the present invention relates to the use of the compound represented by formula (I), (II), (III), (IV), (V) or (VI) or its pharmaceutical composition disclosed in the present invention in the preparation of medicines,
  • the medicine is used to prevent, treat or alleviate diseases related to phosphodiesterase type 4 (PDE4).
  • the disease associated with phosphodiesterase type 4 is respiratory disease, allergy, inflammation, central nervous system disease, or non-insulin dependent diabetes.
  • the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, Acute respiratory distress syndrome or inflammation of the respiratory tract; among which bronchitis includes acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;
  • the inflammation mentioned is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatic Arthritis or psoriatic arthritis.
  • Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I), (II), (III), (IV), (V) or (VI).
  • the present invention relates to intermediates for preparing compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII).
  • the compounds disclosed in the present invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomer forms.
  • the present invention aims to make all stereoisomeric forms of the compound represented by formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers As well as their mixtures, such as racemic mixtures, become an integral part of the present invention.
  • stereochemistry of any specific chiral atom when the stereochemistry of any specific chiral atom is not specified, all stereoisomers of the structure are considered in the present invention and are included in the present invention as the compound disclosed in the present invention .
  • stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, then the stereoisomer of the structure is clear and defined.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) or its individual stereoisomers, Racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient or adsorbent, and optionally, other therapeutic and/or preventive components.
  • Suitable carriers, excipients or adsorbents are well known to those skilled in the art and are described in detail in, for example, Ansel HCet al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro ARet al. ., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
  • the "pharmaceutically acceptable excipient" used in the present invention means a pharmaceutically acceptable material, mixture or vehicle related to the consistency of the dosage form or the pharmaceutical composition.
  • Each excipient must be compatible with other ingredients of the pharmaceutical composition when mixed to avoid interactions that would greatly reduce the efficacy of the compounds disclosed in the present invention when administered to patients and lead to pharmaceutical compositions that are not pharmaceutically acceptable Interaction.
  • each excipient must be pharmaceutically acceptable, for example, with sufficiently high purity.
  • Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected.
  • pharmaceutically acceptable excipients can be selected according to their specific functions in the composition. For example, certain pharmaceutically acceptable excipients can be selected that can help produce a uniform dosage form. Certain pharmaceutically acceptable excipients can be selected that can help produce a stable dosage form. Certain pharmaceutically acceptable excipients can be selected to help carry or transport the compound of the invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients can be selected to enhance patient compliance.
  • excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, Polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose.
  • Suitable pharmaceutically acceptable excipients also include the following types of excipients: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, lubricants Wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjustment Agents, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants and filter aids.
  • solvents solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, lubricants Wetting agents, osmotic
  • Suitable pharmaceutically acceptable carriers depend on the form of the drug and are known to those skilled in the art.
  • pharmaceutically acceptable carrier includes any and all solvents and solvent mixtures, coatings, complexing agents, solid carriers, dispersion media, surface active excipients, antibacterial and antifungal Medicines, isotonic and absorption delaying agents for pharmaceutically active substances, and mixtures thereof, these are also known in the art.
  • Non-limiting examples of pharmaceutically acceptable carriers include those having components selected from lactose, gelatin, sugar alcohols (such as starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, Colloidal silicon dioxide, carboxymethyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, buffered aqueous solution, copovidone, polysorbate, ethanol, propylene glycol, polyglycol (preferably polyethylene glycol, such as PEG400), (Ie PEG(20), sorbitol monooleate), DMSO, a mixture of water and co-solvents, for example, including an aqueous solution of alcohols such as ethanol and/or polyglycols such as polyethylene glycol, polyhydric alcohols such as glycerol and/ Or esters of polyethylene glycol and fatty acids, surfactants such as anionic, cationic, nonionic and amphoteric surfactants, complexing agents such as cyclod
  • Non-limiting examples of further suitable pharmaceutically acceptable carriers and suitable additives that can be used in the pharmaceutical composition of the present invention are mentioned below.
  • the present invention relates to the pharmaceutical composition of the present invention, which forms a lipid-based drug delivery system (DDS) in an aqueous medium.
  • the pharmaceutical composition in addition to at least one compound or a salt thereof among the compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII), At least one surfactant is also included.
  • suitable surfactants are as described above.
  • lipid-based drug delivery systems form the following structures: (1) liposomes (ie, dispersed and closed bilayer assemblies of lamellar phase in water); (2) non-lamellar phase (e.g. cubic , Hexagonal, sponge) nanoparticles; or (3) micelles, emulsions, microemulsions (ie simple self-assembled structures of lipids and surfactants).
  • lipid-based drug delivery systems that form micelles, emulsions, or microemulsions are preferred.
  • the hydrophilic-lipophilic balance (HLB-value) of a suitable surfactant or surfactant mixture used to form micelles, emulsions or microemulsions is generally about 8-18, about 10-18, or about 12 -16.
  • Lipid-based drug delivery systems form a self-emulsifying drug delivery system (SEDDS) or a self-microemulsifying drug delivery system (SMEDDS).
  • SEDDS and SMEDDS are a mixture of oils (ie lipids, such as compounds of formula (I) or salts thereof), at least one surfactant, optionally at least one co-solvent and optionally at least one co-surfactant , Ideally isotropic, when introduced into the water phase under gentle agitation, it spontaneously emulsifies to form an oil-in-water emulsifier.
  • gentle agitation can be provided, for example, by the mobility of the stomach.
  • composition disclosed in the present invention is prepared using techniques and methods known to those skilled in the art. For descriptions of some commonly used methods in this field, please refer to Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the present invention relates to a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed in the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or a combination thereof, the process comprising Mix the various ingredients.
  • the pharmaceutical composition containing the compound disclosed in the present invention can be prepared by mixing at, for example, ambient temperature and atmospheric pressure.
  • the compounds disclosed in the present invention are usually formulated into a dosage form suitable for administration to a patient through a desired route.
  • the dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions Preparations, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3) transdermal administration, such as transdermal patches Tablets; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, Pastes, sprays, foams and gels.
  • Oral administration such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions Preparations, solutions, emulsion
  • solid oral dosage forms are used for the administration of the compound of the present invention, such as solid dosage forms of tablets, capsules, granules, lozenges and bulk powders.
  • the compound of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers and excipients known in the art (for example, sucrose, mannitol, lactose, starch), including but not limited to suspending agents , Solubilizers, buffers, binders, disintegrants, preservatives, coloring agents, flavoring agents, lubricants, etc.
  • Time-release capsules, tablets and gels are also advantageous for the administration of the compounds of the invention.
  • the compound of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents and excipients known in the art, including but not limited to solvents, oily solvents, diluents, stabilizers, absorption Delay agents, disintegrating agents, emulsifiers, antioxidants, adhesives, binding agents, viscosity increasing agents, solubilizers, dispersants, suspoemulsifiers, lubricants, hygroscopic agents, liposomes, microemulsions and ⁇ -cyclopaste Jing etc.
  • various pharmaceutically acceptable carriers including but not limited to solvents, oily solvents, diluents, stabilizers, absorption Delay agents, disintegrating agents, emulsifiers, antioxidants, adhesives, binding agents, viscosity increasing agents, solubilizers, dispersants, suspoemulsifiers, lubricants, hygroscopic agents, liposomes, microemulsions and ⁇
  • the compounds of the present invention are preferably administered by inhalation.
  • Inhalable preparations include inhalable powders, propellant-containing metered aerosols, or propellant-free inhalable preparations.
  • it can be administered directly as a powder (preferably in a micronized form), or via a spray solution or suspension containing them.
  • An excipient or carrier may be added to the powder compound of the present invention, which is generally non-toxic and chemically inert to the compound of the present invention, such as lactose or any other additives suitable for improving the respirable portion .
  • Inhalation aerosols containing gaseous propellants such as hydrofluoroalkanes may contain the compounds of the invention in solution or dispersed form.
  • Propellant-driven formulations may also contain other ingredients, such as co-solvents, stabilizers, and optional other excipients.
  • the propellant-free inhalable formulations containing the compounds of the present invention may be in the form of solutions or suspensions in aqueous media, alcoholic media, or aqueous alcoholic media, and they can be passed through jet nebulizers or ultrasonics known in the art. Nebulizer delivery, or through soft-mist nebulizers such as deliver.
  • terapéuticaally effective amount used in the present invention refers to the total amount of each active ingredient sufficient to show a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate the symptoms of the disease is administered or brought into balance in the body.
  • the effective amount required for a particular treatment regimen depends on many factors, including the disease to be treated, the severity of the disease, the activity of the specific drug used, the method of administration, the clearance rate of the specific drug, the duration of treatment, the combination of drugs, and age , Weight, gender, diet and patient’s health, etc.
  • the dosage of the compound of the present invention depends on a variety of factors, including the specific disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dose interval, the specific compound used, the potency of the compound, the toxicological characteristics and the pharmacokinetics. feature.
  • the amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration.
  • a formulation intended for application to humans may conveniently contain about 5 mg to about 250 mg/kg body weight/day of the active agent together with a suitable and convenient amount of carrier material (which may account for about 5% to about 95% of the total composition. %) phase composite.
  • a unit dosage form will generally contain from about 1 mg to about 500 mg of active ingredient.
  • they are administered at a dose of 5-250 mg/kg body weight/day, preferably 25-150 mg/kg body weight/day.
  • administration refers to providing a therapeutically effective amount of a drug to an individual.
  • the administration methods include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, supradural, intraocular, and intracranial, Inhalation, rectum, vagina, etc.
  • Dosage forms include ointment, lotion, tablet, capsule, pill, dispersible powder, granule, suppository, pill, lozenge, injection, sterile solution or non-aqueous solution, suspension, emulsion, patch ⁇ etc.
  • Active ingredients and non-toxic pharmaceutically acceptable carriers such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea) , Dextran, etc.
  • non-toxic pharmaceutically acceptable carriers such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea
  • the preferred route of administration will vary with clinical characteristics, and the dose must vary depending on the condition of the patient being treated. The doctor will determine the appropriate dose according to the individual patient.
  • the therapeutically effective amount per unit dose depends on body weight, physiological function and the chosen vaccination schedule.
  • the compound per unit dose refers to the weight of the compound per administration, excluding the weight of the carrier (the drug contains the carrier).
  • the pharmaceutical composition provided by the present invention can be formulated for single-dose or multiple-dose administration.
  • the single-dose preparation is packaged in ampoules, vials or syringes.
  • the multi-dose parenteral preparation must contain an antimicrobial agent in a bacteriostatic or fungicidal concentration. All parenteral preparations must be sterile, as known and practiced in the art.
  • the pharmaceutical composition provided by the present invention can be formulated with other active ingredients that will not impair the expected therapeutic effect, or with a substance that supplements the expected effect.
  • the treatment method of the present invention includes administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need.
  • Various embodiments of the present invention include the treatment of the diseases mentioned in the present invention by administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need.
  • the compound of the present invention or a pharmaceutical composition containing the compound of the present invention may be administered at one time, or according to a dosage regimen, administered several times at different time intervals within a specified period of time. For example, it may be administered once, twice, three or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, it is administered twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely.
  • the appropriate dosage regimen of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, which can be determined by the skilled person.
  • the appropriate dosage regimen of the compound of the present invention or the pharmaceutical composition containing the compound of the present invention depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated , The medical history of the patient being treated, the nature of the simultaneous therapy, the desired treatment effect and other factors within the scope of the knowledge and experience of the technicians. Such technicians should also understand that the response of the individual patient to the dosing regimen, or when the individual patient's needs change over time, may require adjustment of the appropriate dosing regimen.
  • the compounds of the invention may be administered simultaneously with, or before or after, one or more other therapeutic agents.
  • the compound of the present invention and other therapeutic agents can be administered separately through the same or different administration routes, or they can be administered in the same pharmaceutical composition. This is selected by those skilled in the art according to the actual physical conditions of the patient, such as the health, age, and weight of the patient. If formulated as a fixed dose, this combination product uses the compound of the present invention (within the dosage range described in the present invention) and other pharmaceutically active agents (within the dosage range).
  • the present invention includes a combination drug, which includes a certain amount of at least one compound of the present invention or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof and an effective amount of one or more of the above Additional therapeutic agent.
  • the compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) can be used in the prevention, treatment or alleviation of formula (I), (II),
  • the compound shown in (III), (IV), (V), (VI) or (VII) is used in combination with other drugs for diseases or symptoms.
  • These other drugs can be administered simultaneously or sequentially with the compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) through their usual routes and amounts.
  • the compounds described in the present invention are combined with other drugs to provide a combination therapy for chronic obstructive pulmonary disease (COPD), atopic dermatitis (AD), psoriasis, or other conditions.
  • COPD chronic obstructive pulmonary disease
  • AD atopic dermatitis
  • psoriasis or other conditions.
  • the pharmaceutical composition of the present invention includes at least one of the PDE4 inhibitors described in the present invention and an additional therapeutic agent. Examples of the additional therapeutic agent include but are not limited to:
  • ⁇ 2-agonists such as salbutamol, formoterol, salmeterol and camoxirol
  • Corticosteroids such as budesonide, beclomethasone dipropionate, fluticasone propionate, flunisolide, mometasone furoate, rofluonide, ciclesonide, fluocinolone acetate, deshydroxyl Methamasone, mometasone, triamcinolone, betamethasone, aclomethasone, dessonide, hydrocortisone, mepaclione;
  • Anticholinergic drugs or antimuscarinic drugs such as ipratropium bromide, oxytropium bromide, tiotropium bromide, glycopyrrolate, and revatorate;
  • Topical preparations of PDE4 inhibitors such as apremilast, ibudilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, crexabor;
  • JAK kinase inhibitors such as tofacitinib, JTE-052, baritinib, and upatinib;
  • Local non-steroidal anti-inflammatory drugs such as WBI-1001, MRX-6;
  • Injectable anti-IL4, IL-31, IL-22, IL-33, IL-12, IL-23, IL-17, IgE, IL-4 therapeutic drugs such as Dupilumab (Dupilumab), Jinlizumab, Nemolizumab, troroginumab, etanercept, adalimumab, infliximab, utekizumab, Secukinumab ), Omazumilab, CIM-331;
  • Vitamin D analogs such as calcipotriol and calcitriol
  • Oral liver X receptor (LXR) selective agonist such as VTP-38543;
  • Oral H4 receptor antagonists such as ZPL-389;
  • Oral NK1 receptor antagonists such as aprepitant and tripipitant
  • Oral CRTH2 receptor antagonists such as Fevipiprant and OC-459;
  • Oral chymotrypsin inhibitors such as SUN 13834.
  • the compound represented by formula (I) or formula (II) administered alone or in combination with other active ingredients is used to prevent and/or treat respiratory diseases or skin inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), Atopic dermatitis (AD) or psoriasis.
  • COPD chronic obstructive pulmonary disease
  • AD Atopic dermatitis
  • psoriasis psoriasis
  • the treatment method comprising the administration of the compound or pharmaceutical composition of the present invention further includes the administration of other anti-chronic obstructive pulmonary disease (COPD) or atopic dermatitis drugs (combination therapy) to the patient, wherein other anti-chronic obstructive pulmonary disease (COPD) or atopic dermatitis are the drugs among the above-mentioned additional therapeutic agents or their combinations.
  • COPD anti-chronic obstructive pulmonary disease
  • atopic dermatitis drugs are the drugs among the above-mentioned additional therapeutic agents or their combinations.
  • the present invention provides a method for treating lung disease (for example, COPD, asthma or fibrocyst) or inflammation (for example, atopic dermatitis or psoriasis) in a patient in need of such treatment, the method comprising a combination of administering to the patient a therapeutically effective Amount of at least one compound represented by formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, and at least one compound selected from the following: steroids (such as glucocorticoids), calcium Regulating phosphatase inhibitors, PDE4 inhibitors, JAK kinase inhibitors, cysteyl leukotriene antagonists, non-steroidal anti-inflammatory drugs, topical ROR agents, anti-IL4 antibodies, IL-31 antibodies, IL-22 antibodies, IL-33 antibody, IL-12 antibody, IL-23 antibody, IL-17 antibody, IgE antibody, IL-4 antibody, vitamin D analog, liver X receptor (LXR) selective agonist, histamine
  • the compound of the present invention or the amount of the compound in the composition of the present invention can effectively and detectably antagonize PDE4 to treat the following diseases: pain (for example, acute pain, acute inflammatory pain, chronic inflammatory pain and neuropathic pain), acute inflammation , Chronic inflammation, psoriatic arthritis, rheumatoid arthritis, psoriasis, proliferative and inflammatory skin diseases (e.g.
  • atopic dermatitis atopic dermatitis, seborrheic dermatitis, contact dermatitis), asthma, chronic obstructive pulmonary disease (COPD) ), arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxin shock, Gram-negative bacterial sepsis, glomerulonephritis, Parkinson's disease, Alzheimer's disease Zheimer's disease, mild cognitive impairment (MCI), depression, anxiety, acute respiratory distress syndrome, osteoarthritis, ankylosing spondylitis, multiple sclerosis, gingivitis, periodontitis, pruritus, Herpes, CNS tumors, interstitial pneumonia, allergies, crystal-induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, acute respiratory distress syndrome, pulmonary hypertension , Gout, alcoholic liver disease, lupus, cancer, allergic rhinitis
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, and the substituents are defined as formula (I), (II), (III), (IV), (V) , (VI) or (VII).
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by refluxing and drying with sodium metal.
  • Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried in advance with anhydrous sodium sulfate.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
  • the glassware is all dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh
  • the test conditions for proton nuclear magnetic resonance spectroscopy are: Bruker 400MHz or 600MHz nuclear magnetometer at room temperature, with CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (reported in ppm) , Use TMS (0ppm) or chloroform (7.26ppm) as the reference standard.
  • MS mass spectrometry
  • the compound purity is characterized by: Agilent 1260 Pre-HPLC or Calesep Pump 250 Pre-HPLC (Column Model: NOVASEP, 50/80mm, DAC), at 210nm /254nm is detected by UV.
  • Important intermediate M-4 can be prepared by the synthetic intermediates obtained, wherein, unless otherwise stated, R 2 and R a have the meanings as described in this invention.
  • the starting material M-1 and the material BnOH undergo a rearrangement reaction under the conditions of a weak base and diphenyl azide phosphate to form an amino protective group to obtain intermediate M-2.
  • Intermediate M-2 is reduced by catalytic hydrogenation to obtain intermediate M -3,
  • Intermediate M-3 undergoes diazotization reaction, and then undergoes substitution reaction with KI to obtain intermediate M-4.
  • the target compound S-8 can be prepared by synthetic method 1, where X represents a halogen atom, R x is -NH 2 or -OH, and R xo is -NH- or -O-, unless otherwise specified, A ring, R 2 , R a , R b , R m , R n , p and n have the meanings as described in the present invention.
  • Compound S-1 undergoes enolization reaction under alkaline conditions (such as DIPEA or TEA, etc.) and then undergoes substitution reaction to obtain compound S-2.
  • Compound S-2 and compound S'-2 undergo boronation under alkaline conditions Compound S-3 is obtained by the reaction.
  • Compound S-3 and intermediate M-4 undergo Suzuki coupling reaction under coupling reagent conditions to obtain compound S-4.
  • Compound S-4 is catalytically hydrogenated to obtain compound S-5, and compound S- 5 Remove the Boc protective group under acidic conditions, and then undergo acylation to obtain compound S-6.
  • Compound S-6 undergoes ester hydrolysis under alkaline conditions to obtain compound S-7, compound S-7 and compound S'- 7 Under the action of a suitable condensing agent, the target compound S-8 is obtained by condensation reaction.
  • S-11 target compound can be obtained by preparing two synthetic methods, wherein, R x is -NH 2 or -OH, R xo is -NH- or -O-, unless stated otherwise, A ring, R 2, R a, R e , R f , R m , R n and p have the meanings as described in the present invention.
  • Compound S-7 and compound S"-7 undergo condensation reaction under the action of a suitable condensing agent to obtain compound S-9, compound S-9 undergoes ester hydrolysis under alkaline conditions to obtain compound S-10, compound S-10 and Compound S'-10 undergoes condensation reaction under the action of a suitable condensing agent to obtain the target compound S-11.
  • Step 1 Synthesis of the compound (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) benzyl carbamate
  • Benzyl (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)carbamate (145mg, 0.45mmol) was dissolved in anhydrous methanol (6mL), and palladium on carbon was added (50mg), the air was removed, and hydrogen was introduced to react at room temperature for 2 hours.
  • the catalyst was removed by suction filtration with diatomaceous earth, and the filtrate was concentrated to obtain 102 mg of light red liquid with a yield of 98%.
  • Step 1 Synthesis of compound ethyl 6-(((tert-butoxycarbonyl)amino)methyl)picolinate
  • Step 3 Synthesis of tert-butyl ((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)carbamate
  • Step 4 Synthesis of 6-(aminomethyl)-N,N-lutidine amide dihydrochloride
  • Step 1 Synthesis of the compound methyl N-(3-((tert-butoxycarbonylamino)methyl)phenyl)carbamate
  • Step 1 Synthesis of compound ((6-bromopyridin-2-yl)methyl) t-butyl carbamate
  • Step 1 Synthesis of compound ethyl 6-(((tert-butoxycarbonyl)amino)methyl)picolinate
  • Step 3 Synthesis of compound ((6-((4,4-difluorocyclohexyl)(methyl)formamido)pyridin-2-yl)methyl) carbamate
  • Step 4 Synthesis of compound 6-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide dihydrochloride
  • Step 1 Synthesis of compound ((6-((4-fluorophenyl)(methyl)formamido)pyridin-2-yl)methyl) carbamate
  • Step 4 Synthesis of compound N-(5-bromo-2-(difluoromethoxy)-4-(methylsulfonyl)phenyl)-N-(cyclopropylmethyl)hydroxylamine
  • Step 1 Synthesis of compound tert-butyl cyclopropyl methyl carbamate
  • Step 2 Synthesis of compound (cyclopropylmethyl)(methyl) t-butyl carbamate
  • Step 1 Synthesis of compound 2,4-difluorobenzyl carbamate tert-butyl ester
  • Step 2 Synthesis of compound (2,4-difluorobenzyl)(methyl) t-butyl carbamate
  • Step 1 Synthesis of compound (pyridin-2-ylmethyl) tert-butyl carbamate
  • Step 2 Synthesis of compound tert-butyl N-methyl-(pyridin-2-ylmethyl)carbamate
  • Step 1 Synthesis of compound ((6-(hydroxymethyl)pyridin-2-yl)methyl) t-butyl carbamate
  • Step 2 Synthesis of compound ((6-formylpyridin-2-yl)methyl) t-butyl carbamate
  • Step 3 Synthesis of compound ((6-(((4,4-difluorocyclohexyl)amino)methyl)pyridin-2-yl)methyl) carbamate
  • Step 4 Synthesis of compound ((6-((N-(4,4-difluorocyclohexyl)acetamido)methyl)pyridin-2-yl)methyl) carbamate
  • Step 5 Synthesis of compound N-((6-(aminomethyl)pyridin-2-yl)methyl)-N-(4,4-difluorocyclohexyl)acetamide dihydrochloride
  • Step 1 Synthesis of methyl 3-oxoisoindoline-5-carboxylate
  • Step 2 Synthesis of methyl 2-methyl-3-oxoisoindoline-5-carboxylate
  • Step 1 Synthesis of methyl 1-oxoisoindoline-5-carboxylate
  • Step 2 Synthesis of methyl 2-methyl-1-oxoisoindoline-5-carboxylate
  • Step 1 Synthesis of compound 6-(p-tolylcarbamoyl) methyl picolinate
  • Step 2 Synthesis of compound 6-(hydroxymethyl)-N-(p-tolyl)pyridine amide
  • Step 1 Synthesis of compound 6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridinecarboxylic acid methyl ester
  • Example 1 Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluoro Benzyl)pyrrolidine-2-carboxamide
  • Step 1 Compound (R)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylic acid Synthesis of esters
  • Step 2 Compound (R)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H Synthesis of -pyrrole-1,2(2H,5H)-dicarboxylate
  • Step 3 Compound (R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1, Synthesis of 2(2H,5H)-dicarboxylate
  • Step 4 Compound (2R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2- Synthesis of dicarboxylic acid esters
  • Step 5 Synthesis of compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
  • Step 6 Synthesis of compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester
  • Step 7 Synthesis of compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid
  • Step 8 Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl) Of pyrrolidine-2-carboxamide
  • Example 2 Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluoro Benzyl)pyrrolidine-2-carboxamide
  • Step 1 Compound (S)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylic acid Synthesis of esters
  • Step 2 Compound (S)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H Synthesis of -pyrrole-1,2(2H,5H)-dicarboxylate
  • Step 3 Compound (S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1, Synthesis of 2(2H,5H)-dicarboxylate
  • Step 4 Compound (2S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2- Synthesis of dicarboxylic acid esters
  • Step 5 Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
  • Step 6 Synthesis of compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester
  • Step 7 Synthesis of compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid
  • Step 8 Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl) Of pyrrolidine-2-carboxamide
  • Example 3 Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(pyridin-2-ylmethyl Yl)pyrrolidine-2-carboxamide
  • Example 5 Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methan Yl) ethyl pyridinecarboxylate
  • Step 1 Compound (R)-1-tert-butyl 2-methyl 4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H ,5H)-Dicarboxylic acid ester synthesis
  • Step 3 Compound (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2- Synthesis of methyl carboxylate
  • Step 4 Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid methyl ester
  • Step 5 Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester
  • Step 6 Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid
  • Step 7 Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methyl ) Synthesis of ethyl picolinate
  • N,N-diisopropylethylamine (58mg, 2.77 mmol)
  • Example 6 Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methan Yl)pyridinecarboxylic acid hydrochloride
  • the pH of the solution was adjusted to 1, the solvent was removed under reduced pressure, the residue was extracted with ethyl acetate (10 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 55 mg of a pale yellow solid with a yield of 98%.
  • Example 7 Compound 3-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methan Yl) methyl benzoate
  • Example 8 Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methan Base) benzoic acid
  • Example 11 Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-ethoxybenzyl) Yl)pyrrolidine-2-carboxamide
  • Example 12 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-dimethylnicotinamide
  • Step 1 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (Amino) Methyl) Methyl Nicotinate
  • Step 2 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)nicotinic acid
  • Step 3 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)-N,N-dimethylnicotinamide
  • Example 13 Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((4-(1- (Hydroxyethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
  • Example 14 Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(1- (Hydroxyethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
  • Example 15 The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(hydroxymethyl (Yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
  • Example 16 Compound (3-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Carboxamido) methyl) phenyl) methyl carbamate
  • Example 17 Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((pyrimidin-2-yl )Methyl)pyrrolidine-2-carboxamide
  • Example 18 The compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(1- (Hydroxyethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
  • Step 1 Synthesis of (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid
  • Step 2 (2S)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(1-hydroxyethyl (Yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
  • Example 19 Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((4-(hydroxymethyl (Yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
  • Example 20 The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((4-(2- Hydroxypropyl-2-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
  • Example 22 The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(2- Hydroxypropyl-2-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
  • Step 2 Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxylic acid synthesis
  • Step 3 Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((4-(2-hydroxypropan-2-yl )Pyridin-2-yl)methyl)-1-(methylsulfonyl)pyrrolidine-2-carboxamide
  • Example 24 The compound (2R)-1-acetyl-N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-4-(3-(cyclopropyl) Methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamide
  • Step 1 Compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido Synthesis of )-2-(2,4-difluorophenyl) ethyl acetate
  • Step 2 Compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido )-2-(2,4-Difluorophenyl)acetic acid synthesis
  • Step 3 Compound (2R)-1-acetyl-N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-4-(3-(cyclopropyl) Synthesis of methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamide
  • Example 25 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-lutidineamide
  • Example 26 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)picolinic acid
  • Step 1 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)ethyl picolinate
  • Step 2 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)picolinic acid
  • Example 27 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)pyridine amide
  • Example 28 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-picolineamide
  • Example 29 Compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-dimethylisonicotinamide
  • Step 1 Compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)isonicotinate methyl ester
  • Step 2 Compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)isonicotinic acid
  • Step 3 Compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)-N,N-dimethylisonicotinamide
  • Example 30 Compound 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl )-N,N-lutidine amide dihydrochloride
  • Step 1 Compound (2R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid Synthesis
  • Step 2 Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((6-(dimethylcarbamoyl) Synthesis of (pyridin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 3 Compound 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl) Synthesis of -N,N-lutidine amide dihydrochloride
  • Example 31 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-ethylpyrrolidine-2-formyl (Amino) methyl) -N,N-lutidine amide and
  • Example 31 And Example 32:
  • Example 33 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl (Acylamino)methyl)-N-ethylpyridineamide
  • Example 34 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-diethylpyridineamide
  • Example 35 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-dipropylpyridineamide
  • Example 36 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-methyl-N-n-propylpyridineamide
  • Example 37 Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(3-(dimethyl Formamide) benzyl) pyrrolidine-2-carboxamide
  • Step 1 Compound 3-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)methyl benzoate
  • Step 2 Compound 3-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)benzoic acid
  • Step 3 Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(3-(dimethylform) (Amide)benzyl)pyrrolidine-2-carboxamide
  • Example 38 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-diisopropylpyridineamide
  • Example 39 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-ethyl-N-picolineamide
  • Example 40 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-di-n-butylpyridine amide
  • Example 41 Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(2-(dimethylamino)ethyl)-N-picolineamide
  • Example 42 Compound 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-propionylpyrrolidine-2-methyl Amido)methyl)-N,N-lutidineamide

Abstract

Disclosed are a substituted pyrrolidine compound and the use thereof in medicine. In particular, disclosed are a substituted pyrrolidine compound or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutical composition containing the above-mentioned compound. Also disclosed is the use of the above-mentioned compound or the pharmaceutical composition thereof in the preparation of a drug, the drug being used to treat PDE4-related diseases, such as atopic dermatitis (AD) or chronic obstructive pulmonary disease (COPD).

Description

取代的吡咯烷类化合物及其在药物中的应用Substituted pyrrolidine compounds and their application in medicine
相关申请Related application
本申请要求中国专利申请号为202010354590.3的优先权，该申请于2020年4月29日递交至国家知识产权局；要求中国专利申请号为202010523655.2的优先权，该申请于2020年06月10日递交至国家知识产权局，其所有内容在此作为引用并入本文。This application claims the priority of Chinese patent application number 202010354590.3, which was submitted to the State Intellectual Property Office on April 29, 2020; requires the priority right of Chinese patent application number 202010523655.2, which was filed on June 10, 2020 To the State Intellectual Property Office, all its contents are incorporated herein by reference.
技术领域Technical field
本发明属于药物领域，具体涉及一类取代的吡咯烷类化合物、包含所述化合物的药物组合物及其用途和使用方法。特别地，本发明所述的化合物是PDE4抑制剂，用于治疗PDE4相关的疾病，例如特应性皮炎(AD)、银屑病或慢性阻塞性肺病(COPD)。The invention belongs to the field of medicine, and specifically relates to a class of substituted pyrrolidine compounds, pharmaceutical compositions containing the compounds, and uses and methods of use thereof. In particular, the compounds of the present invention are PDE4 inhibitors, which are used to treat PDE4-related diseases, such as atopic dermatitis (AD), psoriasis or chronic obstructive pulmonary disease (COPD).
背景技术Background technique
环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)是细胞内两种重要的第二信使，主要通过激活蛋白激酶A(PKA)和蛋白激酶G(PKG)途径参与能量代谢、记忆、免疫反应、视觉及嗅觉形成等生理活动，其细胞内浓度的调节主要由腺(鸟)苷酸环化酶的合成和磷酸二酯酶(PDEs)的水解作用之间的平衡决定。PDEs能特异性地以3,5-环核苷酸为底物，催化细胞内的cGMP和cAMP水解生成相应的无活性的5-核苷酸，从而影响生物体的各种代谢功能。因此，抑制PDEs对引起许多细胞活性是一种很有效的途径，能影响炎症细胞和免疫细胞活化及平滑肌细胞收缩反应。Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are two important second messengers in cells, which are mainly involved in energy metabolism, memory and immunity by activating protein kinase A (PKA) and protein kinase G (PKG) pathways. For physiological activities such as reaction, vision and olfactory formation, the adjustment of its intracellular concentration is mainly determined by the balance between the synthesis of adenylate cyclase and the hydrolysis of phosphodiesterase (PDEs). PDEs can specifically use 3,5-cyclic nucleotides as substrates to catalyze the hydrolysis of cGMP and cAMP in cells into corresponding inactive 5-nucleotides, thereby affecting various metabolic functions of organisms. Therefore, inhibiting PDEs is a very effective way to cause many cell activities, which can affect the activation of inflammatory cells and immune cells and the contraction response of smooth muscle cells.
磷酸二酯酶(PDEs)迄今已报道有11个基因家族，每个家族又包括多个亚家族。PDEs分布于多个组织中，其抑制剂具有广泛的生理作用，其中PDE4、PDE7和PDE8主要特异性水解cAMP，PDE5、PDE6和PDE9特异性水解cGMP，而PDE1、PDE2、PDE3、PDE10和PDE11则对cAMP和cGMP都起作用。其中PDE4主要分布于各种炎性细胞内，其组织分布说明它与中枢神经系统和免疫系统息息相关，其抑制剂可用于治疗各种疾病，包括过敏性和炎性疾病、糖尿病、中枢神经系统疾病和疼痛。Phosphodiesterases (PDEs) have reported 11 gene families so far, and each family includes multiple subfamilies. PDEs are distributed in multiple tissues, and their inhibitors have a wide range of physiological effects. Among them, PDE4, PDE7 and PDE8 mainly specifically hydrolyze cAMP, PDE5, PDE6 and PDE9 specifically hydrolyze cGMP, while PDE1, PDE2, PDE3, PDE10 and PDE11 are It works on both cAMP and cGMP. Among them, PDE4 is mainly distributed in various inflammatory cells. Its tissue distribution shows that it is closely related to the central nervous system and immune system. Its inhibitors can be used to treat various diseases, including allergic and inflammatory diseases, diabetes, and central nervous system diseases. And pain.
目前，对PDE4的研究主要集中在免疫及炎症相关疾病中，世界上许多著名的制药公司都把PDE4作为慢性炎症相关疾病的靶点。PDE4抑制剂发挥抗炎作用主要通过以下几种途径：(1)抑制多种炎症介质的活性；(2)抑制细胞黏附因子的上调和表达；(3)抑制血白细胞的活化；(4)诱导细胞凋亡；(5)诱导具有抑制活性的细胞因子的生成(如白细胞介素-6)；(6)诱导儿茶酚胺类物质和内源性激素的释放。第一代PDE4抑制剂主要有茶碱、咯利普兰(Rolipram)和吡拉米司特(Piclamilast)等，咯利普兰对神经系统疾病，如帕金森病、抑郁症和焦虑等都具有一定的治疗作用。但第一代PDE4抑制剂由于严重的恶心、呕吐等副作用，在临床上的应用受到了限制；第二代PDE4抑制剂有罗氟司特(Roflumilast)和西洛司特(Cilomilast)等，其中罗氟司特用于COPD的治疗，对其他炎症性疾病也有一定的治疗效果，如溃疡性结肠炎和克罗恩病。第三代PDE4抑制剂阿普斯特(Apremilast)已经用于自身免疫性疾病如银屑病的治疗，且副作用更小，病人更易耐受。WO/2000/064260披露了PDE4抑制剂Ro 20-1724 1％霜剂治疗银屑病有效。WO 2000/009504披露了另一个PDE4抑制剂CP-80633(0.5％软膏)，其明显的改善了特应性皮炎的临床计分(红斑、硬结和表皮脱落)。但是，临床上仍需要更多的可以有效治疗特应性皮炎的PDE4抑制剂。At present, research on PDE4 is mainly focused on immune and inflammation-related diseases. Many well-known pharmaceutical companies in the world use PDE4 as a target for chronic inflammation-related diseases. PDE4 inhibitors exert anti-inflammatory effects mainly through the following ways: (1) inhibit the activity of a variety of inflammatory mediators; (2) inhibit the up-regulation and expression of cell adhesion factors; (3) inhibit the activation of white blood cells; (4) induce Apoptosis; (5) Induces the production of inhibitory cytokines (such as interleukin-6); (6) Induces the release of catecholamines and endogenous hormones. The first-generation PDE4 inhibitors mainly include theophylline, Rolipram and Piclamilast, etc. Rolipram has certain effects on neurological diseases, such as Parkinson’s disease, depression and anxiety. Therapeutic effect. However, the first-generation PDE4 inhibitors have limited clinical application due to severe nausea, vomiting and other side effects; the second-generation PDE4 inhibitors include Roflumilast and Cilomilast, among which Roflumilast is used in the treatment of COPD and has certain therapeutic effects on other inflammatory diseases, such as ulcerative colitis and Crohn's disease. The third-generation PDE4 inhibitor, Apremilast, has been used in the treatment of autoimmune diseases such as psoriasis, and has fewer side effects and is easier for patients to tolerate. WO/2000/064260 discloses that the PDE4 inhibitor Ro 20-1724 1% cream is effective in treating psoriasis. WO 2000/009504 discloses another PDE4 inhibitor CP-80633 (0.5% ointment), which significantly improves the clinical scoring of atopic dermatitis (erythema, induration and exfoliation). However, there is still a clinical need for more PDE4 inhibitors that can effectively treat atopic dermatitis.
发明概要Summary of the invention
以下仅概括说明本发明的一些方面，并不局限于此。这些方面和其他部分在后面有更完整的说明。本说明书中的所有参考文献通过整体引用于此。当本说明书的公开内容与引用文献有差异时，以本说明书的公开内容为准。The following only summarizes some aspects of the present invention, and is not limited thereto. These aspects and other parts are explained more fully later. All references in this specification are hereby quoted in their entirety. When there is a discrepancy between the disclosure content of this specification and the cited documents, the disclosure content of this specification shall prevail.
本发明提供了一类具有4型磷酸二酯酶(Phosphodiesterase-4,PDE4)抑制活性的化合物，用于制备预防、治疗或减轻与PDE4有关的呼吸疾病、过敏、炎症、中枢神经系统疾病或非胰岛素依赖糖尿病的药物，比如慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症；其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎、闭塞性细支气管炎、过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎等；本发明化合物能够很好地抑制PDE4，同时具有优良的理化性质以及药代动力学性质。The present invention provides a class of compounds with type 4 phosphodiesterase (Phosphodiesterase-4, PDE4) inhibitory activity for the preparation of prevention, treatment or alleviation of PDE4 related respiratory diseases, allergies, inflammations, central nervous system diseases or non- Insulin-dependent diabetes drugs, such as chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or respiratory tract Inflammation; among which bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis, bronchiolitis obliterans, allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid Arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis, etc.; the compound of the present invention can inhibit PDE4 well, and at the same time has excellent Physical and chemical properties and pharmacokinetic properties.
本发明也提供了这些化合物的制备方法和包含这些化合物的药物组合物以及使用这些化合物或组合物治疗哺乳动物，尤其是人类的上述疾病的方法。The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds or compositions to treat the above-mentioned diseases in mammals, especially humans.
具体地说：Specifically:
一方面，本发明涉及一种如式(I)所示的化合物或式(I)所示化合物的立体异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或它们的前药，In one aspect, the present invention relates to a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of the compound represented by formula (I), Pharmaceutically acceptable salts or their prodrugs,
Figure PCTCN2021090489-appb-000001
Figure PCTCN2021090489-appb-000001
其中：in:
X为CH或N；X is CH or N;
Y为-(CH 2) m-C(＝O)-NH-(CR mR n) p-或-(CH 2) m-C(＝O)-O-(CR mR n) p-； Y is -(CH 2 ) m -C(=O)-NH-(CR m R n ) p -or -(CH 2 ) m -C(=O)-O-(CR m R n ) p -;
A环为C 6-10芳基或5-10个原子组成的杂芳基； Ring A is a C 6-10 aryl group or a heteroaryl group composed of 5-10 atoms;
R 1为氢、氘、-OR a或-NR cR d； R 1 is hydrogen, deuterium, -OR a or -NR c R d ;
R 2为C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、C 3-6环烷基-C 1-4烷基、5-7个原子组成的杂环基或(5-7个原子组成的杂环基)-C 1-4烷基；或 R 2 is a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyl group-C 1-4 alkyl group, a heterocyclic group composed of 5-7 atoms Cyclic group or (heterocyclic group consisting of 5-7 atoms) -C 1-4 alkyl; or
R 2与R a和其相连的原子共同形成5-7个原子组成的杂环基，所述的5-7个原子组成的杂环基任选地被选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷基的取代基所取代； And R a and R 2 which together form a 5-7 atom heterocyclic group of atoms, said heterocyclic group consisting of 5-7 atoms optionally substituted selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl substituents;
R 3为氢、氘、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 1-6烷基-C(＝O)-、HC(＝O)-、C 1-6烷基-O-C(＝O)-、C 1-6烷基-S(＝O) 2-或C 1-6烷基-C(＝NH)-，其中所述的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 1-6烷基-C(＝O)-、C 1-6烷基-O-C(＝O)-、C 1-6烷基-S(＝O) 2-和C 1-6烷基-C(＝NH)-各自独立任选地被1、2或3个选自氘、F、Cl、Br、I、-OH、-CN或-NH 2的取代基所取代； R 3 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-C(=O)-, HC(=O)-, C 1-6 alkyl-OC(=O)-, C 1-6 alkyl-S(=O) 2 -or C 1-6 alkyl-C(=NH)-, Wherein said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-C(=O)-, C 1- 6 alkyl-OC(=O)-, C 1-6 alkyl-S(=O) 2 -and C 1-6 alkyl-C(=NH)- each independently optionally by 1, 2 or 3 Substituted by a substituent selected from deuterium, F, Cl, Br, I, -OH, -CN or -NH 2;
R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8和R 9各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、C 1-4烷基-C(＝O)-或C 1-4烷基-S(＝O) 2-； R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 and R 9 are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 ,- NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, C 1-4 alkyl-C(=O)- or C 1-4 alkyl -S(=O) 2 -;
R a为氢、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基，其中所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或5-10个原子组成的杂环基的取代基所取代； R a is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclic group composed of 5-10 atoms, C 6- 10 aryl groups or heteroaryl groups composed of 5-10 atoms, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 5- 10-atom heterocyclic group, C 6-10 aryl group and 5-10 atom heteroaryl group are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 5-10 atoms Substituted by the substituent of the cyclic group;
各R b独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基-OC(＝O)-、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-8环烷基-C 1-6烷基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基、5-10个原子组成的杂芳基、-NR eC(＝O)C 1-6烷基、-NR eR f、-S(＝O) 2-NR eR f、-C(＝O)-NR eR f或-C 1-6烷基-NR eR f，其中所述的C 1-6烷基、C 1-6烷氧基、C 3-8环烷基-C 1-6烷基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-6烷基、C 1-6烷氨基或C 1-6烷氧基的取代基所取代； Each R b is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, oxo, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkyl-OC(=O)-, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-S(=O) 2 -, C 3-8 cycloalkane -C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 heterocyclic group, C 6-10 aryl, 5-10 heteroaryl, -NR e C (=O)C 1-6 alkyl, -NR e R f , -S(=O) 2 -NR e R f , -C(=O)-NR e R f or -C 1-6 alkyl- NR e R f , wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 A heterocyclic group composed of three atoms, a C 6-10 aryl group and a heteroaryl group composed of 5-10 atoms are each independently optionally selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-6 alkyl, C 1-6 alkylamino or C 1-6 alkoxy substituents;
R c和R d各自独立地为氢、-OH、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基-C 1-4烷基、C 3-6环烷基、5-7个原子组成的杂环基、(5-7个原子组成的杂环基)-C 1-4烷基、C 1-4烷基-C(＝O)-或C 1-4烷基-S(＝O) 2-； R c and R d are each independently hydrogen, -OH, C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 ring Alkyl group, heterocyclic group composed of 5-7 atoms, (heterocyclic group composed of 5-7 atoms) -C 1-4 alkyl, C 1-4 alkyl -C(=O)-or C 1 -4 alkyl-S(=O) 2 -;
R e和R f各自独立地为氢、C 1-6烷基、C 1-6烷基-OC(＝O)-、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-8环烷基、C 6-10芳基、5-10个原子组成的杂环基、5-10个原子组成的杂芳基、11-15个原子组成的杂芳基、C 3-8环烷基-C 1-6烷基、C 6-10芳基-C 1-6烷基、(5-10个原子组成的杂环基)-C 1-6烷基、(5-10个原子组成的杂芳基)-C 1-6烷基或-C 1-6烷基-NR gR j；或者R e和R f与它们相连的N原子一起形成4-7个原子组成的杂环基；其中所述的R e、R f和4-7个原子组成的杂环基各自独立任选地被1、2、3或4个R h所取代； R e and R f are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl-OC(=O)-, C 1-6 alkyl-C(=O)-, C 1-6 Alkyl-S(=O) 2 -, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 heterocyclic group, 5-10 heteroaryl, 11- Heteroaryl composed of 15 atoms, C 3-8 cycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl, (heterocyclic group composed of 5-10 atoms) -C 1-6 alkyl group, (heteroaryl group consisting of 5-10 atoms) -C 1-6 alkyl group or -C 1-6 alkyl group -NR g R j ; or R e and R f are connected to them The N atoms together form a heterocyclic group consisting of 4-7 atoms; wherein said R e , R f and a heterocyclic group consisting of 4-7 atoms are each independently optionally substituted by 1, 2, 3 or 4 Replaced by R h;
各R h独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基或C 1-4烷氧基； Each R h is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy or C 1 -4 alkoxy;
R g和R j各自独立地为氢、C 1-4烷基、C 1-4烷基-OC(＝O)-、C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 2-、C 3-6环烷基、C 6-10芳基、5-6个原子组成的杂环基或5-6个原子组成的杂芳基； R g and R j are each independently hydrogen, C 1-4 alkyl, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-C(=O)-, C 1-4 Alkyl-S(=O) 2 -, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 5-6 atoms or heteroaryl group consisting of 5-6 atoms;
R m和R n各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、C 1-4烷基、卤代C 1-4烷基或-C(＝O)NH 2； R m and R n are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, halo C 1-4 alkyl, or -C( =O)NH 2 ;
各n独立地为0、1、2、3或4；Each n is independently 0, 1, 2, 3, or 4;
m和p各自独立地为0、1、2或3。m and p are each independently 0, 1, 2, or 3.
在一些实施方案中，A环为苯基、萘基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、吲哚基、异吲哚基、
Figure PCTCN2021090489-appb-000002
Figure PCTCN2021090489-appb-000003
In some embodiments, the A ring is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazole Base, indolyl, isoindolyl,
Figure PCTCN2021090489-appb-000002
Figure PCTCN2021090489-appb-000003
在一些实施方案中，R 3为氢、氘、C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 1-4烷基-C(＝O)-、HC(＝O)-、C 1-4烷基-O-C(＝O)-、C 1-4烷基-S(＝O) 2-或C 1-4烷基-C(＝NH)-，其中所述的C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 1-4烷基-C(＝O)-、C 1-4烷基-O-C(＝O)-、C 1-4烷基-S(＝O) 2-和C 1-4烷基-C(＝NH)-各自独立任选地被1、2或3个选自氘、F、Cl、Br、I、-OH、-CN或-NH 2的取代基所取代。 In some embodiments, R 3 is hydrogen, deuterium, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl-C (=O)-, HC(=O)-, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-S(=O) 2 -or C 1-4 alkyl-C (=NH)-, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl-C(=O )-, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-S(=O) 2 -and C 1-4 alkyl-C(=NH)- each independently optionally 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH 2 to substituents.
在一些实施方案中，R a为氢、氘、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基，其中所述的C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、苯基和5-6个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或5-6个原子组成的杂环基的取代基所取代。 In some embodiments, R a is hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 hetero atoms Cyclic group, phenyl group or heteroaryl group consisting of 5-6 atoms, wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, The heterocyclic group composed of 5-6 atoms, the phenyl group and the heteroaryl group composed of 5-6 atoms are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or heterocyclic group consisting of 5-6 atoms The substituents are substituted.
在一些实施方案中，各R b独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、氧代、C 1-4 烷基、C 1-4烷氧基、C 1-4烷基-OC(＝O)-、C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 2-、C 3-6环烷基-C 1-4烷基、C 3-6环烷基、5-6个原子组成的杂环基、苯基、5-6个原子组成的杂芳基、-NR eC(＝O)C 1-4烷基、-NR eR f、-S(＝O) 2-NR eR f、-C(＝O)-NR eR f或-C 1-4烷基-NR eR f，其中所述的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基-C 1-4烷基、C 3-6环烷基、苯基、5-6个原子组成的杂环基和5-6个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-4烷基、C 1-4烷氨基或C 1-4烷氧基的取代基所取代；其中，各R e和R f具有如本发明所述的含义。 In some embodiments, each R b is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-C(=O)-, C 1-4 alkyl-S(=O) 2 -, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclic group composed of 5-6 atoms, phenyl group, heteroaryl group composed of 5-6 atoms, -NR e C(=O)C 1-4 alkyl, -NR e R f , -S(=O) 2 -NR e R f , -C(=O)-NR e R f or -C 1-4 alkane -NR e R f , wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 cycloalkyl, benzene Group, heterocyclic group consisting of 5-6 atoms and heteroaryl group consisting of 5-6 atoms are each independently optionally selected from deuterium, F, Cl, Br, I,- OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkylamino or C 1-4 alkoxy substituents; wherein each R e and R f has the meaning as described in the present invention.
在一些实施方案中，R e和R f各自独立地为氢、C 1-4烷基、C 1-4烷基-OC(＝O)-、C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 2-、C 3-6环烷基、C 6-10芳基、5-7个原子组成的杂环基、5-7个原子组成的杂芳基、14-15个原子组成的杂芳基、C 3-6环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、(5-7个原子组成的杂环基)-C 1-4烷基、(5-7个原子组成的杂芳基)-C 1-4烷基或-C 1-4烷基-NR gR j；或者R e和R f与它们相连的N原子一起形成4-6个原子组成的杂环基；其中所述的R e、R f和4-6个原子组成的杂环基各自独立任选地被1、2、3或4个R h所取代；其中各R h具有如本发明所述的含义。 In some embodiments, R e and R f are each independently hydrogen, C 1-4 alkyl, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-C(=O) -, C 1-4 alkyl-S(=O) 2 -, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group composed of 5-7 atoms, composed of 5-7 atoms Heteroaryl, heteroaryl composed of 14-15 atoms, C 3-6 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (5-7 atoms Heterocyclic group consisting of) -C 1-4 alkyl, (heteroaryl consisting of 5-7 atoms) -C 1-4 alkyl or -C 1-4 alkyl -NR g R j ; or R e And R f together with the N atom to which they are connected to form a heterocyclic group consisting of 4-6 atoms; wherein said R e , R f and heterocyclic group consisting of 4-6 atoms are each independently optionally divided by 1, Substitution with 2, 3 or 4 R h ; wherein each R h has the meaning as described in the present invention.
在一些实施方案中，R 2为甲基、乙基、正丙基、异丙基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CF 2CH 2CH 3、-CH 2Cl、-CHCl 2、环丙基、环丁基、环戊基、环己基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、四氢吡喃基甲基、四氢呋喃基甲基或吡咯烷基甲基；或 In some embodiments, R 2 is methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 ,- CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl,- CHCl 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, piperazinyl, piperidinyl, morpholinyl , Thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl or pyrrolidinylmethyl; or
R 2与R a和其相连的原子共同形成1,3-二氧杂环戊烯、1,3-二氧杂环己烯、2,3-二氢-1,4,2-二噁嗪烯或1,5,3-二氧氮杂环庚烯，所述的1,3-二氧杂环戊烯、1,3-二氧杂环己烯、2,3-二氢-1,4,2-二噁嗪烯或1,5,3-二氧氮杂环庚烯独立任选地被选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CHF 2、-CF 3、-CH 2CHF 2、-CH 2CF 3或-CF 2CH 3的取代基所取代。 R 2 and R a and its connected atoms together form 1,3-dioxole, 1,3-dioxene, 2,3-dihydro-1,4,2-dioxazine Alkene or 1,5,3-dioxazepine, the 1,3-dioxolene, 1,3-dioxolene, 2,3-dihydro-1, 4,2-Dioxazineene or 1,5,3-dioxazepine is independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF 3 or -CF 2 CH 3 substituents.
在一些实施方案中，R 3为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、HC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-O-C(＝O)-、乙基-O-C(＝O)-、正丙基-O-C(＝O)-、异丙基-O-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、甲基-C(＝NH)-、乙基-C(＝NH)-、正丙基-C(＝NH)-或异丙基-C(＝NH)-； In some embodiments, R 3 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy , N-propoxy, isopropoxy, vinyl, 1-propynyl, 2-propynyl, ethynyl, 1-propynyl, 3-propynyl, HC(=O)-, methyl-C (=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC(=O)-, ethyl -OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -, isopropyl-S(=O) 2 -, methyl-C(=NH)-, ethyl-C(=NH)-, n-propyl- C(=NH)- or isopropyl-C(=NH)-;
其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-O-C(＝O)-、乙基-O-C(＝O)-、正丙基-O-C(＝O)-、异丙基-O-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、甲基-C(＝NH)-、乙基-C(＝NH)-、正丙基-C(＝NH)-和异丙基-C(＝NH)-各自独立任选地被1、2或3个选自氘、F、Cl、Br、I、-OH、-CN或-NH 2的取代基所取代。 Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy Base, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, methyl-C(=O)-, ethyl-C(=O)-, N-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O )-, isopropyl-OC(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -, isopropyl Base -S(=O) 2 -, methyl-C(=NH)-, ethyl-C(=NH)-, n-propyl-C(=NH)- and isopropyl-C(=NH) - each independently is optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH 2 to a substituent group.
在一些实施方案中，R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8和R 9各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CF 2CH 2CH 3、-CH 2Cl、-CHCl 2、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-或异丙基-S(＝O) 2-。 In some embodiments, R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 and R 9 are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN , -NH 2 , -NO 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH 2 F,- CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 ,- CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , methyl-C(=O)-, ethyl-C(=O)-, n-propyl-C( =O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -or Isopropyl-S(=O) 2 -.
在一些实施方案中，R a为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、环丙基、环丁基、环戊基、环己基、哌嗪基、 哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基或噁唑基； In some embodiments, R a is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl , 2-propynyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thio Morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, Thiazolyl or oxazolyl;
其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基和噁唑基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基或吡咯烷基的取代基所取代。 The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl , Tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl and oxazolyl each independently Optionally by 1, 2, 3 or 4 selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, n-propyl, Isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, sulfur Substituted by morpholinyl, tetrahydropyranyl, tetrahydrofuranyl or pyrrolidinyl substituents.
在一些实施方案中，各R b独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、氧代、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、甲基-OC(＝O)-、乙基-OC(＝O)-、正丙基-OC(＝O)-、异丙基-OC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、环丙基甲基、环丙基乙基、环丙基正丙基、环丙基异丙基、环丁基甲基、环戊基甲基、环己基甲基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、-NR eC(＝O)甲基、-NR eC(＝O)乙基、-NR eC(＝O)正丙基、-NR eC(＝O)异丙基、-NR eR f、-S(＝O) 2-NR eR f、-C(＝O)-NR eR f、-甲基-NR eR f、-乙基-NR eR f、-正丙基-NR eR f或-异丙基-NR eR f；其中各R e和R f具有如本发明所述的含义。 In some embodiments, each R b is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, oxo, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl-OC(=O)-, Ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, ethyl-C(=O) -, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl- S(=O) 2 -, isopropyl-S(=O) 2 -, cyclopropylmethyl, cyclopropylethyl, cyclopropyl n-propyl, cyclopropyl isopropyl, cyclobutyl methyl, Cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, Tetrahydrofuryl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, -NR e C(=O) methyl, -NR e C(=O) ethyl, -NR e C(=O) n-propyl, -NR e C(=O) isopropyl, -NR e R f ,- S(=O) 2 -NR e R f , -C(=O)-NR e R f , -methyl-NR e R f , -ethyl-NR e R f , -n-propyl-NR e R f or -isopropyl-NR e R f ; wherein each of R e and R f has the meaning as described in the present invention.
其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基甲基、环丙基乙基、环丙基正丙基、环丙基异丙基、环丁基甲基、环戊基甲基、环己基甲基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基和噁唑基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、正丙基、异丙基、甲氨基、二甲氨基、甲氧基、乙氧基、正丙氧基或异丙氧基的取代基所取代。 Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy Cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl n-propyl, cyclopropyl isopropyl, cyclobutyl methyl, cyclopentyl methyl, cyclohexyl methyl, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazine Group, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl and oxazolyl are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, methylamino, dimethylamino, methoxy, ethoxy, N-propoxy or isopropoxy substituents.
在一些实施方案中，R c和R d各自独立地为氢、-OH、甲基、乙基、正丙基、异丙基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CF 2CH 2CH 3、-CH 2Cl、-CHCl 2、环丙基甲基、环丙基乙基、环丁基甲基、环戊基甲基、环己基甲基、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-或异丙基-S(＝O) 2-。 In some embodiments, R c and R d are each independently hydrogen, -OH, methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, methyl-C(=O)- , Ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(= O) 2 -, n-propyl-S(=O) 2 -or isopropyl-S(=O) 2 -.
在一些实施方案中，R e和R f各自独立地为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲基-OC(＝O)-、乙基-OC(＝O)-、正丙基-OC(＝O)-、异丙基-OC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、环丙基、环丁基、环戊基、环己基、苯基、萘基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、环丙基甲基、环丙基乙基、环丙基正丙基、环丙基异丙基、环丁基甲基、环戊基甲基、环己基甲基、苯甲基、苯乙基、5-7个原子组成的杂环基-C 1-4烷基、吡啶基甲基、嘧啶基甲基、呋喃基甲基、噻吩基甲基、吡咯基甲基、吡唑基甲基、咪唑基甲基、噻唑基甲基、噁唑基甲基、-甲基-NR gR j、-乙基-NR gR j、-正丙基-NR gR j、-异丙基-NR gR j或
Figure PCTCN2021090489-appb-000004
In some embodiments, R e and R f are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl- OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, ethyl Base-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -, isopropyl-S(=O) 2 -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, piperazine Alkyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrole Group, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl n-propyl, cyclopropyl isopropyl, cyclobutyl methyl, cyclopentyl methyl Group, cyclohexyl methyl, benzyl, phenethyl, 5-7 atoms heterocyclic group -C 1-4 alkyl, pyridyl methyl, pyrimidinyl methyl, furyl methyl, thienyl Methyl, pyrrolyl methyl, pyrazolyl methyl, imidazolyl methyl, thiazolyl methyl, oxazolyl methyl, -methyl -NR g R j , -ethyl -NR g R j , -normal Propyl-NR g R j , -isopropyl-NR g R j or
Figure PCTCN2021090489-appb-000004
或者R e和R f与它们相连的N原子一起形成氮杂环丁基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基或 哌嗪基； Or R e and R f together with the N atom to which they are connected form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
其中所述的R e、R f、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基和哌嗪基各自独立任选地被1、2、3或4个R h所取代；其中各R h具有如本发明所述的含义。 Wherein said R e , R f , azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently optionally substituted by 1, 2, 3 or 4 substituted with a R h; wherein each R h is as defined in the present invention.
在一些实施方案中，各R h独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、三氟甲氧基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； In some embodiments, each R h is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy , Sec-butoxy or tert-butoxy;
R g和R j各自独立地为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲基-OC(＝O)-、乙基-OC(＝O)-、正丙基-OC(＝O)-、异丙基-OC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、环丙基、环丁基、环戊基、环己基、苯基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基或噁唑基； R g and R j are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl-OC(=O)- , Ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, ethyl-C(=O) )-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl -S(=O) 2 -, isopropyl-S(=O) 2 -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, piperazinyl, piperidinyl, morpholinyl , Thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, Thiazolyl or oxazolyl;
R m和R n各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、甲基、乙基、正丙基、异丙基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2Cl、-CHCl 2或-C(＝O)NH 2。 R m and R n are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 Cl, -CHCl 2 or -C(=O)NH 2 .
另一方面，本发明涉及一种化合物，其为式(II)所示的化合物或式(II)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：In another aspect, the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (II) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
Figure PCTCN2021090489-appb-000005
Figure PCTCN2021090489-appb-000005
其中各X、Y、R 1、R 2、R 3、R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8、R 9、A、R a、R b和n具有本发明所述的含义。 Wherein each of X, Y, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 , R 9 , A, R a , R b and n has the The meaning of the invention.
另一方面，本发明涉及一种化合物，其为式(III)所示的化合物或式(III)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：In another aspect, the present invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (III) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
Figure PCTCN2021090489-appb-000006
Figure PCTCN2021090489-appb-000006
其中各X、Y、R 1、R 2、R 3、R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8、R 9、A、R a、R b和n具有本发明所述的含义。 Wherein each of X, Y, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 , R 9 , A, R a , R b and n has the The meaning of the invention.
在一些实施方案中，药学上可接受的盐是盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、丙酮酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合。In some embodiments, the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate Acid salt, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate Acid salt, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethane Sulfonate or their combination.
另一方面，本发明涉及一种药物组合物，其包含本发明式(I)、(II)或(III)所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，及药学上可接受的赋形剂、载体、附加剂、辅剂、媒介物中的至少一种或它们的组合；On the other hand, the present invention relates to a pharmaceutical composition comprising a compound represented by formula (I), (II) or (III) of the present invention or its stereoisomers, geometric isomers, tautomers, Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs, and at least one of pharmaceutically acceptable excipients, carriers, adjuvants, adjuvants, and vehicles Or a combination of them;
所述的药物组合物进一步包含其它附加治疗剂，其中所述的附加治疗剂是：丙酮酸钠、多索茶碱、替托司特、泰鲁司特、茶碱、福莫特罗、沙美特罗、氟替卡松丙酸酯、咯利普兰、吡拉米斯特、西洛司特、茚达特罗、奥达特罗、米地司坦、齐流通、沙丁醇胺、卡莫昔罗、布地奈德、二丙酸倍氯米松、氟尼缩松、罗氟奈德、环索奈德、异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、芜地溴铵、维兰特罗、阿地溴铵、Benralizumab、Tralokinumab、瑞伐托酯、克瑞沙硼、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、曲安奈德、地索奈德、氢化可的松、氯倍他索、卤贝他索、糠酸莫米松、二氟拉松、美普克莱、他克莫司、吡美莫司、他扎罗汀、环孢素、阿普斯特、E-6005、OPA-15406、LEO-29102、DRM02、罗氟司特、异丁司特、托法替尼、JTE-052、巴瑞替尼、乌帕替尼、WBI-1001、MRX-6、GSK2981278、杜鲁单抗、来金珠单抗、尼莫利珠单抗、曲洛吉努单抗、依那西普、阿达木单抗、英夫利昔单抗、尤特可单抗、塞库吉努、奥马珠、CIM-331、戈利木单抗和聚乙二醇化赛、妥珠单抗、卡泊三醇、骨化三醇、阿利维A酸、VTP-38543、ZPL-389、阿瑞匹坦、曲地匹坦、弗维普兰特、OC-459、SUN 13834、SB-011、VTP-43742、ARN6039、TAK-828、JTE-451、PF-04965842、PF-06651600、PF-06700841、PF-06650833、GR-MD-02或它们的组合。The pharmaceutical composition further comprises other additional therapeutic agents, wherein the additional therapeutic agents are: sodium pyruvate, doxofylline, tetomilast, telukast, theophylline, formoterol, salami Terrol, fluticasone propionate, rolipram, piramistrol, cilomilast, indacaterol, odacaterol, midistein, citradin, salbutamol, camoxirol , Budesonide, beclomethasone dipropionate, flunisolide, rofluronide, ciclesonide, ipratropium bromide, oxitropium bromide, tiotropium bromide, glycopyrrolate bromide, Wudi Ammonium bromide, vilanterol, aclidinium bromide, Benralizumab, Tralokinumab, revatatropate, crenzaboron, fluocinolone acetate, desoxymethasone, mometasone, triamcinolone, betamethasone, alexandrite Clomethasone, Triamcinolone Acetonide, Dexonide, Hydrocortisone, Clobetasol, Halobetasol, Mometasone Furoate, Diflurazone, Meplaxil, Tacrolimus, Pimecrolimus S, Tazarotene, Cyclosporine, Apemilast, E-6005, OPA-15406, LEO-29102, DRM02, Roflumilast, Ibudilast, Tofacitinib, JTE-052, Pakistan Retinib, Upatinib, WBI-1001, MRX-6, GSK2981278, Duluzumab, Lekinizumab, Nimolizumab, Traloginumab, Etanercept, Adal Lumumab, Infliximab, Utecomumab, Secuginu, Omazu, CIM-331, Golimumab and Pegylation, Touzumab, Calcipotriol, Calcitriol, aliretinoin, VTP-38543, ZPL-389, aprepitant, tripipitant, Foviprand, OC-459, SUN 13834, SB-011, VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02 or their combination.
另一方面，本发明涉及式(I)、(II)或(III)所示化合物或其药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻与4型磷酸二酯酶有关的疾病。On the other hand, the present invention relates to the use of a compound represented by formula (I), (II) or (III) or a pharmaceutical composition thereof in the preparation of a medicine for the prevention, treatment or alleviation of type 4 phosphodiester Enzyme-related diseases.
在一些实施方案中，本发明涉及式(I)、(II)或(III)所示化合物或其药物组合物在制备药物中的用途，所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病或非胰岛素依赖糖尿病。In some embodiments, the present invention relates to the use of a compound represented by formula (I), (II) or (III) or a pharmaceutical composition thereof in the preparation of a medicine. The disease related to type 4 phosphodiesterase is respiratory Disease, allergy, inflammation, central nervous system disease or non-insulin dependent diabetes.
在一些实施方案中，所述的呼吸疾病为：慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症；其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎。In some embodiments, the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute Respiratory distress syndrome or inflammation of the respiratory tract; among which bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis.
在一些实施方案中，所述的炎症为：过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。In some embodiments, the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing Spondylitis, rheumatoid arthritis or psoriatic arthritis.
另一方面，本发明涉及式(I)、(II)或(III)所示化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I), (II) or (III).
生物试验结果表明，本发明提供的化合物对PDE4具有较好的抑制活性，同时具有良好的药代动力学特征。Biological test results show that the compound provided by the present invention has good inhibitory activity on PDE4, and at the same time has good pharmacokinetic characteristics.
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。Any embodiment of any aspect of the present invention can be combined with other embodiments as long as they do not appear contradictory. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as they do not conflict.
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The foregoing content only outlines certain aspects of the present invention, but is not limited to these aspects. The content of these and other aspects will be described in more detail and complete below.
本发明详细说明书Detailed description of the invention
定义和一般术语Definitions and general terms
现在详细描述本发明的某些实施方案，其实施例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Now certain embodiments of the present invention are described in detail, and examples thereof are illustrated by the accompanying structural formulas and chemical formulas. The present invention intends to cover all alternatives, modifications and equivalent technical solutions, which are all included in the scope of the present invention as defined by the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is by no means limited to the methods and materials described in the present invention. In the case where one or more of the combined documents, patents and similar materials are different from or contradictory to this application (including but not limited to the defined terms, term application, described technology, etc.), this Application shall prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It should be further recognized that certain features of the present invention, for the sake of clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, the various features of the present invention are described in a single embodiment for the sake of brevity, but they can also be provided individually or in any suitable sub-combination.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise specified, all scientific and technological terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated into the present invention in their entirety by reference.
除非另外说明，应当应用本发明所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本发明。Unless otherwise specified, the following definitions used in the present invention should be applied. For the purpose of the present invention, the chemical elements are consistent with the CAS version of the Periodic Table of Elements, and "Handbook of Chemistry and Physics", 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the description in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , The entire content of which is incorporated into the present invention by reference.
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。Unless otherwise stated or there is an obvious conflict in context, the articles "a", "an" and "said" used herein are intended to include "at least one" or "one or more." Therefore, these articles used herein refer to articles of one or more than one (ie at least one) object. For example, "a component" refers to one or more components, that is, there may be more than one component considered to be adopted or used in the embodiment of the described embodiment.
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。The term "subject" used in the present invention refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to primates (such as humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression, that is, includes the content specified in the present invention, but does not exclude other aspects.
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何(顺/反)异构体、阻转异构体，等等。The term "stereoisomers" refers to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rottamers), geometric (cis/trans) isomers, atropisomers, and the like.
术语“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。The term "chiral" refers to a molecule that can not overlap with its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。The term "enantiomers" refers to two isomers of a compound that cannot overlap but are mirror images of each other.
术语“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。The term "diastereomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
本发明所使用的立体化学定义和规则一般遵循S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994。The definition and rules of stereochemistry used in the present invention generally follow SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley&Sons, Inc., New York, 1994.
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的，前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory, and the compound with the prefix (+) or d is dextrorotatory of. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。Any asymmetric atom (for example, carbon, etc.) of the compound disclosed in the present invention may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration form exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。Depending on the choice of starting materials and method, the compound of the present invention can be one of the possible isomers or a mixture of them, such as racemates and diastereomer mixtures (depending on the number of asymmetric carbon atoms) The form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may have an E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may have a cis or trans configuration.
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。 The racemate of any final product or intermediate obtained can be resolved into optical enantiomers by a method familiar to those skilled in the art using known methods, for example, by performing diastereomeric salts of the obtained diastereomers. Separate. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversion through proton migration, such as keto-enol isomerization and imine- Enamine isomerization. Valence tautomers include interconversion through the recombination of some bond-forming electrons. Specific examples of keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples. A class of compounds.
一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。Generally speaking, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different substitutions.
术语“任选地被……所取代”表示所述结构是未取代的或者被一个或多个本发明所述的取代基取代。本发明所述的取代基包括，但不限于，氘，氟，氯，溴，碘，氰基，羟基，氨基，硝基，羧基，芳基，杂芳基，烷氧基，烷基，烯基，炔基，杂环基，环烷基，环烷基烷基，杂环基烷基，芳基烷基，杂芳基烷基，氧代，卤代烷基，卤代烷氧基，烷基-C(＝O)-，烷基-O-C(＝O)-，烷基-S(＝O)-，烷基-S(＝O) 2-，烷基氨基，NH 2-C(＝O)-，NH 2-S(＝O) 2-，等等。 The term "optionally substituted by" means that the structure is unsubstituted or substituted by one or more substituents described in the present invention. The substituents in the present invention include, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, nitro, carboxy, aryl, heteroaryl, alkoxy, alkyl, alkene Group, alkynyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, oxo, haloalkyl, haloalkoxy, alkyl-C (=O)-, alkyl-OC(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, alkylamino, NH 2 -C(=O)- , NH 2 -S(=O) 2 -, etc.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，结构式“-C(＝O)-N(R aR b)”和结构式“-C 1-6亚烷基-N(R aR b)”两者之间R a的具体选项互相之间不受影响。 In addition, it should be noted that, unless explicitly pointed out in other ways, the description methods used in the present invention are interchangeable with "each ... independently being" and "... each independently being" and "... independently being". Should be understood in a broad sense, it can mean that the specific options expressed between the same symbols in different groups do not affect each other, or it can mean the specific options expressed between the same symbols in the same group Do not affect each other. For example, the specific options of Ra between the structural formula "-C(=O)-N(R a R b )" and the structural formula "-C 1-6 alkylene-N(R a R b )" are mutually exclusive Time is not affected.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-C 6烷基”或“C 1-6烷基”特别指独 立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。 In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or scope. In particular, the present invention includes each independent sub-combination of each member of these group types and ranges. For example, the term "C 1 -C 6 alkyl" or "C 1-6 alkyl" specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl. base.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了如“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In each part of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for the variable lists such as "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the link The alkylene group or arylene group.
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-12个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally Ground is substituted with one or more substituents described in this invention. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.
烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1- Butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-Methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl(-C(CH 3 ) 2 CH (CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and so on.
术语“亚烷基”表示从饱和的直链或支链烃中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一实施方案中，亚烷基基团含有1-6个碳原子；在另一实施方案中，亚烷基基团含有1-4个碳原子；在又一实施方案中，亚烷基基团含有1-3个碳原子；还在一实施方案中，亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH 2-)，亚乙基(-CH 2CH 2-)，亚丙基(-CH 2CH 2CH 2-)，亚异丙基(-CH(CH 3)CH 2-)等等。 The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in another embodiment, the alkylene group The group contains 1-3 carbon atoms; in yet another embodiment, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), isopropylidene (-CH(CH 3 ) CH 2 -) and so on.
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括"cis"和"tans"的定位，或者"E"和"Z"的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)等等。 The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp 2 double bond, wherein the alkenyl group Groups can be optionally substituted with one or more substituents described in the present invention, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), and the like.
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)等等。 The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted by one or more substituents described in the present invention. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH 2 C≡CH), 1-propynyl (-C≡C-CH 3 ), etc. .
术语“羧基”，无论是单独使用还是和其他术语连用，如“羧烷基”，表示-CO 2H或-COOH。 The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means -CO 2 H or -COOH.
术语“氘”表示单个氘原子。例如，一个氘原子取代甲基中的一个氢原子，形成单-氘代甲基(-CDH 2)，两个氘原子取代甲基中的两个氢原子，形成双-氘代甲基(-CD 2H)，以及三个氘原子取代甲基中的三个氢原子，形成三-氘代甲基(-CD 3)。 The term "deuterium" means a single deuterium atom. For example, one deuterium atom replaces a hydrogen atom in a methyl group to form a mono-deuterated methyl group (-CDH 2 ), and two deuterium atoms replace two hydrogen atoms in a methyl group to form a double-deuterated methyl group (- CD 2 H), and three deuterium atoms to replace the three hydrogen atoms in the methyl group to form a tri-deuterated methyl group (-CD 3 ).
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。The term "unsaturated" as used in the present invention means that the group contains one or more degrees of unsaturation.
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷 基中的NH)或NR(像N-取代的吡咯烷基中的NR)。The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or on the nitrogen atom in the heterocyclic ring The form in which hydrogen is substituted, for example, N (like the N in 3,4-dihydro-2H-pyrrolyl), NH (like the NH in the pyrrolidinyl group) or NR (like the N-substituted pyrrolidinyl group NR).
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "alkoxy" means that the alkyl group is connected to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH 3) 2)，1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)，1-戊氧基(n-戊氧基、-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。 Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-but Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy (-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentoxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy Group (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ), etc.
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CF 2CH 2CH 3、-CH 2Cl、-CHCl 2、-OCHF 2、-OCF 3等。 The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted with one or more halogen atoms. Examples of this include, but are not limited to, -CH 2 F, -CHF 2 ,- CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , -OCHF 2 , -OCF 3 and so on.
术语“烷氨基”表示-NH 2基团被一个或两个烷基所取代，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氨基基团含有1-12个碳原子。在一实施方案中，烷氨基基团含有1-6个碳原子；在另一实施方案中，烷氨基基团含有1-4个碳原子；在又一实施方案中，烷氨基基团含有1-3个碳原子。所述烷氨基的实例包括但不限于：甲基氨基、二甲基氨基、乙基氨基、二乙基氨基、甲基乙基氨基等。所述烷氨基基团可以任选地被一个或多个本发明描述的取代基所取代。 The term "alkylamino" means that the -NH 2 group is substituted with one or two alkyl groups, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkylamino group contains 1-12 carbon atoms. In one embodiment, the alkylamino group contains 1 to 6 carbon atoms; in another embodiment, the alkylamino group contains 1 to 4 carbon atoms; in another embodiment, the alkylamino group contains 1 -3 carbon atoms. Examples of the alkylamino group include, but are not limited to: methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, and the like. The alkylamino group may be optionally substituted with one or more substituents described in this invention.
术语“j-k个原子组成的”，其中各j和k独立地为任意非零的自然数，且k＞j；所述“j-k”包括j、k和两者之间的任意自然数。典型地描述分子中成环原子的数目，在所述分子中成环原子的数目是j-k，所述的原子包括碳原子和/或O、N、S、P等杂原子。The term "consisting of j-k atoms", wherein each of j and k is independently any non-zero natural number, and k>j; the "j-k" includes j, k and any natural number in between. Typically describes the number of ring-forming atoms in a molecule, the number of ring-forming atoms in the molecule is j-k, and the atoms include carbon atoms and/or O, N, S, P and other heteroatoms.
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。在一实施方案中，环烷基包含3-12个碳原子；在另一实施方案中，环烷基包含3-8个碳原子；在又一实施方案中，环烷基包含3-6个碳原子。所述环烷基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。The term "cycloalkyl" refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. In one embodiment, the cycloalkyl group contains 3-12 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in another embodiment, the cycloalkyl group contains 3-6 carbon atoms. carbon atom. The cycloalkyl group may be independently optionally substituted with one or more substituents described in the present invention.
术语“环烷基-烷基”或“环烷基-亚烷基”可以交换使用，都是指烷基基团被一个或多个环烷基基团所取代，其中烷基基团和环烷基基团具有如本发明所述的含义，这样的实例包括，但并不限于环丙基甲基、环丙基乙基、环丁基甲基、环丁基乙基、环戊基甲基、环戊基乙基、环己基甲基、环己基乙基等。The terms "cycloalkyl-alkyl" or "cycloalkyl-alkylene" are used interchangeably, and both refer to the alkyl group being substituted by one or more cycloalkyl groups, where the alkyl group and the ring Alkyl groups have the meanings described in the present invention. Examples of such include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, Cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, etc.
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环，其中单环、双环或三环中不包含芳香环，且至少一个环原子选自氮、硫和氧原子。除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括，但不限于：环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，吡咯基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧杂环戊烷基，1,3-二氧杂环戊烯基，二硫环戊基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，四氢吡啶基，吗啉基，硫代吗啉基，1-氧代-硫代吗啉基，1,1-二氧代-硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基。杂环基中-CH 2-基团被-C(＝O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基和3,5-二氧代哌啶基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。 所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 The terms "heterocyclic group" and "heterocyclic ring" are used interchangeably herein, and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms, wherein monocyclic, bicyclic or tricyclic ring The ring does not contain an aromatic ring, and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, the heterocyclic group may be a carbon group or a nitrogen group, and the -CH 2 -group may be optionally replaced by -C(=O)-. The sulfur atom of the ring can optionally be oxidized to S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, imidazolinyl , Imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, 1,3-dioxolyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl , 1,1-Dioxo-thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazinyl, homopiperazinyl, homopiperidinyl, oxepanyl . Examples of the -CH 2 -group substituted by -C(=O)- in the heterocyclic group include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Ketone and 3,5-dioxopiperidinyl. Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
术语“杂环基-烷基”或“杂环基-亚烷基”可以交换使用，都是指杂环基取代的烷基；其中杂环基和烷基基团具有如本发明所述的含义。这样的实例包括，但并不限于硫代吗啉-4-基甲基，四氢呋喃-3-基甲基，四氢吡喃-4基甲基，氧杂环丁烷-3-基甲基，吡咯烷-2-基甲基，吗啉-4-基甲基等。The terms "heterocyclyl-alkyl" or "heterocyclyl-alkylene" can be used interchangeably, and both refer to an alkyl group substituted by a heterocyclyl group; wherein the heterocyclyl group and the alkyl group have the same characteristics as described in the present invention. meaning. Such examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydropyran-4-ylmethyl, oxetan-3-ylmethyl, Pyrrolidin-2-ylmethyl, morpholin-4-ylmethyl, etc.
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。The term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring composed of 3-7 atoms, and has one or more attachment points connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.
术语“芳基-烷基”或“芳基-亚烷基”可以交换使用，都是指一个或多个芳基取代的烷基基团，其中所述芳基和烷基具有本发明所述的含义。其中一些实施方案是，芳基烷基基团是指“较低级的芳基烷基”基团，即芳基基团连接到C 1-6的烷基或亚烷基基团上。另外一些实施方案是，芳基烷基基团是指含C 1-4烷基的“苯烷基”。其中具体实例包括二苯基甲基，苯甲基、苯乙基。芳基-烷基或芳基-亚烷基上的芳基可以进一步被本发明所述的取代基所取代。 The terms "aryl-alkyl" or "aryl-alkylene" can be used interchangeably, and both refer to an alkyl group substituted by one or more aryl groups, wherein the aryl and alkyl groups have the meaning described in the present invention. Meaning. In some embodiments, the arylalkyl group refers to a "lower arylalkyl" group, that is, the aryl group is connected to a C1-6 alkyl or alkylene group. In other embodiments, the arylalkyl group refers to a "phenylalkyl group" containing a C 1-4 alkyl group. Specific examples thereof include diphenylmethyl, benzyl, and phenethyl. The aryl group on the aryl-alkyl group or aryl-alkylene group may be further substituted with the substituents described in the present invention.
术语“杂芳基”表示含有5-15个环原子、5-12个环原子，或5-10个环原子，或5-7个环原子的单环、双环和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含5-7个原子组成的环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”，“芳杂环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在其中一些实施方案中，5-10个原子组成的杂芳基包含1，2，3或4个独立选自O，S，N或B的杂原子。在其中一些实施方案中，11-15个原子组成的杂芳基包含1，2，3或4个独立选自O，S，N或B的杂原子。The term "heteroaryl" means a monocyclic, bicyclic and tricyclic ring system containing 5-15 ring atoms, 5-12 ring atoms, or 5-10 ring atoms, or 5-7 ring atoms, of which at least one The ring system is aromatic, and at least one ring system contains one or more heteroatoms, each of which contains a ring composed of 5-7 atoms, and has one or more attachment points connected to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocyclic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described in the present invention. In some of these embodiments, the 5-10 atom heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, N, or B. In some of these embodiments, the 11-15 atom heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, N, or B.
杂芳基基团的实例包括，但并不限于，呋喃基(如2-呋喃基、3-呋喃基)、咪唑基(如N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)、异噁唑基(如3-异噁唑基、4-异噁唑基、5-异噁唑基)、噁唑基(如2-噁唑基、4-噁唑基、5-噁唑基)、吡咯基(如N-吡咯基、2-吡咯基、3-吡咯基)、吡啶基(如2-吡啶基、3-吡啶基、4-吡啶基)、嘧啶基(如2-嘧啶基、4-嘧啶基、5-嘧啶基)、哒嗪基(如3-哒嗪基)、噻唑基(如2-噻唑基、4-噻唑基、5-噻唑基)、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、噻吩基(如2-噻吩基、3-噻吩基)、吡唑基(如2-吡唑基)、异噻唑基、嘧啶酮基、吡啶酮基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、
Figure PCTCN2021090489-appb-000007
Figure PCTCN2021090489-appb-000008
等等。 Examples of heteroaryl groups include, but are not limited to, furyl (e.g. 2-furyl, 3-furyl), imidazolyl (e.g. N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl), isoxazolyl (e.g. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5 -Oxazolyl), pyrrolyl (e.g. N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazole Group (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), thienyl (such as 2-thienyl, 3-thienyl), pyrazolyl (such as 2- Pyrazolyl), isothiazolyl, pyrimidinone, pyridinone; also include the following bicyclic rings, but are by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl),
Figure PCTCN2021090489-appb-000007
Figure PCTCN2021090489-appb-000008
and many more.
术语“杂芳基-烷基”或“杂芳基-亚烷基”可以交换使用，都是指烷基基团被一个或多个杂芳基所取代，其中杂芳基和烷基基团具有本发明所述的含义，这样的实例包括，但并不限于吡啶-2基甲基，吡啶-3基甲基，吡啶-4基甲基，嘧啶2-基甲基，吡唑-5基甲基，吡唑-4基甲基，咪唑-2-基甲基，呋喃-2-基乙基，吲哚-3-基甲基等。The terms "heteroaryl-alkyl" or "heteroaryl-alkylene" are used interchangeably and both refer to the alkyl group being substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups Having the meaning of the present invention, such examples include, but are not limited to, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4ylmethyl, pyrimidin-2-ylmethyl, pyrazole-5yl Methyl, pyrazol-4-ylmethyl, imidazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl, etc.
像本发明所描述的，取代基画一个键连接到中心的环上形成的环体系(如式c所示)代表取代基在该环 上任何可取代的位置都可以取代。例如，式c代表取代基R可在C环上任何可能被取代的位置上单取代或多取代，如式c1～式c19所示。As described in the present invention, the ring system formed by attaching a substituent to the central ring by drawing a bond (as shown in formula c) represents that the substituent can be substituted at any substitutable position on the ring. For example, the formula c represents that the substituent R can be mono-substituted or multi-substituted at any position on the C ring that may be substituted, as shown in formula c1 to formula c19.
Figure PCTCN2021090489-appb-000009
Figure PCTCN2021090489-appb-000009
像本发明所描述的，一个连接键连接到环体系上(如式d所示)代表连接键可以在环体系上任何可连接的位置与分子其余部分相连。式d代表环上任何可能连接的位置均可与分子其余部分相连，如式d1～式d5所示。As described in the present invention, a linking bond is connected to the ring system (as shown in formula d), which means that the linking bond can be connected to the rest of the molecule at any linkable position on the ring system. The formula d represents that any possible connection position on the ring can be connected to the rest of the molecule, as shown in formula d1 to formula d5.
Figure PCTCN2021090489-appb-000010
Figure PCTCN2021090489-appb-000010
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)或式(II)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。 The term "prodrug" used in the present invention represents the conversion of a compound into a compound represented by formula (I) or formula (II) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissues. The prodrug compounds of the present invention can be esters. In the existing invention, esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters. For example, these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group. For a complete discussion of prodrugs, please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008 ,51,2328-2345.
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰胺化，脱酰胺作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to the product obtained by the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound. Correspondingly, the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,J.Pharmaceutical Sciences,66:1-19,1977所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得 到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。 The "pharmaceutically acceptable salt" used in the present invention refers to the organic and inorganic salts of the compound of the present invention. Pharmaceutically acceptable salts are well known to us in the field, as described in the literature: SMBerge et al., J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or through other methods described in books and literature such as ion exchange These salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3 -Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. The present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
本发明的“水合物”是指溶剂分子是水所形成的缔合物。在一些实施例中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另外一些实施例中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物，还有一些实施例中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。The "hydrate" in the present invention refers to an association formed by the solvent molecule being water. In some embodiments, one compound molecule of the present invention may be combined with one water molecule, such as a monohydrate; in other embodiments, one compound molecule of the present invention may be combined with more than one water molecule, such as dihydrate In other embodiments, one compound molecule of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrate of the present invention retains the bioavailability of the compound in its non-hydrated form.
术语“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂，例如二氯甲烷中，使胺化合物与间-氯过苯甲酸(MCPBA)反应。The term "nitrogen oxide" means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), in which, for example, in an inert solvent, such as methylene chloride, the amine compound is combined with m-chloroperbenzoic acid (MCPBA) reaction.
术语“载体”包括任何溶剂，分散介质，包衣衣料，表面活性剂，抗氧化剂，防腐剂(例如抗细菌剂、抗真菌剂)，等渗剂，盐，药物稳定剂，粘合剂，赋形剂，分散剂，润滑剂，甜味剂，调味剂，着色剂，或其组合物，这些载体都是所属技术领域技术人员已知的(如Remington's Pharmaceutical Sciences,18th Ed.Mack Printing Company,1990,pp.1289-1329所述)。除了任意常规载体与活性成分不相容的情况外，涵盖其在治疗或药物组合物中的用途。The term "carrier" includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (such as antibacterial agents, antifungal agents), isotonic agents, salts, drug stabilizers, binders, excipients Forming agents, dispersing agents, lubricants, sweetening agents, flavoring agents, coloring agents, or combinations thereof, these carriers are known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990 , pp. 1289-1329). Except for the incompatibility of any conventional carrier with the active ingredient, its use in therapeutic or pharmaceutical compositions is encompassed.
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。As used in the present invention, the term "treating" any disease or condition, in some embodiments refers to ameliorating the disease or condition (ie slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treatment" refers to regulating the disease or condition physically (for example, stabilizing the perceptible symptoms) or physiologically (for example, stabilizing the parameters of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
如本发明所使用的术语“治疗有效量”或“治疗有效剂量”是指能够引发个体的生物学或医学响应(例如降低或抑制酶或蛋白质活性，或改善症状、缓解病症、减缓或延迟疾病发展，或预防疾病等)的本发明化合物的量。在一项非限定性的实施方案中，术语“治疗有效量”是指当向个体施用本发明化合物时，对以下情况有效的量：(1)至少部分地缓解、抑制、预防和/或改善(i)与PDE4有关，或者(ii)与PDE4活性相关，或者(iii)与PDE4的异常活性表征的病症或疾病；或者(2)降低或抑制PDE4的活性；或者(3)降低或抑制PDE4的表达。在另一实施方案中，术语“治疗有效量”是指当向细胞、或器官、或非细胞生物物质、或介质施用时，能至少部分地降低或抑制PDE4活性；或者至少部分地降低或抑制PDE4表达的有效的本发明化合物的量。As used in the present invention, the term "therapeutically effective dose" or "therapeutically effective dose" refers to a biological or medical response (such as reducing or inhibiting enzyme or protein activity, or improving symptoms, alleviating symptoms, slowing or delaying disease The amount of the compound of the present invention for the development, or prevention of diseases, etc.). In a non-limiting embodiment, the term "therapeutically effective amount" refers to an amount effective for the following conditions when administering the compound of the present invention to an individual: (1) at least partially alleviating, inhibiting, preventing and/or ameliorating (i) related to PDE4, or (ii) related to PDE4 activity, or (iii) disorders or diseases characterized by abnormal activity of PDE4; or (2) reducing or inhibiting the activity of PDE4; or (3) reducing or inhibiting PDE4 expression. In another embodiment, the term "therapeutically effective amount" refers to the ability to at least partially reduce or inhibit the activity of PDE4 when administered to cells, or organs, or non-cellular biological substances, or media; or at least partially reduce or inhibit the activity of PDE4 The effective amount of the compound of the invention expressed by PDE4.
如本发明所使用的术语化合物“给予”和“给药”化合物应当理解为向需要其的个体提供本发明的化合物或本发明化合物的前药。应当认识到本领域技术人员通过使用有效量的本发明化合物治疗目前患有此障碍的患者或者预防性地治疗患有此障碍的患者。The terms "administering" and "administering" a compound as used in the present invention should be understood as providing a compound of the present invention or a prodrug of a compound of the present invention to an individual in need thereof. It should be recognized that those skilled in the art can treat patients currently suffering from this disorder or preventively treat patients suffering from this disorder by using an effective amount of the compound of the present invention.
如本发明所使用的术语“组合物”是指包含规定量的规定成分的产物，以及规定量的规定成分的组合所直接或间接地产生的任何产物。与药物组合物相关的这种术语的含义包括包含活性成分(单个或者多个)和组成载体的惰性成分(单个或者多个)的产物，以及由任何两种或多种成分混合、复合或聚集，或者由一种或多种成分分解，或者由一种或多种成分的其他类型的反应或相互作用而直接或间接产生的任何产物。因此，本发明药物组合物包括通过将本发明化合物与可药用载体混合而制备的任何组合物。The term "composition" as used in the present invention refers to a product containing a prescribed amount of prescribed ingredients, and any product directly or indirectly produced by a combination of prescribed amounts of prescribed ingredients. The meaning of this term in relation to pharmaceutical compositions includes products containing active ingredients (single or multiple) and inert ingredients (single or multiple) constituting the carrier, as well as products composed of any two or more ingredients mixed, compounded or aggregated , Or any product produced directly or indirectly by the decomposition of one or more components, or by other types of reactions or interactions of one or more components. Therefore, the pharmaceutical composition of the present invention includes any composition prepared by mixing the compound of the present invention with a pharmaceutically acceptable carrier.
另外，本发明公开的化合物、包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of containing their solvents (for example, ethanol, DMSO, etc.), and used for their crystallization. The compounds disclosed in the present invention can form solvates inherently or by design with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include solvated and unsolvated forms.
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 18F， 31P， 32P， 35S， 36Cl和 125I。 Any structural formula given in the present invention is also intended to represent the non-isotopically enriched form and the isotopically enriched form of these compounds. The isotope-enriched compound has the structure described by the general formula given in the present invention, except that one or more atoms are replaced by atoms having the selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C。该类同位素富集的化合物可用于代谢研究(使用 14C)、反应动力学研究(使用例如 2H或 3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。 18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)或式(II)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。 On the other hand, the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes such as 3 H, 14 C and 18 F are present, or non-radioactive isotopes such as 2 H and 13 C. Such isotopically enriched compounds can be used for metabolism studies (using 14 C), reaction kinetics studies (using, for example, 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or including drugs or Single-photon emission computed tomography (SPECT), which measures the distribution of substrate tissue, may be used in radiotherapy of patients. 18 F-enriched compounds are particularly ideal for PET or SPECT research. The isotope-enriched compound represented by formula (I) or formula (II) can be replaced by a suitable isotope labeling reagent using conventional techniques familiar to those skilled in the art or as described in the examples and preparation processes of the present invention. Label the reagent to prepare.
此外，较重同位素特别是氘(即， 2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，本发明中的氘被看做式(I)或式(II)所示化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D 2O、丙酮-d 6、DMSO-d 6的那些溶剂化物。 In addition, the substitution of heavier isotopes, particularly deuterium (ie, 2 H or D), can provide certain therapeutic advantages due to higher metabolic stability. For example, the increase in the half-life in the body or the decrease in the dosage requirement or the improvement of the therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound represented by formula (I) or formula (II). The isotope enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium. The term "isotopic enrichment factor" as used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope. If the substituent of the compound of the present invention is designated as deuterium, the compound has at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), for each designated deuterium atom, At least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping) Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factor. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D 2 O, acetone-d 6 , DMSO-d 6 .
本发明的化合物的描述Description of the compound of the present invention
本发明涉及新的吡咯烷类化合物和治疗特应性皮炎或慢性阻塞性肺病的方法。本发明化合物或包含所述化合物的药物组合物作为PDE4抑制剂，对特应性皮炎或慢性阻塞性肺病有较好的治疗效果。The present invention relates to new pyrrolidine compounds and methods for treating atopic dermatitis or chronic obstructive pulmonary disease. The compound of the present invention or the pharmaceutical composition containing the compound is used as a PDE4 inhibitor, and has a good therapeutic effect on atopic dermatitis or chronic obstructive pulmonary disease.
一方面，本发明涉及一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts or their prodrugs:
Figure PCTCN2021090489-appb-000011
Figure PCTCN2021090489-appb-000011
其中各X、Y、R 1、R 2、R 3、R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8、R 9、A、R b和n具有本发明所述的含义。 Wherein each of X, Y, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 , R 9 , A, R b and n has the meaning of the present invention Meaning.
在一些实施方案中，X为CH或N。In some embodiments, X is CH or N.
在一些实施方案中，Y为-(CH 2) m-C(＝O)-NH-(CR mR n) p-或-(CH 2) m-C(＝O)-O-(CR mR n) p-；其中，R m、R n、m和p具有本发明所述的含义。 In some embodiments, Y is -(CH 2 ) m -C(=O)-NH-(CR m R n ) p -or -(CH 2 ) m -C(=O)-O-(CR m R n ) p -; wherein R m , R n , m and p have the meanings described in the present invention.
在一些实施方案中，A环为C 6-10芳基或5-10个原子组成的杂芳基。 In some embodiments, the A ring is a C 6-10 aryl group or a 5-10 atom heteroaryl group.
在一些实施方案中，R 1为氢、氘、-OR a或-NR cR d；其中，R a、R c和R d具有本发明所述的含义。 In some embodiments, R 1 is hydrogen, deuterium, -OR a, or -NR c R d ; wherein, R a , R c, and Rd have the meanings described in the present invention.
在一些实施方案中，R 2为C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、C 3-6环烷基-C 1-4烷基、5-7个原子组成的杂环基或(5-7个原子组成的杂环基)-C 1-4烷基；或 In some embodiments, R 2 is C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, 5- Heterocyclic group consisting of 7 atoms or (heterocyclic group consisting of 5-7 atoms)-C 1-4 alkyl; or
R 2与R a和其相连的原子共同形成5-7个原子组成的杂环基，所述的5-7个原子组成的杂环基任选地被选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷基的取代基所取代。 And R a and R 2 which together form a 5-7 atom heterocyclic group of atoms, said heterocyclic group consisting of 5-7 atoms optionally substituted selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl substituents.
在一些实施方案中，R 3为氢、氘、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、HC(＝O)-、C 1-6烷基-C(＝O)-、C 1-6烷基-O-C(＝O)-、C 1-6烷基-S(＝O) 2-或C 1-6烷基-C(＝NH)-，其中所述的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O) 2-和C 1-6烷基-C(＝NH)-各自独立任选地被1、2或3个选氘、F、Cl、Br、I、-OH、-CN或-NH 2的取代基所取代。 In some embodiments, R 3 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, HC(=O)-, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-OC(=O)-, C 1-6 alkyl-S(=O) 2 -or C 1-6 alkyl-C (=NH)-, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-C(=O )-, C 1-6 alkyl-S(=O) 2 -and C 1-6 alkyl-C(=NH)- each independently optionally selected from 1, 2 or 3 deuterium, F, Cl, Br, I, -OH, -CN or -NH 2 substituents.
在一些实施方案中，R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8和R 9各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、C 1-4烷基-C(＝O)-或C 1-4烷基-S(＝O) 2-。 In some embodiments, R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 and R 9 are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN , -NH 2 , -NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, C 1-4 alkyl-C(=O)-or C 1-4 alkyl-S(=O) 2 -.
在一些实施方案中，R a为氢、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基，其中所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或5-10个原子组成的杂环基的取代基所取代。 In some embodiments, R a is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, hetero atoms 5-10 Cyclic group, C 6-10 aryl group or heteroaryl group composed of 5-10 atoms, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 Cycloalkyl groups, heterocyclic groups composed of 5-10 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-10 atoms are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 5- A 10-atom heterocyclic group is substituted by a substituent.
在一些实施方案中，各R b独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基-OC(＝O)-、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-8环烷基-C 1-6烷基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基、5-10个原子组成的杂芳基、-NR eC(＝O)C 1-6烷基、-NR eR f、-S(＝O) 2-NR eR f、-C(＝O)-NR eR f或-C 1-6烷基-NR eR f，其中所述的C 1-6烷基、C 1-6烷氧基、C 3-8环烷基-C 1-6烷基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-6烷基、C 1-6烷氨基或C 1-6烷氧基的取代基所取代；其中，各R e和R f具有本发明所述的含义。 In some embodiments, each R b is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-OC(=O)-, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-S(=O) 2 -, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclic group composed of 5-10 atoms, C 6-10 aryl group, heteroaromatic group composed of 5-10 atoms Group, -NR e C(=O)C 1-6 alkyl group, -NR e R f , -S(=O) 2 -NR e R f , -C(=O)-NR e R f or -C 1-6 alkyl-NR e R f , wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-8 ring Alkyl groups, heterocyclic groups composed of 5-10 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-10 atoms are each independently optionally selected from deuterium, F , Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-6 alkyl, C 1-6 alkylamino or C 1-6 alkoxy substituents ; Wherein each of R e and R f has the meaning described in the present invention.
在一些实施方案中，R c和R d各自独立地为氢、-OH、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基-C 1-4烷基、C 3-6环烷基、5-7个原子组成的杂环基、(5-7个原子组成的杂环基)-C 1-4烷基、C 1-4烷基-C(＝O)-或C 1-4烷基-S(＝O) 2-。 In some embodiments, R c and R d are each independently hydrogen, -OH, C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl-C 1-4 alkyl , C 3-6 cycloalkyl, 5-7 heterocyclic group, (5-7 heterocyclic group) -C 1-4 alkyl, C 1-4 alkyl-C(= O)- or C 1-4 alkyl-S(=O) 2 -.
在一些实施方案中，R e和R f各自独立地为氢、C 1-6烷基、C 1-6烷基-OC(＝O)-、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-8环烷基、C 6-10芳基、5-10个原子组成的杂环基、5-10个原子组成的杂芳基、11-15个原子组成的杂芳基、C 3-8环烷基-C 1-6烷基、C 6-10芳基-C 1-6烷基、(5-10个原子组成的杂环基)-C 1-6烷基、(5-10个原子组成的杂芳基)-C 1-6烷基或-C 1-6烷基-NR gR j；或者R e和R f与它们相连的N原子一起形成4-7个原子组成的杂环基；其中所述的R e、R f和4-7个原子组成的杂环基各自独立任选地被1、2、3或4个R h所取代； In some embodiments, R e and R f are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl-OC(=O)-, C 1-6 alkyl-C(=O) -, C 1-6 alkyl-S(=O) 2 -, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 heterocyclic group, 5-10 atom Heteroaryl, heteroaryl composed of 11-15 atoms, C 3-8 cycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl, (5-10 atoms Heterocyclic group consisting of) -C 1-6 alkyl, (heteroaryl consisting of 5-10 atoms) -C 1-6 alkyl or -C 1-6 alkyl -NR g R j ; or R e And R f together with the N atom to which they are connected to form a heterocyclic group consisting of 4-7 atoms; wherein said R e , R f and heterocyclic group consisting of 4-7 atoms are each independently optionally divided by 1, Replaced by 2, 3 or 4 R h;
其中，各R g、R j和R h具有本发明所述的含义。 Wherein, each of R g , R j and R h has the meaning described in the present invention.
在一些实施方案中，各R h独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基或C 1-4烷氧基。 In some embodiments, each R h is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 Haloalkoxy or C 1-4 alkoxy.
R g和R j各自独立地为氢、C 1-4烷基、C 1-4烷基-OC(＝O)-、C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 2-、C 3-6环烷基、C 6-10芳基、5-6个原子组成的杂环基或5-6个原子组成的杂芳基。 R g and R j are each independently hydrogen, C 1-4 alkyl, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-C(=O)-, C 1-4 Alkyl-S(=O) 2 -, C 3-6 cycloalkyl, C 6-10 aryl, 5-6 heterocyclic group or 5-6 heteroaryl.
在一些实施方案中，R m和R n各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、C 1-4烷基、卤代C 1-4烷基或-C(＝O)NH 2。 In some embodiments, R m and R n are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, halo C 1-4 Alkyl group or -C(=O)NH 2 .
在一些实施方案中，各n独立地为0、1、2、3或4。In some embodiments, each n is independently 0, 1, 2, 3, or 4.
在一些实施方案中，m和p各自独立地为0、1、2或3。In some embodiments, m and p are each independently 0, 1, 2, or 3.
在另一些实施方案中，A环为苯基、萘基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、吲哚基、异吲哚基、
Figure PCTCN2021090489-appb-000012
Figure PCTCN2021090489-appb-000013
In other embodiments, the A ring is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazinyl Azolyl, indolyl, isoindolyl,
Figure PCTCN2021090489-appb-000012
Figure PCTCN2021090489-appb-000013
在另一些实施方案中，R 3为氢、氘、C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 1-4烷基-C(＝O)-、C 1-4烷基-O-C(＝O)-、HC(＝O)-、C 1-4烷基-S(＝O) 2-或C 1-4烷基-C(＝NH)-，其中所述的C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 1-4烷基-C(＝O)-、C 1-4烷基-O-C(＝O)-、C 1-4烷基-S(＝O) 2-和C 1-4烷基-C(＝NH)-各自独立任选地被1、2或3个选自氘、F、Cl、Br、I、-OH、-CN或-NH 2的取代基所取代。 In other embodiments, R 3 is hydrogen, deuterium, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl- C(=O)-, C 1-4 alkyl-OC(=O)-, HC(=O)-, C 1-4 alkyl-S(=O) 2 -or C 1-4 alkyl- C(=NH)-, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl-C(= O)-, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-S(=O) 2 -and C 1-4 alkyl-C(=NH)- are independently optional 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH 2 to substituents.
在另一些实施方案中，R a为氢、氘、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基，其中所述的C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、苯基和5-6个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或5-6个原子组成的杂环基的取代基所取代。 In other embodiments, R a is hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 atoms Heterocyclic group, phenyl group or heteroaryl group consisting of 5-6 atoms, wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-6 cycloalkyl group , 5-6 atom heterocyclic group, phenyl group and 5-6 atom heteroaryl group are each independently optionally selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or a heterocyclic ring composed of 5-6 atoms Substituents of the group are substituted.
在另一些实施方案中，各R b独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、氧代、C 1-4烷基、C 1-4烷氧基、C 1-4烷基-OC(＝O)-、C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 2-、C 3-6环烷基-C 1-4烷基、C 3-6环烷基、5-6个原子组成的杂环基、苯基、5-6个原子组成的杂芳基、-NR eC(＝O)C 1-4烷基、-NR eR f、-S(＝O) 2-NR eR f、-C(＝O)-NR eR f或-C 1-4烷基-NR eR f，其中所述的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基-C 1-4烷基、C 3-6环烷基、苯基、5-6个原子组成的杂环基和5-6个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-4烷基、C 1-4烷氨基或C 1-4烷氧基的取代基所取代；其中，各R e和R f具有本发明所述的含义。 In other embodiments, each R b is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-C(=O)-, C 1-4 alkyl-S(=O) 2- , C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclic group composed of 5-6 atoms, phenyl group, heteroaryl group composed of 5-6 atoms,- NR e C(=O)C 1-4 alkyl group, -NR e R f , -S(=O) 2 -NR e R f , -C(=O)-NR e R f or -C 1-4 Alkyl-NR e R f , wherein the C 1-4 alkyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl-C 1-4 alkyl group, C 3-6 cycloalkyl group, The phenyl group, the heterocyclic group consisting of 5-6 atoms and the heteroaryl group consisting of 5-6 atoms are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkylamino or C 1-4 alkoxy substituents; wherein each R e and R f has the meaning described in the present invention.
在另一些实施方案中，R e和R f各自独立地为氢、C 1-4烷基、C 1-4烷基-OC(＝O)-、C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 2-、C 3-6环烷基、C 6-10芳基、5-7个原子组成的杂环基、5-7个原子组成的杂芳基、14-15个原子组成的杂芳基、C 3-6环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、(5-7个原子组成的杂环基)-C 1-4烷基、(5-7个原子组成的杂芳基)-C 1-4烷基或-C 1-4烷基-NR gR j；或者R e和R f与它们相连的N原子一起形成4-6个原子组成的杂环基；其中所述的R e、R f和4-6个原子组成的杂环基各自独立任选地被1、2、3或4个R h所取代；其中，各R h、R g和R j具有本发明所述的含义。 In other embodiments, R e and R f are each independently hydrogen, C 1-4 alkyl, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-C(=O )-, C 1-4 alkyl-S(=O) 2 -, C 3-6 cycloalkyl, C 6-10 aryl, 5-7 atoms heterocyclic group, 5-7 atoms The heteroaryl group, the heteroaryl group composed of 14-15 atoms, C 3-6 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (5-7 Heterocyclic group consisting of atoms) -C 1-4 alkyl, (heteroaryl consisting of 5-7 atoms) -C 1-4 alkyl or -C 1-4 alkyl -NR g R j ; or R e and R f together with the N atom to which they are connected form a heterocyclic group consisting of 4-6 atoms; wherein said R e , R f and a heterocyclic group consisting of 4-6 atoms are each independently optionally substituted by 1 , 2, 3 or 4 R h ; wherein, each of R h , R g and R j has the meaning described in the present invention.
在又一些实施方案中，R 2为甲基、乙基、正丙基、异丙基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CF 2CH 2CH 3、-CH 2Cl、-CHCl 2、环丙基、环丁基、环戊基、环己基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、四氢吡喃基甲基、四氢呋喃基甲基或吡咯烷基甲基；或 In still other embodiments, R 2 is methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, piperazinyl, piperidinyl, morpholine Group, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl or pyrrolidinylmethyl; or
R 2与R a和其相连的原子共同形成1,3-二氧杂环戊烯
Figure PCTCN2021090489-appb-000014
1,3-二氧杂环己烯、2,3-二氢-1,4,2-二噁嗪烯或1,5,3-二氧氮杂环庚烯，所述的1,3-二氧杂环戊烯、1,3-二氧杂环己烯、2,3-二氢-1,4,2-二噁嗪烯或1,5,3-二氧氮杂环庚烯独立任选地被选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CHF 2、-CF 3、-CH 2CHF 2、-CH 2CF 3或-CF 2CH 3的取代基所取代。 R 2 forms 1,3-dioxole together with R a and the atom to which it is connected
Figure PCTCN2021090489-appb-000014
1,3-dioxene, 2,3-dihydro-1,4,2-dioxazine or 1,5,3-dioxazepine, the 1,3- Dioxole, 1,3-dioxene, 2,3-dihydro-1,4,2-dioxazine or 1,5,3-dioxazepine independent Optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Group, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF 3 or -CF 2 CH 3 Substituents are substituted.
在又一些实施方案中，R 3为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、HC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-O-C(＝O)-、乙基-O-C(＝O)-、正丙基-O-C(＝O)-、异丙基-O-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、甲基-C(＝NH)-、乙基-C(＝NH)-、正丙基-C(＝NH)-或异丙基-C(＝NH)-； In still other embodiments, R 3 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy Group, n-propoxy, isopropoxy, vinyl, 1-propynyl, 2-propynyl, ethynyl, 1-propynyl, 3-propynyl, HC(=O)-, methyl- C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC(=O)-, ethyl -OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -, isopropyl-S(=O) 2 -, methyl-C(=NH)-, ethyl-C(=NH)-, n-propyl -C(=NH)- or isopropyl-C(=NH)-;
其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-O-C(＝O)-、乙基-O-C(＝O)-、正丙基-O-C(＝O)-、异丙基-O-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、甲基-C(＝NH)-、乙基-C(＝NH)-、正丙基-C(＝NH)-和异丙基-C(＝NH)-各自独立任选地被1、2或3个选自氘、F、Cl、Br、I、-OH、-CN或-NH 2的取代基所取代。 Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy Base, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, methyl-C(=O)-, ethyl-C(=O)-, N-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O )-, isopropyl-OC(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -, isopropyl Base -S(=O) 2 -, methyl-C(=NH)-, ethyl-C(=NH)-, n-propyl-C(=NH)- and isopropyl-C(=NH) - each independently is optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH 2 to a substituent group.
在又一些实施方案中，R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8和R 9各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CF 2CH 2CH 3、-CH 2Cl、-CHCl 2、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-或异丙基-S(＝O) 2-。 In still other embodiments, R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 and R 9 are each independently hydrogen, deuterium, F, Cl, Br, I, -OH,- CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , methyl-C(=O)-, ethyl-C(=O)-, n-propyl-C (=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl-S(=O) 2- Or isopropyl-S(=O) 2 -.
在又一些实施方案中，R a为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基或噁唑基； In still other embodiments, R a is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl Base, 2-propynyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, sulfur Morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl , Thiazolyl or oxazolyl;
其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、 噻吩基、吡咯基、吡唑基、咪唑基、噻唑基和噁唑基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基或吡咯烷基的取代基所取代。 The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl , Tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl and oxazolyl each independently Optionally by 1, 2, 3 or 4 selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, n-propyl, Isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, sulfur Substituted by morpholinyl, tetrahydropyranyl, tetrahydrofuranyl or pyrrolidinyl substituents.
在又一些实施方案中，各R b独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、氧代、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、甲基-OC(＝O)-、乙基-OC(＝O)-、正丙基-OC(＝O)-、异丙基-OC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、环丙基甲基、环丙基乙基、环丙基正丙基、环丙基异丙基、环丁基甲基、环戊基甲基、环己基甲基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、-NR eC(＝O)甲基、-NR eC(＝O)乙基、-NR eC(＝O)正丙基、-NR eC(＝O)异丙基、-NR eR f、-S(＝O) 2-NR eR f、-C(＝O)-NR eR f、-甲基-NR eR f、-乙基-NR eR f、-正丙基-NR eR f或-异丙基-NR eR f； In still other embodiments, each R b is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, oxo, methyl, ethyl, normal Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl-OC(=O)- , Ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, ethyl-C(=O) )-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl -S(=O) 2 -, isopropyl-S(=O) 2 -, cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl n-propyl, cyclopropyl isopropyl, cyclobutyl methyl , Cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl , Tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, -NR e C(=O) methyl, -NR e C(=O) ethyl, -NR e C(=O) n-propyl, -NR e C(=O) isopropyl, -NR e R f , -S(=O) 2 -NR e R f , -C(=O)-NR e R f , -methyl-NR e R f , -ethyl-NR e R f , -n-propyl-NR e R f or -isopropyl-NR e R f ;
其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基甲基、环丙基乙基、环丙基正丙基、环丙基异丙基、环丁基甲基、环戊基甲基、环己基甲基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基和噁唑基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、正丙基、异丙基、甲氨基、二甲氨基、甲氧基、乙氧基、正丙氧基或异丙氧基的取代基所取代； Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy Cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl n-propyl, cyclopropyl isopropyl, cyclobutyl methyl, cyclopentyl methyl, cyclohexyl methyl, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazine Group, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl and oxazolyl are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, methylamino, dimethylamino, methoxy, ethoxy, Substituted by n-propoxy or isopropoxy substituents;
其中，各R e和R f具有本发明所述的含义。 Here, each of R e and R f has the meaning described in the present invention.
在又一些实施方案中，R c和R d各自独立地为氢、-OH、甲基、乙基、正丙基、异丙基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CF 2CH 2CH 3、-CH 2Cl、-CHCl 2、环丙基甲基、环丙基乙基、环丁基甲基、环戊基甲基、环己基甲基、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-或异丙基-S(＝O) 2-。 In still other embodiments, R c and R d are each independently hydrogen, -OH, methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, methyl-C(=O) -, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S( =O) 2 -, n-propyl-S(=O) 2 -or isopropyl-S(=O) 2 -.
在又一些实施方案中，R e和R f各自独立地为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲基-OC(＝O)-、乙基-OC(＝O)-、正丙基-OC(＝O)-、异丙基-OC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、环丙基、环丁基、环戊基、环己基、苯基、萘基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、环丙基甲基、环丙基乙基、环丙基正丙基、环丙基异丙基、环丁基甲基、环戊基甲基、环己基甲基、苯甲基、苯乙基、5-7个原子组成的杂环基-C 1-4烷基、吡啶基甲基、嘧啶基甲基、呋喃基甲基、噻吩基甲基、吡咯基甲基、吡唑基甲基、咪唑基甲基、噻唑基甲基、噁唑基甲基、-甲基-NR gR j、-乙基-NR gR j、-正丙基-NR gR j、-异丙基-NR gR j或
Figure PCTCN2021090489-appb-000015
In still other embodiments, R e and R f are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl -OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, Ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O ) 2 -, n-propyl-S(=O) 2 -, isopropyl-S(=O) 2 -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, piper Azinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, Pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl n-propyl, cyclopropyl isopropyl, cyclobutyl methyl, cyclopentyl Methyl, cyclohexylmethyl, benzyl, phenethyl, heterocyclic group composed of 5-7 atoms -C 1-4 alkyl, pyridylmethyl, pyrimidinylmethyl, furylmethyl, thiophene Methyl, pyrrolyl methyl, pyrazolyl methyl, imidazolyl methyl, thiazolyl methyl, oxazolyl methyl, -methyl -NR g R j , -ethyl -NR g R j ,- N-propyl-NR g R j , -isopropyl-NR g R j or
Figure PCTCN2021090489-appb-000015
或者R e和R f与它们相连的N原子一起形成氮杂环丁基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基或哌嗪基； Or R e and R f together with the N atom to which they are connected form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
其中所述的R e、R f、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基和哌嗪基各自独立任选地被1、2、3或4个R h所取代； Wherein said R e , R f , azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently optionally substituted by 1, 2, 3 or 4 Replaced by R h;
其中，各R h、R g和R j具有本发明所述的含义。 Among them, each of R h , R g and R j has the meaning described in the present invention.
在又一些实施方案中，各R h独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、三氟甲氧基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。 In still other embodiments, each R h is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy Group, sec-butoxy or tert-butoxy.
在又一些实施方案中，R g和R j各自独立地为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲基-OC(＝O)-、乙基-OC(＝O)-、正丙基-OC(＝O)-、异丙基-OC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、环丙基、环丁基、环戊基、环己基、苯基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基或噁唑基。 In still other embodiments, R g and R j are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl -OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, Ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O ) 2 -, n-propyl-S(=O) 2 -, isopropyl-S(=O) 2 -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, piperazinyl, Piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, Pyrazolyl, imidazolyl, thiazolyl or oxazolyl.
在又一些实施方案中，R m和R n各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、甲基、乙基、正丙基、异丙基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2Cl、-CHCl 2或-C(＝O)NH 2。 In still other embodiments, R m and R n are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl Group, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 Cl, -CHCl 2 or- C(=O)NH 2 .
另一方面，本发明涉及一种化合物，其为式(II)所示的化合物或式(II)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：In another aspect, the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (II) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
Figure PCTCN2021090489-appb-000016
Figure PCTCN2021090489-appb-000016
其中各X、Y、R 1、R 2、R 3、R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8、R 9、A、R a、R b和n具有本发明所述的含义。 Wherein each of X, Y, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 , R 9 , A, R a , R b and n has the The meaning of the invention.
另一方面，本发明涉及一种化合物，其为式(III)所示的化合物或式(III)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：In another aspect, the present invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (III) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
Figure PCTCN2021090489-appb-000017
Figure PCTCN2021090489-appb-000017
其中各X、Y、R 1、R 2、R 3、R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8、R 9、A、R a、R b和n具有本发明所述的含义。 Wherein each of X, Y, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 , R 9 , A, R a , R b and n has the The meaning of the invention.
另一方面，本发明涉及一种化合物，其为式(IV)所示的化合物或式(IV)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：In another aspect, the present invention relates to a compound, which is a compound represented by formula (IV) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (IV) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
Figure PCTCN2021090489-appb-000018
Figure PCTCN2021090489-appb-000018
其中各X、Y、R 1、R 2、R 3、R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8、R 9、A、R a、R b和n具有本发明所述的含义。 Wherein each of X, Y, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 , R 9 , A, R a , R b and n has the The meaning of the invention.
另一方面，本发明涉及一种化合物，其为式(V)所示的化合物或式(V)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：In another aspect, the present invention relates to a compound, which is a compound represented by formula (V) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (V) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
Figure PCTCN2021090489-appb-000019
Figure PCTCN2021090489-appb-000019
其中各X、Y、R 1、R 2、R 3、R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8、R 9、A、R a、R b和n具有本发明所述的含义。 Wherein each of X, Y, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 , R 9 , A, R a , R b and n has the The meaning of the invention.
另一方面，本发明涉及一种化合物，其为式(VI)所示的化合物或式(VI)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：In another aspect, the present invention relates to a compound, which is a compound represented by formula (VI) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of the compound represented by formula (VI) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
Figure PCTCN2021090489-appb-000020
Figure PCTCN2021090489-appb-000020
其中各X、Y、R 1、R 2、R 3、R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8、R 9、A、R a、R b和n具有本发明所述的含义。 Wherein each of X, Y, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 , R 9 , A, R a , R b and n has the The meaning of the invention.
另一方面，本发明涉及一种化合物，其为式(VII)所示的化合物或式(VII)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：In another aspect, the present invention relates to a compound that is a compound represented by formula (VII) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (VII) , Metabolites, pharmaceutically acceptable salts or their prodrugs:
Figure PCTCN2021090489-appb-000021
Figure PCTCN2021090489-appb-000021
其中各X、Y、R 1、R 2、R 3、R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8、R 9、A、R a、R b和n具有本发明所述的含义。 Wherein each of X, Y, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 , R 9 , A, R a , R b and n has the The meaning of the invention.
在一些实施方案中，本发明包含但绝不限于具有下列之一结构的化合物或具有下列之一结构化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：In some embodiments, the present invention includes, but is by no means limited to, compounds having one of the following structures or stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolism of compounds having one of the following structures Products, pharmaceutically acceptable salts or their prodrugs:
Figure PCTCN2021090489-appb-000022
Figure PCTCN2021090489-appb-000022
Figure PCTCN2021090489-appb-000023
Figure PCTCN2021090489-appb-000023
Figure PCTCN2021090489-appb-000024
Figure PCTCN2021090489-appb-000024
Figure PCTCN2021090489-appb-000025
Figure PCTCN2021090489-appb-000025
Figure PCTCN2021090489-appb-000026
Figure PCTCN2021090489-appb-000026
Figure PCTCN2021090489-appb-000027
Figure PCTCN2021090489-appb-000027
Figure PCTCN2021090489-appb-000028
Figure PCTCN2021090489-appb-000028
Figure PCTCN2021090489-appb-000029
Figure PCTCN2021090489-appb-000029
Figure PCTCN2021090489-appb-000030
Figure PCTCN2021090489-appb-000030
Figure PCTCN2021090489-appb-000031
Figure PCTCN2021090489-appb-000031
Figure PCTCN2021090489-appb-000032
Figure PCTCN2021090489-appb-000032
Figure PCTCN2021090489-appb-000033
Figure PCTCN2021090489-appb-000033
Figure PCTCN2021090489-appb-000034
Figure PCTCN2021090489-appb-000034
Figure PCTCN2021090489-appb-000035
Figure PCTCN2021090489-appb-000035
Figure PCTCN2021090489-appb-000036
Figure PCTCN2021090489-appb-000036
Figure PCTCN2021090489-appb-000037
Figure PCTCN2021090489-appb-000037
Figure PCTCN2021090489-appb-000038
Figure PCTCN2021090489-appb-000038
Figure PCTCN2021090489-appb-000039
Figure PCTCN2021090489-appb-000039
在一些实施方案中，本发明式(I)所示的化合物，其药学上可接受的盐是盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、丙酮酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合。In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, and maleic acid. Salt, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucose Alkate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methane Sulfonate, ethanesulfonate, trifluoromethanesulfonate, or a combination thereof.
一方面，本发明涉及一种药物组合物，所述药物组合物包含本发明公开的式(I)、(II)、(III)、(IV)、(V)或(VI)所述的化合物。In one aspect, the present invention relates to a pharmaceutical composition comprising the compound of formula (I), (II), (III), (IV), (V) or (VI) disclosed in the present invention .
在一些实施方案中，本发明所述的药物组合物，其进一步地包含药学上可接受的载体、赋形剂、附加剂、辅剂、媒介物或它们的任意组合。In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, adjuvant, vehicle, or any combination thereof.
在另一些实施方案中，本发明所述的药物组合物，进一步地包含附加治疗剂，其中所述的附加治疗剂是：丙酮酸钠、多索茶碱、替托司特、泰鲁司特、茶碱、福莫特罗、沙美特罗、氟替卡松丙酸酯、咯利普兰、吡拉米斯特、西洛司特、茚达特罗、奥达特罗、米地司坦、齐流通、沙丁醇胺、卡莫昔罗、布地奈德、二丙酸倍氯米松、曲安奈德、氟尼缩松、糠酸莫米松、罗氟奈德、环索奈德、异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、芜地溴铵、维兰特罗、阿地溴铵、Benralizumab、Tralokinumab、瑞伐托酯、克瑞沙硼、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、地索奈德、氢化可的松、氯倍他索(clobatsol)、卤贝他索、二氟拉松、美普克莱、他克莫司、吡美莫司、他扎罗汀、环孢素、阿普斯特、E-6005、OPA-15406、LEO-29102、DRM02、罗氟司特、异丁司特、托法替尼、JTE-052、巴瑞替尼、乌帕替尼、WBI-1001、MRX-6、GSK2981278、杜鲁单抗、来金珠单抗、尼莫利珠单抗、曲洛吉努单抗、依那西普、 阿达木单抗、英夫利昔单抗、尤特可单抗、塞库吉努、奥马珠、CIM-331、戈利木单抗和聚乙二醇化赛、妥珠单抗、卡泊三醇、骨化三醇、阿利维A酸、VTP-38543、ZPL-389、阿瑞匹坦、曲地匹坦、弗维普兰特、、OC-459、SUN 13834、SB-011、VTP-43742、ARN6039、TAK-828、JTE-451、PF-04965842、PF-06651600、PF-06700841、PF-06650833、GR-MD-02或它们的任意组合。In other embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, telukast , Theophylline, Formoterol, Salmeterol, Fluticasone Propionate, Rolipram, Piramister, Cilomilast, Indacaterol, Odaterol, Midistein, Qi Circulation , Salbutamol, carmoxirol, budesonide, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, rofluonide, ciclesonide, ipratropium bromide Ammonium, oxotropium bromide, tiotropium bromide, glycopyrrolate, umeclidinium bromide, vilanterol, aclidinium bromide, Benralizumab, Tralokinumab, revatorate, crisaboron, fluocinolone acetate , Dexamethasone, Mometasone, Triamcinolone, Betamethasone, Alclomethasone, Dessonide, Hydrocortisone, Clobatsol, Halobetasol, Diflurazone, Mepaclil, Tacrolimus, Pimecrolimus, Tazarotene, Cyclosporine, Apemilast, E-6005, OPA-15406, LEO-29102, DRM02, Roflumilast, Isobutyl Ster, Tofacitinib, JTE-052, Baritinib, Upatinib, WBI-1001, MRX-6, GSK2981278, Duluzumab, Lekinizumab, Nimolizumab, Trelocinumumab, Etanercept, Adalimumab, Infliximab, Utecomumab, Secucinum, Omazu, CIM-331, Golimumab, and Polyethylene Dioxide Alcohol, Tocilizumab, Calcipotriol, Calcitriol, Aliretinoin, VTP-38543, ZPL-389, Aprepitant, Tradipitan, Fveveplante, OC-459 , SUN 13834, SB-011, VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02 or any combination thereof.
另一方面，本发明涉及本发明公开的式(I)、(II)、(III)、(IV)、(V)或(VI)所示化合物或其药物组合物在制备药物中的用途，其中所述药物用于预防、治疗或减轻与4型磷酸二酯酶(PDE4)有关的疾病。On the other hand, the present invention relates to the use of the compound represented by formula (I), (II), (III), (IV), (V) or (VI) or its pharmaceutical composition disclosed in the present invention in the preparation of medicines, The medicine is used to prevent, treat or alleviate diseases related to phosphodiesterase type 4 (PDE4).
在一些实施方案中，所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病或非胰岛素依赖糖尿病。In some embodiments, the disease associated with phosphodiesterase type 4 is respiratory disease, allergy, inflammation, central nervous system disease, or non-insulin dependent diabetes.
在另一些实施方案中，所述的呼吸疾病为：慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症；其中支气管炎包括急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎；In other embodiments, the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, Acute respiratory distress syndrome or inflammation of the respiratory tract; among which bronchitis includes acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;
其中所述的炎症为：过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。The inflammation mentioned is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatic Arthritis or psoriatic arthritis.
本发明另一方面涉及式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物的制备、分离和纯化的方法。Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I), (II), (III), (IV), (V) or (VI).
另一方面，本发明涉及制备式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示化合物的中间体。In another aspect, the present invention relates to intermediates for preparing compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII).
本发明公开化合物可含有不对称或手性中心，因此可以不同的立体异构体形式存在。本发明旨在使式(I)所示化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体、阻转异构体和几何(或构象)异构体，以及它们的混合物如外消旋混合物，成为本发明的组成部分。The compounds disclosed in the present invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomer forms. The present invention aims to make all stereoisomeric forms of the compound represented by formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers As well as their mixtures, such as racemic mixtures, become an integral part of the present invention.
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体都考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。In the structure disclosed in the present invention, when the stereochemistry of any specific chiral atom is not specified, all stereoisomers of the structure are considered in the present invention and are included in the present invention as the compound disclosed in the present invention . When stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, then the stereoisomer of the structure is clear and defined.
式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示化合物可以以不同的互变异构体形式存在，并且所有这些互变异构体，都包括在本发明范围内。The compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) can exist in different tautomeric forms, and all these tautomers Body, are all included in the scope of the present invention.
本发明化合物的药物组合物、制剂和给药Pharmaceutical composition, formulation and administration of the compound of the present invention
本发明提供一种药物组合物，包括式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示化合物或其单独的立体异构体，异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂化物。在本发明的一个实施方式中，所述药物组合物进一步包含至少一种药学上可接受的载体、赋形剂或吸附剂，以及任选地，其它的治疗和/或预防成分。The present invention provides a pharmaceutical composition comprising a compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) or its individual stereoisomers, Racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof. In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient or adsorbent, and optionally, other therapeutic and/or preventive components.
合适的载体、赋形剂或吸附剂对于本领域技术人员是熟知的并且详细描述于例如Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al.,Remington：The Science and Practice of Pharmacy(2000)Lippincott,Williams&Wilkins,Philadelphia；和Rowe R.C.,Handbook of Pharmaceutical Excipients(2005)Pharmaceutical Press,Chicago中。Suitable carriers, excipients or adsorbents are well known to those skilled in the art and are described in detail in, for example, Ansel HCet al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro ARet al. ., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
本发明所用“药学上可接受的赋形剂”意指与给药剂型或药物组合物一致性相关的药学上可接受的材料，混合物或溶媒。每种赋形剂在混合时必须与药物组合物的其它成分相容，以避免对患者给药时会大大降低本发明公开化合物的功效的相互作用和会导致不是药学上可接受的药物组合物的相互作用。此外，每种赋形剂必须是药学上可接受的，例如，具有足够高的纯度。The "pharmaceutically acceptable excipient" used in the present invention means a pharmaceutically acceptable material, mixture or vehicle related to the consistency of the dosage form or the pharmaceutical composition. Each excipient must be compatible with other ingredients of the pharmaceutical composition when mixed to avoid interactions that would greatly reduce the efficacy of the compounds disclosed in the present invention when administered to patients and lead to pharmaceutical compositions that are not pharmaceutically acceptable Interaction. In addition, each excipient must be pharmaceutically acceptable, for example, with sufficiently high purity.
合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外，可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。例如，可选择能有助于生产均一剂型的某些药学上可接受的赋形剂。可选择能有助于生产稳定剂型的某些药学上可接受的赋形剂。可选择对患者给药时有助于携带或运输本发明化合 物从身体的一个器官或部分到身体的另一个器官或部分的某些药学上可接受的赋形剂。可选择增强患者依从性的某些药学上可接受的赋形剂。Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, pharmaceutically acceptable excipients can be selected according to their specific functions in the composition. For example, certain pharmaceutically acceptable excipients can be selected that can help produce a uniform dosage form. Certain pharmaceutically acceptable excipients can be selected that can help produce a stable dosage form. Certain pharmaceutically acceptable excipients can be selected to help carry or transport the compound of the invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients can be selected to enhance patient compliance.
一些合适的赋型剂实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、西黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。合适的药学上可接受的赋形剂还包括以下类型的赋形剂：溶媒、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏着剂、抗氧剂、螯合剂、渗透促进剂、pH调节剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂和助滤剂。技术人员可认识到，某些药学上可接受的赋形剂可提供不止一种功能，并提供可供选择的功能，这取决于制剂中存在多少该赋形剂和制剂中存在哪些其他赋形剂。可以采用本领域的已知方法来配制本发明化合物，以便对患者给药后能快速、持续或延缓释放出活性组份。Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, Polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, lubricants Wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjustment Agents, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants and filter aids. The skilled person can recognize that certain pharmaceutically acceptable excipients can provide more than one function and provide alternative functions, depending on how many of these excipients are present in the formulation and what other excipients are present in the formulation Agent. Methods known in the art can be used to formulate the compounds of the present invention so that the active ingredients can be released quickly, continuously or delayed after being administered to the patient.
技术人员掌握本领域的知识和技能，以使他们能选择用于本发明的适当量的合适的药学上可接受的赋形剂。此外，存在大量技术人员可获得的资源，他们描述药学上可接受的赋形剂，并用于选择合适的药学上可接受的赋形剂。实例包括Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。The skilled person has knowledge and skills in the art so that they can select the appropriate amount of suitable pharmaceutically acceptable excipients for use in the present invention. In addition, there are a large number of resources available to technicians who describe pharmaceutically acceptable excipients and use them to select appropriate pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Press).
在Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York中披露了用于配置药学上可接受的组合物的各种载体，和用于其制备的公知技术，这些文献各自的内容通过引用并入本发明。除任何诸如因产生任何不期望的生物作用，或以有害方式与药学上可接受组合物中的任何其它成分发生相互作用而与本发明化合物不相容的任何常用载体外，关注其应用属于本发明的范围。In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.DBTroy, Lippincott Williams&Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.SwarbrickYorkker, New York, 1988-1999, Various carriers for formulating pharmaceutically acceptable compositions and well-known techniques for their preparation are disclosed, and the contents of each of these documents are incorporated into the present invention by reference. Except for any commonly used carriers that are incompatible with the compounds of the present invention due to any undesired biological effects, or interactions with any other ingredients in a pharmaceutically acceptable composition in a harmful manner, the application of concern belongs to the present invention. The scope of the invention.
合适的药学上可接受的载体取决于药物形式并且是本领域技术人员所知的。Suitable pharmaceutically acceptable carriers depend on the form of the drug and are known to those skilled in the art.
如本发明中使用的，“药学上可接受的载体”包括任何和全部的溶剂和溶剂混合物，涂层，络合剂，固体载体，分散体介质，表面活性赋形剂，抗细菌和抗真菌药，用于药物活性物质的等渗和吸收延迟剂，和其混合物，这些同样是本领域已知的。As used in the present invention, "pharmaceutically acceptable carrier" includes any and all solvents and solvent mixtures, coatings, complexing agents, solid carriers, dispersion media, surface active excipients, antibacterial and antifungal Medicines, isotonic and absorption delaying agents for pharmaceutically active substances, and mixtures thereof, these are also known in the art.
用于药学上可接受的载体的非限制性实例包括具有选自如下组分的那些：乳糖，明胶，糖醇(例如淀粉，甘露醇，玉米淀粉等)，植物油，滑石，硬脂酸镁，胶体二氧化硅，羧甲基纤维素，微晶纤维素，十二烷硫酸钠，缓冲水溶液，共聚维酮，聚山梨酸酯，乙醇，丙二醇，聚二醇(优选地聚乙二醇，例如PEG400)，
Figure PCTCN2021090489-appb-000040
(即PEG(20)，山梨糖醇一油酸酯)，DMSO，水和助溶剂的混合物，例如包括醇如乙醇和/或聚二醇如聚乙二醇的水溶液，多元醇如甘油和/或聚乙二醇与脂肪酸的酯，表面活性剂如阴离子、阳离子、非离子和两性表面活性剂，络合剂如环糊精，例如α-环糊精(α-CD)或者羟丙基-β-环糊精(HP-β-CD)，胆汁酸或者脂质，例如动物或者植物磷脂的盐，成胶束剂，和油如玉米油，或前面提及的两种或更多种组分的混合物。 Non-limiting examples of pharmaceutically acceptable carriers include those having components selected from lactose, gelatin, sugar alcohols (such as starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, Colloidal silicon dioxide, carboxymethyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, buffered aqueous solution, copovidone, polysorbate, ethanol, propylene glycol, polyglycol (preferably polyethylene glycol, such as PEG400),
Figure PCTCN2021090489-appb-000040
(Ie PEG(20), sorbitol monooleate), DMSO, a mixture of water and co-solvents, for example, including an aqueous solution of alcohols such as ethanol and/or polyglycols such as polyethylene glycol, polyhydric alcohols such as glycerol and/ Or esters of polyethylene glycol and fatty acids, surfactants such as anionic, cationic, nonionic and amphoteric surfactants, complexing agents such as cyclodextrins, such as α-cyclodextrin (α-CD) or hydroxypropyl- β-cyclodextrin (HP-β-CD), bile acids or lipids, such as salts of animal or plant phospholipids, micelle forming agents, and oils such as corn oil, or two or more of the aforementioned groups Mixture of points.
下面提及可用于本发明的药物组合物的进一步的合适的药学上可接受的载体以及合适的添加剂的非限制性实例。Non-limiting examples of further suitable pharmaceutically acceptable carriers and suitable additives that can be used in the pharmaceutical composition of the present invention are mentioned below.
在一个实施方案中，本发明涉及本发明的药物组合物，其在水介质中形成基于脂质的药物输送系统(DDS)。所述药物组合物，除式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物中的至少一种化合物或其盐以外，还包括至少一种表面活性剂。合适的表面活性剂的非限制性实例是如上所述的。在各种实施方案中，基于脂质的药物输送系统形成以下结构：(1)脂质体(即水中层状相的分散闭合的双层组装 体)；(2)非层状相(例如立方体、六角形、海绵状物)的纳米颗粒；或(3)胶束，乳状液，微乳状液(即脂质和表面活性剂的简单自组装结构)。In one embodiment, the present invention relates to the pharmaceutical composition of the present invention, which forms a lipid-based drug delivery system (DDS) in an aqueous medium. The pharmaceutical composition, in addition to at least one compound or a salt thereof among the compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII), At least one surfactant is also included. Non-limiting examples of suitable surfactants are as described above. In various embodiments, lipid-based drug delivery systems form the following structures: (1) liposomes (ie, dispersed and closed bilayer assemblies of lamellar phase in water); (2) non-lamellar phase (e.g. cubic , Hexagonal, sponge) nanoparticles; or (3) micelles, emulsions, microemulsions (ie simple self-assembled structures of lipids and surfactants).
在一些实施方案中，形成胶束、乳状液或者微乳状液的基于脂质的药物输送系统是优选的。用于形成胶束、乳状液或微乳状液的合适的表面活性剂或者表面活性剂混合物的亲水亲油平衡值(HLB-值)一般为约8-18，约10-18，或约12-16。基于脂质的药物输送系统形成自乳化药物输送系统(SEDDS)或者自微乳化药物输送系统(SMEDDS)。SEDDS和SMEDDS是油(即脂质，例如式(I)的化合物或者其盐)，至少一种表面活性剂，任选地至少一种助溶剂和任选地至少一种助表面活性剂的混合物，理想地各向同性的，在温和的搅拌下当被引入水相时，其自发地乳化而形成水包油乳化剂。温和的搅拌可以例如由胃的活动性提供。In some embodiments, lipid-based drug delivery systems that form micelles, emulsions, or microemulsions are preferred. The hydrophilic-lipophilic balance (HLB-value) of a suitable surfactant or surfactant mixture used to form micelles, emulsions or microemulsions is generally about 8-18, about 10-18, or about 12 -16. Lipid-based drug delivery systems form a self-emulsifying drug delivery system (SEDDS) or a self-microemulsifying drug delivery system (SMEDDS). SEDDS and SMEDDS are a mixture of oils (ie lipids, such as compounds of formula (I) or salts thereof), at least one surfactant, optionally at least one co-solvent and optionally at least one co-surfactant , Ideally isotropic, when introduced into the water phase under gentle agitation, it spontaneously emulsifies to form an oil-in-water emulsifier. Gentle agitation can be provided, for example, by the mobility of the stomach.
本发明公开的药物组合物使用本领域技术人员已知的技术和方法来制备。本领域一些常用方法的描述可参见Remington's Pharmaceutical Sciences(Mack Publishing Company)。The pharmaceutical composition disclosed in the present invention is prepared using techniques and methods known to those skilled in the art. For descriptions of some commonly used methods in this field, please refer to Remington's Pharmaceutical Sciences (Mack Publishing Company).
因此，另一方面，本发明涉及制备药物组合物的工艺，所述药物组合物包含本发明公开化合物和药学上可接受的赋形剂，载体，辅剂，溶媒或它们的组合，该工艺包括混合各种成分。包含本发明公开化合物的药物组合物，可以在例如环境温度和大气压下混合来制备。Therefore, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed in the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or a combination thereof, the process comprising Mix the various ingredients. The pharmaceutical composition containing the compound disclosed in the present invention can be prepared by mixing at, for example, ambient temperature and atmospheric pressure.
本发明公开的化合物通常被配制成适合于通过所需途径对患者给药的剂型。例如，所述剂型包括那些适合于以下给药途径的剂型：(1)口服给药，例如片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、香包剂和扁囊剂；(2)胃肠外给药，例如无菌溶液剂、混悬剂和复溶粉末；(3)透皮给药，例如透皮贴片剂；(4)直肠给药，例如栓剂；(5)吸入，例如气雾剂、溶液剂和干粉剂；和(6)局部给药，例如乳膏剂、油膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。The compounds disclosed in the present invention are usually formulated into a dosage form suitable for administration to a patient through a desired route. For example, the dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions Preparations, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3) transdermal administration, such as transdermal patches Tablets; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, Pastes, sprays, foams and gels.
将各种固体口服剂型用于本发明化合物的给药，例如片剂、胶囊、颗粒、锭剂和散装粉末的固体剂型。可以将本发明化合物单独给药或与本领域已知的各种药学上可接受的载体和赋形剂(例如，蔗糖、甘露醇、乳糖、淀粉)组合给药，包括但不限于助悬剂、增溶剂、缓冲剂、粘合剂、崩解剂、防腐剂、着色剂、调味剂、润滑剂等。定时释放胶囊、片剂和凝胶剂对于本发明化合物的给药也是有利的。Various solid oral dosage forms are used for the administration of the compound of the present invention, such as solid dosage forms of tablets, capsules, granules, lozenges and bulk powders. The compound of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers and excipients known in the art (for example, sucrose, mannitol, lactose, starch), including but not limited to suspending agents , Solubilizers, buffers, binders, disintegrants, preservatives, coloring agents, flavoring agents, lubricants, etc. Time-release capsules, tablets and gels are also advantageous for the administration of the compounds of the invention.
可以将各种外用剂型用于本发明化合物的给药，例如洗剂、软膏剂、酊剂、擦剂、醑剂、粉剂、霜剂、油剂、糊剂、硬膏剂、涂膜剂和气雾剂。局部给药还可以包括通过例如透皮贴片的方式进行的透皮给药。可以将本发明化合物单独给药或与本领域已知的各种药学上可接受的载体、稀释剂和赋形剂组合给药，包括但不限于溶剂、油性溶剂、稀释剂、安定剂、吸收延迟剂、崩散剂、乳化剂、抗氧化剂、粘合剂、结合剂、增粘剂、增溶剂、分散剂、悬乳化剂、润滑剂、吸湿剂、脂质体、微乳和β-环糊精等。Various external dosage forms can be used for the administration of the compounds of the present invention, such as lotions, ointments, tinctures, liniments, spirits, powders, creams, oils, pastes, plasters, coatings and aerosols . Local administration may also include transdermal administration by means of, for example, a transdermal patch. The compound of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents and excipients known in the art, including but not limited to solvents, oily solvents, diluents, stabilizers, absorption Delay agents, disintegrating agents, emulsifiers, antioxidants, adhesives, binding agents, viscosity increasing agents, solubilizers, dispersants, suspoemulsifiers, lubricants, hygroscopic agents, liposomes, microemulsions and β-cyclopaste Jing etc.
对于呼吸道疾病的治疗，优选本发明的化合物通过吸入给药。For the treatment of respiratory diseases, the compounds of the present invention are preferably administered by inhalation.
可吸入制备物包括可吸入的粉剂、含推进剂的计量气雾剂或不含推进剂的可吸入制剂。为此，可以以粉剂(最好为微粒化形式)直接给药，或通过含有它们的喷雾溶液剂或混悬液给药。Inhalable preparations include inhalable powders, propellant-containing metered aerosols, or propellant-free inhalable preparations. For this purpose, it can be administered directly as a powder (preferably in a micronized form), or via a spray solution or suspension containing them.
可以向本发明的粉末化合物加入赋形剂或载体，所述赋形剂或载体通常是无毒的并且对于本发明的化合物为化学惰性的，例如乳糖或适合于改善可呼吸部分的任何其他添加剂。An excipient or carrier may be added to the powder compound of the present invention, which is generally non-toxic and chemically inert to the compound of the present invention, such as lactose or any other additives suitable for improving the respirable portion .
包含气体推进剂例如氢氟烷烃的吸入气雾剂可以包含溶液或分散型形式的本发明化合物。推进剂驱动的制剂还可以包含其他成分，例如共溶剂、稳定剂和任选的其他赋形剂。Inhalation aerosols containing gaseous propellants such as hydrofluoroalkanes may contain the compounds of the invention in solution or dispersed form. Propellant-driven formulations may also contain other ingredients, such as co-solvents, stabilizers, and optional other excipients.
含本发明化合物的不含推进剂的可吸入制剂可以是在含水介质、醇类介质或含水酒精介质中的溶液或悬浮液形式，并且它们可以通过现有技术已知的喷射雾化器或超声雾化器递送，或者通过细雾雾化器(soft-mist nebulizers)例如
Figure PCTCN2021090489-appb-000041
递送。 The propellant-free inhalable formulations containing the compounds of the present invention may be in the form of solutions or suspensions in aqueous media, alcoholic media, or aqueous alcoholic media, and they can be passed through jet nebulizers or ultrasonics known in the art. Nebulizer delivery, or through soft-mist nebulizers such as
Figure PCTCN2021090489-appb-000041
deliver.
本发明所使用的术语“治疗有效量”是指足以显示出有益的治疗效果的各活性组分的总量。例如，给药或使体内达到平衡的足以治疗、治愈或减轻疾病的症状的量。特殊的治疗方案所需的有效量依赖于多种因 素，包括治疗的疾病，疾病的严重程度，使用的特定药物的活性，给药方式，特定药物的清除率，治疗持续时间，联合用药，年龄，体重，性别，饮食和病人的健康等。本领域关于“治疗有效量”需要考虑的其他因素的描述可参见Gilman et al.,eds.,Goodman And Gilman’s:The Pharmacological Bases of Therapeutics,8 th ed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17 th ed.,Mack Publishing Company,Easton,Pa.,1990。 The term "therapeutically effective amount" used in the present invention refers to the total amount of each active ingredient sufficient to show a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate the symptoms of the disease is administered or brought into balance in the body. The effective amount required for a particular treatment regimen depends on many factors, including the disease to be treated, the severity of the disease, the activity of the specific drug used, the method of administration, the clearance rate of the specific drug, the duration of treatment, the combination of drugs, and age , Weight, gender, diet and patient’s health, etc. This art description of other factors "therapeutically effective amount" to be considered may be found in Gilman et al, eds, Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8 th ed, Pergamon Press, 1990; Remington's Pharmaceutical Sciences, 17... th ed., Mack Publishing Company, Easton, Pa., 1990.
本发明的化合物的剂量取决于多种因素，包括要治疗的具体疾病、症状的严重程度、给药途径、剂量间隔频率、所用的具体化合物、化合物的效力、毒理学特征和药代动力学的特征。The dosage of the compound of the present invention depends on a variety of factors, including the specific disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dose interval, the specific compound used, the potency of the compound, the toxicological characteristics and the pharmacokinetics. feature.
可与载体材料相组合从而产生单剂量形式的活性成分的量将取决于被治疗的宿主和特定的施用方式而变化。例如，意欲涂抹施用给人的制剂可以方便地含有约5mg至约250mg/千克体重/天的活性剂，其与合适且方便的量的载体材料(可占总组合物的大约5％至大约95％)相复合。单位剂量形式一般将包含大约1mg至大约500mg的活性成分。The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. For example, a formulation intended for application to humans may conveniently contain about 5 mg to about 250 mg/kg body weight/day of the active agent together with a suitable and convenient amount of carrier material (which may account for about 5% to about 95% of the total composition. %) phase composite. A unit dosage form will generally contain from about 1 mg to about 500 mg of active ingredient.
有利地，它们以5-250mg/千克体重/天，优选地25-150mg/千克体重/天剂量给药。Advantageously, they are administered at a dose of 5-250 mg/kg body weight/day, preferably 25-150 mg/kg body weight/day.
术语“给药”指给个体提供治疗有效量的药物，给药方式包括口服，舌下，静脉，皮下，经皮，肌内，皮内，鞘内，硬膜上，眼内，颅内，吸入，直肠，阴道等。给药剂型包括膏剂，洗剂，片剂，胶囊剂，丸剂，飞散性粉末剂，颗粒剂，栓剂，丹剂，锭剂，注射剂，无菌溶液或非水溶液剂，悬浮剂，乳剂，贴片剂等。活性组分与无毒的药学上可接受的载体(如葡萄糖，乳糖，阿拉伯树胶，明胶，甘露醇，淀粉糊，三硅酸镁，滑石粉，玉米淀粉，角蛋白，硅胶，土豆淀粉，尿素，右旋糖酐等)复合。The term "administration" refers to providing a therapeutically effective amount of a drug to an individual. The administration methods include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, supradural, intraocular, and intracranial, Inhalation, rectum, vagina, etc. Dosage forms include ointment, lotion, tablet, capsule, pill, dispersible powder, granule, suppository, pill, lozenge, injection, sterile solution or non-aqueous solution, suspension, emulsion, patch剂 etc. Active ingredients and non-toxic pharmaceutically acceptable carriers (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea) , Dextran, etc.) compound.
优选的给药途径会随着临床特征而变化，剂量的变化必须依赖于正在治疗的病人的情况，医生会根据个体患者来确定合适的剂量。每单位剂量的治疗有效量取决于体重，生理机能和选择的接种方案。每单位剂量的化合物是指每次给药时化合物的重量，不包括载体的重量(药物里含有载体)。The preferred route of administration will vary with clinical characteristics, and the dose must vary depending on the condition of the patient being treated. The doctor will determine the appropriate dose according to the individual patient. The therapeutically effective amount per unit dose depends on body weight, physiological function and the chosen vaccination schedule. The compound per unit dose refers to the weight of the compound per administration, excluding the weight of the carrier (the drug contains the carrier).
本发明提供的药物组合物可以配制成单剂量或多剂量给药。所述单剂量制剂被包装在安瓿剂、小瓶或注射器中。所述多剂量肠胃外制剂必须包含抑菌或抑真菌浓度的抗微生物剂。所有的肠胃外制剂都必须是无菌的，如本领域已知和实践的。The pharmaceutical composition provided by the present invention can be formulated for single-dose or multiple-dose administration. The single-dose preparation is packaged in ampoules, vials or syringes. The multi-dose parenteral preparation must contain an antimicrobial agent in a bacteriostatic or fungicidal concentration. All parenteral preparations must be sterile, as known and practiced in the art.
本发明提供的药物组合物可以与不会损害预期的治疗作用的其它活性成分共同配制，或者与补充预期的作用的物质共同配制。The pharmaceutical composition provided by the present invention can be formulated with other active ingredients that will not impair the expected therapeutic effect, or with a substance that supplements the expected effect.
在一实施方案中，本发明的治疗方法包括对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物。本发明各实施方案包括通过对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物，来治疗本发明提及的疾病。In one embodiment, the treatment method of the present invention includes administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need. Various embodiments of the present invention include the treatment of the diseases mentioned in the present invention by administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need.
在一实施方案中，本发明化合物或包含本发明化合物的药物组合物可以一次性给药，或者根据给药方案，在指定时间段内，在不同的时间间隔给药若干次。例如，每天给药一次、两次、三次或四次。在一实施方案中，每天给药一次。在又一实施方案中，每天给药两次。可以给药直至达到想要的治疗效果或无限期地维持想要的治疗效果。本发明化合物或包含本发明化合物的药物组合物的合适给药方案取决于该化合物的药代动力学性质，例如吸收、分布和半衰期，这些可以由技术人员测定。此外，本发明化合物或包含本发明化合物的药物组合物的合适给药方案，包括实施该方案的持续时间，取决于被治疗的疾病，被治疗疾病的严重程度、被治疗患者的年龄和身体状况、被治疗患者的医疗史、同时疗法的性质、想要的治疗效果等在技术人员知识和经验范围内的因素。这样的技术人员还应该理解，对于个体患者对给药方案的反应，或随着时间推移个体患者需要变化时，可要求调整适宜的给药方案。In one embodiment, the compound of the present invention or a pharmaceutical composition containing the compound of the present invention may be administered at one time, or according to a dosage regimen, administered several times at different time intervals within a specified period of time. For example, it may be administered once, twice, three or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, it is administered twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosage regimen of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, which can be determined by the skilled person. In addition, the appropriate dosage regimen of the compound of the present invention or the pharmaceutical composition containing the compound of the present invention, including the duration of implementation of the regimen, depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated , The medical history of the patient being treated, the nature of the simultaneous therapy, the desired treatment effect and other factors within the scope of the knowledge and experience of the technicians. Such technicians should also understand that the response of the individual patient to the dosing regimen, or when the individual patient's needs change over time, may require adjustment of the appropriate dosing regimen.
本发明化合物可以与一种或多种其它治疗剂同时，或在其之前或之后给药。本发明化合物可以与其他治疗剂通过相同或不同给药途径分别给药，或与之以同一药物组合物形式给药。这由本领域技术人员根据患者的健康、年龄、体重等身体的实际情况选择。如果配制为固定剂量，这种联用产品使用本发明的化合 物(在本发明所描述的剂量范围之内)和其他药学活性剂(在其剂量范围之内)。The compounds of the invention may be administered simultaneously with, or before or after, one or more other therapeutic agents. The compound of the present invention and other therapeutic agents can be administered separately through the same or different administration routes, or they can be administered in the same pharmaceutical composition. This is selected by those skilled in the art according to the actual physical conditions of the patient, such as the health, age, and weight of the patient. If formulated as a fixed dose, this combination product uses the compound of the present invention (within the dosage range described in the present invention) and other pharmaceutically active agents (within the dosage range).
相应地，在一个方面，本发明包括联合用药，其包括一定数量的至少一种本发明的化合物或其可药用盐、溶剂化物、酯或前体药物和有效量的一种或多种上述附加治疗剂。Accordingly, in one aspect, the present invention includes a combination drug, which includes a certain amount of at least one compound of the present invention or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof and an effective amount of one or more of the above Additional therapeutic agent.
式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物可以与用于预防、治疗或减轻式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物适用的疾病或症状的其它药物联用。这些其它药物可通过其常用的途径和量与式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物同时或相继给药。当式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物与一种或多种其它药物同时使用时，含有这类其它药物以及式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物的药物单位剂型是优选的。The compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) can be used in the prevention, treatment or alleviation of formula (I), (II), The compound shown in (III), (IV), (V), (VI) or (VII) is used in combination with other drugs for diseases or symptoms. These other drugs can be administered simultaneously or sequentially with the compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) through their usual routes and amounts. When the compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) is used simultaneously with one or more other drugs, such other drugs are contained And the pharmaceutical unit dosage form of the compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) is preferred.
在各种实施方案中，本发明中所述的化合物与其它药物结合来提供用于慢性阻塞性肺病(COPD)、特应性皮炎(AD)、银屑病或其它状况的联合治疗。本发明的药物组合物包括本发明中所述的PDE4抑制剂中的至少一种和附加治疗剂，附加治疗剂的实例包括但不限于：In various embodiments, the compounds described in the present invention are combined with other drugs to provide a combination therapy for chronic obstructive pulmonary disease (COPD), atopic dermatitis (AD), psoriasis, or other conditions. The pharmaceutical composition of the present invention includes at least one of the PDE4 inhibitors described in the present invention and an additional therapeutic agent. Examples of the additional therapeutic agent include but are not limited to:
(1)β2-激动剂，例如沙丁醇胺、福莫特罗、沙美特罗和卡莫昔罗；(1) β2-agonists, such as salbutamol, formoterol, salmeterol and camoxirol;
(2)皮质类固醇类，例如布地奈德、二丙酸倍氯米松、丙酸氟替卡松、氟尼缩松、糠酸莫米松、罗氟奈德、环索奈德、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、地索奈德、氢化可的松、美普克莱；(2) Corticosteroids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, flunisolide, mometasone furoate, rofluonide, ciclesonide, fluocinolone acetate, deshydroxyl Methamasone, mometasone, triamcinolone, betamethasone, aclomethasone, dessonide, hydrocortisone, mepaclione;
(3)抗胆碱能药或抗毒蕈碱药，例如异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、瑞伐托酯；(3) Anticholinergic drugs or antimuscarinic drugs, such as ipratropium bromide, oxytropium bromide, tiotropium bromide, glycopyrrolate, and revatorate;
(4)局部钙调磷酸酶抑制剂，例如他克莫司、吡美莫司、环孢素；(4) Local calcineurin inhibitors, such as tacrolimus, pimecrolimus, cyclosporine;
(5)PDE4抑制剂的局部制剂，例如阿普斯特、异丁司特、E-6005、OPA-15406、LEO-29102、DRM02、罗氟司特、克瑞沙硼；(5) Topical preparations of PDE4 inhibitors, such as apremilast, ibudilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, crexabor;
(6)JAK激酶抑制剂的局部制剂，例如托法替尼、JTE-052、巴瑞替尼、乌帕替尼；(6) Local preparations of JAK kinase inhibitors, such as tofacitinib, JTE-052, baritinib, and upatinib;
(7)局部非甾体抗炎药物，例如WBI-1001、MRX-6；(7) Local non-steroidal anti-inflammatory drugs, such as WBI-1001, MRX-6;
(8)局部ROR药剂，例如GSK2981278；(8) Local ROR agents, such as GSK2981278;
(9)可注射抗IL4、IL-31、IL-22、IL-33、IL-12、IL-23、IL-17、IgE、IL-4治疗药物，例如杜鲁单抗(Dupilumab)、来金珠单抗、尼莫利珠单抗(Nemolizumab)、曲洛吉努单抗、依那西普、阿达木单抗、英夫利昔单抗、尤特可单抗、塞库吉努(Secukinumab)、奥马珠(Omazumilab)、CIM-331；(9) Injectable anti-IL4, IL-31, IL-22, IL-33, IL-12, IL-23, IL-17, IgE, IL-4 therapeutic drugs, such as Dupilumab (Dupilumab), Jinlizumab, Nemolizumab, troroginumab, etanercept, adalimumab, infliximab, utekizumab, Secukinumab ), Omazumilab, CIM-331;
(10)维生素D类似物，例如卡泊三醇、骨化三醇；(10) Vitamin D analogs, such as calcipotriol and calcitriol;
(11)口服视黄酸衍生物，例如阿利维A酸；(11) Oral retinoic acid derivatives, such as aliretinoin;
(12)口服肝X受体(LXR)选择性激动剂，例如VTP-38543；(12) Oral liver X receptor (LXR) selective agonist, such as VTP-38543;
(13)口服H4受体拮抗剂，例如ZPL-389；(13) Oral H4 receptor antagonists, such as ZPL-389;
(14)口服NK1受体拮抗剂，例如阿瑞匹坦、曲地匹坦；(14) Oral NK1 receptor antagonists, such as aprepitant and tripipitant;
(15)口服CRTH2受体拮抗剂，例如弗维普兰特(Fevipiprant)、和OC-459；(15) Oral CRTH2 receptor antagonists, such as Fevipiprant and OC-459;
(16)口服糜蛋白酶抑制剂，例如SUN 13834。(16) Oral chymotrypsin inhibitors, such as SUN 13834.
优选地，给与单独的或与其他活性成分组合的式(I)或式(II)所示的化合物用于预防和/或治疗呼吸疾病或皮肤炎症疾病，例如慢性阻塞性肺病(COPD)、特应性皮炎(AD)或银屑病。Preferably, the compound represented by formula (I) or formula (II) administered alone or in combination with other active ingredients is used to prevent and/or treat respiratory diseases or skin inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), Atopic dermatitis (AD) or psoriasis.
包含本发明化合物或药物组合物给药的治疗方法，进一步包括对患者进行其他抗慢性阻塞性肺病(COPD)或特应性皮炎药物(联合治疗)的给药，其中其他抗慢性阻塞性肺病(COPD)或特应性皮炎的药物为上述附加治疗剂中的药物或它们的组合物。The treatment method comprising the administration of the compound or pharmaceutical composition of the present invention further includes the administration of other anti-chronic obstructive pulmonary disease (COPD) or atopic dermatitis drugs (combination therapy) to the patient, wherein other anti-chronic obstructive pulmonary disease ( The drugs for COPD) or atopic dermatitis are the drugs among the above-mentioned additional therapeutic agents or their combinations.
本发明提供在需要这种治疗的患者中治疗肺病(例如，COPD、气喘或纤维囊肿)或炎症(例如，特应性皮炎或银屑病)的方法，该方法包括联合给予所述患者治疗有效量的至少一种式(I)或式(II)所示化合物，或其药学上可接受的盐或溶剂合物，以及至少一种选自下列的化合物：类固醇(如糖皮 质激素)、钙调磷酸酶抑制剂、PDE4抑制剂、JAK激酶抑制剂、半胱氨酰基白三烯拮抗剂、非甾体抗炎药物、局部ROR药剂、抗IL4抗体、IL-31抗体、IL-22抗体、IL-33抗体、IL-12抗体、IL-23抗体、IL-17抗体、IgE抗体、IL-4抗体、维生素D类似物、肝X受体(LXR)选择性激动剂、组胺H1拮抗剂、组胺H3拮抗剂、H4受体拮抗剂、NK1受体拮抗剂、CRTH2受体拮抗剂、糜蛋白酶抑制剂、5-脂氧合酶抑制剂、β-2肾上腺素受体(adrenoceptor)激动剂、α-肾上腺素受体激动剂、蕈毒碱M1拮抗剂、蕈毒碱M3拮抗剂、蕈毒碱M2激动剂、NK3拮抗剂、LTB4拮抗剂、支气管扩张剂、PDE抑制剂。The present invention provides a method for treating lung disease (for example, COPD, asthma or fibrocyst) or inflammation (for example, atopic dermatitis or psoriasis) in a patient in need of such treatment, the method comprising a combination of administering to the patient a therapeutically effective Amount of at least one compound represented by formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, and at least one compound selected from the following: steroids (such as glucocorticoids), calcium Regulating phosphatase inhibitors, PDE4 inhibitors, JAK kinase inhibitors, cysteyl leukotriene antagonists, non-steroidal anti-inflammatory drugs, topical ROR agents, anti-IL4 antibodies, IL-31 antibodies, IL-22 antibodies, IL-33 antibody, IL-12 antibody, IL-23 antibody, IL-17 antibody, IgE antibody, IL-4 antibody, vitamin D analog, liver X receptor (LXR) selective agonist, histamine H1 antagonist , Histamine H3 antagonist, H4 receptor antagonist, NK1 receptor antagonist, CRTH2 receptor antagonist, chymotrypsin inhibitor, 5-lipoxygenase inhibitor, β-2 adrenoceptor agonist Agents, α-adrenergic receptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, bronchodilators, PDE inhibitors.
本发明化合物和药物组合物的用途Use of the compound and pharmaceutical composition of the present invention
本发明化合物或本发明的组合物中化合物的量可以有效地可探测地拮抗PDE4以治疗以下疾病：疼痛(例如，急性疼痛、急性炎性疼痛、慢性炎性疼痛和神经病性疼痛)、急性炎症、慢性炎症、银屑病关节炎、类风湿性关节炎、牛皮癣、增生性和炎性皮肤病(例如特应性皮炎、脂溢性皮炎、接触性皮炎)、哮喘、慢性阻塞性肺病(COPD)、关节炎、炎性肠道疾病、节段性回肠炎、溃疡性结肠炎、败血性休克、内毒素性休克、格兰氏阴性菌败血症、肾小球性肾炎、帕金森氏病、阿尔茨海默氏病、轻度认知损害(MCI)、抑郁症、焦虑症、急性呼吸道窘迫综合征、骨关节炎、强直性脊柱炎、多发性硬化、牙龈炎、牙周炎、搔痒症、疱疹、CNS肿瘤、间质性肺炎、过敏、结晶诱发的关节炎、急性胰腺炎、慢性胰腺炎、急性酒精性肝炎、坏死性小肠结肠炎、慢性鼻窦炎、急性呼吸窘迫综合症、肺高血压、痛风、酒精性肝病、狼疮、癌症、过敏性鼻炎、非过敏性鼻炎、自身免疫性溶血综合征、自身免疫性肝炎、自身免疫性神经病变、肝硬化、纤维化疾病、胃炎、Goodpasture氏综合征、格雷夫斯氏病、Gullain-Barre病、桥本氏甲状腺炎、HIV-相关的自身免疫性综合征和血液疾病、扁平苔癣、心肌炎(包括病毒性心肌炎)、神经病变(包括例如，IgA神经病变、细胞膜神经病变和特发性神经病变)、肾炎综合征、莱特尔氏综合征、斯耶格伦氏综合征、系统性红斑狼疮，该方法包括施于该病患有效量的至少一种式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示化合物或其药学上可接受的盐或溶剂合物。The compound of the present invention or the amount of the compound in the composition of the present invention can effectively and detectably antagonize PDE4 to treat the following diseases: pain (for example, acute pain, acute inflammatory pain, chronic inflammatory pain and neuropathic pain), acute inflammation , Chronic inflammation, psoriatic arthritis, rheumatoid arthritis, psoriasis, proliferative and inflammatory skin diseases (e.g. atopic dermatitis, seborrheic dermatitis, contact dermatitis), asthma, chronic obstructive pulmonary disease (COPD) ), arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxin shock, Gram-negative bacterial sepsis, glomerulonephritis, Parkinson's disease, Alzheimer's disease Zheimer's disease, mild cognitive impairment (MCI), depression, anxiety, acute respiratory distress syndrome, osteoarthritis, ankylosing spondylitis, multiple sclerosis, gingivitis, periodontitis, pruritus, Herpes, CNS tumors, interstitial pneumonia, allergies, crystal-induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, acute respiratory distress syndrome, pulmonary hypertension , Gout, alcoholic liver disease, lupus, cancer, allergic rhinitis, non-allergic rhinitis, autoimmune hemolytic syndrome, autoimmune hepatitis, autoimmune neuropathy, liver cirrhosis, fibrotic disease, gastritis, Goodpasture's synthesis Symptoms, Graves’ disease, Gullain-Barre’s disease, Hashimoto’s thyroiditis, HIV-related autoimmune syndromes and blood diseases, lichen planus, myocarditis (including viral myocarditis), neuropathy (including, for example, IgA neuropathy, cell membrane neuropathy and idiopathic neuropathy), nephritis syndrome, Reiter’s syndrome, Sjogren’s syndrome, systemic lupus erythematosus, the method comprising administering to the patient an effective amount of at least A compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt or solvate thereof.
一般合成步骤General synthesis steps
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, and the substituents are defined as formula (I), (II), (III), (IV), (V) , (VI) or (VII). The following reaction schemes and examples are used to further illustrate the content of the present invention.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described in the present invention can be used to appropriately prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. Inside. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully completed by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or The reaction conditions are modified regularly. In addition, the reactions disclosed in the present invention or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the present invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司和青岛海洋化工厂购买得到。In the examples described below, all temperatures are set to degrees Celsius unless otherwise indicated. Reagents are purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and are used without further purification unless otherwise indicated. General reagents are purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. and Qingdao Ocean Chemical Plant.
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by refluxing and drying with sodium metal. Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried in advance with anhydrous sodium sulfate.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reactions are generally carried out under a positive pressure of nitrogen or argon or a drying tube on an anhydrous solvent (unless otherwise indicated), the reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe. The glassware is all dried.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振氢谱的测试条件是：室温条件下，布鲁克(Bruker)400MHz或600MHz的核磁仪，以CDC1 3，DMSO-d 6，CD 3OD或丙酮-d 6为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)，d(doublet，双峰)，t(triplet，三重峰)，q(quartet，四重峰)，m(multiplet，多重峰)，br(broadened，宽峰)，dd(doublet of doublets，双二重峰)，dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。 The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The test conditions for proton nuclear magnetic resonance spectroscopy are: Bruker 400MHz or 600MHz nuclear magnetometer at room temperature, with CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (reported in ppm) , Use TMS (0ppm) or chloroform (7.26ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, Multiplet), br (broadened, broad peak), dd (doublet of doublets, doublet of doublets), dt (doublet of triplets, doublet of triplets). Coupling constant, expressed in Hertz (Hz).
低分辨率质谱(MS)数据测定的条件是：Agilent 6120 Quadrupole HPLC-MS(柱子型号：Zorbax SB-C18,2.1x 30mm,3.5μm,6min,流速为0.6mL/min，流动相：5％-95％(含0.1％甲酸的CH 3CN)在(含0.1％甲酸的H 2O)中的比例))，在210/254nm用UV检测，用电喷雾电离模式(ESI)。 The conditions for low-resolution mass spectrometry (MS) data measurement are: Agilent 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1x 30mm, 3.5μm, 6min, flow rate 0.6mL/min, mobile phase: 5%- 95% (the proportion of CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid)), detected by UV at 210/254 nm, and used electrospray ionization (ESI).
化合物纯度的表征方式为：Agilent 1260制备型高效液相色谱(Pre-HPLC)或Calesep Pump 250制备型高效液相色谱(Pre-HPLC)(柱子型号：NOVASEP,50/80mm,DAC)，在210nm/254nm用UV检测。The compound purity is characterized by: Agilent 1260 Pre-HPLC or Calesep Pump 250 Pre-HPLC (Column Model: NOVASEP, 50/80mm, DAC), at 210nm /254nm is detected by UV.
本发明所述的各手性化合物的立体构型使用以下其中之一的分析方法进行拆分：The stereo configuration of each chiral compound of the present invention is resolved using one of the following analysis methods:
分析方法：Analytical method:
1.使用AS-H柱(厂家：大赛璐，规格：4.6×250mm，5μm)，流动相条件：柱温30℃，流速1mL/min，30％乙醇(0.1％三氟乙酸)，70％正己烷；1. Use AS-H column (manufacturer: Daicel, specification: 4.6×250mm, 5μm), mobile phase conditions: column temperature 30℃, flow rate 1mL/min, 30% ethanol (0.1% trifluoroacetic acid), 70% n-hexane alkyl;
2.使用OD-H柱(厂家：大赛璐，规格：4.6×250mm，5μm)流动相条件：柱温30℃，流速1mL/min，30％乙醇，70％正己烷；2. Use OD-H column (manufacturer: Daicel, specification: 4.6×250mm, 5μm) mobile phase conditions: column temperature 30℃, flow rate 1mL/min, 30% ethanol, 70% n-hexane;
3.使用IC柱(厂家：大赛璐，规格：4.6×250mm，5μm)流动相条件：柱温30℃，流速0.8mL/min，50％乙醇，50％正己烷。3. Use IC column (manufacturer: Daicel, specification: 4.6×250mm, 5μm) mobile phase conditions: column temperature 30°C, flow rate 0.8mL/min, 50% ethanol, 50% n-hexane.
下面简写词的使用贯穿本发明：The following abbreviations are used throughout the present invention:
CD 3OD           氘代甲醇 CD 3 OD Deuterated methanol
DMSO-d 6         氘代二甲基亚砜 DMSO-d 6 Deuterated Dimethyl Sulfoxide
CDCl 3           氘代氯仿 CDCl 3 Deuterated Chloroform
HCl             盐酸HCl Hydrochloric acid
Pd/C            钯碳Pd/C Palladium on carbon
mol             摩尔mol Moore
h               小时h hours
min             分钟min minutes
L               升L rise
mL,ml           毫升mL,ml ml
M,mol/L         摩尔/升M,mol/L mol/L
HPLC            高效液相色谱HPLC High Performance Liquid Chromatography
GC              气相色谱GC Gas chromatography
MHz             兆赫MHz MHz
BnOH            苄醇BnOH Benzyl alcohol
Tf 2O            三氟甲磺酸酐 Tf 2 O trifluoromethanesulfonic anhydride
DIPEA           N,N-二异丙基乙胺DIPEA N,N-Diisopropylethylamine
TEA             三乙胺TEA Triethylamine
Boc             叔丁氧羰基Boc tert-Butoxycarbonyl
Bu              叔丁基Bu tert-butyl
DMF             N,N-二甲基甲酰胺DMF N,N-Dimethylformamide
DCM             二氯甲烷DCM Dichloromethane
MeOH            甲醇MeOH Methanol
中间体的合成方法：Synthesis method of intermediate:
Figure PCTCN2021090489-appb-000042
Figure PCTCN2021090489-appb-000042
重要中间体M-4可以通过中间体的合成方法制备得到，其中，除非另外说明，R 2和R a具有如本发明所述的含义。起始物料M-1与物料BnOH在弱碱和叠氮磷酸二苯酯条件下发生重排反应，形成氨基保护基得到中间体M-2，中间体M-2经过催化氢化还原得到中间体M-3，中间体M-3经过重氮化反应，再与KI发生取代反应得到中间体M-4。 Important intermediate M-4 can be prepared by the synthetic intermediates obtained, wherein, unless otherwise stated, R 2 and R a have the meanings as described in this invention. The starting material M-1 and the material BnOH undergo a rearrangement reaction under the conditions of a weak base and diphenyl azide phosphate to form an amino protective group to obtain intermediate M-2. Intermediate M-2 is reduced by catalytic hydrogenation to obtain intermediate M -3, Intermediate M-3 undergoes diazotization reaction, and then undergoes substitution reaction with KI to obtain intermediate M-4.
目标产物合成方法：Synthetic method of target product:
合成方法一：Synthesis method one:
Figure PCTCN2021090489-appb-000043
Figure PCTCN2021090489-appb-000043
目标化合物S-8可以通过合成方法一制备得到，其中，X代表卤素原子，R x为-NH 2或-OH，R xo为-NH-或-O-，除非另外说明，A环、R 2、R a、R b、R m、R n、p和n具有如本发明所述的含义。化合物S-1在碱性(例如DIPEA或TEA等)条件下经烯醇化反应后再经过取代反应得到化合物S-2，化合物S-2与化合物S'-2在碱性条件下通过硼基化反应得到化合物S-3，化合物S-3与中间体M-4在偶联试剂条件下发生Suzuki偶联反应得到化合物S-4，化合物S-4经催化氢化得到化合物S-5，化合物S-5在酸性条件下脱去Boc保护基，再经酰化反应得到化合物S-6，化合物S-6在碱性条件下经酯水解反应得到化合物S-7，化合物S-7与化合物S'-7在合适的缩合剂作用下经缩合反应得到目标化合物S-8。 The target compound S-8 can be prepared by synthetic method 1, where X represents a halogen atom, R x is -NH 2 or -OH, and R xo is -NH- or -O-, unless otherwise specified, A ring, R 2 , R a , R b , R m , R n , p and n have the meanings as described in the present invention. Compound S-1 undergoes enolization reaction under alkaline conditions (such as DIPEA or TEA, etc.) and then undergoes substitution reaction to obtain compound S-2. Compound S-2 and compound S'-2 undergo boronation under alkaline conditions Compound S-3 is obtained by the reaction. Compound S-3 and intermediate M-4 undergo Suzuki coupling reaction under coupling reagent conditions to obtain compound S-4. Compound S-4 is catalytically hydrogenated to obtain compound S-5, and compound S- 5 Remove the Boc protective group under acidic conditions, and then undergo acylation to obtain compound S-6. Compound S-6 undergoes ester hydrolysis under alkaline conditions to obtain compound S-7, compound S-7 and compound S'- 7 Under the action of a suitable condensing agent, the target compound S-8 is obtained by condensation reaction.
合成方法二：Synthesis method two:
Figure PCTCN2021090489-appb-000044
Figure PCTCN2021090489-appb-000044
目标化合物S-11可以通过合成方法二制备得到，其中，R x为-NH 2或-OH，R xo为-NH-或-O-，除非另外说明，A环、R 2、R a、R e、R f、R m、R n和p具有如本发明所述的含义。化合物S-7与化合物S”-7在合适的缩合剂作用下经缩合反应得到化合物S-9，化合物S-9在碱性条件下经酯水解反应得到化合物S-10，化合物S-10与化合物S'-10在合适的缩合剂作用下经缩合反应得到目标化合物S-11。 S-11 target compound can be obtained by preparing two synthetic methods, wherein, R x is -NH 2 or -OH, R xo is -NH- or -O-, unless stated otherwise, A ring, R 2, R a, R e , R f , R m , R n and p have the meanings as described in the present invention. Compound S-7 and compound S"-7 undergo condensation reaction under the action of a suitable condensing agent to obtain compound S-9, compound S-9 undergoes ester hydrolysis under alkaline conditions to obtain compound S-10, compound S-10 and Compound S'-10 undergoes condensation reaction under the action of a suitable condensing agent to obtain the target compound S-11.
中间体的合成Synthesis of intermediates
中间体1：2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯Intermediate 1: 2-(Cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene
Figure PCTCN2021090489-appb-000045
Figure PCTCN2021090489-appb-000045
步骤1：化合物(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)氨基甲酸苯甲酯的合成Step 1: Synthesis of the compound (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) benzyl carbamate
将3-(环丙甲氧基)-4-(二氟甲氧基)苯甲酸(5.0g,19.4mmol)溶于甲苯(25mL)中，加入叠氮磷酸二苯酯(5.0mL,23.0mmol)，三乙胺(4.3mL,31.0mmol)，室温下反应1h，加入苯甲醇(3.0mL,29.0mmol)，转移至90℃加热反应3h。减压浓缩除去溶剂，剩余物加入水(100ml)，用乙酸乙酯萃取(25mL×3)，有机相用无水硫酸钠干燥，减压浓缩,进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到白色固体5.01g，收率71％。Dissolve 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (5.0g, 19.4mmol) in toluene (25mL), add diphenyl azide phosphate (5.0mL, 23.0mmol) ), triethylamine (4.3 mL, 31.0 mmol), react at room temperature for 1 h, add benzyl alcohol (3.0 mL, 29.0 mmol), transfer to 90° C. and heat the reaction for 3 h. Concentrate under reduced pressure to remove the solvent, add water (100ml) to the residue, extract with ethyl acetate (25mL×3), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (eluent: petroleum Ether/ethyl acetate (v/v)=4/1) to obtain 5.01 g of a white solid with a yield of 71%.
1H NMR(600MHz,CDCl 3)δ(ppm):δ7.35-7.43(m,5H),7.09(d,J＝8.6Hz,1H),6.65-6.69(m,1H),6.58(t,J F-H＝75.8Hz,1H),5.22(s,3H),3.88(s,3H),1.27-1.34(m,1H),0.58-0.73(m,2H),0.29-0.44(m,2H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm): δ7.35-7.43 (m, 5H), 7.09 (d, J = 8.6Hz, 1H), 6.65-6.69 (m, 1H), 6.58 (t, J FH = 75.8Hz, 1H), 5.22 (s, 3H), 3.88 (s, 3H), 1.27-1.34 (m, 1H), 0.58-0.73 (m, 2H), 0.29-0.44 (m, 2H).
MS(ESI,pos.ion)m/z:364.10[M+H] +. MS(ESI,pos.ion)m/z:364.10[M+H] + .
步骤2：化合物3-(环丙基甲氧基)-4-(二氟甲氧基)苯胺的合成Step 2: Synthesis of compound 3-(cyclopropylmethoxy)-4-(difluoromethoxy)aniline
将(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)氨基甲酸苯甲酯(145mg,0.45mmol)，溶于无水甲醇(6mL)中，加入钯炭(50mg)，排除空气，通入氢气室温反应2h。用硅藻土抽滤除去催化剂，滤液浓缩得到淡红色液体102mg，收率98％。Benzyl (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)carbamate (145mg, 0.45mmol) was dissolved in anhydrous methanol (6mL), and palladium on carbon was added (50mg), the air was removed, and hydrogen was introduced to react at room temperature for 2 hours. The catalyst was removed by suction filtration with diatomaceous earth, and the filtrate was concentrated to obtain 102 mg of light red liquid with a yield of 98%.
1H NMR(400MHz,CDCl 3)δ(ppm):6.94(d,J＝8.4Hz,1H),6.47(t,J F-H＝76.3Hz,1H),6.26(d,J＝2.2 Hz,1H),6.20(dd,J＝8.4,2.4Hz,1H),3.80(d,J＝6.8Hz,2H),1.25-1.31(m,1H),0.58-0.65(m,2H),0.30-0.35(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 6.94 (d, J = 8.4 Hz, 1H), 6.47 (t, J FH = 76.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H) ,6.20(dd,J=8.4,2.4Hz,1H),3.80(d,J=6.8Hz,2H),1.25-1.31(m,1H),0.58-0.65(m,2H),0.30-0.35(m ,2H).
MS(ESI,pos.ion)m/z:230.10[M+H] +. MS(ESI,pos.ion)m/z:230.10[M+H] + .
步骤3：化合物2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯的合成Step 3: Synthesis of compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene
将化合物3-(环丙基甲氧基)-4-(二氟甲氧基)苯胺盐酸盐(17g,64.0mmol)，溶于1,4-二氧六环(85mL)和水(30mL)中，0℃以下加入浓盐酸(17mL)，降温到-15℃，逐滴加入亚硝酸钠(5.3g,77.0mmol)和水(15mL)的溶液，控制温度在-15℃至-5℃之间，0℃下继续反应40min，加入碘化钾(13.8g,83.1mmol)和水(15mL)的溶液，控制温度在-15℃至-5℃之间，滴加完毕后，在0℃下继续反应2h，加入水(200mL)停止反应，用乙酸乙酯萃取(200mL×2)，有机相用饱和亚硫酸钠洗一次，无水硫酸钠干燥，减压浓缩，得到浅棕色液体21g，收率96％。The compound 3-(cyclopropylmethoxy)-4-(difluoromethoxy)aniline hydrochloride (17g, 64.0mmol) was dissolved in 1,4-dioxane (85mL) and water (30mL ), add concentrated hydrochloric acid (17mL) below 0℃, cool to -15℃, add a solution of sodium nitrite (5.3g, 77.0mmol) and water (15mL) dropwise, control the temperature at -15℃ to -5℃ In between, continue the reaction at 0°C for 40min, add a solution of potassium iodide (13.8g, 83.1mmol) and water (15mL), control the temperature between -15°C and -5°C, after the addition is complete, continue at 0°C React for 2h, add water (200mL) to stop the reaction, extract with ethyl acetate (200mL×2), wash the organic phase once with saturated sodium sulfite, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 21g of light brown liquid with a yield of 96% .
1H NMR(400MHz,CDCl 3)δ(ppm):7.21-7.27(m,2H),6.89(d,J＝8.1Hz,1H),6.59(t,J F-H＝75.2Hz,1H),3.84(d,J＝6.9Hz,2H),1.23-1.29(m,1H),0.61-0.69(m,2H),0.32-0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.21-7.27 (m, 2H), 6.89 (d, J = 8.1 Hz, 1H), 6.59 (t, J FH = 75.2 Hz, 1H), 3.84 ( d, J=6.9Hz, 2H), 1.23-1.29 (m, 1H), 0.61-0.69 (m, 2H), 0.32-0.40 (m, 2H).
GC-MS:m/z 340.0.GC-MS: m/z 340.0.
中间体2：中间体2-(苄氧基)-1-(二氟甲氧基)-4-碘苯Intermediate 2: Intermediate 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene
Figure PCTCN2021090489-appb-000046
Figure PCTCN2021090489-appb-000046
步骤1：化合物2-(二氟甲氧基)-5-碘苯酚的合成Step 1: Synthesis of compound 2-(difluoromethoxy)-5-iodophenol
将化合物2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(4.9g,14.0mmol)溶解在乙腈(8mL)中，加入水(10mL)和浓盐酸(10mL)，80℃反应4h，加入氢氧化钠溶液调节pH＝5，用乙酸乙酯萃取(5mL×3)，有机相合用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝5/1)，得到淡黄色液体1.8g，产率44％。The compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (4.9g, 14.0mmol) was dissolved in acetonitrile (8mL), water (10mL) and concentrated hydrochloric acid were added (10mL), react at 80℃ for 4h, add sodium hydroxide solution to adjust pH=5, extract with ethyl acetate (5mL×3), combine the organic phase and dry with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (Eluent: petroleum ether/ethyl acetate (v/v)=5/1), 1.8 g of pale yellow liquid was obtained, and the yield was 44%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):10.30(s,1H),7.28(d,J＝2.0Hz,1H)),7.15(dd,J＝8.4,2.0Hz,1H),7.02(t,J F-H＝74.7Hz,1H),6.90(d,J＝8.4Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 10.30 (s, 1H), 7.28 (d, J = 2.0 Hz, 1H)), 7.15 (dd, J = 8.4, 2.0 Hz, 1H), 7.02(t, J FH = 74.7Hz, 1H), 6.90(d, J = 8.4Hz, 1H).
MS(ESI,pos.ion)m/z:286.00[M].MS(ESI,pos.ion)m/z:286.00[M].
步骤2：化合物2-(苄氧基)-1-(二氟甲氧基)-4-碘苯的合成Step 2: Synthesis of compound 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene
将化合物2-(二氟甲氧基)-5-碘苯酚(3.8g,13.0mmol)和碳酸钾(5.8g,42.0mmol)于N,N-二甲基甲酰胺(30mL)中混合均匀，加入苄溴(2.5mL,21.0mmol)，在100℃反应16h，过滤除去固体，滤液浓缩，加入水(50mL)，用乙酸乙酯(25mL×3)萃取，有机相合用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到淡黄色液体4.8g，产率96％。Mix the compound 2-(difluoromethoxy)-5-iodophenol (3.8g, 13.0mmol) and potassium carbonate (5.8g, 42.0mmol) in N,N-dimethylformamide (30mL). Add benzyl bromide (2.5mL, 21.0mmol), react at 100°C for 16h, filter to remove solids, concentrate the filtrate, add water (50mL), extract with ethyl acetate (25mL×3), and dry the organic phase with anhydrous sodium sulfate. The solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain 4.8 g of pale yellow liquid with a yield of 96%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.57(d,J＝1.9Hz,1H),7.45-7.47(m,2H),7.41(s,1H),7.39(d,J＝3.4Hz,1H),7.33-7.37(m,2H),7.09(t,J F-H＝74.2Hz,1H),7.00(d,J＝8.4Hz,1H),5.18(s,2H). 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 7.57(d,J=1.9Hz,1H),7.45-7.47(m,2H),7.41(s,1H),7.39(d,J= 3.4Hz, 1H), 7.33-7.37 (m, 2H), 7.09 (t, J FH = 74.2Hz, 1H), 7.00 (d, J = 8.4Hz, 1H), 5.18 (s, 2H).
中间体3：中间体6-(氨基甲基)-N,N-二甲基吡啶酰胺二盐酸盐Intermediate 3: Intermediate 6-(aminomethyl)-N,N-lutidine amide dihydrochloride
Figure PCTCN2021090489-appb-000047
Figure PCTCN2021090489-appb-000047
步骤1：化合物6-(((叔丁氧羰基)氨基)甲基)吡啶甲酸乙酯的合成Step 1: Synthesis of compound ethyl 6-(((tert-butoxycarbonyl)amino)methyl)picolinate
将6-(氨基甲基)吡啶甲酸乙酯(2.0g,9.2mmol)溶于无水DMF(15mL)中，0℃下加入N,N-二异丙基乙胺(4.1mL,23mmol)和二碳酸二叔丁酯(2.8mL,12mmol)，室温反应1.5h，加水(20mL)，加二氯甲烷萃取(10mL×3)，有机相合并后用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到黄色液体1.98g，产率77％。Ethyl 6-(aminomethyl)picolinate (2.0g, 9.2mmol) was dissolved in anhydrous DMF (15mL), and N,N-diisopropylethylamine (4.1mL, 23mmol) and Di-tert-butyl dicarbonate (2.8mL, 12mmol), react at room temperature for 1.5h, add water (20mL), add dichloromethane for extraction (10mL×3), combine the organic phases and dry with anhydrous sodium sulfate, remove the solvent, and concentrate the solution Perform silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain 1.98 g of yellow liquid with a yield of 77%.
1H NMR(600MHz,CDCl 3)δ(ppm):8.01(t,J＝8.1Hz,1H),7.79–7.83(m,1H),7.50(t,J＝7.0Hz,1H),4.50–4.55(m,2H),4.45–4.50(m,2H),1.42–1.47(m,12H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm): 8.01 (t, J = 8.1 Hz, 1H), 7.79-7.83 (m, 1H), 7.50 (t, J = 7.0 Hz, 1H), 4.50-4.55 (m, 2H), 4.45-4.50 (m, 2H), 1.42-1.47 (m, 12H).
MS(ESI,pos.ion)m/z:281.25[M+H] +. MS(ESI,pos.ion)m/z:281.25[M+H] + .
步骤2：6-(((叔丁氧羰基)氨基)甲基)吡啶甲酸的合成Step 2: Synthesis of 6-(((tert-butoxycarbonyl)amino)methyl)picolinic acid
将6-(((叔丁氧羰基)氨基)甲基)吡啶甲酸乙酯(700mg,2.5mmol)和一水合氢氧化锂(527mg,12.6mmol)加入至四氢呋喃(5mL)和水(5mL)混合溶剂中，50℃反应1.5h后停止，加稀盐酸调节pH＝6，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，得到浅黄色油状物606mg，收率96％。Add 6-(((tert-butoxycarbonyl)amino)methyl)picolinate (700mg, 2.5mmol) and lithium hydroxide monohydrate (527mg, 12.6mmol) to tetrahydrofuran (5mL) and water (5mL) and mix In the solvent, the reaction was stopped at 50°C for 1.5 hours. Dilute hydrochloric acid was added to adjust the pH=6, extracted with ethyl acetate (10mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 606mg of a pale yellow oil. The rate is 96%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.06(d,J＝7.6Hz,1H),7.99(t,J＝7.7Hz,1H),7.60(d,J＝7.6Hz,1H),4.44(s,2H),1.48(s,9H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.06 (d, J = 7.6 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H) , 4.44(s, 2H), 1.48(s, 9H).
MS(ESI,pos.ion)m/z:253.10[M+H] +. MS(ESI,pos.ion)m/z:253.10[M+H] + .
步骤3：((6-(二甲基氨基甲酰基)吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 3: Synthesis of tert-butyl ((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)carbamate
将6-(((叔丁氧羰基)氨基)甲基)吡啶甲酸(587-1-2)(600mg,2.38mmol)，二甲胺盐酸盐(971mg,11.9mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(2.3g,12mmol)和N-羟基-7-氮杂苯并三氮唑(488mg,3.59mmol)溶于二氯甲烷(10mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(2.4mL,15mmol)，室温搅拌19h，加水(15mL)，用二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到浅黄色粘稠固体554mg，收率83％。Add 6-(((tert-butoxycarbonyl)amino)methyl)picolinic acid (587-1-2) (600mg, 2.38mmol), dimethylamine hydrochloride (971mg, 11.9mmol), 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (2.3g, 12mmol) and N-hydroxy-7-azabenzotriazole (488mg, 3.59mmol) dissolved in dichloromethane ( 10mL), add dropwise N,N-diisopropylethylamine (2.4mL, 15mmol) to this solution at 0℃, stir at room temperature for 19h, add water (15mL), and extract with dichloromethane (10mL×3) , The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 554 mg of a light yellow viscous solid. The yield was 83%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.78(d,J＝7.7Hz,1H),7.50(d,J＝7.6Hz,1H),7.33(d,J＝7.8Hz,1H),4.47(d,J＝5.2Hz,2H),3.16(s,3H),3.07(s,3H),1.48(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.78 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 4.47(d,J=5.2Hz,2H), 3.16(s, 3H), 3.07(s, 3H), 1.48(s, 9H).
MS(ESI,pos.ion)m/z:280.30[M+H] +. MS(ESI,pos.ion)m/z:280.30[M+H] + .
步骤4：6-(氨基甲基)-N,N-二甲基吡啶酰胺二盐酸盐的合成Step 4: Synthesis of 6-(aminomethyl)-N,N-lutidine amide dihydrochloride
将化合物((6-(二甲基氨基甲酰基)吡啶-2-基)甲基)氨基甲酸叔丁酯(587-1-1)(550mg,1.97mmol)溶解于甲醇(5mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(5mL)，室温搅拌1h，除去溶剂，得到白色固体486mg，收率97％。The compound ((6-(dimethylcarbamoyl)pyridin-2-yl)methyl) tert-butyl carbamate (587-1-1) (550mg, 1.97mmol) was dissolved in a solution of methanol (5mL), 4mol/L HCl ethyl acetate solution (5 mL) was added, stirred at room temperature for 1 h, and the solvent was removed to obtain 486 mg of white solid with a yield of 97%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.02(t,J＝7.8Hz,1H),7.59(t,J＝8.1Hz,2H),4.37(s,2H),3.16(s,3H),3.07(s,3H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.02 (t, J = 7.8Hz, 1H), 7.59 (t, J = 8.1Hz, 2H), 4.37 (s, 2H), 3.16 (s, 3H), 3.07(s, 3H).
MS(ESI,pos.ion)m/z:180.15[M+H-2HCl] +. MS(ESI,pos.ion)m/z:180.15[M+H-2HCl] + .
中间体4：中间体(3-(氨甲基)苯基)氨基甲酸甲酯盐酸盐Intermediate 4: Intermediate (3-(aminomethyl)phenyl) methyl carbamate hydrochloride
Figure PCTCN2021090489-appb-000048
Figure PCTCN2021090489-appb-000048
步骤1：化合物N-(3-((叔丁氧羰基氨基)甲基)苯基)氨基甲酸甲酯的合成Step 1: Synthesis of the compound methyl N-(3-((tert-butoxycarbonylamino)methyl)phenyl)carbamate
将化合物3-氨基苄基氨基甲酸叔丁酯(503mg,2.26mmol)溶解在二氯甲烷(6mL)中，0℃条件下加入氯甲酸甲酯(0.35mL,4.5mmol)和N,N-二异丙基乙胺(1.2mL,7.3mmol)，室温搅拌20h后停止反应， 加水溶液洗有机相(10mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到白色固体511mg，产率90％。The compound tert-butyl 3-aminobenzyl carbamate (503 mg, 2.26 mmol) was dissolved in dichloromethane (6 mL), and methyl chloroformate (0.35 mL, 4.5 mmol) and N,N-dichloroform were added at 0°C. Isopropylethylamine (1.2mL, 7.3mmol), stirred at room temperature for 20h, and then stopped the reaction. Add an aqueous solution to wash the organic phase (10mL×3), dry the organic phase with anhydrous sodium sulfate, and separate the concentrated solution by silica gel column chromatography (washing Removal agent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 511 mg of white solid, with a yield of 90%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.26-7.32(m,3H),7.01(d,J＝6.9Hz,1H),6.71(br.s,1H),4.89(br.s,1H),4.30(d,J＝5.2Hz,2H),3.79(s,3H),1.48(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.26-7.32 (m, 3H), 7.01 (d, J = 6.9 Hz, 1H), 6.71 (br.s, 1H), 4.89 (br.s, 1H), 4.30 (d, J = 5.2 Hz, 2H), 3.79 (s, 3H), 1.48 (s, 9H).
MS(ESI,pos.ion)m/z:303.10[M+Na] +. MS(ESI,pos.ion)m/z:303.10[M+Na] + .
步骤2：化合物(3-(氨甲基)苯基)氨基甲酸甲酯盐酸盐的合成Step 2: Synthesis of compound (3-(aminomethyl)phenyl) carbamate hydrochloride
将化合物N-(3-((叔丁氧羰基氨基)甲基)苯基)氨基甲酸甲酯(511mg,1.8mmol)溶解于二氯甲烷(2mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(3mL)，室温搅拌1h，除去溶剂，得到白色固体316mg，收率96％。Dissolve the compound N-(3-((tert-butoxycarbonylamino)methyl)phenyl)carbamate (511mg, 1.8mmol) in dichloromethane (2mL) solution, add 4mol/L HCl in ethyl acetate The ester solution (3 mL) was stirred at room temperature for 1 h, and the solvent was removed to obtain 316 mg of white solid with a yield of 96%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):9.79(s,1H),8.48(br.s,2H),7.56(s,1H),7.43(d,J＝7.8Hz,1H),7.32(t,J＝7.8Hz,1H),7.16(d,J＝7.2Hz,1H),3.94(s,2H),3.67(s,3H). 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 9.79(s,1H), 8.48(br.s,2H), 7.56(s,1H), 7.43(d,J=7.8Hz,1H) , 7.32(t,J=7.8Hz,1H), 7.16(d,J=7.2Hz,1H), 3.94(s,2H), 3.67(s,3H).
MS(ESI,pos.ion)m/z:181.10[M+H-HCl] +. MS(ESI,pos.ion)m/z:181.10[M+H-HCl] + .
中间体5：中间体(6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)甲胺二盐酸盐Intermediate 5: Intermediate (6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methylamine dihydrochloride
Figure PCTCN2021090489-appb-000049
Figure PCTCN2021090489-appb-000049
步骤1：化合物((6-溴吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 1: Synthesis of compound ((6-bromopyridin-2-yl)methyl) t-butyl carbamate
将化合物(6-溴吡啶-2-基)甲胺(1.0g,5.4mmol)溶解于二氯甲烷(15mL)溶液中，加入N,N-二异丙基乙胺(3.0mL,18.0mmol)，在0℃下加入二碳酸二叔丁酯(1.5mL,6.5mmol)，搅拌20min转移至室温反应5h，加水洗(50mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到白色固体1.42g，收率92％。The compound (6-bromopyridin-2-yl)methylamine (1.0g, 5.4mmol) was dissolved in dichloromethane (15mL) solution, and N,N-diisopropylethylamine (3.0mL, 18.0mmol) was added Add di-tert-butyl dicarbonate (1.5mL, 6.5mmol) at 0℃, stir for 20min, transfer to room temperature and react for 5h, wash with water (50mL), and extract with dichloromethane (5mL×3). Use anhydrous organic phase After drying over sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 1.42 g of a white solid with a yield of 92%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.73(t,J＝7.7Hz,1H),7.50(d,J＝7.9Hz,1H),7.48(br.s,1H),7.30(d,J＝7.5Hz,1H),4.19(d,J＝6.0Hz,2H),1.40(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.73 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.48 (br.s, 1H), 7.30 (d,J=7.5Hz,1H), 4.19(d,J=6.0Hz,2H), 1.40(s,9H).
MS(ESI,pos.ion)m/z:233.10[M-55] +. MS(ESI,pos.ion)m/z:233.10[M-55] + .
步骤2：化合物((6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 2: Synthesis of compound ((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl) carbamate
将化合物((6-溴吡啶-2-基)甲基)氨基甲酸叔丁酯(298mg,1.0mmol)，(1-甲基-1H-吡唑-4-基)硼酸(153mg,1.2mmol)，碳酸钠(332mg,3.1mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(42mg,0.06mmol)溶解于无水1,4-二氧六环(6mL)和水(2mL)中，将反应瓶中空气抽走，通入氮气，在100℃下反应21h，加水洗(50mL)，然后乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到196mg淡黄色液体，收率66％。The compound ((6-bromopyridin-2-yl)methyl) tert-butyl carbamate (298mg, 1.0mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (153mg, 1.2mmol) , Sodium carbonate (332mg, 3.1mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (42mg, 0.06mmol) are dissolved in anhydrous 1,4-dioxane (6mL) and water (2mL), the air in the reaction flask was evacuated, nitrogen gas was introduced, and the reaction was carried out at 100°C for 21h, washed with water (50mL), and then extracted with ethyl acetate (5mL×3). After drying with sodium sulfate, the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 196 mg of pale yellow liquid with a yield of 66%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.25(s,1H),7.97(s,1H),7.72(t,J＝7.7Hz,1H),7.49(d,J＝7.8Hz,1H),7.41(br.s,1H),7.04(d,J＝7.6Hz,1H),4.22(d,J＝5.9Hz,2H),3.88(s,3H),1.42(s,9H). 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 8.25(s,1H),7.97(s,1H),7.72(t,J=7.7Hz,1H),7.49(d,J=7.8Hz ,1H),7.41(br.s,1H),7.04(d,J=7.6Hz,1H),4.22(d,J=5.9Hz,2H),3.88(s,3H),1.42(s,9H) .
MS(ESI,pos.ion)m/z:289.25[M+H] +. MS(ESI,pos.ion)m/z:289.25[M+H] + .
步骤3：化合物(6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)甲胺二盐酸盐的合成Step 3: Synthesis of compound (6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methylamine dihydrochloride
将化合物((6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)甲基)氨基甲酸叔丁酯(186mg,0.64mmol)溶解于二氯甲烷(2mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(3mL)，室温搅拌40min，除去溶剂，得到淡黄色固体116mg，收率95％。The compound ((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl) tert-butyl carbamate (186mg, 0.64mmol) was dissolved in dichloromethane (2mL) solution Add 4 mol/L HCl ethyl acetate solution (3 mL), stir at room temperature for 40 min, remove the solvent, and obtain 116 mg of pale yellow solid with a yield of 95%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.52(br.s,2H),8.47(s,1H),8.20(s,1H),7.87(t,J＝7.8Hz,1H),7.67(d,J＝7.8Hz,1H),7.31(d,J＝7.5Hz,1H),4.14-4.26(m,2H),3.90(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.52 (br.s, 2H), 8.47 (s, 1H), 8.20 (s, 1H), 7.87 (t, J = 7.8Hz, 1H) , 7.67(d,J=7.8Hz,1H), 7.31(d,J=7.5Hz,1H), 4.14-4.26(m,2H), 3.90(s,3H).
MS(ESI,pos.ion)m/z:189.20[M+H-HCl] +. MS(ESI,pos.ion)m/z:189.20[M+H-HCl] + .
中间体6：中间体6-(氨基甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺二盐酸盐Intermediate 6: Intermediate 6-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide dihydrochloride
Figure PCTCN2021090489-appb-000050
Figure PCTCN2021090489-appb-000050
步骤1：化合物6-(((叔丁氧羰基)氨基)甲基)吡啶甲酸乙酯的合成Step 1: Synthesis of compound ethyl 6-(((tert-butoxycarbonyl)amino)methyl)picolinate
将6-(氨基甲基)吡啶甲酸乙酯(2.0g,9.2mmol)溶于无水N,N-二甲基甲酰胺(15mL)中，0℃下加入N,N-二异丙基乙胺(4.1mL,23mmol)和二碳酸二叔丁酯(2.8mL,12mmol)，室温反应1.5h，加水(20mL)，加二氯甲烷萃取(10mL×3)，有机相合并后用无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到黄色液体1.98g，收率77％。Dissolve ethyl 6-(aminomethyl)picolinate (2.0g, 9.2mmol) in anhydrous N,N-dimethylformamide (15mL), add N,N-diisopropylethyl at 0℃ Amine (4.1mL, 23mmol) and di-tert-butyl dicarbonate (2.8mL, 12mmol), react at room temperature for 1.5h, add water (20mL), add dichloromethane for extraction (10mL×3), combine the organic phases and use anhydrous sulfuric acid The sodium was dried, the solvent was removed, and the concentrated solution was subjected to column separation (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain 1.98 g of yellow liquid with a yield of 77%.
1H NMR(600MHz,CDCl 3)δ(ppm):8.01(t,J＝8.1Hz,1H),7.79–7.83(m,1H),7.50(t,J＝7.0Hz,1H),4.50–4.55(m,2H),4.45–4.50(m,2H),1.42–1.47(m,12H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm): 8.01 (t, J = 8.1 Hz, 1H), 7.79-7.83 (m, 1H), 7.50 (t, J = 7.0 Hz, 1H), 4.50-4.55 (m, 2H), 4.45-4.50 (m, 2H), 1.42-1.47 (m, 12H).
MS(ESI,pos.ion)m/z:281.25[M+H] +. MS(ESI,pos.ion)m/z:281.25[M+H] + .
步骤2：化合物6-(((叔丁氧羰基)氨基)甲基)吡啶甲酸的合成Step 2: Synthesis of compound 6-(((tert-butoxycarbonyl)amino)methyl)picolinic acid
将6-(((叔丁氧羰基)氨基)甲基)吡啶甲酸乙酯(700mg,2.5mmol)和一水合氢氧化锂(527mg,12.6mmol)加入至四氢呋喃(5mL)和水(5mL)混合溶剂中，50℃反应1.5h后停止，加稀盐酸调节pH＝6，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，得到浅黄色油状物606mg，手率96％。Add 6-(((tert-butoxycarbonyl)amino)methyl)picolinate (700mg, 2.5mmol) and lithium hydroxide monohydrate (527mg, 12.6mmol) to tetrahydrofuran (5mL) and water (5mL) and mix In the solvent, the reaction was stopped at 50°C for 1.5 hours. Dilute hydrochloric acid was added to adjust the pH=6, extracted with ethyl acetate (10mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 606mg of light yellow oil. The rate is 96%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.06(d,J＝7.6Hz,1H),7.99(t,J＝7.7Hz,1H),7.60(d,J＝7.6Hz,1H),4.44(s,2H),1.48(s,9H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.06 (d, J = 7.6 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H) , 4.44(s, 2H), 1.48(s, 9H).
MS(ESI,pos.ion)m/z:253.10[M+H] +. MS(ESI,pos.ion)m/z:253.10[M+H] + .
步骤3：化合物((6-((4,4-二氟环己基)(甲基)甲酰氨基)吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 3: Synthesis of compound ((6-((4,4-difluorocyclohexyl)(methyl)formamido)pyridin-2-yl)methyl) carbamate
将6-(((叔丁氧羰基)氨基)甲基)吡啶甲酸(347mg,1.38mmol)，4,4-二氟-N-甲基环己胺盐酸盐(387mg,2.08mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.4g,7.3mmol)和N-羟基-7-氮杂苯并三氮唑(382mg,2.81mmol)溶于二氯甲烷(5mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(1.8mL,11.0mmol)，室温搅拌5h，加水(35mL)，用二氯甲烷萃取(15mL×3)，有机相用无水硫酸钠干燥，浓缩，硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到白色固体486mg，收率92％。The 6-(((tert-butoxycarbonyl)amino)methyl)picolinic acid (347mg, 1.38mmol), 4,4-difluoro-N-methylcyclohexylamine hydrochloride (387mg, 2.08mmol), 1 -Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4g, 7.3mmol) and N-hydroxy-7-azabenzotriazole (382mg, 2.81mmol) In dichloromethane (5mL), after cooling to 0°C, add N,N-diisopropylethylamine (1.8mL, 11.0mmol), stir at room temperature for 5h, add water (35mL), and extract with dichloromethane (15mL ×3), the organic phase was dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 486 mg of white solid, yield 92 %.
1H NMR(400MHz,CDCl 3)δ(ppm):7.76–7.83(m,1H),7.56(d,J＝7.7Hz,0.5H),7.46(d,J＝7.7Hz,0.5H),7.32–7.37(m,1H),4.67–4.75(m,0.5H),4.47(d,J＝5.0Hz,2H),3.81–3.90(m,0.5H),3.04(s,1.5H),2.89(s,1.5H),2.11–2.28(m,3H),1.86–2.07(m,5H),1.48(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.76-7.83 (m, 1H), 7.56 (d, J = 7.7 Hz, 0.5H), 7.46 (d, J = 7.7 Hz, 0.5H), 7.32 –7.37(m,1H),4.67–4.75(m,0.5H), 4.47(d,J=5.0Hz,2H), 3.81–3.90(m,0.5H),3.04(s,1.5H), 2.89( s, 1.5H), 2.11--2.28 (m, 3H), 1.86--2.07 (m, 5H), 1.48 (s, 9H).
MS(ESI,pos.ion)m/z:384.60[M+H] +. MS(ESI,pos.ion)m/z:384.60[M+H] + .
步骤4：化合物6-(氨基甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺二盐酸盐的合成Step 4: Synthesis of compound 6-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide dihydrochloride
将化合物((6-((4,4-二氟环己基)(甲基)甲酰氨基)吡啶-2-基)甲基)氨基甲酸叔丁酯(486mg,1.27mmol)溶解于甲醇(5mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(10mL)，室温搅拌1.5h，减压浓缩，得白色固体423mg，收率93％。The compound ((6-((4,4-difluorocyclohexyl)(methyl)formamido)pyridin-2-yl)methyl)tert-butyl carbamate (486mg, 1.27mmol) was dissolved in methanol (5mL ) To the solution, add 4mol/L HCl ethyl acetate solution (10 mL), stir at room temperature for 1.5 hours, and concentrate under reduced pressure to obtain 423 mg of white solid with a yield of 93%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.00–8.05(m,1H),7.56–7.61(m,2H),4.57–4.62(m,0.5H),4.36(s,2H),3.59–3.67(m,0.5H),3.03(s,1H),2.91(s,2H),2.04–2.24(m,4H),1.90–1.98(m,4H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.00-8.05 (m, 1H), 7.56-7.61 (m, 2H), 4.57-4.62 (m, 0.5H), 4.36 (s, 2H), 3.59--3.67 (m, 0.5H), 3.03 (s, 1H), 2.91 (s, 2H), 2.04 - 2.24 (m, 4H), 1.90 - 1.98 (m, 4H).
MS(ESI,pos.ion)m/z:284.10[M+H-2HCl] +. MS(ESI,pos.ion)m/z:284.10[M+H-2HCl] + .
中间体7：中间体6-(氨基甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺二盐酸盐Intermediate 7: Intermediate 6-(aminomethyl)-N-(4-fluorophenyl)-N-picolinamide dihydrochloride
Figure PCTCN2021090489-appb-000051
Figure PCTCN2021090489-appb-000051
步骤1：化合物((6-((4-氟苯基)(甲基)甲酰氨基)吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 1: Synthesis of compound ((6-((4-fluorophenyl)(methyl)formamido)pyridin-2-yl)methyl) carbamate
将6-(((叔丁氧羰基)氨基)甲基)吡啶甲酸(236mg,0.94mmol)，4-氟-N-甲基苯胺(182mg,1.45mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(913mg,4.76mmol)和N-羟基-7-氮杂苯并三氮唑(262mg,1.92mmol)溶于二氯甲烷(10mL)中，冷却至0℃后,加入N,N-二异丙基乙胺(0.96mL,5.80mmol)，室温搅拌5h，加水(15mL)，用二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，浓缩，硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到浅黄色油状物287mg，收率85％。The 6-(((tert-butoxycarbonyl)amino)methyl)picolinic acid (236mg, 0.94mmol), 4-fluoro-N-methylaniline (182mg, 1.45mmol), 1-ethyl-(3-di Methylaminopropyl) carbodiimide hydrochloride (913mg, 4.76mmol) and N-hydroxy-7-azabenzotriazole (262mg, 1.92mmol) were dissolved in dichloromethane (10mL), After cooling to 0°C, add N,N-diisopropylethylamine (0.96mL, 5.80mmol), stir at room temperature for 5h, add water (15mL), extract with dichloromethane (10mL×3), and use anhydrous organic phase It was dried over sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 287 mg of light yellow oil with a yield of 85%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.64–7.67(m,1H),7.57–7.58(m,1H),7.06–7.13(m,3H),6.93–6.98(m,2H),4.21(s,2H),3.52(s,3H),1.51(s,9H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.64-7.67(m,1H), 7.57-7.58(m,1H), 7.06-7.13(m,3H), 6.93-6.98(m,2H), 4.21(s, 2H), 3.52(s, 3H), 1.51(s, 9H).
MS(ESI,pos.ion)m/z:360.10[M+H] +. MS(ESI,pos.ion)m/z:360.10[M+H] + .
步骤2：化合物6-(氨基甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺二盐酸盐的合成Step 2: Synthesis of compound 6-(aminomethyl)-N-(4-fluorophenyl)-N-picolineamide dihydrochloride
将化合物((6-((4-氟苯基)(甲基)甲酰氨基)吡啶-2-基)甲基)氨基甲酸叔丁酯(260mg,1.97mmol)溶解于甲醇(5mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(10mL)，室温搅拌1.5h，减压浓缩，得浅黄色粘稠固体184mg，收率93％。The compound ((6-((4-fluorophenyl)(methyl)formamido)pyridin-2-yl)methyl) tert-butyl carbamate (260mg, 1.97mmol) was dissolved in methanol (5mL) solution Add 4mol/L HCl ethyl acetate solution (10mL), stir at room temperature for 1.5h, and concentrate under reduced pressure to obtain 184mg of light yellow viscous solid with a yield of 93%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.73–7.78(m,1H),7.38–7.40(m,1H),7.30–7.32(m,1H),7.22–7.29(m,2H),7.00–7.04(m,2H),4.21(s,2H),3.50(s,3H). 1 H NMR(400MHz,CD 3 OD)δ(ppm): 7.73-7.78(m,1H), 7.38-7.40(m,1H), 7.30-7.32(m,1H), 7.22-7.29(m,2H) ,7.00-7.04(m,2H),4.21(s,2H), 3.50(s,3H).
MS(ESI,pos.ion)m/z:260.10[M+H-2HCl] +. MS(ESI,pos.ion)m/z:260.10[M+H-2HCl] + .
中间体8：中间体N-(5-溴-2-(二氟甲氧基)-4-(甲磺酰基)苯基)-N-(环丙基甲基)羟胺Intermediate 8: Intermediate N-(5-bromo-2-(difluoromethoxy)-4-(methylsulfonyl)phenyl)-N-(cyclopropylmethyl)hydroxylamine
Figure PCTCN2021090489-appb-000052
Figure PCTCN2021090489-appb-000052
步骤1：化合物4-溴-1-(二氟甲氧基)-2-硝基苯的合成Step 1: Synthesis of compound 4-bromo-1-(difluoromethoxy)-2-nitrobenzene
将化合物4-溴-2-硝基苯酚(3.0g,14mmol)溶于N,N-二甲基甲酰胺(15mL)，加入二氟氯乙酸钠(3.8g,25mmol)和碳酸铯(8.1g,25mmol)，120℃反应2h后停止，加水(25mL)，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝5/1)，得到浅红色液体1.6g，产率43％。The compound 4-bromo-2-nitrophenol (3.0g, 14mmol) was dissolved in N,N-dimethylformamide (15mL), and sodium difluorochloroacetate (3.8g, 25mmol) and cesium carbonate (8.1g) were added , 25mmol), the reaction was stopped at 120℃ for 2h, water (25mL) was added, extracted with ethyl acetate (10mL×3), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent : Petroleum ether/ethyl acetate (v/v)=5/1), 1.6 g of light red liquid was obtained, and the yield was 43%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.09(d,J＝2.3Hz,1H),7.76(dd,J＝8.8,2.4Hz,1H),7.32(d,J＝8.8Hz,1H),6.63(t,J F-H＝72.5Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.09 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.8, 2.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H ), 6.63 (t, J FH = 72.5Hz, 1H).
MS(ESI,pos.ion)m/z:267.00[M].MS(ESI,pos.ion)m/z:267.00[M].
步骤2：化合物N-(5-溴-2-(二氟甲氧基)苯基)羟胺的合成Step 2: Synthesis of compound N-(5-bromo-2-(difluoromethoxy)phenyl)hydroxylamine
将化合物4-溴-1-(二氟甲氧基)-2-硝基苯(1.6g,6mmol)，氯化铵(961mg,18mmol)溶于1,4-二氧六环(20mL)和水(10mL)的混合溶剂中，冰浴中加入锌粉(1.2g,18mmol)，室温反应4h，过滤除去固体，滤液浓缩，用乙酸乙酯萃取(50mL×3)，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝15/1)，得到浅黄色液体648mg，产率46％。The compound 4-bromo-1-(difluoromethoxy)-2-nitrobenzene (1.6g, 6mmol), ammonium chloride (961mg, 18mmol) was dissolved in 1,4-dioxane (20mL) and In a mixed solvent of water (10mL), add zinc powder (1.2g, 18mmol) in an ice bath, react at room temperature for 4h, filter to remove solids, concentrate the filtrate, extract with ethyl acetate (50mL×3), and use anhydrous sulfuric acid for the organic phase It was dried with sodium, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=15/1) to obtain 648 mg of pale yellow liquid, with a yield of 46%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.49(d,J＝2.2Hz,1H),7.14(br.s,1H),7.06(dd,J＝8.6,2.3Hz,1H), 6.94(d,J＝8.6Hz,1H),5.34(d,J＝1.8Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.49 (d, J = 2.2 Hz, 1H), 7.14 (br.s, 1H), 7.06 (dd, J = 8.6, 2.3 Hz, 1H), 6.94 (d,J=8.6Hz,1H),5.34(d,J=1.8Hz,1H).
MS(ESI,pos.ion)m/z:254.10[M+H] +. MS(ESI,pos.ion)m/z:254.10[M+H] + .
步骤3：化合物N-(5-溴-2-(二氟甲氧基)苯基)-N-(环丙基甲基)羟胺的合成Step 3: Synthesis of compound N-(5-bromo-2-(difluoromethoxy)phenyl)-N-(cyclopropylmethyl)hydroxylamine
将化合物N-(5-溴-2-(二氟甲氧基)苯基)羟胺(284mg,1.12mmol)，环丙基甲醛(250mg,3.57mmol)溶于乙醇(5mL)和醋酸(358mg,5.97mmol)的混合溶剂中，加入氰基硼氢化钠(374mg,3.95mmol)，室温反应12h，浓缩，加水(10mL)，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝20/1)，得到黄褐色固体243mg，产率69％。The compound N-(5-bromo-2-(difluoromethoxy)phenyl)hydroxylamine (284mg, 1.12mmol), cyclopropylcarbaldehyde (250mg, 3.57mmol) was dissolved in ethanol (5mL) and acetic acid (358mg, 5.97mmol), add sodium cyanoborohydride (374mg, 3.95mmol), react at room temperature for 12h, concentrate, add water (10mL), extract with ethyl acetate (5mL×3), and use anhydrous sodium sulfate for the organic phase It was dried, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=20/1) to obtain 243 mg of yellow-brown solid, with a yield of 69%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.74(d,J＝2.2Hz,1H),7.18(dd,J＝8.5,2.3Hz,1H),6.95(d,J＝8.7Hz,1H),6.51(t,J F-H＝74.7Hz,1H),5.87(s,1H),3.03(d,J＝6.9Hz,1H),1.12–1.22(m,1H),0.51–0.56(m,2H),0.24–0.28(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.74 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 8.5, 2.3 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H ), 6.51(t,J FH =74.7Hz,1H),5.87(s,1H),3.03(d,J=6.9Hz,1H),1.12–1.22(m,1H),0.51–0.56(m,2H ), 0.24–0.28 (m, 2H).
MS(ESI,pos.ion)m/z:308.05[M+H] +. MS(ESI,pos.ion)m/z:308.05[M+H] + .
步骤4：化合物N-(5-溴-2-(二氟甲氧基)-4-(甲磺酰基)苯基)-N-(环丙基甲基)羟胺的合成Step 4: Synthesis of compound N-(5-bromo-2-(difluoromethoxy)-4-(methylsulfonyl)phenyl)-N-(cyclopropylmethyl)hydroxylamine
将化合物N-(5-溴-2-(二氟甲氧基)苯基)-N-(环丙基甲基)羟胺(300mg,1.06mmol)溶解在二氯甲烷(6mL)中，加入N,N-二异丙基乙胺(1.0mL,6.10mmol)，0℃条件下滴加甲磺酰氯(354mg,3.09mmol)，室温搅拌3h后停止，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝8/1)，得到浅褐色液体121mg，产率31％。The compound N-(5-bromo-2-(difluoromethoxy)phenyl)-N-(cyclopropylmethyl)hydroxylamine (300mg, 1.06mmol) was dissolved in dichloromethane (6mL), and N , N-Diisopropylethylamine (1.0mL, 6.10mmol), add methanesulfonyl chloride (354mg, 3.09mmol) dropwise at 0℃, stir at room temperature for 3h and stop, add water (15mL), extract with dichloromethane ( 5mL×3), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=8/1) to obtain a light brown liquid 121mg, yield 31%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.16(s,1H),6.82(s,1H),6.51(t,J F-H＝73.3Hz,1H),4.41(br.s,1H),3.23(s,1H),2.96–2.99(m,1H),1.10–1.16(m,1H),0.61–0.65(m,2H),0.27–0.31(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.16 (s, 1H), 6.82 (s, 1H), 6.51 (t, J FH = 73.3 Hz, 1H), 4.41 (br.s, 1H), 3.23(s,1H), 2.96–2.99(m,1H), 1.10–1.16(m,1H), 0.61–0.65(m,2H), 0.27–0.31(m,2H).
MS(ESI,pos.ion)m/z:386.10[M+H] +. MS(ESI,pos.ion)m/z:386.10[M+H] + .
中间体9：中间体1-环丙基-N-甲基甲胺盐酸盐Intermediate 9: Intermediate 1-cyclopropyl-N-methylmethylamine hydrochloride
Figure PCTCN2021090489-appb-000053
Figure PCTCN2021090489-appb-000053
步骤1：化合物环丙基甲基氨基甲酸叔丁酯的合成Step 1: Synthesis of compound tert-butyl cyclopropyl methyl carbamate
将化合物环丙基甲胺(0.51g,7.11mmol)溶解于二氯甲烷(15mL)溶液中，加入N,N-二异丙基乙胺(3.5mL,21mmol)，在-10℃下加入二碳酸二叔丁酯(1.9mL,8.3mmol)，搅拌15min转移至室温反应3h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到无色液体810mg，收率67％。The compound cyclopropylmethylamine (0.51g, 7.11mmol) was dissolved in a dichloromethane (15mL) solution, N,N-diisopropylethylamine (3.5mL, 21mmol) was added, and two were added at -10°C. Di-tert-butyl carbonate (1.9mL, 8.3mmol), stirred for 15min, transferred to room temperature and reacted for 3h, washed with water (50mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed. The concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain 810 mg of colorless liquid with a yield of 67%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):6.84(br.s,1H),2.80(t,J＝6.1Hz,2H),1.38(s,9H),0.82-0.92(m,1H),0.34-0.38(m,2H),0.09-0.14(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 6.84 (br.s, 1H), 2.80 (t, J = 6.1Hz, 2H), 1.38 (s, 9H), 0.82-0.92 (m, 1H), 0.34-0.38 (m, 2H), 0.09-0.14 (m, 2H).
MS(ESI,pos.ion)m/z:116.25[M-55] +. MS(ESI,pos.ion)m/z:116.25[M-55] + .
步骤2：化合物(环丙基甲基)(甲基)氨基甲酸叔丁酯的合成Step 2: Synthesis of compound (cyclopropylmethyl)(methyl) t-butyl carbamate
将氢化钠(0.47g,11.9mmol)溶解于N,N-二甲基甲酰胺(15mL)溶液中，在冰浴中加入环丙基甲基氨基甲酸叔丁酯(0.81g,4.7mmol)，5min后加入碘甲烷(0.5mL,8.0mmol)，冰浴中继续反应20min，转移至室温反应7h，加水(100mL)，用乙酸乙酯萃取(25mL×3)，有机相用无水硫酸钠干燥，浓缩得到淡黄色液体790mg，收率90％。Dissolve sodium hydride (0.47g, 11.9mmol) in N,N-dimethylformamide (15mL) solution, add tert-butyl cyclopropylmethylcarbamate (0.81g, 4.7mmol) in an ice bath, After 5 minutes, add methyl iodide (0.5mL, 8.0mmol), continue the reaction in an ice bath for 20 minutes, transfer to room temperature and react for 7 hours, add water (100mL), extract with ethyl acetate (25mL×3), and dry the organic phase with anhydrous sodium sulfate , Concentrated to obtain 790 mg of pale yellow liquid, with a yield of 90%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):3.04(d,J＝6.9Hz,1H),2.82(s,1H),1.39(s,9H),0.89-0.97(m,1H),0.41-0.45(m,2H),0.16-0.20(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 3.04 (d, J = 6.9 Hz, 1H), 2.82 (s, 1H), 1.39 (s, 9H), 0.89-0.97 (m, 1H) , 0.41-0.45 (m, 2H), 0.16-0.20 (m, 2H).
MS(ESI,pos.ion)m/z:130.20[M-55] +. MS(ESI,pos.ion)m/z:130.20[M-55] + .
步骤3：化合物1-(环丙基)-N-甲基甲胺盐酸盐的合成Step 3: Synthesis of compound 1-(cyclopropyl)-N-methylmethylamine hydrochloride
将化合物(环丙基甲基)(甲基)氨基甲酸叔丁酯(0.79g,4.3mmol)溶解于二氯甲烷(6mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(8mL)，室温搅拌1.5h，除去溶剂，得到淡黄色液体350mg，收率97％。Dissolve the compound (cyclopropylmethyl)(methyl) tert-butyl carbamate (0.79g, 4.3mmol) in dichloromethane (6mL) solution, add 4mol/L HCl ethyl acetate solution (8mL), Stir at room temperature for 1.5 hours and remove the solvent to obtain 350 mg of light yellow liquid with a yield of 97%.
1H NMR(400MHz,DMSO-d 6):δ(ppm)2.74(d,J＝7.4Hz,2H),1.91(s,3H),1.00-1.11(m,1H),0.53-0.57(m,2H),0.33-0.38(m,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.74 (d, J = 7.4Hz, 2H), 1.91 (s, 3H), 1.00-1.11 (m, 1H), 0.53-0.57 (m, 2H), 0.33-0.38 (m, 2H).
中间体10：中间体1-(2,4-二氟苯基)-N-甲基甲胺盐酸盐Intermediate 10: Intermediate 1-(2,4-difluorophenyl)-N-methylmethylamine hydrochloride
Figure PCTCN2021090489-appb-000054
Figure PCTCN2021090489-appb-000054
步骤1：化合物2,4-二氟苄基氨基甲酸叔丁酯的合成Step 1: Synthesis of compound 2,4-difluorobenzyl carbamate tert-butyl ester
将化合物2,4-二氟苯基甲胺(1.01g,7.1mmol)溶解于二氯甲烷(15mL)溶液中，加入N,N-二异丙基乙胺(3.5mL,21mmol)，在-10℃下加入二碳酸二叔丁酯(2.0mL,8.7mmol)，搅拌15min转移至室温反应5h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到无色液体1.4g，收率82％。The compound 2,4-difluorophenylmethylamine (1.01g, 7.1mmol) was dissolved in dichloromethane (15mL) solution, and N,N-diisopropylethylamine (3.5mL, 21mmol) was added to Add di-tert-butyl dicarbonate (2.0mL, 8.7mmol) at 10°C, stir for 15min, transfer to room temperature and react for 5h, wash with water (50mL), extract with dichloromethane (5mL×3), and use anhydrous sodium sulfate for the organic phase After drying and removing the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 1.4 g of colorless liquid with a yield of 82%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.31-7.39(m,2H),7.15-7.20(m,1H),7.06(t,J＝8.0Hz,1H),4.14(d,J＝5.4Hz,2H),1.39(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.31-7.39 (m, 2H), 7.15-7.20 (m, 1H), 7.06 (t, J = 8.0 Hz, 1H), 4.14 (d, J=5.4Hz, 2H), 1.39(s, 9H).
MS(ESI,pos.ion)m/z:266.15[M+Na] +. MS(ESI,pos.ion)m/z:266.15[M+Na] + .
步骤2：化合物(2,4-二氟苄基)(甲基)氨基甲酸叔丁酯的合成Step 2: Synthesis of compound (2,4-difluorobenzyl)(methyl) t-butyl carbamate
将氢化钠(0.63g,15.8mmol)溶解于N,N-二甲基甲酰胺(15mL)溶液中，在0℃下加入2,4-二氟苄基氨基甲酸叔丁酯(1.4g,5.8mmol)，5min后再加入碘甲烷(0.65mL,10.0mmol)，0℃下反应20min，转移至室温反应12h，加水(100mL)，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到淡黄色液体1.3g，收率88％。Sodium hydride (0.63g, 15.8mmol) was dissolved in N,N-dimethylformamide (15mL) solution, and 2,4-difluorobenzyl carbamate tert-butyl ester (1.4g, 5.8 mmol), add methyl iodide (0.65mL, 10.0mmol) after 5min, react at 0℃ for 20min, transfer to room temperature and react for 12h, add water (100mL), extract with ethyl acetate (5mL×3), and use anhydrous organic phase After drying with sodium sulfate and removing the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 1.3 g of light yellow liquid with a yield of 88%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.27-7.33(m,1H),7.20-7.26(m,1H),7.09(t,J＝7.9Hz,1H),4.39(s,2H),2.78(s,3H),1.38(s,9H). 1 H NMR(400MHz, DMSO-d 6 )δ(ppm): 7.27-7.33(m,1H), 7.20-7.26(m,1H), 7.09(t,J=7.9Hz,1H), 4.39(s, 2H), 2.78(s, 3H), 1.38(s, 9H).
MS(ESI,pos.ion)m/z:280.20[M+Na] +. MS(ESI,pos.ion)m/z:280.20[M+Na] + .
步骤3：化合物1-(2,4-二氟苯基)-N-甲基甲胺盐酸盐的合成Step 3: Synthesis of compound 1-(2,4-difluorophenyl)-N-methylmethylamine hydrochloride
将化合物(2,4-二氟苄基)(甲基)氨基甲酸叔丁酯(1.3g,5.1mmol)溶解于二氯甲烷(6mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(10mL)，室温搅拌1h，除去溶剂，得到淡黄色固体763mg，收率96％。The compound (2,4-difluorobenzyl) (methyl) tert-butyl carbamate (1.3g, 5.1mmol) was dissolved in dichloromethane (6mL) solution, and 4mol/L HCl ethyl acetate solution ( 10 mL), stirred at room temperature for 1 h, and removed the solvent to obtain 763 mg of a pale yellow solid with a yield of 96%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):9.47-9.61(m,1H),7.74-7.81(m,1H),7.34-7.39(m,1H),7.21(t,J＝8.5Hz,1H),4.13(s,2H),2.54(s,2H),2.51(s,1H). 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 9.47-9.61(m,1H),7.74-7.81(m,1H),7.34-7.39(m,1H),7.21(t,J=8.5 Hz, 1H), 4.13 (s, 2H), 2.54 (s, 2H), 2.51 (s, 1H).
MS(ESI,pos.ion)m/z:158.20[M+H-HCl] +. MS(ESI,pos.ion)m/z:158.20[M+H-HCl] + .
中间体11：中间体N-甲基-1-(吡啶-2-基)甲胺二盐酸盐Intermediate 11: Intermediate N-methyl-1-(pyridin-2-yl)methylamine dihydrochloride
Figure PCTCN2021090489-appb-000055
Figure PCTCN2021090489-appb-000055
步骤1：化合物(吡啶-2-基甲基)氨基甲酸叔丁酯的合成Step 1: Synthesis of compound (pyridin-2-ylmethyl) tert-butyl carbamate
将化合物2-吡啶甲胺(510mg,4.70mmol)溶解于二氯甲烷(15mL)溶液中，加入N,N-二异丙基乙胺(2.3mL,14mmol)，在-10℃下加入二碳酸二叔丁酯(1.3mL,5.7mmol)，搅拌15min转移至室温反应8h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到无色液体620mg，收率64％。The compound 2-picolinylmethylamine (510mg, 4.70mmol) was dissolved in dichloromethane (15mL) solution, N,N-diisopropylethylamine (2.3mL, 14mmol) was added, and dicarbonic acid was added at -10°C Di-tert-butyl ester (1.3mL, 5.7mmol), stirred for 15min, transferred to room temperature and reacted for 8h, washed with water (50mL), extracted with dichloromethane (5mL×3), dried the organic phase with anhydrous sodium sulfate, removed the solvent, and concentrated The liquid was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 620 mg of colorless liquid with a yield of 64%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.48(d,J＝4.1Hz,1H),7.76(t,J＝7.3Hz,1H),7.41(br.s,1H),7.21-7.29(m,2H),4.22(d,J＝5.9Hz,2H),1.41(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.48 (d, J = 4.1 Hz, 1H), 7.76 (t, J = 7.3 Hz, 1H), 7.41 (br.s, 1H), 7.21 -7.29(m,2H),4.22(d,J=5.9Hz,2H),1.41(s,9H).
MS(ESI,pos.ion)m/z:209.10[M+H] +. MS(ESI,pos.ion)m/z:209.10[M+H] + .
步骤2：化合物N-甲基-(吡啶-2-基甲基)氨基甲酸叔丁酯的合成Step 2: Synthesis of compound tert-butyl N-methyl-(pyridin-2-ylmethyl)carbamate
将氢化钠(310mg,7.6mmol)溶解于N,N-二甲基甲酰胺(10mL)溶液中，在0℃下加入(吡啶-2-基甲基)氨基甲酸叔丁酯(620mg,2.98mmol)，5min后再加入碘甲烷(0.3mL,5.0mmol)，0℃下反应20min，转移至室温反应18h，加水洗(100mL)，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到淡黄色液体580mg，收率88％。Sodium hydride (310mg, 7.6mmol) was dissolved in N,N-dimethylformamide (10mL) solution, and tert-butyl (pyridin-2-ylmethyl) carbamate (620mg, 2.98mmol) was added at 0°C ), add methyl iodide (0.3mL, 5.0mmol) after 5min, react at 0℃ for 20min, transfer to room temperature and react for 18h, wash with water (100mL), extract with ethyl acetate (5mL×3), and use anhydrous organic phase After drying over sodium sulfate, the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 580 mg of pale yellow liquid with a yield of 88%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.52(d,J＝4.3Hz,1H),7.78(t,J＝7.4Hz,1H),7.26–7.29(m,1H),7.19(d,J＝7.6Hz,1H),4.45(s,2H),2.86(s,3H),1.43(s,4H),1.30(s,5H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.52 (d, J = 4.3 Hz, 1H), 7.78 (t, J = 7.4 Hz, 1H), 7.26-7.29 (m, 1H), 7.19 (d,J=7.6Hz,1H), 4.45 (s, 2H), 2.86 (s, 3H), 1.43 (s, 4H), 1.30 (s, 5H).
MS(ESI,pos.ion)m/z:223.25[M+H] +. MS(ESI,pos.ion)m/z:223.25[M+H] + .
步骤3：化合物N-甲基-1-(吡啶-2-基)甲胺二盐酸盐的合成Step 3: Synthesis of compound N-methyl-1-(pyridin-2-yl)methylamine dihydrochloride
将化合物甲基(吡啶-2-基甲基)氨基甲酸叔丁酯(580mg,2.6mmol)溶解于二氯甲烷(6mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(8mL)，室温搅拌1h，除去溶剂，得到灰色固体310mg，收率98％。Dissolve compound tert-butyl methyl (pyridin-2-ylmethyl) carbamate (580mg, 2.6mmol) in dichloromethane (6mL) solution, add 4mol/L HCl ethyl acetate solution (8mL), room temperature After stirring for 1 h, the solvent was removed to obtain 310 mg of gray solid with a yield of 98%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.69(d,J＝4.4Hz,1H),8.02(t,J＝6.8Hz,1H),7.68–7.70(m,1H),7.52–7.55(m,1H),4.33(t,J＝5.5Hz,2H),2.60(t,J＝4.8Hz,2H). 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 8.69(d,J=4.4Hz,1H), 8.02(t,J=6.8Hz,1H), 7.68–7.70(m,1H), 7.52 –7.55(m,1H),4.33(t,J=5.5Hz,2H),2.60(t,J=4.8Hz,2H).
MS(ESI,pos.ion)m/z:123.30[M+H] +. MS(ESI,pos.ion)m/z:123.30[M+H] + .
中间体12：中间体N-((6-(氨基甲基)吡啶-2-基)甲基)-N-(4,4-二氟环己基)乙酰胺二盐酸盐Intermediate 12: Intermediate N-((6-(aminomethyl)pyridin-2-yl)methyl)-N-(4,4-difluorocyclohexyl)acetamide dihydrochloride
Figure PCTCN2021090489-appb-000056
Figure PCTCN2021090489-appb-000056
步骤1:化合物((6-(羟甲基)吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 1: Synthesis of compound ((6-(hydroxymethyl)pyridin-2-yl)methyl) t-butyl carbamate
将化合物6-(((叔丁氧羰基)氨基)甲基)吡啶甲酸乙酯(747mg,2.67mmol)溶于无水四氢呋喃(10mL)，冰浴下加入硼氢化锂(304mg,14.0mmol)，室温反应2h后停止，加入碎冰，用乙酸乙酯萃取(10mL×3)，合并有机相后，用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到白色固体515mg，收率81％。Compound 6-(((tert-butoxycarbonyl)amino)methyl)picolinate (747mg, 2.67mmol) was dissolved in anhydrous tetrahydrofuran (10mL), lithium borohydride (304mg, 14.0mmol) was added under ice bath, The reaction was stopped after 2 hours at room temperature, crushed ice was added, extracted with ethyl acetate (10mL×3), the organic phases were combined, dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum Ether/ethyl acetate (v/v) = 1/2) to obtain 515 mg of a white solid with a yield of 81%.
MS(ESI,pos.ion)m/z:239.30[M+H] +. MS(ESI,pos.ion)m/z:239.30[M+H] + .
步骤2：化合物((6-甲酰基吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 2: Synthesis of compound ((6-formylpyridin-2-yl)methyl) t-butyl carbamate
将二甲基亚砜(669mg,8.56mmol)溶于二氯甲烷(2mL)，-78℃下加入草酰氯(1.1g,8.70mmol)的二氯甲烷溶液(3mL)，在此温度下反应30min后加入化合物((6-(羟甲基)吡啶-2-基)甲基)氨基甲酸叔丁酯(510mg,2.14mmol)的二氯甲烷溶液(10mL)，继续反应30min，-78℃下加入三乙胺(1.5mL,11mmol)，缓慢升高到室温，水洗有机相(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到白色固体459mg，收率90％。Dissolve dimethyl sulfoxide (669mg, 8.56mmol) in dichloromethane (2mL), add oxalyl chloride (1.1g, 8.70mmol) in dichloromethane solution (3mL) at -78℃, and react at this temperature for 30min Then add the compound ((6-(hydroxymethyl)pyridin-2-yl)methyl) tert-butyl carbamate (510mg, 2.14mmol) in dichloromethane solution (10mL), continue the reaction for 30min, add at -78℃ Triethylamine (1.5mL, 11mmol) was slowly raised to room temperature, the organic phase (10mL×3) was washed with water, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: Petroleum ether/ethyl acetate (v/v)=3/1) to obtain 459 mg of white solid with a yield of 90%.
MS(ESI,pos.ion)m/z:237.10[M+H] +. MS(ESI,pos.ion)m/z:237.10[M+H] + .
步骤3：化合物((6-(((4,4-二氟环己基)氨基)甲基)吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 3: Synthesis of compound ((6-(((4,4-difluorocyclohexyl)amino)methyl)pyridin-2-yl)methyl) carbamate
将化合物((6-甲酰基吡啶-2-基)甲基)氨基甲酸叔丁酯(233mg,0.99mmol)和4,4-二氟环己胺盐酸盐(217mg,1.26mmol)溶于乙醇(5mL)中，加入乙酸(59mg,0.98mmol)和氰基硼氢化钠(187mg,2.98mmol)，50℃反应6h，减压除去乙醇，加水洗(10mL)，乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/5)，得到无色液体323mg，收率92％。The compound ((6-formylpyridin-2-yl)methyl) tert-butyl carbamate (233mg, 0.99mmol) and 4,4-difluorocyclohexylamine hydrochloride (217mg, 1.26mmol) were dissolved in ethanol (5mL), add acetic acid (59mg, 0.98mmol) and sodium cyanoborohydride (187mg, 2.98mmol), react at 50℃ for 6h, remove ethanol under reduced pressure, wash with water (10mL), and extract with ethyl acetate (10mL×3 ), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/5) to obtain 323 mg of colorless liquid. The yield was 92%.
MS(ESI,pos.ion)m/z:356.25[M+H] +. MS(ESI,pos.ion)m/z:356.25[M+H] + .
步骤4：化合物((6-((N-(4,4-二氟环己基)乙酰氨基)甲基)吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 4: Synthesis of compound ((6-((N-(4,4-difluorocyclohexyl)acetamido)methyl)pyridin-2-yl)methyl) carbamate
将化合物((6-(((4,4-二氟环己基)氨基)甲基)吡啶-2-基)甲基)氨基甲酸叔丁酯(322mg,0.91mmol)溶解在二氯甲烷(8mL)中，加入N,N-二异丙基乙胺(0.75mL,4.5mmol)，0℃条件下滴加乙酰氯(0.2mL,3.0mmol)，室温搅拌5h后停止反应，加水(20mL)，二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/4)，得到白色固体212mg，产率59％。The compound ((6-(((4,4-difluorocyclohexyl)amino)methyl)pyridin-2-yl)methyl)tert-butyl carbamate (322mg, 0.91mmol) was dissolved in dichloromethane (8mL ), add N,N-diisopropylethylamine (0.75mL, 4.5mmol), add acetyl chloride (0.2mL, 3.0mmol) dropwise at 0°C, stir at room temperature for 5h, then stop the reaction, add water (20mL), Dichloromethane extraction (10mL×3), the organic phase was dried with anhydrous sodium sulfate, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/4) to obtain White solid 212mg, yield 59%.
MS(ESI,pos.ion)m/z:398.30[M+H] +. MS(ESI,pos.ion)m/z:398.30[M+H] + .
步骤5：化合物N-((6-(氨基甲基)吡啶-2-基)甲基)-N-(4,4-二氟环己基)乙酰胺二盐酸盐的合成Step 5: Synthesis of compound N-((6-(aminomethyl)pyridin-2-yl)methyl)-N-(4,4-difluorocyclohexyl)acetamide dihydrochloride
将化合物((6-((N-(4,4-二氟环己基)乙酰氨基)甲基)吡啶-2-基)甲基)氨基甲酸叔丁酯(200mg,0.5mmol)溶解于二氯甲烷(4mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(6mL)，室温搅拌30min，除去溶剂，得到182mg白色固体，收率97％。The compound ((6-((N-(4,4-difluorocyclohexyl)acetamido)methyl)pyridin-2-yl)methyl)t-butyl carbamate (200mg, 0.5mmol) was dissolved in dichloromethane To the methane (4 mL) solution, add 4 mol/L HCl ethyl acetate solution (6 mL), stir at room temperature for 30 min, remove the solvent, and obtain 182 mg of white solid with a yield of 97%.
MS(ESI,pos.ion)m/z:298.30[M+H-HCl] +. MS(ESI,pos.ion)m/z:298.30[M+H-HCl] + .
中间体13：6-(氨基甲基)-2-甲基异吲哚啉-1-酮Intermediate 13: 6-(Aminomethyl)-2-methylisoindolin-1-one
Figure PCTCN2021090489-appb-000057
Figure PCTCN2021090489-appb-000057
步骤1：3-氧代异吲哚啉-5-甲酸甲酯的合成Step 1: Synthesis of methyl 3-oxoisoindoline-5-carboxylate
将化合物3-氧代异吲哚啉-5-甲酸(1.00g,5.60mmol)，N,N’-羰基二咪唑(960mg,5.92mmol)溶于N,N’-二甲基甲酰胺(20mL)中，60℃下搅拌30min，依次加入N，N-二异丙基乙胺(1.90mL，11.0mmol)与甲醇(0.50mL，11.0mmol)，60℃下搅拌3.5h。减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝20/1)，得到浅黄色固体(900mg,产率83％)。The compound 3-oxoisoindoline-5-carboxylic acid (1.00g, 5.60mmol), N,N'-carbonyldiimidazole (960mg, 5.92mmol) was dissolved in N,N'-dimethylformamide (20mL ), stirring at 60°C for 30 min, adding N,N-diisopropylethylamine (1.90 mL, 11.0 mmol) and methanol (0.50 mL, 11.0 mmol) in turn, and stirring at 60°C for 3.5 h. The solvent was removed by concentration under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain a pale yellow solid (900 mg, yield 83%).
1H NMR(400MHz,DMSO-d 6):δ(ppm)8.15–8.18(m,1H),7.95(s,2H),4.47(s,2H),3.89(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ (ppm) 8.15-8.18 (m, 1H), 7.95 (s, 2H), 4.47 (s, 2H), 3.89 (s, 3H).
MS(ESI,pos.ion)m/z:192.10[M+H] +. MS(ESI,pos.ion)m/z:192.10[M+H] + .
步骤2：2-甲基-3-氧代异吲哚啉-5-甲酸甲酯的合成Step 2: Synthesis of methyl 2-methyl-3-oxoisoindoline-5-carboxylate
将化合物3-氧代异吲哚啉-5-甲酸甲酯(1.00g,5.23mmol)，氢化钠(271mg,6.78mmol)溶于N,N’-二甲基甲酰胺(40mL)中，在氮气氛围下50℃下搅拌20min，加入硫酸二甲酯(866mg,6.79mmol)，升温至100℃搅拌反应2h。停止反应，减压浓缩除去溶剂，用乙酸乙酯(40mL)溶解，用水(20mL×2)洗涤，无水硫酸钠干燥有机相，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯(v/v)＝1/4)，得到褐色固体(450mg,产率42％)。The compound 3-oxoisoindoline-5-carboxylic acid methyl ester (1.00g, 5.23mmol), sodium hydride (271mg, 6.78mmol) were dissolved in N,N'-dimethylformamide (40mL), in Stir at 50°C for 20min under a nitrogen atmosphere, add dimethyl sulfate (866mg, 6.79mmol), heat up to 100°C and stir for 2h. The reaction was stopped, concentrated under reduced pressure to remove the solvent, dissolved with ethyl acetate (40mL), washed with water (20mL×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the concentrated solution was subjected to silica gel column chromatography (washing) Removal: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain a brown solid (450 mg, yield 42%).
1H NMR(400MHz,CDCl 3):δ(ppm)8.50(s,1H),8.20–8.26(m,1H),7.51(d,J＝7.9Hz,1H),4.43(s,2H),3.95(s,3H),3.22(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 8.50 (s, 1H), 8.20-8.26 (m, 1H), 7.51 (d, J = 7.9 Hz, 1H), 4.43 (s, 2H), 3.95 (s,3H),3.22(s,3H).
MS(ESI,pos.ion)m/z:206.15[M+H] +. MS(ESI,pos.ion)m/z:206.15[M+H] + .
步骤3：6-(羟甲基)-2-甲基异吲哚啉-1-酮的合成Step 3: Synthesis of 6-(hydroxymethyl)-2-methylisoindolin-1-one
将化合物2-甲基-3-氧代异吲哚啉-5-羧酸甲酯(460mg,2.24mmol)，溶于四氢呋喃(25mL)中，加入硼氢化锂(195mg,8.95mmol)，50℃下搅拌6h，停止反应，加水(10mL)搅拌5min，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝10/1)，得到白色固体(370mg,产率93％)。The compound 2-methyl-3-oxoisoindoline-5-carboxylic acid methyl ester (460 mg, 2.24 mmol) was dissolved in tetrahydrofuran (25 mL), and lithium borohydride (195 mg, 8.95 mmol) was added at 50°C After stirring for 6h, the reaction was stopped, water (10mL) was added and stirred for 5min, concentrated under reduced pressure to remove the solvent, and the concentrate was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=10/1) to obtain White solid (370 mg, yield 93%).
1H NMR(400MHz,CD 3OD):δ(ppm)7.76(s,1H),7.57–7.64(m,1H),7.51–7.56(m,1H),4.71(s,2H),4.49(s,2H),3.21(s,3H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.76 (s, 1H), 7.57 - 7.64 (m, 1H), 7.51 - 7.56 (m, 1H), 4.71 (s, 2H), 4.49 (s) ,2H),3.21(s,3H).
MS(ESI,pos.ion)m/z:178.20[M+H] +. MS(ESI,pos.ion)m/z:178.20[M+H] + .
步骤4：(2-甲基-3-氧代异吲哚啉-5-基)甲基甲磺酸酯的合成Step 4: Synthesis of (2-methyl-3-oxoisoindolin-5-yl)methanesulfonate
将化合物6-(羟甲基)-2-甲基异吲哚-1-酮(252mg,1.42mmol)溶于二氯甲烷(10mL)中，加入N，N-二异丙基乙胺(737mg，0.94mmol)，冰浴下搅拌5min后，加入甲磺酰氯(325mg，2.84mmol)，室温下搅拌1h，停止反应，加水(10mL)搅拌5min，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯(v/v)＝1/4)，得到浅黄色固体(240mg,产率66％)。The compound 6-(hydroxymethyl)-2-methylisoindol-1-one (252mg, 1.42mmol) was dissolved in dichloromethane (10mL), and N,N-diisopropylethylamine (737mg , 0.94mmol), after stirring for 5min in an ice bath, add methanesulfonyl chloride (325mg, 2.84mmol), stir at room temperature for 1h, stop the reaction, add water (10mL) and stir for 5min, concentrate under reduced pressure to remove the solvent, and apply the concentrated solution to silica gel column layer Analysis and separation (eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain a pale yellow solid (240 mg, yield 66%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.87(s,1H),7.57–7.63(m,1H),7.46–7.52(m,1H),5.31(s,2H),4.40(s,2H),3.21(s,3H),2.98(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.87 (s, 1H), 7.57 - 7.63 (m, 1H), 7.46 - 7.52 (m, 1H), 5.31 (s, 2H), 4.40 (s, 2H), 3.21(s, 3H), 2.98(s, 3H).
MS(ESI,pos.ion)m/z:256.15[M+H] +. MS(ESI,pos.ion)m/z:256.15[M+H] + .
步骤5：6-(叠氮甲基)-2-甲基异吲哚啉-1-酮的合成Step 5: Synthesis of 6-(azidomethyl)-2-methylisoindolin-1-one
将化合物(2-甲基-3-氧代异吲哚啉-5-基)甲基甲磺酸酯(240mg,0.94mmol)与叠氮化钠(305mg,4.69mmol)溶于N,N’-二甲基甲酰胺(10mL)中，80℃下搅拌2.5h，减压浓缩除去溶剂，乙酸乙酯(20mL)溶解，用水(10mL×2)洗涤，有机相用无水硫酸钠干燥，减压浓缩得到浅黄色固体(181mg,产率95％)。The compound (2-methyl-3-oxoisoindolin-5-yl) methyl methanesulfonate (240mg, 0.94mmol) and sodium azide (305mg, 4.69mmol) were dissolved in N, N' -In dimethylformamide (10mL), stir at 80°C for 2.5h, concentrate under reduced pressure to remove the solvent, dissolve in ethyl acetate (20mL), wash with water (10mL×2), dry the organic phase with anhydrous sodium sulfate, reduce It was concentrated under pressure to obtain a pale yellow solid (181 mg, yield 95%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.79(s,1H),7.43–7.53(m,2H),4.43(s,2H),4.39(s,2H),3.21(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.79 (s, 1H), 7.43-7.53 (m, 2H), 4.43 (s, 2H), 4.39 (s, 2H), 3.21 (s, 3H) .
MS(ESI,pos.ion)m/z:203.15[M+H] +. MS(ESI,pos.ion)m/z:203.15[M+H] + .
步骤6：6-(氨基甲基)-2-甲基异吲哚啉-1-酮的合成Step 6: Synthesis of 6-(aminomethyl)-2-methylisoindolin-1-one
将化合物6-(叠氮甲基)-2-甲基异吲哚啉-1-酮(180mg,0.89mmol)溶于甲醇(10mL)中，加入Pd/C(20mg,0.10g/g)，通入氢气，室温下搅拌30min，通过硅藻土抽滤除去催化剂，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝10/1)，得到白色固体(67mg,42％)。The compound 6-(azidomethyl)-2-methylisoindolin-1-one (180mg, 0.89mmol) was dissolved in methanol (10mL), Pd/C (20mg, 0.10g/g) was added, Pass in hydrogen gas, stir at room temperature for 30 min, remove the catalyst by suction filtration through diatomaceous earth, concentrate under reduced pressure to remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=10/ 1) A white solid (67 mg, 42%) was obtained.
1H NMR(400MHz,CD 3OD):δ(ppm)7.73(s,1H),7.27–7.63(m,1H),7.50–7.56(m,1H),4.48(s,2H),3.93(s,2H),3.19(s,3H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.73 (s, 1H), 7.27 - 7.63 (m, 1H), 7.50 - 7.56 (m, 1H), 4.48 (s, 2H), 3.93 (s) ,2H),3.19(s,3H).
MS(ESI,pos.ion)m/z:177.20[M+H] +. MS(ESI,pos.ion)m/z:177.20[M+H] + .
中间体14：5-(氨基甲基)-2-甲基异吲哚啉-1-酮Intermediate 14: 5-(Aminomethyl)-2-methylisoindolin-1-one
Figure PCTCN2021090489-appb-000058
Figure PCTCN2021090489-appb-000058
步骤1：1-氧代异吲哚啉-5-甲酸甲酯的合成Step 1: Synthesis of methyl 1-oxoisoindoline-5-carboxylate
将化合物1-氧代异吲哚啉-5-甲酸(2.00g,11.0mmol)，N,N’-羰基二咪唑(2.00g,12.0mmol)溶于N,N’-二甲基甲酰胺(40mL)中，60℃下搅拌30min，依次加入N,N-二异丙基乙胺(7.50mL，45.0mmol)与甲醇(1.80mL，45.0mmol)，60℃下搅拌3.5h。减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝20/1)，得到浅黄色固体(1.00g,产率46％)。Compound 1-oxoisoindoline-5-carboxylic acid (2.00g, 11.0mmol), N,N'-carbonyldiimidazole (2.00g, 12.0mmol) were dissolved in N,N'-dimethylformamide ( 40mL), stirred at 60°C for 30min, added N,N-diisopropylethylamine (7.50mL, 45.0mmol) and methanol (1.80mL, 45.0mmol) in sequence, and stirred at 60°C for 3.5h. The solvent was removed by concentration under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain a pale yellow solid (1.00 g, yield 46%).
1H NMR(600MHz,DMSO-d 6):δ(ppm)8.81(s,1H),8.16(s,1H),8.05(d,J＝7.9Hz,1H),7.79(d,J＝7.9Hz,1H),4.44(s,2H),3.89(s,3H). 1 H NMR (600MHz, DMSO-d 6 ): δ (ppm) 8.81 (s, 1H), 8.16 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.9 Hz ,1H), 4.44(s, 2H), 3.89(s, 3H).
MS(ESI,pos.ion)m/z:192.20[M+H] +. MS(ESI,pos.ion)m/z:192.20[M+H] + .
步骤2：2-甲基-1-氧代异吲哚啉-5-甲酸甲酯的合成Step 2: Synthesis of methyl 2-methyl-1-oxoisoindoline-5-carboxylate
将化合物1-氧代异吲哚啉-5-甲酸甲酯(945mg,4.94mmol)，氢化钠(300mg,7.50mmol)溶于N,N’-二甲基甲酰胺(30mL)中，在氮气氛围下50℃下搅拌20min，加入硫酸二甲酯(944mg,7.41mmol)，升温至100℃搅拌反应2h。停止反应，减压浓缩除去溶剂，用乙酸乙酯(20mL)溶解，用水(10mL)洗涤，无水硫酸钠干燥有机相，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯(v/v)＝1/4)，得到褐色固体(600mg,产率59％)。The compound 1-oxoisoindoline-5-carboxylic acid methyl ester (945mg, 4.94mmol), sodium hydride (300mg, 7.50mmol) were dissolved in N,N'-dimethylformamide (30mL), under nitrogen Stir at 50°C for 20min under the atmosphere, add dimethyl sulfate (944mg, 7.41mmol), heat up to 100°C and stir for 2h. Stop the reaction, concentrate under reduced pressure to remove the solvent, dissolve with ethyl acetate (20mL), wash with water (10mL), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and subject the concentrate to silica gel column chromatography (eluent : Petroleum ether/ethyl acetate (v/v) = 1/4) to obtain a brown solid (600 mg, yield 59%).
1H NMR(600MHz,CDCl3):δ(ppm)8.14(d,J＝8.0Hz,1H),8.12(s,1H),7.89(d,J＝7.9Hz,1H),4.43 (s,2H),3.95(s,3H),3.22(s,3H). 1 H NMR (600MHz, CDCl3): δ (ppm) 8.14 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 4.43 (s, 2H) ,3.95(s,3H),3.22(s,3H).
MS(ESI,pos.ion)m/z:206.20[M+H] +. MS(ESI,pos.ion)m/z:206.20[M+H] + .
步骤3：5-(羟甲基)-2-甲基异吲哚-1-酮的合成Step 3: Synthesis of 5-(hydroxymethyl)-2-methylisoindol-1-one
将化合物2-甲基-1-氧代异吲哚啉-5-甲酸甲酯(600mg,2.92mmol)，溶于四氢呋喃(25mL)中，加入硼氢化锂(254mg,11.7mmol)，50℃下搅拌5h，停止反应，加水(10mL)搅拌5min，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体(437mg,84％)。The compound 2-methyl-1-oxoisoindoline-5-carboxylic acid methyl ester (600 mg, 2.92 mmol) was dissolved in tetrahydrofuran (25 mL), and lithium borohydride (254 mg, 11.7 mmol) was added at 50°C. Stir for 5h, stop the reaction, add water (10mL) and stir for 5min. Concentrate under reduced pressure to remove the solvent. The concentrate is subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain white Solid (437 mg, 84%).
1H NMR(600MHz,CDCl 3):δ(ppm)7.76(d,J＝7.8Hz,1H),7.46(s,1H),7.40(d,J＝7.7Hz,1H),4.76–4.83(m,2H),4.34(s,2H),3.18(s,3H). 1 H NMR (600MHz, CDCl 3 ): δ (ppm) 7.76 (d, J = 7.8 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J = 7.7 Hz, 1H), 4.76-4.83 (m ,2H), 4.34(s, 2H), 3.18(s, 3H).
MS(ESI,pos.ion)m/z:178.20[M+H] +. MS(ESI,pos.ion)m/z:178.20[M+H] + .
步骤4：(2-甲基-1-氧代异吲哚啉-5-基)甲基甲磺酸酯的合成Step 4: Synthesis of (2-methyl-1-oxoisoindolin-5-yl)methanesulfonate
将化合物5-(羟甲基)-2-甲基异吲哚-1-酮(250mg,1.41mmol)溶于二氯甲烷(10mL)中，加入N,N-二异丙烯基乙酰胺(732mg，5.64mmol)，冰浴下搅拌5min后，加入甲磺酰氯(326mg，2.84mmol)，室温下搅拌1h，停止反应，加水(10mL)搅拌5min，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯(v/v)＝1/4)，得到白色固体(250mg,产率69％)。The compound 5-(hydroxymethyl)-2-methylisoindol-1-one (250mg, 1.41mmol) was dissolved in dichloromethane (10mL), and N,N-diisopropenylacetamide (732mg , 5.64mmol), after stirring for 5min in an ice bath, add methanesulfonyl chloride (326mg, 2.84mmol), stir at room temperature for 1h, stop the reaction, add water (10mL) and stir for 5min, concentrate under reduced pressure to remove the solvent, and apply the concentrated solution to silica gel column layer Analyze and separate (eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain a white solid (250 mg, yield 69%).
化合物206-4: 1H NMR(600MHz,CDCl 3):δ(ppm)7.86(d,J＝7.8Hz,1H),7.51(s,1H),7.49(d,J＝7.8Hz,1H),5.31(s,2H),4.40(s,2H),3.21(s,3H),2.99(s,3H). Compound 206-4: 1 H NMR (600MHz, CDCl 3 ): δ (ppm) 7.86 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 5.31 (s, 2H), 4.40 (s, 2H), 3.21 (s, 3H), 2.99 (s, 3H).
MS(ESI,pos.ion)m/z:256.15[M+H] +. MS(ESI,pos.ion)m/z:256.15[M+H] + .
步骤5：5-(叠氮甲基)-2-甲基异吲哚啉-1-酮的合成Step 5: Synthesis of 5-(azidomethyl)-2-methylisoindolin-1-one
将化合物(2-甲基-1-氧代异吲哚啉-5-基)甲基甲磺酸酯(250mg,0.98mmol)与叠氮化钠(318mg,4.89mmol)溶于N,N’-二甲基甲酰胺(10mL)中，80℃下搅拌3h，减压浓缩除去溶剂，乙酸乙酯(20mL)溶解，用水(10mL×2)洗涤，有机相用无水硫酸钠干燥，减压浓缩除去溶剂得到浅黄色固体(198mg,产率100％)。The compound (2-methyl-1-oxoisoindolin-5-yl) methyl methanesulfonate (250mg, 0.98mmol) and sodium azide (318mg, 4.89mmol) were dissolved in N, N' -In dimethylformamide (10mL), stir at 80°C for 3h, concentrate under reduced pressure to remove the solvent, dissolve in ethyl acetate (20mL), wash with water (10mL×2), dry the organic phase with anhydrous sodium sulfate, and reduce pressure The solvent was removed by concentration to obtain a pale yellow solid (198 mg, yield 100%).
1H NMR(600MHz,CDCl 3):δ(ppm)7.84(d,J＝7.7Hz,1H),7.37–7.43(m,2H),4.45(s,2H),4.39(s,2H),3.20(s,3H). 1 H NMR (600MHz, CDCl 3 ): δ (ppm) 7.84 (d, J = 7.7 Hz, 1H), 7.37-7.43 (m, 2H), 4.45 (s, 2H), 4.39 (s, 2H), 3.20 (s,3H).
MS(ESI,pos.ion)m/z:203.20[M+H] +. MS(ESI,pos.ion)m/z:203.20[M+H] + .
步骤6：5-(氨基甲基)-2-甲基异吲哚啉-1-酮的合成Step 6: Synthesis of 5-(aminomethyl)-2-methylisoindolin-1-one
将化合物5-(叠氮甲基)-2-甲基异吲哚啉-1-酮(206-5)(198mg,0.98mmol)溶于甲醇(10ml)中，加入Pd/C(30mg,0.10g/g)，通入氢气，室温下搅拌30min，通过硅藻土抽滤除去催化剂，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝10/1)，得到白色固体(84mg,49％)。The compound 5-(azidomethyl)-2-methylisoindolin-1-one (206-5) (198mg, 0.98mmol) was dissolved in methanol (10ml), and Pd/C (30mg, 0.10 g/g), add hydrogen, stir at room temperature for 30 min, filter through diatomaceous earth to remove the catalyst, concentrate under reduced pressure to remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: dichloromethane/methanol (v/ v)=10/1), a white solid (84mg, 49%) was obtained.
1H NMR(600MHz,CD 3OD):δ(ppm)7.71(d,J＝7.8Hz,1H),7.54(s,1H),7.47(d,J＝7.8Hz,1H),4.48(s,2H),3.92(s,2H),3.19(s,3H). 1 H NMR (600MHz, CD 3 OD): δ (ppm) 7.71 (d, J = 7.8Hz, 1H), 7.54 (s, 1H), 7.47 (d, J = 7.8Hz, 1H), 4.48 (s, 2H), 3.92(s, 2H), 3.19(s, 3H).
MS(ESI,pos.ion)m/z:177.20[M+H] +. MS(ESI,pos.ion)m/z:177.20[M+H] + .
中间体15：6-(羟基甲基)-N-(对甲苯基)吡啶酰胺Intermediate 15: 6-(hydroxymethyl)-N-(p-tolyl)pyridine amide
Figure PCTCN2021090489-appb-000059
Figure PCTCN2021090489-appb-000059
步骤1：化合物6-(对甲苯甲氨甲酰基)吡啶甲酸甲酯的合成Step 1: Synthesis of compound 6-(p-tolylcarbamoyl) methyl picolinate
将化合物6-(甲氧羰基)吡啶甲酸(2.00g,11mol)，对甲苯胺(1.42g,13.3mmol)溶解在二氯甲烷(50mL)溶液中，加入1-羟基-7-偶氮苯并三氮唑(HOAT)(2.30g,16.9mmol)，在0℃下冷却，再加入N,N-二异丙基乙胺(DIPEA)(4.3g,33.3mmol)，1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDCI)(4.2g,21.9mmol)， 转移到室温下搅拌反应17h。加水停止反应，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到淡黄色固体(2.37g,79.40％)。The compound 6-(methoxycarbonyl)picolinic acid (2.00g, 11mol) and p-toluidine (1.42g, 13.3mmol) were dissolved in dichloromethane (50mL) solution, and 1-hydroxy-7-azobenzoic acid was added. Triazole (HOAT) (2.30g, 16.9mmol), cooled at 0°C, then added N,N-diisopropylethylamine (DIPEA) (4.3g, 33.3mmol), 1-(3-dimethyl Ethylaminopropyl)-3-ethylcarbodiimide (EDCI) (4.2g, 21.9mmol), transferred to room temperature and stirred for 17h. Add water to stop the reaction, extract with dichloromethane (100mL×3), dry the organic phase with anhydrous sodium sulfate for 30min, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) )=4/1) to obtain a pale yellow solid (2.37g, 79.40%).
1H NMR(400MHz,CDCl 3)δ9.97(s,1H),8.49(dd,J＝7.8,1.1Hz,1H),8.26(dd,J＝7.7,1.1Hz,1H),8.06(t,J＝7.8Hz,1H),7.69(d,J＝8.4Hz,2H),7.20(d,J＝8.2Hz,2H),4.05(s,3H),2.35(s,3H). 1 H NMR(400MHz, CDCl 3 )δ9.97(s,1H), 8.49(dd,J=7.8,1.1Hz,1H), 8.26(dd,J=7.7,1.1Hz,1H), 8.06(t, J = 7.8Hz, 1H), 7.69 (d, J = 8.4Hz, 2H), 7.20 (d, J = 8.2Hz, 2H), 4.05 (s, 3H), 2.35 (s, 3H).
MS(ESI,pos.ion)m/z:271.10[M+H] +. MS(ESI,pos.ion)m/z:271.10[M+H] + .
步骤2：化合物6-(羟基甲基)-N-(对甲苯基)吡啶酰胺的合成Step 2: Synthesis of compound 6-(hydroxymethyl)-N-(p-tolyl)pyridine amide
将化合物6-(对甲苯甲氨甲酰基)吡啶甲酸甲酯(1.68g,6.22mmol)溶解在干燥的四氢呋喃溶液(15mL)中，再加入硼氢化钠(400mg,10.58mmol)，在室温下搅拌反应24h。加饱和食盐水(15mL)及(20mL)水，停止反应，用乙酸乙酯(20mL×2)萃取，有机相用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：石油醚/EtOAc(v/v)＝3/2)，得到白色固体(1.26g,84.70％)。The compound 6-(p-tolylcarbamoyl) methyl picolinate (1.68g, 6.22mmol) was dissolved in a dry tetrahydrofuran solution (15mL), then sodium borohydride (400mg, 10.58mmol) was added and stirred at room temperature Reaction for 24h. Add saturated brine (15mL) and (20mL) water, stop the reaction, extract with ethyl acetate (20mL×2), dry the organic phase with anhydrous sodium sulfate for 30min, concentrate under reduced pressure, and purify by silica gel column chromatography (elution Agent: petroleum ether/EtOAc (v/v)=3/2) to obtain a white solid (1.26 g, 84.70%).
1H NMR(400MHz,CDCl 3)δ9.77(s,1H),8.21(d,J＝7.6Hz,1H),7.91(t,J＝7.7Hz,1H),7.65(d,J＝8.3Hz,2H),7.54(d,J＝7.7Hz,1H),7.19(d,J＝8.1Hz,2H),4.88(s,2H),2.83(br.s,1H),2.35(s,3H). 1 H NMR(400MHz,CDCl 3 )δ9.77(s,1H), 8.21(d,J=7.6Hz,1H), 7.91(t,J=7.7Hz,1H), 7.65(d,J=8.3Hz , 2H), 7.54 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 4.88 (s, 2H), 2.83 (br.s, 1H), 2.35 (s, 3H) .
MS(ESI,pos.ion)m/z:243.10[M+H] +. MS(ESI,pos.ion)m/z:243.10[M+H] + .
中间体16：6-(羟甲基)-N-甲基吡啶甲酰胺Intermediate 16: 6-(hydroxymethyl)-N-picolinamide
Figure PCTCN2021090489-appb-000060
Figure PCTCN2021090489-appb-000060
步骤1：6-(甲基氨基甲酰基)吡啶甲酸甲酯的合成Step 1: Synthesis of methyl 6-(methylcarbamoyl)picolinate
将化合物6-(甲氧羰基)吡啶甲酸(2.00g,11mol)，盐酸甲胺(2.3g,34.1mmol)溶解在二氯甲烷(50mL)溶液中，加入1-羟基-7-偶氮苯并三氮唑(HOAT)(2.30g,16.9mmol)，在0℃下冷却，再加入N,N-二异丙基乙胺(DIPEA)(5.7g,44.1mmol)，1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDCI)(4.2g,21.9mmol)，转移到室温下搅拌反应9h。加水停止反应，用二氯甲烷(100mL×2)萃取，有机相用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：石油醚/EtOAc＝1:2)，得到白色固体(1.63g,产率76.00％)。The compound 6-(methoxycarbonyl)picolinic acid (2.00g, 11mol), methylamine hydrochloride (2.3g, 34.1mmol) were dissolved in dichloromethane (50mL) solution, and 1-hydroxy-7-azobenzoic acid was added. Triazole (HOAT) (2.30g, 16.9mmol), cooled at 0°C, then added N,N-diisopropylethylamine (DIPEA) (5.7g, 44.1mmol), 1-(3-dimethyl Ethylaminopropyl)-3-ethylcarbodiimide (EDCI) (4.2g, 21.9mmol), transferred to room temperature and stirred for 9h. Add water to stop the reaction, extract with dichloromethane (100mL×2), dry the organic phase with anhydrous sodium sulfate for 30min, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: petroleum ether/EtOAc=1:2), A white solid (1.63 g, yield 76.00%) was obtained.
1H NMR(400MHz,CDCl 3)δ8.39(dd,J＝7.8,0.9Hz,1H),8.22(dd,J＝7.8,1.0Hz,1H),8.11(br.s,1H),8.01(t,J＝7.8Hz,1H),4.02(s,3H),3.06(d,J＝5.1Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ 8.39 (dd, J = 7.8, 0.9 Hz, 1H), 8.22 (dd, J = 7.8, 1.0 Hz, 1H), 8.11 (br.s, 1H), 8.01 ( t,J=7.8Hz,1H),4.02(s,3H),3.06(d,J=5.1Hz,3H).
MS(ESI,pos.ion)m/z:195.10[M+H] +. MS(ESI,pos.ion)m/z:195.10[M+H] + .
步骤2：6-(羟甲基)-N-甲基吡啶甲酰胺的合成Step 2: Synthesis of 6-(hydroxymethyl)-N-picolinamide
将化合物6-(甲基氨基甲酰基)吡啶甲酸甲酯(800mg,4.12mmol)溶于干燥的四氢呋喃(15mL)溶液中，在0℃下冷却，加入硼氢化锂(230mg,10.56mmol)，再转移到室温下搅拌反应1h。加入饱和食盐水(15mL)搅拌，停止反应，用乙酸乙酯(20mL×3)萃取，有机相用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：石油醚/EtOAc＝3:7)，得到白色固体(610mg,产率89.10％)。The compound 6-(methylcarbamoyl) methyl picolinate (800mg, 4.12mmol) was dissolved in a dry tetrahydrofuran (15mL) solution, cooled at 0°C, lithium borohydride (230mg, 10.56mmol) was added, and then Transfer to room temperature and stir for 1h. Add saturated brine (15 mL) and stir to stop the reaction, and extract with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether /EtOAc=3:7) to obtain a white solid (610 mg, yield 89.10%).
1H NMR(400MHz,CDCl 3)δ8.11(d,J＝7.7Hz,1H),7.96(br.s,1H),7.85(t,J＝7.7Hz,1H),7.46(d,J＝7.8Hz,1H),4.81(s,2H),3.12(br.s,1H),3.04(d,J＝5.1Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.11 (d, J = 7.7 Hz, 1H), 7.96 (br.s, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.46 (d, J = 7.8Hz, 1H), 4.81 (s, 2H), 3.12 (br.s, 1H), 3.04 (d, J = 5.1 Hz, 3H).
MS(ESI,pos.ion)m/z:167.20[M+H] +. MS(ESI,pos.ion)m/z:167.20[M+H] + .
中间体17：6-(羟甲基)吡啶甲酸叔丁酯Intermediate 17: tert-Butyl 6-(hydroxymethyl)picolinate
Figure PCTCN2021090489-appb-000061
Figure PCTCN2021090489-appb-000061
步骤1：2-叔丁基6-甲基吡啶-2,6-二甲酸酯的合成Step 1: Synthesis of 2-tert-butyl 6-methylpyridine-2,6-dicarboxylate
将化合物6-(甲氧羰基)吡啶甲酸(500mg,2.76mmol)，溶解在四氢呋喃(10mL)溶剂中，氮气置换三次后，氮气氛围下加入N,N'-二异丙基氨基甲酸叔丁酯(600mg,2.99mmol)，原料加入完之后，转入到60℃温度下搅拌反应3h。减压浓缩除去四氢呋喃溶剂，再加入二氯甲烷(10mL)溶剂溶解，减压浓缩，通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到白色固体产物(190mg,产率29.01％)。The compound 6-(methoxycarbonyl)picolinic acid (500mg, 2.76mmol) was dissolved in tetrahydrofuran (10mL) solvent, replaced with nitrogen three times, and N,N'-diisopropylcarbamate tert-butyl ester was added under nitrogen atmosphere (600mg, 2.99mmol), after the raw materials were added, the temperature was transferred to 60°C and the reaction was stirred for 3h. Concentrate under reduced pressure to remove the tetrahydrofuran solvent, add dichloromethane (10 mL) to dissolve it, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1), A white solid product (190 mg, 29.01% yield) was obtained.
1H NMR(400MHz,CDCl 3)δ8.27(d,J＝7.8Hz,1H),8.21(d,J＝7.8Hz,1H),7.97(t,J＝7.8Hz,1H),4.01(s,3H),1.65(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ 8.27 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.97 (t, J = 7.8 Hz, 1H), 4.01 (s ,3H),1.65(s,9H).
MS(ESI,pos.ion)m/z:182.15[M+H] +. MS(ESI,pos.ion)m/z:182.15[M+H] + .
步骤2：6-(羟甲基)吡啶甲酸叔丁酯的合成Step 2: Synthesis of tert-butyl 6-(hydroxymethyl)picolinate
将化合物2-叔丁基6-甲基吡啶-2,6-二甲酸酯(190mg,0.80mmol)溶解在干燥四氢呋喃(10mL)溶剂中，再加入硼氢化钠(99mg,2.62mmol)，在室温下搅拌反应2.5h。加入饱和食盐水(20mL)搅拌，停止反应，用乙酸乙酯(20mL×2)萃取，有机相用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯(v/v)＝3/7)，得到白色固体(60mg,35.81％)。The compound 2-tert-butyl 6-methylpyridine-2,6-dicarboxylate (190mg, 0.80mmol) was dissolved in dry tetrahydrofuran (10mL) solvent, then sodium borohydride (99mg, 2.62mmol) was added, in The reaction was stirred at room temperature for 2.5h. Add saturated brine (20mL) and stir, stop the reaction, extract with ethyl acetate (20mL×2), dry the organic phase with anhydrous sodium sulfate for 30min, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: petroleum ether /Ethyl acetate (v/v)=3/7) to obtain a white solid (60 mg, 35.81%).
1H NMR(400MHz,CDCl 3)δ7.94(d,J＝7.7Hz,1H),7.80(t,J＝7.7Hz,1H),7.44(d,J＝7.8Hz,1H),4.84(s,2H),3.92(br.s,1H),1.63(s,9H). 1 H NMR(400MHz, CDCl 3 )δ7.94(d,J=7.7Hz,1H), 7.80(t,J=7.7Hz,1H), 7.44(d,J=7.8Hz,1H), 4.84(s ,2H),3.92(br.s,1H),1.63(s,9H).
MS(ESI,pos.ion)m/z:210.15[M+H] +. MS(ESI,pos.ion)m/z:210.15[M+H] + .
中间体18：6-(羟甲基)-N-(4-羟苯基)-N-甲基吡啶酰胺Intermediate 18: 6-(hydroxymethyl)-N-(4-hydroxyphenyl)-N-picolineamide
Figure PCTCN2021090489-appb-000062
Figure PCTCN2021090489-appb-000062
步骤1：化合物6-((4-羟苯基)(甲基)氨基甲酰基)吡啶羧酸甲酯的合成Step 1: Synthesis of compound 6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridinecarboxylic acid methyl ester
将化合物6-(甲氧羰基)吡啶甲酸(1.00g,5.52mmol)，对甲氨基酚(820mg,6.62mmol)溶解在DMF(15ml)溶液中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(3.15g,8.28mmol)，在0℃下冷却，再加入N,N-二异丙基乙胺(DIPEA)(1.28g,9.94mmol)，转移到室温下搅拌反应1h。加水停止反应，用乙酸乙酯(10mL×4)萃取，有机相用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(PE/EtOAc(v/v)＝1/4)，得到淡褐色液体(1.2g,产率76％)。The compound 6-(methoxycarbonyl)picolinic acid (1.00g, 5.52mmol), p-cresol (820mg, 6.62mmol) was dissolved in DMF (15ml) solution, and 2-(7-azobenzotriazide) was added Azole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (3.15g, 8.28mmol), cooled at 0℃, and then added N,N-diisopropylethylamine (DIPEA) (1.28 g, 9.94 mmol), transferred to room temperature and stirred for 1 h. Add water to stop the reaction, extract with ethyl acetate (10mL×4), dry the organic phase with anhydrous sodium sulfate for 30min, concentrate under reduced pressure, and purify by silica gel column chromatography (PE/EtOAc(v/v)=1/4), A light brown liquid (1.2 g, yield 76%) was obtained.
1H NMR(400MHz,DMSO-d 6)9.49(br.s,1H),7.90–7.83(m,2H),7.54–7.48(m,1H),6.95(d,J＝8.5Hz,2H),6.55(d,J＝8.5Hz,2H),3.84(s,3H),3.34(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) 9.49 (br.s, 1H), 7.90-7.83 (m, 2H), 7.54-7.48 (m, 1H), 6.95 (d, J = 8.5 Hz, 2H), 6.55(d,J=8.5Hz,2H), 3.84(s,3H), 3.34(s,3H).
MS(ESI,pos.ion)m/z:287.10[M+H] +. MS(ESI,pos.ion)m/z:287.10[M+H] + .
步骤2：化合物6-(羟甲基)-N-(4-羟苯基)-N-甲基吡啶酰胺的合成Step 2: Synthesis of compound 6-(hydroxymethyl)-N-(4-hydroxyphenyl)-N-picolinamide
将化合物6-((4-羟苯基)(甲基)氨基甲酰基)吡啶羧酸甲酯(1.20g,4.19mmol)溶解在干燥的四氢呋喃溶液(15mL)中，再加入硼氢化钠(480mg,12.57mmol)，在室温下搅拌反应13h停止，加稀盐酸调节pH＝6，减压浓缩，通过硅胶柱层析纯化(MeOH/DCM(v/v)＝1:25)，得到浅黄色固体(604mg,56％)。The compound 6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridinecarboxylic acid methyl ester (1.20g, 4.19mmol) was dissolved in dry tetrahydrofuran solution (15mL), and sodium borohydride (480mg , 12.57mmol), stirred at room temperature for 13h to stop the reaction, added dilute hydrochloric acid to adjust pH=6, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH/DCM(v/v)=1:25) to obtain a pale yellow solid (604mg, 56%).
1H NMR(400MHz,DMSO-d 6)9.44(s,1H),7.67(d,J＝7.6Hz,1H),7.28(d,J＝7.5Hz,1H),7.17(d,J＝7.3Hz,1H),6.91(d,J＝8.0Hz,2H),6.55(d,J＝7.9Hz,2H),5.33(s,1H),4.33(d,J＝4.9Hz,2H),3.30(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) 9.44 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.3 Hz ,1H),6.91(d,J=8.0Hz,2H),6.55(d,J=7.9Hz,2H),5.33(s,1H),4.33(d,J=4.9Hz,2H), 3.30(s ,3H).
MS(ESI,pos.ion)m/z:259.20[M+H] +. MS(ESI,pos.ion)m/z:259.20[M+H] + .
实施例Example
实施例1：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(2,4-二氟苄基)吡咯烷-2-甲酰胺Example 1: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluoro Benzyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000063
Figure PCTCN2021090489-appb-000063
步骤1：化合物(R)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 1: Compound (R)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylic acid Synthesis of esters
将化合物Boc-4-氧代-D-脯氨酸甲酯(0.98g,4.0mmol)溶解在二氯甲烷(15mL)溶液中，-15℃下加入N,N-二异丙基乙胺(3.4mL,20.5mmol)，三氟甲磺酸酐(1.3mL,7.7mmol)，-15℃下搅拌10min后，转移至室温反应18h，停止反应，加入水(50mL)，用二氯甲烷萃取(5mL×3)，无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝6/1)，得黄色油状物1.3g，产率86％。The compound Boc-4-oxo-D-proline methyl ester (0.98g, 4.0mmol) was dissolved in dichloromethane (15mL) solution, and N,N-diisopropylethylamine ( 3.4mL, 20.5mmol), trifluoromethanesulfonic anhydride (1.3mL, 7.7mmol), stirred at -15°C for 10min, transferred to room temperature and reacted for 18h, stopped the reaction, added water (50mL), extracted with dichloromethane (5mL ×3), dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=6/1) to obtain 1.3 g of yellow oil, yield 86 %.
1H NMR(400MHz,CDCl 3)δ(ppm):5.71(dd,J＝18.8,1.6Hz,1H),4.99-5.06(m,1H),4.24-4.41(m,2H),3.76(s,3H),1.42–1.47(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 5.71 (dd, J = 18.8, 1.6 Hz, 1H), 4.99-5.06 (m, 1H), 4.24-4.41 (m, 2H), 3.76 (s, 3H), 1.42-1.47 (m, 9H).
MS(ESI,pos.ion)m/z:398.10[M+Na] +. MS(ESI,pos.ion)m/z:398.10[M+Na] + .
步骤2：化合物(R)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 2: Compound (R)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H Synthesis of -pyrrole-1,2(2H,5H)-dicarboxylate
将化合物(R)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(1.3g,3.5mmol)，联硼酸频那醇酯(1.3g,5.1mmol)，醋酸钾(1.1g,11.2mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(130mg,0.2mmol)混合在干燥的1,4-二氧六环(30mL)溶液中，氮气保护下100℃反应13h，冷却至室温，将反应液抽滤，滤液中加入50mL水，用乙酸乙酯(5mL×3)萃取，合并有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝6/1)，得淡红色液体1.05g，产率85％。The compound (R)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate ( 1.3g, 3.5mmol), pinacol biborate (1.3g, 5.1mmol), potassium acetate (1.1g, 11.2mmol) and [1,1'-bis(diphenylphosphino)ferrocene] two Palladium chloride (130mg, 0.2mmol) was mixed in dry 1,4-dioxane (30mL) solution, reacted at 100℃ for 13h under nitrogen protection, cooled to room temperature, the reaction solution was suction filtered, and 50mL of water was added to the filtrate , Extracted with ethyl acetate (5mL×3), the combined organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)= 6/1), 1.05 g of light red liquid was obtained, and the yield was 85%.
1H NMR(400MHz,CDCl 3)δ(ppm):6.33(dd,J＝23.4,1.9Hz,1H),5.01-5.12(m,1H),4.26-4.40(m,2H),3.71–3.73(m,3H),1.42–1.47(m,9H),1.26(s,12H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 6.33 (dd, J = 23.4, 1.9 Hz, 1H), 5.01-5.12 (m, 1H), 4.26-4.40 (m, 2H), 3.71-3.73 ( m, 3H), 1.42-1.47 (m, 9H), 1.26 (s, 12H).
MS(ESI,pos.ion)m/z:376.15[M+Na] +. MS(ESI,pos.ion)m/z:376.15[M+Na] + .
步骤3：化合物(R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 3: Compound (R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1, Synthesis of 2(2H,5H)-dicarboxylate
将化合物(R)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(1.15g,3.3mmol)，2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(1.1g,3.2mmol)，磷酸钾(2.1g,9.9mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(120mg,0.16mmol)混合在干燥的1,4-二氧六环(15mL)溶液中，氮气保护下100℃反应3h，将反应液抽滤，滤液中加入50mL水，再用乙酸乙酯(5mL×3)萃取，合并有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝8/1)得淡红色液体1.13g，产率80％。The compound (R)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrrole -1,2(2H,5H)-dicarboxylate (1.15g, 3.3mmol), 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (1.1g , 3.2mmol), potassium phosphate (2.1g, 9.9mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (120mg, 0.16mmol) mixed in dry 1,4 -Dioxane (15mL) solution, react at 100°C for 3h under nitrogen protection, filter the reaction solution with suction, add 50mL water to the filtrate, and then extract with ethyl acetate (5mL×3), combine the organic phases with anhydrous sulfuric acid The sodium was dried, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=8/1) to obtain 1.13 g of light red liquid, with a yield of 80%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.14(d,J＝8.2Hz,1H),6.90-6.97(m,2H),6.63(t,J F-H＝75.4Hz, 1H),6.00-6.03(m,1H),5.11-5.19(m,1H),4.47-4.66(m,2H),3.86-3.90(m,2H),3.76(d,J＝4.0Hz,3H),1.46–1.52(m,9H),1.26-1.31(m,1H),0.61-0.70(m,2H),0.33-0.38(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.14 (d, J = 8.2Hz, 1H), 6.90-6.97 (m, 2H), 6.63 (t, J FH = 75.4Hz, 1H), 6.00- 6.03(m,1H),5.11-5.19(m,1H),4.47-4.66(m,2H),3.86-3.90(m,2H),3.76(d,J=4.0Hz,3H),1.46-1.52( m, 9H), 1.26-1.31 (m, 1H), 0.61-0.70 (m, 2H), 0.33-0.38 (m, 2H).
MS(ESI,pos.ion)m/z:462.20[M+Na] +. MS(ESI,pos.ion)m/z:462.20[M+Na] + .
步骤4：化合物(2R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯的合成Step 4: Compound (2R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2- Synthesis of dicarboxylic acid esters
将化合物(R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(1.1g,2.5mmol)溶于甲醇(15mL)，加入Pd/C(260mg,10％)，通入氢气室温反应7h，然后将反应液抽滤，滤液浓缩得到990mg黄色液体，收率90％。The compound (R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2( 2H,5H)-dicarboxylic acid ester (1.1g, 2.5mmol) was dissolved in methanol (15mL), Pd/C (260mg, 10%) was added, hydrogen gas was introduced to react at room temperature for 7 hours, then the reaction solution was filtered with suction, and the filtrate was concentrated Obtain 990 mg of yellow liquid with a yield of 90%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.10(d,J＝8.0Hz,1H),6.77-6.81(m,2H),6.60(t,J F-H＝74.2Hz,1H),4.30-4.40(m,1H),3.91-3.95(m,0.5H),4.02-4.06(m,0.5H),3.84-3.87(m,2H),3.76(d,J＝6.7Hz,3H),3.30-3.45(m,2H),2.62-2.68(m,1H),1.99-2.07(m,1H),1.43–1.47(m,9H),1.28-1.31(m,1H),0.62-0.67(m,2H),0.33-0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.10 (d, J = 8.0Hz, 1H), 6.77-6.81 (m, 2H), 6.60 (t, J FH = 74.2Hz, 1H), 4.30- 4.40(m,1H),3.91-3.95(m,0.5H),4.02-4.06(m,0.5H),3.84-3.87(m,2H), 3.76(d,J=6.7Hz,3H), 3.30- 3.45(m,2H),2.62-2.68(m,1H),1.99-2.07(m,1H),1.43-1.47(m,9H),1.28-1.31(m,1H),0.62-0.67(m,2H) ), 0.33-0.37 (m, 2H).
MS(ESI,pos.ion)m/z:464.25[M+Na] +. MS(ESI,pos.ion)m/z:464.25[M+Na] + .
步骤5：化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成Step 5: Synthesis of compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R)-1-叔丁基-2-甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(990mg,2.2mmol)溶解于二氯甲烷(6mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(8mL)，室温搅拌50min，除去溶剂，得白色固体751mg，收率98％。The compound (2R)-1-tert-butyl-2-methyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2- Dicarboxylic acid ester (990mg, 2.2mmol) was dissolved in dichloromethane (6mL) solution, 4mol/L HCl ethyl acetate solution (8mL) was added, stirred at room temperature for 50min, and the solvent was removed to obtain white solid 751mg, yield 98 %.
1H NMR(400MHz,CD 3OD)δ(ppm):7.14(d,J＝8.2Hz,1H),7.07(s,1H),6.91-6.94(m,1H),6.76(t,J F-H＝75.5Hz,2H),4.60-4.64(m,1H),3.94(d,J＝6.9Hz,2H),3.90(s,3H),3.78-3.83(m,1H),3.65-3.72(m,1H),3.33-3.39(m,1H),2.82-2.89(m,1H),2.20-2.29(m,1H),1.28-1.36(m,1H),0.63-0.66(m,2H),0.37-0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.14 (d, J = 8.2 Hz, 1H), 7.07 (s, 1H), 6.91-6.94 (m, 1H), 6.76 (t, J FH = 75.5Hz, 2H), 4.60-4.64 (m, 1H), 3.94 (d, J = 6.9 Hz, 2H), 3.90 (s, 3H), 3.78-3.83 (m, 1H), 3.65-3.72 (m, 1H) ),3.33-3.39(m,1H),2.82-2.89(m,1H),2.20-2.29(m,1H),1.28-1.36(m,1H),0.63-0.66(m,2H),0.37-0.41 (m,2H).
MS(ESI,pos.ion)m/z:342.20[M+H-HCl] +. MS(ESI,pos.ion)m/z:342.20[M+H-HCl] + .
步骤6：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯的合成Step 6: Synthesis of compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐(203mg,0.6mmol)溶解在二氯甲烷(5mL)中，0℃条件下滴加N,N-二异丙基乙胺(0.2mL,1.0mmol)和乙酰氯(0.1mL,1.0mmol)，室温搅拌5h后停止反应，加水溶液洗有机相(10mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得浅黄色液体186mg，产率82％。Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (203mg, 0.6mmol) Dissolve in dichloromethane (5mL), add dropwise N,N-diisopropylethylamine (0.2mL, 1.0mmol) and acetyl chloride (0.1mL, 1.0mmol) at 0℃, and stop the reaction after stirring at room temperature for 5h , Add aqueous solution to wash the organic phase (10mL×3), dry the organic phase with anhydrous sodium sulfate, and perform silica gel column chromatography to separate the concentrated solution (eluent: petroleum ether/ethyl acetate (v/v)=1/1) , 186 mg of light yellow liquid was obtained, and the yield was 82%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.11(d,J＝8.2Hz,1H),7.04(s,1H),6.90-6.94(m,1H),6.74(t,J F-H＝75.6Hz,1H),4.45-4.49(m,1H),4.08-4.12(m,1H),3.93(d,J＝6.8Hz,2H),3.75(s,3H),3.50-3.64(m,2H),2.67-2.74(m,1H),2.13(s,3H),1.99-2.06(m,1H),1.27-1.33(m,1H),0.62-0.67(m,2H),0.36-0.40(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.11 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.90-6.94 (m, 1H), 6.74 (t, J FH = 75.6Hz, 1H), 4.45-4.49 (m, 1H), 4.08-4.12 (m, 1H), 3.93 (d, J = 6.8Hz, 2H), 3.75 (s, 3H), 3.50-3.64 (m, 2H) ), 2.67-2.74 (m, 1H), 2.13 (s, 3H), 1.99-2.06 (m, 1H), 1.27-1.33 (m, 1H), 0.62-0.67 (m, 2H), 0.36-0.40 (m ,2H).
MS(ESI,pos.ion)m/z:384.20[M+H] +. MS(ESI,pos.ion)m/z:384.20[M+H] + .
步骤7：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸的合成Step 7: Synthesis of compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯(426mg,1.1mmol)溶于四氢呋喃(6mL)和水(4mL)的混合溶剂中，再加入一水合氢氧化锂(203mg，4.8mmol)，50℃反应3h后停止，加盐酸调节溶液pH＝1，再用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得无色液体388mg，产率95％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (426mg, 1.1 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6mL) and water (4mL), and then lithium hydroxide monohydrate (203mg, 4.8mmol) was added, and the reaction was stopped at 50°C for 3 hours. Hydrochloric acid was added to adjust the pH of the solution to 1, then acetic acid Ethyl ester extraction (5 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 388 mg of colorless liquid with a yield of 95%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.12(d,J＝8.1Hz,1H),7.05(d,J＝1.5Hz,1H),6.878-6.93(m,1H),6.74(t,J F-H＝74.9Hz,1H),4.43–4.47(m,1H),4.08–4.15(m,1H),3.94(d,J＝6.8Hz,2H),3.50–3.64(m,2H),2.72–2.78(m,1H),2.09(s,3H),2.00–2.08(m,1H),1.27-1.36(m,1H),0.63-0.67(m,2H),0.37-0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.12 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.878-6.93 (m, 1H), 6.74 ( t, J FH = 74.9Hz, 1H), 4.43–4.47 (m, 1H), 4.08–4.15 (m, 1H), 3.94 (d, J = 6.8 Hz, 2H), 3.50–3.64 (m, 2H), 2.72--2.78(m,1H),2.09(s,3H),2.00--2.08(m,1H),1.27-1.36(m,1H),0.63-0.67(m,2H),0.37-0.41(m,2H) ).
MS(ESI,pos.ion)m/z:370.25[M+H] +. MS(ESI,pos.ion)m/z:370.25[M+H] + .
步骤8：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(2,4-二氟苄基)吡咯烷-2-甲酰胺的合成Step 8: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl) Of pyrrolidine-2-carboxamide
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(123mg,0.33mmol)，(2,4-二氟苯基)甲胺(96mg,0.67mmol)，1-乙基-3-(3-二甲胺基丙基)碳二亚胺盐酸盐(160mg,0.83mmol)和N-羟基-7-氮杂苯并三氮唑(82mg,0.60mmol)溶于二氯甲烷(6mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌21h，加水(15mL)，用二氯甲烷萃取(5mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得白色固体113mg，收率68％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (123mg, 0.33mmol) , (2,4-Difluorophenyl)methylamine (96mg, 0.67mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160mg, 0.83mmol) And N-hydroxy-7-azabenzotriazole (82mg, 0.60mmol) were dissolved in dichloromethane (6mL), and N,N-diisopropylethylamine was added dropwise to this solution at 0℃ (0.4mL, 2.0mmol), stirred at room temperature for 21h, added water (15mL), extracted with dichloromethane (5mL×3), combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected the residue to silica gel column chromatography After separation (eluent: petroleum ether/ethyl acetate (v/v) = 1/2), 113 mg of white solid was obtained, with a yield of 68%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.46-7.52(m,1H),7.08-7.12(m,2H),6.93-6.97(m,3H),6.74(t,J F-H＝75.7Hz,1H),4.44-4.49(m,3H),4.05-4.11(m,1H),3.93(d,J＝6.8Hz,2H),3.61-3.66(m,1H),3.44-3.53(m,1H),2.61-2.68(m,1H),2.14(s,3H),2.00-2.09(m,1H),1.27-1.35(m,1H),0.62-0.67(m,2H),0.37-0.40(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.46-7.52 (m, 1H), 7.08-7.12 (m, 2H), 6.93-6.97 (m, 3H), 6.74 (t, J FH = 75.7 Hz,1H),4.44-4.49(m,3H),4.05-4.11(m,1H),3.93(d,J=6.8Hz,2H),3.61-3.66(m,1H),3.44-3.53(m, 1H),2.61-2.68(m,1H),2.14(s,3H),2.00-2.09(m,1H),1.27-1.35(m,1H),0.62-0.67(m,2H),0.37-0.40( m,2H).
MS(ESI,pos.ion)m/z:495.25[M+H] +. MS(ESI,pos.ion)m/z:495.25[M+H] + .
实施例2：化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(2,4-二氟苄基)吡咯烷-2-甲酰胺Example 2: Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluoro Benzyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000064
Figure PCTCN2021090489-appb-000064
步骤1：化合物(S)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 1: Compound (S)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylic acid Synthesis of esters
将化合物Boc-4-氧代-L-脯氨酸甲酯(5.0g,20.6mmol)溶解在二氯甲烷(100mL)溶液中，冷却至-10℃，加入N,N-二异丙基乙胺(17.0mL,103mmol)，缓慢滴加三氟甲磺酸酐(9.9g,35mmol)，转移至室温反应16h，加入水(100mL)淬灭反应，搅拌10min后分离有机相，无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝10/1)，得浅黄色油状物7.1g，产率92％。The compound Boc-4-oxo-L-proline methyl ester (5.0g, 20.6mmol) was dissolved in a dichloromethane (100mL) solution, cooled to -10°C, and N,N-diisopropylethyl was added Amine (17.0mL, 103mmol), slowly add trifluoromethanesulfonic anhydride (9.9g, 35mmol) dropwise, transfer to room temperature to react for 16h, add water (100mL) to quench the reaction, stir for 10min, separate the organic phase, dry with anhydrous sodium sulfate It was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=10/1) to obtain 7.1 g of light yellow oil, with a yield of 92%.
1H NMR(400MHz,CDCl 3)δ(ppm):5.70–5.74(m,1H),5.00–5.02(m,1H),4.28–4.36(m,2H),3.75–3.77(m,3H),1.43–1.48(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 5.70-5.74 (m, 1H), 5.00-5.02 (m, 1H), 4.28-4.36 (m, 2H), 3.75-3.77 (m, 3H), 1.43-1.48 (m, 9H).
MS(ESI,pos.ion)m/z:320.90[M-55] +. MS(ESI,pos.ion)m/z:320.90[M-55] + .
步骤2：化合物(S)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 2: Compound (S)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H Synthesis of -pyrrole-1,2(2H,5H)-dicarboxylate
将化合物(S)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(2.9g,7.7mmol)，联硼酸频那醇酯(2.9g,11mmol)，醋酸钾(2.3g,23mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(50mg,0.068mmol)混合在干燥的1,4-二氧六环(40mL)溶液中，氮气保护下100℃反应5h，冷却至室温，过滤，滤液浓缩，剩余物加水溶液(30mL)和乙酸乙酯(50mL)，搅拌均匀后分离出有机相，有机相合用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到浅褐色液体1.44g，产率51％。The compound (S)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate ( 2.9g, 7.7mmol), pinacol diborate (2.9g, 11mmol), potassium acetate (2.3g, 23mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium (50mg, 0.068mmol) was mixed in a dry solution of 1,4-dioxane (40mL), reacted at 100°C for 5h under nitrogen protection, cooled to room temperature, filtered, the filtrate was concentrated, and the remainder was added with an aqueous solution (30mL) and Ethyl acetate (50mL), stir well and separate the organic phase. Combine the organic phases and dry with anhydrous sodium sulfate. Remove the solvent. The concentrate is subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) )=3/1), 1.44 g of light brown liquid was obtained, and the yield was 51%.
1H NMR(400MHz,CD 3OD)δ(ppm):6.23–6.32(m,1H),5.03–5.09(m,1H),4.23–4.29(m,2H),3.77(s, 3H),1.44(s,6H),1.26–1.30(m,9H),1.22(s,3H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 6.23-6.32 (m, 1H), 5.03-5.09 (m, 1H), 4.23-4.29 (m, 2H), 3.77 (s, 3H), 1.44 (s,6H),1.26--1.30(m,9H),1.22(s,3H).
步骤3：化合物(S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 3: Compound (S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1, Synthesis of 2(2H,5H)-dicarboxylate
将化合物(S)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(886mg,3.2mmol)，2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(1.1g,3.2mmol)，磷酸钾(2.7g,13mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(110mg,0.15mmol)混合在干燥的1,4-二氧六环(25mL)溶液中，氮气保护下100℃反应5h，冷却至室温，浓缩，剩余物加水溶液(20mL)和乙酸乙酯(30mL)，搅拌均匀后分离出有机相，有机相合用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到浅褐色液体576mg，产率41％。The compound (S)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole -1,2(2H,5H)-dicarboxylate (886mg, 3.2mmol), 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (1.1g, 3.2mmol), potassium phosphate (2.7g, 13mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (110mg, 0.15mmol) were mixed in dry 1,4-bis In oxane (25mL) solution, react for 5h at 100°C under nitrogen protection, cool to room temperature, concentrate, add aqueous solution (20mL) and ethyl acetate (30mL) to the remainder, stir well and separate the organic phase. Combine the organic phase. After drying with sodium sulfate and removing the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain 576 mg of light brown liquid with a yield of 41%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.12–7.15(m,1H),6.93–6.96(m,2H),6.63(t,J F-H＝75.4Hz,1H),5.99–6.02(m,1H),5.10–5.19(m,1H),4.47–4.65(m,2H),3.85–5.90(m,2H),3.75(s,3H),1.45–1.52(m,9H),1.23-1.33(m,1H),0.63–0.67(m,2H),0.33–0.38(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.12–7.15(m,1H), 6.93–6.96(m,2H), 6.63(t,J FH = 75.4Hz,1H), 5.99–6.02(m ,1H), 5.10--5.19(m,1H), 4.47--4.65(m,2H), 3.85--5.90(m,2H), 3.75(s,3H), 1.45--1.52(m,9H), 1.23-1.33 (m,1H), 0.63-0.67 (m, 2H), 0.33-0.38 (m, 2H).
MS(ESI,pos.ion)m/z:462.10[M+Na] +. MS(ESI,pos.ion)m/z:462.10[M+Na] + .
步骤4：化合物(2S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯的合成Step 4: Compound (2S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2- Synthesis of dicarboxylic acid esters
将化合物(S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(263mg,0.6mmol)，加入甲醇(8mL)溶解，加入Pd/C(54mg,)，常温常压下氢气反应6h，抽滤，滤液浓缩得到无色液体258mg，收率97％。The compound (S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2( 2H,5H)-dicarboxylate (263mg, 0.6mmol), add methanol (8mL) to dissolve, add Pd/C (54mg,), react with hydrogen at room temperature and pressure for 6h, filter with suction, and concentrate the filtrate to obtain 258mg of colorless liquid , The yield is 97%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.10(d,J＝7.9Hz,1H),6.77–6.81(m,2H),6.59(t,J F-H＝75.6Hz,1H),4.30–4.40(m,1H),4.02–4.06(m,0.6H),3.91–3.95(m,0.4H),3.85(t,J＝6.7Hz,2H),3.75–3.77(m,3H),3.38–3.44(m,1H),3.27–3.36(m,1H),2.60–2.68(m,1H),1.96–2.07(m,1H),1.43–1.46(m,9H),1.23–1.36(m,1H),0.63–0.66(m,2H),0.33–0.36(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.10 (d, J = 7.9 Hz, 1H), 6.77-6.81 (m, 2H), 6.59 (t, J FH = 75.6 Hz, 1H), 4.30- 4.40(m,1H),4.02–4.06(m,0.6H), 3.91–3.95(m,0.4H), 3.85(t,J=6.7Hz,2H), 3.75–3.77(m,3H), 3.38– 3.44(m,1H), 3.27–3.36(m,1H), 2.60–2.68(m,1H), 1.96–2.07(m,1H), 1.43–1.46(m,9H), 1.23–1.36(m,1H) ), 0.63-0.66 (m, 2H), 0.33-0.36 (m, 2H).
MS(ESI,pos.ion)m/z:464.10[M+Na] +. MS(ESI,pos.ion)m/z:464.10[M+Na] + .
步骤5：化合物(2S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成Step 5: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(252mg,0.57mmol)溶解于二氯甲烷(5mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(5mL)，室温搅拌30min，减压浓缩，得到无色液体202mg，收率94％。The compound (2S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxy Ester (252mg, 0.57mmol) was dissolved in dichloromethane (5mL), added 4mol/L HCl in ethyl acetate solution (5mL), stirred at room temperature for 30min, concentrated under reduced pressure to obtain 202mg of colorless liquid, yield 94 %.
1H NMR(400MHz,CD 3OD)δ(ppm):7.14(d,J＝8.4Hz,1H),7.08(d,J＝1.6Hz,1H),6.92(dd,J＝8.3,1.6Hz,1H),6.76(t,J F-H＝75.5Hz,1H),4.60–4.65(m,1H),3.94(d,J＝6.9Hz,2H),3.90(s,3H),3.78–3.83(m,1H),3.63–3.73(m,1H),3.33–3.40(m,1H),2.82–2.89(m,1H),2.20–2.29(m,1H),1.27–1.35(m,1H),0.63–0.68(m,2H),0.37–0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.14 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 6.92 (dd, J = 8.3, 1.6 Hz, 1H), 6.76(t, J FH = 75.5Hz, 1H), 4.60–4.65(m, 1H), 3.94(d, J = 6.9Hz, 2H), 3.90(s, 3H), 3.78–3.83(m, 1H), 3.63--3.73 (m, 1H), 3.33--3.40 (m, 1H), 2.82--2.89 (m, 1H), 2.20--2.29 (m, 1H), 1.27--1.35 (m, 1H), 0.63- 0.68 (m, 2H), 0.37-0.41 (m, 2H).
MS(ESI,pos.ion)m/z:342.40[M+H-HCl] +. MS(ESI,pos.ion)m/z:342.40[M+H-HCl] + .
步骤6：化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯的合成Step 6: Synthesis of compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(2S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐(198mg,0.53mmol)溶解在二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(0.2mL,1.0mmol)，冰浴中滴加乙酰氯(70mg,0.8mmol)，室温搅拌5.5h后停止反应，加水(10mL)，二氯甲烷萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到浅褐色液体176mg，产率87％。Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (198mg, 0.53mmol) Dissolve in dichloromethane (10mL), add N,N-diisopropylethylamine (0.2mL, 1.0mmol), add acetyl chloride (70mg, 0.8mmol) dropwise in an ice bath, and stop the reaction after stirring at room temperature for 5.5h , Add water (10mL), extract with dichloromethane (10mL×3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1), 176 mg of light brown liquid was obtained, and the yield was 87%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.12(d,J＝8.6Hz,1H),6.82(s,1H),6.78-6.82(m,1H),6.60(t,J F-H＝75.5Hz,1H),4.45–4.49(m,1H),3.91–3.95(m,1H),3.86(d,J＝6.9Hz,2H),3.77(s,3H),3.60(t,J＝10.4 Hz,1H),3.36–3.45(m,1H),2.62–2.68(m,1H),2.11(s,3H),2.02–2.09(m,1H),1.27-1.33(m,1H),0.63-0.68(m,2H),0.34-0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.12 (d, J = 8.6Hz, 1H), 6.82 (s, 1H), 6.78-6.82 (m, 1H), 6.60 (t, J FH = 75.5 Hz, 1H), 4.45–4.49 (m, 1H), 3.91–3.95 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.77 (s, 3H), 3.60 (t, J = 10.4 Hz ,1H), 3.36–3.45(m,1H), 2.62–2.68(m,1H), 2.11(s,3H), 2.02–2.09(m,1H), 1.27-1.33(m,1H), 0.63-0.68 (m, 2H), 0.34-0.37 (m, 2H).
MS(ESI,pos.ion)m/z:384.15[M+H] +. MS(ESI,pos.ion)m/z:384.15[M+H] + .
步骤7：化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸的合成Step 7: Synthesis of compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid
将化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯(92mg,0.24mmol)溶解在四氢呋喃(5mL)中，加入一水合氢氧化锂(51mg,1.22mmol)和水(3mL)，45℃反应50min，加稀盐酸调节pH＝1，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，得白色固体84mg，产率94％。The compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (92mg, 0.24 mmol) was dissolved in tetrahydrofuran (5mL), added lithium hydroxide monohydrate (51mg, 1.22mmol) and water (3mL), reacted at 45℃ for 50min, added dilute hydrochloric acid to adjust pH=1, extracted with ethyl acetate (10mL×3 ), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 84 mg of a white solid with a yield of 94%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.09–7.13(m,1H),7.05(d,J＝1.5Hz,1H),6.88–6.93(m,1H),6.74(t,J F-H＝74.9Hz,1H),4.43–4.47(m,1H),4.08–4.12(m,1H),3.94(d,J＝6.8Hz,2H),3.58–3.64(m,1H),3.50–3.57(m,1H),2.72–2.78(m,1H),2.14(s,3H),2.00–2.05(m,1H),1.27-1.36(m,1H),0.63-0.67(m,2H),0.37-0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.09-7.13 (m, 1H), 7.05 (d, J = 1.5Hz, 1H), 6.88-6.93 (m, 1H), 6.74 (t, J FH = 74.9 Hz, 1H), 4.43–4.47 (m, 1H), 4.08–4.12 (m, 1H), 3.94 (d, J = 6.8 Hz, 2H), 3.58–3.64 (m, 1H), 3.50–3.57 (m,1H),2.72-2.78(m,1H),2.14(s,3H),2.00-2.05(m,1H),1.27-1.36(m,1H),0.63-0.67(m,2H),0.37 -0.41(m,2H).
MS(ESI,pos.ion)m/z:370.10[M+H] +. MS(ESI,pos.ion)m/z:370.10[M+H] + .
步骤8：化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(2,4-二氟苄基)吡咯烷-2-甲酰胺的合成Step 8: Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl) Of pyrrolidine-2-carboxamide
将化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(107mg,0.29mmol)，2,4-二氟苄胺(48mg,0.34mmol)和N-羟基-7-氮杂苯并三氮唑(59mg,0.43mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(254mg,1.33mmol)和N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌4h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：EA(v)＝100％)，得到白色固体101mg，收率70％。The compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (107mg, 0.29mmol) , 2,4-Difluorobenzylamine (48mg, 0.34mmol) and N-hydroxy-7-azabenzotriazole (59mg, 0.43mmol) were dissolved in dichloromethane (5mL) and cooled to 0℃, Add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (254mg, 1.33mmol) and N,N-diisopropylethylamine (0.3mL, 2.0mmol) at room temperature Stir for 4h, add water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: EA(v)=100 %) to obtain 101 mg of a white solid with a yield of 70%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.34–7.40(m,1H),7.22(br.s,1H),7.13(d,J＝8.2Hz,1H),6.91(d,J＝1.6Hz,1H),6.83–6.89(m,2H),6.63(t,J F-H＝75.6Hz,1H),4.55–4.59(m,1H),4.44–4.52(m,2H),3.90–3.96(m,1H),3.89(d,J＝6.9Hz,2H),3.48–3.54(m,1H),3.27–3.36(m,1H),2.47–2.62(m,2H),2.14(s,3H),1.28-1.37(m,1H),0.65-0.69(m,2H),0.36-0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.34–7.40 (m, 1H), 7.22 (br.s, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 1.6Hz, 1H), 6.83–6.89(m, 2H), 6.63(t, J FH = 75.6Hz, 1H), 4.55–4.59(m, 1H), 4.44–4.52(m, 2H), 3.90–3.96( m,1H), 3.89(d,J=6.9Hz,2H), 3.48–3.54(m,1H), 3.27–3.36(m,1H), 2.47–2.62(m,2H), 2.14(s,3H) , 1.28-1.37 (m, 1H), 0.65-0.69 (m, 2H), 0.36-0.40 (m, 2H).
MS(ESI,pos.ion)m/z:495.20[M+H] +. MS(ESI,pos.ion)m/z:495.20[M+H] + .
实施例3：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(吡啶-2-基甲基)吡咯烷-2-甲酰胺Example 3: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(pyridin-2-ylmethyl Yl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000065
Figure PCTCN2021090489-appb-000065
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(123mg,0.33mmol)，2-吡啶甲胺(96mg,0.89mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(160mg,0.83mmol)和N-羟基-7-氮杂苯并三氮唑(82mg,0.60mmol)溶于二氯甲烷(6mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌20h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相 用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到淡黄色液体53mg，收率34％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (123mg, 0.33mmol) , 2-picolinylmethylamine (96mg, 0.89mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (160mg, 0.83mmol) and N-hydroxy-7-nitrogen Heterobenzotriazole (82mg, 0.60mmol) was dissolved in dichloromethane (6mL), and N,N-diisopropylethylamine (0.4mL, 2.0mmol) was added dropwise to this solution at 0°C, Stir at room temperature for 20h, add water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1), 53 mg of pale yellow liquid was obtained, and the yield was 34%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.47(d,J＝4.6Hz,1H),7.84(t,J＝7.7Hz,1H),7.57(d,J＝7.9Hz,1H),7.30-7.33(m,1H),7.09-7.10(m,2H),6.93-6.94(m,1H),6.75(t,J F-H＝75.8Hz,1H),4.45-4.55(m,3H),4.09-4.13(m,1H),3.93(d,J＝6.9Hz,2H),3.63-3.69(m,1H),3.48-3.56(m,1H),2.66-2.73(m,1H),2.16(s,3H),2.05-2.12(m,1H),1.28-1.34(m,1H),0.62-0.67(m,2H),0.37-0.40(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.47 (d, J = 4.6 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H) ,7.30-7.33(m,1H),7.09-7.10(m,2H),6.93-6.94(m,1H),6.75(t,J FH =75.8Hz,1H),4.45-4.55(m,3H), 4.09-4.13(m,1H),3.93(d,J=6.9Hz,2H),3.63-3.69(m,1H),3.48-3.56(m,1H),2.66-2.73(m,1H), 2.16( s, 3H), 2.05-2.12 (m, 1H), 1.28-1.34 (m, 1H), 0.62-0.67 (m, 2H), 0.37-0.40 (m, 2H).
MS(ESI,pos.ion)m/z:460.30[M+H] +. MS(ESI,pos.ion)m/z:460.30[M+H] + .
实施例4：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((5-氟吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 4: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((5-fluoropyridine- 2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000066
Figure PCTCN2021090489-appb-000066
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(121mg,0.33mmol)，(5-氟吡啶-2-基)甲胺(91mg,0.72mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(143mg,0.75mmol)和N-羟基-7-氮杂苯并三氮唑(81mg,0.60mmol)溶于二氯甲烷(6mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌18h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到无色液体61mg，收率39％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (121mg, 0.33mmol) , (5-fluoropyridin-2-yl) methylamine (91 mg, 0.72 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (143 mg, 0.75 mmol) and N-hydroxy-7-azabenzotriazole (81mg, 0.60mmol) was dissolved in dichloromethane (6mL), and N,N-diisopropylethylamine ( 0.4mL, 2.0mmol), stirred at room temperature for 18h, washed with water (15mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (washing Removal agent: dichloromethane/methanol (v/v)=15/1) to obtain 61 mg of colorless liquid with a yield of 39%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.38(s,1H),7.59-7.62(m,2H),7.09-7.12(m,2H),6.93-6.94(m,1H),6.75(t,J F-H＝75.4Hz,1H),4.60(s,2H),4.48-4.55(m,1H),4.08-4.13(m,1H),3.93(d,J＝6.9Hz,2H),3.63-3.68(m,1H),3.47-3.56(m,1H),2.65-2.72(m,1H),2.16(s,3H),1.98-2.11(m,1H),1.27-1.33(m,1H),0.62-0.65(m,2H),0.37-0.40(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.38 (s, 1H), 7.59-7.62 (m, 2H), 7.09-7.12 (m, 2H), 6.93-6.94 (m, 1H), 6.75 (t, J FH = 75.4Hz, 1H), 4.60 (s, 2H), 4.48-4.55 (m, 1H), 4.08-4.13 (m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.63 -3.68 (m, 1H), 3.47-3.56 (m, 1H), 2.65-2.72 (m, 1H), 2.16 (s, 3H), 1.98-2.11 (m, 1H), 1.27-1.33 (m, 1H) ,0.62-0.65(m,2H),0.37-0.40(m,2H);
MS(ESI,pos.ion)m/z:478.30[M+H] +. MS(ESI,pos.ion)m/z:478.30[M+H] + .
实施例5：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-甲酰氨基)甲基)吡啶羧酸乙酯Example 5: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methan Yl) ethyl pyridinecarboxylate
Figure PCTCN2021090489-appb-000067
Figure PCTCN2021090489-appb-000067
步骤1：化合物(R)-1-叔丁基2-甲基4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 1: Compound (R)-1-tert-butyl 2-methyl 4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H ,5H)-Dicarboxylic acid ester synthesis
将化合物(R)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡咯-1,2(2H,5H)-二羧 酸酯(2.1g,5.9mmol)，2-(苄氧基)-1-(二氟甲氧基)-4-碘苯(861-1-2)(5.8g,2.2mmol)，磷酸钾(5.0g,24.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(88mg,0.12mmol)混合在干燥的1,4-二氧六环(20mL)溶液中，氮气保护下100℃反应5h，将反应液抽滤，滤液中加入20mL水，用乙酸乙酯(15mL×3)萃取，有机相合用无水硫酸钠干燥，除去溶剂，浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到黄褐色液体2.1g，产率74％。The compound (R)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Pyrrole-1,2(2H,5H)-dicarboxylate (2.1g, 5.9mmol), 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene (861-1- 2) (5.8g, 2.2mmol), potassium phosphate (5.0g, 24.0mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (88mg, 0.12mmol) mixed in In a dry 1,4-dioxane (20mL) solution, react for 5h at 100°C under nitrogen protection, filter the reaction solution with suction, add 20mL of water to the filtrate, extract with ethyl acetate (15mL×3), and combine the organic phases. Dry with anhydrous sodium sulfate, remove the solvent, concentrate, and perform silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1) to obtain 2.1 g of yellowish brown liquid, with a yield of 74% .
1H NMR(400MHz,CDCl 3)δ(ppm):7.37–7.44(m,5H),7.18–7.20(m,1H),7.04(s,1H),6.95–7.01(m,1H),6.60(t,J F-H＝75.0Hz,1H),6.00–6.03(m,1H),5.13–5.21(m,3H),4.54–4.67(m,2H),3.78–3.79(m,3H),1.48–1.55(m,9H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.37-7.44(m,5H), 7.18-7.20(m,1H), 7.04(s,1H), 6.95-7.01(m,1H), 6.60( t,J FH =75.0Hz,1H),6.00–6.03(m,1H),5.13–5.21(m,3H),4.54–4.67(m,2H),3.78–3.79(m,3H),1.48–1.55 (m,9H).
MS(ESI,pos.ion)m/z:498.20[M+Na] +. MS(ESI,pos.ion)m/z:498.20[M+Na] + .
步骤2：化合物(R)-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸甲酯盐酸盐的合成Step 2: Compound (R)-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester salt Synthesis of acid salt
将化合物(R)-1-叔丁基2-甲基4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(2.3g,4.8mmol)溶解于二氯甲烷(5mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(15mL)，室温反应1h，除去溶剂，得到浅黄色液体2.02g，收率100％。The compound (R)-1-tert-butyl 2-methyl 4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H )-Dicarboxylic acid ester (2.3g, 4.8mmol) was dissolved in dichloromethane (5mL) solution, added 4mol/L HCl in ethyl acetate solution (15mL), reacted at room temperature for 1h, and the solvent was removed to obtain a light yellow liquid 2.02 g, the yield is 100%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.48–7.50(m,2H),7.33–7.43(m,4H),7.23(d,J＝8.3Hz,1H),7.12(dd,J＝8.3,1.9Hz,1H),6.81(t,J F-H＝74.8Hz,1H),6.45–6.46(m,1H),5.40–5.43(m,1H),5.24(s,2H),4.53–4.62(m,2H),3.93(s,3H). 1 H NMR(400MHz,CD 3 OD)δ(ppm): 7.48–7.50(m,2H), 7.33–7.43(m,4H), 7.23(d,J=8.3Hz,1H), 7.12(dd,J =8.3,1.9Hz,1H),6.81(t,J FH =74.8Hz,1H),6.45–6.46(m,1H),5.40–5.43(m,1H),5.24(s,2H),4.53–4.62 (m,2H),3.93(s,3H).
MS(ESI,pos.ion)m/z:376.05[M+H-HCl] +. MS(ESI,pos.ion)m/z:376.05[M+H-HCl] + .
步骤3：化合物(R)-1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸甲酯的合成Step 3: Compound (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2- Synthesis of methyl carboxylate
将化合物(R)-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸甲酯盐酸盐(2.0g,4.9mmol)溶解在二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(4.0mL,24mmol)，冷却至0℃后加入乙酰氯(1.1g,14mmol)，室温搅拌3h后停止反应，加水(20mL×3)搅拌，二氯甲烷萃取(20mL×3)，有机相用无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到浅黄色液体1.8g，产率89％。The compound (R)-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride (2.0g, 4.9mmol) was dissolved in dichloromethane (10mL), N,N-diisopropylethylamine (4.0mL, 24mmol) was added, and after cooling to 0°C, acetyl chloride (1.1g, 14mmol) was added, After stirring at room temperature for 3 hours, the reaction was stopped, water (20mL×3) was added, and the mixture was extracted with dichloromethane (20mL×3). The organic phase was dried with anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (eluent: petroleum ether/ Ethyl acetate (v/v)=1/2) to obtain 1.8 g of pale yellow liquid with a yield of 89%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.36–7.47(m,5H),7.20(d,J＝8.2Hz,1H),7.05–7.06(m,1H),6.95(dd,J＝8.3,1.9Hz,1H),6.61(t,J F-H＝74.8Hz,1H),6.07–6.10(m,1H),5.27–5.35(m,1H),5.17(s,2H),5.16(s,1H),4.73–4.80(m,1H),4.58–4.66(m,1H),3.83(s,1H),3.79(s,2H),2.22(s,2H),2.11(s,1H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.36–7.47(m,5H), 7.20(d,J=8.2Hz,1H), 7.05–7.06(m,1H), 6.95(dd,J= 8.3,1.9Hz,1H),6.61(t,J FH =74.8Hz,1H),6.07–6.10(m,1H), 5.27–5.35(m,1H), 5.17(s,2H), 5.16(s, 1H), 4.73 - 4.80 (m, 1H), 4.58 - 4.66 (m, 1H), 3.83 (s, 1H), 3.79 (s, 2H), 2.22 (s, 2H), 2.11 (s, 1H).
MS(ESI,pos.ion)m/z:418.60[M+H] +. MS(ESI,pos.ion)m/z:418.60[M+H] + .
步骤4：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-羧酸甲酯的合成Step 4: Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(R)-1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸甲酯(4.5g,11mmol)溶于甲醇(30mL)，加入Pd/C(450mg,10％)，通入氢气，室温反应5h，过滤除去催化剂，滤液浓缩得到浅褐色液体3.1g，产率87％。The compound (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid Methyl ester (4.5g, 11mmol) was dissolved in methanol (30mL), Pd/C (450mg, 10%) was added, hydrogen gas was added, and the reaction was carried out at room temperature for 5 hours. The catalyst was removed by filtration. The filtrate was concentrated to obtain 3.1g of light brown liquid, yield 87 %.
1H NMR(400MHz,CDCl 3)δ(ppm):7.10(d,J＝8.3Hz,1H),6.96(d,J＝1.9Hz,1H),6.79(dd,J＝8.3,2.0Hz,1H),6.56(t,J F-H＝73.7Hz,1H),4.48–4.53(m,1H),3.94–3.98(m,1H),3.78(s,3H),3.63(t,J＝10.5Hz,1H),3.38–3.47(m,1H),2.65–2.71(m,1H),2.14(s,3H),2.05–2.11(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.10 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 1.9 Hz, 1H), 6.79 (dd, J = 8.3, 2.0 Hz, 1H ), 6.56(t, J FH = 73.7Hz, 1H), 4.48–4.53(m, 1H), 3.94–3.98(m, 1H), 3.78(s, 3H), 3.63(t, J=10.5Hz, 1H ), 3.38–3.47(m,1H), 2.65–2.71(m,1H), 2.14(s,3H), 2.05–2.11(m,1H).
MS(ESI,pos.ion)m/z:330.00[M+H] +. MS(ESI,pos.ion)m/z:330.00[M+H] + .
步骤5：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-羧酸甲酯的合成Step 5: Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-羧酸甲酯(1.3g,3.9mmol)溶于无水N,N-二甲基甲酰胺(10mL)，加入碳酸钾(1.8g,13mmol)和2-碘丙烷(1.5g,8.8mmol)，80℃加热反应4h，减压除去溶剂，剩余物加水(50mL)，乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)，得到浅褐色液体1.5g，产率100％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid methyl ester (1.3g, 3.9mmol) was dissolved in anhydrous N,N-dimethylformamide (10mL), potassium carbonate (1.8g, 13mmol) and 2-iodopropane (1.5g, 8.8mmol) were added, the reaction was heated at 80°C for 4h, the solvent was removed under reduced pressure, and the residue was added with water ( 50mL), ethyl acetate extraction (20mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=50/ 1) 1.5 g of light brown liquid is obtained, and the yield is 100%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.14(d,J＝8.1Hz,1H),6.87(s,1H),6.83(dd,J＝8.0,1.9Hz,1H),6.56(t,J F-H＝75.5Hz,1H),4.56–4.61(m,1H),4.48–4.55(m,1H),3.94–3.98(m,1H),3.79(s,3H),3.63(t,J＝10.5Hz,1H),3.40–3.48(m,1H),2.65–2.72(m,1H),2.14(s,3H),2.02–2.11(m,1H),1.37(d,J＝6.0Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.14 (d, J = 8.1 Hz, 1H), 6.87 (s, 1H), 6.83 (dd, J = 8.0, 1.9 Hz, 1H), 6.56 (t ,J FH =75.5Hz,1H),4.56–4.61(m,1H), 4.48–4.55(m,1H), 3.94–3.98(m,1H), 3.79(s,3H), 3.63(t,J= 10.5Hz,1H), 3.40–3.48(m,1H), 2.65–2.72(m,1H), 2.14(s,3H), 2.02–2.11(m,1H), 1.37(d,J=6.0Hz,6H ).
MS(ESI,pos.ion)m/z:372.30[M+H] +. MS(ESI,pos.ion)m/z:372.30[M+H] + .
步骤6：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-羧酸的合成Step 6: Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-羧酸甲酯(750mg,2.02mmol)溶于四氢呋喃(10mL)和水(5mL)的混合溶剂中，加入一水合氢氧化锂(297mg,7.08mmol)，50℃反应1h后停止，加稀盐酸调节溶液pH＝1，减压除去四氢呋喃，剩余物用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到浅褐色液体665mg，产率92％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester (750mg, 2.02mmol) was dissolved in To the mixed solvent of tetrahydrofuran (10mL) and water (5mL), add lithium hydroxide monohydrate (297mg, 7.08mmol), and stop the reaction at 50°C for 1 hour. Add dilute hydrochloric acid to adjust the pH of the solution to 1, and remove the tetrahydrofuran under reduced pressure. It was extracted with ethyl acetate (5 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 665 mg of light brown liquid with a yield of 92%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.12(d,J＝8.2Hz,1H),7.04–7.08(m,1H),6.93(dd,J＝8.3,1.8Hz,1H),6.69(t,J F-H＝75.6Hz,1H),4.63–4.71(m,1H),4.44–4.48(m,1H),4.09–4.13(m,1H),3.57–3.63(m,1H),3.50–3.56(m,1H),2.72–2.79(m,1H),2.14(s,3H),1.99–2.08(m,1H),1.35(d,J＝6.0Hz,6H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.12 (d, J = 8.2 Hz, 1H), 7.04-7.08 (m, 1H), 6.93 (dd, J = 8.3, 1.8 Hz, 1H), 6.69(t,J FH =75.6Hz,1H),4.63–4.71(m,1H),4.44–4.48(m,1H),4.09–4.13(m,1H),3.57–3.63(m,1H),3.50 –3.56(m,1H), 2.72–2.79(m,1H), 2.14(s,3H), 1.99–2.08(m,1H), 1.35(d,J=6.0Hz,6H).
MS(ESI,pos.ion)m/z:358.30[M+H] +. MS(ESI,pos.ion)m/z:358.30[M+H] + .
步骤7：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-甲酰氨基)甲基)吡啶羧酸乙酯的合成Step 7: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methyl ) Synthesis of ethyl picolinate
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-羧酸(110mg,0.31mmol)，6-氨基甲基吡啶-2-羧酸乙酯盐酸盐(132mg,0.52mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(295mg,1.54mmol)和N-羟基-7-氮杂苯并三氮唑(83mg,0.61mmol)溶于二氯甲烷(10mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(358mg,2.77mmol)，室温反应6h，加水洗(10mL×3)搅拌，分离有机相，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)，得到浅黄色固体107mg，产率66％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid (110mg, 0.31mmol), 6-amino Methylpyridine-2-carboxylic acid ethyl ester hydrochloride (132mg, 0.52mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (295mg, 1.54mmol) and N-Hydroxy-7-azabenzotriazole (83mg, 0.61mmol) was dissolved in dichloromethane (10mL). After cooling to 0℃, N,N-diisopropylethylamine (358mg, 2.77 mmol), react at room temperature for 6 hours, wash with water (10 mL×3) and stir, separate the organic phase, dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (eluent: dichloromethane/methanol ( v/v)=50/1), 107 mg of pale yellow solid was obtained, and the yield was 66%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.02(d,J＝7.6Hz,1H),7.84(t,J＝7.8Hz,1H),7.57(d,J＝7.8Hz,1H),7.48(br.s,1H),7.11(d,J＝8.2Hz,1H),6.93(s,1H),6.87(d,J＝7.3Hz,1H),6.55(t,J F-H＝75.6Hz,1H),4.66–4.78(m,2H),4.53–4.64(m,2H),4.12(q,J＝7.0Hz,2H),3.96–4.01(m,1H),3.61(t,J＝10.7Hz,1H),3.30–3.42(m,1H),2.59–2.66(m,1H),2.40–2.49(m,1H),2.17(s,3H),1.44(t,J＝7.1Hz,3H),1.37(d,J＝6.1Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.02 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.48(br.s,1H), 7.11(d,J=8.2Hz,1H), 6.93(s,1H), 6.87(d,J=7.3Hz,1H), 6.55(t,J FH ＝75.6Hz, 1H), 4.66–4.78(m,2H), 4.53–4.64(m,2H), 4.12(q,J=7.0Hz,2H), 3.96–4.01(m,1H),3.61(t,J=10.7Hz ,1H), 3.30–3.42(m,1H), 2.59–2.66(m,1H), 2.40–2.49(m,1H), 2.17(s,3H), 1.44(t,J=7.1Hz,3H), 1.37(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:520.10[M+H] +. MS(ESI,pos.ion)m/z:520.10[M+H] + .
实施例6：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-甲酰氨基)甲基)吡啶羧酸盐酸盐Example 6: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methan Yl)pyridinecarboxylic acid hydrochloride
Figure PCTCN2021090489-appb-000068
Figure PCTCN2021090489-appb-000068
将化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-甲酰氨基)甲基)吡啶羧酸乙酯(55mg,0.11mmol)溶于四氢呋喃(6mL)和水(3mL)的混合溶剂中，加入一水合氢氧化锂(22mg, 0.52mmol)，50℃反应1.5h后停止，加稀盐酸调节溶液pH＝1，减压除去溶剂，剩余物用乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，除去溶剂得到55mg浅黄色固体，产率98％。The compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methyl)pyridine Ethyl carboxylate (55mg, 0.11mmol) was dissolved in a mixed solvent of tetrahydrofuran (6mL) and water (3mL). Lithium hydroxide monohydrate (22mg, 0.52mmol) was added. The reaction was stopped at 50℃ for 1.5h, and diluted hydrochloric acid was added. The pH of the solution was adjusted to 1, the solvent was removed under reduced pressure, the residue was extracted with ethyl acetate (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 55 mg of a pale yellow solid with a yield of 98%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.06(d,J＝7.0Hz,1H),7.99(t,J＝7.5Hz,1H),7.76(d,J＝7.4Hz,1H),7.06–7.15(m,2H),6.94(d,J＝7.8Hz,1H),6.70(t,J F-H＝75.6Hz,1H),4.64–4.74(m,2H),4.51–4.58(m,2H),4.10–4.14(m,1H),3.66(t,J＝10.4Hz,1H),3.47–3.56(m,1H),2.67–2.75(m,1H),2.16(s,3H),2.04–2.13(m,1H),1.35(d,J＝5.7Hz,6H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.06 (d, J = 7.0Hz, 1H), 7.99 (t, J = 7.5Hz, 1H), 7.76 (d, J = 7.4Hz, 1H) ,7.06–7.15(m,2H),6.94(d,J=7.8Hz,1H), 6.70(t,J FH =75.6Hz,1H), 4.64–4.74(m,2H),4.51–4.58(m, 2H), 4.10–4.14(m,1H), 3.66(t,J=10.4Hz,1H), 3.47–3.56(m,1H), 2.67–2.75(m,1H), 2.16(s,3H), 2.04 –2.13(m,1H),1.35(d,J=5.7Hz,6H).
MS(ESI,pos.ion)m/z:492.10[M+H-HCl] +. MS(ESI,pos.ion)m/z:492.10[M+H-HCl] + .
实施例7：化合物3-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-甲酰氨基)甲基)苯甲酸甲酯Example 7: Compound 3-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methan Yl) methyl benzoate
Figure PCTCN2021090489-appb-000069
Figure PCTCN2021090489-appb-000069
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-羧酸(110mg,0.31mmol)，3-氨基甲基苯甲酸甲酯(86mg,0.52mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(297mg,1.55mmol)和N-羟基-7-氮杂苯并三氮唑(81mg,0.60mmol)溶于二氯甲烷(10mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(278mg,2.15mmol)，室温反应3h，加水洗(10mL×3)搅拌，分离有机相，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)，得到无色液体112mg，产率72％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid (110mg, 0.31mmol), 3-amino Methyl methylbenzoate (86mg, 0.52mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (297mg, 1.55mmol) and N-hydroxy-7-nitrogen Heterobenzotriazole (81mg, 0.60mmol) was dissolved in dichloromethane (10mL), and after cooling to 0°C, N,N-diisopropylethylamine (278mg, 2.15mmol) was added and reacted at room temperature for 3h, Wash with water (10mL×3) and stir, separate the organic phase, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=50/ 1) 112 mg of colorless liquid was obtained, and the yield was 72%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.95–7.96(m,2H),7.53(d,J＝7.7Hz,1H),7.43(d,J＝7.9Hz,1H),7.13(d,J＝8.2Hz,1H),6.97(s,1H),6.88(dd,J＝8.2,1.7Hz,1H),6.57(t,J F-H＝75.6Hz,1H),4.57–4.68(m,2H),4.49–4.58(m,2H),3.94–3.99(m,1H),3.92(s,3H),3.52(t,J＝10.8Hz,1H),3.29–3.35(m,1H),2.63–2.71(m,1H),2.50–2.57(m,1H),2.17(s,3H),1.36–1.38(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.95–7.96 (m, 2H), 7.53 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.13 (d ,J=8.2Hz,1H),6.97(s,1H),6.88(dd,J=8.2,1.7Hz,1H),6.57(t,J FH =75.6Hz,1H),4.57–4.68(m,2H ), 4.49–4.58(m,2H), 3.94–3.99(m,1H), 3.92(s,3H), 3.52(t,J=10.8Hz,1H), 3.29–3.35(m,1H), 2.63– 2.71 (m, 1H), 2.50-2.57 (m, 1H), 2.17 (s, 3H), 1.36-1.38 (m, 6H).
MS(ESI,pos.ion)m/z:505.10[M+H] +. MS(ESI,pos.ion)m/z:505.10[M+H] + .
实施例8：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-甲酰氨基)甲基)苯甲酸Example 8: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methan Base) benzoic acid
Figure PCTCN2021090489-appb-000070
Figure PCTCN2021090489-appb-000070
将化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-甲酰氨基)甲基)苯甲酸甲酯(63mg,0.12mmol)溶于四氢呋喃(6mL)和水(3mL)的混合溶剂中，再加入一水合氢氧化锂(26mg,0.62mmol)，50℃反应1.5h后停止，加稀盐酸调节溶液pH＝1，减压除去四氢呋喃，剩余物用乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，除去溶剂得到白色固体53mg，产率86％。The compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxamido)methyl)benzene Methyl formate (63mg, 0.12mmol) was dissolved in a mixed solvent of tetrahydrofuran (6mL) and water (3mL), and then lithium hydroxide monohydrate (26mg, 0.62mmol) was added. The reaction was stopped at 50°C for 1.5 hours, and diluted hydrochloric acid was added. The pH of the solution was adjusted to 1, the tetrahydrofuran was removed under reduced pressure, the residue was extracted with ethyl acetate (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain a white solid of 53 mg with a yield of 86%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.99(s,1H),7.93(d,J＝7.7Hz,1H),7.62(d,J＝7.2Hz,1H),7.46 (d,J＝7.6Hz,1H),7.06–7.12(m,2H),6.93(d,J＝8.5Hz,1H),6.69(t,J F-H＝75.6Hz,1H),4.63–4.70(m,1H),4.50(s,2H),4.08–4.12(m,1H),3.52(t,J＝10.5Hz,1H),3.44–3.55(m,1H),3.31–3.38(m,1H),2.64–2.72(m,1H),2.15(s,3H),2.01–2.12(m,1H),1.35(d,J＝5.8Hz,6H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.99 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.46 (d, J = 7.6Hz, 1H), 7.06–7.12(m, 2H), 6.93(d, J = 8.5Hz, 1H), 6.69(t, J FH = 75.6Hz, 1H), 4.63–4.70(m, 1H) ,4.50(s,2H),4.08–4.12(m,1H),3.52(t,J=10.5Hz,1H),3.44–3.55(m,1H),3.31–3.38(m,1H),2.64–2.72 (m, 1H), 2.15 (s, 3H), 2.01-2.12 (m, 1H), 1.35 (d, J = 5.8 Hz, 6H).
MS(ESI,pos.ion)m/z:491.40[M+H] +. MS(ESI,pos.ion)m/z:491.40[M+H] + .
实施例9：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)-N-(3-(羟基甲基)苯基)吡咯烷-2-甲酰胺Example 9: Compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-N-(3-(hydroxymethyl)phenyl) Pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000071
Figure PCTCN2021090489-appb-000071
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-羧酸(60mg,0.17mmol)，3-氨基苯甲醇(62mg,0.50mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(163mg,0.85mmol)和N-羟基-7-氮杂苯并三氮唑(46mg,0.34mmol)溶于二氯甲烷(10mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(153mg,1.18mmol)，室温反应12h，加水洗(10mL)，用二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝35/1)，得到浅褐色固体53mg，产率68％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid (60mg, 0.17mmol), 3-amino Benzyl alcohol (62mg, 0.50mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (163mg, 0.85mmol) and N-hydroxy-7-azabenzotriazole Nitrozazole (46mg, 0.34mmol) was dissolved in dichloromethane (10mL), after cooling to 0°C, N,N-diisopropylethylamine (153mg, 1.18mmol) was added, reacted at room temperature for 12h, and washed with water (10mL ), extracted with dichloromethane (10mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)= 35/1), 53 mg of light brown solid was obtained, and the yield was 68%.
1H NMR(400MHz,CDCl 3)δ(ppm):9.68(s,1H),7.42(d,J＝7.8Hz,1H),7.37(s,1H),7.12–7.15(m,2H),6.96(s,1H),6.93(d,J＝7.5Hz,1H),6.87(d,J＝8.0Hz,1H),6.56(t,J F-H＝75.5Hz,1H),4.74–4.78(m,1H),4.52–4.64(m,3H),3.97–4.01(m,1H),3.62–3.67(m,1H),3.34–3.45(m,1H),2.58–2.66(m,1H),2.46–2.54(m,1H),2.20(s,3H),1.37(t,J＝5.9Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.68 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.12-7.15 (m, 2H), 6.96 (s,1H),6.93(d,J=7.5Hz,1H),6.87(d,J=8.0Hz,1H),6.56(t,J FH =75.5Hz,1H),4.74-4.78(m,1H ), 4.52–4.64(m,3H), 3.97–4.01(m,1H), 3.62–3.67(m,1H), 3.34–3.45(m,1H), 2.58–2.66(m,1H), 2.46–2.54 (m, 1H), 2.20 (s, 3H), 1.37 (t, J = 5.9 Hz, 6H).
MS(ESI,pos.ion)m/z:463.30[M+H] +. MS(ESI,pos.ion)m/z:463.30[M+H] + .
实施例10：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)-N-(2-乙氧基苄基)吡咯烷-2-甲酰胺Example 10: Compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-N-(2-ethoxybenzyl)pyrrolidine- 2-formamide
Figure PCTCN2021090489-appb-000072
Figure PCTCN2021090489-appb-000072
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-羧酸(60mg,0.17mmol)，2-乙氧基苄胺(52mg,0.34mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(163mg,0.85mmol)和N-羟基-7-氮杂苯并三氮唑(46mg,0.34mmol)溶于二氯甲烷(10mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(153mg,1.18mmol)，室温反应12h，加水洗(10mL)，用二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝35/1)，得到白色粘稠固体79mg，产率96％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid (60mg, 0.17mmol), 2-ethyl Oxybenzylamine (52mg, 0.34mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (163mg, 0.85mmol) and N-hydroxy-7-azabenzene Triazole (46mg, 0.34mmol) was dissolved in dichloromethane (10mL), after cooling to 0°C, N,N-diisopropylethylamine (153mg, 1.18mmol) was added, reacted at room temperature for 12h, and washed with water (10mL), extracted with dichloromethane (10mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) )=35/1), 79 mg of white viscous solid was obtained, and the yield was 96%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.23–7.29(m,2H),7.08–7.14(m,2H),6.96(s,1H),6.84–6.92(m, 2H),6.56(t,J F-H＝75.6Hz,1H),4.51–4.62(m,3H),4.37–4.47(m,1H),4.10(q,J＝6.9Hz,2H),3.92–3.96(m,1H),3.51(t,J＝10.8Hz,1H),3.23–3.32(m,1H),2.47–2.63(m,2H),2.14(s,3H),1.47(t,J＝6.9Hz,3H),1.37(d,J＝5.7Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.23-7.29 (m, 2H), 7.08-7.14 (m, 2H), 6.96 (s, 1H), 6.84-6.92 (m, 2H), 6.56 ( t,J FH =75.6Hz,1H),4.51–4.62(m,3H), 4.37–4.47(m,1H), 4.10(q,J=6.9Hz,2H), 3.92–3.96(m,1H), 3.51(t,J＝10.8Hz,1H), 3.23–3.32(m,1H), 2.47–2.63(m,2H), 2.14(s,3H), 1.47(t,J＝6.9Hz,3H), 1.37 (d,J=5.7Hz,6H).
MS(ESI,pos.ion)m/z:491.25[M+H] +. MS(ESI,pos.ion)m/z:491.25[M+H] + .
实施例11：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(2-乙氧基苄基)吡咯烷-2-甲酰胺Example 11: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-ethoxybenzyl) Yl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000073
Figure PCTCN2021090489-appb-000073
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(50mg,0.14mmol)，(2-乙氧基苯基)甲胺(41mg,0.27mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(132mg,0.69mmol)和N-羟基-7-氮杂苯并三氮唑(37mg,0.27mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入N,N-二异丙基乙胺(107mg,0.83mmol)，室温反应11h，加入二氯甲烷(15mL)，加水洗有机相(20mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到白色粘稠固体39mg，产率57％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (50mg, 0.14mmol) , (2-Ethoxyphenyl) methylamine (41mg, 0.27mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (132mg, 0.69mmol) and N -Hydroxy-7-azabenzotriazole (37mg, 0.27mmol) was dissolved in dichloromethane (10mL), cooled to 0℃, and N,N-diisopropylethylamine (107mg, 0.83mmol) was added , React at room temperature for 11h, add dichloromethane (15mL), add water to wash the organic phase (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the residue by silica gel column chromatography (eluent: petroleum Ether/ethyl acetate (v/v) = 1/2) to obtain 39 mg of a white viscous solid with a yield of 57%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.23–7.28(m,1H),7.09–7.12(m,2H),6.85–6.94(m,4H),6.62(t,J F-H＝75.5Hz,1H),4.53–4.59(m,2H),4.39–4.47(m,1H),4.09(q,J＝7.0Hz,2H),3.84–3.95(m,3H),3.51(t,J＝10.7Hz,1H),3.24–3.34(m,1H),2.89–2.95(m,0.3H),2.48–2.61(m,1.7H),2.14(s,2.4H),1.90(s,0.6H),1.45(t,J＝7.0Hz,3H),1.28–1.36(m,1H),0.69–0.70(m,2H),0.36–0.39(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.23–7.28(m,1H), 7.09–7.12(m,2H), 6.85–6.94(m,4H), 6.62(t,J FH = 75.5Hz ,1H),4.53–4.59(m,2H),4.39–4.47(m,1H),4.09(q,J=7.0Hz,2H),3.84–3.95(m,3H),3.51(t,J=10.7 Hz,1H), 3.24–3.34(m,1H), 2.89–2.95(m,0.3H), 2.48–2.61(m,1.7H), 2.14(s,2.4H), 1.90(s,0.6H), 1.45(t,J=7.0Hz,3H), 1.28–1.36(m,1H), 0.69–0.70(m,2H), 0.36–0.39(m,2H).
MS(ESI,pos.ion)m/z:503.10[M+H] +. MS(ESI,pos.ion)m/z:503.10[M+H] + .
实施例12：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基烟酰胺Example 12: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-dimethylnicotinamide
Figure PCTCN2021090489-appb-000074
Figure PCTCN2021090489-appb-000074
步骤1：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)烟酸甲酯的合成Step 1: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (Amino) Methyl) Methyl Nicotinate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(300mg,0.81mmol)，6-(氨基甲基)烟酸甲酯(206mg,1.24mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(780mg,4.07mmol)和N-羟基-7-氮杂苯并三氮唑(166mg,1.22mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.6mL,4.0mmol)，室温反应17h，加水洗(15mL)，然后二氯甲烷萃取(10 mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到浅黄色粘稠固体213mg，收率51％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (300mg, 0.81mmol) , 6-(Aminomethyl) nicotinic acid methyl ester (206mg, 1.24mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (780mg, 4.07mmol) and N -Hydroxy-7-azabenzotriazole (166mg, 1.22mmol) was dissolved in dichloromethane (5mL), and N,N-diisopropylethylamine (0.6 mL, 4.0mmol), reacted at room temperature for 17h, washed with water (15mL), and extracted with dichloromethane (10 mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (washing Removal agent: dichloromethane/methanol (v/v)=40/1) to obtain 213 mg of light yellow viscous solid with a yield of 51%.
1H NMR(400MHz,CDCl 3)δ(ppm):9.15(s,1H),8.28(dd,J＝8.1,2.0Hz,1H),7.43(d,J＝8.1Hz,1H),7.12(d,J＝8.2Hz,1H),6.91(s,1H),6.87(d,J＝8.2Hz,1H),6.62(t,J F-H＝75.6Hz,1H),4.61–4.69(m,3H),3.94–3.99(m,1H),3.97(s,3H),3.88(d,J＝6.9Hz,2H),3.57(t,J＝10.7Hz,1H),3.31–3.41(m,1H),2.46–2.63(m,2H),2.16(s,3H),1.27–1.35(m,1H),0.65–0.69(m,2H),0.36–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.15 (s, 1H), 8.28 (dd, J = 8.1, 2.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.12 (d ,J=8.2Hz,1H),6.91(s,1H),6.87(d,J=8.2Hz,1H),6.62(t,J FH =75.6Hz,1H),4.61-4.69(m,3H), 3.94–3.99 (m, 1H), 3.97 (s, 3H), 3.88 (d, J = 6.9 Hz, 2H), 3.57 (t, J = 10.7 Hz, 1H), 3.31–3.41 (m, 1H), 2.46 --2.63 (m, 2H), 2.16 (s, 3H), 1.27 - 1.35 (m, 1H), 0.65 - 0.69 (m, 2H), 0.36 - 0.39 (m, 2H).
MS(ESI,pos.ion)m/z:518.10[M+H] +. MS(ESI,pos.ion)m/z:518.10[M+H] + .
步骤2：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)烟酸的合成Step 2: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)nicotinic acid
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)烟酸甲酯(154mg,0.3mmol)溶于四氢呋喃(10mL)和水(5mL)的混合溶剂中，再加入一水合氢氧化锂(86mg,2.05mmol)，50℃反应3h后停止，加稀盐酸调节溶液pH＝1，再用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到白色固体137mg，收率91％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl) nicotinate (154mg, 0.3mmol) was dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (5mL), then lithium hydroxide monohydrate (86mg, 2.05mmol) was added, and the reaction was stopped at 50°C for 3 hours. Dilute hydrochloric acid was added to adjust the pH of the solution to 1, and then extracted with ethyl acetate (10 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 137 mg of white solid with a yield of 91%.
1H NMR(400MHz,CD 3OD)δ(ppm):9.07(s,1H),8.42(dd,J＝8.2,1.9Hz,1H),7.71(d,J＝8.2Hz,1H),7.12(d,J＝8.2Hz,1H),7.09(s,1H),6.93–6.96(m,1H),6.75(t,J F-H＝75.7Hz,1H),4.51–4.73(m,2H),4.10–4.14(m,1H),3.93(d,J＝6.9Hz,2H),3.66(t,J＝10.6Hz,1H),3.51–3.56(m,1H),2.68–2.74(m,1H),2.17(s,3H),2.01–2.13(m,2H),1.27–1.35(m,1H),0.62–0.67(m,2H),0.37–0.40(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 9.07 (s, 1H), 8.42 (dd, J = 8.2, 1.9 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.12 ( d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.93–6.96 (m, 1H), 6.75 (t, J FH = 75.7 Hz, 1H), 4.51–4.73 (m, 2H), 4.10– 4.14 (m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.66 (t, J = 10.6 Hz, 1H), 3.51–3.56 (m, 1H), 2.68–2.74 (m, 1H), 2.17 (s,3H), 2.01--2.13(m,2H), 1.27--1.35(m,1H), 0.62--0.67(m,2H), 0.37--0.40(m,2H).
MS(ESI,pos.ion)m/z:504.10[M+H] +. MS(ESI,pos.ion)m/z:504.10[M+H] + .
步骤3：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基烟酰胺的合成Step 3: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)-N,N-dimethylnicotinamide
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)烟酸(130mg,0.26mmol)，二甲胺盐酸盐(103mg,1.26mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(249mg,1.3mmol)和N-羟基-7-氮杂苯并三氮唑(58mg,0.43mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.28mL,1.7mmol)，室温反应19h，加水洗(15mL)，然后二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体103mg，收率75％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl) nicotinic acid (130mg, 0.26mmol), dimethylamine hydrochloride (103mg, 1.26mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (249mg , 1.3mmol) and N-hydroxy-7-azabenzotriazole (58mg, 0.43mmol) dissolved in dichloromethane (5mL), add N,N-diiso to this solution dropwise at 0℃ Propylethylamine (0.28mL, 1.7mmol), reacted at room temperature for 19h, washed with water (15mL), and extracted with dichloromethane (10mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 103 mg of white solid with a yield of 75%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.60(s,1H),7.74(d,J＝7.5Hz,1H),7.61(br.s,1H),7.39(d,J＝7.9Hz,1H),7.11(d,J＝8.1Hz,1H),6.90(s,1H),6.86(d,J＝8.0Hz,1H),6.62(t,J F-H＝75.6Hz,1H),4.49-4.68(m,3H),3.91-3.98(m,1H),3.88(d,J＝6.8Hz,2H),3.54-3.60(m,1H),3.26-3.41(m,1H),3.13(s,3H),3.01(s,3H),2.41-2.62(m,2H),2.14(s,3H),1.24-1.35(m,1H),0.62-0.67(m,2H),0.34-0.39(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 8.60(s,1H), 7.74(d,J=7.5Hz,1H), 7.61(br.s,1H), 7.39(d,J=7.9Hz ,1H),7.11(d,J=8.1Hz,1H),6.90(s,1H),6.86(d,J=8.0Hz,1H),6.62(t,J FH =75.6Hz,1H),4.49- 4.68(m,3H),3.91-3.98(m,1H),3.88(d,J=6.8Hz,2H),3.54-3.60(m,1H),3.26-3.41(m,1H),3.13(s, 3H),3.01(s,3H),2.41-2.62(m,2H),2.14(s,3H),1.24-1.35(m,1H),0.62-0.67(m,2H),0.34-0.39(m, 2H).
MS(ESI,pos.ion)m/z:531.15[M+H] +. MS(ESI,pos.ion)m/z:531.15[M+H] + .
实施例13：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((4-(1-羟乙基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 13: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((4-(1- (Hydroxyethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000075
Figure PCTCN2021090489-appb-000075
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(748-1)(92mg,0.25mmol)，化合物1-(2-(氨甲基)吡啶-4-基)乙醇(101mg,0.54mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(143mg,0.75mmol)和N-羟基-7-氮杂苯并三氮唑(72mg,0.53mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌17h，加水(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体52mg，收率41％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (748-1)( 92mg, 0.25mmol), compound 1-(2-(aminomethyl)pyridin-4-yl)ethanol (101mg, 0.54mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (143mg, 0.75mmol) and N-hydroxy-7-azabenzotriazole (72mg, 0.53mmol) were dissolved in dichloromethane (6mL), and N, N-diisopropylethylamine (0.3mL, 2.0mmol), stir at room temperature for 17h, add water (50mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate Silica gel column chromatography was performed (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 52 mg of white solid with a yield of 41%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.81-8.84(m,0.3H),8.53-8.58(m,0.7H),8.39-8.41(m,1H),7.36(s,0.7H),7.28(s,0.3H),7.22(s,1H),7.10-7.14(m,1H),7.05-7.06(m,1H),7.03(t,J F-H＝78.2Hz,1H),6.89(d,J＝8.5Hz,1H),5.33-5.39(m,1H),4.64-4.73(m,1H),4.35-4.42(m,3H),4.19-4.23(m,0.3H),4.05-4.09(m,0.7H),3.90(d,J＝6.9Hz,2H),3.34-3.47(m,2H),2.51-2.64(m,1H),2.02(s,3H),1.89-1.98(m,1H),1.31(d,J＝6.5Hz,3H),1.24-1.27(m,1H),0.54-0.60(m,2H),0.31-0.38(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.81-8.84 (m, 0.3H), 8.53-8.58 (m, 0.7H), 8.39-8.41 (m, 1H), 7.36 (s, 0.7 H),7.28(s,0.3H),7.22(s,1H),7.10-7.14(m,1H),7.05-7.06(m,1H),7.03(t,J FH =78.2Hz,1H),6.89 (d,J=8.5Hz,1H),5.33-5.39(m,1H),4.64-4.73(m,1H),4.35-4.42(m,3H),4.19-4.23(m,0.3H),4.05- 4.09(m,0.7H),3.90(d,J=6.9Hz,2H),3.34-3.47(m,2H),2.51-2.64(m,1H),2.02(s,3H),1.89-1.98(m ,1H),1.31(d,J=6.5Hz,3H),1.24-1.27(m,1H),0.54-0.60(m,2H),0.31-0.38(m,2H).
MS(ESI,pos.ion)m/z:504.20[M+H] +. MS(ESI,pos.ion)m/z:504.20[M+H] + .
实施例14：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(1-羟乙基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 14: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(1- (Hydroxyethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000076
Figure PCTCN2021090489-appb-000076
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(82mg,0.22mmol)，化合物1-(6-(氨甲基)吡啶-2-基)乙醇(73mg,0.48mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(123mg,0.64mmol)和N-羟基-7-氮杂苯并三氮唑(74mg,0.54mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌17h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体43mg，收率38％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (82mg, 0.22mmol) , Compound 1-(6-(aminomethyl)pyridin-2-yl)ethanol (73mg, 0.48mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 123mg, 0.64mmol) and N-hydroxy-7-azabenzotriazole (74mg, 0.54mmol) were dissolved in dichloromethane (6mL), and N,N-diisopropyl was added dropwise to this solution at room temperature Ethylethylamine (0.4mL, 2.0mmol), stirred at room temperature for 17h, washed with water (50mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 43 mg of white solid with a yield of 38%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.75-8.83(m,0.2H),8.50-8.62(m,0.8H),7.70-7.79(m,1H),7.32-7.39(m,1H),7.24-7.26(m,1H),7.06-7.14(m,2H),7.03(t,J F-H＝74.6Hz,1H),6.86-6.90(m,1H),5.26-5.43(m,1H),4.64-4.75(m,1H),4.28-4.44(m,3H),4.02-4.12(m,1H),3.90(d,J＝6.1Hz,2H),3.43-3.57(m,2H),2.56-2.67(m,1H),2.03(s,3H),1.86-1.98(m,1H),1.30-1.36(m,3H),1.23-1.26(m,1H),0.51-0.62(m,2H),0.28-0.38(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.75-8.83 (m, 0.2H), 8.50-8.62 (m, 0.8H), 7.70-7.79 (m, 1H), 7.32-7.39 (m ,1H),7.24-7.26(m,1H),7.06-7.14(m,2H),7.03(t,J FH =74.6Hz,1H),6.86-6.90(m,1H),5.26-5.43(m, 1H),4.64-4.75(m,1H),4.28-4.44(m,3H),4.02-4.12(m,1H),3.90(d,J=6.1Hz,2H),3.43-3.57(m,2H) ,2.56-2.67(m,1H),2.03(s,3H),1.86-1.98(m,1H),1.30-1.36(m,3H),1.23-1.26(m,1H),0.51-0.62(m, 2H), 0.28-0.38 (m, 2H).
MS(ESI,pos.ion)m/z:504.20[M+H] +. MS(ESI,pos.ion)m/z:504.20[M+H] + .
实施例15：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(羟甲基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 15: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(hydroxymethyl (Yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000077
Figure PCTCN2021090489-appb-000077
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(85mg,0.23mmol)，化合物(6-(氨甲基)吡啶-2-基)甲醇(61mg,0.35mmol)，1-乙基-3-(3-二甲胺基丙基)碳二亚胺盐酸盐(143mg,0.75mmol)和N-羟基-7-氮杂苯并三氮唑(72mg,0.53mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌20h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体64mg，收率56％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (85mg, 0.23mmol) , Compound (6-(aminomethyl)pyridin-2-yl)methanol (61mg, 0.35mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (143mg , 0.75mmol) and N-hydroxy-7-azabenzotriazole (72mg, 0.53mmol) dissolved in dichloromethane (6mL), add N,N-diisopropyl to this solution dropwise at room temperature Ethylamine (0.3mL, 2.0mmol), stirred at room temperature for 20h, washed with water (50mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography After separation (eluent: dichloromethane/methanol (v/v)=15/1), 64 mg of white solid was obtained with a yield of 56%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.52-8.55(m,1H),7.71-7.75(m,1H),7.25-7.35(m,2H),7.12(d,J＝7.7Hz,1H),7.06(s,1H),7.03(t,J F-H＝74.8Hz,1H),6.89(d,J＝8.4Hz,1H),5.36-5.41(m,1H),4.52(d,J＝4.8Hz,2H),4.27-4.42(m,3H),4.05-4.09(m,1H),3.90(d,J＝6.5Hz,2H),3.40-3.51(m,2H),2.55-2.64(m,1H),2.03(s,3H),1.88-1.98(m,1H),1.23-1.35(m,1H),0.53-0.59(m,2H),0.31-0.37(m,2H). 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 8.52-8.55(m,1H),7.71-7.75(m,1H),7.25-7.35(m,2H),7.12(d,J=7.7 Hz, 1H), 7.06 (s, 1H), 7.03 (t, J FH = 74.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.36-5.41 (m, 1H), 4.52 (d, J = 4.8Hz, 2H), 4.27-4.42 (m, 3H), 4.05-4.09 (m, 1H), 3.90 (d, J = 6.5 Hz, 2H), 3.40-3.51 (m, 2H), 2.55-2.64 (m, 1H), 2.03 (s, 3H), 1.88-1.98 (m, 1H), 1.23-1.35 (m, 1H), 0.53-0.59 (m, 2H), 0.31-0.37 (m, 2H).
MS(ESI,pos.ion)m/z:490.20[M+H] +. MS(ESI,pos.ion)m/z:490.20[M+H] + .
实施例16：化合物(3-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)苯基)氨基甲酸甲酯Example 16: Compound (3-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Carboxamido) methyl) phenyl) methyl carbamate
Figure PCTCN2021090489-appb-000078
Figure PCTCN2021090489-appb-000078
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(748-1)(85mg,0.23mmol)，化合物(3-(氨甲基)苯基)氨基甲酸甲酯盐酸盐(803-2)(96mg,0.53mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(148mg,0.77mmol)和N-羟基-7-氮杂苯并三氮唑(74mg,0.54mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌14h，加水(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体46mg，收率38％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (748-1)( 85mg, 0.23mmol), compound (3-(aminomethyl)phenyl) methyl carbamate hydrochloride (803-2) (96mg, 0.53mmol), 1-ethyl-(3-dimethylaminopropyl) Yl) carbodiimide hydrochloride (148mg, 0.77mmol) and N-hydroxy-7-azabenzotriazole (74mg, 0.54mmol) dissolved in dichloromethane (6mL), add to this at room temperature Add N,N-diisopropylethylamine (0.4mL, 2.0mmol) dropwise to the solution, stir at room temperature for 14h, add water (50mL), extract with dichloromethane (5mL×3), and dry the organic phase with anhydrous sodium sulfate After removing the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 46 mg of white solid with a yield of 38%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):9.60-9.64(m,1H),8.72-8.75(m,0.3H),8.41-8.43(m,0.7H),7.37-7.42(m,1H),7.28-7.32(m,1H),7.20-7.23(m,1H),7.09-7.13(m,1H),7.04-7.05(m,1H),7.02(t,J F-H＝69.5Hz,1H),6.88-6.94(m,2H),4.18-4.34(m,3H),4.03-4.07(m,1H),3.89(d,J＝6.8Hz,2H),3.63(s,3H), 3.39-3.49(m,2H),2.56-2.61(m,1H),2.01(s,3H),1.87-1.96(m,1H),1.22-1.33(m,1H),0.54-0.60(m,2H),0.31-0.35(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 9.60-9.64 (m, 1H), 8.72-8.75 (m, 0.3H), 8.41-8.43 (m, 0.7H), 7.37-7.42 (m ,1H),7.28-7.32(m,1H),7.20-7.23(m,1H),7.09-7.13(m,1H),7.04-7.05(m,1H),7.02(t,J FH = 69.5Hz, 1H), 6.88-6.94 (m, 2H), 4.18-4.34 (m, 3H), 4.03-4.07 (m, 1H), 3.89 (d, J = 6.8 Hz, 2H), 3.63 (s, 3H), 3.39 -3.49(m,2H),2.56-2.61(m,1H),2.01(s,3H),1.87-1.96(m,1H),1.22-1.33(m,1H),0.54-0.60(m,2H) ,0.31-0.35(m,2H).
MS(ESI,pos.ion)m/z:532.20[M+H] +. MS(ESI,pos.ion)m/z:532.20[M+H] + .
实施例17：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((嘧啶-2-基)甲基)吡咯烷-2-甲酰胺Example 17: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((pyrimidin-2-yl )Methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000079
Figure PCTCN2021090489-appb-000079
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(92mg,0.25mmol)，化合物嘧啶-2-甲胺(103mg,0.71mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(150mg,0.78mmol)和N-羟基-7-氮杂苯并三氮唑(71mg,0.52mmol)溶于二氯甲烷(6mL)中，室温下加入N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌15h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体49mg，收率42％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (92mg, 0.25mmol) , The compound pyrimidine-2-methylamine (103mg, 0.71mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (150mg, 0.78mmol) and N-hydroxy-7 -Azabenzotriazole (71mg, 0.52mmol) dissolved in dichloromethane (6mL), add N,N-diisopropylethylamine (0.4mL, 2.0mmol) at room temperature, stir at room temperature for 15h, add Washed with water (50mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) )=15/1) to obtain 49 mg of white solid with a yield of 42%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.75(d,J＝4.7Hz,2H),7.39(t,J＝4.4Hz,1H),7.12(t,J＝8.0Hz,1H),7.06(s,1H),7.03(t,J F-H＝74.9Hz,1H),6.86-6.90(m,1H),4.38-4.56(m,3H),4.19-4.24(m,0.5H),4.03-4.07(m,0.5H),3.87-3.90(m,2H),3.39-3.48(m,2H),2.74-2.80(m,0.5H),2.74-2.80(m,0.5H),1.98-2.07(m,1H),2.01(s,3H),1.23-1.32(m,1H),0.53-0.61(m,2H),0.29-0.36(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.75 (d, J = 4.7Hz, 2H), 7.39 (t, J = 4.4Hz, 1H), 7.12 (t, J = 8.0Hz, 1H ), 7.06 (s, 1H), 7.03 (t, J FH = 74.9 Hz, 1H), 6.86-6.90 (m, 1H), 4.38-4.56 (m, 3H), 4.19-4.24 (m, 0.5H), 4.03-4.07(m,0.5H),3.87-3.90(m,2H),3.39-3.48(m,2H),2.74-2.80(m,0.5H),2.74-2.80(m,0.5H),1.98- 2.07 (m, 1H), 2.01 (s, 3H), 1.23-1.32 (m, 1H), 0.53-0.61 (m, 2H), 0.29-0.36 (m, 2H).
MS(ESI,pos.ion)m/z:461.25[M+H] +. MS(ESI,pos.ion)m/z:461.25[M+H] + .
实施例18：化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(1-羟基乙基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 18: The compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(1- (Hydroxyethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000080
Figure PCTCN2021090489-appb-000080
步骤1：(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸的合成Step 1: Synthesis of (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid
将化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯(410mg,1.07mmol)溶于四氢呋喃(5mL)和水(5mL)的混合溶剂中，加入一水合氢氧化锂(230mg,5.48mmol)，50℃反应4h后停止。除去溶剂，加稀盐酸调节溶液pH＝1，用乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥，减压浓缩得白色固体365mg，产率92％。The compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (410mg, 1.07 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide monohydrate (230 mg, 5.48 mmol) was added, and the reaction was stopped at 50°C for 4 hours. The solvent was removed, diluted hydrochloric acid was added to adjust the pH of the solution to 1, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 365 mg of white solid with a yield of 92%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.13(d,J＝8.0Hz,1H),6.83(s,1H),6.80-6.81(m,1H),6.61(t,J F-H＝75.5Hz,1H),4.56-4.60(m,1H),3.94-3.98(m,1H),3.87(d,J＝6.9Hz,2H),3.51-3.57(m,1H),3.34-3.43(m, 1H),2.62–2.69(m,1H),2.33-2.41(m,1H),2.18(s,3H),1.25–1.34(m,1H),0.63-0.68(m,2H),0.34-0.38(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.13 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6.80-6.81 (m, 1H), 6.61 (t, J FH = 75.5 Hz,1H),4.56-4.60(m,1H),3.94-3.98(m,1H), 3.87(d,J=6.9Hz,2H),3.51-3.57(m,1H),3.34-3.43(m, 1H), 2.62-2.69(m, 1H), 2.33-2.41(m, 1H), 2.18(s, 3H), 1.25-1.34(m, 1H), 0.63-0.68(m, 2H), 0.34-0.38( m,2H).
MS(ESI,pos.ion)m/z:370.20[M+H] +. MS(ESI,pos.ion)m/z:370.20[M+H] + .
步骤2：(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(1-羟基乙基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺的合成Step 2: (2S)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(1-hydroxyethyl (Yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
将化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(97mg,0.26mmol)，1-(6-(氨基甲基)吡啶-2-基)乙醇二盐酸盐(84mg,0.55mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(103mg,0.54mmol)和N-羟基-7-氮杂苯并三氮唑(69mg,0.51mmol)溶于二氯甲烷(4mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.22mL,1.3mmol)，室温搅拌7h，反应液水洗(5mL×3)，无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得淡黄色固体68mg，产率51％。The compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (97mg, 0.26mmol) , 1-(6-(Aminomethyl)pyridin-2-yl)ethanol dihydrochloride (84mg, 0.55mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt Salt (103mg, 0.54mmol) and N-hydroxy-7-azabenzotriazole (69mg, 0.51mmol) were dissolved in dichloromethane (4mL), cooled to 0℃, and N,N-diiso Propylethylamine (0.22mL, 1.3mmol), stirred at room temperature for 7h, the reaction solution was washed with water (5mL×3), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane) /Methanol (v/v)=20/1), 68 mg of pale yellow solid was obtained, and the yield was 51%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.55(t,J＝5.9Hz,1H),7.72(t,J＝7.8Hz,1H),7.34-7.40(m,1H),7.26(d,J＝7.7Hz,1H),7.10-7.14(m,1H),7.05-7.07(m,1H),7.03(t,J F-H＝74.9Hz,1H),6.89(d,J＝9.5Hz,1H),5.33-5.35(m,1H),4.64-4.72(m,1H),4.32-4.41(m,3H),4.06-4.10(m,1H),3.90(d,J＝6.9Hz,2H),3.37-3.52(m,2H),2.58-2.65(m,1H),2.03(s,3H),1.84-1.93(m,1H),1.33-1.36(m,3H),1.24-1.27(m,1H),0.55-0.60(m,2H),0.31-0.38(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.55 (t, J = 5.9 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.34 to 7.40 (m, 1H), 7.26 (d,J=7.7Hz,1H),7.10-7.14(m,1H),7.05-7.07(m,1H),7.03(t,J FH =74.9Hz,1H),6.89(d,J=9.5Hz ,1H),5.33-5.35(m,1H),4.64-4.72(m,1H),4.32-4.41(m,3H),4.06-4.10(m,1H),3.90(d,J=6.9Hz,2H ), 3.37-3.52 (m, 2H), 2.58-2.65 (m, 1H), 2.03 (s, 3H), 1.84-1.93 (m, 1H), 1.33-1.36 (m, 3H), 1.24-1.27 (m ,1H),0.55-0.60(m,2H),0.31-0.38(m,2H).
MS(ESI,pos.ion)m/z:504.30[M+H] +. MS(ESI,pos.ion)m/z:504.30[M+H] + .
实施例19：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((4-(羟基甲基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 19: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((4-(hydroxymethyl (Yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000081
Figure PCTCN2021090489-appb-000081
将化合物2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)异烟酸甲酯(79mg,0.15mmol)溶于四氢呋喃(6mL)中，在冰浴中加入硼氢化锂(48mg，2.20mmol)，室温反应4h后停止，加水(50mL)，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体36mg，收率48％。The compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)isonicotinate (79mg, 0.15mmol) was dissolved in tetrahydrofuran (6mL). Lithium borohydride (48mg, 2.20mmol) was added to the ice bath. The reaction was stopped after 4h at room temperature. Water (50mL) was added and acetic acid was used. Ethyl extraction (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1), 36 mg of white solid was obtained with a yield of 48%.
MS(ESI,pos.ion)m/z:490.20[M+H] +. MS(ESI,pos.ion)m/z:490.20[M+H] + .
实施例20：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((4-(2-羟丙基-2-基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 20: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((4-(2- Hydroxypropyl-2-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000082
Figure PCTCN2021090489-appb-000082
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(203mg,0.55mmol)，2-(2-(氨甲基)吡啶-4-基)异丙醇二盐酸盐(186mg,1.12mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(223mg,1.16mmol)和N-羟基-7-氮杂苯并三氮唑(115mg,0.85mmol)溶于二氯甲烷(6mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.5mL,3.0mmol)，室温搅拌21h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，合并有机相，用无水硫酸钠干燥，除去溶剂，剩余物进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得白色固体221mg，收率77％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (203mg, 0.55mmol) , 2-(2-(Aminomethyl)pyridin-4-yl)isopropanol dihydrochloride (186mg, 1.12mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (223mg, 1.16mmol) and N-hydroxy-7-azabenzotriazole (115mg, 0.85mmol) were dissolved in dichloromethane (6mL), cooled to 0℃, and N,N- Diisopropylethylamine (0.5mL, 3.0mmol), stirred at room temperature for 21h, washed with water (15mL), extracted with dichloromethane (5mL×3), combined the organic phases, dried with anhydrous sodium sulfate, removed the solvent, and left The substance was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) to obtain 221 mg of white solid, with a yield of 77%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.41(d,J＝5.2Hz,1H),7.64(s,1H),7.43(d,J＝3.9Hz,1H),7.08-7.12(m,2H),6.90-6.94(m,1H),6.75(t,J F-H＝75.7Hz,1H),4.50-4.65(m,1H),4.50-4.60(m,2H),4.09-4.13(m,1H),3.93(d,J＝6.8Hz,2H),3.65(d,J＝10.6Hz,1H),3.47-3.55(m,1H),2.67-2.74(m,1H),2.15(s,3H),2.08-2.15(m,1H),1.54(d,J＝3.4Hz,6H),1.27-1.34(m,1H),0.62-0.67(m,2H),0.36-0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.41 (d, J = 5.2 Hz, 1H), 7.64 (s, 1H), 7.43 (d, J = 3.9 Hz, 1H), 7.08-7.12 ( m, 2H), 6.90-6.94 (m, 1H), 6.75 (t, J FH = 75.7 Hz, 1H), 4.50-4.65 (m, 1H), 4.50-4.60 (m, 2H), 4.09-4.13 (m ,1H),3.93(d,J=6.8Hz,2H), 3.65(d,J=10.6Hz,1H), 3.47-3.55(m,1H), 2.67-2.74(m,1H), 2.15(s, 3H),2.08-2.15(m,1H),1.54(d,J=3.4Hz,6H),1.27-1.34(m,1H),0.62-0.67(m,2H),0.36-0.41(m,2H) .
MS(ESI,pos.ion)m/z:518.20[M+H] +. MS(ESI,pos.ion)m/z:518.20[M+H] + .
实施例21：(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((4-(2-羟基丙烷-2-基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 21: (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((4-(2-hydroxyl Propan-2-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000083
Figure PCTCN2021090489-appb-000083
将化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(100mg,0.27mmol)，2-(2-(氨基甲基)吡啶-4-基)异丙醇二盐酸盐(77mg,0.33mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(408mg,2.13mmol)和N-羟基-7-氮杂苯并三氮唑(87mg,0.64mmol)溶于二氯甲烷(5mL)中，0℃条件下冷却，滴加N,N-二异丙基乙胺(0.45mL,2.6mmol)，室温搅拌12h，加水(20mL)，用二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体91mg，收率64％。The compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100mg, 0.27mmol) , 2-(2-(Aminomethyl)pyridin-4-yl)isopropanol dihydrochloride (77mg, 0.33mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (408mg, 2.13mmol) and N-hydroxy-7-azabenzotriazole (87mg, 0.64mmol) were dissolved in dichloromethane (5mL), cooled at 0℃, and N, N-Diisopropylethylamine (0.45mL, 2.6mmol), stir at room temperature for 12h, add water (20mL), extract with dichloromethane (10mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate the solution Perform silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 91 mg of white solid with a yield of 64%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.45(d,J＝5.1Hz,1H),7.67(s,1H),7.19(d,J＝4.4Hz,1H),7.13(d,J＝8.1Hz,1H),6.91(s,1H),6.86(d,J＝8.3Hz,1H),6.63(t,J F-H＝75.6Hz,1H),4.78–4.84(m,1H),4.51–4.55(m,1H),4.41–4.46(m,1H),3.93–3.97(m,1H),3.88(d,J＝6.9Hz,2H),3.60–3.65(m,1H),3.32–3.43(m,1H),2.57–2.64(m,1H),2.37–2.45(m,1H),2.14(s,3H),1.55(s,3H),1.57(s,3H),1.25-1.37(m,1H),0.65-0.69(m,2H),0.36-0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.45 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 7.19 (d, J = 4.4 Hz, 1H), 7.13 (d, J =8.1Hz,1H),6.91(s,1H),6.86(d,J=8.3Hz,1H),6.63(t,J FH =75.6Hz,1H),4.78–4.84(m,1H),4.51– 4.55(m,1H), 4.41–4.46(m,1H), 3.93–3.97(m,1H), 3.88(d,J=6.9Hz,2H), 3.60–3.65(m,1H), 3.32–3.43( m, 1H), 2.57--2.64 (m, 1H), 2.37 - 2.45 (m, 1H), 2.14 (s, 3H), 1.55 (s, 3H), 1.57 (s, 3H), 1.25-1.37 (m, 1H), 0.65-0.69 (m, 2H), 0.36-0.39 (m, 2H).
MS(ESI,pos.ion)m/z:518.15[M+H] +. MS(ESI,pos.ion)m/z:518.15[M+H] + .
实施例22：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(2-羟基丙基-2-基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 22: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(2- Hydroxypropyl-2-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000084
Figure PCTCN2021090489-appb-000084
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(67mg,0.18mmol)，2-(6-(氨基甲基)吡啶-2-基)丙烷-2-羟基(93mg,0.56mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(103mg,0.54mmol)和N-羟基-7-氮杂苯并三氮唑(65mg,0.48mmol)溶于二氯甲烷(6mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌18h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体32mg，收率34％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (67mg, 0.18mmol) , 2-(6-(Aminomethyl)pyridin-2-yl)propane-2-hydroxy (93mg, 0.56mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt Salt (103mg, 0.54mmol) and N-hydroxy-7-azabenzotriazole (65mg, 0.48mmol) were dissolved in dichloromethane (6mL), cooled to 0℃, and N,N-diiso Propylethylamine (0.3mL, 2.0mmol), stirred at room temperature for 18h, added water (15mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 32 mg of white solid with a yield of 34%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.76(t,J＝7.8Hz,1H),7.49(d,J＝7.8Hz,1H),7.34(d,J＝7.7Hz,1H),7.09-7.12(m,2H),6.92-6.94(m,1H),6.74(t,J F-H＝75.7Hz,1H),4.50-4.60(m,3H)，4.09-4.13(m,1H),3.93(d,J＝6.9Hz,2H),3.63-3.68(m,1H),3.48-3.55(m,1H),2.66-2.73(m,1H),2.16(s,3H),2.03-2.12(m,1H),1.54(s,6H),1.27-1.35(m,1H),0.62-0.67(m,2H),0.37-0.40(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.76 (t, J = 7.8Hz, 1H), 7.49 (d, J = 7.8Hz, 1H), 7.34 (d, J = 7.7Hz, 1H) ,7.09-7.12(m,2H),6.92-6.94(m,1H),6.74(t,J FH =75.7Hz,1H),4.50-4.60(m,3H),4.09-4.13(m,1H), 3.93(d,J=6.9Hz,2H),3.63-3.68(m,1H),3.48-3.55(m,1H),2.66-2.73(m,1H),2.16(s,3H),2.03-2.12( m, 1H), 1.54 (s, 6H), 1.27-1.35 (m, 1H), 0.62-0.67 (m, 2H), 0.37-0.40 (m, 2H).
MS(ESI,pos.ion)m/z:518.20[M+H] +. MS(ESI,pos.ion)m/z:518.20[M+H] + .
实施例23：(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((4-(2-羟基丙烷-2-基)吡啶-2-基)甲基)-1-(甲磺酰基)吡咯烷-2-甲酰胺Example 23: (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((4-(2-hydroxypropan-2-yl )Pyridin-2-yl)methyl)-1-(methylsulfonyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000085
Figure PCTCN2021090489-appb-000085
步骤1：化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-(甲磺酰基)吡咯烷-2-羧酸甲酯的合成Step 1: Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxylic acid methyl Synthesis of esters
将化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐(418mg,1.1mmol)溶解在二氯甲烷(5mL)中，0℃条件下加入N,N-二异丙基乙胺(0.36mL,2.2mmol)和甲磺酰氯(0.13mL,1.7mmol)，室温搅拌4h后停止反应，加水(15mL)，二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：EtOAc(v)＝100％)，得到白色固体154mg，产率33％。Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (418mg, 1.1mmol) Dissolve in dichloromethane (5mL), add N,N-diisopropylethylamine (0.36mL, 2.2mmol) and methanesulfonyl chloride (0.13mL, 1.7mmol) at 0℃, stop the reaction after stirring at room temperature for 4h , Add water (15mL), extract with dichloromethane (10mL×3), dry the organic phase with anhydrous sodium sulfate, and perform silica gel column chromatography on the concentrated solution (eluent: EtOAc(v)=100%) to obtain a white solid 154mg, the yield is 33%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.11(d,J＝7.9Hz,1H),6.77-6.79(m,2H),6.59(t,J F-H＝71.0Hz,1H),4.63–4.67(m,1H),4.05–4.08(m,1H),3.86(d,J＝6.9Hz,2H),3.78(s,3H),3.38–3.46(m,1H),3.30–3.37(m,1H),3.08(s,3H),2.74–2.81(m,1H),2.04–2.13(m,1H),1.24–1.33(m,1H),0.63–0.68(m,2H),0.34–0.38(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.11 (d, J = 7.9Hz, 1H), 6.77-6.79 (m, 2H), 6.59 (t, J FH = 71.0Hz, 1H), 4.63- 4.67(m,1H),4.05–4.08(m,1H), 3.86(d,J=6.9Hz,2H), 3.78(s,3H), 3.38–3.46(m,1H), 3.30–3.37(m, 1H), 3.08(s, 3H), 2.74–2.81(m, 1H), 2.04–2.13(m, 1H), 1.24–1.33(m, 1H), 0.63–0.68(m, 2H), 0.34–0.38( m,2H).
MS(ESI,pos.ion)m/z:420.20[M+H] +. MS(ESI,pos.ion)m/z:420.20[M+H] + .
步骤2：化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-(甲磺酰基)吡咯烷-2-羧酸的合成Step 2: Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxylic acid synthesis
将化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-(甲磺酰基)吡咯烷-2-羧酸甲酯(151mg, 0.36mmol)溶解在四氢呋喃(5mL)中，加入一水合氢氧化锂(75mg,1.79mmol)和水(5mL)，45℃反应1h，加稀盐酸调节pH＝1，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，得白色固体143mg，产率98％。The compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxylic acid methyl ester ( 151mg, 0.36mmol) was dissolved in tetrahydrofuran (5mL), lithium hydroxide monohydrate (75mg, 1.79mmol) and water (5mL) were added, reacted at 45℃ for 1h, added dilute hydrochloric acid to adjust pH=1, and extracted with ethyl acetate ( 10 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 143 mg of white solid, with a yield of 98%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.10(d,J＝8.2Hz,1H),7.05(d,J＝1.7Hz,1H),6.90(dd,J＝8.2,1.8Hz,1H),6.73(t,J F-H＝74.9Hz,1H),4.49–4.53(m,1H),3.96–4.00(m,1H),3.93(d,J＝6.9Hz,2H),3.41–3.50(m,2H),3.08(s,3H),2.80–2.84(m,1H),2.09–2.17(m,1H),1.28-1.36(m,1H),0.62-0.67(m,2H),0.37-0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.10 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 6.90 (dd, J = 8.2, 1.8 Hz, 1H), 6.73(t, J FH = 74.9Hz, 1H), 4.49–4.53(m, 1H), 3.96–4.00(m, 1H), 3.93(d, J = 6.9Hz, 2H), 3.41–3.50( m,2H),3.08(s,3H),2.80-2.84(m,1H),2.09-2.17(m,1H),1.28-1.36(m,1H),0.62-0.67(m,2H),0.37- 0.41(m,2H).
MS(ESI,pos.ion)m/z:406.20[M+H] +. MS(ESI,pos.ion)m/z:406.20[M+H] + .
步骤3：化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((4-(2-羟基丙烷-2-基)吡啶-2-基)甲基)-1-(甲磺酰基)吡咯烷-2-甲酰胺的合成Step 3: Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((4-(2-hydroxypropan-2-yl )Pyridin-2-yl)methyl)-1-(methylsulfonyl)pyrrolidine-2-carboxamide
将化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-(甲磺酰基)吡咯烷-2-羧酸(66mg,0.16mmol)，2-(2-(氨基甲基)吡啶-4-基)异丙醇二盐酸盐(58mg,0.24mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156mg,0.81mmol)和N-羟基-7-氮杂苯并三氮唑(33mg,0.24mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.2mL,1.0mmol)，室温搅拌5h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到浅黄色固体87mg，收率96％。Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxylic acid (66mg, 0.16mmol), 2-(2-(aminomethyl)pyridin-4-yl)isopropanol dihydrochloride (58mg, 0.24mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Diimide hydrochloride (156mg, 0.81mmol) and N-hydroxy-7-azabenzotriazole (33mg, 0.24mmol) were dissolved in dichloromethane (5mL) and added to this solution at 0℃ Add N,N-diisopropylethylamine (0.2mL, 1.0mmol) dropwise to the mixture, stir at room temperature for 5h, add water (15mL), extract with dichloromethane (5mL×3), and dry the organic phase with anhydrous sodium sulfate. The solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 87 mg of pale yellow solid with a yield of 96%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.44(d,J＝5.2Hz,1H),7.54(br.s,1H),7.43(s,1H),7.25(d,J＝5.9Hz,1H),7.08(d,J＝8.0Hz,1H),6.80(s,1H),6.79(d,J＝10.3Hz,1H),6.59(t,J F-H＝75.6Hz,1H),4.47–4.65(m,3H),3.99–4.03(m,1H),3.85(d,J＝6.8Hz,2H),3.33–3.47(m,2H),3.02(s,3H),2.76–2.82(m,1H),2.25–2.33(m,1H),1.54(s,6H),1.25-1.32(m,1H),0.61-0.66(m,2H),0.32-0.36(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 8.44(d,J=5.2Hz,1H),7.54(br.s,1H),7.43(s,1H),7.25(d,J=5.9Hz ,1H), 7.08(d,J=8.0Hz,1H), 6.80(s,1H), 6.79(d,J=10.3Hz,1H), 6.59(t,J FH ＝75.6Hz,1H), 4.47– 4.65(m,3H),3.99–4.03(m,1H), 3.85(d,J=6.8Hz,2H),3.33–3.47(m,2H),3.02(s,3H),2.76–2.82(m, 1H), 2.25-2.33 (m, 1H), 1.54 (s, 6H), 1.25-1.32 (m, 1H), 0.61-0.66 (m, 2H), 0.32-0.36 (m, 2H).
MS(ESI,pos.ion)m/z:554.30[M+H] +. MS(ESI,pos.ion)m/z:554.30[M+H] + .
实施例24：化合物(2R)-1-乙酰基-N-(2-氨基-1-(2,4-二氟苯基)-2-氧代乙基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰胺Example 24: The compound (2R)-1-acetyl-N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-4-(3-(cyclopropyl) Methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000086
Figure PCTCN2021090489-appb-000086
步骤1：化合物2-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)-2-(2,4-二氟苯基)乙酸乙酯的合成Step 1: Compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido Synthesis of )-2-(2,4-difluorophenyl) ethyl acetate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸)(178mg,0.48mmol)，2-氨基-2-(2,4-二氟苯基)乙酸乙酯盐酸盐(149mg,0.59mmol)和N-羟基-7-氮杂苯并三氮唑(101mg,0.74mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(467mg,2.44mmol)和N,N-二异丙基乙胺(0.5mL,3.0mmol)，室温反应16h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/3)，得到白色固体147mg，收率54％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid) (178mg, 0.48mmol ), 2-amino-2-(2,4-difluorophenyl) ethyl acetate hydrochloride (149mg, 0.59mmol) and N-hydroxy-7-azabenzotriazole (101mg, 0.74mmol) Dissolve in dichloromethane (5mL), cool to 0°C, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (467mg, 2.44mmol) and N,N- Diisopropylethylamine (0.5mL, 3.0mmol), react at room temperature for 16h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate the solution. Separation by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/3) to obtain 147 mg of white solid with a yield of 54%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.33-7.44(m,1H),7.09-7.12(m,1H),6.82-6.91(m,4H),6.62(t,J F-H ＝75.6Hz,1H),5.71–5.74(m,1H),4.62–4.68(m,1H),4.17–4.27(m,2H),3.90–3.98(m,1H),3.88(d,J＝6.8Hz,2H),3.44–3.52(m,1H),3.28–3.38(m,1H),2.46–2.57(m,2H),2.10–2.19(m,3H),1.27-1.35(m,1H),1.20–1.23(m,3H),0.64-0.69(m,2H),0.37-0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.33-7.44 (m, 1H), 7.09-7.12 (m, 1H), 6.82-6.91 (m, 4H), 6.62 (t, J FH = 75.6Hz ,1H),5.71–5.74(m,1H),4.62–4.68(m,1H),4.17–4.27(m,2H),3.90–3.98(m,1H),3.88(d,J=6.8Hz,2H ), 3.44–3.52(m,1H), 3.28–3.38(m,1H), 2.46–2.57(m,2H), 2.10–2.19(m,3H), 1.27-1.35(m,1H), 1.20–1.23 (m, 3H), 0.64-0.69 (m, 2H), 0.37-0.39 (m, 2H).
MS(ESI,pos.ion)m/z:567.30[M+H] +. MS(ESI,pos.ion)m/z:567.30[M+H] + .
步骤2：化合物2-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)-2-(2,4-二氟苯基)乙酸的合成Step 2: Compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido )-2-(2,4-Difluorophenyl)acetic acid synthesis
将化合物2-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)-2-(2,4-二氟苯基)乙酸乙酯(140mg,0.25mmol)溶于四氢呋喃(5mL)和水(5mL)的混合溶剂中，再加入一水合氢氧化锂(54mg，1.29mmol)，50℃反应3h后停止，加浓盐酸调节溶液pH＝1，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到白色固体131mg，收率98％。The compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)- Ethyl 2-(2,4-difluorophenyl)acetate (140mg, 0.25mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (5mL), and then lithium hydroxide monohydrate (54mg, 1.29mmol) was added The reaction was stopped at 50°C for 3 hours. Concentrated hydrochloric acid was added to adjust the pH of the solution to 1, and the solution was extracted with ethyl acetate (5 mL×3). The organic phase was dried with anhydrous sodium sulfate and the solvent was removed to obtain a white solid of 131 mg with a yield of 98%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.43–7.53(m,1H),6.91–7.12(m,5H),6.53–6.94(m,1H),5.74–5.78(m,1H),4.54–4.68(m,1H),4.05–4.15(m,1H),3.89–3.95(m,2H),3.56–3.63(m,1H),3.44–3.52(m,1H),2.57–2.76(m,1H),2.03–2.13(m,4H),1.27-1.36(m,1H),0.61-0.67(m,2H),0.37-0.40(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.43 - 7.53 (m, 1H), 6.91 - 7.12 (m, 5H), 6.53 - 6.94 (m, 1H), 5.74 - 5.78 (m, 1H) ,4.54–4.68(m,1H),4.05–4.15(m,1H),3.89–3.95(m,2H),3.56–3.63(m,1H),3.44–3.52(m,1H),2.57–2.76( m, 1H), 2.03-2.13 (m, 4H), 1.27-1.36 (m, 1H), 0.61-0.67 (m, 2H), 0.37-0.40 (m, 2H).
MS(ESI,pos.ion)m/z:539.20[M+H] +. MS(ESI,pos.ion)m/z:539.20[M+H] + .
步骤3：化合物(2R)-1-乙酰基-N-(2-氨基-1-(2,4-二氟苯基)-2-氧代乙基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰胺的合成Step 3: Compound (2R)-1-acetyl-N-(2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-4-(3-(cyclopropyl) Synthesis of methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamide
将化合物2-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)-2-(2,4-二氟苯基)乙酸(130mg,0.24mmol)，氯化铵(132mg,2.4mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(242mg,1.26mmol)和N-羟基-7-氮杂苯并三氮唑(51mg,0.37mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温反应16h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/3)，得到白色固体37mg，收率29％。The compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)- 2-(2,4-Difluorophenyl)acetic acid (130mg, 0.24mmol), ammonium chloride (132mg, 2.4mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Hydrochloride (242mg, 1.26mmol) and N-hydroxy-7-azabenzotriazole (51mg, 0.37mmol) were dissolved in dichloromethane (5mL), and N was added dropwise to this solution at 0℃. , N-Diisopropylethylamine (0.4mL, 2.0mmol), react at room temperature for 16h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, The concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/3) to obtain 37 mg of white solid with a yield of 29%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.41-7.50(m,1H),7.05-7.14(m,2H),6.96-7.05(m,2H),6.88-6.95(m,1H),6.73(t,J F-H＝75.6Hz,1H),5.72(s,1H),4.44–4.52(m,1H),4.03–4.12(m,1H),3.92(d,J＝5.9Hz,1H),3.61–3.67(m,1H),3.43–3.55(m,1H),2.50–2.57(m,3H),3.13(m,3H),2.03–2.09(m,1H),1.31-1.40(m,1H),0.60-0.66(m,2H),0.35-0.40(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.41-7.50 (m, 1H), 7.05-7.14 (m, 2H), 6.96-7.05 (m, 2H), 6.88-6.95 (m, 1H) ,6.73(t,J FH =75.6Hz,1H),5.72(s,1H),4.44-4.52(m,1H),4.03-4.12(m,1H),3.92(d,J=5.9Hz,1H) ,3.61–3.67(m,1H),3.43–3.55(m,1H), 2.50–2.57(m,3H), 3.13(m,3H), 2.03–2.09(m,1H),1.31-1.40(m, 1H), 0.60-0.66 (m, 2H), 0.35-0.40 (m, 2H).
MS(ESI,pos.ion)m/z:538.15[M+H] +. MS(ESI,pos.ion)m/z:538.15[M+H] + .
实施例25：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺Example 25: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-lutidineamide
Figure PCTCN2021090489-appb-000087
Figure PCTCN2021090489-appb-000087
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(172mg,0.34mmol)，二甲胺盐酸盐(142mg,1.74mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(321mg,1.67mmol)和N-羟基-7-氮杂苯并三氮唑(72mg,0.53mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温反应12h，加水洗(15mL)，用二氯 甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体94mg，收率52％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl) picolinic acid (172mg, 0.34mmol), dimethylamine hydrochloride (142mg, 1.74mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (321mg , 1.67mmol) and N-hydroxy-7-azabenzotriazole (72mg, 0.53mmol) dissolved in dichloromethane (5mL), add N,N-diiso to this solution dropwise at 0℃ Propylethylamine (0.4mL, 2.0mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to a silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 94 mg of white solid with a yield of 52%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.92(t,J＝7.9Hz,1H),7.60(d,J＝7.9Hz,1H),7.45(d,J＝7.7Hz,1H),7.12(d,J＝8.2Hz,1H),7.09(s,1H),6.92–6.94(m,1H),6.75(t,J F-H＝75.7Hz,1H),4.48–4.65(m,3H),4.09–4.13(m,1H),3.93(d,J＝6.8Hz,2H),3.66(t,J＝10.6Hz,1H),3.49–3.56(m,1H),3.10(s,3H),3.01(s,3H),2.66–2.73(m,1H),2.19(s,3H),2.06–2.16(m,1H),1.27–1.33(m,1H),0.62–0.67(m,2H),0.36–0.40(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.92 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H) ,7.12(d,J=8.2Hz,1H),7.09(s,1H),6.92–6.94(m,1H),6.75(t,J FH =75.7Hz,1H),4.48–4.65(m,3H) ,4.09–4.13(m,1H),3.93(d,J=6.8Hz,2H), 3.66(t,J=10.6Hz,1H), 3.49–3.56(m,1H), 3.10(s,3H), 3.01(s,3H), 2.66–2.73(m,1H), 2.19(s,3H), 2.06–2.16(m,1H), 1.27–1.33(m,1H), 0.62–0.67(m,2H), 0.36--0.40 (m, 2H).
MS(ESI,pos.ion)m/z:531.10[M+H] +. MS(ESI,pos.ion)m/z:531.10[M+H] + .
实施例26：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸Example 26: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)picolinic acid
Figure PCTCN2021090489-appb-000088
Figure PCTCN2021090489-appb-000088
步骤1：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸乙酯的合成Step 1: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)ethyl picolinate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(201mg,0.54mmol)，6-(氨甲基)吡啶甲酸乙酯盐酸盐(142mg,0.66mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(516mg,2.69mmol)和N-羟基-7-氮杂苯并三氮唑(111mg,0.82mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.6mL,4.0mmol)，室温反应16h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色粘稠固体216mg，收率74％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (201mg, 0.54mmol) , 6-(Aminomethyl) ethyl picolinate hydrochloride (142mg, 0.66mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (516mg, 2.69mmol) ) And N-hydroxy-7-azabenzotriazole (111mg, 0.82mmol) were dissolved in dichloromethane (5mL), and N,N-diisopropylethyl was added dropwise to this solution at 0℃ Amine (0.6mL, 4.0mmol), react at room temperature for 16h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (Eluent: dichloromethane/methanol (v/v)=40/1) to obtain 216 mg of a white viscous solid with a yield of 74%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.02(d,J＝7.5Hz,1H),7.83(t,J＝7.7Hz,1H),7.56(d,J＝7.7Hz,1H),7.11(d,J＝8.1Hz,1H),6.89(s,1H),6.86(d,J＝8.2Hz,1H),6.62(t,J F-H＝75.7Hz,1H),4.59–4.77(m,3H),4.47(q,J＝7.1Hz,2H),3.95–4.00(m,1H),3.88(d,J＝6.9Hz,2H),3.61(t,J＝10.6Hz,1H),3.32–3.39(m,1H),2.58–2.65(m,1H),2.40–2.48(m,1H),2.17(s,3H),1.44(t,J＝7.2Hz,3H),1.27–1.33(m,1H),0.64–0.69(m,2H),0.35–0.38(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 8.02(d,J=7.5Hz,1H), 7.83(t,J=7.7Hz,1H), 7.56(d,J=7.7Hz,1H), 7.11 (d, J = 8.1 Hz, 1H), 6.89 (s, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.62 (t, J FH = 75.7 Hz, 1H), 4.59–4.77 (m, 3H), 4.47 (q, J = 7.1 Hz, 2H), 3.95–4.00 (m, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.61 (t, J = 10.6 Hz, 1H), 3.32– 3.39(m,1H), 2.58–2.65(m,1H), 2.40–2.48(m,1H), 2.17(s,3H), 1.44(t,J=7.2Hz,3H), 1.27–1.33(m, 1H), 0.64--0.69 (m, 2H), 0.35--0.38 (m, 2H).
MS(ESI,pos.ion)m/z:532.30[M+H] +. MS(ESI,pos.ion)m/z:532.30[M+H] + .
步骤2：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸的合成Step 2: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)picolinic acid
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸乙酯(232mg,0.44mmol)溶于四氢呋喃(6mL)和水(4mL)的混合溶剂中，加入一水合氢氧化锂(72mg,1.72mmol)，50℃反应3h后停止，加盐酸调节溶液pH＝1，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到白色固体213mg，收率97％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Ethyl picolinate (232 mg, 0.44 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (4 mL), lithium hydroxide monohydrate (72 mg, 1.72 mmol) was added, and the reaction was stopped at 50°C for 3 hours. The solution was adjusted to pH=1 with hydrochloric acid, extracted with ethyl acetate (5 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 213 mg of white solid with a yield of 97%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.06(d,J＝7.5Hz,1H),7.99(t,J＝7.7Hz,1H),7.75(d,J＝7.7Hz,1H),7.11(d,J＝8.2Hz,1H),7.09(s,1H),6.92–6.94(m,1H),6.74(t,J F-H＝75.7Hz,1H),4.51–4.73(m,3H), 4.09–4.14(m,1H),3.93(d,J＝6.9Hz,2H),3.66(t,J＝10.6Hz,1H),3.49–3.55(m,1H),2.67–2.73(m,1H),2.16(s,3H),2.07–2.12(m,1H),1.27–1.35(m,1H),0.62–0.67(m,2H),0.37–0.40(m,2H). 1 H NMR(400MHz,CD 3 OD)δ(ppm): 8.06(d,J=7.5Hz,1H),7.99(t,J=7.7Hz,1H),7.75(d,J=7.7Hz,1H) ,7.11(d,J=8.2Hz,1H),7.09(s,1H),6.92–6.94(m,1H),6.74(t,J FH =75.7Hz,1H),4.51–4.73(m,3H) , 4.09–4.14(m,1H), 3.93(d,J=6.9Hz,2H), 3.66(t,J=10.6Hz,1H), 3.49–3.55(m,1H), 2.67–2.73(m,1H ), 2.16 (s, 3H), 2.07-2.12 (m, 1H), 1.27-1.35 (m, 1H), 0.62-0.67 (m, 2H), 0.37-0.40 (m, 2H).
MS(ESI,pos.ion)m/z:504.30[M+H] +. MS(ESI,pos.ion)m/z:504.30[M+H] + .
实施例27：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶酰胺Example 27: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)pyridine amide
Figure PCTCN2021090489-appb-000089
Figure PCTCN2021090489-appb-000089
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(101mg,0.20mmol)，氯化铵(112mg,2.09mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(96mg,0.50mmol)和N-羟基-7-氮杂苯并三氮唑(67mg,0.49mmol)溶于二氯甲烷(6mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.2mL,1.0mmol)，室温搅拌6h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体73mg，收率72％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (101mg, 0.20mmol), ammonium chloride (112mg, 2.09mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (96mg, 0.50mmol) ) And N-hydroxy-7-azabenzotriazole (67mg, 0.49mmol) were dissolved in dichloromethane (6mL), and N,N-diisopropylethyl was added dropwise to this solution at 0℃. Amine (0.2mL, 1.0mmol), stirred at room temperature for 6h, added water (15mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v)=15/1) to obtain 73 mg of white solid with a yield of 72%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.01(d,J＝7.8Hz,1H),7.95(t,J＝7.6Hz,1H),7.65(d,J＝7.6Hz,1H),7.08-7.12(m,2H),6.91-6.95(m,1H),6.74(t,J F-H＝75.7Hz,1H),4.54-4.71(m,3H),4.09-4.13(m,1H),3.93(d,J＝6.9Hz,2H),3.63-3.68(m,1H),3.47-3.56(m,1H),2.66-2.73(m,1H),2.16(s,3H),2.03-2.13(m,1H),1.27-1.35(m,1H),0.62-0.67(m,2H),0.34-0.40(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.01 (d, J = 7.8Hz, 1H), 7.95 (t, J = 7.6Hz, 1H), 7.65 (d, J = 7.6Hz, 1H) ,7.08-7.12(m,2H),6.91-6.95(m,1H),6.74(t,J FH =75.7Hz,1H),4.54-4.71(m,3H),4.09-4.13(m,1H), 3.93(d,J=6.9Hz,2H),3.63-3.68(m,1H),3.47-3.56(m,1H),2.66-2.73(m,1H),2.16(s,3H),2.03-2.13( m,1H),1.27-1.35(m,1H),0.62-0.67(m,2H),0.34-0.40(m,2H);
MS(ESI,pos.ion)m/z:503.30[M+H] +. MS(ESI,pos.ion)m/z:503.30[M+H] + .
实施例28：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-甲基吡啶酰胺Example 28: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-picolineamide
Figure PCTCN2021090489-appb-000090
Figure PCTCN2021090489-appb-000090
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(97mg,0.19mmol)，甲胺盐酸盐(81mg,1.20mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(86mg,0.45mmol)和N-羟基-7-氮杂苯并三氮唑(56mg,0.41mmol)溶于二氯甲烷(6mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.2mL,1.0mmol)，室温搅拌20h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体58mg，收率58％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl) picolinic acid (97mg, 0.19mmol), methylamine hydrochloride (81mg, 1.20mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg, 0.45mmol) and N-hydroxy-7-azabenzotriazole (56mg, 0.41mmol) were dissolved in dichloromethane (6mL). Add N,N-diisopropyl to this solution at 0℃. Ethylethylamine (0.2mL, 1.0mmol), stirred at room temperature for 20h, added water (15mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography After separation (eluent: dichloromethane/methanol (v/v)=15/1), 58 mg of white solid was obtained with a yield of 58%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.91-7.98(m,2H),7.60(d,J＝7.3Hz,1H),7.08-7.12(m,2H), 6.92-6.94(m,1H),6.74(t,J F-H＝75.7Hz,1H),4.51-4.61(m,3H),4.07-4.17(m,1H),3.92(d,J＝6.6Hz,2H),3.61-3.72(m,1H),3.46-3.57(m,1H),2.97(s,3H),2.65-2.76(m,1H),2.16(s,3H),2.06-2.14(m,1H),1.27-1.34(m,1H),0.62-0.66(m,2H),0.36-0.40(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.91-7.98 (m, 2H), 7.60 (d, J = 7.3Hz, 1H), 7.08-7.12 (m, 2H), 6.92-6.94 (m ,1H),6.74(t,J FH =75.7Hz,1H),4.51-4.61(m,3H),4.07-4.17(m,1H),3.92(d,J=6.6Hz,2H),3.61-3.72 (m,1H),3.46-3.57(m,1H),2.97(s,3H),2.65-2.76(m,1H),2.16(s,3H),2.06-2.14(m,1H),1.27-1.34 (m,1H),0.62-0.66(m,2H),0.36-0.40(m,2H);
MS(ESI,pos.ion)m/z:517.30[M+H] +. MS(ESI,pos.ion)m/z:517.30[M+H] + .
实施例29：化合物2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基异烟酰胺Example 29: Compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-dimethylisonicotinamide
Figure PCTCN2021090489-appb-000091
Figure PCTCN2021090489-appb-000091
步骤1：化合物2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)异烟酸甲酯的合成Step 1: Compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)isonicotinate methyl ester
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(103mg,0.28mmol)，2-(氨基甲基)异烟酸甲酯(102mg,0.61mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(113mg,0.59mmol)和N-羟基-7-氮杂苯并三氮唑(65mg,0.48mmol)溶于二氯甲烷(6mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌17h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到淡黄色液体103mg，收率71％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (103mg, 0.28mmol) , 2-(Aminomethyl)isonicotinic acid methyl ester (102mg, 0.61mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (113mg, 0.59mmol) and N-hydroxy-7-azabenzotriazole (65mg, 0.48mmol) was dissolved in dichloromethane (6mL), cooled to 0℃, and N,N-diisopropylethylamine (0.3mL, 2.0 mmol), stirred at room temperature for 17h, added water (15mL), extracted with dichloromethane (5mL×3), dried the organic phase with anhydrous sodium sulfate, removed the solvent, and separated the concentrated solution by silica gel column chromatography (eluent: dichloro Methane/methanol (v/v)=15/1), 103 mg of pale yellow liquid was obtained, and the yield was 71%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.67-8.70(m,1H),7.96(s,1H),7.80-7.81(m,1H),7.09-7.12(m,2H),6.93-6.95(m,1H),6.74(t,J F-H＝75.7Hz,1H),4.52-4.66(m,3H),4.09-4.14(m,1H),3.93(s,3H),3.93(d,J＝4.6Hz,2H),3.63-3.68(m,1H),3.47-3.57(m,1H),2.69-2.76(m,1H),2.15(s,3H),2.07-2.15(m,1H),1.27-1.33(m,1H),0.62-0.66(m,2H),0.32-0.40(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.67-8.70 (m, 1H), 7.96 (s, 1H), 7.80-7.81 (m, 1H), 7.09-7.12 (m, 2H), 6.93 -6.95(m,1H),6.74(t,J FH =75.7Hz,1H),4.52-4.66(m,3H),4.09-4.14(m,1H),3.93(s,3H),3.93(d, J = 4.6Hz, 2H), 3.63-3.68 (m, 1H), 3.47-3.57 (m, 1H), 2.69-2.76 (m, 1H), 2.15 (s, 3H), 2.07-2.15 (m, 1H) ,1.27-1.33(m,1H),0.62-0.66(m,2H),0.32-0.40(m,2H).
MS(ESI,pos.ion)m/z:518.30[M+H] +. MS(ESI,pos.ion)m/z:518.30[M+H] + .
步骤2：化合物2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)异烟酸的合成Step 2: Compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)isonicotinic acid
将化合物2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)异烟酸甲酯(97mg,0.19mmol)溶于四氢呋喃(6mL)和水(4mL)的混合溶剂中，加入一水合氢氧化锂(43mg,1.03mmol)，50℃反应2h后停止，加盐酸调节溶液pH＝1，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到白色固体92mg，收率97％。The compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)isonicotinate (97mg, 0.19mmol) was dissolved in a mixed solvent of tetrahydrofuran (6mL) and water (4mL), lithium hydroxide monohydrate (43mg, 1.03mmol) was added, and the reaction was stopped at 50°C for 2h. Add hydrochloric acid to adjust the pH of the solution to 1, extract with ethyl acetate (5 mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent to obtain 92 mg of white solid, with a yield of 97%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.66-8.69(m,1H),7.96(s,1H),7.82(d,J＝4.8Hz,1H),7.05-7.12(m,2H),6.91-6.95(m,1H),6.74(t,J F-H＝75.7Hz,1H),4.52-4.69(m,3H),4.09-4.13(m,1H),3.92(d,J＝6.8Hz,2H),3.61-3.67(m,1H),3.47-3.56(m,1H),2.69-2.75(m,1H),2.13-2.23(m,1H),2.15(s,3H),1.24-1.35(m,1H),0.61-0.66(m,2H),0.35-0.39(m,2H). 1 H NMR(400MHz,CD 3 OD)δ(ppm):8.66-8.69(m,1H),7.96(s,1H),7.82(d,J=4.8Hz,1H),7.05-7.12(m,2H) ),6.91-6.95(m,1H),6.74(t,J FH =75.7Hz,1H),4.52-4.69(m,3H),4.09-4.13(m,1H),3.92(d,J=6.8Hz ,2H),3.61-3.67(m,1H),3.47-3.56(m,1H),2.69-2.75(m,1H),2.13-2.23(m,1H),2.15(s,3H),1.24-1.35 (m, 1H), 0.61-0.66 (m, 2H), 0.35-0.39 (m, 2H).
MS(ESI,pos.ion)m/z:504.10[M+H] +. MS(ESI,pos.ion)m/z:504.10[M+H] + .
步骤3：化合物2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基异烟酰胺的合成Step 3: Compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)-N,N-dimethylisonicotinamide
将化合物2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)异烟酸 (92mg,0.18mmol)，二甲胺盐酸盐(71mg,0.87mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(76mg,0.40mmol)和N-羟基-7-氮杂苯并三氮唑(46mg,0.34mmol)溶于二氯甲烷(6mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.2mL,1.0mmol)，室温搅拌18h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体71mg，收率73％。The compound 2-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)isonicotinic acid (92mg, 0.18mmol), dimethylamine hydrochloride (71mg, 0.87mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 76mg, 0.40mmol) and N-hydroxy-7-azabenzotriazole (46mg, 0.34mmol) dissolved in dichloromethane (6mL), cooled to 0℃, added N,N-diisopropylethyl Amine (0.2mL, 1.0mmol), stirred at room temperature for 18h, added water (15mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v)=15/1) to obtain 71 mg of white solid with a yield of 73%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.59(d,J＝5.0Hz,1H),7.55(s,1H),7.32(d,J＝5.0Hz,1H),7.05-7.12(m,2H),6.92-6.94(m,1H),6.75(t,J F-H＝75.7Hz,1H),4.49-4.61(m,3H),4.09-4.13(m,1H),3.94(d,J＝6.8Hz,2H),3.63-3.68(m,1H),3.48-3.54(m,1H),3.12(s,3H),2.96(s,3H),2.66-2.73(m,1H),2.15(s,3H),2.05-2.13(m,1H),1.26-1.33(m,1H),0.63-0.66(m,2H),0.37-0.40(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.59 (d, J = 5.0 Hz, 1H), 7.55 (s, 1H), 7.32 (d, J = 5.0 Hz, 1H), 7.05-7.12 ( m, 2H), 6.92-6.94 (m, 1H), 6.75 (t, J FH = 75.7Hz, 1H), 4.49-4.61 (m, 3H), 4.09-4.13 (m, 1H), 3.94 (d, J ＝6.8Hz, 2H), 3.63-3.68(m, 1H), 3.48-3.54(m, 1H), 3.12(s, 3H), 2.96(s, 3H), 2.66-2.73(m, 1H), 2.15( s, 3H), 2.05-2.13 (m, 1H), 1.26-1.33 (m, 1H), 0.63-0.66 (m, 2H), 0.37-0.40 (m, 2H).
MS(ESI,pos.ion)m/z:531.25[M+H] +. MS(ESI,pos.ion)m/z:531.25[M+H] + .
实施例30：化合物6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺二盐酸盐Example 30: Compound 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl )-N,N-lutidine amide dihydrochloride
Figure PCTCN2021090489-appb-000092
Figure PCTCN2021090489-appb-000092
步骤1：化合物(2R)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸的合成Step 1: Compound (2R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid Synthesis
将化合物(2R)-1-叔丁基-2-甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(362mg,0.82mmol)溶于四氢呋喃(3mL)和水(5mL)的混合溶剂中，再加入一水合氢氧化锂(176mg,4.2mmol)，50℃反应2.5h后停止，加盐酸调节溶液pH＝4，再用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到白色固体338mg，收率96％。The compound (2R)-1-tert-butyl-2-methyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2- Dicarboxylate (362mg, 0.82mmol) was dissolved in a mixed solvent of tetrahydrofuran (3mL) and water (5mL), and then lithium hydroxide monohydrate (176mg, 4.2mmol) was added. The reaction was stopped at 50°C for 2.5 hours, and hydrochloric acid was added. The pH of the solution was adjusted to 4, and then extracted with ethyl acetate (10 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 338 mg of white solid with a yield of 96%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.10(d,J＝8.2Hz,1H),7.03(s,1H),6.88-6.90(m,1H),6.73(t,J F-H＝75.7Hz,1H),4.31–4.37(m,1H),3.92–3.99(m,1H),3.93(d,J＝6.9Hz,2H),3.35–3.45(m,2H),2.69–2.74(m,1H),1.87–1.96(m,1H),1.44–1.46(m,9H),1.29-1.36(m,1H),0.62-0.66(m,2H),0.37-0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.10 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.88-6.90 (m, 1H), 6.73 (t, J FH = 75.7Hz, 1H), 4.31–4.37(m, 1H), 3.92–3.99(m, 1H), 3.93(d, J=6.9Hz, 2H), 3.35–3.45(m, 2H), 2.69–2.74(m ,1H), 1.87-1.96(m,1H), 1.44-1.46(m,9H), 1.29-1.36(m,1H), 0.62-0.66(m,2H), 0.37-0.41(m,2H).
MS(ESI,pos.ion)m/z:450.20[M+Na] +. MS(ESI,pos.ion)m/z:450.20[M+Na] + .
步骤2：化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((6-(二甲基氨基甲酰基)吡啶-2-基)甲基)氨基甲酰基)吡咯烷-1-羧酸叔丁酯的合成Step 2: Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((6-(dimethylcarbamoyl) Synthesis of (pyridin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester
将化合物(2R)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(334mg,0.78mmol)，6-(氨基甲基)-N,N-二甲基吡啶酰胺二盐酸盐(238mg,0.94mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(746mg,3.89mmol)和N-羟基-7-氮杂苯并三氮唑(162mg,1.19mmol)溶于二氯甲烷(10mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.8mL,5.0mmol)，室温反应12h，加水洗(15mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到浅黄色粘稠固体356mg，收率77％。Compound (2R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (334mg , 0.78mmol), 6-(aminomethyl)-N,N-dimethylpyridine amide dihydrochloride (238mg, 0.94mmol), 1-ethyl-(3-dimethylaminopropyl) carbonyl Diimine hydrochloride (746 mg, 3.89 mmol) and N-hydroxy-7-azabenzotriazole (162 mg, 1.19 mmol) were dissolved in dichloromethane (10 mL), and added to this solution at 0°C N,N-diisopropylethylamine (0.8mL, 5.0mmol) was added dropwise, reacted at room temperature for 12h, washed with water (15mL), and then extracted with dichloromethane (5mL×3), and the organic phase was dried with anhydrous sodium sulfate. The solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 356 mg of a light yellow viscous solid with a yield of 77%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.75–7.81(m,1H),7.49–7.57(m,1H),7.33–7.40(m,1H),7.11(d,J＝8.1Hz,1H),6.80–6.86(m,2H),6.61(t,J F-H＝75.7Hz,1H),4.60–4.70(m,2H),4.34–4.49(m,1H),4.02–4.24(m,1H),3.87(d,J＝6.8Hz,2H),3.37–3.36(m,2H),3.15(s,3H),3.06(s,3H),2.61–2.75(m,1H),2.15 –2.39(m,1H),1.38–1.49(m,9H),1.27–1.36(m,1H),0.64–0.68(m,2H),0.35–0.39(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.75–7.81(m,1H), 7.49–7.57(m,1H), 7.33–7.40(m,1H), 7.11(d,J=8.1Hz, 1H), 6.80–6.86(m, 2H), 6.61(t, J FH = 75.7Hz, 1H), 4.60–4.70(m, 2H), 4.34–4.49(m, 1H), 4.02–4.24(m, 1H ), 3.87(d,J=6.8Hz,2H), 3.37–3.36(m,2H),3.15(s,3H),3.06(s,3H),2.61–2.75(m,1H),2.15 –2.39( m, 1H), 1.38-1.49 (m, 9H), 1.27-1.36 (m, 1H), 0.64--0.68 (m, 2H), 0.35--0.39 (m, 2H).
MS(ESI,pos.ion)m/z:589.20[M+H] +. MS(ESI,pos.ion)m/z:589.20[M+H] + .
步骤3：化合物6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺二盐酸盐的合成Step 3: Compound 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl) Synthesis of -N,N-lutidine amide dihydrochloride
将化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((6-(二甲基氨基甲酰基)吡啶-2-基)甲基)氨基甲酰基)吡咯烷-1-羧酸叔丁酯(350mg,0.59mmol)溶解于甲醇(5mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(5mL)，室温搅拌2h，除去溶剂，得到白色固体332mg，收率97％。The compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((6-(dimethylcarbamoyl)pyridine- 2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 0.59mmol) was dissolved in methanol (5mL), and 4mol/L HCl in ethyl acetate (5mL) was added, After stirring for 2 hours at room temperature, the solvent was removed to obtain 332 mg of white solid with a yield of 97%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.08(t,J＝7.8Hz,1H),7.61(d,J＝7.6Hz,2H),7.14(d,J＝8.2Hz,1H),7.08(s,1H),6.93(d,J＝9.9Hz,1H),6.76(t,J F-H＝75.5Hz,1H),4.64-4.73(m,2H),4.55-4.60(m,1H),3.94(d,J＝6.9Hz,2H),3.78-3.83(m,1H),3.66-3.76(m,1H),3.34-3.42(m,1H),3.10(s,3H),3.02(s,3H),2.89-2.97(m,1H),2.12-2.21(m,1H),1.28-1.37(m,1H),0.63-0.67(m,2H),0.37-0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.08 (t, J = 7.8Hz, 1H), 7.61 (d, J = 7.6Hz, 2H), 7.14 (d, J = 8.2Hz, 1H) ,7.08(s,1H),6.93(d,J=9.9Hz,1H),6.76(t,J FH =75.5Hz,1H),4.64-4.73(m,2H),4.55-4.60(m,1H) ,3.94(d,J=6.9Hz,2H),3.78-3.83(m,1H),3.66-3.76(m,1H),3.34-3.42(m,1H),3.10(s,3H),3.02(s , 3H), 2.89-2.97 (m, 1H), 2.12-2.21 (m, 1H), 1.28-1.37 (m, 1H), 0.63-0.67 (m, 2H), 0.37-0.41 (m, 2H).
MS(ESI,pos.ion)m/z:489.30[M+H-2HCl] +. MS(ESI,pos.ion)m/z:489.30[M+H-2HCl] + .
实施例31：6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-乙基吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺和Example 31: 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-ethylpyrrolidine-2-formyl (Amino) methyl) -N,N-lutidine amide and
实施例32：6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-乙烯基吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺Example 32: 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-vinylpyrrolidine-2-formyl (Amino)methyl)-N,N-lutidineamide
实施例31：
Figure PCTCN2021090489-appb-000093
和实施例32：
Figure PCTCN2021090489-appb-000094
Example 31:
Figure PCTCN2021090489-appb-000093
And Example 32:
Figure PCTCN2021090489-appb-000094
将化合物6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺二盐酸盐(74mg,0.13mmol)和对甲苯磺酸(4mg,0.023mmol)溶解于乙醇(3mL)溶液中，加入40％乙醛水溶液(0.15mL)，50℃加热反应50min，冷却后加入硼氢化钠室继续反应2h，除去溶剂，加入水(3mL)，乙酸乙酯萃取(5mL×3)，无水硫酸钠干燥，浓缩后经硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-乙基吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺(实施例31)，浅黄色粘稠固体26mg，收率38％，和6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-乙烯基吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺(实施例32)，浅黄色粘稠固体12mg，收率17％。The compound 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)-N , N-lutidine amide dihydrochloride (74mg, 0.13mmol) and p-toluenesulfonic acid (4mg, 0.023mmol) were dissolved in ethanol (3mL) solution, and 40% acetaldehyde aqueous solution (0.15mL) was added, 50 The reaction was heated at ℃ for 50min, after cooling, added to the sodium borohydride chamber to continue the reaction for 2h, remove the solvent, add water (3mL), extract with ethyl acetate (5mL×3), dry with anhydrous sodium sulfate, concentrate and separate by silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v)=40/1) to obtain 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) (Phenyl)phenyl)-1-ethylpyrrolidine-2-carboxamido)methyl)-N,N-dimethylpyridineamide (Example 31), light yellow viscous solid 26mg, yield 38%, And 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-vinylpyrrolidine-2-carboxamido)methyl Yl)-N,N-lutidine amide (Example 32), light yellow viscous solid 12 mg, yield 17%.
实施例31： 1H NMR(400MHz,CDCl 3)δ(ppm):7.76(t,J＝7.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.23(d,J＝7.8Hz,1H),7.05(d,J＝8.6Hz,1H),6.84(d,J＝6.3Hz,1H),6.83(s,1H),6.60(t,J F-H＝75.7Hz,1H),4.51-4.68(m,2H),3.84(d,J＝6.9Hz,2H),3.32-3.40(m,2H),3.24-3.30(m,1H),3.13(s,3H),3.03(s,3H),2.88-2.97(m,1H),2.71-2.81(m,2H),2.48-2.59(m,1H),2.22-2.25(m,1H),1.28-1.37(m,1H),1.13(t,J＝7.1Hz,3H),0.62-0.66(m,2H),0.32-0.36(m,2H). Example 31: 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.76 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz ,1H),7.05(d,J=8.6Hz,1H),6.84(d,J=6.3Hz,1H),6.83(s,1H),6.60(t,J FH =75.7Hz,1H),4.51- 4.68(m,2H),3.84(d,J=6.9Hz,2H),3.32-3.40(m,2H),3.24-3.30(m,1H),3.13(s,3H),3.03(s,3H) ,2.88-2.97(m,1H),2.71-2.81(m,2H),2.48-2.59(m,1H),2.22-2.25(m,1H),1.28-1.37(m,1H),1.13(t, J = 7.1Hz, 3H), 0.62-0.66 (m, 2H), 0.32-0.36 (m, 2H).
MS(ESI,pos.ion)m/z:517.20[M+H] +. MS(ESI,pos.ion)m/z:517.20[M+H] + .
实施例32： 1H NMR(400MHz,CDCl 3)δ(ppm):7.78(t,J＝7.8Hz,1H),7.55(d,J＝7.6Hz,1H),7.32(d,J＝7.8Hz,1H),7.11(d,J＝8.5Hz,1H),6.82(s,1H),6.81(d,J＝6.3Hz,1H),6.62(t,J F-H＝75.7Hz,1H), 5.30-5.45(m,1H),4.76-4.88(m,2H),4.42(d,J＝15.8Hz,1H),3.93-3.97(m,1H),3.88(d,J＝6.8Hz,2H),3.36-3.45(m,1H),3.13-3.21(m,1H),3.13(s,3H),3.05(s,3H),2.58-2.68(m,2H),2.19-2.25(m,1H),2.00-2.05(m,1H),1.28-1.37(m,1H),0.64-0.69(m,2H),0.36-0.40(m,2H). Example 32: 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.78 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.8 Hz ,1H),7.11(d,J=8.5Hz,1H),6.82(s,1H),6.81(d,J=6.3Hz,1H),6.62(t,J FH =75.7Hz,1H), 5.30- 5.45(m,1H),4.76-4.88(m,2H), 4.42(d,J=15.8Hz,1H),3.93-3.97(m,1H), 3.88(d,J=6.8Hz,2H), 3.36 -3.45(m,1H),3.13-3.21(m,1H),3.13(s,3H),3.05(s,3H),2.58-2.68(m,2H),2.19-2.25(m,1H),2.00 -2.05 (m, 1H), 1.28-1.37 (m, 1H), 0.64-0.69 (m, 2H), 0.36-0.40 (m, 2H).
MS(ESI,pos.ion)m/z:515.35[M+H] +. MS(ESI,pos.ion)m/z:515.35[M+H] + .
实施例33：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-乙基吡啶酰胺Example 33: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl (Acylamino)methyl)-N-ethylpyridineamide
Figure PCTCN2021090489-appb-000095
Figure PCTCN2021090489-appb-000095
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.2mmol)，乙胺盐酸盐(163mg,2.0mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.0mmol)和N-羟基-7-氮杂苯并三氮唑(41mg,0.3mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体58mg，收率55％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl) picolinic acid (100mg, 0.2mmol), ethylamine hydrochloride (163mg, 2.0mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (192mg, 1.0mmol) and N-hydroxy-7-azabenzotriazole (41mg, 0.3mmol) were dissolved in dichloromethane (5mL), and N,N-diisopropyl was added dropwise to this solution at 0℃ Ethylethylamine (0.4mL, 2.0mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 58 mg of white solid with a yield of 55%.
1H NMR(400MHz,CDCl 3)δ(ppm):9.00(br.s,1H),8.65(s,1H),8.12(d,J＝7.1Hz,1H),7.82(br.s,1H),7.38(d,J＝7.1Hz,1H),7.13(d,J＝7.6Hz,1H),6.87–6.93(m,2H),6.62(t,J F-H＝75.7Hz,1H),4.81–4.86(m,1H),4.58–4.71(m,2H),3.91–4.00(m,1H),3.89(d,J＝7.3Hz,2H),3.49–3.67(m,2H),3.44–3.50(m,1H),3.29–3.38(m,1H),2.77–2.86(m,1H),2.47–2.55(m,1H),2.18(s,3H),1.26–1.35(m,4H),0.61–0.70(m,2H),0.32–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.00 (br.s, 1H), 8.65 (s, 1H), 8.12 (d, J = 7.1Hz, 1H), 7.82 (br.s, 1H) ,7.38(d,J=7.1Hz,1H),7.13(d,J=7.6Hz,1H), 6.87–6.93(m,2H), 6.62(t,J FH =75.7Hz,1H), 4.81–4.86 (m,1H),4.58–4.71(m,2H),3.91–4.00(m,1H), 3.89(d,J=7.3Hz,2H), 3.49–3.67(m,2H),3.44–3.50(m ,1H), 3.29–3.38(m,1H), 2.77–2.86(m,1H), 2.47–2.55(m,1H), 2.18(s,3H), 1.26–1.35(m,4H), 0.61–0.70 (m, 2H), 0.32-0.39 (m, 2H).
MS(ESI,pos.ion)m/z:531.30[M+H] +. MS(ESI,pos.ion)m/z:531.30[M+H] + .
实施例34：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二乙基吡啶酰胺Example 34: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-diethylpyridineamide
Figure PCTCN2021090489-appb-000096
Figure PCTCN2021090489-appb-000096
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.2mmol)，二乙胺(73mg,1.0mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.0mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.3mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.0mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v) ＝40/1)，得到白色固体63mg，收率56％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (100mg, 0.2mmol), diethylamine (73mg, 1.0mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (192mg, 1.0mmol) ) And N-hydroxy-7-azabenzotriazole (43mg, 0.3mmol) were dissolved in dichloromethane (5mL), and N,N-diisopropylethyl was added dropwise to this solution at 0℃. Amine (0.17mL, 1.0mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (Eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 63 mg of white solid with a yield of 56%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.76(t,J＝7.6Hz,1H),7.48(br.s,1H),7.42(d,J＝7.4Hz,1H),7.37(d,J＝7.6Hz,1H),7.12(d,J＝7.9Hz,1H),6.90(s,1H),6.86(d,J＝8.1Hz,1H),6.62(t,J F-H＝75.5Hz,1H),4.55–4.61(m,3H),3.93–3.97(m,1H),3.88(d,J＝6.8Hz,2H),3.56–3.62(m,3H),3.27–3.38(m,3H),3.55–3.62(m,1H),2.39–2.49(m,1H),2.14(s,3H),1.26–1.35(m,1H),1.28(t,J＝6.7Hz,3H),1.18(t,J＝6.7Hz,3H),0.64–0.69(m,2H),0.35–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.76 (t, J = 7.6 Hz, 1H), 7.48 (br.s, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.37 (d ,J=7.6Hz,1H), 7.12(d,J=7.9Hz,1H), 6.90(s,1H), 6.86(d,J=8.1Hz,1H), 6.62(t,J FH =75.5Hz, 1H), 4.55–4.61(m,3H), 3.93–3.97(m,1H), 3.88(d,J=6.8Hz,2H), 3.56–3.62(m,3H), 3.27–3.38(m,3H) ,3.55–3.62(m,1H),2.39–2.49(m,1H),2.14(s,3H),1.26–1.35(m,1H),1.28(t,J=6.7Hz,3H),1.18(t ,J=6.7Hz,3H),0.64–0.69(m,2H),0.35–0.39(m,2H).
MS(ESI,pos.ion)m/z:559.30[M+H] +. MS(ESI,pos.ion)m/z:559.30[M+H] + .
实施例35：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰胺基)甲基)-N,N-二丙基吡啶酰胺Example 35: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-dipropylpyridineamide
Figure PCTCN2021090489-appb-000097
Figure PCTCN2021090489-appb-000097
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.2mmol)，二正丙胺(64mg,0.63mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.0mmol)和N-羟基-7-氮杂苯并三氮唑(42mg,0.3mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.0mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体76mg，收率65％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (100mg, 0.2mmol), di-n-propylamine (64mg, 0.63mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (192mg, 1.0mmol) ) And N-hydroxy-7-azabenzotriazole (42mg, 0.3mmol) were dissolved in dichloromethane (5mL), and N,N-diisopropylethyl was added dropwise to this solution at 0℃. Amine (0.17mL, 1.0mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (Eluent: dichloromethane/methanol (v/v)=20/1) to obtain 76 mg of white solid with a yield of 65%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.76(t,J＝7.7Hz,1H),7.43(br.s,1H),7.40(d,J＝7.8Hz,1H),7.37(d,J＝7.8Hz,1H),7.12(d,J＝8.0Hz,1H),6.90(s,1H),6.86(d,J＝8.1Hz,1H),6.62(t,J F-H＝75.5Hz,1H),4.50–4.62(m,3H),3.93–3.98(m,1H),3.88(d,J＝6.8Hz,2H),3.55–3.61(m,1H),3.45–3.49(m,2H),3.32–3.39(m,1H),3.19–3.25(m,2H),2.55–2.62(m,1H),2.40–2.48(m,1H),2.15(s,3H),1.58–1.62(m,2H),1.26–1.35(m,1H),1.00(t,J＝7.3Hz,3H),0.85–0.91(m,2H),0.77(t,J＝7.3Hz,3H),0.64–0.68(m,2H),0.36–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.76 (t, J = 7.7 Hz, 1H), 7.43 (br.s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.37 (d ,J=7.8Hz,1H), 7.12(d,J=8.0Hz,1H), 6.90(s,1H), 6.86(d,J=8.1Hz,1H), 6.62(t,J FH ＝75.5Hz, 1H), 4.50–4.62(m,3H), 3.93–3.98(m,1H), 3.88(d,J=6.8Hz,2H), 3.55–3.61(m,1H), 3.45–3.49(m,2H) , 3.32–3.39(m,1H), 3.19–3.25(m,2H), 2.55–2.62(m,1H), 2.40–2.48(m,1H), 2.15(s,3H), 1.58–1.62(m, 2H), 1.26–1.35(m,1H),1.00(t,J=7.3Hz,3H),0.85–0.91(m,2H),0.77(t,J=7.3Hz,3H),0.64–0.68(m ,2H),0.36--0.39(m,2H).
MS(ESI,pos.ion)m/z:587.45[M+H] +. MS(ESI,pos.ion)m/z:587.45[M+H] + .
实施例36：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-甲基-N-正丙基吡啶酰胺Example 36: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-methyl-N-n-propylpyridineamide
Figure PCTCN2021090489-appb-000098
Figure PCTCN2021090489-appb-000098
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲 酸(102mg,0.2mmol)，N-甲基正丙胺(43mg,0.6mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.0mmol)和N-羟基-7-氮杂苯并三氮唑(45mg,0.33mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.15mL,0.9mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体59mg，收率52％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (102mg, 0.2mmol), N-methyl n-propylamine (43mg, 0.6mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (192mg , 1.0mmol) and N-hydroxy-7-azabenzotriazole (45mg, 0.33mmol) were dissolved in dichloromethane (5mL). Add N,N-diiso to this solution at 0℃. Propylethylamine (0.15mL, 0.9mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 59 mg of white solid with a yield of 52%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.76(t,J＝7.1Hz,1H),7.36–7.49(m,2H),7.12(d,J＝7.6Hz,1H),6.90(s,1H),6.86(d,J＝7.8Hz,1H),6.62(t,J F-H＝75.4Hz,1H),4.47–4.67(m,3H),3.90–3.98(m,1H),3.88(d,J＝6.5Hz,2H),3.52–3.60(m,2H),3.25–3.39(m,2H),3.10(s,1.5H),3.00(s,1.5H),2.52–2.63(m,1H),2.38–2.50(m,1H),2.14(s,3H),1.58–1.74(m,2H),1.26–1.35(m,1H),0.94–1.04(m,1.5H),0.72–0.81(m,1.5H),0.62–0.70(m,2H),0.33–0.41(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.76 (t, J = 7.1 Hz, 1H), 7.36-7.49 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H), 6.90 (s ,1H), 6.86(d,J=7.8Hz,1H),6.62(t,J FH =75.4Hz,1H),4.47–4.67(m,3H),3.90–3.98(m,1H),3.88(d ,J=6.5Hz,2H),3.52–3.60(m,2H), 3.25–3.39(m,2H), 3.10(s,1.5H), 3.00(s,1.5H), 2.52–2.63(m,1H) ), 2.38–2.50(m,1H), 2.14(s,3H), 1.58–1.74(m,2H), 1.26–1.35(m,1H), 0.94–1.04(m,1.5H), 0.72–0.81( m, 1.5H), 0.62--0.70 (m, 2H), 0.33--0.41 (m, 2H).
MS(ESI,pos.ion)m/z:559.20[M+H] +. MS(ESI,pos.ion)m/z:559.20[M+H] + .
实施例37：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(3-(二甲基甲酰胺)苄基)吡咯烷-2-甲酰胺Example 37: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(3-(dimethyl Formamide) benzyl) pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000099
Figure PCTCN2021090489-appb-000099
步骤1：化合物3-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)苯甲酸甲酯的合成Step 1: Compound 3-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)methyl benzoate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(83mg,0.22mmol)，3-(氨甲基)苯甲酸甲酯(97mg,0.48mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(93mg,0.48mmol)和N-羟基-7-氮杂苯并三氮唑(47mg,0.34mmol)溶于二氯甲烷(6mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌5h，加水(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到无色液体81mg，收率70％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (83mg, 0.22mmol) , 3-(Aminomethyl) methyl benzoate (97mg, 0.48mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (93mg, 0.48mmol) and N -Hydroxy-7-azabenzotriazole (47mg, 0.34mmol) was dissolved in dichloromethane (6mL), and N,N-diisopropylethylamine (0.3 mL, 2.0mmol), stir at room temperature for 5h, add water (50mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent : Dichloromethane/methanol (v/v)=20/1) to obtain 81 mg of a colorless liquid with a yield of 70%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.98(s,1H),7.91(d,J＝7.8Hz,1H),7.62(d,J＝7.6Hz,1H),7.47(t,J＝7.7Hz,1H),7.11(d,J＝8.2Hz,1H),7.08(s,1H),6.92-6.93(m,1H),6.74(t,J F-H＝73.6Hz,1H),4.57-4.64(m,1H),4.49(s,2H),4.08-4.12(m,1H),3.92(d,J＝6.9Hz,2H),3.89(s,3H),3.62-3.67(m,1H),3.47-3.51(m,1H),2.65-2.72(m,1h),2.15(s,3H),2.01-2.12(m,1H),1.32-1.36(m,1H),0.62-0.65(m,2H),0.35-0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.98 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 6.92-6.93 (m, 1H), 6.74 (t, J FH = 73.6 Hz, 1H), 4.57 -4.64(m,1H),4.49(s,2H),4.08-4.12(m,1H),3.92(d,J=6.9Hz,2H),3.89(s,3H),3.62-3.67(m,1H) ), 3.47-3.51 (m, 1H), 2.65-2.72 (m, 1h), 2.15 (s, 3H), 2.01-2.12 (m, 1H), 1.32-1.36 (m, 1H), 0.62-0.65 (m ,2H),0.35-0.41(m,2H).
MS(ESI,pos.ion)m/z:517.20[M+H] +. MS(ESI,pos.ion)m/z:517.20[M+H] + .
步骤2：化合物3-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)苯甲酸的合成Step 2: Compound 3-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)benzoic acid
将化合物3-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)苯甲酸甲酯(78mg,0.15mmol)溶于四氢呋喃(4mL)和水(2mL)的混合溶剂中，加入一水合氢氧化锂(32mg,0.76mmol)，50℃反应2h后停止，加盐酸调节溶液pH＝1，用乙酸乙酯萃取(5mL×3)，有机相用无 水硫酸钠干燥，除去溶剂得到白色固体70mg，收率94％。The compound 3-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl) benzoate (78mg, 0.15mmol) was dissolved in a mixed solvent of tetrahydrofuran (4mL) and water (2mL), lithium hydroxide monohydrate (32mg, 0.76mmol) was added, and the reaction was stopped at 50°C for 2 hours. The solution was adjusted to pH=1 with hydrochloric acid, extracted with ethyl acetate (5 mL×3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 70 mg of white solid with a yield of 94%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.51(t,J＝5.8Hz,1H),7.79-7.88(m,2H),7.50-7.56(m,1H),7.42-7.47(m,1H),7.09-7.13(m,1H),7.05(s,1H),7.02(t,J F-H＝74.9Hz,1H),6.88(d,J＝9.6Hz,1H),4.30-4.38(m,3H),4.04-4.08(m,1H),3.89(d,J＝6.9Hz,2H),3.40-3.50(m,2H),2.56-2.62(m,1H),2.02(s,3H),1.84-1.92(m,1H),1.26-1.32(m,1H),0.54-0.59(m,2H),0.32-0.35(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.51 (t, J = 5.8 Hz, 1H), 7.79-7.88 (m, 2H), 7.50-7.56 (m, 1H), 7.42-7.47 ( m, 1H), 7.09-7.13 (m, 1H), 7.05 (s, 1H), 7.02 (t, J FH = 74.9 Hz, 1H), 6.88 (d, J = 9.6 Hz, 1H), 4.30-4.38 ( m,3H),4.04-4.08(m,1H),3.89(d,J=6.9Hz,2H),3.40-3.50(m,2H),2.56-2.62(m,1H),2.02(s,3H) ,1.84-1.92(m,1H),1.26-1.32(m,1H),0.54-0.59(m,2H),0.32-0.35(m,2H).
MS(ESI,pos.ion)m/z:503.10[M+H] +. MS(ESI,pos.ion)m/z:503.10[M+H] + .
步骤3：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(3-(二甲基甲酰胺)苄基)吡咯烷-2-甲酰胺的合成Step 3: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(3-(dimethylform) (Amide)benzyl)pyrrolidine-2-carboxamide
将化合物3-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)苯甲酸(71mg,0.14mmol)，二甲胺盐酸盐(67mg,0.82mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(76mg,0.40mmol)和N-羟基-7-氮杂苯并三氮唑(42mg,0.31mmol)溶于二氯甲烷(6mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.2mL,1.0mmol)，室温搅拌15h，加水(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体54mg，收率72％。The compound 3-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)benzoic acid (71mg, 0.14mmol), dimethylamine hydrochloride (67mg, 0.82mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (76mg , 0.40mmol) and N-hydroxy-7-azabenzotriazole (42mg, 0.31mmol) were dissolved in dichloromethane (6mL). Add N,N-diiso to this solution at 0℃. Propylethylamine (0.2mL, 1.0mmol), stirred at room temperature for 15h, added water (50mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 54 mg of white solid with a yield of 72%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.49(t,J＝5.6Hz,1H),7.33-7.38(m,2H),7.28-7.32(m,1H),7.23-7.27(m,1H),7.12(d,J＝8.0Hz,1H),7.05(s,1H),7.03(t,J F-H＝74.9Hz,1H),6.88(d,J＝8.8Hz,1H),4.31-4.37(m,2H),4.04-4.08(m,1H),3.90(d,J＝6.8Hz,2H),3.41-3.51(m,2H),2.96(s,3H),2.88(s,3H),2.55-2.62(m,1H),2.02(s,3H),1.82-1.91(m,1H),1.23-1.35(m,1H),0.54-0.60(m,2H),0.31-0.35(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.49 (t, J = 5.6 Hz, 1H), 7.33-7.38 (m, 2H), 7.28-7.32 (m, 1H), 7.23-7.27 ( m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 7.03 (t, J FH = 74.9 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.31 -4.37(m,2H),4.04-4.08(m,1H),3.90(d,J=6.8Hz,2H),3.41-3.51(m,2H),2.96(s,3H),2.88(s,3H) ), 2.55-2.62 (m, 1H), 2.02 (s, 3H), 1.82-1.91 (m, 1H), 1.23-1.35 (m, 1H), 0.54-0.60 (m, 2H), 0.31-0.35 (m ,2H).
MS(ESI,pos.ion)m/z:530.30[M+H] +. MS(ESI,pos.ion)m/z:530.30[M+H] + .
实施例38：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二异丙基吡啶酰胺Example 38: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-diisopropylpyridineamide
Figure PCTCN2021090489-appb-000100
Figure PCTCN2021090489-appb-000100
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(92mg,0.18mmol)，N,N-二异丙基胺(89mg,0.88mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(143mg,0.75mmol)和N-羟基-7-氮杂苯并三氮唑(81mg,0.60mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌5h，加水(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体51mg，收率47％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (92mg, 0.18mmol), N,N-diisopropylamine (89mg, 0.88mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (143mg, 0.75mmol) and N-hydroxy-7-azabenzotriazole (81mg, 0.60mmol) were dissolved in dichloromethane (6mL), and N,N-di was added dropwise to this solution at room temperature. Isopropylethylamine (0.4mL, 2.0mmol), stir at room temperature for 5h, add water (50mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to a silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 51 mg of white solid with a yield of 47%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.60(t,J＝5.8Hz,1H),7.82(t,J＝7.6Hz,1H),7.43(d,J＝7.8Hz,1H),7.24-7.30(m,1H),7.12(d,J＝8.3Hz,1H),7.06(s,1H),7.03(t,J F-H＝74.8Hz,1H)，6.89(d,J＝8.9Hz,1H),4.33-4.42(m,3H),4.05-4.09(m,1H),3.90(d,J＝6.8Hz,2H),3.55-3.65(m,2H),3.39-3.52(m,2H),2.56-2.65(m,1H),2.03(s,3H),1.89-1.99(m,1H),1.43(d,J＝5.7Hz,6H),1.24-1.27(m,1H),1.09(d,J＝6.1Hz,6H),0.54-0.60(m,2H),0.30-0.36(m,2H). 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 8.60(t,J=5.8Hz,1H),7.82(t,J=7.6Hz,1H),7.43(d,J=7.8Hz,1H ), 7.24-7.30 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.06 (s, 1H), 7.03 (t, J FH = 74.8 Hz, 1H), 6.89 (d, J = 8.9 Hz,1H),4.33-4.42(m,3H),4.05-4.09(m,1H),3.90(d,J=6.8Hz,2H),3.55-3.65(m,2H),3.39-3.52(m, 2H),2.56-2.65(m,1H),2.03(s,3H),1.89-1.99(m,1H),1.43(d,J=5.7Hz,6H),1.24-1.27(m,1H),1.09 (d,J=6.1Hz,6H),0.54-0.60(m,2H),0.30-0.36(m,2H).
MS(ESI,pos.ion)m/z:587.45[M+H] +. MS(ESI,pos.ion)m/z:587.45[M+H] + .
实施例39：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-乙基-N-甲基吡啶酰胺Example 39: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-ethyl-N-picolineamide
Figure PCTCN2021090489-appb-000101
Figure PCTCN2021090489-appb-000101
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(102mg,0.20mmol)，N-乙基甲基胺(59mg,1.00mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(198mg,1.03mmol)和N-羟基-7-氮杂苯并三氮唑(46mg,0.34mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到浅黄色固体28mg，收率25％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (102mg, 0.20mmol), N-ethylmethylamine (59mg, 1.00mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 198mg, 1.03mmol) and N-hydroxy-7-azabenzotriazole (46mg, 0.34mmol) were dissolved in dichloromethane (5mL), and N,N-di was added dropwise to this solution at 0℃. Isopropylethylamine (0.17mL, 1.00mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel It was separated by column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 28 mg of a pale yellow solid with a yield of 25%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.77(t,J＝7.6Hz,1H),7.36–7.46(m,2H),7.12(d,J＝8.0Hz,1H),6.90(s,1H),6.86(d,J＝7.2Hz,1H),6.62(t,J F-H＝75.4Hz,1H),4.49–4.67(m,3H),3.91–3.97(m,1H),3.88(d,J＝6.9Hz,2H),3.55–3.63(m,2H),3.30–3.39(m,2H),3.11(s,2H),3.01(s,1H),2.54–2.62(m,1H),2.41–2.49(m,1H),2.14(s,3H),1.26–1.35(m,1H),1.20(t,J＝7.0Hz,3H),0.63–0.70(m,2H),0.35–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.77 (t, J = 7.6 Hz, 1H), 7.36-7.46 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.90 (s ,1H), 6.86(d,J=7.2Hz,1H),6.62(t,J FH =75.4Hz,1H),4.49–4.67(m,3H),3.91–3.97(m,1H),3.88(d ,J=6.9Hz,2H),3.55–3.63(m,2H),3.30–3.39(m,2H),3.11(s,2H),3.01(s,1H),2.54–2.62(m,1H), 2.41–2.49(m,1H), 2.14(s,3H), 1.26–1.35(m,1H), 1.20(t,J=7.0Hz,3H), 0.63–0.70(m,2H),0.35–0.39( m,2H).
MS(ESI,pos.ion)m/z:545.30[M+H] +. MS(ESI,pos.ion)m/z:545.30[M+H] + .
实施例40：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二正丁基吡啶酰胺Example 40: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-di-n-butylpyridine amide
Figure PCTCN2021090489-appb-000102
Figure PCTCN2021090489-appb-000102
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(97mg,0.19mmol)，二正丁基胺(57mg,0.44mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(41mg,0.30mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.16mL,0.97mmol)，室温反应12h，加水洗(15mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体41mg，收率35％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl) picolinic acid (97mg, 0.19mmol), di-n-butylamine (57mg, 0.44mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (192mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (41mg, 0.30mmol) were dissolved in dichloromethane (5mL), and N,N-diisopropyl was added dropwise to this solution at 0℃ Ethylethylamine (0.16mL, 0.97mmol), react at room temperature for 12h, wash with water (15mL), then extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 41 mg of white solid with a yield of 35%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.76(t,J＝7.7Hz,1H),7.40(d,J＝7.1Hz,1H),7.37(d,J＝7.9Hz, 1H),7.13(d,J＝8.0Hz,1H),6.90(s,1H),6.86(d,J＝8.5Hz,1H),6.62(t,J F-H＝75.5Hz,1H),4.54–4.67(m,3H),3.93–3.99(m,1H),3.89(d,J＝6.7Hz,2H),3.55–3.61(m,1H),3.49–3.52(m,2H),3.31–3.39(m,1H),3.25–3.29(m,2H),2.53–2.63(m,1H),2.41–2.49(m,1H),2.15(s,3H),1.63–1.73(m,2H),1.51–1.59(m,2H),1.39–1.47(m,2H),1.26–1.34(m,1H),1.13–1.19(m,2H),0.99(t,J＝7.2Hz,3H),0.80(t,J＝7.3Hz,3H),0.64–0.70(m,2H),0.35–0.40(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.76(t,J=7.7Hz,1H), 7.40(d,J=7.1Hz,1H), 7.37(d,J=7.9Hz, 1H), 7.13(d,J=8.0Hz,1H),6.90(s,1H),6.86(d,J=8.5Hz,1H),6.62(t,J FH =75.5Hz,1H),4.54-4.67(m, 3H), 3.93–3.99(m,1H), 3.89(d,J=6.7Hz,2H), 3.55–3.61(m,1H), 3.49–3.52(m,2H),3.31–3.39(m,1H) , 3.25–3.29(m, 2H), 2.53–2.63(m, 1H), 2.41–2.49(m, 1H), 2.15(s, 3H), 1.63–1.73(m, 2H), 1.51–1.59(m, 2H), 1.39–1.47(m,2H), 1.26–1.34(m,1H), 1.13–1.19(m,2H), 0.99(t,J=7.2Hz,3H),0.80(t,J=7.3Hz ,3H),0.64-0.70(m,2H),0.35-0.40(m,2H).
MS(ESI,pos.ion)m/z:615.35[M+H] +. MS(ESI,pos.ion)m/z:615.35[M+H] + .
实施例41：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(2-(二甲氨基)乙基)-N-甲基吡啶酰胺Example 41: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(2-(dimethylamino)ethyl)-N-picolineamide
Figure PCTCN2021090489-appb-000103
Figure PCTCN2021090489-appb-000103
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，N 1,N 1,N 2-三甲基乙二胺(60mg,0.59mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(191mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(56mg,0.41mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入N,N-二异丙基乙胺(152mg,1.18mmol)，室温反应4.5h，加水(30mL)搅拌5min，分离有机相，水相用二氯甲烷萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝24/1)，得到白色固体55mg，收率47％。 The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (100mg, 0.20mmol), N 1 , N 1 , N 2 -trimethylethylenediamine (60mg, 0.59mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Diimide hydrochloride (191mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (56mg, 0.41mmol) were dissolved in dichloromethane (5mL), cooled to 0℃, added N , N-Diisopropylethylamine (152mg, 1.18mmol), react at room temperature for 4.5h, add water (30mL) and stir for 5min, separate the organic phase, extract the aqueous phase with dichloromethane (10mL×2), and use anhydrous organic phase It was dried over sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=24/1) to obtain 55 mg of white solid with a yield of 47%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.71–7.79(m,1H),7.44–7.53(m,1H),7.37–7.40(m,1H),7.10(d,J＝8.1Hz,1H),6.87(s,1H),6.83(d,J＝8.2,Hz,1H),6.60(t,J F-H＝75.6Hz,1H),4.46–4.63(m,2H),3.90–3.94(m,1H),3.86(d,J＝6.9Hz,2H),3.67–3.70(m,1H),3.57(d,J＝10.6Hz,1H),3.48–3.51(m,1H),3.20–3.37(m,2H),3.12(s,1.5H),3.03(s,1.5H),2.52–2.64(m,3H),2.37–2.42(m,1H),2.32(s,3H),2.13(s,3H),2.11(s,3H),1.21–1.28(m,1H),0.62–0.67(m,2H),0.33–0.37(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.71–7.79(m,1H), 7.44–7.53(m,1H), 7.37–7.40(m,1H), 7.10(d,J=8.1Hz, 1H), 6.87 (s, 1H), 6.83 (d, J = 8.2, Hz, 1H), 6.60 (t, J FH = 75.6 Hz, 1H), 4.46-4.63 (m, 2H), 3.90-3.94 (m ,1H), 3.86(d,J=6.9Hz,2H), 3.67–3.70(m,1H), 3.57(d,J=10.6Hz,1H), 3.48–3.51(m,1H), 3.20–3.37( m,2H),3.12(s,1.5H),3.03(s,1.5H),2.52-2.64(m,3H),2.37-2.42(m,1H),2.32(s,3H),2.13(s, 3H), 2.11 (s, 3H), 1.21 - 1.28 (m, 1H), 0.62 - 0.67 (m, 2H), 0.33 - 0.37 (m, 2H).
MS(ESI,pos.ion)m/z:588.30[M+H] +. MS(ESI,pos.ion)m/z:588.30[M+H] + .
实施例42：化合物6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-丙酰基吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺Example 42: Compound 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-propionylpyrrolidine-2-methyl Amido)methyl)-N,N-lutidineamide
Figure PCTCN2021090489-appb-000104
Figure PCTCN2021090489-appb-000104
将丙酸(33mg,0.45mmol)，6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺二盐酸盐(70mg,0.12mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(121mg,0.63mmol)和N-羟基-7-氮杂苯并三氮唑(32mg,0.24mmol)溶于二氯甲烷(8mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.1mL,0.6mmol)，室温搅拌19h，加水(15mL)，用二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v) ＝30/1)，得到白色固体41mg，收率60％。Add propionic acid (33mg, 0.45mmol), 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-dimethylpyridine amide dihydrochloride (70mg, 0.12mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (121mg, 0.63mmol) and N-hydroxy-7-azabenzotriazole (32mg, 0.24mmol) were dissolved in dichloromethane (8mL), and N,N- was added dropwise to this solution at 0℃. Diisopropylethylamine (0.1mL, 0.6mmol), stir at room temperature for 19h, add water (15mL), extract with dichloromethane (10mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel It was separated by column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 41 mg of white solid with a yield of 60%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.77(t,J＝7.3Hz,1H),7.52(br.s,1H),7.47(d,J＝7.3Hz,1H),7.37(d,J＝7.3Hz,1H),7.12(d,J＝7.8Hz,1H),6.90(s,1H),6.86(d,J＝7.8Hz,1H),6.62(t,J F-H＝75.4Hz,1H),4.53–4.65(m,3H),3.95–3.99(m,1H),3.88(d,J＝6.6Hz,2H),3.52(t,J＝10.4Hz,1H),3.27–3.38(m,1H),3.14(s,3H),3.06(s,3H),2.52–2.64(m,1H),2.32–2.49(m,3H),1.27–1.33(m,1H),1.17(t,J＝7.0Hz,3H),0.64–0.68(m,2H),0.34–0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.77 (t, J = 7.3Hz, 1H), 7.52 (br.s, 1H), 7.47 (d, J = 7.3Hz, 1H), 7.37 (d ,J=7.3Hz,1H), 7.12(d,J=7.8Hz,1H), 6.90(s,1H), 6.86(d,J=7.8Hz,1H), 6.62(t,J FH ＝75.4Hz, 1H), 4.53–4.65(m, 3H), 3.95–3.99(m, 1H), 3.88(d, J = 6.6Hz, 2H), 3.52(t, J = 10.4Hz, 1H), 3.27–3.38(m ,1H),3.14(s,3H),3.06(s,3H),2.52-2.64(m,1H),2.32-2.49(m,3H),1.27-1.33(m,1H),1.17(t,J ＝7.0Hz,3H),0.64–0.68(m,2H),0.34–0.40(m,2H).
MS(ESI,pos.ion)m/z:545.20[M+H] +. MS(ESI,pos.ion)m/z:545.20[M+H] + .
实施例43：化合物6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-(2-氟乙酰基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺Example 43: Compound 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(2-fluoroacetyl)pyrrole Alkyl-2-carboxamido)methyl)-N,N-dimethylpyridine amide
Figure PCTCN2021090489-appb-000105
Figure PCTCN2021090489-appb-000105
将2-氟乙酸(37mg,0.47mmol)，6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺二盐酸盐(90mg,0.16mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(152mg,0.79mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.14mL,0.85mmol)，室温搅拌7h，加水(15mL)，用二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体73mg，收率83％。The 2-fluoroacetic acid (37mg, 0.47mmol), 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxamido)methyl)-N,N-dimethylpyridine amide dihydrochloride (90mg, 0.16mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt The acid salt (152mg, 0.79mmol) and N-hydroxy-7-azabenzotriazole (43mg, 0.32mmol) were dissolved in dichloromethane (5mL). Add N, N-Diisopropylethylamine (0.14mL, 0.85mmol), stir at room temperature for 7h, add water (15mL), extract with dichloromethane (10mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate the solution Perform silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 73 mg of white solid with a yield of 83%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.77(t,J＝7.3Hz,1H),7.57(br.s,1H),7.35–7.45(m,2H),7.13(d,J＝7.8Hz,1H),6.89(s,1H),6.81–6.89(m,1H),6.62(t,J F-H＝75.6Hz,1H),4.91–5.05(m,2H),4.55–4.68(m,3H),3.93–4.02(m,1H),3.88(d,J＝5.5Hz,2H),3.53–3.58(m,1H),3.29–3.40(m,1H),3.14(s,3H),3.04(s,3H),2.56–2.66(m,1H),2.33–2.43(m,1H),1.24–1.36(m,1H),0.60–0.70(m,2H),0.33–0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.77 (t, J = 7.3 Hz, 1H), 7.57 (br.s, 1H), 7.35-7.45 (m, 2H), 7.13 (d, J = 7.8Hz, 1H), 6.89 (s, 1H), 6.81-6.89 (m, 1H), 6.62 (t, J FH = 75.6 Hz, 1H), 4.91-5.05 (m, 2H), 4.55-4.68 (m, 3H),3.93-4.02(m,1H),3.88(d,J=5.5Hz,2H),3.53-3.58(m,1H),3.29-3.40(m,1H),3.14(s,3H),3.04 (s,3H),2.56–2.66(m,1H),2.33–2.43(m,1H),1.24–1.36(m,1H),0.60–0.70(m,2H),0.33–0.40(m,2H) .
MS(ESI,pos.ion)m/z:549.20[M+H] +. MS(ESI,pos.ion)m/z:549.20[M+H] + .
实施例44：化合物6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-(2,2-二氟乙酰基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺Example 44: Compound 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(2,2-difluoroacetyl (Yl)pyrrolidine-2-carboxamido)methyl)-N,N-dimethylpyridineamide
Figure PCTCN2021090489-appb-000106
Figure PCTCN2021090489-appb-000106
将2,2-二氟乙酸(36mg,0.38mmol)，6-(((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺二盐酸盐(70mg,0.12mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(118mg,0.62mmol)和N-羟基-7-氮杂苯并三氮唑(32mg,0.24mmol)溶于二氯甲烷(8mL)中，0℃条 件下向此溶液中滴加N,N-二异丙基乙胺(0.1mL,0.6mmol)，室温搅拌12h，加水(15mL)，用二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体46mg，收率65％。2,2-Difluoroacetic acid (36mg, 0.38mmol), 6-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrole Alkyl-2-carboxamido)methyl)-N,N-dimethylpyridine amide dihydrochloride (70mg, 0.12mmol), 1-ethyl-(3-dimethylaminopropyl)carbonyl dihydrochloride Imine hydrochloride (118mg, 0.62mmol) and N-hydroxy-7-azabenzotriazole (32mg, 0.24mmol) were dissolved in dichloromethane (8mL) and dropped into this solution at 0℃. Add N,N-diisopropylethylamine (0.1mL, 0.6mmol), stir at room temperature for 12h, add water (15mL), extract with dichloromethane (10mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 46 mg of white solid with a yield of 65%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.77(t,J＝7.6Hz,1H),7.46(d,J＝6.8Hz,1H),7.34(d,J＝7.7Hz,1H),7.14(d,J＝7.9Hz,1H),6.89(s,1H),6.84(d,J＝7.8Hz,1H),6.62(t,J F-H＝75.6Hz,1H),6.08(t,J F-H＝53.4Hz,1H),4.55–4.68(m,3H),4.24–4.32(m,1H),3.89(d,J＝6.7Hz,2H),3.63(t,J＝11.1Hz,1H),3.32–3.44(m,1H),3.15(s,3H),3.04(s,3H),2.60–2.69(m,1H),2.35–2.43(m,1H),1.27–1.39(m,1H),0.64–0.69(m,2H),0.36–0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.77 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 6.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.14(d,J=7.9Hz,1H), 6.89(s,1H), 6.84(d,J=7.8Hz,1H), 6.62(t,J FH ＝75.6Hz,1H), 6.08(t,J FH = 53.4Hz, 1H), 4.55–4.68 (m, 3H), 4.24–4.32 (m, 1H), 3.89 (d, J = 6.7Hz, 2H), 3.63 (t, J = 11.1Hz, 1H), 3.32 --3.44(m,1H),3.15(s,3H),3.04(s,3H),2.60–2.69(m,1H),2.35–2.43(m,1H),1.27–1.39(m,1H),0.64 --0.69(m,2H),0.36--0.40(m,2H).
MS(ESI,pos.ion)m/z:567.30[M+H] +. MS(ESI,pos.ion)m/z:567.30[M+H] + .
实施例45：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺Example 45: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxamido)methyl)- N,N-lutidine amide
Figure PCTCN2021090489-appb-000107
Figure PCTCN2021090489-appb-000107
步骤1：化合物(R)-1-叔丁基2-甲基4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 1: Compound (R)-1-tert-butyl 2-methyl 4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H ,5H)-Dicarboxylic acid ester synthesis
将化合物(R)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(5.6g,16.0mmol)，2-(苄氧基)-1-(二氟甲氧基)-4-碘苯(861-1-2)(4.79g,12.7mmol)，磷酸钾(8.1g,38.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(478mg,0.65mmol)混合在干燥的1,4-二氧六环(60mL)溶液中，氮气保护下100℃反应4h，将反应液抽滤，滤液中加入水(50mL)，用乙酸乙酯(25mL×3)萃取，有机相合用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到淡红色液体3.6g，收率59％。The compound (R)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Pyrrole-1,2(2H,5H)-dicarboxylate (5.6g, 16.0mmol), 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene (861-1- 2) (4.79g, 12.7mmol), potassium phosphate (8.1g, 38.0mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (478mg, 0.65mmol) mixed in In a dry solution of 1,4-dioxane (60mL), react at 100℃ for 4h under nitrogen protection. The reaction solution was filtered off with suction. Water (50mL) was added to the filtrate, and it was extracted with ethyl acetate (25mL×3). It was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain 3.6 g of light red liquid, with a yield 59%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.37–7.44(m,5H),7.18–7.20(m,1H),7.04(s,1H),6.95–7.01(m,1H),6.60(t,J F-H＝75.0Hz,1H),6.00–6.03(m,1H),5.12–5.22(m,1H),5.16(d,J＝9.1Hz,2H),4.54–4.67(m,2H),3.78(s,3H),1.48–1.55(m,9H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.37-7.44(m,5H), 7.18-7.20(m,1H), 7.04(s,1H), 6.95-7.01(m,1H), 6.60( t,J FH =75.0Hz,1H),6.00–6.03(m,1H),5.12–5.22(m,1H), 5.16(d,J=9.1Hz,2H),4.54–4.67(m,2H), 3.78(s,3H),1.48-1.55(m,9H).
MS(ESI,pos.ion)m/z:498.20[M+Na] +. MS(ESI,pos.ion)m/z:498.20[M+Na] + .
步骤2：化合物(2R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-(羟基)苯基)吡咯烷-1,2-二羧酸酯的合成Step 2: Compound (2R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-(hydroxy)phenyl)pyrrolidine-1,2-dicarboxylate synthesis
将化合物(R)-1-叔丁基2-甲基4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(1.48g,3.1mmol)溶于甲醇(30mL)，加入Pd/C(1.0g,10％)，通入氢气室温反应24h，过滤除去催化剂，滤液浓缩得到黄色液体860mg，收率71％。The compound (R)-1-tert-butyl 2-methyl 4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H )-Dicarboxylic acid ester (1.48g, 3.1mmol) was dissolved in methanol (30mL), Pd/C (1.0g, 10%) was added, hydrogen gas was introduced to react at room temperature for 24h, the catalyst was removed by filtration, and the filtrate was concentrated to obtain 860mg of yellow liquid. The yield was 71%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):9.93(s,1H),7.04(d,J＝8.2Hz,1H),6.99(t,J F-H＝75.2Hz,1H),6.85(d,J＝1.8Hz,1H),6.72(d,J＝8.3Hz,1H),4.26-4.30(m,1H),3.84-3.88(m,1H),3.69(s,2H),3.66(s,1H),3.11-3.19(m,2H),2.58-2.65(m,1H),1.77-1.88(m,1H),1.49(m,3H),1.39(m,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 9.93 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.99 (t, J FH = 75.2 Hz, 1H), 6.85 ( d,J=1.8Hz,1H), 6.72(d,J=8.3Hz,1H), 4.26-4.30(m,1H), 3.84-3.88(m,1H), 3.69(s,2H), 3.66(s ,1H),3.11-3.19(m,2H),2.58-2.65(m,1H),1.77-1.88(m,1H), 1.49(m,3H), 1.39(m,6H).
MS(ESI,pos.ion)m/z:410.15[M+Na] +. MS(ESI,pos.ion)m/z:410.15[M+Na] + .
步骤3：化合物(2R)-4-(4-(二氟甲氧基)-3-(羟基)苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成Step 3: Synthesis of compound (2R)-4-(4-(difluoromethoxy)-3-(hydroxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-(羟基)苯基)吡咯烷-1,2-二羧酸酯(860mg,2.2 mmol)溶解于二氯甲烷(3mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(3mL)，室温搅拌1h，除去溶剂，得到白色固体623mg，收率97％。Compound (2R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-(hydroxy)phenyl)pyrrolidine-1,2-dicarboxylate (860mg, 2.2 mmol) was dissolved in dichloromethane (3mL) solution, 4mol/L HCl ethyl acetate solution (3mL) was added, stirred at room temperature for 1h, and the solvent was removed to obtain 623mg of white solid with a yield of 97%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):10.02(s,1H),7.08(d,J＝8.2Hz,1H),7.00(t,J F-H＝75.1Hz,1H),6.92(d,J＝1.8Hz,1H),6.79(dd,J＝8.3,1.9Hz,1H),4.49-4.54(m,1H),3.79(s,3H),3.61-3.66(m,1H),3.42-3.51(m,1H),3.11-3.17(m,1H),2.64-2.70(m,1H),1.99-2.10(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 10.02 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 7.00 (t, J FH = 75.1 Hz, 1H), 6.92 ( d, J = 1.8Hz, 1H), 6.79 (dd, J = 8.3, 1.9Hz, 1H), 4.49-4.54 (m, 1H), 3.79 (s, 3H), 3.61-3.66 (m, 1H), 3.42 -3.51(m,1H),3.11-3.17(m,1H),2.64-2.70(m,1H),1.99-2.10(m,1H).
MS(ESI,pos.ion)m/z:288.10[M+H-HCl] +. MS(ESI,pos.ion)m/z:288.10[M+H-HCl] + .
步骤4：化合物(2R)-1-乙酰基-4-(3-(乙酰氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸甲酯的合成Step 4: Synthesis of compound (2R)-1-acetyl-4-(3-(acetoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(2R)-4-(4-(二氟甲氧基)-3-(羟基)苯基)吡咯烷-2-羧酸甲酯盐酸盐(269mg,0.93mmol)溶解在二氯甲烷(6mL)中，加入N,N-二异丙基乙胺(0.6mL,4.0mmol)，冰浴中加入乙酰氯(0.3mL,4.0mmol)，室温搅拌19h后停止反应，加入水(15mL)，用二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到浅黄色液体263mg，收率75％。The compound (2R)-4-(4-(difluoromethoxy)-3-(hydroxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (269mg, 0.93mmol) was dissolved in dichloromethane (6mL), add N,N-diisopropylethylamine (0.6mL, 4.0mmol), add acetyl chloride (0.3mL, 4.0mmol) to the ice bath, stir at room temperature for 19h, stop the reaction, add water (15mL) , Extracted with dichloromethane (10mL×3), the organic phase was dried with anhydrous sodium sulfate, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) 263 mg of light yellow liquid was obtained with a yield of 75%.
MS(ESI,pos.ion)m/z:372.20[M+H] +. MS(ESI,pos.ion)m/z:372.20[M+H] + .
步骤5：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-(羟基)苯基)吡咯烷-2-甲酸的合成Step 5: Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-(hydroxy)phenyl)pyrrolidine-2-carboxylic acid
将化合物(2R)-1-乙酰基-4-(3-(乙酰氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸甲酯(263mg,0.71mmol)溶于四氢呋喃(5mL)和水(4mL)的混合溶剂中，加入一水合氢氧化锂(172mg,3.1mmol)，50℃反应2h后停止，加浓盐酸调节溶液pH＝1，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到淡黄色固体213mg，收率95％。The compound (2R)-1-acetyl-4-(3-(acetoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (263mg, 0.71mmol) was dissolved in To a mixed solvent of tetrahydrofuran (5mL) and water (4mL), lithium hydroxide monohydrate (172mg, 3.1mmol) was added, and the reaction was stopped at 50°C for 2 hours. Concentrated hydrochloric acid was added to adjust the pH of the solution to 1, and extracted with ethyl acetate (5mL ×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 213 mg of a pale yellow solid with a yield of 95%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):9.89(s,1H),7.06(d,J＝8.2Hz,1H),6.99(t,J F-H＝75.1Hz,1H),6.85-6.88(m,1H),6.74-6.76(m,1H),4.19-4.24(m,1H),4.01-4.06(m,1H),3.27-3.42(m,2H),2.59-2.67(m,1H),2.00(s,3H),1.75-1.83(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 9.89 (s, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.99 (t, J FH = 75.1 Hz, 1H), 6.85 6.88 (m, 1H), 6.74-6.76 (m, 1H), 4.19-4.24 (m, 1H), 4.01-4.06 (m, 1H), 3.27-3.42 (m, 2H), 2.59-2.67 (m, 1H) ), 2.00 (s, 3H), 1.75-1.83 (m, 1H).
MS(ESI,pos.ion)m/z:316.10[M+H] +. MS(ESI,pos.ion)m/z:316.10[M+H] + .
步骤6：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺的合成Step 6: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxamido)methyl)-N , Synthesis of N-dimethylpyridine amide
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酸(72mg,0.23mmol)，6-(氨基甲基)-N,N-二甲基吡啶酰胺二盐酸盐(94mg,0.52mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(88mg,0.46mmol)和N-羟基-7-氮杂苯并三氮唑(61mg,0.45mmol)溶于二氯甲烷(6mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌4h，加水洗(50mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体23mg，收率21％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid (72mg, 0.23mmol), 6-(aminomethyl) -N,N-lutidine amide dihydrochloride (94mg, 0.52mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (88mg, 0.46mmol) And N-hydroxy-7-azabenzotriazole (61mg, 0.45mmol) were dissolved in dichloromethane (6mL), and N,N-diisopropylethylamine was added dropwise to this solution at 0℃ (0.3mL, 2.0mmol), stirred at room temperature for 4h, washed with water (50mL), and then extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v)=20/1) to obtain 23 mg of white solid with a yield of 21%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):9.88(s,1H),8.61(t,J＝5.9Hz,1H),7.86(t,J＝7.7Hz,1H),7.46(d,J＝7.9Hz,1H),7.32-7.40(m,1H),7.03-7.07(m,1H),6.99(t,J F-H＝75.1Hz,1H),6.86-6.89(m,1H),6.72-6.77(m,1H),4.32-4.50(m,3H),4.02-4.05(m,1H),3.38-3.46(m,2H),2.96-2.98(m,3H),2.88-2.89(m,3H),2.51-2.62(m,1H),2.02(s,3H),1.82-1.87(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 9.88 (s, 1H), 8.61 (t, J = 5.9 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.46 (d ,J=7.9Hz,1H),7.32-7.40(m,1H),7.03-7.07(m,1H),6.99(t,J FH =75.1Hz,1H),6.86-6.89(m,1H),6.72 -6.77(m,1H),4.32-4.50(m,3H),4.02-4.05(m,1H),3.38-3.46(m,2H),2.96-2.98(m,3H),2.88-2.89(m, 3H), 2.51-2.62 (m, 1H), 2.02 (s, 3H), 1.82-1.87 (m, 1H).
MS(ESI,pos.ion)m/z:477.25[M+H] +. MS(ESI,pos.ion)m/z:477.25[M+H] + .
实施例46：化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺Example 46: Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)-N ,N-lutidine amide
Figure PCTCN2021090489-appb-000108
Figure PCTCN2021090489-appb-000108
步骤1：化合物2-(二氟甲氧基)-5-碘苯酚的合成Step 1: Synthesis of compound 2-(difluoromethoxy)-5-iodophenol
将化合物2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(5.0g,14.71mmol)溶于乙腈(25mL)和浓盐酸(10mL)的混合溶剂中，80℃反应6h后停止，减压浓缩，加水(10mL)，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，减压浓缩，经硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝10/1)，得到浅黄色液体3.23g，产率76％。The compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (5.0g, 14.71mmol) was dissolved in a mixed solvent of acetonitrile (25mL) and concentrated hydrochloric acid (10mL) The reaction was stopped at 80°C for 6 hours, concentrated under reduced pressure, added water (10 mL), extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluted Reagent: petroleum ether/ethyl acetate (v/v) = 10/1) to obtain 3.23 g of light yellow liquid, with a yield of 76%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.39(d,J＝2.0Hz,1H),7.23(dd,J＝8.5,2.0Hz,1H),6.87(d,J＝8.5Hz,1H),6.53(t,J F-H＝73.2Hz,1H),5.72(br.s,1H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.39(d,J=2.0Hz,1H), 7.23(dd,J=8.5,2.0Hz,1H), 6.87(d,J=8.5Hz,1H ), 6.53(t,J FH =73.2Hz,1H),5.72(br.s,1H).
MS(ESI,pos.ion)m/z:285.90[M].MS(ESI,pos.ion)m/z:285.90[M].
步骤2：化合物1,2-双(二氟甲氧基)-4-碘苯的合成Step 2: Synthesis of compound 1,2-bis(difluoromethoxy)-4-iodobenzene
将化合物2-(二氟甲氧基)-5-碘苯酚(770mg,2.69mmol)溶于N,N-二甲基甲酰胺(10mL)，加入二氟氯乙酸钠(733mg,4.81mmol)和碳酸铯(1.6g,4.90mmol)，120℃反应4h后停止，加水(25mL)，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，浓缩得到浅黄色液体831mg，产率91％。The compound 2-(difluoromethoxy)-5-iodophenol (770mg, 2.69mmol) was dissolved in N,N-dimethylformamide (10mL), sodium difluorochloroacetate (733mg, 4.81mmol) and Cesium carbonate (1.6g, 4.90mmol), the reaction was stopped at 120°C for 4h, water (25mL) was added, and the mixture was extracted with ethyl acetate (5mL×3). The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a pale yellow liquid 831mg. The rate is 91%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.61(s,1H),7.58(dd,J＝8.5,2.0Hz,1H),7.03(d,J＝8.5Hz,1H),6.53(t,J F-H＝73.1Hz,1H),6.52(t,J F-H＝73.1Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.61 (s, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.53 (t ,J FH ＝73.1Hz,1H),6.52(t,J FH ＝73.1Hz,1H).
MS(ESI,pos.ion)m/z:335.90[M].MS(ESI,pos.ion)m/z:335.90[M].
步骤3：化合物(R)-1-叔丁基2-甲基4-(3,4-双(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 3: Compound (R)-1-tert-butyl 2-methyl 4-(3,4-bis(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-bis Synthesis of carboxylic acid esters
将(R)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(800mg,2.27mmol)，1,2-双(二氟甲氧基)-4-碘苯(868-1)(790mg,2.35mmol)，磷酸钾(2.0g,9.4mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(35mg,0.05mmol)混合在干燥的1,4-二氧六环(10mL)溶液中，氮气保护下100℃反应2.5h，将反应液抽滤，滤液中加入水(20mL)，用乙酸乙酯(10mL×3)萃取，有机相合用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝6/1)，得到765mg褐色液体，产率77％。Add (R)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole -1,2(2H,5H)-dicarboxylate (800mg, 2.27mmol), 1,2-bis(difluoromethoxy)-4-iodobenzene (868-1) (790mg, 2.35mmol), Potassium phosphate (2.0g, 9.4mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (35mg, 0.05mmol) mixed in dry 1,4-dioxane (10mL) in the solution, react at 100℃ for 2.5h under nitrogen protection, filter the reaction solution with suction, add water (20mL) to the filtrate, extract with ethyl acetate (10mL×3), combine the organic phase and dry with anhydrous sodium sulfate to remove The solvent and concentrated solution were separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=6/1) to obtain 765 mg of brown liquid with a yield of 77%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.25–7.31(m,3H),6.56(t,J F-H＝73.4Hz,1H),6.55(t,J F-H＝73.4Hz,1H),6.07-6.12(m,1H),5.14-5.23(m,1H),4.49-4.68(m,2H),3.78-3.79(m,3H),1.48–1.54(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.25–7.31 (m, 3H), 6.56 (t, J FH = 73.4 Hz, 1H), 6.55 (t, J FH = 73.4 Hz, 1H), 6.07 -6.12(m,1H), 5.14-5.23(m,1H), 4.49-4.68(m,2H), 3.78-3.79(m,3H), 1.48-1.54(m,9H).
MS(ESI,pos.ion)m/z:458.05[M+Na] +. MS(ESI,pos.ion)m/z:458.05[M+Na] + .
步骤4：化合物(2R)-1-叔丁基2-甲基4-(3,4-双(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯的合成Step 4: Synthesis of compound (2R)-1-tert-butyl 2-methyl 4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate
将化合物(R)-1-叔丁基2-甲基4-(3,4-双(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(755mg,1.74mmol)溶于甲醇(6mL)，加入Pd/C(76mg,10％)，通入氢气室温反应19h，将反应液抽滤，滤液浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到无色液体653mg，产率86％。The compound (R)-1-tert-butyl 2-methyl 4-(3,4-bis(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylic acid The ester (755mg, 1.74mmol) was dissolved in methanol (6mL), Pd/C (76mg, 10%) was added, and hydrogen was introduced to react at room temperature for 19 hours. The reaction solution was filtered off, the filtrate was concentrated, and silica gel column chromatography was performed (elution Reagent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain 653 mg of colorless liquid, with a yield of 86%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.24(d,J＝8.3Hz,1H),7.12-7.16(m,2H),6.54(t,J F-H＝73.5Hz,1H),6.52(t,J F-H＝73.5Hz,1H),4.34-4.44(m,1H),3.96-4.10(m,1H),3.78–3.79(m,3H),3.34-3.46(m,2H),2.67-2.73(m,1H),2.01-2.09(m,1H),1.45–1.49(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.24 (d, J = 8.3Hz, 1H), 7.12-7.16 (m, 2H), 6.54 (t, J FH = 73.5Hz, 1H), 6.52 ( t, J FH = 73.5Hz, 1H), 4.34-4.44 (m, 1H), 3.96-4.10 (m, 1H), 3.78-3.79 (m, 3H), 3.34-3.46 (m, 2H), 2.67-2.73 (m,1H),2.01-2.09(m,1H),1.45-1.49(m,9H).
MS(ESI,pos.ion)m/z:460.20[M+Na] +. MS(ESI,pos.ion)m/z:460.20[M+Na] + .
步骤5：化合物(2R)-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成Step 5: Synthesis of compound (2R)-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R)-1-叔丁基2-甲基4-(3,4-双(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(650mg,1.49mmol)溶解于二氯甲烷(4mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(6mL)，室温搅拌1.5h，除去溶剂，得到浅黄色液体552mg，收率98％。Compound (2R)-1-tert-butyl 2-methyl 4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (650mg, 1.49mmol) Dissolve in dichloromethane (4mL) solution, add 4mol/L HCl ethyl acetate solution (6mL), stir at room temperature for 1.5h, remove the solvent, obtain light yellow liquid 552mg, yield 98%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.28-7.34(m,3H),6.86(t,J F-H＝73.6Hz,1H),4.62–4.64(m,1H),3.90(s,3H),3.81-3.87(m,1H),3.69-3.77(m,1H),3.37(d,J＝11.0Hz,1H),2.85-2.92(m,1H),2.20-2.29(m,1H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.28-7.34 (m, 3H), 6.86 (t, J FH = 73.6 Hz, 1H), 4.62-4.64 (m, 1H), 3.90 (s, 3H), 3.81-3.87(m,1H), 3.69-3.77(m,1H), 3.37(d,J=11.0Hz,1H), 2.85-2.92(m,1H), 2.20-2.29(m,1H) .
MS(ESI,pos.ion)m/z:338.15[M+H-HCl] +. MS(ESI,pos.ion)m/z:338.15[M+H-HCl] + .
步骤6：化合物(2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯的合成Step 6: Synthesis of compound (2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(2R)-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐(550mg,1.48mmol)溶解在二氯甲烷(8mL)中，加入N,N-二异丙基乙胺(0.95mL,5.70mmol)，0℃条件下加入乙酰氯(0.35mL,4.90mmol)，室温搅拌4h后停止反应，加水(20mL)搅拌，二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/4)，得到浅黄色液体586mg，产率95％。Compound (2R)-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (550mg, 1.48mmol) was dissolved in dichloromethane (8mL) Add N,N-diisopropylethylamine (0.95mL, 5.70mmol), add acetyl chloride (0.35mL, 4.90mmol) at 0°C, stir at room temperature for 4h, then stop the reaction, add water (20mL) and stir. Extraction with methyl chloride (10mL×3), dry the organic phase with anhydrous sodium sulfate, and separate the concentrated solution by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/4) to obtain 586 mg of yellow liquid, 95% yield.
1H NMR(400MHz,CD 3OD)δ(ppm):7.24-7.314(m,3H),6.85(t,J F-H＝73.7Hz,1H),6.81(t,J F-H＝73.7Hz,1H),4.46–4.51(m,1H),4.09-4.15(m,1H),3.76(s,3H),3.62(t,J＝8.2Hz,1H),3.57-3.61(m,1H),2.72-2.77(m,1H),2.14(s,3H),2.01-2.07(m,1H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.24-7.314 (m, 3H), 6.85 (t, J FH = 73.7Hz, 1H), 6.81 (t, J FH = 73.7Hz, 1H), 4.46–4.51(m,1H),4.09-4.15(m,1H),3.76(s,3H),3.62(t,J=8.2Hz,1H),3.57-3.61(m,1H),2.72-2.77( m, 1H), 2.14 (s, 3H), 2.01-2.07 (m, 1H).
MS(ESI,pos.ion)m/z:380.10[M+H] +. MS(ESI,pos.ion)m/z:380.10[M+H] + .
步骤7：化合物(2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-羧酸的合成Step 7: Synthesis of compound (2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid
将化合物(2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯(530mg,1.40mmol)溶于四氢呋喃(8mL)和水(5mL)的混合溶剂中，加入一水合氢氧化锂(203mg,4.8mmol)，50℃反应2h后停止，加盐酸调节溶液pH＝6，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到白色固体552mg，收率92％。The compound (2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (530mg, 1.40mmol) was dissolved in tetrahydrofuran (8mL) In the mixed solvent of water (5mL), add lithium hydroxide monohydrate (203mg, 4.8mmol), react at 50℃ for 2h, stop, add hydrochloric acid to adjust the solution pH=6, extract with ethyl acetate (10mL×3), organic The phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 552 mg of white solid with a yield of 92%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.25–7.31(m,3H),6.85(t,J F-H＝73.7Hz,1H),6.81(t,J F-H＝73.7Hz,1H),4.44–4.49(m,1H),4.11-4.15(m,1H),3.54–3.64(m,2H),3.54-3.60(m,1H),2.74-2.81(m,1H),2.14(s,3H),2.00-2.08(m,1H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.25–7.31 (m, 3H), 6.85 (t, J FH = 73.7Hz, 1H), 6.81 (t, J FH = 73.7Hz, 1H), 4.44–4.49(m,1H),4.11-4.15(m,1H),3.54–3.64(m,2H),3.54-3.60(m,1H),2.74-2.81(m,1H),2.14(s,3H) ), 2.00-2.08 (m, 1H).
MS(ESI,pos.ion)m/z:366.15[M+H] +. MS(ESI,pos.ion)m/z:366.15[M+H] + .
步骤8：化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸乙酯的合成Step 8: Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)picolinic acid ethyl Synthesis of esters
将化合物(2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-羧酸(500mg,1.37mmol)，6-(氨基甲基)吡啶甲酸乙酯盐酸盐(415mg,1.64mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.3g,6.80mmol)和N-羟基-7-氮杂苯并三氮唑(280mg,2.06mmol)溶于二氯甲烷(15mL)中，0℃条件下滴加N,N-二异丙基乙胺(1.4mL,8.5mmol)，室温反应16h，加水洗(10mL×3)有机相，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到浅黄色固体482mg，收率66％。The compound (2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (500mg, 1.37mmol), 6-(aminomethyl) Ethyl picolinate hydrochloride (415mg, 1.64mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.3g, 6.80mmol) and N-hydroxy-7 -Azabenzotriazole (280mg, 2.06mmol) was dissolved in dichloromethane (15mL), N,N-diisopropylethylamine (1.4mL, 8.5mmol) was added dropwise at 0°C, and reacted at room temperature 16h, wash the organic phase with water (10mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/ 1) To obtain 482 mg of light yellow solid with a yield of 66%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.02(d,J＝7.6Hz,1H),7.83(t,J＝7.8Hz,1H),7.55(d,J＝7.8Hz,1H),7.48(br.s,1H),7.14–7.24(m,3H),6.55(t,J F-H＝73.5Hz,1H),6.52(t,J F-H＝73.5Hz,1H),4.61–4.76(m,3H),4.47(q＝7.1Hz,2H),3.99–4.04(m,1H),3.62(t,J＝10.6Hz,1H),3.38–3.45(m,1H),2.61–2.68(m,1H),2.42–2.50(m,1H),2.18(s,3H),1.44(t,J＝7.1Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.02 (d, J = 7.6 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.48(br.s,1H),7.14–7.24(m,3H),6.55(t,J FH =73.5Hz,1H),6.52(t,J FH =73.5Hz,1H),4.61–4.76(m, 3H), 4.47(q=7.1Hz,2H),3.99–4.04(m,1H),3.62(t,J=10.6Hz,1H), 3.38–3.45(m,1H), 2.61–2.68(m,1H ), 2.42-2.50 (m, 1H), 2.18 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).
MS(ESI,pos.ion)m/z:528.15[M+H] +. MS(ESI,pos.ion)m/z:528.15[M+H] + .
步骤9：化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸的合成Step 9: Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)picolinic acid synthesis
将化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸乙酯(470mg,0.39mmol)溶于四氢呋喃(8mL)和水(5mL)的混合溶剂中，加入一水合氢氧化锂(183mg,4.36mmol)，50℃反应2h后停止，加稀盐酸调节溶液pH＝6，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到白色固体426mg，收率95％。The compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)picolinate ( 470mg, 0.39mmol) was dissolved in a mixed solvent of tetrahydrofuran (8mL) and water (5mL), lithium hydroxide monohydrate (183mg, 4.36mmol) was added, the reaction was stopped at 50°C for 2h, and diluted hydrochloric acid was added to adjust the pH of the solution to 6. It was extracted with ethyl acetate (10 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 426 mg of white solid with a yield of 95%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.06(d,J＝7.5Hz,1H),7.99(t,J＝7.7Hz,1H),7.75(d,J＝7.7Hz,1H),7.26–7.32(m,3H),6.85(t,J F-H＝73.8Hz,1H),6.81(t,J F-H＝73.8Hz,1H),4.53–4.73(m,3H),4.11–4.17(m,1H),3.66(t,J＝10.9Hz,1H),3.55–3.60(m,1H),2.70–2.76(m,1H),2.16(s,3H),2.06–2.15(m,1H). 1 H NMR(400MHz,CD 3 OD)δ(ppm): 8.06(d,J=7.5Hz,1H),7.99(t,J=7.7Hz,1H),7.75(d,J=7.7Hz,1H) ,7.26–7.32(m,3H),6.85(t,J FH =73.8Hz,1H),6.81(t,J FH =73.8Hz,1H),4.53–4.73(m,3H),4.11–4.17(m ,1H), 3.66(t,J=10.9Hz,1H), 3.55-3.60(m,1H), 2.70-2.76(m,1H), 2.16(s,3H), 2.06-2.15(m,1H).
MS(ESI,pos.ion)m/z:500.10[M+H] +. MS(ESI,pos.ion)m/z:500.10[M+H] + .
步骤10：化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺的合成Step 10: Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)-N, Synthesis of N-dimethylpyridine amide
将化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(80mg,0.16mmol)，二甲胺盐酸盐(66mg,0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(151mg,0.79mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.27mL,1.60mmol)，室温反应10h，加水洗(15mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体52mg，收率61％。Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)picolinic acid (80mg, 0.16mmol), dimethylamine hydrochloride (66mg, 0.81mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (151mg, 0.79mmol) and N-hydroxyl -7-azabenzotriazole (43mg, 0.32mmol) was dissolved in dichloromethane (5mL), and N,N-diisopropylethylamine (0.27mL, 1.60mmol), reacted at room temperature for 10h, washed with water (15mL), and extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: Dichloromethane/methanol (v/v)=30/1) to obtain 52 mg of a white solid with a yield of 61%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.77(t,J＝7.7Hz,1H),7.56(br.s,1H),7.47(d,J＝7.5Hz,1H),7.38(d,J＝7.8Hz,1H),7.13–7.25(m,3H),6.56(t,J F-H＝73.5Hz,1H),6.53(t,J F-H＝73.5Hz,1H),4.51–4.67(m,3H),3.99(dd,J＝9.9,7.6Hz,1H),3.58(t,J＝10.6Hz,1H),3.34–3.43(m,1H),3.14(s,3H),3.06(s,3H),2.58–2.65(m,1H),2.42–2.50(m,1H),2.15(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.77 (t, J = 7.7 Hz, 1H), 7.56 (br.s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.38 (d ,J=7.8Hz,1H),7.13–7.25(m,3H),6.56(t,J FH =73.5Hz,1H),6.53(t,J FH =73.5Hz,1H),4.51–4.67(m, 3H), 3.99 (dd, J = 9.9, 7.6 Hz, 1H), 3.58 (t, J = 10.6 Hz, 1H), 3.34–3.43 (m, 1H), 3.14 (s, 3H), 3.06 (s, 3H) ), 2.58–2.65(m,1H), 2.42–2.50(m,1H), 2.15(s,3H).
13C NMR(100MHz,CDCl 3)δ(ppm):171.3,169.8,168.8,156.0,153.9,142.4,141.3,138.51,137.7,125.3,122.6,122.2,121.6,118.3,115.7,113.1,59.9,54.7,44.7,43.3,39.0,35.6,35.5,22.6. 13 C NMR (100MHz, CDCl 3 ) δ (ppm): 171.3, 169.8, 168.8, 156.0, 153.9, 142.4, 141.3, 138.51, 137.7, 125.3, 122.6, 122.2, 121.6, 118.3, 115.7, 113.1, 59.9, 54.7, 44.7, 43.3, 39.0, 35.6, 35.5, 22.6.
MS(ESI,pos.ion)m/z:527.15[M+H] +. MS(ESI,pos.ion)m/z:527.15[M+H] + .
实施例47：化合物6-(((2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺Example 47: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido )Methyl)-N,N-lutidine amide
Figure PCTCN2021090489-appb-000109
Figure PCTCN2021090489-appb-000109
步骤1：化合物(2R)-1-叔丁基2-甲基4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯的合成Step 1: Compound (2R)-1-tert-butyl 2-methyl 4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxy Synthesis of acid esters
将化合物(2R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-1,2-二羧酸酯(487mg,1.25mmol)，碳酸钾(364mg,2.63mmol)溶于N,N-二甲基甲酰胺(10mL)中，室温下向此溶液中加入环戊基溴(303mg,2.03mmol)，70℃下反应5h，加水洗(50mL)，用乙酸乙酯萃取(15mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到淡 黄色液体273mg，收率47％。Compound (2R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-1,2-dicarboxylate (487mg, 1.25mmol ), potassium carbonate (364mg, 2.63mmol) was dissolved in N,N-dimethylformamide (10mL), cyclopentyl bromide (303mg, 2.03mmol) was added to this solution at room temperature, and reacted at 70℃ for 5h, Washed with water (50mL), extracted with ethyl acetate (15mL×3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v /v)=2/1) to obtain 273 mg of pale yellow liquid with a yield of 47%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.09(d,J＝8.2Hz,1H),7.04(s,1H),6.94(t,J F-H＝74.8Hz,1H),6.84(d,J＝8.3Hz,1H),4.91-4.94(m,1H),4.27-4.31(m,1H),3.86-3.93(m,1H),3.69(s,2H),3.66(s,1H),3.37-3.45(m,1H),3.18-3.267(m,1H),2.60-2.68(m,1H),1.85-1.93(m,3H),1.66-1.76(m,4H),1.55-1.61(m,2H),1.35-1.40(m,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.09 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.94 (t, J FH = 74.8 Hz, 1H), 6.84 ( d,J=8.3Hz,1H),4.91-4.94(m,1H),4.27-4.31(m,1H),3.86-3.93(m,1H), 3.69(s,2H), 3.66(s,1H) , 3.37-3.45(m,1H),3.18-3.267(m,1H),2.60-2.68(m,1H),1.85-1.93(m,3H),1.66-1.76(m,4H),1.55-1.61( m,2H),1.35-1.40(m,9H).
MS(ESI,pos.ion)m/z:478.30[M+Na] +. MS(ESI,pos.ion)m/z:478.30[M+Na] + .
步骤2：化合物(2R)-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成Step 2: Synthesis of compound (2R)-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R)-1-叔丁基2-甲基4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(412mg,0.88mmol)溶解于二氯甲烷(4mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(3mL)，室温搅拌1h，除去溶剂，得到无色液体269mg，收率76％。The compound (2R)-1-tert-butyl 2-methyl 4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (412mg, 0.88mmol) was dissolved in dichloromethane (4mL) solution, 4mol/L HCl ethyl acetate solution (3mL) was added, stirred at room temperature for 1h, and the solvent was removed to obtain 269mg of colorless liquid with a yield of 76%.
MS(ESI,pos.ion)m/z:356.20[M+H-HCl] +. MS(ESI,pos.ion)m/z:356.20[M+H-HCl] + .
步骤3：化合物(2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯的合成Step 3: Synthesis of compound (2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(2R)-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐(269mg,0.76mmol)溶解在二氯甲烷(6mL)中，加入N,N-二异丙基乙胺(0.5mL,3.0mmol)，0℃条件下滴加乙酰氯(0.2mL,3.0mmol)，室温搅拌4h后停止反应，加入50mL水洗，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到浅黄色液体213mg，收率70％。The compound (2R)-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (269mg, 0.76mmol) was dissolved in Add N,N-diisopropylethylamine (0.5mL, 3.0mmol) to dichloromethane (6mL), add acetyl chloride (0.2mL, 3.0mmol) dropwise at 0°C, stir at room temperature for 4h and then stop the reaction. Wash with 50mL of water, extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, and separate the concentrated solution by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1 /2) to obtain 213 mg of light yellow liquid with a yield of 70%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.11(d,J＝8.3Hz,1H),7.04-7.08(m,1H),6.94(t,J F-H＝74.8Hz,1H),6.87(d,J＝8.3,1.7Hz,1H),4.91-4.94(m,1H),4.29-4.34(m,1H),4.06-4.09(m,1H),3.63(s,3H),3.41-3.49(m,2H),2.61-2.68(m,1H),2.01(s,3H),1.83-1.91(m,3H),1.68-1.77(m,4H),1.54-1.62(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.11 (d, J = 8.3 Hz, 1H), 7.04-7.08 (m, 1H), 6.94 (t, J FH = 74.8 Hz, 1H), 6.87(d,J=8.3,1.7Hz,1H),4.91-4.94(m,1H),4.29-4.34(m,1H),4.06-4.09(m,1H),3.63(s,3H),3.41- 3.49 (m, 2H), 2.61-2.68 (m, 1H), 2.01 (s, 3H), 1.83-1.91 (m, 3H), 1.68-1.77 (m, 4H), 1.54-1.62 (m, 2H).
MS(ESI,pos.ion)m/z:398.25[M+H] +. MS(ESI,pos.ion)m/z:398.25[M+H] + .
步骤4：化合物(2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸的合成Step 4: Synthesis of compound (2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid
将化合物(2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯(213mg,0.54mmol)溶于四氢呋喃(6mL)和水(3mL)的混合溶剂中，加入一水合氢氧化锂(113mg,2.69mmol)，50℃反应2h后停止，加盐酸调节溶液pH＝1，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到淡黄色液体197mg，收率96％。The compound (2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (213mg, 0.54mmol) Dissolved in a mixed solvent of tetrahydrofuran (6mL) and water (3mL), added lithium hydroxide monohydrate (113mg, 2.69mmol), reacted at 50°C for 2h and then stopped, added hydrochloric acid to adjust the pH of the solution to 1, and extracted with ethyl acetate ( 5 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 197 mg of pale yellow liquid with a yield of 96%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.11(d,J＝8.3Hz,1H),7.04-7.08(m,1H),6.95(t,J F-H＝74.8Hz,1H),6.87(d,J＝8.3,1.7Hz,1H),4.91-4.94(m,1H),4.21-4.25(m,1H),4.03-4.10(m,1H),3.40-3.49(m,2H),2.63-2.69(m,1H),2.01(s,3H),1.82-1.95(m,3H),1.67-1.78(m,4H),1.53-1.63(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.11 (d, J = 8.3 Hz, 1H), 7.04-7.08 (m, 1H), 6.95 (t, J FH = 74.8 Hz, 1H), 6.87(d,J=8.3,1.7Hz,1H),4.91-4.94(m,1H),4.21-4.25(m,1H),4.03-4.10(m,1H),3.40-3.49(m,2H), 2.63-2.69 (m, 1H), 2.01 (s, 3H), 1.82-1.95 (m, 3H), 1.67-1.78 (m, 4H), 1.53-1.63 (m, 2H).
MS(ESI,pos.ion)m/z:384.10[M+H] +. MS(ESI,pos.ion)m/z:384.10[M+H] + .
步骤5：化合物6-(((2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸乙酯的合成Step 5: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Synthesis of ethyl picolinate
将化合物(2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(197mg,0.51mmol)，6-(氨基甲基)吡啶甲酸乙酯盐酸盐(164mg,0.76mmol)，1-乙基-(3-二甲氨基丙基)碳酰二亚胺盐酸盐(213mg,1.11mmol)和N-羟基-7-氮杂苯并三氮唑(106mg,0.78mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.6mL,4.0mmol)，室温搅拌7h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到淡黄色固体231mg，收率82％。The compound (2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (197mg, 0.51mmol), 6 -(Aminomethyl) ethyl picolinate hydrochloride (164mg, 0.76mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (213mg, 1.11mmol) and N -Hydroxy-7-azabenzotriazole (106mg, 0.78mmol) was dissolved in dichloromethane (6mL), and N,N-diisopropylethylamine (0.6mL, 4.0mmol), stirred at room temperature for 7h, washed with water (50mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: Dichloromethane/methanol (v/v)=20/1) to obtain 231 mg of light yellow solid with a yield of 82%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.65-8.68(m,1H),7.90-7.98(m,2H),7.67(d,J＝7.3Hz,1H), 7.11(d,J＝8.3Hz,1H),7.04-7.06(m,1H),6.95(t,J F-H＝74.8Hz,1H),6.87-6.89(m,1H),4.85-4.90(m,1H),4.29-4.52(m,5H),4.04-4.10(m,1H),3.44-3.56(m,2H),2.60-2.67(m,1H),2.04(s,3H),1.85-1.94(m,3H),1.66-1.78(m,4H),1.52-1.62(m,2H),1.31(t,J＝7.1Hz,3H) 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.65-8.68 (m, 1H), 7.90-7.98 (m, 2H), 7.67 (d, J = 7.3Hz, 1H), 7.11 (d, J = 8.3Hz, 1H), 7.04-7.06 (m, 1H), 6.95 (t, J FH = 74.8Hz, 1H), 6.87-6.89 (m, 1H), 4.85-4.90 (m, 1H), 4.29- 4.52(m,5H),4.04-4.10(m,1H),3.44-3.56(m,2H),2.60-2.67(m,1H),2.04(s,3H),1.85-1.94(m,3H), 1.66-1.78(m,4H),1.52-1.62(m,2H),1.31(t,J=7.1Hz,3H)
MS(ESI,pos.ion)m/z:546.30[M+H] +. MS(ESI,pos.ion)m/z:546.30[M+H] + .
步骤6：化合物6-(((2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸的合成Step 6: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Synthesis of (methyl)picolinic acid
将化合物6-(((2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸乙酯(231mg,0.42mmol)溶于四氢呋喃(6mL)和水(4mL)的混合溶剂中，再加入一水合氢氧化锂(96mg,1.71mmol)，50℃反应2h后停止，加盐酸调节溶液pH＝1，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到淡黄色固体215mg，收率98％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl ) Ethyl picolinate (231mg, 0.42mmol) was dissolved in a mixed solvent of tetrahydrofuran (6mL) and water (4mL), and then lithium hydroxide monohydrate (96mg, 1.71mmol) was added. The reaction was stopped at 50°C for 2h, and hydrochloric acid was added. The solution was adjusted to pH=1, extracted with ethyl acetate (5 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 215 mg of a pale yellow solid with a yield of 98%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.67(t,J＝6.0Hz,1H),7.90-7.96(m,2H),7.65(d,J＝7.3Hz,1H),7.12(d,J＝8.4Hz,1H),7.08-7.24(m,1H),6.95(t,J F-H＝74.8Hz,1H),6.87-6.90(m,1H),4.88-4.92(m,1H),4.35-4.53(m,3H),4.08-4.10(m,1H),3.43-3.52(m,2H),2.60-2.67(m,1H),2.04(s,3H),1.85-1.94(m,3H),1.67-1.77(m,4H),1.54-1.63(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.67 (t, J = 6.0 Hz, 1H), 7.90-7.96 (m, 2H), 7.65 (d, J = 7.3 Hz, 1H), 7.12 (d,J=8.4Hz,1H),7.08-7.24(m,1H),6.95(t,J FH =74.8Hz,1H),6.87-6.90(m,1H),4.88-4.92(m,1H) ,4.35-4.53(m,3H),4.08-4.10(m,1H),3.43-3.52(m,2H),2.60-2.67(m,1H),2.04(s,3H),1.85-1.94(m, 3H), 1.67-1.77 (m, 4H), 1.54-1.63 (m, 2H).
MS(ESI,pos.ion)m/z:518.25[M+H] +. MS(ESI,pos.ion)m/z:518.25[M+H] + .
步骤7：化合物6-(((2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺的合成Step 7: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Synthesis of (methyl)-N,N-lutidineamide
将化合物6-(((2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(76mg,0.15mmol)，二甲胺盐酸盐(45mg,1.0mmol)，1-乙基-(3-二甲氨基丙基)碳酰二亚胺盐酸盐(86mg,0.45mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.31mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌20h，加水洗(50mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体37mg，收率46％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl ) Picolinic acid (76mg, 0.15mmol), dimethylamine hydrochloride (45mg, 1.0mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg, 0.45mmol) ) And N-hydroxy-7-azabenzotriazole (43mg, 0.31mmol) were dissolved in dichloromethane (6mL), and N,N-diisopropylethylamine ( 0.3mL, 2.0mmol), stirred at room temperature for 20h, washed with water (50mL), and then extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column separation (eluent: Dichloromethane/methanol (v/v)=15/1) to obtain 37 mg of white solid with a yield of 46%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.56-8.86(m,1H),7.80-7.92(m,1H),7.47(d,J＝7.5Hz,1H),7.32-7.41(m,1H),7.01-7.15(m,2H),6.95(t,J F-H＝74.8Hz,1H),6.82-6.91(m,1H),4.84-4.97(m,1H),4.30-4.52(m,3H),4.02-4.26(m,1H),3.39-3.57(m,2H),2.98(s,3H),2.91(s,3H),2.56-2.71(m,1H),2.04(s,3H),1.83-1.94(m,3H),1.67-1.77(m,4H),1.54-1.63(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.56-8.86 (m, 1H), 7.80-7.92 (m, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.32-7.41 ( m,1H),7.01-7.15(m,2H),6.95(t,J FH =74.8Hz,1H),6.82-6.91(m,1H),4.84-4.97(m,1H),4.30-4.52(m , 3H), 4.02-4.26 (m, 1H), 3.39-3.57 (m, 2H), 2.98 (s, 3H), 2.91 (s, 3H), 2.56-2.71 (m, 1H), 2.04 (s, 3H) ), 1.83-1.94 (m, 3H), 1.67-1.77 (m, 4H), 1.54-1.63 (m, 2H).
MS(ESI,pos.ion)m/z:545.30[M+H] +. MS(ESI,pos.ion)m/z:545.30[M+H] + .
实施例48：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-(乙氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺Example 48: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-(ethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)-N,N-lutidine amide
Figure PCTCN2021090489-appb-000110
Figure PCTCN2021090489-appb-000110
步骤1：化合物(2R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-乙氧基苯基)吡咯烷-1,2-二羧酸酯的合成Step 1: Compound (2R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-1,2-dicarboxylate synthesis
将化合物(2R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-羟基苯基)吡咯-1,2-二羧酸酯(489mg,1.26 mmol)，碳酸钾(364mg,2.63mmol)溶于N,N-二甲基甲酰胺(10mL)中，室温下向此溶液中加入碘乙烷(0.2mL,3.0mmol)，70℃下反应3h，加水洗(50mL)，然后乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到淡黄色液体323mg，收率62％。Compound (2R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrole-1,2-dicarboxylate (489 mg, 1.26 mmol) , Potassium carbonate (364mg, 2.63mmol) was dissolved in N,N-dimethylformamide (10mL), and iodoethane (0.2mL, 3.0mmol) was added to this solution at room temperature, and reacted at 70°C for 3h. Washed with water (50mL), then extracted with ethyl acetate (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/ v)=2/1), 323 mg of pale yellow liquid was obtained, with a yield of 62%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.10(d,J＝8.2Hz,1H),7.06(s,1H),7.01(t,J F-H＝74.9Hz,1H),6.86(dd,J＝8.3,1.7Hz,1H),4.26-4.32(m,1H),4.10(q,J＝7.0Hz,2H),3.85-3.95(m,1H),3.65-3.72(m,3H),3.39-3.47(m,1H),3.16-3.26(m,1H),2.58-2.69(m,1H),1.88-2.00(m,1H),1.39-1.40(m,3H),1.33-1.35(m,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.10 (d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 7.01 (t, J FH = 74.9 Hz, 1H), 6.86 ( dd,J=8.3,1.7Hz,1H),4.26-4.32(m,1H),4.10(q,J=7.0Hz,2H),3.85-3.95(m,1H),3.65-3.72(m,3H) , 3.39-3.47 (m, 1H), 3.16-3.26 (m, 1H), 2.58-2.69 (m, 1H), 1.88-2.00 (m, 1H), 1.39-1.40 (m, 3H), 1.33-1.35 ( m,9H).
MS(ESI,pos.ion)m/z:438.20[M+Na] +. MS(ESI,pos.ion)m/z:438.20[M+Na] + .
步骤2：化合物(2R)-4-(4-(二氟甲氧基)-3-乙氧基苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成Step 2: Synthesis of compound (2R)-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-乙氧基苯基)吡咯烷-1,2-二羧酸酯(323mg,0.58mmol)溶解于二氯甲烷(4mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(3mL)，室温搅拌1h，除去溶剂，得到淡黄色液体175mg，收率94％。Compound (2R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-1,2-dicarboxylate (323mg, 0.58mmol) was dissolved in dichloromethane (4mL) solution, 4mol/L HCl ethyl acetate solution (3mL) was added, stirred at room temperature for 1h, and the solvent was removed to obtain 175mg of pale yellow liquid with a yield of 94%.
MS(ESI,pos.ion)m/z:316.10[M+H-HCl] +. MS(ESI,pos.ion)m/z:316.10[M+H-HCl] + .
步骤3：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-乙氧基苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成Step 3: Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R)-4-(4-(二氟甲氧基)-3-乙氧基苯基)吡咯烷-2-羧酸甲酯盐酸盐(175mg,0.56mmol)溶解在二氯甲烷(6mL)中，加入N,N-二异丙基乙胺(0.3mL,2.0mmol)，0℃条件下滴加乙酰氯(0.1mL,1.0mmol)，室温搅拌16h后停止反应，加入水(50mL)有机相，水相用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到浅黄色液体166mg，收率84％。Compound (2R)-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (175mg, 0.56mmol) was dissolved in dichloromethane (6mL), add N,N-diisopropylethylamine (0.3mL, 2.0mmol), add acetyl chloride (0.1mL, 1.0mmol) dropwise at 0℃, stir at room temperature for 16h, then stop the reaction, add water ( 50mL) the organic phase, the aqueous phase was extracted with dichloromethane (5mL×3), the organic phase was dried over anhydrous sodium sulfate, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) )=1/2) to obtain 166 mg of light yellow liquid with a yield of 84%.
MS(ESI,pos.ion)m/z:358.10[M+H] +. MS(ESI,pos.ion)m/z:358.10[M+H] + .
步骤4：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-乙氧基苯基)吡咯烷-2-羧酸的合成Step 4: Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylic acid
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-乙氧基苯基)吡咯烷-2-羧酸甲酯盐酸盐(166mg,0.46mmol)溶于四氢呋喃(6mL)和水(3mL)的混合溶剂中，再加入一水合氢氧化锂(113mg,2.69mmol)，50℃反应2h后停止，加盐酸调节溶液pH＝1，再用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到淡黄色液体149mg，收率93％。Compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (166mg, 0.46mmol) Dissolve in a mixed solvent of tetrahydrofuran (6mL) and water (3mL), add lithium hydroxide monohydrate (113mg, 2.69mmol), stop at 50°C for 2h, add hydrochloric acid to adjust the pH of the solution to 1, then use ethyl acetate After extraction (5 mL×3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 149 mg of a pale yellow liquid with a yield of 93%.
MS(ESI,pos.ion)m/z:344.20[M+H] +. MS(ESI,pos.ion)m/z:344.20[M+H] + .
步骤5：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-(乙氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基吡啶酰胺的合成Step 5: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-(ethoxy)phenyl)pyrrolidine-2-carboxamido)methan Yl)-N,N-dimethylpyridine amide
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-(乙氧基)苯基)吡咯烷-2-羧酸(67mg,0.20mmol)，6-(氨基甲基)-N,N-二甲基吡啶酰胺二盐酸盐(96mg,0.54mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(88mg,0.46mmol)和N-羟基-7-氮杂苯并三氮唑(56mg,0.41mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌16h，加水洗(50mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体56mg，收率57％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-(ethoxy)phenyl)pyrrolidine-2-carboxylic acid (67mg, 0.20mmol), 6- (Aminomethyl)-N,N-lutidine amide dihydrochloride (96mg, 0.54mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride ( 88mg, 0.46mmol) and N-hydroxy-7-azabenzotriazole (56mg, 0.41mmol) were dissolved in dichloromethane (6mL), and N,N-diisopropyl was added dropwise to this solution at room temperature Ethylethylamine (0.3mL, 2.0mmol), stirred at room temperature for 16h, washed with water (50mL), and then extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column separation ( Eluent: dichloromethane/methanol (v/v)=20/1) to obtain 56 mg of white solid with a yield of 57%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.61-8.83(m,1H),7.81-7.92(m,1H),7.31-7.52(m,2H),7.04-7.16(m,2H),7.01(t,J F-H＝74.8Hz,1H),6.89(d,J＝7.9Hz,1H),4.29-4.56(m,3H),3.99-4.21(m,3H),3.39-3.56(m,2H),2.97(s,3H),2.90(s,3H),2.54-2.69(m,1H),2.03(s,3H),1.81-1.90(m,1H),1.28-1.38(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.61-8.83 (m, 1H), 7.81-7.92 (m, 1H), 7.31-7.52 (m, 2H), 7.04-7.16 (m, 2H) ), 7.01 (t, J FH = 74.8 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 4.29-4.56 (m, 3H), 3.99-4.21 (m, 3H), 3.39-3.56 (m ,2H),2.97(s,3H),2.90(s,3H),2.54-2.69(m,1H),2.03(s,3H),1.81-1.90(m,1H),1.28-1.38(m,3H) ).
MS(ESI,pos.ion)m/z:505.20[M+H] +. MS(ESI,pos.ion)m/z:505.20[M+H] + .
实施例49：化合物6-((2R-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基-d 6-吡啶酰胺 Example 49: Compound 6-((2R-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido )Methyl)-N,N-dimethyl-d 6 -pyridine amide
Figure PCTCN2021090489-appb-000111
Figure PCTCN2021090489-appb-000111
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(90mg,0.18mmol)，N,N-二甲基-d 6-胺盐酸盐(77mg,0.88mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(173mg,0.9mmol)和N-羟基-7-氮杂苯并三氮唑(48mg,0.35mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.15mL,0.91mmol)，室温反应12h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝25/1)，得到白色固体68mg，收率70％。 The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (90mg, 0.18mmol), N,N-dimethyl-d 6 -amine hydrochloride (77mg, 0.88mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Diimide hydrochloride (173mg, 0.9mmol) and N-hydroxy-7-azabenzotriazole (48mg, 0.35mmol) were dissolved in dichloromethane (5mL) and added to this solution at 0℃ Add N,N-diisopropylethylamine (0.15mL, 0.91mmol) dropwise to the mixture, react at room temperature for 12h, add water (15mL), extract with dichloromethane (5mL×3), and dry the organic phase with anhydrous sodium sulfate. The solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=25/1) to obtain 68 mg of white solid with a yield of 70%.
1H NMR(600MHz,CD 3OD)δ(ppm):7.93(t,J＝7.7Hz,1H),7.61(d,J＝7.6Hz,1H),7.46(d,J＝7.3Hz,1H),7.12(d,J＝7.9Hz,1H),7.09(s,1H),6.94(d,J＝7.9Hz,1H),6.75(t,J F-H＝75.7Hz,1H),4.49–4.65(m,3H),4.10–4.13(m,1H),3.94(d,J＝6.7Hz,2H),3.66(t,J＝10.5Hz,1H),3.48–3.56(m,1H),2.68–2.72(m,1H),2.16(s,3H),2.05–2.21(m,1H),1.32–1.39(m,1H),0.63–0.67(m,2H),0.37–0.41(m,2H). 1 H NMR (600MHz, CD 3 OD) δ (ppm): 7.93 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H) ,7.12(d,J=7.9Hz,1H),7.09(s,1H),6.94(d,J=7.9Hz,1H),6.75(t,J FH =75.7Hz,1H),4.49–4.65(m ,3H), 4.10–4.13(m,1H), 3.94(d,J=6.7Hz,2H), 3.66(t,J=10.5Hz,1H), 3.48–3.56(m,1H), 2.68–2.72( m,1H), 2.16(s,3H), 2.05-2.21(m,1H), 1.32-1.39(m,1H), 0.63-0.67(m,2H), 0.37-0.41(m,2H).
MS(ESI,pos.ion)m/z:537.25[M+H] +. MS(ESI,pos.ion)m/z:537.25[M+H] + .
实施例50：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二甲基-d 6-吡啶酰胺 Example 50: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy) )Phenyl)pyrrolidine-2-carboxamido)methyl)-N,N-dimethyl-d 6 -pyridine amide
Figure PCTCN2021090489-appb-000112
Figure PCTCN2021090489-appb-000112
步骤1：化合物(2R)-1-叔丁基2-甲基4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯的合成Step 1: Compound (2R)-1-tert-butyl 2-methyl 4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy) Synthesis of phenyl)pyrrolidine-1,2-dicarboxylate
将(2R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-1,2-二羧酸酯(630mg,1.63mmol)，1,1-二氘代环丙基甲醇(247mg,3.33mmol)，三苯基膦(1.08g,14.12mmol)溶解在干燥的四氢呋喃(10mL)溶液中，冰浴条件下缓慢加入偶氮二甲酸二异丙酯(247mg,3.33mmol)，室温反应4h，加入水(20mL)，再用乙酸乙酯(5mL×3)萃取，有机相合用无水硫酸钠干燥，除去溶剂，减压浓缩，经硅胶柱层析色谱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到无色液体653mg，收率90％。(2R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-1,2-dicarboxylate (630mg, 1.63mmol) , 1,1-Dideuterated cyclopropyl methanol (247mg, 3.33mmol), triphenylphosphine (1.08g, 14.12mmol) were dissolved in dry tetrahydrofuran (10mL) solution, and azobis was slowly added under ice bath conditions Diisopropyl formate (247mg, 3.33mmol) was reacted at room temperature for 4h, water (20mL) was added, and then extracted with ethyl acetate (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and concentrated under reduced pressure. It was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain 653 mg of colorless liquid with a yield of 90%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.12(d,J＝7.9Hz,1H),6.80–6.83(m,2H),6.61(t,J F-H＝73.6Hz,1H),4.94–5.00(m,1H),4.32–4.42(m,1H),3.94–4.08(m,1H),3.78–3.79(m,3H),3.40–3.47(m,1H),3.29–3.38(m,1H),2.62–2.70(m,1H),1.98–2.09(m,1H),1.45–1.48(m,9H),0.64–0.68(m,2H),0.36–0.39 (m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.12 (d, J = 7.9 Hz, 1H), 6.80-6.83 (m, 2H), 6.61 (t, J FH = 73.6 Hz, 1H), 4.94- 5.00 (m, 1H), 4.32-4.42 (m, 1H), 3.94-4.08 (m, 1H), 3.78-3.79 (m, 3H), 3.40-3.47 (m, 1H), 3.29-3.38 (m, 1H) ), 2.62--2.70(m,1H), 1.98--2.09(m,1H), 1.45--1.48(m,9H), 0.64--0.68(m,2H), 0.36--0.39 (m,2H).
MS(ESI,pos.ion)m/z:466.10[M+Na] +. MS(ESI,pos.ion)m/z:466.10[M+Na] + .
步骤2：化合物(2R)-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成Step 2: Compound (2R)-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxy Synthesis of acid methyl ester hydrochloride
将化合物(2R)-1-叔丁基2-甲基4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(400mg,0.9mmol)溶解于二氯甲烷(5mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(10mL)，室温反应3h，除去溶剂，得到浅黄色粘稠固体314mg，收率92％。The compound (2R)-1-tert-butyl 2-methyl 4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl ) Pyrrolidine-1,2-dicarboxylate (400mg, 0.9mmol) was dissolved in dichloromethane (5mL) solution, 4mol/L HCl ethyl acetate solution (10mL) was added, reacted at room temperature for 3h, and the solvent was removed. 314 mg of light yellow viscous solid was obtained with a yield of 92%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.14(d,J＝8.2Hz,1H),7.07(d,J＝2.0Hz,1H),6.92(dd,J＝8.3,1.9Hz,1H),6.76(t,J F-H＝75.5Hz,1H),4.60–4.64(m,1H),3.90(s,3H),3.76–3.83(m,1H),3.63–3.71(m,1H),3.32–3.39(m,1H),2.82–2.89(m,1H),2.20–2.29(m,1H),1.26–1.34(m,1H),0.62–0.68(m,2H),0.37–0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.14 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 8.3, 1.9 Hz, 1H), 6.76(t, J FH = 75.5Hz, 1H), 4.60–4.64(m,1H), 3.90(s,3H), 3.76–3.83(m,1H), 3.63–3.71(m,1H), 3.32–3.39(m,1H), 2.82–2.89(m,1H), 2.20–2.29(m,1H), 1.26–1.34(m,1H), 0.62–0.68(m,2H), 0.37–0.41(m ,2H).
MS(ESI,pos.ion)m/z:344.10[M+H-HCl] +. MS(ESI,pos.ion)m/z:344.10[M+H-HCl] + .
步骤3：化合物(2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯的合成Step 3: Compound (2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrole Synthesis of alkane-2-carboxylic acid methyl ester
将化合物(2R)-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐(343mg,0.91mmol)溶解在二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(1.0mL,6.1mmol)，0℃条件下加入乙酰氯(0.3mL,4.0mmol)，室温搅拌16h后停止反应，加水溶液洗有机相(10mL×3)，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到无色液体222mg，产率63％。The compound (2R)-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl Ester hydrochloride (343mg, 0.91mmol) was dissolved in dichloromethane (10mL), N,N-diisopropylethylamine (1.0mL, 6.1mmol) was added, and acetyl chloride (0.3mL, 4.0mmol), stirred at room temperature for 16h, and then stopped the reaction. Add aqueous solution to wash the organic phase (10mL×3), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (eluent: petroleum ether/acetic acid Ethyl ester (v/v)=1/1), 222 mg of colorless liquid was obtained, and the yield was 63%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.15(d,J＝8.7Hz,1H),6.80–6.84(m,2H),6.63(t,J F-H＝73.6Hz,1H),4.48–4.52(m,1H),3.93–3.98(m,1H),3.79(s,3H),3.63(t,J＝10.5Hz,1H),3.38–3.47(m,2H),2.64–2.71(m,1H),2.13(s,3H),2.02–2.07(m,1H),1.27–1.33(m,1H),0.65–0.70(m,2H),0.36–0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.15 (d, J = 8.7 Hz, 1H), 6.80-6.84 (m, 2H), 6.63 (t, J FH = 73.6 Hz, 1H), 4.48- 4.52(m,1H),3.93-3.98(m,1H),3.79(s,3H),3.63(t,J=10.5Hz,1H),3.38-3.47(m,2H),2.64-2.71(m, 1H), 2.13(s, 3H), 2.02--2.07(m,1H), 1.27--1.33(m,1H), 0.65--0.70(m,2H), 0.36--0.40(m,2H).
MS(ESI,pos.ion)m/z:386.50[M+H] +. MS(ESI,pos.ion)m/z:386.50[M+H] + .
步骤4：化合物(2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸的合成Step 4: Compound (2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrole Synthesis of alkane-2-carboxylic acid
将化合物(2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯(217mg,0.56mmol)溶于四氢呋喃(5mL)和水(5mL)的混合溶剂中，加入一水合氢氧化锂(121mg,2.88mmol)，50℃反应1h后停止，加稀盐酸调节溶液pH＝1，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到浅黄色液体208mg，收率99％。The compound (2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- Methyl 2-carboxylate (217mg, 0.56mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (5mL). Lithium hydroxide monohydrate (121mg, 2.88mmol) was added. The reaction was stopped at 50°C for 1 hour and diluted The solution was adjusted to pH=1 with hydrochloric acid, extracted with ethyl acetate (5 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 208 mg of light yellow liquid with a yield of 99%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.11(d,J＝8.2Hz,1H),7.05(d,J＝1.9Hz,1H),6.90–6.93(m,1H),6.74(t,J F-H＝74.9Hz,1H),4.43–4.47(m,1H),4.08–4.15(m,1H),3.49–3.56(m,1H),3.56–3.64(m,1H),2.72–2.78(m,1H),2.14(s,3H),2.00–2.08(m,1H),1.28–1.346(m,1H),0.62–0.67(m,2H),0.37–0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.11 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.90-6.93 (m, 1H), 6.74 ( t,J FH = 74.9Hz, 1H), 4.43–4.47(m,1H), 4.08–4.15(m,1H), 3.49–3.56(m,1H), 3.56–3.64(m,1H), 2.72–2.78 (m, 1H), 2.14 (s, 3H), 2.00-2.08 (m, 1H), 1.28-1.346 (m, 1H), 0.62-0.67 (m, 2H), 0.37-0.41 (m, 2H).
MS(ESI,pos.ion)m/z:372.10[M+H] +. MS(ESI,pos.ion)m/z:372.10[M+H] + .
步骤5：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸乙酯的合成Step 5: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy) Synthesis of phenyl)pyrrolidine-2-carboxamido)methyl)ethyl picolinate
将化合物(2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(205mg,0.55mmol)，6-(氨基甲基)吡啶甲酸乙酯盐酸盐(267mg,1.09mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(523mg,2.73mmol)和N-羟基-7-氮杂苯并三氮唑(158mg,1.16mmol)溶于二氯甲烷(10mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.7mL,4.0mmol)，室温反应17h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩，进行硅胶柱层析分离(洗脱剂： 二氯甲烷/甲醇(v/v)＝40/1)，得到白色粘稠固体267mg，产率90％。The compound (2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 2-carboxylic acid (205mg, 0.55mmol), ethyl 6-(aminomethyl)picolinate hydrochloride (267mg, 1.09mmol), 1-ethyl-(3-dimethylaminopropyl) carbonyl di Imine hydrochloride (523mg, 2.73mmol) and N-hydroxy-7-azabenzotriazole (158mg, 1.16mmol) were dissolved in dichloromethane (10mL), and after cooling to 0℃, N, N-Diisopropylethylamine (0.7mL, 4.0mmol), react at room temperature for 17h, add water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate. Carry out silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 267 mg of a white viscous solid with a yield of 90%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.02(d,J＝7.5Hz,1H),7.84(t,J＝7.8Hz,1H),7.56(d,J＝7.8Hz,1H),7.11(d,J＝8.1Hz,1H),6.89(s,1H),6.86(dd,J＝8.2,1.8Hz,1H),6.62(t,J F-H＝75.7Hz,1H),4.59–4.77(m,3H),4.47(q,J＝7.1Hz,2H),3.95–3.99(m,1H),3.62(t,J＝10.6Hz,1H),3.29–3.41(m,1H),2.58–2.65(m,1H),2.39–2.48(m,1H),2.16(s,3H),1.44(t,J＝7.2Hz,3H),1.25–1.31(m,1H),0.64–0.68(m,2H),0.35–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.02 (d, J = 7.5 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.89 (s, 1H), 6.86 (dd, J = 8.2, 1.8 Hz, 1H), 6.62 (t, J FH = 75.7 Hz, 1H), 4.59–4.77 ( m, 3H), 4.47 (q, J = 7.1 Hz, 2H), 3.95–3.99 (m, 1H), 3.62 (t, J = 10.6 Hz, 1H), 3.29–3.41 (m, 1H), 2.58–2.65 (m,1H),2.39–2.48(m,1H),2.16(s,3H),1.44(t,J=7.2Hz,3H),1.25–1.31(m,1H),0.64–0.68(m,2H ), 0.35--0.39 (m, 2H).
MS(ESI,pos.ion)m/z:534.70[M+H] +. MS(ESI,pos.ion)m/z:534.70[M+H] + .
步骤6：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸的合成Step 6: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)benzene (Yl)pyrrolidine-2-carboxamido)methyl)picolinic acid
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸乙酯(267mg,0.5mmol)溶于四氢呋喃(5mL)和水(5mL)的混合溶剂中，加入一水合氢氧化锂(101mg,2.5mmol)，50℃反应1h后停止，加稀盐酸调节溶液pH＝6，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到242mg浅黄色固体，产率95％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl )Pyrrolidine-2-carboxamido)methyl)ethyl picolinate (267mg, 0.5mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (5mL), and lithium hydroxide monohydrate (101mg, 2.5mmol) was added ), the reaction was stopped at 50°C for 1 hour. Dilute hydrochloric acid was added to adjust the pH of the solution to 6, and the solution was extracted with ethyl acetate (5mL×3). The organic phase was dried with anhydrous sodium sulfate and the solvent was removed to obtain 242mg of light yellow solid. The yield was 95%. .
MS(ESI,pos.ion)m/z:506.70[M+H] +. MS(ESI,pos.ion)m/z:506.70[M+H] + .
步骤7：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰胺基)甲基)-N,N-二甲基-d 6-吡啶酰胺的合成 Step 7: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy) Synthesis of (phenyl)pyrrolidine-2-carboxamido)methyl)-N,N-dimethyl-d 6 -pyridine amide
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(94mg,0.18mmol)，N,N-二甲基-d 6-胺盐酸盐(77mg,0.88mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(173mg,0.91mmol)和N-羟基-7-氮杂苯并三氮唑(48mg,0.35mmol)溶于二氯甲烷(5mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.15mL,0.91mmol)，室温反应18h，加水(15mL)，二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝25/1)，得到白色固体42mg，产率42％。 The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl) Pyrrolidine-2-carboxamido)methyl)picolinic acid (94mg, 0.18mmol), N,N-dimethyl-d 6 -amine hydrochloride (77mg, 0.88mmol), 1-ethyl-(3 -Dimethylaminopropyl)carbodiimide hydrochloride (173mg, 0.91mmol) and N-hydroxy-7-azabenzotriazole (48mg, 0.35mmol) dissolved in dichloromethane (5mL) After cooling to 0℃, add N,N-diisopropylethylamine (0.15mL, 0.91mmol), react at room temperature for 18h, add water (15mL), extract with dichloromethane (5mL×3), and use the organic phase without Drying with sodium sulfate, removing the solvent, concentrating, and performing silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=25/1) to obtain 42 mg of white solid with a yield of 42%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.90–7.95(m,1H),7.60(d,J＝7.5Hz,1H),7.45(d,J＝7.1Hz,1H),7.05–7.12(m,2H),6.90(s,1H),6.75(t,J F-H＝75.6Hz,1H),4.48–4.65(m,3H),4.07–4.15(m,1H),3.63–3.69(m,1H),3.47–3.57(m,1H),2.65–2.74(m,1H),2.16(s,3H),2.01–2.13(m,1H),1.24–1.37(m,1H),0.60–0.68(m,2H),0.34–0.42(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.90–7.95 (m, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 7.1 Hz, 1H), 7.05– 7.12 (m, 2H), 6.90 (s, 1H), 6.75 (t, J FH = 75.6Hz, 1H), 4.48-4.65 (m, 3H), 4.07-4.15 (m, 1H), 3.63-3.69 (m ,1H), 3.47-3.57(m,1H), 2.65-2.74(m,1H), 2.16(s,3H), 2.01-2.13(m,1H), 1.24-1.37(m,1H), 0.60-0.68 (m,2H),0.34-0.42(m,2H).
MS(ESI,pos.ion)m/z:539.30[M+H] +. MS(ESI,pos.ion)m/z:539.30[M+H] + .
实施例51：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-环丙基吡啶酰胺Example 51: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-cyclopropylpyridineamide
Figure PCTCN2021090489-appb-000113
Figure PCTCN2021090489-appb-000113
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(102mg,0.2mmol)，环丙胺(43mg,0.6mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.0mmol)和N-羟基-7-氮杂苯并三氮唑(45mg,0.33mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.15mL,0.9mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5 mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体59mg，收率52％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (102mg, 0.2mmol), cyclopropylamine (43mg, 0.6mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (192mg, 1.0mmol) And N-hydroxy-7-azabenzotriazole (45mg, 0.33mmol) dissolved in dichloromethane (5mL), add N,N-diisopropylethylamine dropwise to this solution at 0℃ (0.15mL, 0.9mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5 mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (Eluent: dichloromethane/methanol (v/v)=30/1) to obtain 59 mg of white solid with a yield of 52%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.96(br.s,1H),8.77(br.s,1H),8.14(d,J＝7.5Hz,1H),7.83(t,J＝7.7Hz,1H),7.37(d,J＝7.6Hz,1H),7.14(d,J＝8.0Hz,1H),6.94(s,1H),6.89(d,J＝8.0Hz,1H),6.63(t,J F-H＝75.6Hz,1H),4.85(t,J＝8.0Hz,1H),4.56–4.71(m,2H),3.94–4.00(m,1H),3.90(d,J＝6.7Hz,2H),3.42–3.47(m,1H),3.29–3.38(m,1H),2.99–3.06(m,1H),2.82–2.90(m,1H),2.47–2.54(m,1H),2.21(s,3H),1.23–1.37(m,3H),0.80–0.92(m,2H),0.62–0.70(m,2H),0.33–0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.96 (br.s, 1H), 8.77 (br.s, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.83 (t, J = 7.7Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.63 (t,J FH ＝75.6Hz,1H), 4.85(t,J＝8.0Hz,1H),4.56–4.71(m,2H),3.94–4.00(m,1H),3.90(d,J＝6.7Hz ,2H),3.42–3.47(m,1H), 3.29–3.38(m,1H), 2.99–3.06(m,1H), 2.82–2.90(m,1H), 2.47–2.54(m,1H),2.21 (s,3H), 1.23--1.37(m,3H), 0.80-0.92(m,2H), 0.62-0.70(m,2H), 0.33-0.40(m,2H).
MS(ESI,pos.ion)m/z:543.20[M+H] +. MS(ESI,pos.ion)m/z:543.20[M+H] + .
实施例52：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-环丙基-N-甲基吡啶酰胺Example 52: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-cyclopropyl-N-picolinamide
Figure PCTCN2021090489-appb-000114
Figure PCTCN2021090489-appb-000114
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(80mg,0.16mmol)，N-甲基环丙胺(35mg,0.33mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(154mg,0.8mmol)和N-羟基-7-氮杂苯并三氮唑(33mg,0.24mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.15mL,0.91mmol)，室温反应5h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体71mg，收率63％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (80mg, 0.16mmol), N-methylcyclopropylamine (35mg, 0.33mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (154mg , 0.8mmol) and N-hydroxy-7-azabenzotriazole (33mg, 0.24mmol) were dissolved in dichloromethane (5mL). Add N,N-diiso to this solution at 0℃. Propylethylamine (0.15mL, 0.91mmol), react at room temperature for 5h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 71 mg of white solid with a yield of 63%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.77(t,J＝7.4Hz,1H),7.54(br.s,1H),7.42–7.44(m,1H),7.36(d,J＝7.6Hz,1H),7.12(d,J＝7.9Hz,1H),6.90(s,1H),6.86(d,J＝7.6Hz,1H),6.62(t,J F-H＝75.6Hz,1H),4.49–4.67(m,3H),3.93–3.97(m,1H),3.88(d,J＝6.8Hz,2H),3.56(t,J＝10.6Hz,1H),3.27–3.38(m,1H),3.15(s,3H),2.97–3.07(m,1H),2.43–2.62(m,2H),2.14(s,3H),1.24–1.37(m,1H),0.62–0.71(m,2H),0.47–0.55(m,2H),0.31–0.42(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.77 (t, J = 7.4 Hz, 1H), 7.54 (br.s, 1H), 7.42-7.44 (m, 1H), 7.36 (d, J = 7.6Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.90 (s, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.62 (t, J FH = 75.6 Hz, 1H), 4.49–4.67 (m, 3H), 3.93–3.97 (m, 1H), 3.88 (d, J = 6.8 Hz, 2H), 3.56 (t, J = 10.6 Hz, 1H), 3.27–3.38 (m, 1H) , 3.15 (s, 3H), 2.97 - 3.07 (m, 1H), 2.43 - 2.62 (m, 2H), 2.14 (s, 3H), 1.24 - 1.37 (m, 1H), 0.62 - 0.71 (m, 2H) ,0.47-0.55(m,2H),0.31-0.42(m,4H).
MS(ESI,pos.ion)m/z:557.20[M+H] +. MS(ESI,pos.ion)m/z:557.20[M+H] + .
实施例53：化合物6-(((2R)-1-乙酰基-4-(3-(环丙甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-环己基-N-甲基吡啶酰胺Example 53: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl (Amino)methyl)-N-cyclohexyl-N-picolinamide
Figure PCTCN2021090489-appb-000115
Figure PCTCN2021090489-appb-000115
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲 酸(102mg,0.20mmol)，N-甲基环己胺(46mg,0.41mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(196mg,1.02mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体39mg，收率32％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (102mg, 0.20mmol), N-methylcyclohexylamine (46mg, 0.41mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 196mg, 1.02mmol) and N-hydroxy-7-azabenzotriazole (43mg, 0.32mmol) were dissolved in dichloromethane (5mL), and N,N-di was added dropwise to this solution at 0℃. Isopropylethylamine (0.17mL, 1.00mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel It was separated by column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 39 mg of a white solid with a yield of 32%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.73–7.79(m,1H),7.35–7.44(m,2H),7.12(d,J＝8.4Hz,1H),6.90(s,1H),6.86(d,J＝7.0Hz,1H),6.62(t,J F-H＝75.5Hz,1H),4.48–4.67(m,3H),3.90–3.98(m,1H),3.88(d,J＝6.2Hz,2H),3.53–3.61(m,1H),3.35–3.45(m,2H),3.01(s,2H),2.83(s,1H),2.51–2.62(m,1H),2.39–2.50(m,1H),2.14(s,3H),1.69–1.83(m,4H),1.44–1.60(m,4H),1.26–1.34(m,1H),1.02–1.19(m,2H),0.63–0.70(m,2H),0.34–0.39(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.73–7.79(m,1H), 7.35–7.44(m,2H), 7.12(d,J=8.4Hz,1H), 6.90(s,1H) , 6.86 (d, J = 7.0Hz, 1H), 6.62 (t, J FH = 75.5 Hz, 1H), 4.48-4.67 (m, 3H), 3.90-3.98 (m, 1H), 3.88 (d, J = 6.2Hz, 2H), 3.53-3.61(m, 1H), 3.35-3.45(m, 2H), 3.01(s, 2H), 2.83(s, 1H), 2.51--2.62(m, 1H), 2.39-2.50 (m,1H),2.14(s,3H),1.69-1.83(m,4H),1.44-1.60(m,4H),1.26-1.34(m,1H),1.02-1.19(m,2H),0.63 –0.70(m,2H),0.34–0.39(m,2H).
MS(ESI,pos.ion)m/z:599.20[M+H] +. MS(ESI,pos.ion)m/z:599.20[M+H] + .
实施例54：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-((5-氟吡啶-2-基)甲基)-N-甲基吡啶酰胺Example 54: The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-((5-fluoropyridin-2-yl)methyl)-N-picolineamide
Figure PCTCN2021090489-appb-000116
Figure PCTCN2021090489-appb-000116
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(102mg,0.21mmol)，1-(5-氟吡啶-2-基)-N-甲基甲胺(57mg,0.41mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(40mg,0.29mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.0mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体47mg，收率37％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (102mg, 0.21mmol), 1-(5-fluoropyridin-2-yl)-N-methylmethylamine (57mg, 0.41mmol), 1-ethyl-(3-dimethylamino) Propyl) carbodiimide hydrochloride (192mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (40mg, 0.29mmol) dissolved in dichloromethane (5mL) at 0℃ N,N-diisopropylethylamine (0.17mL, 1.0mmol) was added dropwise to this solution, reacted at room temperature for 12h, washed with water (15mL), extracted with dichloromethane (5mL×3), and the organic phase After drying with sodium sulfate and removing the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 47 mg of white solid with a yield of 37%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.38–8.42(m,1H),7.72–7.80(m,1H),7.34–7.54(m,4H),7.10(d,J＝7.7Hz,1H),6.88(s,1H),6.84(d,J＝7.5Hz,1H),6.60(t,J F-H＝75.5Hz,1H),4.77–4.85(m,2H),4.47–4.61(m,3H),3.84–3.94(m,1H),3.86(d,J＝6.9Hz,2H),3.46–3.56(m,1H),3.26–3.36(m,1H),3.10(s,3H),2.40–2.56(m,2H),2.11(s,3H),1.24–1.34(m,1H),0.61–0.66(m,2H),0.31–0.37(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 8.38–8.42(m,1H), 7.72–7.80(m,1H), 7.34–7.54(m,4H), 7.10(d,J=7.7Hz, 1H), 6.88 (s, 1H), 6.84 (d, J = 7.5 Hz, 1H), 6.60 (t, J FH = 75.5 Hz, 1H), 4.77-4.85 (m, 2H), 4.47-4.61 (m, 3H), 3.84–3.94(m,1H), 3.86(d,J=6.9Hz,2H), 3.46–3.56(m,1H), 3.26–3.36(m,1H), 3.10(s,3H), 2.40 --2.56 (m, 2H), 2.11 (s, 3H), 1.24 - 1.34 (m, 1H), 0.61 - 0.66 (m, 2H), 0.31 - 0.37 (m, 2H).
MS(ESI,pos.ion)m/z:626.20[M+H] +. MS(ESI,pos.ion)m/z:626.20[M+H] + .
实施例55：化合物(2R)-1-乙酰基-N-(3-(环己基(甲基)氨甲酰基)苯甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰胺Example 55: Compound (2R)-1-acetyl-N-(3-(cyclohexyl(methyl)carbamoyl)benzyl)-4-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000117
Figure PCTCN2021090489-appb-000117
将化合物3-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)苯甲酸(97mg,0.19mmol)，N-甲基环己基胺(76mg,0.67mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(103mg,0.53mmol)和N-羟基-7-氮杂苯并三氮唑(69mg,0.50mmol)溶于二氯甲烷(6mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌17h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体63mg，收率54％。The compound 3-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)benzoic acid (97mg, 0.19mmol), N-methylcyclohexylamine (76mg, 0.67mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 103mg, 0.53mmol) and N-hydroxy-7-azabenzotriazole (69mg, 0.50mmol) dissolved in dichloromethane (6mL), cooled to 0℃, added N,N-diisopropylethyl Amine (0.3mL, 2.0mmol), stirred at room temperature for 17h, washed with water (50mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (Eluent: dichloromethane/methanol (v/v)=20/1) to obtain 63 mg of white solid with a yield of 54%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.31-7.38(m,2H),7.16-7.26(m,2H),7.09-7.13(m,1H),7.05(d,J＝1.6Hz,1H),7.03(t,J F-H＝74.9Hz,1H),6.87(d,J＝9.8Hz,1H),4.30-4.35(m,3H),4.04-4.08(m,1H),3.90(d,J＝6.9Hz,2H),3.37-3.51(m,2H),3.15-3.28(m,1H),2.70-2.82(m,3H),2.55-2.62(m,1H),2.01(s,3H),1.84-1.97(m,1H),1.40-1.61(m,6H),1.22-1.28(m,3H),0.80-0.87(m,2H),0.52-0.62(m,2H),0.30-0.37(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.31-7.38 (m, 2H), 7.16-7.26 (m, 2H), 7.09-7.13 (m, 1H), 7.05 (d, J = 1.6 Hz, 1H), 7.03 (t, J FH = 74.9 Hz, 1H), 6.87 (d, J = 9.8 Hz, 1H), 4.30-4.35 (m, 3H), 4.04-4.08 (m, 1H), 3.90 ( d, J = 6.9Hz, 2H), 3.37-3.51 (m, 2H), 3.15-3.28 (m, 1H), 2.70-2.82 (m, 3H), 2.55-2.62 (m, 1H), 2.01 (s, 3H),1.84-1.97(m,1H),1.40-1.61(m,6H),1.22-1.28(m,3H),0.80-0.87(m,2H),0.52-0.62(m,2H),0.30- 0.37(m,2H).
实施例56：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-甲基-N-(四氢-2H-吡喃-4-基)吡啶酰胺Example 56: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)pyridineamide
Figure PCTCN2021090489-appb-000118
Figure PCTCN2021090489-appb-000118
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，N-甲基四氢-2H-吡喃-4-胺(93mg,0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.40mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到74mg白色固体，产率62％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (100mg, 0.20mmol), N-methyltetrahydro-2H-pyran-4-amine (93mg, 0.81mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Diimide hydrochloride (192mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (54mg, 0.40mmol) were dissolved in dichloromethane (5mL), cooled to 0℃, and N , N-Diisopropylethylamine (0.17mL, 1.00mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 74 mg of white solid with a yield of 62%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.91–7.94(m,1H),7.57–7.63(m,1H),7.41–7.45(m,1H),7.12(d,J＝8.2Hz,1H),7.09(s,1H),6.92–6.94(m,1H),6.56–6.92(m,1H),4.45–4.59(m,3H),4.09–4.13(m,1H),3.98–4.05(m,1H),3.93(d,J＝6.7Hz,2H),3.69–3.79(m,1H),3.66(t,J＝10.5Hz,1H),3.48–3.56(m,2H),3.20–3.26(m,1H),3.01(s,1.5H),2.84(s,1.5H),2.65–2.74(m,1H),2.15(s,3H),2.05–2.13(m,1H),1.82–2.01(m,3H),1.60–1.76(m,2H),1.26–1.34(m,1H),0.62–0.66(m,2H),0.37–0.40(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.91–7.94(m,1H), 7.57–7.63(m,1H), 7.41–7.45(m,1H), 7.12(d,J=8.2Hz, 1H), 7.09(s, 1H), 6.92-6.94(m, 1H), 6.56-6.92(m, 1H), 4.45-4.59(m, 3H), 4.09-4.13(m, 1H), 3.98-4.05( m, 1H), 3.93 (d, J = 6.7 Hz, 2H), 3.69–3.79 (m, 1H), 3.66 (t, J = 10.5 Hz, 1H), 3.48–3.56 (m, 2H), 3.20–3.26 (m,1H),3.01(s,1.5H),2.84(s,1.5H),2.65-2.74(m,1H),2.15(s,3H),2.05-2.13(m,1H),1.82-2.01 (m,3H), 1.60-1.76(m,2H), 1.26-1.34(m,1H), 0.62-0.66(m,2H), 0.37-0.40(m,2H).
MS(ESI,pos.ion)m/z:601.30[M+H] +. MS(ESI,pos.ion)m/z:601.30[M+H] + .
实施例57：化合物(2R)-1-乙酰基-N-((6-(氮杂环丁烷-1-羰基)吡啶-2-基)甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-2-甲酰胺Example 57: The compound (2R)-1-acetyl-N-((6-(azetidine-1-carbonyl)pyridin-2-yl)methyl)-4-(3-(cyclopropyl) Methoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000119
Figure PCTCN2021090489-appb-000119
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(102mg,0.20mmol)，氮杂环丁烷(96mg,1.68mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156mg,0.81mmol)和N-羟基-7-氮杂苯并三氮唑(87mg,0.64mmol)溶于二氯甲烷(6mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌18h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到淡黄色固体5mg，收率5％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl) picolinic acid (102mg, 0.20mmol), azetidine (96mg, 1.68mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (156mg, 0.81mmol) and N-hydroxy-7-azabenzotriazole (87mg, 0.64mmol) dissolved in dichloromethane (6mL), cooled to 0℃, added N,N-diisopropylethylamine ( 0.3mL, 2.0mmol), stirred at room temperature for 18h, added water (15mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (elution Reagent: dichloromethane/methanol (v/v)=15/1) to obtain 5 mg of pale yellow solid with a yield of 5%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.89(t,J＝7.7Hz,1H),7.75-7.80(m,1H),7.52(d,J＝7.7Hz,1H),7.13(d,J＝8.1Hz,1H),7.06(s,1H),7.03(t,J F-H＝74.9Hz,1H),6.88(d,J＝9.2Hz,1H),4.57-4.61(m,2H),4.35-4.45(m,3H),4.03-4.07(m,3H),3.90(d,J＝6.8Hz,2H),3.43-3.52(m,2H),2.21-2.28(m,2H),2.03(s,3H),1.91-1.99(m,2H),1.28-1.31(m,1H),0.53-0.59(m,2H),0.30-0.34(m,2H). 1 H NMR(400MHz, DMSO-d 6 )δ(ppm): 7.89(t,J=7.7Hz,1H),7.75-7.80(m,1H),7.52(d,J=7.7Hz,1H),7.13 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 7.03 (t, J FH = 74.9 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 4.57-4.61 (m, 2H ), 4.35-4.45(m,3H),4.03-4.07(m,3H),3.90(d,J=6.8Hz,2H),3.43-3.52(m,2H),2.21-2.28(m,2H), 2.03 (s, 3H), 1.91-1.99 (m, 2H), 1.28-1.31 (m, 1H), 0.53-0.59 (m, 2H), 0.30-0.34 (m, 2H).
MS(ESI,pos.ion)m/z:543.20[M+H] +. MS(ESI,pos.ion)m/z:543.20[M+H] + .
实施例58：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(吡咯烷-1-羰基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 58: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(pyrrolidine) -1-Carbonyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000120
Figure PCTCN2021090489-appb-000120
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(94mg,0.18mmol)，四氢吡咯(69mg,0.97mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(86mg,0.45mmol)和N-羟基-7-氮杂苯并三氮唑(52mg,0.38mmol)溶于二氯甲烷(6mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.2mL,1.0mmol)，室温搅拌7h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体48mg，收率46％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (94mg, 0.18mmol), tetrahydropyrrole (69mg, 0.97mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (86mg, 0.45mmol) ) And N-hydroxy-7-azabenzotriazole (52mg, 0.38mmol) were dissolved in dichloromethane (6mL), cooled to 0℃, and N,N-diisopropylethylamine (0.2mL , 1.0mmol), stirred at room temperature for 7h, added water (15mL), extracted with dichloromethane (5mL×3), dried the organic phase with anhydrous sodium sulfate, removed the solvent, and separated the concentrated solution by silica gel column chromatography (eluent: Dichloromethane/methanol (v/v)=15/1) to obtain 48 mg of a white solid with a yield of 46%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.59(t,J＝6.0Hz,1H),7.84-7.90(m,1H),7.48-7.55(m,2H),7.12-7.14(m,1H),7.06(s,1H),7.03(t,J F-H＝74.9Hz,1H),6.88(d,J＝9.5Hz,1H),4.41-4.53(m,1H),4.33-4.39(m,2H),4.06-4.09(m,1H),3.90(d,J＝6.9Hz,2H),3.51-3.59(m,2H),3.39-3.49(m,4H),2.58-2.63 (m,1H),2.03(s,3H),1.89-1.94(m,1H),1.80-1.83(m,4H),1.23-1.26(m,1H),0.54-0.59(m,2H),0.33-0.36(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.59 (t, J = 6.0 Hz, 1H), 7.84-7.90 (m, 1H), 7.48-7.55 (m, 2H), 7.12-7.14 ( m, 1H), 7.06 (s, 1H), 7.03 (t, J FH = 74.9 Hz, 1H), 6.88 (d, J = 9.5 Hz, 1H), 4.41-4.53 (m, 1H), 4.33-4.39 ( m,2H),4.06-4.09(m,1H),3.90(d,J=6.9Hz,2H),3.51-3.59(m,2H),3.39-3.49(m,4H),2.58-2.63 (m, 1H),2.03(s,3H),1.89-1.94(m,1H),1.80-1.83(m,4H),1.23-1.26(m,1H),0.54-0.59(m,2H),0.33-0.36( m,2H).
MS(ESI,pos.ion)m/z:557.40[M+H] +. MS(ESI,pos.ion)m/z:557.40[M+H] + .
实施例59：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(哌啶-1-羰基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 59: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(piperidine -1-Carbonyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000121
Figure PCTCN2021090489-appb-000121
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(103mg,0.20mmol)，哌啶(68mg,0.80mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(154mg,0.80mmol)和N-羟基-7-氮杂苯并三氮唑(86mg,0.63mmol)溶于二氯甲烷(6mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌20h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体75mg，收率64％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl) picolinic acid (103 mg, 0.20 mmol), piperidine (68 mg, 0.80 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (154 mg, 0.80 mmol) And N-hydroxy-7-azabenzotriazole (86mg, 0.63mmol) dissolved in dichloromethane (6mL), cooled to 0℃, added N,N-diisopropylethylamine (0.3mL, 2.0mmol), stirred at room temperature for 20h, added water (15mL), extracted with dichloromethane (5mL×3), dried the organic phase with anhydrous sodium sulfate, removed the solvent, and separated the concentrated solution by silica gel column chromatography (eluent: two Chloroform/methanol (v/v)=15/1) to obtain 75 mg of white solid with a yield of 64%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.59(t,J＝5.7Hz,1H),7.85(t,J＝7.5Hz,1H),7.46(d,J＝7.8Hz,1H),7.32-7.38(m,1H),7.10-7.14(m,1H),7.06(s,1H),7.03(t,J F-H＝74.8Hz,1H),6.88(d,J＝8.9Hz,1H),4.33-4.43(m,3H),4.05-4.09(m,1H),3.90(d,J＝6.8Hz,2H),3.53-3.59(m,2H),3.39-3.52(m,2H),3.21-3.27(m,2H),2.56-2.64(m,1H),2.03(s,3H),1.87-1.97(m,1H),1.53-1.58(m,4H),1.40-1.43(m,2H),1.25-1.34(m,1H),0.53-0.59(m,2H),0.30-0.35(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.59 (t, J = 5.7 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H) ,7.32-7.38(m,1H),7.10-7.14(m,1H),7.06(s,1H),7.03(t,J FH =74.8Hz,1H),6.88(d,J=8.9Hz,1H) ,4.33-4.43(m,3H),4.05-4.09(m,1H),3.90(d,J=6.8Hz,2H),3.53-3.59(m,2H),3.39-3.52(m,2H),3.21 -3.27(m,2H),2.56-2.64(m,1H),2.03(s,3H),1.87-1.97(m,1H),1.53-1.58(m,4H),1.40-1.43(m,2H) ,1.25-1.34(m,1H),0.53-0.59(m,2H),0.30-0.35(m,2H).
MS(ESI,pos.ion)m/z:571.40[M+H] +. MS(ESI,pos.ion)m/z:571.40[M+H] + .
实施例60：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(吗啉-4-羰基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 60: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(morpholine) -4-carbonyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000122
Figure PCTCN2021090489-appb-000122
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(103mg,0.20mmol)，吗啉(75mg,0.86mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(165mg,0.86mmol)和N-羟基-7-氮杂苯并三氮唑(86mg,0.62mmol)溶于二氯甲烷(6mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌14h，加水(15mL)，用二氯甲烷萃取(5mL×3)， 有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体72mg，收率61％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (103mg, 0.20mmol), morpholine (75mg, 0.86mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (165mg, 0.86mmol) And N-hydroxy-7-azabenzotriazole (86mg, 0.62mmol) dissolved in dichloromethane (6mL), cooled to 0℃, added N,N-diisopropylethylamine (0.4mL, 2.0mmol), stirred at room temperature for 14h, added water (15mL), extracted with dichloromethane (5mL×3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: two Methyl chloride/methanol (v/v)=15/1), 72 mg of white solid was obtained, with a yield of 61%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.60(t,J＝5.8Hz,1H),7.88(t,J＝7.6Hz,1H),7.49(d,J＝7.9Hz,1H),7.43(d,J＝7.8Hz,1H),7.13(d,J＝8.1Hz,1H),7.06(s,1H),7.03(t,J F-H＝74.9Hz,1H),6.89(d,J＝9.1Hz,1H),4.33-4.44(m,3H),4.05-4.09(m,1H),3.90(d,J＝6.9Hz,2H),3.60-3.66(m,4H),3.50-3.55(m,2H),3.40-3.48(m,4H),2.55-2.64(m,1H),2.03(s,3H),1.87-1.98(m,1H),1.25-1.29(m,1H),0.54-0.60(m,2H),0.33-0.37(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.60 (t, J = 5.8Hz, 1H), 7.88 (t, J = 7.6Hz, 1H), 7.49 (d, J = 7.9Hz, 1H ), 7.43 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 7.03 (t, J FH = 74.9 Hz, 1H), 6.89 (d, J = 9.1Hz, 1H), 4.33-4.44 (m, 3H), 4.05-4.09 (m, 1H), 3.90 (d, J = 6.9Hz, 2H), 3.60-3.66 (m, 4H), 3.50-3.55 (m, 2H), 3.40-3.48 (m, 4H), 2.55-2.64 (m, 1H), 2.03 (s, 3H), 1.87-1.98 (m, 1H), 1.25-1.29 (m, 1H), 0.54 -0.60 (m, 2H), 0.33-0.37 (m, 2H).
MS(ESI,pos.ion)m/z:573.25[M+H] +. MS(ESI,pos.ion)m/z:573.25[M+H] + .
实施例61：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(4-甲基哌嗪-1-羰基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 61: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(4- Methylpiperazine-1-carbonyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000123
Figure PCTCN2021090489-appb-000123
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(92mg,0.18mmol)，1-甲基哌嗪(89mg,0.89mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(163mg,0.85mmol)和N-羟基-7-氮杂苯并三氮唑(89mg,0.65mmol)溶于二氯甲烷(6mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌14h，加水(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到淡黄色固体67mg，收率63％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (92mg, 0.18mmol), 1-methylpiperazine (89mg, 0.89mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (163mg , 0.85mmol) and N-hydroxy-7-azabenzotriazole (89mg, 0.65mmol) were dissolved in dichloromethane (6mL). Add N,N-diiso to this solution at 0℃. Propylethylamine (0.4mL, 2.0mmol), stirred at room temperature for 14h, added water (50mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 67 mg of pale yellow solid with a yield of 63%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.61(t,J＝5.8Hz,1H),7.87(t,J＝7.6Hz,1H),7.48(d,J＝7.8Hz,1H),7.40(d,J＝7.8Hz,1H),7.13(d,J＝8.1Hz,1H),7.06(s,1H),7.03(t,J F-H＝74.8Hz,1H),6.88(d,J＝8.8Hz,1H),4.42-4.53(m,1H),4.33-4.39(m,2H),4.05-4.09(m,1H),3.90(d,J＝6.8Hz,2H),3.57-3.69(m,2H),3.37-3.51(m,4H),2.58-2.64(m,1H),2.40-2.451(m,2H),2.25-2.40(m,2H),2.24(s,3H),2.03(s,3H),1.89-1.99(m,1H),1.25-1.34(m,1H),0.54-0.60(m,2H),0.31-0.36(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.61 (t, J = 5.8 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H ),7.40(d,J=7.8Hz,1H),7.13(d,J=8.1Hz,1H),7.06(s,1H),7.03(t,J FH =74.8Hz,1H),6.88(d, J=8.8Hz,1H),4.42-4.53(m,1H),4.33-4.39(m,2H),4.05-4.09(m,1H),3.90(d,J=6.8Hz,2H),3.57-3.69 (m, 2H), 3.37-3.51 (m, 4H), 2.58-2.64 (m, 1H), 2.40-2.451 (m, 2H), 2.25-2.40 (m, 2H), 2.24 (s, 3H), 2.03 (s, 3H), 1.89-1.99 (m, 1H), 1.25-1.34 (m, 1H), 0.54-0.60 (m, 2H), 0.31-0.36 (m, 2H).
MS(ESI,pos.ion)m/z:586.20[M+H] +. MS(ESI,pos.ion)m/z:586.20[M+H] + .
实施例62：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(1-甲基-1H-吡唑-5-基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 62: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(1- (Methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000124
Figure PCTCN2021090489-appb-000124
步骤1：化合物((6-溴吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 1: Synthesis of compound ((6-bromopyridin-2-yl)methyl) t-butyl carbamate
将化合物(6-溴吡啶-2-基)甲胺(1.0g,5.4mmol)溶解于二氯甲烷(15mL)溶液中，加入N,N-二异丙基乙胺(3.0mL,18.0mmol)，在0℃下加入二叔丁基二碳酸酯(1.5mL,6.5mmol)，搅拌20min转移至室温反应5h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到白色固体1.42g，收率92％。The compound (6-bromopyridin-2-yl)methylamine (1.0g, 5.4mmol) was dissolved in dichloromethane (15mL) solution, and N,N-diisopropylethylamine (3.0mL, 18.0mmol) was added , Add di-tert-butyl dicarbonate (1.5mL, 6.5mmol) at 0°C, stir for 20min, transfer to room temperature and react for 5h, wash with water (50mL), extract with dichloromethane (5mL×3), and use no organic phase After drying with sodium sulfate and removing the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 1.42 g of a white solid with a yield of 92%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.73(t,J＝7.7Hz,1H),7.50(d,J＝7.9Hz,1H),7.48(br.s,1H),7.30(d,J＝7.5Hz,1H),4.19(d,J＝6.0Hz,2H),1.40(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.73 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.48 (br.s, 1H), 7.30 (d,J=7.5Hz,1H), 4.19(d,J=6.0Hz,2H), 1.40(s,9H).
MS(ESI,pos.ion)m/z:233.10[M-55] +. MS(ESI,pos.ion)m/z:233.10[M-55] + .
步骤2：化合物((6-(1-甲基-1H-吡唑-5-基)吡啶-2-基)甲基)氨基甲酸叔丁酯的合成Step 2: Synthesis of compound ((6-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl) carbamate
将化合物((6-溴吡啶-2-基)甲基)氨基甲酸叔丁酯(198mg,0.69mmol)，1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑(153mg,0.74mmol)、碳酸钠(232mg,2.19mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(29mg,0.04mmol)溶于无水1,4-二氧六环(6mL)中，排除空气，通入氮气，在100℃下反应18h，加水(50mL)，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到淡黄色液体143mg，收率72％。The compound ((6-bromopyridin-2-yl)methyl) tert-butyl carbamate (198mg, 0.69mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazole (153mg, 0.74mmol), sodium carbonate (232mg, 2.19mmol) and (1,1'-bis(diphenylphosphino) two Ferrocene] palladium dichloride (29mg, 0.04mmol) was dissolved in anhydrous 1,4-dioxane (6mL), the air was removed, nitrogen gas was introduced, and the reaction was carried out at 100°C for 18h, and water (50mL) was added. Ethyl acetate extraction (5mL×3), the organic phase was dried with anhydrous sodium sulfate, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain Light yellow liquid 143mg, yield 72%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.86(t,J＝7.8Hz,1H),7.65(d,J＝7.8Hz,1H),7.45-7.48(m,2H),7.24(d,J＝7.6Hz,1H),6.78(d,J＝1.4Hz,1H),4.30(d,J＝6.0Hz,2H),4.16(s,3H),1.41(s,9H). 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 7.86(t,J=7.8Hz,1H), 7.65(d,J=7.8Hz,1H),7.45-7.48(m,2H), 7.24 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 4.30 (d, J = 6.0 Hz, 2H), 4.16 (s, 3H), 1.41 (s, 9H).
MS(ESI,pos.ion)m/z:289.15[M+H] +. MS(ESI,pos.ion)m/z:289.15[M+H] + .
步骤3：化合物(6-(1-甲基-1H-吡唑-5-基)吡啶-2-基)甲胺二盐酸盐的合成Step 3: Synthesis of compound (6-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methylamine dihydrochloride
将化合物((6-(1-甲基-1H-吡唑-5-基)吡啶-2-基)甲基)氨基甲酸叔丁酯(112mg,0.39mmol)溶解于二氯甲烷(2mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(3mL)，室温搅拌1h，除去溶剂，得到淡黄色固体71mg，收率97％。The compound ((6-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl) tert-butyl carbamate (112mg, 0.39mmol) was dissolved in dichloromethane (2mL) solution Add 4 mol/L HCl ethyl acetate solution (3 mL), stir at room temperature for 1 h, remove the solvent, and obtain 71 mg of pale yellow solid with a yield of 97%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.48-8.63(m,2H),7.96(t,J＝7.8Hz,1H),7.78(d,J＝7.8Hz,1H),7.47-7.50(m,2H),6.84(d,J＝1.7Hz,1H),4.27(d,J＝4.9Hz,2H),4.19(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.48-8.63 (m, 2H), 7.96 (t, J = 7.8Hz, 1H), 7.78 (d, J = 7.8Hz, 1H), 7.47 -7.50(m,2H), 6.84(d,J=1.7Hz,1H), 4.27(d,J=4.9Hz,2H), 4.19(s,3H).
MS(ESI,pos.ion)m/z:189.30[M+H-HCl] +. MS(ESI,pos.ion)m/z:189.30[M+H-HCl] + .
步骤4：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(1-甲基-1H-吡唑-5-基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺的合成Step 4: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(1-methyl Synthesis of 1-H-pyrazol-5-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(92mg,0.25mmol)，化合物(6-(1-甲基-1H-吡唑-5-基)吡啶-2-基)甲胺二盐酸盐(811-3)(103mg,0.55mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(150mg,0.78mmol)和N-羟基-7-氮杂苯并三氮唑(71mg,0.52mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌6h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体67mg，收率50％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (92mg, 0.25mmol) , Compound (6-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)methylamine dihydrochloride (811-3) (103mg, 0.55mmol), 1-ethyl-( 3-Dimethylaminopropyl) carbodiimide hydrochloride (150mg, 0.78mmol) and N-hydroxy-7-azabenzotriazole (71mg, 0.52mmol) dissolved in dichloromethane (6mL ), N,N-diisopropylethylamine (0.4mL, 2.0mmol) was added dropwise to this solution at room temperature, stirred at room temperature for 6h, washed with water (50mL), extracted with dichloromethane (5mL×3), The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 67 mg of white solid, with a yield of 50% .
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.62(s,1H),7.84-7.90(m,1H),7.64-7.67(m,1H),7.48(s,1H),7.39-7.40(m,1H),7.10-7.16(m,1H),7.06(s,2H),7.04(t,J F-H＝75.0Hz,1H),6.88-6.91(m,1H),6.78(s,1H),4.38-4.53(m,3H),4.15(s,3H),4.05-4.10(m,1H),3.90(d,J＝4.7Hz,2H),3.43-3.50(m,2H),2.57-2.67(m,1H),2.04(s,3H),1.88-1.96(m,1H),1.23-1.26(m,1H),0.50-0.61(m,2H),0.28-0.38(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.62 (s, 1H), 7.84-7.90 (m, 1H), 7.64-7.67 (m, 1H), 7.48 (s, 1H), 7.39- 7.40 (m, 1H), 7.10-7.16 (m, 1H), 7.06 (s, 2H), 7.04 (t, J FH = 75.0Hz, 1H), 6.88-6.91 (m, 1H), 6.78 (s, 1H) ), 4.38-4.53 (m, 3H), 4.15 (s, 3H), 4.05-4.10 (m, 1H), 3.90 (d, J = 4.7 Hz, 2H), 3.43-3.50 (m, 2H), 2.57- 2.67 (m, 1H), 2.04 (s, 3H), 1.88-1.96 (m, 1H), 1.23-1.26 (m, 1H), 0.50-0.61 (m, 2H), 0.28-0.38 (m, 2H).
MS(ESI,pos.ion)m/z:540.15[M+H] +. MS(ESI,pos.ion)m/z:540.15[M+H] + .
实施例63：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 63: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-(1- Methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000125
Figure PCTCN2021090489-appb-000125
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(91mg,0.25mmol)，化合物(6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)甲胺二盐酸盐(96mg,0.51mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(153mg,0.79mmol)和N-羟基-7-氮杂苯并三氮唑(71mg,0.52mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌6h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体53mg，收率39％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (91mg, 0.25mmol) , Compound (6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methylamine dihydrochloride (96mg, 0.51mmol), 1-ethyl-(3-dimethyl Aminopropyl) carbodiimide hydrochloride (153mg, 0.79mmol) and N-hydroxy-7-azabenzotriazole (71mg, 0.52mmol) dissolved in dichloromethane (6mL) at room temperature Add N,N-diisopropylethylamine (0.4mL, 2.0mmol) dropwise to this solution, stir at room temperature for 6h, wash with water (50mL), extract with dichloromethane (5mL×3), and use anhydrous organic phase After drying over sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 53 mg of a white solid with a yield of 39%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.55(br.s,1H),8.26(s,1H),7.99(s,1H),7.68-7.72(m,1H),7.48-7.52(m,1H),7.18-7.21(m,1H),7.09-7.13(m,1H),7.05-7.08(m,2H),7.03(t,J F-H＝74.9Hz,1H),6.89(d,J＝8.3Hz,1H),4.31-4.48(m,3H),4.00-4.20(m,1H),3.84-3.93(m,5H),3.40-3.57(m,2H),2.56-2.74(m,1H),2.04(s,3H),1.91-1.96(m,1H),1.22-1.29(m,1H),0.49-0.65(m,2H),0.27-0.40(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.55 (br.s, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.68-7.72 (m, 1H), 7.48- 7.52(m,1H),7.18-7.21(m,1H),7.09-7.13(m,1H),7.05-7.08(m,2H),7.03(t,J FH =74.9Hz,1H),6.89(d ,J=8.3Hz,1H),4.31-4.48(m,3H),4.00-4.20(m,1H),3.84-3.93(m,5H),3.40-3.57(m,2H),2.56-2.74(m ,1H),2.04(s,3H),1.91-1.96(m,1H),1.22-1.29(m,1H),0.49-0.65(m,2H),0.27-0.40(m,2H).
MS(ESI,pos.ion)m/z:540.20[M+H] +. MS(ESI,pos.ion)m/z:540.20[M+H] + .
实施例64：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-甲基-N-苯基吡啶酰胺Example 64: The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-methyl-N-phenylpyridineamide
Figure PCTCN2021090489-appb-000126
Figure PCTCN2021090489-appb-000126
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.19mmol)，N-甲基苯胺(578mg,0.53mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1925mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(40mg,0.29mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.13mL,0.79mmol)，室温反应18h，加水洗(15mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体41mg，收率36％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl) picolinic acid (100mg, 0.19mmol), N-methylaniline (578mg, 0.53mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1925mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (40mg, 0.29mmol) were dissolved in dichloromethane (5mL), and N,N-diisopropyl was added dropwise to this solution at 0℃ Ethylethylamine (0.13mL, 0.79mmol), react at room temperature for 18h, wash with water (15mL), then extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 41 mg of white solid with a yield of 36%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.48–7.61(m,1H),7.09–7.26(m,8H),6.88(s,1H),6.84(d,J＝7.7Hz,1H),6.60(t,J F-H＝75.5Hz,1H),4.430–4.55(m,1H),4.31–4.45(m,2H),3.87–3.96(m,1H),3.86(d,J＝6.7Hz,2H),3.50–3.61(m,1H),3.51(s,3H),3.26–3.41(m,1H),2.50–2.61(m,1H),2.28–2.39(m,1H),2.11(s,3H),1.24–1.37(m,1H),0.60–0.66(m,2H),0.30–0.37(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.48–7.61(m,1H), 7.09–7.26(m,8H), 6.88(s,1H), 6.84(d,J=7.7Hz,1H) ,6.60(t,J FH =75.5Hz,1H),4.430–4.55(m,1H),4.31–4.45(m,2H),3.87–3.96(m,1H),3.86(d,J=6.7Hz, 2H), 3.50--3.61(m,1H), 3.51(s,3H), 3.26--3.41(m,1H), 2.50--2.61(m,1H), 2.28--2.39(m,1H), 2.11(s, 3H), 1.24--1.37 (m, 1H), 0.60--0.66 (m, 2H), 0.30--0.37 (m, 2H).
MS(ESI,pos.ion)m/z:593.25[M+H] +. MS(ESI,pos.ion)m/z:593.25[M+H] + .
实施例65：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N- 甲基-N-(4-甲基苯基)吡啶酰胺Example 65: The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-methyl-N-(4-methylphenyl)pyridineamide
Figure PCTCN2021090489-appb-000127
Figure PCTCN2021090489-appb-000127
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，N-甲基-4-甲基苯胺(62mg,0.51mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(251mg,1.31mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.40mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入N,N-二异丙基乙胺(183mg,1.42mmol)，室温反应22h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体84mg，产率69％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (100mg, 0.20mmol), N-methyl-4-methylaniline (62mg, 0.51mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt Salt (251mg, 1.31mmol) and N-hydroxy-7-azabenzotriazole (54mg, 0.40mmol) were dissolved in dichloromethane (5mL), cooled to 0℃, and N,N-diiso Propylethylamine (183mg, 1.42mmol), react at room temperature for 22h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 84 mg of white solid, with a yield of 69%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.52(br.s,1H),7.10-7.27(m,4H),6.86-7.00(m,5H),6.61(t,J＝75.5Hz,1H),4.43-4.50(m,3H),3.87-3.94(m,3H),3.53-3.65(m,1H),3.45(s,3H),3.25-3.42(m,1H),2.50-2.64(m,1H),2.26-2.40(m,1H),2.26(s,3H),2.13(s,3H),1.26-1.35(m,1H),0.60-0.72(m,2H),0.29-0.45(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.52 (br.s, 1H), 7.10-7.27 (m, 4H), 6.86-7.00 (m, 5H), 6.61 (t, J = 75.5 Hz, 1H), 4.43-4.50 (m, 3H), 3.87-3.94 (m, 3H), 3.53-3.65 (m, 1H), 3.45 (s, 3H), 3.25-3.42 (m, 1H), 2.50-2.64 ( m,1H),2.26-2.40(m,1H),2.26(s,3H),2.13(s,3H),1.26-1.35(m,1H),0.60-0.72(m,2H),0.29-0.45( m,2H).
MS(ESI,pos.ion)m/z:607.40[M+H] +. MS(ESI,pos.ion)m/z:607.40[M+H] + .
实施例66：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺Example 66: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(4-fluorophenyl)-N-picolineamide
Figure PCTCN2021090489-appb-000128
Figure PCTCN2021090489-appb-000128
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(102mg,0.20mmol)，4-氟-N-甲基苯胺(50mg,0.40mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(40mg,0.29mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到49mg白色固体，收率39％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (102mg, 0.20mmol), 4-fluoro-N-methylaniline (50mg, 0.40mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (192mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (40mg, 0.29mmol) were dissolved in dichloromethane (5mL), and N,N was added dropwise to this solution at 0℃. -Diisopropylethylamine (0.17mL, 1.00mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate the solution Perform silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 49 mg of white solid with a yield of 39%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.55–7.68(m,1H),7.28–7.43(m,1H),7.04–7.17(m,4H),6.84–6.98(m,4H),6.62(t,J F-H＝75.6Hz,1H),4.40–4.51(m,3H),3.86–3.98(m,1H),3.88(d,J＝5.8Hz,2H),3.49–3.59(m,1H),3.50(s,3H),3.28–3.43(m,1H),2.49–2.60(m,1H),2.36–2.48(m,1H),2.15(s,3H),1.26–1.36(m,1H),0.66–0.70(m,2H),0.33–0.342(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.55-7.68(m,1H), 7.28-7.43(m,1H), 7.04-7.17(m,4H), 6.84-6.98(m,4H), 6.62(t,J FH =75.6Hz,1H), 4.40–4.51(m,3H), 3.86–3.98(m,1H), 3.88(d,J=5.8Hz,2H), 3.49–3.59(m,1H) ), 3.50 (s, 3H), 3.28-3.43 (m, 1H), 2.49-2.60 (m, 1H), 2.36-2.48 (m, 1H), 2.15 (s, 3H), 1.26-1.36 (m, 1H) ), 0.66 - 0.70 (m, 2H), 0.33 - 0.342 (m, 2H).
MS(ESI,pos.ion)m/z:611.30[M+H] +. MS(ESI,pos.ion)m/z:611.30[M+H] + .
实施例67：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(2,4-二氟苯基)-N-甲基吡啶酰胺Example 67: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(2,4-difluorophenyl)-N-picolineamide
Figure PCTCN2021090489-appb-000129
Figure PCTCN2021090489-appb-000129
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(86mg,0.17mmol)，2,4-二氟-N-甲基苯胺(41mg,0.29mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(173mg,0.90mmol)和N-羟基-7-氮杂苯并三氮唑(48mg,0.35mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.15mL,0.91mmol)，室温反应12h，加水洗(15mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到33mg白色固体，收率30％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl) picolinic acid (86 mg, 0.17 mmol), 2,4-difluoro-N-methylaniline (41 mg, 0.29 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide Amine hydrochloride (173mg, 0.90mmol) and N-hydroxy-7-azabenzotriazole (48mg, 0.35mmol) were dissolved in dichloromethane (5mL) and added dropwise to this solution at 0℃ N,N-Diisopropylethylamine (0.15mL, 0.91mmol), react at room temperature for 12h, wash with water (15mL), then extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 33 mg of white solid with a yield of 30%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.60–7.66(m,1H),7.44–7.52(m,1H),7.18(d,J＝7.5Hz,1H),7.06–7.13(m,3H),6.89(s,1H),6.84(d,J＝8.0Hz,1H),6.69–6.76(m,1H),6.60(t,J F-H＝75.6Hz,1H),4.45–4.58(m,1H),4.25–4.38(m,2H),3.88–3.98(m,1H),3.86(d,J＝6.6Hz,2H),3.56(d,J＝10.4Hz,1H),3.42(s,3H),3.25–3.41(m,1H),2.48–2.62(m,1H),2.34–2.44(m,1H),2.13(s,3H),1.24–1.36(m,1H),0.62–0.66(m,2H),0.32–0.39(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.60–7.66(m,1H), 7.44–7.52(m,1H), 7.18(d,J=7.5Hz,1H), 7.06–7.13(m, 3H), 6.89 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.69–6.76 (m, 1H), 6.60 (t, J FH = 75.6 Hz, 1H), 4.45–4.58 (m, 1H), 4.25–4.38 (m, 2H), 3.88–3.98 (m, 1H), 3.86 (d, J = 6.6 Hz, 2H), 3.56 (d, J = 10.4 Hz, 1H), 3.42 (s, 3H) ), 3.25–3.41(m,1H), 2.48–2.62(m,1H), 2.34–2.44(m,1H), 2.13(s,3H), 1.24–1.36(m,1H), 0.62–0.66(m ,2H),0.32-0.39(m,2H).
MS(ESI,pos.ion)m/z:629.30[M+H] +. MS(ESI,pos.ion)m/z:629.30[M+H] + .
实施例68：化合物6-(((2R)-1-乙酰基-4-(3-((2-环丙基丙烷-2-基)氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺Example 68: Compound 6-(((2R)-1-acetyl-4-(3-((2-cyclopropylpropan-2-yl)oxy)-4-(difluoromethoxy)benzene Yl)pyrrolidine-2-carboxamido)methyl)-N-(4-fluorophenyl)-N-picolineamide
Figure PCTCN2021090489-appb-000130
Figure PCTCN2021090489-appb-000130
步骤1：化合物(R)-1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸的合成Step 1: Compound (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2- Synthesis of carboxylic acid
将化合物(R)-1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸甲酯(1.8g,0.56mmol)溶于四氢呋喃(15mL)和水(8mL)的混合溶剂中，加入一水合氢氧化锂(964mg，23mmol)，50℃反应2h后停止，加稀盐酸调节溶液pH＝1，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到浅黄色固体1.6g，收率94％。The compound (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid Methyl ester (1.8g, 0.56mmol) was dissolved in a mixed solvent of tetrahydrofuran (15mL) and water (8mL), lithium hydroxide monohydrate (964mg, 23mmol) was added, the reaction was stopped at 50°C for 2 hours, and diluted hydrochloric acid was added to adjust the pH of the solution. =1, extracted with ethyl acetate (10 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 1.6 g of light yellow solid with a yield of 94%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.49–7.51(m,2H),7.38–7.42(m,2H),7.29–7.32(m,2H),7.19(d,J＝8.3Hz,1H),7.08–7.11(m,1H),6.78(t,J F-H＝74.8Hz,1H),6.31–6.34(m,1H),5.39–5.42(m,0.3H),5.22–5.25(m,0.7H),5.22(s,2H),4.75–4.82(m,2H),2.22(s,2H),2.07(s,1H). 1 H NMR(400MHz, CD 3 OD)δ(ppm): 7.49–7.51(m,2H), 7.38–7.42(m,2H), 7.29–7.32(m,2H), 7.19(d,J=8.3Hz) ,1H),7.08–7.11(m,1H),6.78(t,J FH =74.8Hz,1H),6.31–6.34(m,1H),5.39–5.42(m,0.3H),5.22–5.25(m ,0.7H),5.22(s,2H),4.75-4.82(m,2H),2.22(s,2H),2.07(s,1H).
MS(ESI,pos.ion)m/z:404.05[M+H] +. MS(ESI,pos.ion)m/z:404.05[M+H] + .
步骤2：化合物(R)-6-((1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺的合成Step 2: Compound (R)-6-((1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H- Synthesis of pyrrole-2-carboxamido)methyl)-N-(4-fluorophenyl)-N-picolineamide
将化合物(R)-1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸(200mg,0.50mmol)，6-(氨基甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺二盐酸盐(889-1)(181mg,0.54mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(476mg,2.48mmol)和N-羟基-7-氮杂苯并三氮唑(136mg,1.00mmol)溶于二氯甲烷(10mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.6mL,4.0mmol)，室温反应12h，加水洗(20mL)搅拌，分离有机相，有机相用无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到301mg白色固体，收率94％。The compound (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (200mg, 0.50mmol), 6-(aminomethyl)-N-(4-fluorophenyl)-N-picolineamide dihydrochloride (889-1) (181mg, 0.54mmol), 1-ethyl -(3-Dimethylaminopropyl)carbodiimide hydrochloride (476mg, 2.48mmol) and N-hydroxy-7-azabenzotriazole (136mg, 1.00mmol) dissolved in dichloromethane After cooling to 0°C in methane (10mL), add N,N-diisopropylethylamine (0.6mL, 4.0mmol), react at room temperature for 12h, wash with water (20mL) and stir, separate the organic phase. It was dried with sodium sulfate and concentrated, and subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 301 mg of white solid with a yield of 94%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.37–7.47(m,6H),7.16–7.22(m,2H),7.00–7.12(m,4H),6.86–6.98(m,3H),6.60(t,J F-H＝74.9Hz,1H),6.17–6.20(m,1H),5.30–5.36(m,0.7H),5.19–5.23(m,0.3H),5.17(s,2H),4.61–4.78(m,2H),4.29–4.49(m,2H),3.50(s,3H),2.22(s,2H),2.07(s,1H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.37-7.47(m,6H), 7.16-7.22(m,2H), 7.00-7.12(m,4H), 6.86-6.98(m,3H), 6.60(t,J FH =74.9Hz,1H), 6.17–6.20(m,1H), 5.30–5.36(m,0.7H), 5.19–5.23(m,0.3H), 5.17(s,2H), 4.61 --4.78 (m, 2H), 4.29 - 4.49 (m, 2H), 3.50 (s, 3H), 2.22 (s, 2H), 2.07 (s, 1H).
MS(ESI,pos.ion)m/z:645.10[M+H] +. MS(ESI,pos.ion)m/z:645.10[M+H] + .
步骤3：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺的合成Step 3: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxamido)methyl)-N Synthesis of -(4-fluorophenyl)-N-picolineamide
将化合物(R)-6-((1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺(301mg,0.47mmol)溶于甲醇(10mL)，加入Pd/C(33mg,10％)，通入氢气室温反应8h，过滤除去催化剂，滤液浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝25/1)，得到白色固体227mg，收率87％。Compound (R)-6-((1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole- 2-Formylamino)methyl)-N-(4-fluorophenyl)-N-picolineamide (301mg, 0.47mmol) was dissolved in methanol (10mL), Pd/C (33mg, 10%) was added, Hydrogen was introduced to react at room temperature for 8 hours, the catalyst was removed by filtration, the filtrate was concentrated, and silica gel column chromatography was performed (eluent: dichloromethane/methanol (v/v)=25/1) to obtain a white solid of 227 mg, with a yield of 87% .
1H NMR(600MHz,CDCl 3)δ(ppm):7.54–7.58(m,1H),7.17–7.24(m,2H),7.00–7.14(m,4H),6.92–6.98(m,2H),6.78(d,J＝8.0Hz,1H),6.55(t,J F-H＝74.4Hz,1H),4.55–4.63(m,0.4H),4.43–4.53(m,2H),4.28–4.33(m,0.6H),4.13–4.16(m,0.4H),3.92–3.96(m,0.7H),3.61–3.65(m,1H),3.52–3.54(m,3H),3.29–3.40(m,1H),2.81–2.86(m,0.3H),2.55–2.61(m,0.7H),2.32–2.39(m,1H),2.17(s,2H),2.08(s,1H). 1 H NMR(600MHz, CDCl 3 )δ(ppm): 7.54-7.58(m,1H), 7.17-7.24(m,2H), 7.00-7.14(m,4H), 6.92-6.98(m,2H), 6.78(d,J=8.0Hz,1H),6.55(t,J FH =74.4Hz,1H),4.55-4.63(m,0.4H),4.43-4.53(m,2H),4.28-4.33(m, 0.6H), 4.13--4.16(m,0.4H), 3.92--3.96(m,0.7H), 3.61--3.65(m,1H), 3.52--3.54(m,3H), 3.29--3.40(m,1H) , 2.81-2.86 (m, 0.3H), 2.55--2.61 (m, 0.7H), 2.32-2.39 (m, 1H), 2.17 (s, 2H), 2.08 (s, 1H).
MS(ESI,pos.ion)m/z:557.15[M+H] +. MS(ESI,pos.ion)m/z:557.15[M+H] + .
步骤4：化合物6-(((2R)-1-乙酰基-4-(3-((2-环丙基丙烷-2-基)氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺的合成Step 4: Compound 6-(((2R)-1-acetyl-4-(3-((2-cyclopropylpropan-2-yl)oxy)-4-(difluoromethoxy)phenyl ) Synthesis of pyrrolidine-2-carboxamido)methyl)-N-(4-fluorophenyl)-N-picolineamide
将6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺(112mg,0.20mmol)，1-环丙基-1-甲基乙醇(60mg,0.60mmol)，三苯基膦(101mg,0.50mmol)溶解在干燥的四氢呋喃(10mL)溶液中，冰浴条件下缓慢加入偶氮二甲酰胺(100mg,0.58mmol)，30℃反应12h，加入水(10mL)，用乙酸乙酯(5mL×3)萃取，有机相合用无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体56mg，收率43％。Add 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxamido)methyl)-N-(4 -Fluorophenyl)-N-picolineamide (112mg, 0.20mmol), 1-cyclopropyl-1-methylethanol (60mg, 0.60mmol), triphenylphosphine (101mg, 0.50mmol) dissolved in dry In tetrahydrofuran (10mL) solution, slowly add azodicarbonamide (100mg, 0.58mmol) under ice-bath conditions, react at 30℃ for 12h, add water (10mL), extract with ethyl acetate (5mL×3), organic phase It was dried with anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 56 mg of a white solid with a yield of 43%.
1H NMR(600MHz,CDCl 3)δ(ppm):7.57–7.65(m,1H),7.31–7.38(m,1H),7.17–7.20(m,1H),7.12(d,J＝8.2Hz,1H),7.05–7.09(m,3H),7.00(d,J＝8.2Hz,1H),6.90–6.96(m,2H),6.58(t,J F-H＝75.7Hz,1H),4.50–4.54(m,1H),4.36–4.44(m,2H),3.95–3.98(m,1H),3.57(t,J＝10.7Hz,1H),3.51(s,3H),3.31–3.39(m,1H),3.54–3.59(m,1H),3.38–3.46(m,1H),2.16(s,3H),1.26(s,6H),1.16–1.23(m,1H),0.48–0.51(m,2H),0.38–0.40(m,2H). 1 H NMR(600MHz, CDCl 3 )δ(ppm): 7.57–7.65(m,1H), 7.31–7.38(m,1H), 7.17–7.20(m,1H), 7.12(d,J=8.2Hz, 1H), 7.05–7.09 (m, 3H), 7.00 (d, J = 8.2 Hz, 1H), 6.90–6.96 (m, 2H), 6.58 (t, J FH = 75.7 Hz, 1H), 4.50–4.54 ( m, 1H), 4.36–4.44 (m, 2H), 3.95–3.98 (m, 1H), 3.57 (t, J = 10.7 Hz, 1H), 3.51 (s, 3H), 3.31–3.39 (m, 1H) ,3.54–3.59(m,1H), 3.38–3.46(m,1H), 2.16(s,3H), 1.26(s,6H), 1.16–1.23(m,1H), 0.48–0.51(m,2H) ,0.38--0.40(m,2H).
MS(ESI,pos.ion)m/z:661.15[M+Na] +. MS(ESI,pos.ion)m/z:661.15[M+Na] + .
实施例69：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺 Example 69: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-2-formyl (Amino)methyl)-N-(4-fluorophenyl)-N-picolinamide
Figure PCTCN2021090489-appb-000131
Figure PCTCN2021090489-appb-000131
步骤1：化合物(2R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-1,2-二羧酸酯合成 Step 1: Compound (2R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-1,2-di Carboxylate synthesis
将化合物(2R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-1,2-二羧酸酯(510mg,1.32mmol)溶于干燥的四氢呋喃(10mL)中，冷却至0℃后，加入60％氢化钠(71mg,1.78mmol)，室温反应30min，冰浴中加入碘甲烷-d 3(382mg,2.64mmol)，室温反应7h后停止，缓慢加冰水(10mL)，乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，减压浓缩，进行硅胶柱层析色分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到无色液体127mg，产率24％。 Compound (2R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-1,2-dicarboxylate (510mg, 1.32mmol ) Was dissolved in dry tetrahydrofuran (10mL), after cooling to 0°C, 60% sodium hydride (71mg, 1.78mmol) was added, reacted at room temperature for 30min, and methyl iodide-d 3 (382mg, 2.64mmol) was added to the ice bath at room temperature The reaction was stopped after 7h, ice water (10mL) was slowly added, ethyl acetate extraction (10mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, concentrated under reduced pressure, and silica gel column chromatography was performed (eluent : Petroleum ether/ethyl acetate (v/v)=4/1), 127 mg of colorless liquid was obtained, and the yield was 24%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.13(d,J＝8.1Hz,1H),6.81–6.85(m,2H),6.54(t,J F-H＝75.2Hz,1H),4.34–4.44(m,1H),4.06–4.10(m,0.6H),3.95–3.99(m,0.4H),3.79(d,J＝6.9Hz,1H),3.43–3.49(m,1H),3.33–3.39(m,1H),2.64–2.72(m,1H),2.01–2.12(m,1H),1.46–1.49(m,9H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.13 (d, J = 8.1 Hz, 1H), 6.81-6.85 (m, 2H), 6.54 (t, J FH = 75.2 Hz, 1H), 4.34 –4.44(m,1H),4.06–4.10(m,0.6H), 3.95–3.99(m,0.4H), 3.79(d,J=6.9Hz,1H), 3.43–3.49(m,1H),3.33 --3.39(m,1H), 2.64–2.72(m,1H), 2.01–2.12(m,1H), 1.46–1.49(m,9H).
MS(ESI,pos.ion)m/z:349.20[M-55] +. MS(ESI,pos.ion)m/z:349.20[M-55] + .
步骤2：化合物(2R)-4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成 Step 2: Synthesis of compound (2R)-4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-1,2-二羧酸酯(123mg,0.30mmol)溶解于二氯甲烷(6mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(5mL)，室温反应1h，除去溶剂，得到无色液体102mg，产率98％。 The compound (2R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-1,2-dicarboxylic acid The ester (123 mg, 0.30 mmol) was dissolved in a dichloromethane (6 mL) solution, 4 mol/L HCl in ethyl acetate (5 mL) was added, and reacted at room temperature for 1 h. After removing the solvent, 102 mg of a colorless liquid was obtained with a yield of 98%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.14(d,J＝8.2Hz,1H),7.10(d,J＝1.9Hz,1H),6.92(dd,J＝8.2,1.9Hz,1H),6.71(t,J F-H＝75.4Hz,1H),4.61–4.65(m,1H),3.90(s,3H),3.80–3.84(m,1H),3.68–3.75(m,1H),3.36–3.41(m,1H),2.84–2.90(m,1H),2.22–2.31(m,1H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.14 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.92 (dd, J = 8.2, 1.9 Hz, 1H), 6.71(t, J FH = 75.4Hz, 1H), 4.61–4.65(m,1H), 3.90(s,3H), 3.80–3.84(m,1H), 3.68–3.75(m,1H), 3.36–3.41(m,1H), 2.84–2.90(m,1H), 2.22–2.31(m,1H).
MS(ESI,pos.ion)m/z:305.15[M+H-HCl] +. MS(ESI,pos.ion)m/z:305.15[M+H-HCl] + .
步骤3：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-2-羧酸甲酯的合成 Step 3: Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(2R)-4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-2-羧酸甲酯盐酸盐(100mg,0.29mmol)溶解在二氯甲烷(3mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.15mL,0.91mmol)，乙酰氯(69mg,0.88mmol)，室温反应4h后停止，加水(15mL)，二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析色谱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到浅黄色液体93mg，产率91％。 The compound (2R)-4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (100mg, 0.29mmol) was dissolved In dichloromethane (3mL), after cooling to 0°C, add N,N-diisopropylethylamine (0.15mL, 0.91mmol), acetyl chloride (69mg, 0.88mmol), and stop reacting at room temperature for 4h, add water (15mL), dichloromethane extraction (10mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)) = 1/1), 93 mg of light yellow liquid was obtained, and the yield was 91%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.14(d,J＝7.9Hz,1H),6.85(s,1H),6.79–6.83(m,1H),6.55(t,J F-H＝75.1Hz,1H),4.49–4.53(m,1H),3.95–3.99(m,1H),3.79(s,3H),3.65(t,J＝10.4Hz,1H),3.41–3.48(m,1H),2.66–2.73(m,1H),2.14(s,3H),2.04–2.10(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.14 (d, J = 7.9 Hz, 1H), 6.85 (s, 1H), 6.79-6.83 (m, 1H), 6.55 (t, J FH = 75.1 Hz, 1H), 4.49–4.53 (m, 1H), 3.95–3.99 (m, 1H), 3.79 (s, 3H), 3.65 (t, J = 10.4 Hz, 1H), 3.41–3.48 (m, 1H) ,2.66-2.73(m,1H), 2.14(s,3H), 2.04--2.10(m,1H).
MS(ESI,pos.ion)m/z:347.10[M+H] +. MS(ESI,pos.ion)m/z:347.10[M+H] + .
步骤4：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-2-羧酸的合成 Step 4: Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-2-carboxylic acid
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-2-羧酸甲酯(92mg,0.27mmol)溶于四氢呋喃(3mL)和水(3mL)的混合溶剂中，加入一水合氢氧化锂(56mg,1.34mmol)，50℃反应30min后停止，加稀盐酸调节溶液pH＝1，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到浅黄色液体87mg，收率98％。 Compound (2R) -1- acetyl-4- (4- (difluoromethoxy) -3-methoxy -d 3 - phenyl) pyrrolidine-2-carboxylate (92mg, 0.27mmol ) Dissolve in a mixed solvent of tetrahydrofuran (3mL) and water (3mL), add lithium hydroxide monohydrate (56mg, 1.34mmol), stop the reaction at 50°C for 30 minutes, add dilute hydrochloric acid to adjust the solution pH=1, use ethyl acetate After extraction (10 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 87 mg of pale yellow liquid with a yield of 98%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.12(d,J＝8.2Hz,1H),7.08(d,J＝1.8Hz,1H),6.93(dd,J＝8.3,2.0Hz,1H),6.69(t,J F-H＝75.5Hz,1H),4.44–4.49(m,1H),4.09–4.15(m,1H),3.49–3.56(m,1H),3.58–3.65(m,1H),2.73–2.80(m,1H),2.14(s,3H),2.02–2.10(m,1H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.12 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 8.3, 2.0 Hz, 1H), 6.69(t, J FH = 75.5Hz, 1H), 4.44–4.49(m,1H), 4.09–4.15(m,1H), 3.49–3.56(m,1H), 3.58–3.65(m,1H) ), 2.73-2.80(m,1H), 2.14(s,3H), 2.02--2.10(m,1H).
MS(ESI,pos.ion)m/z:333.10[M+H] +. MS(ESI,pos.ion)m/z:333.10[M+H] + .
步骤5：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺的合成 Step 5: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-2-carboxamido )Methyl)-N-(4-fluorophenyl)-N-methylpyridine amide
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-2-羧酸(45mg,0.14mmol)，6-(氨基甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺二盐酸盐(889-1)(61mg,0.18mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(132mg,0.69mmol)和N-羟基-7-氮杂苯并三氮唑(36mg,0.26mmol)溶于二氯甲烷(10mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.16mL,0.97mmol)，室温反应11h，加水(20mL)搅拌5min，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，减压浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体37mg，产率47％。 The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-2-carboxylic acid (45mg, 0.14mmol), 6-(Aminomethyl)-N-(4-fluorophenyl)-N-picolineamide dihydrochloride (889-1) (61mg, 0.18mmol), 1-ethyl-(3-dimethyl Aminopropyl) carbodiimide hydrochloride (132mg, 0.69mmol) and N-hydroxy-7-azabenzotriazole (36mg, 0.26mmol) were dissolved in dichloromethane (10mL) and cooled After reaching 0°C, add N,N-diisopropylethylamine (0.16mL, 0.97mmol), react at room temperature for 11h, add water (20mL), stir for 5min, extract with dichloromethane (5mL×3), and use no organic phase. Drying with sodium sulfate, removing the solvent, concentrating under reduced pressure, and performing silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 37 mg of a white solid with a yield of 47%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.52–7.67(m,1H),7.34(br.s,1H),7.00–7.20(m,5H),6.83–6.99(m,4H),6.55(t,J F-H＝75.2Hz,1H),4.47–4.57(m,1H),4.32–4.47(m,2H),3.95–3.99(m,1H),3.60(t,J＝10.5Hz,1H),3.49(s,3H),3.30–3.45(m,1H),2.52–2.62(m,1H),2.39–2.48(m,1H),2.15(s,3H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.52-7.67(m,1H), 7.34(br.s,1H), 7.00-7.20(m,5H), 6.83-6.99(m,4H), 6.55(t,J FH =75.2Hz,1H), 4.47–4.57(m,1H), 4.32–4.47(m,2H), 3.95–3.99(m,1H), 3.60(t,J=10.5Hz,1H ), 3.49 (s, 3H), 3.30-3.45 (m, 1H), 2.52-2.62 (m, 1H), 2.39-2.48 (m, 1H), 2.15 (s, 3H).
MS(ESI,pos.ion)m/z:574.35[M+H] +. MS(ESI,pos.ion)m/z:574.35[M+H] + .
实施例70：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘代)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺Example 70: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy) )Phenyl)pyrrolidine-2-carboxamido)methyl)-N-(4-fluorophenyl)-N-picolineamide
Figure PCTCN2021090489-appb-000132
Figure PCTCN2021090489-appb-000132
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(90mg,0.18mmol)，4-氟-N-甲基苯(44mg,0.35mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(172mg,0.9mmol)和N-羟基-7-氮杂苯并三氮唑(49mg,0.36mmol)溶于二氯甲烷(5mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.21mL,1.3mmol)，室温反应18h，加水(15mL)，二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体46mg，产率43％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl) Pyrrolidine-2-carboxamido)methyl)picolinic acid (90mg, 0.18mmol), 4-fluoro-N-methylbenzene (44mg, 0.35mmol), 1-ethyl-(3-dimethylaminopropyl) Base) carbodiimide hydrochloride (172mg, 0.9mmol) and N-hydroxy-7-azabenzotriazole (49mg, 0.36mmol) dissolved in dichloromethane (5mL), cooled to 0℃ Then, add N,N-diisopropylethylamine (0.21mL, 1.3mmol), react at room temperature for 18h, add water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, and remove The solvent was concentrated and subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 46 mg of white solid with a yield of 43%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.63–7.77(m,1H),7.34–7.48(m,1H),7.08–7.28(m,5H),6.90–7.02(m,3H),6.74(t,J F-H＝75.2Hz,1H),4.38–4.53(m,2H),4.21–4.32(m,1H),4.06–4.15(m,1H),3.62–3.67(m,1H),3.37–3.54(m,1H),3.46(s,3H),2.61–2.75(m,1H),2.14(s,3H),1.99–2.13(m,1H),1.26–1.40(m,1H),0.60–0.68(m,2H),0.32–0.44(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.63 - 7.77 (m, 1H), 7.34 - 7.48 (m, 1H), 7.08 - 7.28 (m, 5H), 6.90 - 7.02 (m, 3H) ,6.74(t,J FH =75.2Hz,1H), 4.38–4.53(m,2H),4.21–4.32(m,1H),4.06–4.15(m,1H),3.62–3.67(m,1H), 3.37–3.54(m,1H), 3.46(s,3H), 2.61–2.75(m,1H), 2.14(s,3H), 1.99–2.13(m,1H), 1.26–1.40(m,1H), 0.60-0.68 (m, 2H), 0.32-0.44 (m, 2H).
MS(ESI,pos.ion)m/z:613.80[M+H] +. MS(ESI,pos.ion)m/z:613.80[M+H] + .
实施例71：化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺Example 71: Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)-N -(4-Fluorophenyl)-N-picolinamide
Figure PCTCN2021090489-appb-000133
Figure PCTCN2021090489-appb-000133
将化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(80mg,0.16mmol)，4-氟-N-甲基苯胺(26mg,0.21mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(151mg,0.79mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.13mL,0.79mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体81mg，收率83％。Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)picolinic acid (80mg, 0.16mmol), 4-fluoro-N-methylaniline (26mg, 0.21mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (151mg, 0.79mmol) and N-hydroxy-7-azabenzotriazole (43mg, 0.32mmol) was dissolved in dichloromethane (5mL), and N,N-diisopropylethylamine ( 0.13mL, 0.79mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (wash Removal agent: dichloromethane/methanol (v/v)=30/1) to obtain 81 mg of white solid with a yield of 83%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.56–7.65(m,1H),7.31–7.38(m,1H),7.17–7.25(m,3H),7.05–7.14(m,3H),6.91–6.98(m,2H),6.56(t,J F-H＝73.6Hz,1H),6.53(t,J F-H＝73.6Hz,1H),4.48–4.60(m,1H),4.34–4.48(m,2H),3.97–4.01(m,1H),3.58(t,J＝10.6Hz,1H),3.50(s,3H),3.30–3.45(m,1H),2.55–2.60(m,1H),2.38–2.40(m,1H),2.16(s,3H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.56-7.65(m,1H), 7.31-7.38(m,1H), 7.17-7.25(m,3H), 7.05-7.14(m,3H), 6.91–6.98(m,2H), 6.56(t, J FH = 73.6Hz, 1H), 6.53(t, J FH = 73.6Hz, 1H), 4.48–4.60(m, 1H), 4.34–4.48(m, 2H), 3.97–4.01(m,1H), 3.58(t,J=10.6Hz,1H), 3.50(s,3H), 3.30–3.45(m,1H), 2.55–2.60(m,1H), 2.38 --2.40(m,1H), 2.16(s,3H).
MS(ESI,pos.ion)m/z:607.20[M+H] +. MS(ESI,pos.ion)m/z:607.20[M+H] + .
实施例72：化合物6-(((2R)-1-乙酰基-4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺Example 72: Compound 6-(((2R)-1-acetyl-4-(2,2-difluorobenzo[d][1,3]dioxocene-5-yl)pyrrolidine-2- Carboxamido)methyl)-N-(4-fluorophenyl)-N-picolineamide
Figure PCTCN2021090489-appb-000134
Figure PCTCN2021090489-appb-000134
步骤1：化合物(R)-1-叔丁基2-甲基4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 1: Compound (R)-1-tert-butyl 2-methyl 4-(2,2-difluorobenzo[d][1,3]dioxan-5-yl)-1H-pyrrole-1 Synthesis of ,2(2H,5H)-dicarboxylate
将(R)-1-叔丁基-2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(320mg,0.9mmol)，5-溴-2,2-二氟苯并[d][1,3]二噁茂(475mg,2.0mmol)，磷酸钾(1.1g,5.2mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(26mg)混合在干燥的1,4-二氧六环(8mL)溶液中，氮气保护下100℃反应12h，冷却至室温，减压浓缩，剩余物加入水(20mL)，用乙酸乙酯(15mL×3)萃取，有机相合用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到浅褐色液体324mg，产率93％。Add (R)-1-tert-butyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -Pyrrole-1,2(2H,5H)-dicarboxylate (320mg, 0.9mmol), 5-bromo-2,2-difluorobenzo[d][1,3]dioxolene (475mg, 2.0 mmol), potassium phosphate (1.1g, 5.2mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (26mg) mixed in dry 1,4-dioxane (8mL) in the solution, react at 100°C under nitrogen protection for 12h, cool to room temperature, concentrate under reduced pressure, add water (20mL) to the residue, extract with ethyl acetate (15mL×3), and dry the organic phase with anhydrous sodium sulfate. It was concentrated under reduced pressure and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain 324 mg of light brown liquid, with a yield of 93%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.14(s,1H),7.05–7.11(m,2H),6.05–6.07(m,0.4H),6.00–6.02(m,0.6H),5.20–5.23(m,0.4H),5.12–5.15(m,0.6H),4.50–4.67(m,2H),3.79(s,1H),3.78(s,2H),1.54(s,3.4H),1.48(s,5.6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.14 (s, 1H), 7.05-7.11 (m, 2H), 6.05-6.07 (m, 0.4H), 6.00-6.02 (m, 0.6H), 5.20–5.23(m,0.4H), 5.12–5.15(m,0.6H), 4.50–4.67(m,2H), 3.79(s,1H), 3.78(s,2H), 1.54(s,3.4H) , 1.48(s,5.6H).
MS(ESI,pos.ion)m/z:406.00[M+Na] +. MS(ESI,pos.ion)m/z:406.00[M+Na] + .
步骤2：化合物(2R)-1-叔丁基2-甲基4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-1,2-二羧酸酯的合成Step 2: Compound (2R)-1-tert-butyl 2-methyl 4-(2,2-difluorobenzo[d][1,3]dioxocene-5-yl)pyrrolidine-1,2 -Synthesis of dicarboxylic acid esters
将化合物(R)-1-叔丁基2-甲基4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(320mg,0.83mmol)溶于甲醇(8mL)，加入Pd/C(32mg)，通入氢气室温反应5h，过滤除去催化剂，滤液浓缩，得到无色液体306mg，产率95％。The compound (R)-1-tert-butyl 2-methyl 4-(2,2-difluorobenzo[d][1,3]dioxan-5-yl)-1H-pyrrole-1,2 (2H,5H)-Dicarboxylic acid ester (320mg, 0.83mmol) was dissolved in methanol (8mL), Pd/C (32mg) was added, hydrogen gas was added to react at room temperature for 5h, the catalyst was filtered off, the filtrate was concentrated to obtain a colorless liquid 306mg , The yield is 95%.
1H NMR(400MHz,CDCl 3)δ(ppm):6.95–7.03(m,3H),4.33–4.43(m,1H),4.04–4.10(m,0.6H),3.94–4.00(m,0.4H),3.79(s,1H),3.78(s,2H),3.42(t,J＝10.1Hz,1H),3.32–3.41(m,1H),2.64–2.71(m,1H),2.00–2.09(m,1H),1.49(s,3H),1.45(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 6.95-7.03 (m, 3H), 4.33-4.43 (m, 1H), 4.04--4.10 (m, 0.6H), 3.94-4.00 (m, 0.4H) ), 3.79(s, 1H), 3.78(s, 2H), 3.42(t, J = 10.1Hz, 1H), 3.32–3.41(m, 1H), 2.64–2.71(m, 1H), 2.00–2.09( m,1H), 1.49(s,3H), 1.45(s,6H).
MS(ESI,pos.ion)m/z:408.10[M+Na] +. MS(ESI,pos.ion)m/z:408.10[M+Na] + .
步骤3：化合物(2R)-4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-2-羧酸甲酯盐酸盐的合成Step 3: Synthesis of compound (2R)-4-(2,2-difluorobenzo[d][1,3]dioxocene-5-yl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R)-1-叔丁基2-甲基4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-1,2-二羧酸酯(300mg,0.78mmol)溶解于二氯甲烷(5mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(5mL)，室温反应1h，除去溶剂，得到白色固体248mg，产率99％。The compound (2R)-1-tert-butyl 2-methyl 4-(2,2-difluorobenzo[d][1,3]dioxan-5-yl)pyrrolidine-1,2-di Carboxylic acid ester (300mg, 0.78mmol) was dissolved in dichloromethane (5mL) solution, 4mol/L HCl ethyl acetate solution (5mL) was added, reacted at room temperature for 1h, and the solvent was removed to obtain white solid 248mg, yield 99% .
1H NMR(400MHz,CD 3OD)δ(ppm):7.29(s,1H),7.20–7.22(m,1H),7.16–7.18(m,1H),4.61–4.66(m,1H),3.90(s,3H),3.69–3.85(m,2H),3.34–3.38(m,1H),2.84–2.91(m,1H),2.20–2.28(m,1H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.29 (s, 1H), 7.20-7.22 (m, 1H), 7.16-7.18 (m, 1H), 4.61-4.66 (m, 1H), 3.90 (s,3H), 3.69--3.85(m,2H), 3.34--3.38(m,1H), 2.84--2.91(m,1H), 2.20--2.28(m,1H).
MS(ESI,pos.ion)m/z:286.00[M+H-HCl] +. MS(ESI,pos.ion)m/z:286.00[M+H-HCl] + .
步骤4：化合物(2R)-1-乙酰基-4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-2-羧酸甲酯的合成Step 4: Compound (2R)-1-acetyl-4-(2,2-difluorobenzo[d][1,3]dioxan-5-yl)pyrrolidine-2-carboxylic acid methyl ester synthesis
将化合物(2R)-4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-2-羧酸甲酯盐酸盐(245mg,0.76mmol)溶解在二氯甲烷(6mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.63mL,3.8mmol)和乙酰氯(181mg,2.3mmol)，室温搅拌3h后停止，加水(15mL)，分离有机相，有机相用无水硫酸钠干燥，浓缩，进行硅胶柱层析色谱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到浅黄色液体221mg，产率88％。The compound (2R)-4-(2,2-difluorobenzo[d][1,3]dioxan-5-yl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (245mg, 0.76mmol ) Was dissolved in dichloromethane (6mL), cooled to 0°C, added N,N-diisopropylethylamine (0.63mL, 3.8mmol) and acetyl chloride (181mg, 2.3mmol), stirred at room temperature for 3h and then stopped. Add water (15 mL), separate the organic phase, dry the organic phase with anhydrous sodium sulfate, concentrate, and perform silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) to obtain Light yellow liquid 221mg, yield 88%.
1H NMR(400MHz,CDCl 3)δ(ppm):6.95–7.05(m,3H),6.55(t,J F-H＝75.1Hz,1H),4.49–4.53(m,1H),3.95–3.99(m,1H),3.79(s,3H),3.62(t,J＝10.4Hz,1H),3.42–3.51(m,1H),2.66–2.73(m,1H),2.13(s,3H),2.00–2.10(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 6.95-7.05 (m, 3H), 6.55 (t, J FH = 75.1Hz, 1H), 4.49-4.53 (m, 1H), 3.95-3.99 (m ,1H),3.79(s,3H),3.62(t,J=10.4Hz,1H),3.42-3.51(m,1H),2.66-2.73(m,1H),2.13(s,3H),2.00- 2.10(m,1H).
MS(ESI,pos.ion)m/z:328.20[M+H] +. MS(ESI,pos.ion)m/z:328.20[M+H] + .
步骤5：化合物(2R)-1-乙酰基-4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-2-羧酸的合成Step 5: Synthesis of compound (2R)-1-acetyl-4-(2,2-difluorobenzo[d][1,3]dioxan-5-yl)pyrrolidine-2-carboxylic acid
将化合物(2R)-1-乙酰基-4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-2-羧酸甲酯(220mg,0.67mmol)溶于四氢呋喃(3mL)和水(3mL)的混合溶剂中，再加入一水合氢氧化锂(56mg,1.34mmol)，50℃反应30min后停止，加稀盐酸调节溶液pH＝1，再用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到浅黄色液体207mg，收率98％。Compound (2R)-1-acetyl-4-(2,2-difluorobenzo[d][1,3]dioxin-5-yl)pyrrolidine-2-carboxylic acid methyl ester (220mg, 0.67mmol) was dissolved in a mixed solvent of tetrahydrofuran (3mL) and water (3mL), and then lithium hydroxide monohydrate (56mg, 1.34mmol) was added. The reaction was stopped at 50°C for 30 minutes, and diluted hydrochloric acid was added to adjust the pH of the solution to 1. It was extracted with ethyl acetate (10 mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 207 mg of light yellow liquid with a yield of 98%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.26(s,1H),7.14–7.19(m,2H),4.44–4.48(m,1H),4.09–4.15(m,1H),3.56–3.63(m,2H),2.74–2.80(m,1H),2.14(s,3H),2.00–2.08(m,1H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.26 (s, 1H), 7.14-7.19 (m, 2H), 4.44-4.48 (m, 1H), 4.09-4.15 (m, 1H), 3.56 --3.63 (m, 2H), 2.74 - 2.80 (m, 1H), 2.14 (s, 3H), 2.00 - 2.08 (m, 1H).
MS(ESI,pos.ion)m/z:314.20[M+H] +. MS(ESI,pos.ion)m/z:314.20[M+H] + .
步骤6：化合物6-(((2R)-1-乙酰基-4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺的合成Step 6: Compound 6-(((2R)-1-acetyl-4-(2,2-difluorobenzo[d][1,3]dioxan-5-yl)pyrrolidine-2-methan Synthesis of acylamino)methyl)-N-(4-fluorophenyl)-N-picolineamide
将化合物(2R)-1-乙酰基-4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-2-羧酸(60mg,0.19mmol)，6-(氨基甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺二盐酸盐(889-1)(77mg,0.23mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(182mg,0.95mmol)和N-羟基-7-氮杂苯并三氮唑(52mg,0.38mmol)溶于二氯甲烷(6mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.22mL,1.3mmol)，室温反应11h，加水(20mL)搅拌5min，分离有机相，有机相用无水硫酸钠干燥，浓缩，进行硅胶柱层析色谱分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体64mg，再经过高效液相色谱制备分离得到白色固体39mg，收率36％。The compound (2R)-1-acetyl-4-(2,2-difluorobenzo[d][1,3]dioxin-5-yl)pyrrolidine-2-carboxylic acid (60mg, 0.19mmol ), 6-(aminomethyl)-N-(4-fluorophenyl)-N-picolineamide dihydrochloride (889-1) (77mg, 0.23mmol), 1-ethyl-(3- Dimethylaminopropyl) carbodiimide hydrochloride (182mg, 0.95mmol) and N-hydroxy-7-azabenzotriazole (52mg, 0.38mmol) dissolved in dichloromethane (6mL) After cooling to 0°C, add N,N-diisopropylethylamine (0.22mL, 1.3mmol), react at room temperature for 11h, add water (20mL) and stir for 5min, separate the organic phase, and dry the organic phase with anhydrous sodium sulfate. Concentrate, perform silica gel column chromatography separation (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 64 mg of white solid, and then prepare and separate by high performance liquid chromatography to obtain 39 mg of white solid. Yield 36%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.50–7.63(m,2H),7.19–7.28(m,1H),7.13–6.92(m,7H),4.53–4.57(m,1H),4.34–4.47(m,2H),3.93–3.98(m,1H),3.57(t,J＝10.6Hz,1H),3.50(s,3H),3.35–3.49(m,1H),2.55–2.62(m,1H),2.33–2.47(m,1H),2.13(s,3H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.50-7.63(m,2H), 7.19-7.28(m,1H), 7.13-6.92(m,7H), 4.53-4.57(m,1H), 4.34–4.47(m,2H), 3.93–3.98(m,1H), 3.57(t,J=10.6Hz,1H), 3.50(s,3H), 3.35–3.49(m,1H), 2.55–2.62( m,1H),2.33-2.47(m,1H),2.13(s,3H).
MS(ESI,pos.ion)m/z:555.85[M+H] +. MS(ESI,pos.ion)m/z:555.85[M+H] + .
实施例73：化合物6-(((2R)-1-乙酰基-4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺Example 73: Compound 6-(((2R)-1-acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-( (Methylsulfonyl)phenyl)pyrrolidine-2-carboxamido)methyl)-N-(4-fluorophenyl)-N-picolineamide
Figure PCTCN2021090489-appb-000135
Figure PCTCN2021090489-appb-000135
步骤1：化合物(R)-1-叔丁基2-甲基4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成Step 1: Compound (R)-1-tert-butyl 2-methyl 4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methyl Synthesis of sulfonyl)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate
将化合物(R)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(300mg,0.85mmol)，N-(5-溴-2-(二氟甲氧基)-4-(甲磺酰基)苯基)-N-(环丙基甲基)羟胺(334mg,0.86mmol)，磷酸钾(721mg,3.40mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(24mg)混合在干燥的1,4-二氧六环(8mL)溶液中，氮气保护下100℃反应3h，冷却至室温，减压浓缩，剩余物加入水(20mL)，用乙酸乙酯(15mL×3)萃取，有机相合用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝5/1)，得到浅黄色液体381mg，产率84％。The compound (R)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Pyrrole-1,2(2H,5H)-dicarboxylate (300mg, 0.85mmol), N-(5-bromo-2-(difluoromethoxy)-4-(methylsulfonyl)phenyl)- N-(cyclopropylmethyl)hydroxylamine (334mg, 0.86mmol), potassium phosphate (721mg, 3.40mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (24mg ) Was mixed with dry 1,4-dioxane (8mL) solution, reacted at 100℃ for 3h under nitrogen protection, cooled to room temperature, concentrated under reduced pressure, the residue was added with water (20mL), and ethyl acetate (15mL× 3) Extraction, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=5/1) to obtain 381 mg of light yellow liquid , The yield is 84%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.14–7.15(m,1H),6.53(t,J F-H＝73.3Hz,1H),6.49(s,1H),6.19–6.21(m,0.7H),6.10–6.12(m,0.3H),5.19–5.23(m,0.3H),5.14–5.17(m,0.7H),4.58–4.67(m,2H),3.79(s,3H),3.03–3.05(m,3H),2.95–2.98(m,2H),1.45–1.53(m,9H),1.08–1.16(m,1H),0.60–0.65(m,2H),0.26–0.30(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.14-7.15 (m, 1H), 6.53 (t, J FH = 73.3 Hz, 1H), 6.49 (s, 1H), 6.19-6.21 (m, 0.7 H), 6.10--6.12(m, 0.3H), 5.19-5.23(m, 0.3H), 5.14-5.17(m, 0.7H), 4.58-4.67(m, 2H), 3.79(s, 3H), 3.03 --3.05 (m, 3H), 2.95 - 2.98 (m, 2H), 1.45 - 1.53 (m, 9H), 1.08 - 1.16 (m, 1H), 0.60 - 0.65 (m, 2H), 0.26 - 0.30 (m, 2H).
MS(ESI,pos.ion)m/z:533.90[M+H] +. MS(ESI,pos.ion)m/z:533.90[M+H] + .
步骤2：化合物(2R)-1-叔丁基2-甲基4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-1,2-二羧酸酯的合成Step 2: Compound (2R)-1-tert-butyl 2-methyl 4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methyl Synthesis of sulfonyl)phenyl)pyrrolidine-1,2-dicarboxylate
将化合物(R)-1-叔丁基2-甲基4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(380mg,0.71mmol)溶于甲醇(8mL)，加入Pd/C(32mg,10％)，通入氢气室温反应24h，过滤除去催化剂，滤液浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到无色液体226mg，产率59％。The compound (R)-1-tert-butyl 2-methyl 4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl) )Phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (380mg, 0.71mmol) dissolved in methanol (8mL), add Pd/C (32mg, 10%), bubbling hydrogen at room temperature After reacting for 24 hours, the catalyst was removed by filtration, the filtrate was concentrated, and subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain 226 mg of colorless liquid with a yield of 59%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.01(s,1H),6.65(s,1H),6.48(t,J F-H＝73.6Hz,1H),4.33–4.42(m,2H),3.92–4.04(m,1H),3.80(s,1H),3.64–3.73(m,1H),3.43–3.50(m,1H),3.24(s,3H),2.96–3.00(m,2H),2.67–2.75(m,1H),1.96–2.04(m,1H),1.48(s,3.4H),1.45(s,5.6H),1.07–1.14(m,1H),0.60–0.64(m,2H),0.27–0.31(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.01 (s, 1H), 6.65 (s, 1H), 6.48 (t, J FH = 73.6 Hz, 1H), 4.33-4.42 (m, 2H), 3.92–4.04(m,1H), 3.80(s,1H), 3.64–3.73(m,1H), 3.43–3.50(m,1H), 3.24(s,3H), 2.96–3.00(m,2H), 2.67-2.75(m,1H),1.96-2.04(m,1H),1.48(s,3.4H),1.45(s,5.6H),1.07-1.14(m,1H),0.60-0.64(m,2H) ), 0.27--0.31 (m, 2H).
MS(ESI,pos.ion)m/z:535.10[M+H] +. MS(ESI,pos.ion)m/z:535.10[M+H] + .
步骤3：化合物(2R)-4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成Step 3: Compound (2R)-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl)phenyl)pyrrolidine- Synthesis of 2-carboxylic acid methyl ester hydrochloride
将化合物(2R)-1-叔丁基2-甲基4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-1,2-二羧酸酯(221mg,0.41mmol)溶解于二氯甲烷(3mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(6mL)，室温反应1h，除去溶剂，得到白色固体191mg，产率98％。The compound (2R)-1-tert-butyl 2-methyl 4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl) )Phenyl)pyrrolidine-1,2-dicarboxylate (221mg, 0.41mmol) was dissolved in dichloromethane (3mL) solution, 4mol/L HCl ethyl acetate solution (6mL) was added, and reacted at room temperature for 1h, The solvent was removed to obtain 191 mg of white solid with a yield of 98%.
1H NMR(600MHz,CD 3OD)δ(ppm):7.30(s,1H),7.29(s,1H),6.99(t,J F-H＝72.8Hz,1H),4.65–4.68(m,1H),4.05–4.08(m,1H),3.92(s,3H),3.82–3.86(m,1H),3.46(s,3H),3.37–3.41(m,1H),3.21(d,J＝7.0Hz,2H),2.84–2.88(m,1H),2.29–2.35(m,1H),1.15–1.20(m,1H),0.64–0.67(m,2H),0.35–0.37(m,2H). 1 H NMR (600MHz, CD 3 OD) δ (ppm): 7.30 (s, 1H), 7.29 (s, 1H), 6.99 (t, J FH = 72.8 Hz, 1H), 4.65-4.68 (m, 1H) ,4.05–4.08(m,1H),3.92(s,3H), 3.82–3.86(m,1H), 3.46(s,3H), 3.37–3.41(m,1H), 3.21(d,J=7.0Hz ,2H), 2.84–2.88(m,1H), 2.29–2.35(m,1H), 1.15–1.20(m,1H), 0.64–0.67(m,2H), 0.35–0.37(m,2H).
MS(ESI,pos.ion)m/z:435.05[M+H-HCl] +. MS(ESI,pos.ion)m/z:435.05[M+H-HCl] + .
步骤4：化合物(2R)-1-乙酰基-4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-2-羧酸甲酯的合成Step 4: Compound (2R)-1-acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl)benzene Of pyrrolidine-2-carboxylic acid methyl ester
将化合物(2R)-4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-2-羧酸甲酯盐酸盐(190mg,0.41mmol)溶解在二氯甲烷(6mL)中，在冰浴中加入N,N-二异丙基乙胺(0.41mL,2.5mmol)和乙酰氯(96mg,1.22mmol)，室温搅拌40min后停止，加水(15mL)，用二氯甲烷(15mL×3)萃取，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到无色液体162mg，产率84％。The compound (2R)-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl)phenyl)pyrrolidine-2- Methyl carboxylate hydrochloride (190mg, 0.41mmol) was dissolved in dichloromethane (6mL), and N,N-diisopropylethylamine (0.41mL, 2.5mmol) and acetyl chloride (96mg , 1.22mmol), stirred at room temperature for 40min, then stopped, added water (15mL), extracted with dichloromethane (15mL×3), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent : Petroleum ether/ethyl acetate (v/v) = 1/2), 162 mg of colorless liquid was obtained, and the yield was 84%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.00(s,1H),6.56(s,1H),6.50(t,J F-H＝73.4Hz,1H),4.48–4.52(m,1H),4.33–4.40(m,1H),3.98–4.02(m,1H),3.80(s,3H),3.74–3.80(m,1H),3.57–3.62(m,1H),3.26(s,3H),3.37–3.41(m,1H),2.98–3.02(m,2H),2.64–2.71(m,1H),2.12(s,3H),2.01–2.09(m,1H),1.07–1.16(m,1H),0.61–0.66(m,2H),0.29–0.33(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.00 (s, 1H), 6.56 (s, 1H), 6.50 (t, J FH = 73.4 Hz, 1H), 4.48-4.52 (m, 1H), 4.33-4.40(m,1H), 3.98-4.02(m,1H), 3.80(s,3H), 3.74-3.80(m,1H), 3.57-3.62(m,1H), 3.26(s,3H), 3.37–3.41(m,1H), 2.98–3.02(m,2H), 2.64–2.71(m,1H), 2.12(s,3H), 2.01–2.09(m,1H), 1.07–1.16(m,1H) ), 0.61--0.66 (m, 2H), 0.29--0.33 (m, 2H).
MS(ESI,pos.ion)m/z:477.90[M+H] +. MS(ESI,pos.ion)m/z:477.90[M+H] + .
步骤5：化合物(2R)-1-乙酰基-4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-2-羧酸的合成Step 5: Compound (2R)-1-acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl)benzene Yl) pyrrolidine-2-carboxylic acid synthesis
将化合物(2R)-1-乙酰基-4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-2-羧酸甲酯(153mg,0.32mmol)溶于四氢呋喃(4mL)和水(4mL)的混合溶剂中，加入一水合氢氧化锂(67mg,1.60mmol)，50℃反应1h后停止，加稀盐酸调节溶液pH＝1，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到浅褐色固体133mg，收率89％。The compound (2R)-1-acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl)phenyl) Methyl pyrrolidine-2-carboxylate (153mg, 0.32mmol) was dissolved in a mixed solvent of tetrahydrofuran (4mL) and water (4mL), lithium hydroxide monohydrate (67mg, 1.60mmol) was added, and the reaction was stopped at 50°C for 1 hour. Add dilute hydrochloric acid to adjust the pH of the solution to 1, extract with ethyl acetate (5 mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent to obtain 133 mg of light brown solid, with a yield of 89%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.10(s,1H),6.79(t,J F-H＝73.8Hz,1H),7.14–7.19(m,2H),6.77(s,1H),4.45–4.49(m,1H),4.05–4.13(m,1H),3.80–3.89(m,1H),3.61–3.73(m,1H),3.35(s,3H),3.05–3.08(m,2H),2.71–2.78(m,1H),2.12(s,2H),2.01(s,1H),2.01–2.10(m,1H),1.10–1.14(m,1H),0.55–0.60(m,2H),0.28–0.31(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.10 (s, 1H), 6.79 (t, J FH = 73.8Hz, 1H), 7.14-7.19 (m, 2H), 6.77 (s, 1H) ,4.45-4.49(m,1H),4.05--4.13(m,1H),3.80-3.89(m,1H),3.61-3.73(m,1H),3.35(s,3H),3.05-3.08(m, 2H), 2.71–2.78(m,1H), 2.12(s,2H), 2.01(s,1H), 2.01–2.10(m,1H), 1.10–1.14(m,1H), 0.55–0.60(m, 2H), 0.28--0.31 (m, 2H).
MS(ESI,pos.ion)m/z:463.90[M+H] +. MS(ESI,pos.ion)m/z:463.90[M+H] + .
步骤6：化合物6-(((2R)-1-乙酰基-4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺的合成Step 6: Compound 6-(((2R)-1-acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methyl Synthesis of (sulfonyl)phenyl)pyrrolidine-2-carboxamido)methyl)-N-(4-fluorophenyl)-N-picolinamide
将化合物(2R)-1-乙酰基-4-(5-((环丙基甲基)(羟基)氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-2-羧酸(60mg,0.13mmol)，6-(氨基甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺二盐酸盐(51mg,0.15mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(124mg,0.65mmol)和N-羟基-7-氮杂苯并三氮唑(36mg,0.26mmol)溶于二氯甲烷(5mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.15mL,0.91mmol)，室温反应12h，加水(20mL)搅拌5min，分离有机相，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体53mg，产率58％。The compound (2R)-1-acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl)phenyl) Pyrrolidine-2-carboxylic acid (60mg, 0.13mmol), 6-(aminomethyl)-N-(4-fluorophenyl)-N-picolinamide dihydrochloride (51mg, 0.15mmol), 1 -Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (124mg, 0.65mmol) and N-hydroxy-7-azabenzotriazole (36mg, 0.26mmol) are dissolved in After cooling to 0°C in dichloromethane (5mL), add N,N-diisopropylethylamine (0.15mL, 0.91mmol), react at room temperature for 12h, add water (20mL) and stir for 5min, separate the organic phase and the organic phase It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain a white solid of 53 mg with a yield of 58%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.61(br.s,1H),7.33–7.46(m,1H),7.16–7.24(m,1H),6.98–7.09(m,5H),6.68(s,1H),6.50(t,J F-H＝74.0Hz,1H),4.35–4.83(m,4H),3.97–4.07(m,1H),3.63–3.74(m,1H), 3.50(s,3H),3.65(s,3H),2.93–3.04(m,2H),2.48–2.59(m,1H),2.36–2.48(m,1H),2.13(s,3H),1.05–1.14(m,1H),0.56–0.64(m,2H),0.25–0.32(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.61 (br.s, 1H), 7.33-7.46 (m, 1H), 7.16-7.24 (m, 1H), 6.98-7.09 (m, 5H), 6.68(s,1H),6.50(t,J FH =74.0Hz,1H),4.35-4.83(m,4H),3.97-4.07(m,1H),3.63-3.74(m,1H), 3.50(s ,3H),3.65(s,3H),2.93-3.04(m,2H),2.48-2.59(m,1H),2.36-2.48(m,1H),2.13(s,3H),1.05-1.14(m ,1H),0.56--0.64(m,2H),0.25--0.32(m,2H).
MS(ESI,pos.ion)m/z:704.40[M+H] +. MS(ESI,pos.ion)m/z:704.40[M+H] + .
实施例74：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-甲基-N-(4-甲氧基苯基)吡啶酰胺Example 74: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-methyl-N-(4-methoxyphenyl)pyridineamide
Figure PCTCN2021090489-appb-000136
Figure PCTCN2021090489-appb-000136
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，N-甲基-4-甲氧基苯胺(68mg,0.50mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(251mg,1.31mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.40mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入N,N-二异丙基乙胺(180mg,1.39mmol)，室温反应22h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到灰色固体73mg，收率59％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (100mg, 0.20mmol), N-methyl-4-methoxyaniline (68mg, 0.50mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Hydrochloride (251mg, 1.31mmol) and N-hydroxy-7-azabenzotriazole (54mg, 0.40mmol) were dissolved in dichloromethane (5mL), cooled to 0℃, and N,N-di Isopropylethylamine (180mg, 1.39mmol), react at room temperature for 22h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 73 mg of gray solid with a yield of 59%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.63(br.s,1H),7.19-7.31(m,2H),7.05-7.12(m,3H),6.77-6.92(m,4H),6.62(t,J＝75.5Hz,1H),4.38-4.62(m,3H),3.81-3.99(m,1H),3.89(s,2H),3.64-3.80(m,1H),3.74(s,3H),3.49(s,3H),3.33-3.57(m,1H),2.50-2.78(m,1H),2.17(s,3H),1.26-1.35(m,1H),0.60-0.71(m,2H),0.35-0.43(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.63 (br.s, 1H), 7.19-7.31 (m, 2H), 7.05-7.12 (m, 3H), 6.77-6.92 (m, 4H), 6.62(t,J=75.5Hz,1H), 4.38-4.62(m,3H),3.81-3.99(m,1H),3.89(s,2H),3.64-3.80(m,1H),3.74(s, 3H), 3.49 (s, 3H), 3.33-3.57 (m, 1H), 2.50-2.78 (m, 1H), 2.17 (s, 3H), 1.26-1.35 (m, 1H), 0.60-0.71 (m, 2H), 0.35-0.43 (m, 2H).
MS(ESI,pos.ion)m/z:623.1 0[M+H] +. MS(ESI,pos.ion)m/z:623.1 0[M+H] + .
实施例75：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(2-环丙基丙烷-2-基)吡啶酰胺Example 75: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(2-cyclopropylpropan-2-yl)pyridineamide
Figure PCTCN2021090489-appb-000137
Figure PCTCN2021090489-appb-000137
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，1-环丙基-1-甲基乙胺盐酸盐(59mg,0.43mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(191mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应16h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体59mg，产率50％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (100mg, 0.20mmol), 1-cyclopropyl-1-methylethylamine hydrochloride (59mg, 0.43mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Diimide hydrochloride (191mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (43mg, 0.32mmol) dissolved in dichloromethane (5mL), cooled to 0℃, added N , N-Diisopropylethylamine (0.17mL, 1.00mmol), react at room temperature for 16h, add water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate The liquid was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 59 mg of a white solid with a yield of 50%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.92–7.99(m,2H),7.66(d,J＝5.4Hz,1H),7.11(d,J＝8.2Hz, 1H),7.07(s,1H),6.93(s,1H),6.73(t,J F-H＝71.4Hz,1H),4.51–4.65(m,3H),4.08–4.13(m,1H),3.91(d,J＝6.8Hz,2H),3.66(d,J＝10.5Hz,1H),3.47–3.56(m,1H),2.68–2.74(m,1H),2.15(s,3H),2.03–2.14(m,1H),3.16(s,3H),3.15(s,3H),1.24–1.36(m,2H),0.60–0.65(m,2H),0.40–0.46(m,4H),0.31–0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.92–7.99 (m, 2H), 7.66 (d, J = 5.4 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.07 ( s,1H),6.93(s,1H),6.73(t,J FH =71.4Hz,1H),4.51–4.65(m,3H),4.08–4.13(m,1H),3.91(d,J＝6.8 Hz, 2H), 3.66 (d, J = 10.5 Hz, 1H), 3.47–3.56 (m, 1H), 2.68–2.74 (m, 1H), 2.15 (s, 3H), 2.03–2.14 (m, 1H) , 3.16 (s, 3H), 3.15 (s, 3H), 1.24-1.36 (m, 2H), 0.60-0.65 (m, 2H), 0.40-0.46 (m, 4H), 0.31-0.41 (m, 2H) .
MS(ESI,pos.ion)m/z:585.20[M+H] +. MS(ESI,pos.ion)m/z:585.20[M+H] + .
实施例76：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(环丙基甲基)-N-甲基吡啶酰胺Example 76: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(cyclopropylmethyl)-N-picolineamide
Figure PCTCN2021090489-appb-000138
Figure PCTCN2021090489-appb-000138
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(98mg,0.19mmol)，1-环丙基-N-甲基甲胺盐酸盐(，合成方法参见中间体9)(63mg,0.52mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(127mg,0.66mmol)和N-羟基-7-氮杂苯并三氮唑(89mg,0.65mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌6h，加水(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体46mg，收率41％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl) picolinic acid (98mg, 0.19mmol), 1-cyclopropyl-N-methylmethylamine hydrochloride (, see Intermediate 9 for the synthesis method) (63mg, 0.52mmol), 1-ethyl-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (127mg, 0.66mmol) and N-hydroxy-7-azabenzotriazole (89mg, 0.65mmol) dissolved in dichloromethane (6mL) Add N,N-diisopropylethylamine (0.3mL, 2.0mmol) to this solution dropwise at room temperature, stir at room temperature for 6h, add water (50mL), extract with dichloromethane (5mL×3), organic phase It was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain a white solid 46 mg with a yield of 41%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.64(br.s,1H),7.86(t,J＝7.7Hz,1H),7.47(d,J＝7.8Hz,1H),7.32-7.40(m,1H),7.13(d,J＝8.1Hz,1H),7.07(s,1H),7.03(t,J F-H＝75.0Hz,1H),6.89(d,J＝7.1Hz,1H),4.30-4.56(m,3H),4.05-4.10(m,1H),3.91(d,J＝6.4Hz,2H),3.38-3.52(m,2H),3.10-3.12(m,1H),2.92-3.03(m,3H),2.55-2.66(m,1H),2.03(s,3H),1.85-1.96(m,1H),1.23-1.29(m,1H),0.95-1.06(m,1H),0.53-0.60(m,2H),0.37-0.51(m,2H),0.30-0.36(m,2H),0.22-0.29(m,1H),0.02-0.09(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.64 (br.s, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.32 -7.40(m,1H),7.13(d,J=8.1Hz,1H),7.07(s,1H),7.03(t,J FH =75.0Hz,1H), 6.89(d,J=7.1Hz,1H ), 4.30-4.56 (m, 3H), 4.05-4.10 (m, 1H), 3.91 (d, J = 6.4 Hz, 2H), 3.38-3.52 (m, 2H), 3.10-3.12 (m, 1H), 2.92-3.03(m,3H),2.55-2.66(m,1H),2.03(s,3H),1.85-1.96(m,1H),1.23-1.29(m,1H),0.95-1.06(m,1H) ), 0.53-0.60 (m, 2H), 0.37-0.51 (m, 2H), 0.30-0.36 (m, 2H), 0.22-0.29 (m, 1H), 0.02-0.09 (m, 1H).
MS(ESI,pos.ion)m/z:571.20[M+H] +. MS(ESI,pos.ion)m/z:571.20[M+H] + .
实施例77：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(环己基甲基)-N-甲基吡啶酰胺Example 77: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(cyclohexylmethyl)-N-picolinamide
Figure PCTCN2021090489-appb-000139
Figure PCTCN2021090489-appb-000139
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，N-甲基-环己基甲胺(51mg,0.40mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(196mg,1.02mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应12h，加水洗(15mL)，用 二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到浅黄色固体39mg，收率32％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (100mg, 0.20mmol), N-methyl-cyclohexylmethylamine (51mg, 0.40mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (196mg, 1.02mmol) and N-hydroxy-7-azabenzotriazole (43mg, 0.32mmol) were dissolved in dichloromethane (5mL), and N,N was added dropwise to this solution at 0℃. -Diisopropylethylamine (0.17mL, 1.00mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate the solution Carry out silica gel column chromatography separation (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 39 mg of pale yellow solid with a yield of 32%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.72–7.76(m,1H),7.32–7.42(m,2H),7.10(d,J＝8.1Hz,1H),6.88(s,1H),6.84(d,J＝8.0Hz,1H),6.60(t,J F-H＝75.6Hz,1H),4.48–4.65(m,3H),3.91–3.95(m,1H),3.86(d,J＝6.9Hz,2H),3.53–3.58(m,1H),3.36–3.41(m,1H),3.27–3.36(m,1H),3.18–3.22(m,1H),3.08(s,1.5H),2.98(s,1.5H),2.52–2.60(m,1H),2.39–2.47(m,1H),2.12(s,3H),1.71–1.78(m,3H),1.54–1.66(m,6H),1.26–1.34(m,1H),1.02–1.17(m,2H),0.62–0.67(m,2H),0.33–0.37(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.72–7.76(m,1H), 7.32–7.42(m,2H), 7.10(d,J=8.1Hz,1H), 6.88(s,1H) , 6.84 (d, J = 8.0 Hz, 1H), 6.60 (t, J FH = 75.6 Hz, 1H), 4.48-4.65 (m, 3H), 3.91-3.95 (m, 1H), 3.86 (d, J = 6.9Hz, 2H), 3.53-3.58 (m, 1H), 3.36-3.41 (m, 1H), 3.27-3.36 (m, 1H), 3.18-3.22 (m, 1H), 3.08 (s, 1.5H), 2.98(s, 1.5H), 2.52–2.60(m, 1H), 2.39–2.47(m, 1H), 2.12(s, 3H), 1.71–1.78(m, 3H), 1.54–1.66(m, 6H) , 1.26--1.34(m,1H), 1.02--1.17(m,2H), 0.62--0.67(m,2H), 0.33--0.37(m,2H).
MS(ESI,pos.ion)m/z:613.30[M+H] +. MS(ESI,pos.ion)m/z:613.30[M+H] + .
实施例78：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-苄基-N-甲基吡啶酰胺Example 78: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-benzyl-N-picolinamide
Figure PCTCN2021090489-appb-000140
Figure PCTCN2021090489-appb-000140
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(80mg,0.16mmol)，N-甲基苄胺(38mg,0.24mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(155mg,0.81mmol)和N-羟基-7-氮杂苯并三氮唑(32mg,0.24mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.15mL,0.91mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体81mg，收率84％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (80mg, 0.16mmol), N-methylbenzylamine (38mg, 0.24mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (155mg , 0.81mmol) and N-hydroxy-7-azabenzotriazole (32mg, 0.24mmol) dissolved in dichloromethane (5mL), add N,N-diiso to this solution dropwise at 0℃ Propylethylamine (0.15mL, 0.91mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v)=40/1) to obtain a white solid 81 mg with a yield of 84%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.76–7.80(m,1H),7.51–7.61(m,1H),7.28–7.38(m,6H),7.12(d,J＝7.2Hz,1H),6.79–6.90(m,2H),6.62(t,J F-H＝75.6Hz,1H),4.50–4.83(m,4H),4.08–4.14(m,1H),3.84–3.96(m,1H),3.87(d,J＝6.3Hz,2H),3.50–3.57(m,1H),3.22–3.36(m,1H),3.04(s,2H),2.96(s,1H),2.42–2.61(m,1H),2.25–2.39(m,1H),2.10(s,3H),1.24–1.37(m,1H),0.64–0.68(m,2H),0.35–0.39(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.76–7.80(m,1H), 7.51–7.61(m,1H), 7.28–7.38(m,6H), 7.12(d,J=7.2Hz, 1H), 6.79–6.90(m, 2H), 6.62(t, J FH = 75.6Hz, 1H), 4.50–4.83(m, 4H), 4.08–4.14(m, 1H), 3.84–3.96(m, 1H) ), 3.87(d,J=6.3Hz,2H),3.50–3.57(m,1H),3.22–3.36(m,1H),3.04(s,2H),2.96(s,1H),2.42–2.61( m,1H), 2.25–2.39(m,1H), 2.10(s,3H), 1.24–1.37(m,1H), 0.64–0.68(m,2H), 0.35–0.39(m,2H).
MS(ESI,pos.ion)m/z:607.40[M+H] +. MS(ESI,pos.ion)m/z:607.40[M+H] + .
实施例79：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(嘧啶-2-基甲基)吡啶酰胺Example 79: The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(pyrimidin-2-ylmethyl)pyridine amide
Figure PCTCN2021090489-appb-000141
Figure PCTCN2021090489-appb-000141
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(80mg,0.16mmol)，2-氨基甲基嘧啶盐酸盐(36mg,0.25mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚 胺盐酸盐(153mg,0.8mmol)和N-羟基-7-氮杂苯并三氮唑(33mg,0.24mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.15mL,0.91mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体71mg，收率74％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (80mg, 0.16mmol), 2-aminomethylpyrimidine hydrochloride (36mg, 0.25mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (153mg, 0.8mmol) and N-hydroxy-7-azabenzotriazole (33mg, 0.24mmol) were dissolved in dichloromethane (5mL), and N,N was added dropwise to this solution at 0℃. -Diisopropylethylamine (0.15mL, 0.91mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate Perform silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 71 mg of white solid with a yield of 74%.
1H NMR(400MHz,CDCl 3)δ(ppm):9.64(br.s,1H),8.71(s,2H),8.42(br.s,1H),8.09–8.16(m,1H),7.77–7.87(m,1H),7.36–7.44(m,1H),7.09–7.18(m,2H),6.81–6.91(m,2H),6.60(t,J F-H＝75.6Hz,1H),4.88–5.05(m,2H),4.56–4.79(m,3H),3.78–3.96(m,3H),3.40–3.49(m,1H),3.24–3.32(m,1H),2.65–2.75(m,1H),2.46–2.55(m,1H),2.05(s,3H),1.23–1.37(m,1H),0.62–0.69(m,2H),0.34–0.38(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.64 (br.s, 1H), 8.71 (s, 2H), 8.42 (br.s, 1H), 8.09 - 8.16 (m, 1H), 7.77 - 7.87(m,1H), 7.36–7.44(m,1H), 7.09–7.18(m,2H), 6.81–6.91(m,2H), 6.60(t,J FH = 75.6Hz,1H), 4.88–5.05 (m,2H), 4.56--4.79(m,3H), 3.78--3.96(m,3H), 3.40--3.49(m,1H), 3.24--3.32(m,1H), 2.65--2.75(m,1H) ,2.46-2.55(m,1H),2.05(s,3H),1.23-1.37(m,1H),0.62-0.69(m,2H),0.34-0.38(m,2H).
MS(ESI,pos.ion)m/z:595.40[M+H] +. MS(ESI,pos.ion)m/z:595.40[M+H] + .
实施例80：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-苄基吡啶酰胺Example 80: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-benzylpyridineamide
Figure PCTCN2021090489-appb-000142
Figure PCTCN2021090489-appb-000142
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(98mg,0.19mmol)，苄胺(43mg,0.4mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.0mmol)和N-羟基-7-氮杂苯并三氮唑(40mg,0.3mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.16mL,0.97mmol)，室温反应12h，加水洗(15mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体82mg，收率71％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (98mg, 0.19mmol), benzylamine (43mg, 0.4mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (192mg, 1.0mmol) And N-hydroxy-7-azabenzotriazole (40mg, 0.3mmol) dissolved in dichloromethane (5mL), add N,N-diisopropylethylamine dropwise to this solution at 0℃ (0.16mL, 0.97mmol), react at room temperature for 12h, wash with water (15mL), and then extract with dichloromethane (5mL×3). The organic phase is dried with anhydrous sodium sulfate, the solvent is removed, and the concentrated solution is separated by silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v)=40/1) to obtain 82 mg of white solid with a yield of 71%.
1H NMR(400MHz,CDCl 3)δ(ppm):9.50(br.s,1H),8.68(br.s,1H),8.17(d,J＝7.5Hz,1H),7.85(t,J＝7.6Hz,1H),7.24–7.44(m,6H),7.13(d,J＝8.1Hz,1H),6.92(s,1H),6.87(d,J＝7.9Hz,1H),6.63(t,J F-H＝75.6Hz,1H),4.78–4.89(m,2H),4.58–4.71(m,3H),3.84–3.93(m,1H),3.89(d,J＝6.8Hz,2H),3.38–3.43(m,1H),3.25–3.33(m,1H),2.77–2.85(m,1H),2.45–2.52(m,1H),1.93(s,3H),1.23–1.37(m,1H),0.65–0.69(m,2H),0.36–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.50 (br.s, 1H), 8.68 (br.s, 1H), 8.17 (d, J = 7.5 Hz, 1H), 7.85 (t, J = 7.6Hz, 1H), 7.24–7.44 (m, 6H), 7.13 (d, J = 8.1 Hz, 1H), 6.92 (s, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.63 (t, J FH = 75.6Hz, 1H), 4.78–4.89 (m, 2H), 4.58–4.71 (m, 3H), 3.84–3.93 (m, 1H), 3.89 (d, J = 6.8 Hz, 2H), 3.38– 3.43(m,1H), 3.25–3.33(m,1H), 2.77–2.85(m,1H), 2.45–2.52(m,1H), 1.93(s,3H), 1.23–1.37(m,1H), 0.65--0.69 (m, 2H), 0.36--0.39 (m, 2H).
MS(ESI,pos.ion)m/z:593.20[M+H] +. MS(ESI,pos.ion)m/z:593.20[M+H] + .
实施例81：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(2,4-二氟苯基)-N-甲基吡啶酰胺Example 81: The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(2,4-difluorophenyl)-N-picolineamide
Figure PCTCN2021090489-appb-000143
Figure PCTCN2021090489-appb-000143
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(96mg,0.19mmol)，1-(2,4-二氟苯基)-N-甲基甲胺(73mg,0.46mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(131mg,0.68mmol)和N-羟基-7-氮杂苯并三氮唑(85mg,0.62mmol)溶于二氯甲烷(6mL)中，室温下加入N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌13h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体52mg，收率42％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (96mg, 0.19mmol), 1-(2,4-difluorophenyl)-N-methylmethylamine (73mg, 0.46mmol), 1-ethyl-(3-dimethylamino) Propyl) carbodiimide hydrochloride (131 mg, 0.68 mmol) and N-hydroxy-7-azabenzotriazole (85 mg, 0.62 mmol) are dissolved in dichloromethane (6 mL) and added at room temperature N,N-Diisopropylethylamine (0.3mL, 2.0mmol), stirred at room temperature for 13h, washed with water (50mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 52 mg of white solid with a yield of 42%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.62(br.s,1H),7.85-7.92(m,1H),7.38-7.51(m,3H),7.24-7.36(m,1H),7.09-7.13(m,2H),7.05(s,1H),7.03(t,J F-H＝75.0Hz,1H),6.87(d,J＝8.8Hz,1H),4.60-4.71(m,2H),4.31-4.52(m,3H),4.05-4.08(m,1H),3.90(d,J＝6.5Hz,2H),3.39-3.50(m,2H),2.90(s,3H),2.55-2.65(m,1H),2.02(s,3H),1.84-1.97(m,1H),1.24-1.31(m,1H),0.53-0.59(m,2H),0.31-0.36(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.62 (br.s, 1H), 7.85-7.92 (m, 1H), 7.38-7.51 (m, 3H), 7.24-7.36 (m, 1H) ), 7.09-7.13 (m, 2H), 7.05 (s, 1H), 7.03 (t, J FH = 75.0 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.60-4.71 (m, 2H ), 4.31-4.52 (m, 3H), 4.05-4.08 (m, 1H), 3.90 (d, J = 6.5 Hz, 2H), 3.39-3.50 (m, 2H), 2.90 (s, 3H), 2.55- 2.65 (m, 1H), 2.02 (s, 3H), 1.84-1.97 (m, 1H), 1.24-1.31 (m, 1H), 0.53-0.59 (m, 2H), 0.31-0.36 (m, 2H).
MS(ESI,pos.ion)m/z:643.20[M+H] +. MS(ESI,pos.ion)m/z:643.20[M+H] + .
实施例82：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4-氟苄基)-N-甲基吡啶酰胺Example 82: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(4-fluorobenzyl)-N-picolinamide
Figure PCTCN2021090489-appb-000144
Figure PCTCN2021090489-appb-000144
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，N-甲基-4-氟苄胺(55mg,0.40mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(196mg,1.02mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体37mg，收率30％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (100mg, 0.20mmol), N-methyl-4-fluorobenzylamine (55mg, 0.40mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt The acid salt (196mg, 1.02mmol) and N-hydroxy-7-azabenzotriazole (43mg, 0.32mmol) were dissolved in dichloromethane (5mL), and N, N-Diisopropylethylamine (0.17mL, 1.00mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate The liquid was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 37 mg of white solid with a yield of 30%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.75–7.86(m,1H),7.53–7.61(m,1H),7.25–7.39(m,3H),7.05–7.13(m,3H),6.82–6.96(m,2H),6.62(t,J F-H＝75.7Hz,1H),4.48–4.73(m,4H),4.11–4.19(m,0.5H),3.85–3.95(m,0.5H),3.88(d,J＝5.8Hz,2H),3.51–3.57(m,1H),3.25–3.38(m,1H),3.02(s,2H),2.96(s,1H),2.27 –2.60(m,2H),2.11(s,3H),2.06–1.94(m,1H),1.29–1.36(m,1H),0.62–0.70(m,2H),0.33–0.40(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.75-7.86(m,1H), 7.53-7.61(m,1H), 7.25-7.39(m,3H), 7.05-7.13(m,3H), 6.82–6.96(m,2H),6.62(t,J FH =75.7Hz,1H), 4.48–4.73(m,4H), 4.11–4.19(m,0.5H), 3.85–3.95(m,0.5H) ,3.88(d,J=5.8Hz,2H),3.51–3.57(m,1H), 3.25–3.38(m,1H),3.02(s,2H),2.96(s,1H),2.27 –2.60(m ,2H), 2.11(s,3H), 2.06–1.94(m,1H), 1.29–1.36(m,1H), 0.62–0.70(m,2H), 0.33–0.40(m,2H).
MS(ESI,pos.ion)m/z:625.20[M+H] +. MS(ESI,pos.ion)m/z:625.20[M+H] + .
实施例83：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-甲基-N-((吡啶-2-基)甲基)吡啶酰胺Example 83: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-methyl-N-((pyridin-2-yl)methyl)pyridineamide
Figure PCTCN2021090489-appb-000145
Figure PCTCN2021090489-appb-000145
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(93mg,0.18mmol)，化合物N-甲基-1-(吡啶-2-基)甲胺二盐酸盐(63mg,0.52mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(121mg,0.63mmol)和N-羟基-7-氮杂苯并三氮唑(87mg,0.64mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌5h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体52mg，收率46％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (93mg, 0.18mmol), compound N-methyl-1-(pyridin-2-yl)methylamine dihydrochloride (63mg, 0.52mmol), 1-ethyl-(3-dimethyl Aminopropyl) carbodiimide hydrochloride (121mg, 0.63mmol) and N-hydroxy-7-azabenzotriazole (87mg, 0.64mmol) dissolved in dichloromethane (6mL) at room temperature N,N-diisopropylethylamine (0.3mL, 2.0mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (50mL), extracted with dichloromethane (5mL×3), and the organic phase After drying with sodium sulfate and removing the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 52 mg of a white solid with a yield of 46%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.48-8.63(m,2H),7.73-7.91(m,2H),7.40-7.45(m,1H),7.25-7.38(m,2H),7.10-7.13(m,1H),7.06(s,1H),7.03(t,J F-H＝74.7Hz,1H),6.88(d,J＝8.5Hz,1H),4.67-4.74(m,2H),4.26-4.50(m,3H),4.03-4.10(m,1H),3.90(d,J＝6.4Hz,2H),3.42-3.52(m,2H),2.94-2.98(m,3H),2.55-2.65(m,1H),2.03(d,J＝3.8Hz,3H),1.86-1.95(m,1H),1.22-1.26(m,1H),0.51-0.60(m,2H),0.30-0.38(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.48-8.63 (m, 2H), 7.73-7.91 (m, 2H), 7.40-7.45 (m, 1H), 7.25-7.38 (m, 2H) ), 7.10-7.13 (m, 1H), 7.06 (s, 1H), 7.03 (t, J FH = 74.7 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 4.67-4.74 (m, 2H ),4.26-4.50(m,3H),4.03-4.10(m,1H),3.90(d,J=6.4Hz,2H),3.42-3.52(m,2H),2.94-2.98(m,3H), 2.55-2.65(m,1H),2.03(d,J=3.8Hz,3H),1.86-1.95(m,1H),1.22-1.26(m,1H),0.51-0.60(m,2H),0.30- 0.38(m,2H).
MS(ESI,pos.ion)m/z:608.25[M+H] +. MS(ESI,pos.ion)m/z:608.25[M+H] + .
实施例84：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N,N-二环己基吡啶酰胺Example 84: The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N,N-dicyclohexylpyridineamide
Figure PCTCN2021090489-appb-000146
Figure PCTCN2021090489-appb-000146
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(86mg,0.17mmol)，二环己基胺(96mg,0.53mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(96mg,0.50mmol)和N-羟基-7-氮杂苯并三氮唑(46mg,0.34mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌13h，加水(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体53mg，收率46％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (86mg, 0.17mmol), dicyclohexylamine (96mg, 0.53mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (96mg, 0.50 mmol) and N-hydroxy-7-azabenzotriazole (46mg, 0.34mmol) were dissolved in dichloromethane (6mL), and N,N-diisopropylethylamine was added dropwise to this solution at room temperature (0.3mL, 2.0mmol), stirred at room temperature for 13h, added water (50mL), extracted with dichloromethane (5mL×3), dried the organic phase with anhydrous sodium sulfate, removed the solvent, and separated the concentrated solution by silica gel column chromatography (washing Removal agent: dichloromethane/methanol (v/v)=15/1) to obtain 53 mg of white solid with a yield of 46%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.51-8.74(m,1H),7.76-7.88(m,1H),7.39-7.41(m,1H),7.20-7.31(m,1H),7.04-7.12(m,2H),7.03(t,J F-H＝75.0Hz,1H),6.89(d,J＝7.3Hz,1H),4.30-4.52(m,3H),4.02-4.13(m,1H),3.84-3.96(m,2H),3.40-3.53(m,1H),3.05-3.22(m,2H),2.52-2.67(m,1H),2.37-2.49(m,1H),2.04(s,3H),1.84-1.99(m,1H),1.60-1.79(m,6H),1.42-1.58(m,6H),1.11-1.32(m,5H),0.84-1.02(m,4H),0.51-0.61(m,2H),0.28-0.39(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.51-8.74 (m, 1H), 7.76-7.88 (m, 1H), 7.39-7.41 (m, 1H), 7.20-7.31 (m, 1H) ), 7.04-7.12 (m, 2H), 7.03 (t, J FH = 75.0Hz, 1H), 6.89 (d, J = 7.3Hz, 1H), 4.30-4.52 (m, 3H), 4.02-4.13 (m ,1H),3.84-3.96(m,2H),3.40-3.53(m,1H),3.05-3.22(m,2H),2.52-2.67(m,1H),2.37-2.49(m,1H),2.04 (s,3H),1.84-1.99(m,1H),1.60-1.79(m,6H),1.42-1.58(m,6H),1.11-1.32(m,5H),0.84-1.02(m,4H) , 0.51-0.61 (m, 2H), 0.28-0.39 (m, 2H).
MS(ESI,pos.ion)m/z:667.30[M+H] +. MS(ESI,pos.ion)m/z:667.30[M+H] + .
实施例85：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-环己基-N-(环丙基甲基)吡啶酰胺Example 85: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-cyclohexyl-N-(cyclopropylmethyl)pyridine amide
Figure PCTCN2021090489-appb-000147
Figure PCTCN2021090489-appb-000147
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，N-(环丙基甲基)环己胺(60mg,0.39mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(40mg,0.29mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体59mg，收率46％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (100mg, 0.20mmol), N-(cyclopropylmethyl)cyclohexylamine (60mg, 0.39mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (192mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (40mg, 0.29mmol) were dissolved in dichloromethane (5mL) and added dropwise to this solution at 0℃ N,N-Diisopropylethylamine (0.17mL, 1.00mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 59 mg of white solid with a yield of 46%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.66–7.76(m,1H),7.53(br.s,1H),7.26–7.37(m,2H),7.08(d,J＝6.4Hz,1H),6.78–6.88(m,2H),6.59(t,J F-H＝75.5Hz,1H),4.45–4.61(m,3H),3.85–3.96(m,3H),3.50–3.60(m,1H),3.34–3.45(m,1H),3.22–3.35(m,2H),3.07–3.21(m,1H),2.50–2.64(m,1H),2.30–2.44(m,1H),2.11(s,3H),1.84–1.98(m,6H),1.34–1.54(m,4H),1.14–1.33(m,2H),0.58–0.66(m,2H),0.47–0.56(m,2H),0.29–0.39(m,4H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.66–7.76(m,1H), 7.53(br.s,1H), 7.26–7.37(m,2H), 7.08(d,J=6.4Hz, 1H), 6.78–6.88(m, 2H), 6.59(t, J FH = 75.5Hz, 1H), 4.45–4.61(m, 3H), 3.85–3.96(m, 3H), 3.50–3.60(m, 1H) ), 3.34–3.45(m,1H), 3.22–3.35(m,2H), 3.07–3.21(m,1H), 2.50–2.64(m,1H), 2.30–2.44(m,1H), 2.11(s ,3H),1.84–1.98(m,6H),1.34–1.54(m,4H),1.14–1.33(m,2H),0.58–0.66(m,2H),0.47–0.56(m,2H),0.29 –0.39(m,4H).
MS(ESI,pos.ion)m/z:639.35[M+H] +. MS(ESI,pos.ion)m/z:639.35[M+H] + .
实施例86：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺Example 86: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide
Figure PCTCN2021090489-appb-000148
Figure PCTCN2021090489-appb-000148
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(102mg,0.20mmol)，4,4-二氟-N-甲基环己胺盐酸盐(56mg,0.30mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(55mg,0.40mmol)溶于二氯甲烷 (5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到色固体82mg白，收率63％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (102mg, 0.20mmol), 4,4-difluoro-N-methylcyclohexylamine hydrochloride (56mg, 0.30mmol), 1-ethyl-(3-dimethylaminopropyl) ) Carbodiimide hydrochloride (192mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (55mg, 0.40mmol) dissolved in dichloromethane (5mL) at 0℃ Add N,N-diisopropylethylamine (0.17mL, 1.00mmol) dropwise to this solution, react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), and use anhydrous sulfuric acid for the organic phase The sodium was dried, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain a white solid of 82 mg with a yield of 63%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.71–7.82(m,1H),7.48(br.s,1H),7.35–7.45(m,2H),7.10(d,J＝6.4Hz,1H),6.88(s,1H),6.84(d,J＝6.9Hz,1H),6.60(t,J F-H＝75.6Hz,1H),4.49–4.68(m,3H),3.87–3.96(m,1H),3.86(d,J＝5.5Hz,2H),3.67–3.80(m,1H),3.48–3.56(m,1H),3.25–3.38(m,1H),2.99(s,1.5H),2.86(s,1.5H),2.42–2.51(m,2H),2.13–2.27(m,2H),2.11(s,3H),1.84–1.96(m,6H),1.24–1.35(m,1H),0.59–0.68(m,2H),0.31–0.38(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.71-7.82(m,1H), 7.48(br.s,1H), 7.35-7.45(m,2H), 7.10(d,J=6.4Hz, 1H), 6.88 (s, 1H), 6.84 (d, J = 6.9 Hz, 1H), 6.60 (t, J FH = 75.6 Hz, 1H), 4.49-4.68 (m, 3H), 3.87-3.96 (m, 1H), 3.86(d,J=5.5Hz,2H), 3.67–3.80(m,1H), 3.48–3.56(m,1H), 3.25–3.38(m,1H), 2.99(s,1.5H), 2.86(s,1.5H),2.42-2.51(m,2H),2.13-2.27(m,2H),2.11(s,3H),1.84-1.96(m,6H),1.24-1.35(m,1H) ,0.59-0.68(m,2H),0.31-0.38(m,2H).
MS(ESI,pos.ion)m/z:635.30[M+H] +. MS(ESI,pos.ion)m/z:635.30[M+H] + .
实施例87：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(环丙基甲基)-N-(4,4-二氟环己基)吡啶酰胺Example 87: The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(cyclopropylmethyl)-N-(4,4-difluorocyclohexyl)pyridineamide
Figure PCTCN2021090489-appb-000149
Figure PCTCN2021090489-appb-000149
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，N-(环丙基甲基)-4,4-二氟环己胺盐酸盐(68mg,0.30mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(193mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.40mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.2mL,1.00mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到浅黄色固体101mg，收率75％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (100mg, 0.20mmol), N-(cyclopropylmethyl)-4,4-difluorocyclohexylamine hydrochloride (68mg, 0.30mmol), 1-ethyl-(3-di Methylaminopropyl) carbodiimide hydrochloride (193mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (54mg, 0.40mmol) were dissolved in dichloromethane (5mL), Add N,N-diisopropylethylamine (0.2mL, 1.00mmol) dropwise to this solution at 0℃, react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), organic The phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 101 mg of light yellow solid, with a yield of 75% .
1H NMR(400MHz,CDCl 3)δ(ppm):7.71–7.81(m,1H),7.57(br.s,1H),7.40–7.50(m,2H),7.12(d,J＝5.4Hz,1H),6.90(s,1H),6.86(d,J＝6.9Hz,1H),6.62(t,J F-H＝75.6Hz,1H),4.46–4.65(m,3H),3.88–3.96(m,1H),3.88(d,J＝4.1Hz,2H),3.67–3.82(m,1H),3.53–3.58(m,1H),3.26–3.37(m,2H),3.16–3.27(m,1H),2.46–2.55(m,2H),2.13–2.23(m,2H),2.13(s,3H),1.94–2.05(m,6H),1.55–1.73(m,1H),1.26–1.34(m,1H),0.81–0.94(m,1H),0.62–0.70(m,2H),0.52–0.62(m,1H),0.35–0.44(m,4H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.71-7.81(m,1H), 7.57(br.s,1H), 7.40-7.50(m,2H), 7.12(d,J=5.4Hz, 1H), 6.90 (s, 1H), 6.86 (d, J = 6.9 Hz, 1H), 6.62 (t, J FH = 75.6 Hz, 1H), 4.46-4.65 (m, 3H), 3.88-3.96 (m, 1H), 3.88(d,J=4.1Hz,2H), 3.67–3.82(m,1H), 3.53–3.58(m,1H), 3.26–3.37(m,2H), 3.16–3.27(m,1H) ,2.46-2.55(m,2H),2.13-2.23(m,2H),2.13(s,3H),1.94-2.05(m,6H),1.55-1.73(m,1H),1.26-1.34(m, 1H), 0.81--0.94(m,1H), 0.62--0.70(m,2H), 0.52--0.62(m,1H), 0.35--0.44(m,4H).
MS(ESI,pos.ion)m/z:675.30[M+H] +. MS(ESI,pos.ion)m/z:675.30[M+H] + .
实施例88：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺Example 88: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxamido)methyl)- N-(4,4-difluorocyclohexyl)-N-picolinamide
Figure PCTCN2021090489-appb-000150
Figure PCTCN2021090489-appb-000150
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酸(67mg,0.21mmol)，6-(氨基甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺二盐酸盐(94mg,0.33mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(88mg,0.46mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.39mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌17h，加水洗(50mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体65mg，收率52％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid (67mg, 0.21mmol), 6-(aminomethyl) -N-(4,4-Difluorocyclohexyl)-N-picolineamide dihydrochloride (94mg, 0.33mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide Amine hydrochloride (88mg, 0.46mmol) and N-hydroxy-7-azabenzotriazole (54mg, 0.39mmol) were dissolved in dichloromethane (6mL), and N, N-diisopropylethylamine (0.3mL, 2.0mmol), stirred at room temperature for 17h, washed with water (50mL), and then extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and concentrated The liquid was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 65 mg of white solid with a yield of 52%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):9.87(s,1H),8.60(t,J＝5.9Hz,1H),7.82-7.93(m,1H),7.34-7.50(m,2H),7.04-7.07(m,1H),6.99(t,J F-H＝75.1Hz,1H),6.86-6.89(m,1H),6.75(d,J＝9.8Hz,1H),4.30-4.53(m,3H),3.99-4.07(m,1H),3.61-3.69(m,1H),3.36-3.45(m,1H),2.71–2.78(m,3H),2.53-2.62(m,1H),1.91-2.15(m,3H),2.02(s,3H),1.65-1.90(m,7H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 9.87 (s, 1H), 8.60 (t, J = 5.9 Hz, 1H), 7.82-7.93 (m, 1H), 7.34-7.50 (m, 2H), 7.04-7.07 (m, 1H), 6.99 (t, J FH = 75.1 Hz, 1H), 6.86-6.89 (m, 1H), 6.75 (d, J = 9.8 Hz, 1H), 4.30-4.53 ( m,3H),3.99-4.07(m,1H),3.61-3.69(m,1H),3.36-3.45(m,1H),2.71-2.78(m,3H),2.53-2.62(m,1H), 1.91-2.15 (m, 3H), 2.02 (s, 3H), 1.65-1.90 (m, 7H).
MS(ESI,pos.ion)m/z:581.30[M+H] +. MS(ESI,pos.ion)m/z:581.30[M+H] + .
实施例89：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-乙氧基苯基)吡咯烷-2-甲酰氨基)甲基)-N-环己基-N-甲基吡啶酰胺Example 89: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxamido)methyl )-N-cyclohexyl-N-picolinamide
Figure PCTCN2021090489-appb-000151
Figure PCTCN2021090489-appb-000151
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-乙氧基苯基)吡咯烷-2-羧酸(67mg,0.20mmol)，6-(氨基甲基)-N-环己基-N-甲基吡啶酰胺二盐酸盐(94mg,0.38mmol，合成方法参考中间体6)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(88mg,0.46mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.40mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌16h，加水洗(50mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体96mg，收率85％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylic acid (67mg, 0.20mmol), 6-(amino Methyl)-N-cyclohexyl-N-picolineamide dihydrochloride (94mg, 0.38mmol, synthesis method refers to intermediate 6), 1-ethyl-(3-dimethylaminopropyl)carbonyl Diimine hydrochloride (88mg, 0.46mmol) and N-hydroxy-7-azabenzotriazole (54mg, 0.40mmol) were dissolved in dichloromethane (6mL) and added dropwise to this solution at room temperature N,N-Diisopropylethylamine (0.3mL, 2.0mmol), stirred at room temperature for 16h, washed with water (50mL), and extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 96 mg of white solid with a yield of 85%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.55-8.67(m,1H),7.82-7.88(m,1H),7.44-7.49(m,1H),7.31-7.36(m,1H),7.13(d,J＝8.2Hz,1H),7.07(t,J＝8.3Hz,1H),7.02(t,J F-H＝74.8Hz,1H),6.85-6.93(m,1H),4.26-4.45(m,3H),4.01-4.15(m,3H),3.40-3.52(m,2H),2.86(s,1.6H),2.70(s,1.4H),2.57-2.66(m,1H),2.04(d,J＝4.2Hz,3H),1.86-1.96(m,1H),1.40-1.81(m,8H),1.31-1.37(m,3H),1.21-1.29(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.55-8.67 (m, 1H), 7.82-7.88 (m, 1H), 7.44-7.49 (m, 1H), 7.31-7.36 (m, 1H) ), 7.13 (d, J = 8.2 Hz, 1H), 7.07 (t, J = 8.3 Hz, 1H), 7.02 (t, J FH = 74.8 Hz, 1H), 6.85-6.93 (m, 1H), 4.26 4.45 (m, 3H), 4.01-4.15 (m, 3H), 3.40-3.52 (m, 2H), 2.86 (s, 1.6H), 2.70 (s, 1.4H), 2.57-2.66 (m, 1H), 2.04(d,J=4.2Hz,3H),1.86-1.96(m,1H),1.40-1.81(m,8H),1.31-1.37(m,3H),1.21-1.29(m,2H).
MS(ESI,pos.ion)m/z:573.35[M+H] +. MS(ESI,pos.ion)m/z:573.35[M+H] + .
实施例90：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-((N-(4,4-二氟环己基)乙酰氨基)甲基)吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 90: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-((N -(4,4-Difluorocyclohexyl)acetamido)methyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000152
Figure PCTCN2021090489-appb-000152
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(150mg,0.41mmol)，N-((6-(氨基甲基)吡啶-2-基)甲基)-N-(4,4-二氟环己基)乙酰胺二盐酸盐(166mg,0.45mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(391mg,2.04mmol)和N-羟基-7-氮杂苯并三氮唑(112mg,0.82mmol)溶于二氯甲烷(15mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温反应3h，加水洗(15mL)，用二氯甲烷萃取(20mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体117mg，收率44％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150mg, 0.41mmol) , N-((6-(Aminomethyl)pyridin-2-yl)methyl)-N-(4,4-difluorocyclohexyl)acetamide dihydrochloride (166mg, 0.45mmol), 1-ethyl -(3-Dimethylaminopropyl) carbodiimide hydrochloride (391mg, 2.04mmol) and N-hydroxy-7-azabenzotriazole (112mg, 0.82mmol) dissolved in dichloride In methane (15mL), N,N-diisopropylethylamine (0.4mL, 2.0mmol) was added dropwise to this solution at 0℃, reacted at room temperature for 3h, washed with water (15mL), and extracted with dichloromethane ( 20mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 117 mg of white solid , The yield is 44%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.71–7.81(m,1H),7.36–7.42(m,1H),7.22–7.26(m,1H),7.10–7.13(m,2H),6.93–6.94(m,1H),6.74(t,J F-H＝75.7Hz,1H),4.61–4.66(m,2H),4.44–4.56(m,3H),4.09–4.13(m,1H),4.00–4.11(m,1H),3.93–3.95(m,2H),3.67(t,J＝10.6Hz,1H),3.50–3.56(m,1H),2.67–2.73(m,1H),2.31(s,1H),2.16(s,3H),2.13(s,2H),2.06–2.10(m,1H),1.99–2.03(m,4H),1.63–1.81(m,4H),1.27–1.35(m,1H),0.62–0.67(m,2H),0.37–0.40(m,2H). 1 H NMR(400MHz, CD 3 OD)δ(ppm): 7.71-7.81(m,1H), 7.36-7.42(m,1H), 7.22-7.26(m,1H), 7.10-7.13(m,2H) ,6.93-6.94(m,1H),6.74(t,J FH =75.7Hz,1H),4.61-4.66(m,2H),4.44-4.56(m,3H),4.09-4.13(m,1H), 4.00–4.11(m,1H), 3.93–3.95(m,2H), 3.67(t,J=10.6Hz,1H), 3.50–3.56(m,1H), 2.67–2.73(m,1H), 2.31( s, 1H), 2.16 (s, 3H), 2.13 (s, 2H), 2.06-2.10 (m, 1H), 1.99-2.03 (m, 4H), 1.63-1.81 (m, 4H), 1.27-1.35 ( m, 1H), 0.62--0.67 (m, 2H), 0.37--0.40 (m, 2H).
MS(ESI,pos.ion)m/z:649.30[M+H] +. MS(ESI,pos.ion)m/z:649.30[M+H] + .
实施例91：化合物6-(((2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺Example 91: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido )Methyl)-N-(4,4-Difluorocyclohexyl)-N-picolinamide
Figure PCTCN2021090489-appb-000153
Figure PCTCN2021090489-appb-000153
将化合物6-(((2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(76mg,0.15mmol)，4,4-二氟-N-甲基环己基胺盐酸盐(96mg,0.64mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(96mg,0.50mmol)和N-羟基-7-氮杂苯并三氮唑(46mg,0.34mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌17h，加水(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体46mg，收率48％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl ) Picolinic acid (76mg, 0.15mmol), 4,4-difluoro-N-methylcyclohexylamine hydrochloride (96mg, 0.64mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Diimide hydrochloride (96mg, 0.50mmol) and N-hydroxy-7-azabenzotriazole (46mg, 0.34mmol) were dissolved in dichloromethane (6mL), and dropped into this solution at room temperature Add N,N-diisopropylethylamine (0.3mL, 2.0mmol), stir at room temperature for 17h, add water (50mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 46 mg of white solid with a yield of 48%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.61(t,J＝6.0Hz,1H),7.84-7.89(m,1H),7.34-7.51(m,2H),7.12(d,J＝8.2Hz,1H),7.04-7.07(m,1H),6.95(t,J F-H＝74.8Hz,1H),6.84-6.89(m,1H),4.87-4.93(m,1H),4.34-4.52(m,3H),4.01-4.12(m,1H),3.41-3.52(m,2H),2.71-2.87(m,3H),2.58-2.67(m,1H),2.04(m,3H),1.99-2.13(m,4H),1.83-1.93(m,4H),1.53-1.74(m,10H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.61 (t, J = 6.0 Hz, 1H), 7.84-7.89 (m, 1H), 7.34-7.51 (m, 2H), 7.12 (d, J = 8.2Hz, 1H), 7.04-7.07 (m, 1H), 6.95 (t, J FH = 74.8Hz, 1H), 6.84-6.89 (m, 1H), 4.87-4.93 (m, 1H), 4.34 4.52(m,3H),4.01-4.12(m,1H),3.41-3.52(m,2H),2.71-2.87(m,3H),2.58-2.67(m,1H),2.04(m,3H), 1.99-2.13 (m, 4H), 1.83-1.93 (m, 4H), 1.53-1.74 (m, 10H).
MS(ESI,pos.ion)m/z:649.20[M+H] +. MS(ESI,pos.ion)m/z:649.20[M+H] + .
实施例92：化合物6-(((2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(环丙基甲基)-N-(4,4-二氟环己基)吡啶酰胺Example 92: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido )Methyl)-N-(cyclopropylmethyl)-N-(4,4-difluorocyclohexyl)pyridine amide
Figure PCTCN2021090489-appb-000154
Figure PCTCN2021090489-appb-000154
将化合物6-(((2R)-1-乙酰基-4-(3-(环戊氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(76mg,0.15mmol)，N-(环丙基甲基)-4,4-二氟环己基胺盐酸盐(96mg,0.51mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(96mg,0.50mmol)和N-羟基-7-氮杂苯并三氮唑(46mg,0.34mmol)溶于二氯甲烷(6mL)中，室温下加入N,N-二异丙基乙胺(0.3mL,2.0mmol)，室温搅拌17h，加水(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体66mg，收率65％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl ) Picolinic acid (76mg, 0.15mmol), N-(cyclopropylmethyl)-4,4-difluorocyclohexylamine hydrochloride (96mg, 0.51mmol), 1-ethyl-(3-dimethyl Aminopropyl) carbodiimide hydrochloride (96mg, 0.50mmol) and N-hydroxy-7-azabenzotriazole (46mg, 0.34mmol) dissolved in dichloromethane (6mL) at room temperature Add N,N-diisopropylethylamine (0.3mL, 2.0mmol), stir at room temperature for 17h, add water (50mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent The concentrated solution was subjected to column separation (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 66 mg of white solid with a yield of 65%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.61(t,J＝6.0Hz,1H),7.83-7.87(m,1H),7.31-7.51(m,2H),7.12(d,J＝8.4Hz,1H),7.04-7.08(m,1H),6.95(t,J F-H＝74.8Hz,1H),6.84-6.91(m,1H),4.88-4.93(m,1H),4.34-4.50(m,3H),4.05-4.12(m,1H),3.40-3.52(m,2H),3.18-3.25(m,1H),3.08-3.12(m,1H),2.58-2.65(m,1H),2.39(d,J＝6.7Hz,2H),2.04(s,3H),1.96-2.10(m,4H),1.84-1.92(m,4H),1.74-1.80(m,8H),1.32-1.39(m,1H),0.37-0.40(m,2H),0.09-0.11(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.61 (t, J = 6.0 Hz, 1H), 7.83-7.87 (m, 1H), 7.31-7.51 (m, 2H), 7.12 (d, J = 8.4Hz, 1H), 7.04-7.08 (m, 1H), 6.95 (t, J FH = 74.8Hz, 1H), 6.84-6.91 (m, 1H), 4.88-4.93 (m, 1H), 4.34 4.50 (m, 3H), 4.05-4.12 (m, 1H), 3.40-3.52 (m, 2H), 3.18-3.25 (m, 1H), 3.08-3.12 (m, 1H), 2.58-2.65 (m, 1H) ), 2.39(d,J=6.7Hz,2H),2.04(s,3H),1.96-2.10(m,4H),1.84-1.92(m,4H),1.74-1.80(m,8H),1.32- 1.39 (m, 1H), 0.37-0.40 (m, 2H), 0.09-0.11 (m, 2H).
MS(ESI,pos.ion)m/z:689.35[M+H] +. MS(ESI,pos.ion)m/z:689.35[M+H] + .
实施例93：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-乙氧基苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺Example 93: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxamido)methyl )-N-(4,4-Difluorocyclohexyl)-N-picolinamide
Figure PCTCN2021090489-appb-000155
Figure PCTCN2021090489-appb-000155
将化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺(60mg,0.10mmol)，碳酸钾(36mg,0.26mmol)溶于N,N-二甲基甲酰胺(3mL)中，室温加入碘乙烷(0.1mL,1.0mmol)，70℃下反应17h，加水(50mL)，用乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体33mg，收率52％。The compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxamido)methyl)-N-( 4,4-Difluorocyclohexyl)-N-picolineamide (60mg, 0.10mmol), potassium carbonate (36mg, 0.26mmol) dissolved in N,N-dimethylformamide (3mL), add iodine at room temperature Ethane (0.1mL, 1.0mmol), react at 70℃ for 17h, add water (50mL), extract with ethyl acetate (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 33 mg of white solid with a yield of 52%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.60(t,J＝5.9Hz,1H),7.84-7.90(m,1H),7.34-7.51(m,2H),7.05-7.14(m,2H),7.02(t,J F-H＝74.9Hz,1H),6.89(d,J＝8.5Hz,1H),4.33-4.51(m,3H),4.08-4.12(m,3H),3.41-3.52(m,2H),2.71-2.87(m,3H),2.58-2.64(m,1H),2.03(s,3H),1.63-2.12(m,10H),1.34(t,J＝6.7Hz, 3H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.60 (t, J = 5.9 Hz, 1H), 7.84-7.90 (m, 1H), 7.34-7.51 (m, 2H), 7.05-7.14 ( m, 2H), 7.02 (t, J FH = 74.9 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.33-4.51 (m, 3H), 4.08-4.12 (m, 3H), 3.41- 3.52(m,2H),2.71-2.87(m,3H),2.58-2.64(m,1H),2.03(s,3H),1.63-2.12(m,10H),1.34(t,J=6.7Hz, 3H).
MS(ESI,pos.ion)m/z:609.30[M+H] +. MS(ESI,pos.ion)m/z:609.30[M+H] + .
实施例94：化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-环己基-N-甲基吡啶酰胺Example 94: Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)-N -Cyclohexyl-N-picolineamide
Figure PCTCN2021090489-appb-000156
Figure PCTCN2021090489-appb-000156
将化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(80mg,0.16mmol)，N-甲基环己胺(36mg,0.32mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156mg,0.81mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，0℃条件下滴加N,N-二异丙基乙胺(0.13mL,0.79mmol)，室温反应22h，加水洗(15mL)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体42mg，收率43％。Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)picolinic acid (80mg, 0.16mmol), N-methylcyclohexylamine (36mg, 0.32mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (156mg, 0.81mmol) and N- Hydroxy-7-azabenzotriazole (43mg, 0.32mmol) was dissolved in dichloromethane (5mL), and N,N-diisopropylethylamine (0.13mL, 0.79mmol) was added dropwise at 0℃ React at room temperature for 22h, wash with water (15mL), and extract with dichloromethane (5mL×3). The organic phase is dried with anhydrous sodium sulfate, the solvent is removed, and the concentrated solution is subjected to silica gel column chromatography (eluent: dichloromethane). /Methanol (v/v)=30/1) to obtain 42 mg of a white solid with a yield of 43%.
1H NMR(600MHz,CDCl 3)δ(ppm):7.76(s,1H),7.51–7.54(m,1H),7.35–7.38(m,2H),7.12–7.28(m,3H),6.56(t,J F-H＝73.5Hz,1H),6.53(t,J F-H＝73.5Hz,1H),4.50–4.63(m,3H),3.99(dd,J＝9.9,7.6Hz,1H),3.58(t,J＝10.6Hz,1H),3.30–3.46(m,2H),3.00(s,2H),2.84(s,1H),2.58–2.64(m,1H),2.40–2.47(m,1H),2.15(s,3H),1.70–1.85(m,6H),1.48–1.56(m,4H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm): 7.76 (s, 1H), 7.51-7.54 (m, 1H), 7.35-7.38 (m, 2H), 7.12-7.28 (m, 3H), 6.56 ( t,J FH =73.5Hz,1H),6.53(t,J FH =73.5Hz,1H),4.50–4.63(m,3H),3.99(dd,J=9.9,7.6Hz,1H),3.58(t ,J=10.6Hz,1H), 3.30–3.46(m,2H), 3.00(s,2H), 2.84(s,1H), 2.58–2.64(m,1H), 2.40–2.47(m,1H), 2.15 (s, 3H), 1.70 - 1.85 (m, 6H), 1.48 - 1.56 (m, 4H).
MS(ESI,pos.ion)m/z:595.30[M+H] +. MS(ESI,pos.ion)m/z:595.30[M+H] + .
实施例95：化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺Example 95: Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)-N -(4,4-Difluorocyclohexyl)-N-picolinamide
Figure PCTCN2021090489-appb-000157
Figure PCTCN2021090489-appb-000157
将化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(80mg,0.16mmol)，4,4-二氟-N-甲基环己胺盐酸盐(36mg,0.19mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(151mg,0.79mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.13mL,0.79mmol)，室温反应15h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体23mg，收率22％。Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)picolinic acid (80mg, 0.16mmol), 4,4-difluoro-N-methylcyclohexylamine hydrochloride (36mg, 0.19mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (151mg, 0.79mmol) and N-hydroxy-7-azabenzotriazole (43mg, 0.32mmol) were dissolved in dichloromethane (5mL), and N, N was added dropwise to this solution at 0℃. -Diisopropylethylamine (0.13mL, 0.79mmol), react at room temperature for 15h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate the solution Carry out silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain a white solid of 23 mg with a yield of 22%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.79(br.s,1H),7.36–7.50(m,3H),7.13–7.26(m,3H),6.56(t,J F-H＝73.6Hz,1H),6.53(t,J F-H＝73.6Hz,1H),4.51–4.67(m,4H),3.93–4.03(m,1H),3.50–3.62(m,1H),3.30– 3.46(m,1H),3.02(s,1H),2.90(s,2H),2.45–2.64(m,2H),2.05–2.29(m,2H),2.16(s,3H),1.91–2.04(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.79 (br.s, 1H), 7.36-7.50 (m, 3H), 7.13-7.26 (m, 3H), 6.56 (t, J FH = 73.6 Hz ,1H),6.53(t,J FH =73.6Hz,1H),4.51–4.67(m,4H),3.93-4.03(m,1H),3.50–3.62(m,1H),3.30– 3.46(m, 1H), 3.02 (s, 1H), 2.90 (s, 2H), 2.45-2.64 (m, 2H), 2.05-2.29 (m, 2H), 2.16 (s, 3H), 1.91-2.04 (m, 6H) .
MS(ESI,pos.ion)m/z:631.30[M+H] +. MS(ESI,pos.ion)m/z:631.30[M+H] + .
实施例96：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-环戊基-N-甲基吡啶酰胺Example 96: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-cyclopentyl-N-picolinamide
Figure PCTCN2021090489-appb-000158
Figure PCTCN2021090489-appb-000158
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，N-甲基环戊胺盐酸盐(55mg,0.410mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(191mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应12h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体59mg，收率50％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (100mg, 0.20mmol), N-methylcyclopentylamine hydrochloride (55mg, 0.410mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt The acid salt (191mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (43mg, 0.32mmol) were dissolved in dichloromethane (5mL). Add N, N-Diisopropylethylamine (0.17mL, 1.00mmol), react at room temperature for 12h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate The liquid was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 59 mg of a white solid with a yield of 50%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.76(s,1H),7.50(br.s,1H),7.35–7.41(m,2H),7.12(d,J＝7.1Hz,1H),6.90(s,1H),6.86(d,J＝7.1Hz,1H),6.62(t,J F-H＝75.6Hz,1H),5.02–5.10(m,0.4H),4.48–4.65(m,3H),3.99–4.09(m,0.6H),3.91–3.97(m,1H),3.88(d,J＝5.8Hz,2H),3.55–3.61(m,1H),3.29–3.38(m,1H),3.00(s,2H),2.85(s,1H),2.56–2.61(m,1H),2.40–2.47(m,1H),2.14(s,3H),1.68–1.84(m,8H),1.26–1.34(m,1H),0.65–0.68(m,2H),0.35–0.39(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.76(s,1H),7.50(br.s,1H),7.35-7.41(m,2H),7.12(d,J=7.1Hz,1H) ,6.90(s,1H),6.86(d,J=7.1Hz,1H),6.62(t,J FH =75.6Hz,1H),5.02–5.10(m,0.4H),4.48–4.65(m,3H ), 3.99–4.09(m,0.6H), 3.91–3.97(m,1H), 3.88(d,J=5.8Hz,2H), 3.55–3.61(m,1H), 3.29–3.38(m,1H) , 3.00 (s, 2H), 2.85 (s, 1H), 2.56-2.61 (m, 1H), 2.40-2.47 (m, 1H), 2.14 (s, 3H), 1.68-1.84 (m, 8H), 1.26 --1.34 (m, 1H), 0.65 - 0.68 (m, 2H), 0.35 - 0.39 (m, 2H).
MS(ESI,pos.ion)m/z:585.30[M+H] +. MS(ESI,pos.ion)m/z:585.30[M+H] + .
实施例97：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-环丁基-N-甲基吡啶酰胺Example 97: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-cyclobutyl-N-picolinamide
Figure PCTCN2021090489-appb-000159
Figure PCTCN2021090489-appb-000159
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(114mg,0.23mmol)，N-甲基环丁胺盐酸盐(48mg,0.40mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(191mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应12h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体82mg，收率63％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (114mg, 0.23mmol), N-methylcyclobutylamine hydrochloride (48mg, 0.40mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt Salt (191mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (43mg, 0.32mmol) were dissolved in dichloromethane (5mL), cooled to 0℃, and N,N-diiso Propylethylamine (0.17mL, 1.00mmol), react at room temperature for 12h, add water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 82 mg of white solid with a yield of 63%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.74(s,1H),7.58(br.s,1H),7.29–7.39(m,2H),7.12(d,J＝5.8Hz,1H),6.89(s,1H),6.85(d,J＝6.6Hz,1H),6.61(t,J F-H＝75.6Hz,1H),4.97–5.12(m,0.4H),4.48–4.66(m,3H),4.15–4.28(m,0.6H),3.78–3.96(m,3H),3.51–3.63(m,1H),3.25–3.39(m,1H),3.09(s,2H),2.94(s,1H),2.52–2.63(m,1H),2.35–2.45(m,1H),2.12(s,3H),1.94–2.04(m,4H),1.62–1.74(m,2H),1.26–1.34(m,1H),0.58–0.68(m,2H),0.31–0.41(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.74 (s, 1H), 7.58 (br.s, 1H), 7.29-7.39 (m, 2H), 7.12 (d, J = 5.8 Hz, 1H) ,6.89(s,1H),6.85(d,J=6.6Hz,1H),6.61(t,J FH =75.6Hz,1H),4.97–5.12(m,0.4H),4.48–4.66(m,3H ), 4.15–4.28(m,0.6H), 3.78–3.96(m,3H), 3.51–3.63(m,1H), 3.25–3.39(m,1H), 3.09(s,2H), 2.94(s, 1H), 2.52–2.63(m, 1H), 2.35–2.45(m, 1H), 2.12(s, 3H), 1.94–2.04(m, 4H), 1.62–1.74(m, 2H), 1.26–1.34( m,1H),0.58-0.68(m,2H),0.31-0.41(m,2H).
MS(ESI,pos.ion)m/z:571.30[M+H] +. MS(ESI,pos.ion)m/z:571.30[M+H] + .
实施例98：化合物6-(((2R)-1-乙酰基-4-(3-(2,2-二氟乙氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺Example 98: Compound 6-(((2R)-1-acetyl-4-(3-(2,2-difluoroethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 2-Formylamino)methyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide
Figure PCTCN2021090489-appb-000160
Figure PCTCN2021090489-appb-000160
将化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺(53mg,0.09mmol)，碳酸钾(36mg,0.26mmol)溶于N,N-二甲基甲酰胺(3mL)中，室温下向此溶液中加入2-溴-1,1-二氟乙烷(0.1mL,1.0mmol)，70℃下反应12h，加水洗(50mL)，然后乙酸乙酯萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体31mg，收率52％。The compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxamido)methyl)-N-( 4,4-Difluorocyclohexyl)-N-picolineamide (53mg, 0.09mmol), potassium carbonate (36mg, 0.26mmol) dissolved in N,N-dimethylformamide (3mL), Add 2-bromo-1,1-difluoroethane (0.1mL, 1.0mmol) to this solution, react at 70°C for 12h, wash with water (50mL), and extract with ethyl acetate (5mL×3). Use the organic phase After drying with anhydrous sodium sulfate and removing the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 31 mg of white solid with a yield of 52%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.60-8.63(m,1H),7.81-7.95(m,1H),7.31-7.51(m,2H),7.12-7.24(m,2H),7.04(t,J F-H＝74.9Hz,1H),6.91-7.01(m,1H),6.40(t,J F-H＝54.6Hz,1H),4.30-4.57(m,5H),4.09-4.23(m,1H),3.41-3.74(m,3H),2.86(s,1.5H),2.73(s,1.5H),2.55-2.67(m,1H),1.95-2.15(m,6H),1.62-1.88(m,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.60-8.63 (m, 1H), 7.81-7.95 (m, 1H), 7.31-7.51 (m, 2H), 7.12-7.24 (m, 2H) ), 7.04 (t, J FH = 74.9 Hz, 1H), 6.91-7.01 (m, 1H), 6.40 (t, J FH = 54.6 Hz, 1H), 4.30-4.57 (m, 5H), 4.09-4.23 ( m, 1H), 3.41-3.74 (m, 3H), 2.86 (s, 1.5H), 2.73 (s, 1.5H), 2.55-2.67 (m, 1H), 1.95-2.15 (m, 6H), 1.62- 1.88(m,6H).
MS(ESI,pos.ion)m/z:645.30[M+H] +. MS(ESI,pos.ion)m/z:645.30[M+H] + .
实施例99：化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氘环己基)-N-甲基吡啶酰胺Example 99: Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)-N -(4,4-Dideuterium cyclohexyl)-N-picolinamide
Figure PCTCN2021090489-appb-000161
Figure PCTCN2021090489-appb-000161
将化合物6-(((2R)-1-乙酰基-4-(3,4-双(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，4,4-二氘-N-甲基环己胺盐酸盐(67mg,0.44mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(193mg,1.01mmol)和N-羟基-7-氮杂苯并三氮唑(53mg,0.39mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.26mL,1.60mmol)，室温反应12h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二 氯甲烷/甲醇(v/v)＝30/1)，得到白色固体66mg，收率55％。Compound 6-(((2R)-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)methyl)picolinic acid (100mg, 0.20mmol), 4,4-Dideuterium-N-methylcyclohexylamine hydrochloride (67mg, 0.44mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (193mg, 1.01mmol) and N-hydroxy-7-azabenzotriazole (53mg, 0.39mmol) were dissolved in dichloromethane (5mL), and N, N was added dropwise to this solution at 0℃. -Diisopropylethylamine (0.26mL, 1.60mmol), react at room temperature for 12h, add water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate the solution. Separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 66 mg of white solid with a yield of 55%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.92(br.s,1H),7.58–7.63(m,1H),7.40(d,J＝6.7Hz,1H),7.25–7.34(m,3H),6.86(t,J F-H＝73.6Hz,1H),6.82(t,J F-H＝73.6Hz,1H),4.48–4.65(m,3H),4.10–4.20(m,1H),3.61–3.69(m,1H),3.51–3.60(m,1H),3.36–3.46(m,1H),3.00(s,1.6H),2.82(s,1.4H),2.68–2.79(m,1H),2.17(s,3H),2.01–2.12(m,1H),1.71–1.88(m,4H),1.53–1.66(m,2H),1.37–1.49(m,1H),1.04–1.12(m,1H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.92 (br.s, 1H), 7.58-7.63 (m, 1H), 7.40 (d, J = 6.7 Hz, 1H), 7.25-7.34 (m ,3H),6.86(t,J FH =73.6Hz,1H),6.82(t,J FH =73.6Hz,1H),4.48–4.65(m,3H),4.10–4.20(m,1H),3.61– 3.69(m,1H),3.51–3.60(m,1H), 3.36–3.46(m,1H), 3.00(s,1.6H), 2.82(s,1.4H), 2.68–2.79(m,1H), 2.17(s,3H),2.01–2.12(m,1H),1.71–1.88(m,4H),1.53–1.66(m,2H),1.37–1.49(m,1H),1.04–1.12(m,1H) ).
MS(ESI,pos.ion)m/z:597.70[M+H] +. MS(ESI,pos.ion)m/z:597.70[M+H] + .
实施例100：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氘环己基)-N-甲基吡啶酰胺Example 100: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(4,4-dideuterocyclohexyl)-N-picolineamide
Figure PCTCN2021090489-appb-000162
Figure PCTCN2021090489-appb-000162
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(90mg,0.18mmol)，4,4-二氘-N-甲基环己胺盐酸盐(42mg,0.28mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(173mg,0.9mmol)和N-羟基-7-氮杂苯并三氮唑(49mg,0.36mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.21mL,1.3mmol)，室温反应10h，加水(25mL)，二氯甲烷萃取(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体46mg，收率42％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (90mg, 0.18mmol), 4,4-Dideuterium-N-methylcyclohexylamine hydrochloride (42mg, 0.28mmol), 1-ethyl-(3-dimethylaminopropyl) ) Carbodiimide hydrochloride (173mg, 0.9mmol) and N-hydroxy-7-azabenzotriazole (49mg, 0.36mmol) were dissolved in dichloromethane (5mL), at 0℃ Add N,N-diisopropylethylamine (0.21mL, 1.3mmol) dropwise to this solution, react at room temperature for 10 hours, add water (25mL), extract with dichloromethane (10mL×3), and dry the organic phase with anhydrous sodium sulfate After removing the solvent, the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 46 mg of white solid with a yield of 42%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.92(s,1H),7.57–7.64(m,1H),7.40(d,J＝7.3Hz,1H),7.12(d,J＝8.3Hz,1H),7.10(s,1H),6.92–6.95(m,1H),6.75(t,J F-H＝75.6Hz,1H),4.51–4.64(m,3H),4.08–4.15(m,1H),3.94(d,J＝5.7Hz,2H),3.67(t,J＝10.2Hz,1H),3.46–3.56(m,1H),3.36–3.45(m,1H),3.00(s,1.7H),2.81(s,1.3H),2.64–2.75(m,1H),2.17(s,3H),2.01–2.12(m,1H),1.71–1.88(m,4H),1.53–1.65(m,2H),1.35–1.47(m,2H),1.03–1.11(m,1H),0.62–0.68(m,2H),0.38–0.42(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.92 (s, 1H), 7.57-7.64 (m, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.10 (s, 1H), 6.92-6.95 (m, 1H), 6.75 (t, J FH = 75.6 Hz, 1H), 4.51-4.64 (m, 3H), 4.08-4.15 (m, 1H) ), 3.94 (d, J = 5.7 Hz, 2H), 3.67 (t, J = 10.2 Hz, 1H), 3.46–3.56 (m, 1H), 3.36–3.45 (m, 1H), 3.00 (s, 1.7H) ), 2.81(s, 1.3H), 2.64–2.75(m, 1H), 2.17(s, 3H), 2.01–2.12(m, 1H), 1.71–1.88(m, 4H), 1.53–1.65(m, 2H), 1.35--1.47(m,2H), 1.03--1.11(m,1H), 0.62--0.68(m,2H), 0.38--0.42(m,2H).
MS(ESI,pos.ion)m/z:601.30[M+H] +. MS(ESI,pos.ion)m/z:601.30[M+H] + .
实施例101：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氘环己基)-N-甲基吡啶酰胺Example 101: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy) (Phenyl)pyrrolidine-2-carboxamido)methyl)-N-(4,4-dideuterocyclohexyl)-N-picolineamide
Figure PCTCN2021090489-appb-000163
Figure PCTCN2021090489-appb-000163
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基(1,1-二氘)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(90mg,0.18mmol)，4,4-二氘-N-甲基环己胺盐酸盐(40mg,0.26mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(175mg,0.91mmol)和N-羟基-7-氮杂苯并三氮唑(53mg,0.39mmol)溶于二 氯甲烷(5mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.26mL,1.6mmol)，室温反应15h，加水(15mL)，二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体46mg，收率43％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrole Alkyl-2-carboxamido)methyl)picolinic acid (90mg, 0.18mmol), 4,4-dideuterium-N-methylcyclohexylamine hydrochloride (40mg, 0.26mmol), 1-ethyl-( 3-Dimethylaminopropyl) carbodiimide hydrochloride (175mg, 0.91mmol) and N-hydroxy-7-azabenzotriazole (53mg, 0.39mmol) dissolved in dichloromethane (5mL ), after cooling to 0°C, add N,N-diisopropylethylamine (0.26mL, 1.6mmol), react at room temperature for 15h, add water (15mL), extract with dichloromethane (5mL×3), and use the organic phase Drying with anhydrous sodium sulfate, removing the solvent, concentrating, and performing silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain a white solid 46 mg with a yield of 43%.
1H NMR(600MHz,CD 3OD)δ(ppm):7.90–7.94(m,1H),7.57–7.63(m,1H),7.40(d,J＝7.5Hz,1H),7.12(d,J＝7.9Hz,1H),7.09(s,1H),6.93(d,J＝7.7Hz,1H),6.75(t,J F-H＝75.8Hz,1H),4.47–4.64(m,3H),4.09–4.14(m,1H),3.66(t,J＝10.4Hz,1H),3.47–3.55(m,1H),3.37–3.44(m,1H),3.00(s,1.5H),2.81(s,1.5H),2.67–2.72(m,1H),2.17(s,3H),2.07–2.12(m,1H),1.73–1.87(m,4H),1.51–1.66(m,2H),1.38–1.45(m,1H),1.28–1.36(m,1H),1.05–1.10(m,1H),0.63–0.66(m,2H),0.38–0.40(m,2H). 1 H NMR(600MHz, CD 3 OD)δ(ppm): 7.90-7.94(m,1H), 7.57-7.63(m,1H), 7.40(d,J=7.5Hz,1H), 7.12(d,J =7.9Hz,1H),7.09(s,1H),6.93(d,J=7.7Hz,1H), 6.75(t,J FH =75.8Hz,1H), 4.47–4.64(m,3H),4.09– 4.14(m,1H), 3.66(t,J=10.4Hz,1H), 3.47–3.55(m,1H), 3.37–3.44(m,1H), 3.00(s,1.5H), 2.81(s,1.5 H), 2.67–2.72(m,1H), 2.17(s,3H), 2.07–2.12(m,1H), 1.73–1.87(m,4H), 1.51–1.66(m,2H), 1.38–1.45( m, 1H), 1.28--1.36 (m, 1H), 1.05 - 1.10 (m, 1H), 0.63 - 0.66 (m, 2H), 0.38 - 0.40 (m, 2H).
MS(ESI,pos.ion)m/z:603.35[M+H] +. MS(ESI,pos.ion)m/z:603.35[M+H] + .
实施例102：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺Example 102: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy) (Phenyl)pyrrolidine-2-carboxamido)methyl)-N-(4,4-difluorocyclohexyl)-N-picolinamide
Figure PCTCN2021090489-appb-000164
Figure PCTCN2021090489-appb-000164
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基-(1,1-二氘)甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(90mg,0.18mmol)，4,4-二氟-N-甲基环己胺盐酸盐(49mg,0.27mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(172mg,0.9mmol)和N-羟基-7-氮杂苯并三氮唑(49mg,0.36mmol)溶于二氯甲烷(5mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.21mL,1.3mmol)，室温反应18h，加水(15mL)，二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体77mg，收率68％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl) Pyrrolidine-2-carboxamido)methyl)picolinic acid (90mg, 0.18mmol), 4,4-difluoro-N-methylcyclohexylamine hydrochloride (49mg, 0.27mmol), 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (172mg, 0.9mmol) and N-hydroxy-7-azabenzotriazole (49mg, 0.36mmol) dissolved in dichloromethane ( 5mL), after cooling to 0℃, add N,N-diisopropylethylamine (0.21mL, 1.3mmol), react at room temperature for 18h, add water (15mL), dichloromethane extraction (5mL×3), organic phase Drying with anhydrous sodium sulfate, removing the solvent, concentrating, and performing silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain a white solid of 77 mg with a yield of 68%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.90–7.95(m,1H),7.58–7.63(m,1H),7.42–7.47(m,1H),7.12(d,J＝7.9Hz,1H),7.09(s,1H),6.91–6.95(m,1H),6.75(t,J F-H＝75.6Hz,1H),4.45–4.64(m,3H),4.07–4.14(m,1H),3.66–3.78(m,0.5H),3.66(t,J＝10.5Hz,1H),3.46–3.57(m,1H),3.33–3.42(m,0.5H),3.00(s,1.5H),2.84(s,1.5H),2.64–2.74(m,1H),2.16(s,3H),2.01–2.12(m,1H),1.80–2.10(m,8H),1.29–1.38(m,1H),0.61–0.67(m,2H),0.35–0.41(m,2H). 1 H NMR(400MHz, CD 3 OD)δ(ppm): 7.90-7.95(m,1H), 7.58-7.63(m,1H), 7.42-7.47(m,1H), 7.12(d,J=7.9Hz ,1H),7.09(s,1H),6.91–6.95(m,1H), 6.75(t,J FH = 75.6Hz,1H), 4.45–4.64(m,3H),4.07–4.14(m,1H) , 3.66–3.78(m,0.5H), 3.66(t,J=10.5Hz,1H), 3.46–3.57(m,1H), 3.33–3.42(m,0.5H), 3.00(s,1.5H), 2.84(s,1.5H), 2.64–2.74(m,1H), 2.16(s,3H), 2.01–2.12(m,1H), 1.80–2.10(m,8H), 1.29–1.38(m,1H) ,0.61--0.67(m,2H),0.35--0.41(m,2H).
MS(ESI,pos.ion)m/z:637.80[M+H] +. MS(ESI,pos.ion)m/z:637.80[M+H] + .
实施例103：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺 Example 103: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-2-formyl (Amino)methyl)-N-(4,4-difluorocyclohexyl)-N-picolinamide
Figure PCTCN2021090489-appb-000165
Figure PCTCN2021090489-appb-000165
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-甲氧基-d 3-苯基)吡咯烷-2-羧酸(45mg,0.14mmol)，6-(氨基甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺二盐酸盐(62mg,0.17mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(132mg,0.69mmol)和N-羟基-7-氮杂苯并三氮唑(39mg,0.29mmol)溶于二氯甲烷(10mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.16mL,0.97mmol)，室温反应11h，加水(20mL)搅拌5min，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，减压浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体32mg，收率39％。 The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-methoxy-d 3 -phenyl)pyrrolidine-2-carboxylic acid (45mg, 0.14mmol), 6-(Aminomethyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide dihydrochloride (62mg, 0.17mmol), 1-ethyl-(3-dimethylamino) Propyl) carbodiimide hydrochloride (132mg, 0.69mmol) and N-hydroxy-7-azabenzotriazole (39mg, 0.29mmol) were dissolved in dichloromethane (10mL) and cooled to 0 After temperature, add N,N-diisopropylethylamine (0.16mL, 0.97mmol), react at room temperature for 11h, add water (20mL), stir for 5min, extract with dichloromethane (5mL×3), and use anhydrous sulfuric acid for the organic phase The sodium was dried, the solvent was removed, concentrated under reduced pressure, and silica gel column chromatography was performed (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 32 mg of a white solid with a yield of 39%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.76–7.82(m,1H),7.37–7.49(m,3H),7.13(d,J＝8.0Hz,1H),6.93(s,1H),6.87(d,J＝7.9Hz,1H),6.55(t,J F-H＝75.2Hz,1H),4.64–4.72(m,0.6H),4.54–4.64(m,3H),3.95–3.99(m,1H),3.72–3861(m,0.4H),3.55–3.61(m,1H),3.30–3.41(m,1H),3.02(s,1.3H),2.89(s,1.7H),2.50–2.61(m,2H),2.17–2.27(m,2H),2.15(s,3H),1.85–2.03(m,6H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.76–7.82(m,1H), 7.37–7.49(m,3H), 7.13(d,J=8.0Hz,1H), 6.93(s,1H) ,6.87(d,J=7.9Hz,1H),6.55(t,J FH =75.2Hz,1H),4.64-4.72(m,0.6H),4.54-4.64(m,3H),3.95-3.99(m ,1H), 3.72–3861(m,0.4H), 3.55–3.61(m,1H), 3.30–3.41(m,1H), 3.02(s,1.3H), 2.89(s,1.7H), 2.50-- 2.61(m,2H), 2.17-2.27(m,2H), 2.15(s,3H), 1.85-2.03(m,6H).
MS(ESI,pos.ion)m/z:598.40[M+H] +. MS(ESI,pos.ion)m/z:598.40[M+H] + .
实施例104：化合物6-(((2R)-1-乙酰基-4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺Example 104: Compound 6-(((2R)-1-acetyl-4-(2,2-difluorobenzo[d][1,3]dioxocene-5-yl)pyrrolidine-2- (Carboxamido)methyl)-N-(4,4-difluorocyclohexyl)-N-picolinamide
Figure PCTCN2021090489-appb-000166
Figure PCTCN2021090489-appb-000166
将化合物(2R)-1-乙酰基-4-(2,2-二氟苯并[d][1,3]二噁茂-5-基)吡咯烷-2-羧酸(60mg,0.19mmol)，6-(氨基甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺二盐酸盐(82mg,0.23mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(182mg,0.95mmol)和N-羟基-7-氮杂苯并三氮唑(53mg,0.39mmol)溶于二氯甲烷(6mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.23mL,1.4mmol)，室温反应11h，加水(20mL)搅拌5min，用二氯甲烷萃取(15mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体72mg，收率65％。The compound (2R)-1-acetyl-4-(2,2-difluorobenzo[d][1,3]dioxin-5-yl)pyrrolidine-2-carboxylic acid (60mg, 0.19mmol ), 6-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide dihydrochloride (82mg, 0.23mmol), 1-ethyl-(3-dimethyl Aminopropyl) carbodiimide hydrochloride (182mg, 0.95mmol) and N-hydroxy-7-azabenzotriazole (53mg, 0.39mmol) were dissolved in dichloromethane (6mL) and cooled After reaching 0°C, add N,N-diisopropylethylamine (0.23mL, 1.4mmol), react at room temperature for 11h, add water (20mL) and stir for 5min, extract with dichloromethane (15mL×3), and combine the organic phases It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 72 mg of white solid with a yield of 65%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.72–7.83(m,1H),7.57(br.s,1H),7.34–7.48(m,2H),6.94–7.07(m,3H),4.47–4.72(m,3.6H),3.90–4.02(m,1H),3.70–3.80(m,0.4H),3.52–3.57(m,1H),3.29–3.43(m,1H),3.01(s,1.3H),2.88(s,1.7H),2.46–2.56(m,2H),2.12–2.25(m,2H),2.13(s,3H),1.90–1.99(m,6H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.72-7.83(m,1H), 7.57(br.s,1H), 7.34-7.48(m,2H), 6.94-7.07(m,3H), 4.47–4.72(m,3.6H), 3.90–4.02(m,1H), 3.70–3.80(m,0.4H), 3.52–3.57(m,1H), 3.29–3.43(m,1H), 3.01(s ,1.3H), 2.88(s,1.7H), 2.46-2.56(m,2H), 2.12-2.25(m,2H), 2.13(s,3H), 1.90-1.99(m,6H).
MS(ESI,pos.ion)m/z:579.10[M+H] +. MS(ESI,pos.ion)m/z:579.10[M+H] + .
实施例105：化合物6-(((2R)-1-乙酰基-4-(5-((环丙基甲基)-羟基氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺Example 105: The compound 6-(((2R)-1-acetyl-4-(5-((cyclopropylmethyl)-hydroxyamino)-4-(difluoromethoxy)-2-(methyl (Sulfonyl)phenyl)pyrrolidine-2-carboxamido)methyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide
Figure PCTCN2021090489-appb-000167
Figure PCTCN2021090489-appb-000167
将化合物(2R)-1-乙酰基-4-(5-((环丙基甲基)-羟基氨基)-4-(二氟甲氧基)-2-(甲磺酰基)苯基)吡咯烷-2-羧 酸(60mg,0.13mmol)，6-(氨基甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺二盐酸盐(55mg,0.15mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(164mg,0.65mmol)和N-羟基-7-氮杂苯并三氮唑(35mg,0.26mmol)溶于二氯甲烷(5mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.15mL,0.91mmol)，室温反应12h，加水(20mL)搅拌5min，分离有机相，水相用二氯甲烷萃取(5mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体63mg，收率67％。The compound (2R)-1-acetyl-4-(5-((cyclopropylmethyl)-hydroxyamino)-4-(difluoromethoxy)-2-(methylsulfonyl)phenyl)pyrrole Alkyl-2-carboxylic acid (60mg, 0.13mmol), 6-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-picolinamide dihydrochloride (55mg, 0.15mmol) , 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (164mg, 0.65mmol) and N-hydroxy-7-azabenzotriazole (35mg, 0.26mmol) Dissolve in dichloromethane (5mL), cool to 0°C, add N,N-diisopropylethylamine (0.15mL, 0.91mmol), react at room temperature for 12h, add water (20mL) and stir for 5min, separate the organic phase, The aqueous phase was extracted with dichloromethane (5mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)= 30/1) to obtain 63 mg of a white solid with a yield of 67%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.74–7.87(m,1H),7.52–7.63(m,1H),7.37–7.49(m,2H),6.97(s,1H),6.69(s,1H),6.50(t,J F-H＝73.6Hz,1H),4.54–4.74(m,4H),4.30–4.39(m,1H),3.99–4.08(m,1H),3.64–3.81(m,1H),3.46–3.53(m,1H),3.25(s,3H),2.89–3.02(m,5H),2.45–2.60(m,2H),2.12–2.27(m,2H),2.12(s,3H),1.83–2.04(m,6H),1.05–1.13(m,1H),0.55–0.65(m,2H),0.22–0.34(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.74-7.87(m,1H), 7.52-7.63(m,1H), 7.37-7.49(m,2H), 6.97(s,1H), 6.69( s,1H),6.50(t,J FH =73.6Hz,1H),4.54–4.74(m,4H), 4.30–4.39(m,1H),3.99–4.08(m,1H), 3.64–3.81(m ,1H),3.46-3.53(m,1H),3.25(s,3H),2.89-3.02(m,5H),2.45-2.60(m,2H),2.12-2.27(m,2H),2.12(s ,3H),1.83-2.04(m,6H),1.05-1.13(m,1H),0.55-0.65(m,2H),0.22-0.34(m,2H).
MS(ESI,pos.ion)m/z:728.80[M+H] +. MS(ESI,pos.ion)m/z:728.80[M+H] + .
实施例106：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-甲基-N-((1r,4R)-4-甲基环己基)吡啶酰胺Example 106: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-methyl-N-((1r,4R)-4-methylcyclohexyl)pyridineamide
Figure PCTCN2021090489-appb-000168
Figure PCTCN2021090489-appb-000168
步骤1：化合物叔丁基((1r,4r)-4-甲基环己基)氨基甲酸酯的合成Step 1: Synthesis of compound tert-butyl ((1r,4r)-4-methylcyclohexyl) carbamate
将(1r,4r)-4-甲基环己胺(800mg,7.06mmol)和N,N-二异丙基乙胺(1.4mL,8.50mmol)溶于二氯甲烷(8mL)中，冰浴下加入二碳酸二叔丁酯(1.7g,7.80mmol)，室温反应9h，加水(20mL)搅拌5min，分离有机相，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝20/1)，得到白色固体612mg，收率40％。Dissolve (1r,4r)-4-methylcyclohexylamine (800mg, 7.06mmol) and N,N-diisopropylethylamine (1.4mL, 8.50mmol) in dichloromethane (8mL), ice bath Add di-tert-butyl dicarbonate (1.7g, 7.80mmol), react at room temperature for 9h, add water (20mL) and stir for 5min, separate the organic phase, dry the organic phase with anhydrous sodium sulfate, remove the solvent, and perform silica gel column chromatography on the concentrated solution After separation (eluent: petroleum ether/ethyl acetate (v/v)=20/1), 612 mg of white solid was obtained with a yield of 40%.
1H NMR(600MHz,CDCl 3)δ(ppm):4.36(brs,1H),3.31–3.41(m,1H),1.97–2.00(m,2H),1.69–1.72(m,2H),1.46(s,9H),1.27–1.37(m,1H),1.01–1.14(m,4H),0.90(d,J＝6.5Hz,3H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm): 4.36 (brs, 1H), 3.31-3.41 (m, 1H), 1.97-2.00 (m, 2H), 1.69-1.72 (m, 2H), 1.46 ( s,9H), 1.27–1.37(m,1H), 1.01–1.14(m,4H), 0.90(d,J=6.5Hz,3H).
MS(ESI,pos.ion)m/z:158.25[M-55] +. MS(ESI,pos.ion)m/z:158.25[M-55] + .
步骤2：化合物叔丁基甲基((1r,4r)-4-甲基环己基)氨基甲酸酯的合成Step 2: Synthesis of compound tert-butyl methyl ((1r, 4r)-4-methylcyclohexyl) carbamate
将叔丁基((1r,4r)-4-甲基环己基)氨基甲酸酯(300mg,1.41mmol)溶于无水N,N-二甲基甲酰胺(8mL)中，冰浴下加入60％氢化钠(84mg,2.10mmol)，室温反应30min，冰浴下加入碘甲烷(260mg,1.83mmol)，室温反应9h，加水(25mL)，用乙酸乙酯萃取(10mL×3)，分离有机相，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝25/1)，得到无色液体129mg，收率40％。Dissolve tert-butyl((1r,4r)-4-methylcyclohexyl)carbamate (300mg, 1.41mmol) in anhydrous N,N-dimethylformamide (8mL) and add under ice bath 60% sodium hydride (84mg, 2.10mmol), react at room temperature for 30min, add methyl iodide (260mg, 1.83mmol) under ice bath, react at room temperature for 9h, add water (25mL), extract with ethyl acetate (10mL×3), separate organic The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=25/1) to obtain 129 mg of colorless liquid. The yield was 40%.
1H NMR(600MHz,CDCl 3)δ(ppm):3.75–4.04(m,1H),2.72(s,3H),1.73–1.76(m,2H),1.64–1.67(m,2H),1.39–1.51(m,2H),1.47(s,9H),1.25–1.34(m,1H),1.01–1.10(m,2H),0.90(d,J＝6.5Hz,3H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm): 3.75-4.04 (m, 1H), 2.72 (s, 3H), 1.73-1.76 (m, 2H), 1.64-1.67 (m, 2H), 1.39- 1.51 (m, 2H), 1.47 (s, 9H), 1.25-1.34 (m, 1H), 1.01-1.10 (m, 2H), 0.90 (d, J = 6.5 Hz, 3H).
MS(ESI,pos.ion)m/z:172.25[M-55] +. MS(ESI,pos.ion)m/z:172.25[M-55] + .
步骤3：化合物(1r,4r)-N,4-二甲基环己胺盐酸盐的合成Step 3: Synthesis of compound (1r,4r)-N,4-dimethylcyclohexylamine hydrochloride
将化合物叔丁基甲基((1r,4r)-4-甲基环己基)氨基甲酸酯(120mg,0.53mmol)溶解于二氯甲烷(3 mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(6mL)，室温搅拌1h，减压浓缩，得到白色固体83mg，收率96％。Dissolve the compound tert-butyl methyl ((1r, 4r)-4-methylcyclohexyl) carbamate (120mg, 0.53mmol) in dichloromethane (3 mL) solution, add 4mol/L HCl in ethyl acetate The solution (6 mL) was stirred at room temperature for 1 h, and concentrated under reduced pressure to obtain 83 mg of a white solid with a yield of 96%.
1H NMR(400MHz,CD 3OD)δ(ppm):2.94–3.00(m,1H),2.69(s,3H),2.11–2.14(m,2H),1.85–1.88(m,2H),1.32–1.43(m,3H),1.02–1.12(m,2H),0.95(d,J＝6.5Hz,3H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 2.94-3.00 (m, 1H), 2.69 (s, 3H), 2.11-2.14 (m, 2H), 1.85-1.88 (m, 2H), 1.32 –1.43(m,3H),1.02–1.12(m,2H),0.95(d,J=6.5Hz,3H).
MS(ESI,pos.ion)m/z:128.30[M+H-HCl] +. MS(ESI,pos.ion)m/z:128.30[M+H-HCl] + .
步骤4：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-甲基-N-((1r,4R)-4-甲基环己基)吡啶酰胺的合成Step 4: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)-N-methyl-N-((1r,4R)-4-methylcyclohexyl)pyridineamide
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，(1r,4r)-N,4-二甲基环己胺盐酸盐(59mg,0.36mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(191mg,1.00mmol)和N-羟基-7-氮杂苯并三氮唑(43mg,0.32mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入N,N-二异丙基乙胺(0.17mL,1.00mmol)，室温反应6h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体41mg，收率33％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (100mg, 0.20mmol), (1r,4r)-N,4-dimethylcyclohexylamine hydrochloride (59mg, 0.36mmol), 1-ethyl-(3-dimethylamino) Propyl) carbodiimide hydrochloride (191mg, 1.00mmol) and N-hydroxy-7-azabenzotriazole (43mg, 0.32mmol) were dissolved in dichloromethane (5mL) and cooled to 0 ℃, add N,N-diisopropylethylamine (0.17mL, 1.00mmol), react at room temperature for 6h, wash with water (15mL), extract with dichloromethane (5mL×3), and dry the organic phase with anhydrous sodium sulfate After removing the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 41 mg of white solid with a yield of 33%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.72–7.80(m,1H),7.34–7.50(m,3H),7.12(d,J＝7.6Hz,1H),6.90(s,1H),6.86(d,J＝7.7Hz,1H),6.62(t,J F-H＝75.5Hz,1H),4.47–4.65(m,3.6H),3.90–3.99(m,1H),3.88(d,J＝6.6Hz,2H),3.55–3.62(m,1H),3.29–3.45(m,1.4H),3.00(s,1.7H),2.83(s,1.3H),2.53–2.63(m,1H),2.38–2.48(m,1H),2.14(s,3H),1.52–1.72(m,5H),1.14–1.37(m,5H),0.94(d,J＝5.5Hz,1.5H),0.83(d,J＝5.5Hz,1.5H),0.63–0.70(m,2H),0.33–0.41(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.72–7.80(m,1H), 7.34–7.50(m,3H), 7.12(d,J=7.6Hz,1H), 6.90(s,1H) ,6.86(d,J=7.7Hz,1H),6.62(t,J FH =75.5Hz,1H),4.47–4.65(m,3.6H),3.90–3.99(m,1H),3.88(d,J =6.6Hz,2H),3.55–3.62(m,1H), 3.29–3.45(m,1.4H), 3.00(s,1.7H), 2.83(s,1.3H), 2.53–2.63(m,1H) ,2.38–2.48(m,1H),2.14(s,3H),1.52–1.72(m,5H),1.14–1.37(m,5H),0.94(d,J=5.5Hz,1.5H),0.83( d, J=5.5Hz, 1.5H), 0.63-0.70 (m, 2H), 0.33-0.41 (m, 2H).
MS(ESI,pos.ion)m/z:613.45[M+H] +. MS(ESI,pos.ion)m/z:613.45[M+H] + .
实施例107：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-甲基-N-(4-氯苯基)吡啶酰胺Example 107: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-methyl-N-(4-chlorophenyl)pyridineamide
Figure PCTCN2021090489-appb-000169
Figure PCTCN2021090489-appb-000169
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，N-甲基-4-氯苯胺(70mg,0.50mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(251mg,1.31mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.40mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入N,N-二异丙基乙胺(183mg,1.42mmol)，室温反应22h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到白色固体82mg，收率65％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Methyl)picolinic acid (100mg, 0.20mmol), N-methyl-4-chloroaniline (70mg, 0.50mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (251mg, 1.31mmol) and N-hydroxy-7-azabenzotriazole (54mg, 0.40mmol) dissolved in dichloromethane (5mL), cooled to 0℃, added N,N-diisopropyl Ethylethylamine (183mg, 1.42mmol), reacted at room temperature for 22h, washed with water (15mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography After separation (eluent: dichloromethane/methanol (v/v)=40/1), 82 mg of a white solid was obtained with a yield of 65%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.64(br.s,1H),7.35-7.48(m,1H),7.18-7.28(m,2H),6.97-7.16(m,4H),6.83-6.95(m,2H),6.63(t,J F-H＝75.5Hz,1H),4.42-4.51(m,3H),3.88-4.00(m,3H),3.51-3.65(m,1H),3.51(s,3H),3.29-3.45(m,1H),2.51-2.64(m,1H),2.35-2.63(m,1H),2.15(s,3H),1.26-1.35(m,1H),0.64-0.71(m,2H),0.36-0.43(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.64 (br.s, 1H), 7.35-7.48 (m, 1H), 7.18-7.28 (m, 2H), 6.97-7.16 (m, 4H), 6.83-6.95(m,2H),6.63(t,J FH =75.5Hz,1H),4.42-4.51(m,3H),3.88-4.00(m,3H),3.51-3.65(m,1H),3.51 (s,3H),3.29-3.45(m,1H),2.51-2.64(m,1H),2.35-2.63(m,1H),2.15(s,3H),1.26-1.35(m,1H),0.64 -0.71 (m, 2H), 0.36-0.43 (m, 2H).
MS(ESI,pos.ion)m/z:627.10[M+H] +. MS(ESI,pos.ion)m/z:627.10[M+H] + .
实施例108：化合物6-(((2R)-1-乙酰基-4-(3-(异丙氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺Example 108: Compound 6-(((2R)-1-acetyl-4-(3-(isopropoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido )Methyl)-N-(4,4-Difluorocyclohexyl)-N-picolinamide
Figure PCTCN2021090489-appb-000170
Figure PCTCN2021090489-appb-000170
步骤1：化合物(R)-6-((1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺的合成Step 1: Compound (R)-6-((1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H- Synthesis of pyrrole-2-carboxamido)methyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide
将化合物(R)-1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸(300mg,0.74mmol)，6-(氨基甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺二盐酸盐(301mg,0.85mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(718mg,3.75mmol)和N-羟基-7-氮杂苯并三氮唑(203mg,1.49mmol)溶于二氯甲烷(10mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(0.9mL,5.0mmol)，室温反应7h，加水洗(20mL)搅拌，分离有机相，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析色谱分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体387mg，收率77％。The compound (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (300mg, 0.74mmol), 6-(aminomethyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide dihydrochloride (301mg, 0.85mmol), 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride (718mg, 3.75mmol) and N-hydroxy-7-azabenzotriazole (203mg, 1.49mmol) dissolved in dichloromethane ( 10mL), after cooling to 0°C, add N,N-diisopropylethylamine (0.9mL, 5.0mmol), react at room temperature for 7h, wash with water (20mL) and stir, separate the organic phase, and use anhydrous sulfuric acid for the organic phase It was dried with sodium, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 387 mg of white solid with a yield of 77%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.75–7.81(m,1H),7.41–7.49(m,5H),7.34–7.40(m,2H),7.18–7.20(m,1H),7.07–7.10(m,1H),6.93–7.01(m,1H),6.61(t,J F-H＝74.9Hz,1H),6.18–6.23(m,1H),5.37–5.41(m,0.7H),5.23–5.27(m,0.3H),5.17(s,2H),4.66–4.74(m,2H),4.55–4.65(m,3H),2.87(s,2H),2.78(s,1H),2.24(s,3H),2.07(s,1H),2.06–2.16(m,2H),1.82–2.04(m,6H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.75-7.81(m,1H), 7.41-7.49(m,5H), 7.34-7.40(m,2H), 7.18-7.20(m,1H), 7.07–7.10(m,1H), 6.93–7.01(m,1H), 6.61(t,J FH = 74.9Hz,1H), 6.18–6.23(m,1H), 5.37–5.41(m,0.7H), 5.23–5.27(m,0.3H), 5.17(s,2H), 4.66–4.74(m,2H), 4.55–4.65(m,3H), 2.87(s,2H), 2.78(s,1H), 2.24 (s,3H),2.07(s,1H),2.06-2.16(m,2H),1.82-2.04(m,6H).
MS(ESI,pos.ion)m/z:669.15[M+H] +. MS(ESI,pos.ion)m/z:669.15[M+H] + .
步骤2：化合物6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺的合成Step 2: Compound 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxamido)methyl)-N Synthesis of -(4,4-difluorocyclohexyl)-N-picolinamide
将化合物(R)-6-((1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺(380mg,0.57mmol)溶于甲醇(10mL)，加入Pd/C(53mg)，通入氢气室温反应12h，过滤除去催化剂，滤液浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝25/1)，得到白色固体316mg，收率95％。Compound (R)-6-((1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole- 2-Formylamino)methyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide (380mg, 0.57mmol) was dissolved in methanol (10mL), Pd/C (53mg) was added, Hydrogen was allowed to react at room temperature for 12 hours, the catalyst was removed by filtration, the filtrate was concentrated, and silica gel column chromatography was performed (eluent: dichloromethane/methanol (v/v)=25/1) to obtain a white solid of 316 mg, with a yield of 95% .
MS(ESI,pos.ion)m/z:581.10[M+H] +. MS(ESI,pos.ion)m/z:581.10[M+H] + .
步骤3：化合物6-(((2R)-1-乙酰基-4-(3-(异丙氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺的合成Step 3: Compound 6-(((2R)-1-acetyl-4-(3-(isopropoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) Synthesis of (methyl)-N-(4,4-difluorocyclohexyl)-N-picolineamide
将6-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酰氨基)甲基)-N-(4,4-二氟环己基)-N-甲基吡啶酰胺(70mg,0.12mmol)，2-碘丙烷(61mg,0.36mmol)，碳酸钾(83mg,0.60mmol)溶解在干燥的N,N-二甲基甲酰胺(3mL)溶液中，80℃反应2h，加入水(30mL)，用乙酸乙酯(10mL×3)萃取，有机相合用无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到白色固体63mg，收率83％。Add 6-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxamido)methyl)-N-(4 ,4-Difluorocyclohexyl)-N-picolineamide (70mg, 0.12mmol), 2-iodopropane (61mg, 0.36mmol), potassium carbonate (83mg, 0.60mmol) were dissolved in dry N,N-di In methylformamide (3mL) solution, react at 80°C for 2h, add water (30mL), extract with ethyl acetate (10mL×3), combine the organic phase, dry with anhydrous sodium sulfate, concentrate, and perform silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v)=30/1) to obtain 63 mg of white solid with a yield of 83%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.91–7.95(m,1H),7.59–7.64(m,1H),7.42–7.48(m,1H),7.12–7.13(m,2H),6.94(d,J＝8.0Hz,1H),6.70(t,J F-H＝75.7Hz,1H),4.61–4.70(m,2H),4.45–4.55(m,2H),4.10–4.15(m,1H),3.70–3.77(m,1H),3.52–3.69(m,1H),3.47–3.58(m,1H),3.30(s,1.5H),2.84(s,1.5H),2.66–2.74(m,1H),2.16(s,3H),2.01–2.08(m,1H),1.76–2.00(m,8H),1.35(d,J＝5.7Hz,6H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.91-7.95 (m, 1H), 7.59-7.64 (m, 1H), 7.42-7.48 (m, 1H), 7.12-7.13 (m, 2H) ,6.94(d,J=8.0Hz,1H),6.70(t,J FH =75.7Hz,1H),4.61–4.70(m,2H),4.45–4.55(m,2H),4.10–4.15(m, 1H), 3.70--3.77(m,1H), 3.52--3.69(m,1H), 3.47--3.58(m,1H), 3.30(s,1.5H), 2.84(s,1.5H), 2.66--2.74( m,1H), 2.16(s,3H), 2.01–2.08(m,1H), 1.76–2.00(m,8H), 1.35(d,J=5.7Hz,6H).
MS(ESI,pos.ion)m/z:623.20[M+H] +. MS(ESI,pos.ion)m/z:623.20[M+H] + .
实施例109：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(9-氨基-5,7-二氢二苯并[c,e]氧杂卓-3-基)吡啶酰胺Example 109: The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Amido)methyl)-N-(9-amino-5,7-dihydrodibenzo[c,e]oxazepine-3-yl)pyridineamide
Figure PCTCN2021090489-appb-000171
Figure PCTCN2021090489-appb-000171
步骤1：化合物4,4'-二硝基-[1,1'-联苯]-2,2'-二甲醛的合成Step 1: Synthesis of compound 4,4'-dinitro-[1,1'-biphenyl]-2,2'-dicarbaldehyde
将2-溴-5-硝基苯甲醛(1.0g,4.3mmol)，联硼酸频那醇酯(1.3g,5.1mmol)，醋酸钾(1.3g,13mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(50mg,0.07mmol)混合在干燥的1,4-二氧六环(15mL)溶液中，氮气保护下100℃反应4h，冷却至室温，将反应液抽滤，滤液浓缩后加入水(30mL)，用乙酸乙酯(10mL×3)萃取，有机相合用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝5/1)，得到浅黄色固体752mg，收率58％。Combine 2-bromo-5-nitrobenzaldehyde (1.0g, 4.3mmol), pinacol diborate (1.3g, 5.1mmol), potassium acetate (1.3g, 13mmol) and [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride (50mg, 0.07mmol) was mixed in a dry solution of 1,4-dioxane (15mL), reacted at 100°C for 4h under nitrogen protection, and cooled to room temperature. The reaction solution was suction filtered, the filtrate was concentrated, water (30mL) was added, and the mixture was extracted with ethyl acetate (10mL×3). The organic phase was combined and dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent : Petroleum ether/ethyl acetate (v/v)=5/1) to obtain 752 mg of pale yellow solid, with a yield of 58%.
1H NMR(400MHz,CDCl 3)δ(ppm):9.91(s,2H),8.87(d,J＝2.3Hz,2H),8.56(dd,J＝8.3,2.3Hz,2H),7.53(d,J＝8.3Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.91 (s, 2H), 8.87 (d, J = 2.3 Hz, 2H), 8.56 (dd, J = 8.3, 2.3 Hz, 2H), 7.53 (d ,J=8.3Hz,2H).
MS(ESI,pos.ion)m/z:301.20[M+H] +. MS(ESI,pos.ion)m/z:301.20[M+H] + .
步骤2：化合物4,4'-二硝基-[1,1'-联苯]-2,2'-二甲醇的合成Step 2: Synthesis of compound 4,4'-dinitro-[1,1'-biphenyl]-2,2'-dimethanol
将化合物4,4'-二硝基-[1,1'-联苯]-2,2'-二甲醛(740mg,2.47mmol)溶解在甲醇(10mL)中，冷却至0℃，加入硼氢化钠(203mg,5.37mmol)，室温搅拌30min后停止反应，加水(25mL)，乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到浅黄色固体255mg，收率34％。Dissolve the compound 4,4'-dinitro-[1,1'-biphenyl]-2,2'-diformaldehyde (740mg, 2.47mmol) in methanol (10mL), cool to 0℃, add borohydride Sodium (203mg, 5.37mmol), stirred at room temperature for 30 minutes, the reaction was stopped, water (25mL) was added, ethyl acetate extraction (10mL×3), the organic phase was dried with anhydrous sodium sulfate, the concentrated solution was subjected to silica gel column chromatography (elution Reagent: petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 255 mg of light yellow solid, with a yield of 34%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.50(s,2H),8.26(dd,J＝8.3,2.3Hz,2H),7.35(d,J＝8.3Hz,2H),4.46(dd,J＝37.0,12.7Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.50 (s, 2H), 8.26 (dd, J = 8.3, 2.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 4.46 (dd ,J=37.0,12.7Hz,4H).
MS(ESI,pos.ion)m/z:327.20[M+Na] +. MS(ESI,pos.ion)m/z:327.20[M+Na] + .
步骤3：化合物3,9-二硝基-5,7-二氢二苯并[c,e]氧杂卓的合成Step 3: Synthesis of compound 3,9-dinitro-5,7-dihydrodibenzo[c,e]oxazepine
将4,4'-二硝基-[1,1'-联苯]-2,2'-二甲醇(152mg,0.50mmol)，三丁基膦(231mg,1.14mmol)溶解在干燥的四氢呋喃(5mL)溶液中，冰浴条件下缓慢加入偶氮二甲酰胺(196mg,1.14mmol)，室温反应3h，加入水(30mL)，用乙酸乙酯(15mL×3)萃取，有机相合用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析色谱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝3/1)，得到浅黄色固体106mg，收率74％。Dissolve 4,4'-dinitro-[1,1'-biphenyl]-2,2'-dimethanol (152mg, 0.50mmol), tributylphosphine (231mg, 1.14mmol) in dry tetrahydrofuran ( 5mL) solution, slowly add azodicarbonamide (196mg, 1.14mmol) under ice bath conditions, react at room temperature for 3h, add water (30mL), extract with ethyl acetate (15mL×3), combine the organic phase with anhydrous sulfuric acid It was dried with sodium, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain 106 mg of light yellow solid with a yield of 74%.
1H NMR(400MHz,d 6-DMSO)δ(ppm):8.51(d,J＝2.2Hz,2H),8.44(dd,J＝8.5,2.3Hz,2H),7.99(d,J＝8.5Hz,2H),4.43(s,4H). 1 H NMR(400MHz,d 6 -DMSO)δ(ppm): 8.51(d,J=2.2Hz,2H), 8.44(dd,J=8.5,2.3Hz,2H),7.99(d,J=8.5Hz ,2H),4.43(s,4H).
步骤4：化合物5,7-二氢二苯并[c,e]氧杂卓-3,9-二胺的合成Step 4: Synthesis of compound 5,7-dihydrodibenzo[c,e]oxazepine-3,9-diamine
将化合物3,9-二硝基-5,7-二氢二苯并[c,e]氧杂卓(100mg,0.35mmol)溶于甲醇(10mL)，加入Pd/C(20mg)，通入氢气室温反应5h，过滤除去催化剂，滤液浓缩，得浅黄色固体64mg，收率81％。Dissolve compound 3,9-dinitro-5,7-dihydrodibenzo[c,e]oxazepine (100mg, 0.35mmol) in methanol (10mL), add Pd/C (20mg), and pass Hydrogen was reacted at room temperature for 5 hours, the catalyst was removed by filtration, and the filtrate was concentrated to obtain 64 mg of light yellow solid with a yield of 81%.
1H NMR(400MHz,d 6-DMSO)δ(ppm):7.11(d,J＝8.1Hz,2H),6.65(dd,J＝8.1,2.2Hz,2H),6.60(d,J＝2.1Hz,2H),5.11(s,4H),4.08(s,4H). 1 H NMR (400MHz, d 6 -DMSO) δ (ppm): 7.11 (d, J = 8.1 Hz, 2H), 6.65 (dd, J = 8.1, 2.2 Hz, 2H), 6.60 (d, J = 2.1 Hz ,2H),5.11(s,4H),4.08(s,4H).
MS(ESI,pos.ion)m/z:227.20[M+H] +. MS(ESI,pos.ion)m/z:227.20[M+H] + .
步骤5：化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)-N-(9-氨基-5,7-二氢二苯并[c,e]氧杂卓-3-基)吡啶酰胺的合成Step 5: Compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-formyl Synthesis of (amino)methyl)-N-(9-amino-5,7-dihydrodibenzo[c,e]oxazepine-3-yl)pyridineamide
将化合物6-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)甲基)吡啶甲酸(100mg,0.20mmol)，5,7-二氢二苯并[c,e]氧杂卓-3,9-二胺(73mg,0.32mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(251mg,1.31mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.40mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入N,N-二异丙基乙胺(183mg,1.42mmol)，室温反应3h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到浅褐色固体44mg，收率31％。The compound 6-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido) (Methyl)picolinic acid (100mg, 0.20mmol), 5,7-dihydrodibenzo[c,e]oxazepine-3,9-diamine (73mg, 0.32mmol), 1-ethyl-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (251mg, 1.31mmol) and N-hydroxy-7-azabenzotriazole (54mg, 0.40mmol) dissolved in dichloromethane (5mL) After cooling to 0℃, adding N,N-diisopropylethylamine (183mg, 1.42mmol), reacting at room temperature for 3h, washing with water (15mL), extracting with dichloromethane (5mL×3), and the organic phase After drying with sodium sulfate and removing the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 44 mg of light brown solid with a yield of 31%.
1H NMR(400MHz,CDCl 3)δ(ppm):10.74(s,1H),8.98(s,1H),8.24(d,J＝7.4Hz,1H),8.19(d,J＝7.9Hz,1H),8.04(s,1H),7.86-7.90(m,1H),7.49(d,J＝7.2Hz,1H),7.43(d,J＝7.5Hz,1H),7.36(d,J＝8.0Hz,1H),7.11(d,J＝8.1Hz,1H),6.92(s,1H),6.87(d,J＝8.1Hz,1H),6.81(d,J＝7.8Hz,1H),6.76(s,1H),6.61(t,J F-H＝75.6Hz,1H),4.86-4.90(m,1H),4.62-4.80(m,2H),4.39(s,2H),4.30(s,2H),3.93-3.97(m,1H),3.88(d,J＝6.7Hz,2H),3.34-3.45(m,2H),2.82-2.90(m,1H),2.47-2.54(m,1H),2.10(s,3H),1.68-1.79(m,1H),0.63-0.66(m,2H),0.34-0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 10.74 (s, 1H), 8.98 (s, 1H), 8.24 (d, J = 7.4 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H ), 8.04(s,1H),7.86-7.90(m,1H),7.49(d,J=7.2Hz,1H),7.43(d,J=7.5Hz,1H),7.36(d,J=8.0Hz ,1H), 7.11(d,J=8.1Hz,1H), 6.92(s,1H), 6.87(d,J=8.1Hz,1H), 6.81(d,J=7.8Hz,1H), 6.76(s ,1H),6.61(t,J FH =75.6Hz,1H),4.86-4.90(m,1H),4.62-4.80(m,2H),4.39(s,2H),4.30(s,2H),3.93 -3.97(m,1H),3.88(d,J=6.7Hz,2H),3.34-3.45(m,2H),2.82-2.90(m,1H),2.47-2.54(m,1H),2.10(s , 3H), 1.68-1.79 (m, 1H), 0.63-0.66 (m, 2H), 0.34-0.37 (m, 2H).
MS(ESI,pos.ion)m/z:712.50[M+H] +. MS(ESI,pos.ion)m/z:712.50[M+H] + .
实施例110：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((3-氧代异吲哚-5-基)甲基)吡咯烷-2-甲酰胺Example 110: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((3-oxoiso Indol-5-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000172
Figure PCTCN2021090489-appb-000172
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(120mg,0.32mmol)和6-(氨基甲基)异吲哚-1-酮(57mg,0.35mmol)溶于二氯甲烷(8mL)和N,N-二甲基甲酰胺(1mL)中，加入N-羟基-7-氮杂苯并三氮唑(88mg,0.65mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(186mg,0.97mmol)和N,N-二异丙基乙胺(167mg,1.29mmol)，室温反应5h，减压浓缩除去溶剂，加水(40mL)，用乙酸乙酯萃取(25mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体97mg，收率58％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120mg, 0.32mmol) And 6-(aminomethyl) isoindol-1-one (57mg, 0.35mmol) dissolved in dichloromethane (8mL) and N,N-dimethylformamide (1mL), add N-hydroxy-7 -Azabenzotriazole (88mg, 0.65mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (186mg, 0.97mmol) and N,N-di Isopropylethylamine (167mg, 1.29mmol), react at room temperature for 5h, concentrate under reduced pressure to remove the solvent, add water (40mL), extract with ethyl acetate (25mL×2), dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure The residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 97 mg of white solid with a yield of 58%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.42(br.s,1H),7.84(br.s,1H),7.43–7.60(m,2H),7.25–7.33(m,1H),7.12(d,J＝7.4Hz,1H),6.83–6.95(m,2H),6.61(t,J F-H＝75.7Hz,1H),4.91–5.08(m,1H),4.62–4.78(m,1H),4.10–4.26(m,1H),3.90–4.03(m,2H),3.88(d,J＝4.7Hz,2H),3.61–3.76(m,1H),3.26–3.46(m,1H),2.55–2.73(m,1H),2.29–2.44(m,1H),2.16(s,3H),1.21–1.36(m,1H),0.59–0.69(m,2H),0.31–0.42(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.42 (br.s, 1H), 7.84 (br.s, 1H), 7.43-7.60 (m, 2H), 7.25-7.33 (m, 1H), 7.12(d,J=7.4Hz,1H), 6.83–6.95(m,2H), 6.61(t,J FH = 75.7Hz,1H), 4.91–5.08(m,1H), 4.62–4.78(m,1H ), 4.10–4.26(m,1H), 3.90–4.03(m,2H), 3.88(d,J=4.7Hz,2H), 3.61–3.76(m,1H), 3.26–3.46(m,1H), 2.55–2.73(m,1H), 2.29–2.44(m,1H), 2.16(s,3H), 1.21–1.36(m,1H), 0.59–0.69(m,2H), 0.31–0.42(m,2H) ).
MS(ESI,pos.ion)m/z:514.15[M+H] +. MS(ESI,pos.ion)m/z:514.15[M+H] + .
实施例111：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((1-氧代异吲哚-5-基)甲基)吡咯烷-2-甲酰胺Example 111: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((1-oxoiso Indol-5-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000173
Figure PCTCN2021090489-appb-000173
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(100mg,0.27mmol)和5-(氨基甲基)异吲哚-1-酮(43mg,0.27mmol)溶于二氯甲烷(4mL)和N,N-二甲基甲酰胺(4mL)中，加入N-羟基-7-氮杂苯并三氮唑(73mg,0.54mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(156mg,0.81mmol)和N,N-二异丙基乙胺(141mg,1.09mmol)，室温反应15h，减压浓缩除去溶剂，加水(40mL)，用乙酸乙酯萃取(25mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体57mg，收率41％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100mg, 0.27mmol) And 5-(aminomethyl) isoindol-1-one (43mg, 0.27mmol) dissolved in dichloromethane (4mL) and N,N-dimethylformamide (4mL), add N-hydroxy-7 -Azabenzotriazole (73mg, 0.54mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (156mg, 0.81mmol) and N,N-di Isopropylethylamine (141mg, 1.09mmol), react at room temperature for 15h, concentrate under reduced pressure to remove the solvent, add water (40mL), extract with ethyl acetate (25mL×2), dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure The residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 57 mg of white solid with a yield of 41%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.01(brs,1H),7.63(br.s,1H),7.46(d,J＝7.1Hz,1H),7.34(s,1H),7.30(d,J＝7.3Hz,1H),7.12(d,J＝7.9Hz,1H),6.91(s,1H),6.86(d,J＝7.5Hz,1H),6.61(t,J F-H＝75.6Hz,1H),4.65–4.80(m,2H),4.16–4.33(m,3H),3.87–3.98(m,1H),3.87(d,J＝6.5Hz,2H),3.66(d,J＝10.5Hz,1H),3.28–3.43(m,1H),2.56–2.69(m,1H),2.34–2.48(m,1H),2.15(s,3H),1.21–1.36(m,1H),0.59–0.69(m,2H),0.31–0.42(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.01 (brs, 1H), 7.63 (br.s, 1H), 7.46 (d, J = 7.1 Hz, 1H), 7.34 (s, 1H), 7.30 (d,J=7.3Hz,1H), 7.12(d,J=7.9Hz,1H), 6.91(s,1H), 6.86(d,J=7.5Hz,1H), 6.61(t,J FH =75.6 Hz,1H), 4.65–4.80(m,2H), 4.16–4.33(m,3H), 3.87–3.98(m,1H), 3.87(d,J=6.5Hz,2H), 3.66(d,J= 10.5Hz, 1H), 3.28–3.43(m,1H), 2.56–2.69(m,1H), 2.34–2.48(m,1H), 2.15(s,3H), 1.21–1.36(m,1H), 0.59 --0.69(m,2H),0.31--0.42(m,2H).
MS(ESI,pos.ion)m/z:514.25[M+H] +. MS(ESI,pos.ion)m/z:514.25[M+H] + .
实施例112：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(3,5-二氯吡啶-4-基)吡咯烷-2-甲酰胺Example 112: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(3,5-dichloro (Pyridin-4-yl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000174
Figure PCTCN2021090489-appb-000174
第一步反应：将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(200mg,0.54mmol)溶于二氯甲烷(5mL)中，-20℃条件下加入三乙胺(0.3mL,2.0mmol)和三聚氟氰(0.14mL,1.7mmol)，-20℃反应1h，加冰水洗(20mL×3)，然后二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，减压浓缩。The first step reaction: the compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid ( 200mg, 0.54mmol) dissolved in dichloromethane (5mL), add triethylamine (0.3mL, 2.0mmol) and cyanuric fluoride (0.14mL, 1.7mmol) at -20℃, react at -20℃ for 1h, Wash with ice water (20 mL×3), then extract with dichloromethane (5 mL×3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure.
第二步反应：将3,5-二氯-4-氨基吡啶(108mg,0.66mmol)溶于干燥的N,N-二甲基甲酰胺(7mL)中，冰浴下加入60％氢化钠(34mg,0.85mmol)，室温反应1h，在冰浴下加入第一步反应的浓缩液，室温反应2h后停止。减压除去N,N-二甲基甲酰胺，剩余物加水(10mL)，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(洗脱剂：乙酸乙酯(v)＝100％)，得到白色固体183mg，收率65％。The second step of the reaction: 3,5-dichloro-4-aminopyridine (108mg, 0.66mmol) was dissolved in dry N,N-dimethylformamide (7mL), and 60% sodium hydride ( 34mg, 0.85mmol), react at room temperature for 1 hour, add the concentrated solution of the first step in an ice bath, and stop after reacting at room temperature for 2 hours. The N,N-dimethylformamide was removed under reduced pressure, the residue was added with water (10 mL), extracted with ethyl acetate (10 mL×3), the organic phase was dried with anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (washing Removal: ethyl acetate (v)=100%) to obtain 183 mg of white solid with a yield of 65%.
1H NMR(400MHz,CDCl 3)δ(ppm):9.48(br.s,1H),8.54(s,2H),7.15(d,J＝8.1Hz,1H),6.93(s,1H),6.90(d,J＝8.2Hz,1H),6.73(t,J F-H＝75.5Hz,1H),4.97(t,J＝8.1Hz,1H),4.01–4.06(m,1H),3.90(d,J＝6.9Hz,2H),3.50(t,J＝10.6Hz,1H),3.36–3.45(m,1H),2.81–2.89(m,1H),2.58–2.65(m,1H),2.24(s, 3H),1.27–1.36(m,1H),0.65–0.69(m,2H),0.36–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.48 (br.s, 1H), 8.54 (s, 2H), 7.15 (d, J = 8.1 Hz, 1H), 6.93 (s, 1H), 6.90 (d,J=8.2Hz,1H),6.73(t,J FH =75.5Hz,1H), 4.97(t,J=8.1Hz,1H),4.01-4.06(m,1H),3.90(d,J =6.9Hz,2H), 3.50(t,J=10.6Hz,1H), 3.36–3.45(m,1H), 2.81–2.89(m,1H), 2.58–2.65(m,1H), 2.24(s, 3H), 1.27--1.36 (m, 1H), 0.65 - 0.69 (m, 2H), 0.36 - 0.39 (m, 2H).
MS(ESI,pos.ion)m/z:514.20[M+H] +. MS(ESI,pos.ion)m/z:514.20[M+H] + .
实施例113：化合物(2R)-1-乙酰基-N-(3-(氨基甲基)苯基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰胺盐酸盐Example 113: Compound (2R)-1-acetyl-N-(3-(aminomethyl)phenyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) )Phenyl)pyrrolidine-2-carboxamide hydrochloride
Figure PCTCN2021090489-appb-000175
Figure PCTCN2021090489-appb-000175
步骤1：化合物3-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)苄基氨基甲酸叔丁酯的合成Step 1: Compound 3-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido ) Synthesis of tert-butyl benzyl carbamate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(82mg,0.22mmol)，化合物3-氨基苄基氨基甲酸叔丁酯(96mg,0.43mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(143mg,0.74mmol)和N-羟基-7-氮杂苯并三氮唑(72mg,0.53mmol)溶于二氯甲烷(6mL)中，室温下向此溶液中滴加N,N-二异丙基乙胺(0.4mL,2.0mmol)，室温搅拌21h，加水洗(50mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体112mg，收率88％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (82mg, 0.22mmol) , Compound tert-butyl 3-aminobenzyl carbamate (96mg, 0.43mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (143mg, 0.74mmol) and N -Hydroxy-7-azabenzotriazole (72mg, 0.53mmol) was dissolved in dichloromethane (6mL), and N,N-diisopropylethylamine (0.4mL, 2.0mmol), stirred at room temperature for 21h, washed with water (50mL), extracted with dichloromethane (5mL×3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: Dichloromethane/methanol (v/v)=20/1) to obtain 112 mg of white solid with a yield of 88%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.44-7.52(m,3H),7.33-7.39(m,1H),7.20-7.24(m,1H),7.10-7.14(m,1H),7.05-7.07(m,1H),7.03(t,J F-H＝74.9Hz,1H),6.88-6.93(m,2H),4.42-4.47(m,1H),4.05-4.12(m,3H),3.91(d,J＝6.9Hz,2H),3.44-3.52(m,2H),2.60-2.65(m,1H),2.02(s,3H),1.95-2.00(m,1H),1.40(s,9H),1.31-1.35(m,1H),0.55-0.59(m,2H),0.30-0.37(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.44-7.52 (m, 3H), 7.33-7.39 (m, 1H), 7.20-7.24 (m, 1H), 7.10-7.14 (m, 1H) ),7.05-7.07(m,1H),7.03(t,J FH =74.9Hz,1H),6.88-6.93(m,2H),4.42-4.47(m,1H),4.05-4.12(m,3H) ,3.91(d,J=6.9Hz,2H),3.44-3.52(m,2H),2.60-2.65(m,1H),2.02(s,3H),1.95-2.00(m,1H),1.40(s , 9H), 1.31-1.35 (m, 1H), 0.55-0.59 (m, 2H), 0.30-0.37 (m, 2H).
MS(ESI,pos.ion)m/z:596.25[M+Na] +. MS(ESI,pos.ion)m/z:596.25[M+Na] + .
步骤2：化合物(2R)-1-乙酰基-N-(3-(氨基甲基)苯基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰胺盐酸盐的合成Step 2: Compound (2R)-1-acetyl-N-(3-(aminomethyl)phenyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)pyrrolidine-2-carboxamide hydrochloride
将化合物3-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酰氨基)苄基氨基甲酸叔丁酯(112mg,0.2mmol)溶解于二氯甲烷(2mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(3mL)，室温搅拌30min，除去溶剂，得到白色固体53mg，收率96％。The compound 3-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamido)benzyl Tert-Butyl carbamate (112mg, 0.2mmol) was dissolved in dichloromethane (2mL) solution, 4mol/L HCl ethyl acetate solution (3mL) was added, stirred at room temperature for 30min, and the solvent was removed to obtain a white solid 53mg. The rate is 96%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):10.36(s,1H),7.77-7.79(m,1H),7.59-7.64(m,1H),7.33(t,J＝8.0Hz,1H),7.19-7.23(m,1H),7.09-7.14(m,2H),7.03(t,J F-H＝74.9Hz,1H),6.87-6.91(m,1H),4.49-4.53(m,1H),4.08-4.11(m,1H),3.2(s,2H),3.91(d,J＝6.9Hz,2H),3.45-3.54(m,2H),2.60-2.70(m,1H),2.02(s,3H),1.87-1.98(m,1H),1.23-1.27(m,1H),0.51-0.61(m,2H),0.29-0.36(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 10.36 (s, 1H), 7.77-7.79 (m, 1H), 7.59-7.64 (m, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.19-7.23 (m, 1H), 7.09-7.14 (m, 2H), 7.03 (t, J FH = 74.9 Hz, 1H), 6.87-6.91 (m, 1H), 4.49-4.53 (m, 1H) ),4.08-4.11(m,1H),3.2(s,2H),3.91(d,J=6.9Hz,2H),3.45-3.54(m,2H),2.60-2.70(m,1H),2.02( s, 3H), 1.87-1.98 (m, 1H), 1.23-1.27 (m, 1H), 0.51-0.61 (m, 2H), 0.29-0.36 (m, 2H).
MS(ESI,pos.ion)m/z:474.15[M+H-HCl] +. MS(ESI,pos.ion)m/z:474.15[M+H-HCl] + .
实施例114：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(3-(羟甲基)苯基)吡咯烷-2-甲酰胺Example 114: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(3-(hydroxymethyl )Phenyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000176
Figure PCTCN2021090489-appb-000176
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(100mg,0.27mmol)，(3-氨基苯基)甲醇(52mg,0.42mmol)溶于干燥的N,N-二甲基甲酰胺(5mL)中，加入N-羟基-7-氮杂苯并三氮唑(73mg,0.54mmol)，在冰浴中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(259mg,1.35mmol)和N,N-二异丙基乙胺(174mg,1.35mmol)，室温反应12h，加水(20mL)搅拌5min，乙酸乙酯萃取(10mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝54/1)，得到浅红色固体85mg，收率62％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100mg, 0.27mmol) , (3-Aminophenyl) methanol (52mg, 0.42mmol) was dissolved in dry N,N-dimethylformamide (5mL), and N-hydroxy-7-azabenzotriazole (73mg, 0.54mmol), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (259mg, 1.35mmol) and N,N-diisopropylethylamine ( 174mg, 1.35mmol), react at room temperature for 12h, add water (20mL) and stir for 5min, extract with ethyl acetate (10mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and subject the concentrated solution to silica gel column chromatography (washing Removal agent: dichloromethane/methanol (v/v)=54/1) to obtain 85 mg of light red solid with a yield of 62%.
1H NMR(400MHz,CDCl 3)δ(ppm):9.64(s,1H),7.39(d,J＝8.1Hz,1H),7.36(s,1H),7.13(d,J＝8.1Hz,1H),7.11(d,J＝8.2Hz,1H),6.92(d,J＝9.3Hz,1H),6.91(s,1H),6.85(d,J＝8.1Hz,1H),6.61(t,J F-H＝75.6Hz,1H),4.75(t,J＝8.1Hz,1H),4.50–4.57(m,2H),3.94–3.98(m,1H),3.87(d,J＝6.9Hz,2H),3.61(t,J＝10.7Hz,1H),3.31–3.40(m,1H),2.87(br.s,1H),2.46–2.63(m,2H),2.17(s,3H),1.25–1.36(m,1H),0.62–0.67(m,2H),0.33–0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.64 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 7.13 (d, J = 8.1 Hz, 1H ), 7.11 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 9.3 Hz, 1H), 6.91 (s, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.61 (t, J FH = 75.6 Hz, 1H), 4.75 (t, J = 8.1 Hz, 1H), 4.50–4.57 (m, 2H), 3.94–3.98 (m, 1H), 3.87 (d, J = 6.9 Hz, 2H), 3.61(t,J=10.7Hz,1H), 3.31–3.40(m,1H), 2.87(br.s,1H), 2.46–2.63(m,2H), 2.17(s,3H), 1.25–1.36( m, 1H), 0.62--0.67 (m, 2H), 0.33--0.37 (m, 2H).
MS(ESI,pos.ion)m/z:475.15[M+H] +. MS(ESI,pos.ion)m/z:475.15[M+H] + .
实施例115：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(1-羟基-1,3-二氢苯并[c][1,2]噁硼烷-5-基)吡咯烷-2-甲酰胺Example 115: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-hydroxy-1, 3-Dihydrobenzo[c][1,2]oxborin-5-yl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000177
Figure PCTCN2021090489-appb-000177
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(100mg,0.27mmol)，2-羟甲基-5-氨基苯硼酸半酯(48mg,0.32mmol)溶于干燥的N,N-二甲基甲酰胺(5mL)中，加入N-羟基-7-氮杂苯并三氮唑(73mg,0.54mmol)，在冰浴中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(259mg,1.35mmol)和N,N-二异丙基乙胺(174mg,1.35mmol)，室温反应5h，加水(20mL)搅拌5min，乙酸乙酯萃取(10mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝54/1)，得到白色固体35mg，收率25％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100mg, 0.27mmol) , 2-Hydroxymethyl-5-aminophenylboronic acid half ester (48mg, 0.32mmol) was dissolved in dry N,N-dimethylformamide (5mL), and N-hydroxy-7-azabenzotriazole was added Nitrozazole (73mg, 0.54mmol), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (259mg, 1.35mmol) and N,N-diiso in an ice bath Propylethylamine (174mg, 1.35mmol), react at room temperature for 5h, add water (20mL) and stir for 5min, extract with ethyl acetate (10mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the concentrated solution to silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v)=54/1) to obtain 35 mg of white solid with a yield of 25%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.78(s,1H),7.62(d,J＝7.8Hz,1H),7.47(d,J＝7.7Hz,1H),7.06–7.12(m,2H),6.94(d,J＝10.2Hz,1H),6.74(t,J F-H＝75.0Hz,1H),5.06(s,2H),4.56–4.62(m,1H),4.10–4.15(m,1H),3.93(d,J＝6.9Hz,2H),3.68(t,J＝10.5Hz,1H),3.49–3.59(m,1H),2.68–2.75(m,1H),2.05–2.20(m,1H),2.16(s,3H),1.25–1.37(m,1H),0.61–0.66(m,2H),0.35–0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.78 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.06–7.12 (m ,2H),6.94(d,J=10.2Hz,1H),6.74(t,J FH =75.0Hz,1H),5.06(s,2H),4.56–4.62(m,1H),4.10–4.15(m ,1H),3.93(d,J=6.9Hz,2H), 3.68(t,J=10.5Hz,1H), 3.49–3.59(m,1H), 2.68–2.75(m,1H),2.05–2.20( m, 1H), 2.16 (s, 3H), 1.25 - 1.37 (m, 1H), 0.61 - 0.66 (m, 2H), 0.35 - 0.40 (m, 2H).
MS(ESI,pos.ion)m/z:501.10[M+H] +. MS(ESI,pos.ion)m/z:501.10[M+H] + .
实施例116：化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)-N-(2-乙氧基苯基)吡咯烷-2-甲酰胺Example 116: The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-N-(2-ethoxyphenyl)pyrrolidine -2-carboxamide
Figure PCTCN2021090489-appb-000178
Figure PCTCN2021090489-appb-000178
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-羧酸(60mg,0.17mmol)，2-乙氧基苯胺(69mg,0.50mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(160mg,0.83mmol)和N-羟基-7-氮杂苯并三氮唑(45mg,0.33mmol)溶于二氯甲烷(10mL)中，冷却至0℃后，加入N,N-二异丙基乙胺(155mg,1.20mmol)，室温反应3h，加水洗(10mL×3)搅拌，分离有机相，有机相用无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)，得到浅褐色固体71mg，收率88％。The compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid (60mg, 0.17mmol), 2-ethyl Oxyaniline (69mg, 0.50mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (160mg, 0.83mmol) and N-hydroxy-7-azabenzo Triazole (45mg, 0.33mmol) was dissolved in dichloromethane (10mL), after cooling to 0°C, N,N-diisopropylethylamine (155mg, 1.20mmol) was added, reacted at room temperature for 3h, washed with water ( 10mL×3) Stir, separate the organic phase, dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=50/1), 71 mg of light brown solid was obtained with a yield of 88%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.98(s,1H),8.38(d,J＝7.8Hz,1H),7.13(d,J＝8.2Hz,1H),7.03(d,J＝7.7Hz,1H),6.94–6.99(m,2H),6.85–6.91(m,2H),6.55(t,J F-H＝75.6Hz,1H),4.79(t,J＝8.1Hz,1H),4.52–4.64(m,1H),4.12(q,J＝7.0Hz,2H),3.99–4.03(m,1H),3.56(t,J＝10.6Hz,1H),3.34–3.43(m,1H),2.64(t,J＝8.7Hz,2H),2.20(s,3H),1.51(t,J＝6.9Hz,3H),1.37(d,J＝6.0Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.98 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.03 (d, J =7.7Hz,1H), 6.94–6.99(m,2H), 6.85–6.91(m,2H), 6.55(t,J FH =75.6Hz,1H), 4.79(t,J=8.1Hz,1H), 4.52–4.64(m,1H), 4.12(q,J=7.0Hz,2H), 3.99–4.03(m,1H), 3.56(t,J=10.6Hz,1H), 3.34–3.43(m,1H) ,2.64(t,J=8.7Hz,2H),2.20(s,3H),1.51(t,J=6.9Hz,3H),1.37(d,J=6.0Hz,6H).
MS(ESI,pos.ion)m/z:477.15[M+H] +. MS(ESI,pos.ion)m/z:477.15[M+H] + .
实施例117：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(1-氧代异吲哚-5-基)吡咯烷-2-甲酰胺Example 117: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-oxoisoindyl) Dol-5-yl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000179
Figure PCTCN2021090489-appb-000179
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(150mg,0.41mmol)，5-氨基异吲哚-1-酮(72mg,0.49mmol)和N-羟基-7-氮杂苯并三氮唑(110mg,0.81mmol)溶于二氯甲烷(12mL)和N,N-二甲基甲酰胺(4mL)中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(233mg,1.22mmol)和N,N-二异丙基乙胺(210mg,1.62mmol)，室温反应5h，减压浓缩除去溶剂，加水(20mL)，用乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝25/1)，得到浅褐色固体126mg，收率62％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150mg, 0.41mmol) , 5-Aminoisoindole-1-one (72mg, 0.49mmol) and N-hydroxy-7-azabenzotriazole (110mg, 0.81mmol) were dissolved in dichloromethane (12mL) and N,N- To dimethylformamide (4mL), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (233mg, 1.22mmol) and N,N-diisopropylethyl Amine (210mg, 1.62mmol), react at room temperature for 5h, concentrate under reduced pressure to remove the solvent, add water (20mL), extract with ethyl acetate (10mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and carry out the residue Separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=25/1) to obtain 126 mg of light brown solid with a yield of 62%.
1H NMR(400MHz,CDCl 3)δ(ppm):10.22(s,1H),8.61(s,1H),8.10(s,1H),7.39–7.59(m,1H),7.04–7.17(m,1H),6.85–6.97(m,3H),6.61(t,J＝75.3Hz,1H),4.68–4.87(m,1H),4.15–4.36(m,2H),3.95–4.09(m,1H),3.78–3.93(m,2H),3.62–3.77(m,1H),3.32–3.56(m,1H),2.56–2.78(m,1H),2.29–2.46(m,1H),2.24(s,3H),1.26–1.37(m,1H),0.57–0.71(m,2H),0.27–0.41(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 10.22 (s, 1H), 8.61 (s, 1H), 8.10 (s, 1H), 7.39-7.59 (m, 1H), 7.04-7.17 (m, 1H), 6.85–6.97(m,3H), 6.61(t,J=75.3Hz,1H), 4.68–4.87(m,1H), 4.15–4.36(m,2H), 3.95–4.09(m,1H) ,3.78–3.93(m,2H),3.62–3.77(m,1H), 3.32–3.56(m,1H), 2.56–2.78(m,1H), 2.29–2.46(m,1H), 2.24(s, 3H), 1.26-1.37(m,1H), 0.57-0.71(m,2H), 0.27-0.41(m,2H).
MS(ESI,pos.ion)m/z:500.10[M+H] +. MS(ESI,pos.ion)m/z:500.10[M+H] + .
实施例118：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(3-氧代异吲哚-5-基)吡咯烷-2-甲酰胺Example 118: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(3-oxoisoindyl Dol-5-yl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000180
Figure PCTCN2021090489-appb-000180
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(203mg,0.55mmol)，6-氨基异吲哚-1-酮(98mg,0.66mmol)和N-羟基-7-氮杂苯并三氮唑(149mg,1.09mmol)溶于无水N,N-二甲基甲酰胺(8mL)中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(310mg,1.62mmol)和N,N-二异丙基乙胺(283mg,2.19mmol)，室温反应10h，减压浓缩除去溶剂，加水(30mL)，用乙酸乙酯萃取(20mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体203mg，收率74％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (203mg, 0.55mmol) , 6-Aminoisoindole-1-one (98mg, 0.66mmol) and N-hydroxy-7-azabenzotriazole (149mg, 1.09mmol) are dissolved in anhydrous N,N-dimethylformamide (8mL), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (310mg, 1.62mmol) and N,N-diisopropylethylamine (283mg, 2.19 mmol), react at room temperature for 10h, concentrate under reduced pressure to remove the solvent, add water (30mL), extract with ethyl acetate (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the residue by silica gel column chromatography (Eluent: dichloromethane/methanol (v/v)=20/1) to obtain 203 mg of white solid with a yield of 74%.
1H NMR(400MHz,CDCl 3)δ(ppm):10.18(br.s,1H),8.10(s,1H),7.90(s,1H),7.05–7.19(m,2H),6.80–6.93(m,2H),6.59(t,J F-H＝75.8Hz,1H),4.87–5.05(m,1H),4.11–4.35(m,2H),3.90–4.03(m,1H),3.77–3.90(m,2H),3.56–3.70(m,1H),3.31–3.50(m,1H),2.70–2.87(m,1H),2.26–2.43(m,1H),2.11–2.20(s,3H),1.23–1.32(m,1H),0.55–0.68(m,2H),0.26–0.33(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 10.18 (br.s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.05-7.19 (m, 2H), 6.80-6.93 ( m,2H),6.59(t,J FH =75.8Hz,1H),4.87–5.05(m,1H),4.11–4.35(m,2H),3.90–4.03(m,1H),3.77–3.90(m ,2H),3.56–3.70(m,1H),3.31–3.50(m,1H),2.70–2.87(m,1H),2.26–2.43(m,1H),2.11–2.20(s,3H),1.23 --1.32 (m, 1H), 0.55 - 0.68 (m, 2H), 0.26 - 0.33 (m, 2H).
MS(ESI,pos.ion)m/z:500.45[M+H] +. MS(ESI,pos.ion)m/z:500.45[M+H] + .
实施例119：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(1-羟基-1,3-二氢苯并[c][1,2]氧杂环戊硼烷-6-基)吡咯烷-2-甲酰胺Example 119: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-hydroxy-1, 3-Dihydrobenzo[c][1,2]oxaborolan-6-yl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000181
Figure PCTCN2021090489-appb-000181
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(200mg,0.54mmol)，2-羟甲基-6-氨基苯硼酸半酯(96mg,0.65mmol)和N-羟基-7-氮杂苯并三氮唑(147mg,1.08mmol)溶于无水N,N-二甲基甲酰胺(5mL)中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(312mg,1.63mmol)和N,N-二异丙基乙胺(279mg,2.16mmol)，室温反应10h，减压浓缩除去溶剂，加水(30mL)，用乙酸乙酯萃取(20mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝25/1)，得到白色固体166mg，收率61％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (200mg, 0.54mmol) , 2-hydroxymethyl-6-aminophenylboronic acid half ester (96mg, 0.65mmol) and N-hydroxy-7-azabenzotriazole (147mg, 1.08mmol) are dissolved in anhydrous N,N-dimethyl Methyl formamide (5mL), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (312mg, 1.63mmol) and N,N-diisopropylethylamine ( 279mg, 2.16mmol), react at room temperature for 10h, concentrate under reduced pressure to remove the solvent, add water (30mL), extract with ethyl acetate (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the residue to a silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v)=25/1) to obtain 166 mg of white solid with a yield of 61%.
1H NMR(400MHz,CDCl 3)δ(ppm):9.45(br.s,1H),7.70(s,2H),7.03–7.16(m,2H),6.94(s,1H),6.75–6.87(m,1H),6.61(t,J F-H＝75.4Hz,1H),4.77–5.00(m,1H),4.88(s,2H),3.85–4.00(m,1H),3.83–3.90(m,2H),3.61–3.76(m,1H),3.30–3.50(m,1H),2.56–2.74(m,1H),2.38–2.52(m,1H),2.13(s,3H),1.23–1.32(m,1H),0.55–0.68(m,2H),0.27–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.45 (br.s, 1H), 7.70 (s, 2H), 7.03-7.16 (m, 2H), 6.94 (s, 1H), 6.75-6.87 ( m,1H),6.61(t,J FH =75.4Hz,1H),4.77–5.00(m,1H), 4.88(s,2H), 3.85–4.00(m,1H), 3.83–3.90(m,2H ), 3.61–3.76(m,1H), 3.30–3.50(m,1H), 2.56–2.74(m,1H), 2.38–2.52(m,1H), 2.13(s,3H), 1.23–1.32(m ,1H),0.55-0.68(m,2H),0.27-0.39(m,2H).
MS(ESI,pos.ion)m/z:501.40[M+H] +. MS(ESI,pos.ion)m/z:501.40[M+H] + .
实施例120：化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)氧基)甲基)烟酸甲酯Example 120: Compound 6-(((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- (Carbonyl)oxy)methyl)methyl nicotinate
Figure PCTCN2021090489-appb-000182
Figure PCTCN2021090489-appb-000182
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(60mg,0.16mmol)，6-羟甲基烟酸甲酯(32mg,0.19mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(155mg,0.81mmol)和N-羟基-7-氮杂苯并三氮唑(44mg,0.32mmol)溶于二氯甲烷(20mL)中，冷却至0℃，加入N,N-二异丙基乙胺(126mg,0.97mmol)，室温反应20h，加水洗有机相(10mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到浅黄色粘稠固体54mg，收率64％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (60mg, 0.16mmol) ,6-Hydroxymethylnicotinic acid methyl ester (32mg, 0.19mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (155mg, 0.81mmol) and N-hydroxyl -7-Azabenzotriazole (44mg, 0.32mmol) was dissolved in dichloromethane (20mL), cooled to 0℃, and N,N-diisopropylethylamine (126mg, 0.97mmol) was added at room temperature React for 20 hours, add water to wash the organic phase (10mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30 /1) to obtain 54 mg of a light yellow viscous solid with a yield of 64%.
1H NMR(400MHz,CDCl 3)δ(ppm):9.16(s,1H),8.35(dd,J＝8.2,2.0Hz,1H),7.61(d,J＝8.2Hz,1H),7.15(d,J＝8.7Hz,1H),6.85(s,1H),6.82–6.85(m,1H),6.63(t,J F-H＝75.5Hz,1H),5.30–5.52(m,2H),4.61–4.66(m,1H),3.97–4.03(m,1H),3.97(s,3H),3.88(d,J＝6.9Hz,2H),3.63–3.68(m,1H),3.43–3.52(m,1H),2.72–2.79(m,1H),2.09–2.22(m,1H),2.15(s,3H),1.27–1.36(m,1H),0.65–0.70(m,2H),0.36–0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.16 (s, 1H), 8.35 (dd, J = 8.2, 2.0 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.15 (d ,J=8.7Hz,1H),6.85(s,1H),6.82–6.85(m,1H),6.63(t,J FH =75.5Hz,1H),5.30–5.52(m,2H),4.61–4.66 (m,1H),3.97–4.03(m,1H),3.97(s,3H), 3.88(d,J=6.9Hz,2H),3.63–3.68(m,1H),3.43–3.52(m,1H ), 2.72–2.79(m,1H), 2.09–2.22(m,1H), 2.15(s,3H), 1.27–1.36(m,1H), 0.65–0.70(m,2H), 0.36–0.40(m ,2H).
MS(ESI,pos.ion)m/z:519.25[M+H] +. MS(ESI,pos.ion)m/z:519.25[M+H] + .
实施例121：化合物(2R)-2-乙氧基苄基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 121: Compound (2R)-2-ethoxybenzyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 2-carboxylate
Figure PCTCN2021090489-appb-000183
Figure PCTCN2021090489-appb-000183
将化合物(2R)-1-乙酰基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(50mg,0.14mmol)，2-乙氧基苄醇(61mg,0.40mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(130mg,0.68mmol)和N-羟基-7-氮杂苯并三氮唑(36mg,0.26mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入N,N-二异丙基乙胺(105mg,0.81mmol)，室温反应44h，加水洗有机相(20mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到白色粘稠固体33mg，收率48％。The compound (2R)-1-acetyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (50mg, 0.14mmol), 2-ethoxybenzyl alcohol (61mg, 0.40mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (130mg, 0.68mmol) and N-hydroxy-7- Azabenzotriazole (36mg, 0.26mmol) was dissolved in dichloromethane (10mL), cooled to 0°C, N,N-diisopropylethylamine (105mg, 0.81mmol) was added, and reacted at room temperature for 44h, The organic phase was washed with water (20mL×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/ 1) To obtain 33 mg of a white viscous solid with a yield of 48%.
1H NMR(600MHz,CDCl 3)δ(ppm):7.37(d,J＝7.4Hz,1H),7.28–7.32(m,1H),7.10–7.14(m,1H),6.94–6.97(m,1H),6.87–6.91(m,1H),6.83(s,1H),6.67–6.81(m,1H),6.62(t,J F-H＝75.5Hz,1H),5.23–5.37(m,2H),4.51–4.60(m,1H),4.06(q,J＝6.9Hz,2H),3.94–3.97(m,1H),3.87(d,J＝6.9Hz,2H),3.62–3.65(m,1H),3.38–3.45(m,1H),2.84–2.89(m,0.3H),2.69–2.73(m,0.7H),2.14(s,2.3H),1.98(s,0.7H),2.02–2.11(m,1H),1.41(t,J＝6.9Hz,3H),1.29–1.36(m,1H),0.66–0.69(m,2H),0.35–0.39(m,2H). 1 H NMR(600MHz, CDCl 3 )δ(ppm): 7.37(d,J=7.4Hz,1H), 7.28–7.32(m,1H), 7.10–7.14(m,1H), 6.94–6.97(m, 1H), 6.87–6.91(m, 1H), 6.83(s, 1H), 6.67–6.81(m, 1H), 6.62(t, J FH = 75.5Hz, 1H), 5.23–5.37(m, 2H), 4.51–4.60(m,1H),4.06(q,J=6.9Hz,2H), 3.94–3.97(m,1H), 3.87(d,J=6.9Hz,2H), 3.62–3.65(m,1H) , 3.38–3.45(m,1H), 2.84–2.89(m,0.3H), 2.69–2.73(m,0.7H), 2.14(s,2.3H), 1.98(s,0.7H), 2.02–2.11( m,1H),1.41(t,J=6.9Hz,3H), 1.29–1.36(m,1H), 0.66–0.69(m,2H), 0.35–0.39(m,2H).
MS(ESI,pos.ion)m/z:504.20[M+H] +. MS(ESI,pos.ion)m/z:504.20[M+H] + .
实施例122：化合物(2R)-(2-乙氧基-3-氟苄基)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 122: Compound (2R)-(2-ethoxy-3-fluorobenzyl)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) )Phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000184
Figure PCTCN2021090489-appb-000184
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(50mg,0.14mmol)，2-乙氧基-3-氟苄醇(46mg,0.27mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(130mg,0.68mmol)和N-羟基-7-氮杂苯并三氮唑(36mg,0.26mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入N,N-二异丙基乙胺(105mg,0.81mmol)，室温反应11h，加水洗有机相(20mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到白色粘稠固体17mg，收率24％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (50mg, 0.14mmol) , 2-ethoxy-3-fluorobenzyl alcohol (46mg, 0.27mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (130mg, 0.68mmol) and N -Hydroxy-7-azabenzotriazole (36mg, 0.26mmol) was dissolved in dichloromethane (10mL), cooled to 0℃, and N,N-diisopropylethylamine (105mg, 0.81mmol) was added , React at room temperature for 11h, add water to wash the organic phase (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/ v)=1/1), 17 mg of white viscous solid was obtained, with a yield of 24%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.01–7.18(m,4H),6.83(s,1H),6.82(d,J＝7.1Hz,1H),6.62(t,J F-H＝75.5Hz,1H),5.25–5.35(m,2H),4.52–4.58(m,1H),4.19(q,J＝7.0Hz,2H),3.94–3.98(m,1H),3.87(d,J＝7.0Hz,2H),3.63(t,J＝10.4Hz,1H),3.37–3.47(m,1H),2.65–2.72(m,1H),2.14(s,2.4H),1.97(s,0.6H),2.02–2.11(m,1H),1.40(t,J＝7.0Hz,3H),1.27–1.36(m,1H),0.66–0.70(m,2H),0.36–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.01–7.18 (m, 4H), 6.83 (s, 1H), 6.82 (d, J = 7.1 Hz, 1H), 6.62 (t, J FH = 75.5 Hz,1H), 5.25–5.35(m,2H), 4.52–4.58(m,1H), 4.19(q,J=7.0Hz,2H), 3.94–3.98(m,1H), 3.87(d,J= 7.0Hz, 2H), 3.63(t, J=10.4Hz, 1H), 3.37–3.47(m, 1H), 2.65–2.72(m, 1H), 2.14(s, 2.4H), 1.97(s, 0.6H) ), 2.02–2.11(m,1H), 1.40(t,J=7.0Hz,3H), 1.27–1.36(m,1H), 0.66–0.70(m,2H), 0.36–0.39(m,2H).
MS(ESI,pos.ion)m/z:522.15[M+H] +. MS(ESI,pos.ion)m/z:522.15[M+H] + .
实施例123：化合物(2R)-(6-(异丙基(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 123: Compound (2R)-(6-(isopropyl(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy) -4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000185
Figure PCTCN2021090489-appb-000185
步骤1：化合物6-(异丙基(甲基)氨基甲酰基)吡啶甲酸甲酯的合成Step 1: Synthesis of compound methyl 6-(isopropyl(methyl)carbamoyl)picolinate
将化合物2,6-吡啶二羧酸单甲酯(500mg,2.76mmol)，N-异丙基甲胺(264mg,2.64mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.30g,6.80mmol)和N-羟基-7-氮杂苯并三氮唑(751mg,5.52mmol)溶于二氯甲烷(20mL)中，冷却至0℃，加入N,N-二异丙基乙胺(1.10g,8.51mmol)，室温反应1h，加水洗(20mL×2)有机相，分离有机相，用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到白色固体622mg，收率95％。The compound 2,6-pyridinedicarboxylic acid monomethyl ester (500mg, 2.76mmol), N-isopropylmethylamine (264mg, 2.64mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Diimide hydrochloride (1.30g, 6.80mmol) and N-hydroxy-7-azabenzotriazole (751mg, 5.52mmol) were dissolved in dichloromethane (20mL), cooled to 0℃, and added N,N-Diisopropylethylamine (1.10g, 8.51mmol), react at room temperature for 1h, wash the organic phase with water (20mL×2), separate the organic phase, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and concentrate Separation by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 622 mg of white solid with a yield of 95%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.17(d,J＝7.6Hz,1H),7.96(t,J＝7.8Hz,1H),7.78(t,J＝7.8Hz,1H),4.93–5.00(m,0.4H),4.01–4.09(m,0.6H),4.01(s,3H),3.00(s,2H),2.92(s,1H),1.24–1.77(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.17 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 4.93-5.00 (m, 0.4H), 4.01-4.09 (m, 0.6H), 4.01 (s, 3H), 3.00 (s, 2H), 2.92 (s, 1H), 1.24-1.77 (m, 6H).
MS(ESI,pos.ion)m/z:237.25[M+H] +. MS(ESI,pos.ion)m/z:237.25[M+H] + .
步骤2：化合物6-(羟甲基)-N-异丙基-N-甲基吡啶酰胺的合成Step 2: Synthesis of compound 6-(hydroxymethyl)-N-isopropyl-N-picolineamide
将化合物6-(异丙基(甲基)氨基甲酰基)吡啶甲酸甲酯(680mg,2.39mmol)溶于干燥四氢呋喃(5mL)中，冰浴中加入硼氢化锂(96mg,4.51mmol)，室温反应30min后停止，加入饱和氯化钠水溶液(10mL)，乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝100/1)，得到白色固体423mg，收率78％。Compound 6-(isopropyl(methyl)carbamoyl) methyl picolinate (680mg, 2.39mmol) was dissolved in dry tetrahydrofuran (5mL), lithium borohydride (96mg, 4.51mmol) was added to the ice bath, room temperature The reaction was stopped after 30 min, saturated sodium chloride aqueous solution (10 mL) was added, and ethyl acetate extraction (20 mL×3) was performed. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (eluent : Dichloromethane/methanol (v/v)=100/1) to obtain 423 mg of white solid with a yield of 78%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.17(t,J＝7.7Hz,1H),7.447.35–7.24(m,1H),4.94–5.01(m,0.4H),4.78(s,3H),2.99(s,1.8H),2.83(s,1.2H),1.20–1.26(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.17 (t, J = 7.7 Hz, 1H), 7.447.35-7.24 (m, 1H), 4.94-5.01 (m, 0.4H), 4.78 (s ,3H), 2.99(s,1.8H), 2.83(s,1.2H), 1.20-1.26(m,6H).
MS(ESI,pos.ion)m/z:209.20[M+H] +. MS(ESI,pos.ion)m/z:209.20[M+H] + .
步骤3：化合物(2R)-(6-(异丙基(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯的合成Step 3: Compound (2R)-(6-(isopropyl(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(80mg,0.22mmol)，6-(羟甲基)-N-异丙基-N-甲基吡啶酰胺(56mg,0.27mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(207mg,1.08mmol)和N-羟基-7-氮杂苯并三氮唑(58mg,0.43mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入N,N-二异丙基乙胺(141mg,1.09mmol)，室温反应6h，加水(15mL)，有机相水洗(10mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝54/1)，得到浅褐色粘稠固体56mg，收率46％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (80mg, 0.22mmol) , 6-(Hydroxymethyl)-N-isopropyl-N-picolineamide (56mg, 0.27mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (207mg, 1.08mmol) and N-hydroxy-7-azabenzotriazole (58mg, 0.43mmol) were dissolved in dichloromethane (10mL), cooled to 0℃, added N,N-diisopropyl Ethylethylamine (141mg, 1.09mmol), react at room temperature for 6h, add water (15mL), wash the organic phase with water (10mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the concentrated solution by silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v)=54/1) to obtain 56 mg of light brown viscous solid with a yield of 46%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.80(t,J＝7.7Hz,1H),7.41–7.52(m,2H),7.12(d,J＝8.3Hz,1H),6.82(s,1H),6.77–6.81(m,1H),6.60(t,J F-H＝75.5Hz,1H),5.23–5.44(m,2H),4.89–4.96(m,0.4H),4.57–4.61(m,1H),3.92–4.00(m,0.6H),3.92–3.97(m,1H),3.86(d,J＝6.9Hz,2H),3.63(t,J＝10.4Hz,1H),3.38–3.50(m,1H),2.94(s,1.8H),2.80(s,1.2H),2.68–2.74(m,1H),2.04–2.16(m,1H),2.12(s,3H),1.25–1.32(m,1H),1.15–1.21(m,6H),0.63–0.67(m,2H),0.34–0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.80 (t, J = 7.7 Hz, 1H), 7.41-7.52 (m, 2H), 7.12 (d, J = 8.3 Hz, 1H), 6.82 (s ,1H),6.77–6.81(m,1H),6.60(t,J FH =75.5Hz,1H),5.23–5.44(m,2H),4.89–4.96(m,0.4H),4.57–4.61(m ,1H),3.92–4.00(m,0.6H),3.92–3.97(m,1H), 3.86(d,J＝6.9Hz,2H),3.63(t,J＝10.4Hz,1H),3.38–3.50 (m,1H), 2.94(s,1.8H), 2.80(s,1.2H), 2.68–2.74(m,1H), 2.04–2.16(m,1H), 2.12(s,3H), 1.25–1.32 (m, 1H), 1.15-1.21 (m, 6H), 0.63-0.67 (m, 2H), 0.34--0.37 (m, 2H).
MS(ESI,pos.ion)m/z:560.20[M+H] +. MS(ESI,pos.ion)m/z:560.20[M+H] + .
实施例124：化合物(2R)-(6-((2-(二甲氨基)乙基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 124: Compound (2R)-(6-((2-(dimethylamino)ethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3- (Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000186
Figure PCTCN2021090489-appb-000186
步骤1：化合物6-((2-(二甲氨基)乙基)(甲基)氨基甲酰基)吡啶甲酸甲酯的合成Step 1: Synthesis of compound methyl 6-((2-(dimethylamino)ethyl)(methyl)carbamoyl)picolinate
将化合物2,6-吡啶二羧酸单甲酯(500mg,2.76mmol)，N 1,N 1,N 2-三甲基乙二胺(368mg,3.60mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.30g,6.80mmol)和N-羟基-7-氮杂苯并三氮唑(753mg,5.53mmol)溶于二氯甲烷(20mL)中，冷却至0℃，加入N,N-二异丙基乙胺(1.10g,8.51mmol)，室温反应8.5h，加水(20mL×2)洗有机相，分离有机相，用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到浅褐色液体667mg，收率91％。 The compound 2,6-pyridinedicarboxylic acid monomethyl ester (500mg, 2.76mmol), N 1 , N 1 , N 2 -trimethylethylenediamine (368mg, 3.60mmol), 1-ethyl-(3- Dimethylaminopropyl) carbodiimide hydrochloride (1.30g, 6.80mmol) and N-hydroxy-7-azabenzotriazole (753mg, 5.53mmol) dissolved in dichloromethane (20mL) After cooling to 0℃, add N,N-diisopropylethylamine (1.10g, 8.51mmol), react at room temperature for 8.5h, add water (20mL×2) to wash the organic phase, separate the organic phase, and use anhydrous sodium sulfate After drying and concentration under reduced pressure, the concentrated solution was separated by silica gel column (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 667 mg of light brown liquid with a yield of 91%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.17(d,J＝7.7Hz,1H),7.84–7.89(m,1H),4.01(s,3H),2.33(s,2H),2.24(s,1H),2.10(s,3H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 8.17(d,J=7.7Hz,1H),7.84-7.89(m,1H),4.01(s,3H),2.33(s,2H),2.24 (s,1H),2.10(s,3H).
MS(ESI,pos.ion)m/z:266.10[M+H] +. MS(ESI,pos.ion)m/z:266.10[M+H] + .
步骤2：化合物N-(2-(二甲氨基)乙基)-6-(羟甲基)-N-甲基吡啶酰胺的合成Step 2: Synthesis of compound N-(2-(dimethylamino)ethyl)-6-(hydroxymethyl)-N-picolineamide
将化合物6-((2-(二甲氨基)乙基)(甲基)氨基甲酰基)吡啶甲酸甲酯(360mg,1.36mmol)溶于甲醇(5 mL)中，冰浴下加入硼氢化钠(410mg，10.8mmol)，室温反应3h后停止，减压浓缩，浓缩液进行硅胶柱分离(洗脱剂：二氯甲烷/甲醇(v/v)＝10/1)，得到无色液体214mg，产率66％。The compound 6-((2-(dimethylamino)ethyl)(methyl)carbamoyl)picolinic acid methyl ester (360mg, 1.36mmol) was dissolved in methanol (5 mL), and sodium borohydride was added under ice bath (410mg, 10.8mmol), the reaction was stopped at room temperature for 3h, concentrated under reduced pressure, and the concentrated solution was separated on silica gel column (eluent: dichloromethane/methanol (v/v)=10/1) to obtain 214mg of colorless liquid, The yield was 66%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.75–7.79(m,1H),7.69(d,J＝7.7,Hz,0.6H),7.50(d,J＝7.6,Hz,0.4H),7.31(d,J＝7.9,Hz,0.4H),7.27(d,J＝7.8,Hz,0.6H),4.47(s,0.8H),4.72(s,1.2H),3.69(t,J＝6.8,Hz,0.7H),3.59(t,J＝6.8,Hz,1.3H),3.14(s,2.2H),3.05(s,0.8H),2.73(t,J＝6.8,Hz,1.3H),2.62(t,J＝6.8,Hz,0.7H),2.33(s,2H),2.19(s,4H) 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.75–7.79 (m, 1H), 7.69 (d, J = 7.7, Hz, 0.6H), 7.50 (d, J = 7.6, Hz, 0.4H) ,7.31(d,J=7.9,Hz,0.4H), 7.27(d,J=7.8,Hz,0.6H), 4.47(s,0.8H), 4.72(s,1.2H), 3.69(t,J ＝6.8,Hz,0.7H),3.59(t,J＝6.8,Hz,1.3H),3.14(s,2.2H),3.05(s,0.8H),2.73(t,J＝6.8,Hz,1.3 H), 2.62 (t, J = 6.8, Hz, 0.7H), 2.33 (s, 2H), 2.19 (s, 4H)
MS(ESI,pos.ion)m/z:238.20[M+H] +. MS(ESI,pos.ion)m/z:238.20[M+H] + .
步骤3：化合物(2R)-(6-((2-(二甲氨基)乙基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯的合成Step 3: Compound (2R)-(6-((2-(dimethylamino)ethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-( Synthesis of (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(60mg,0.16mmol)，N-(2-(二甲氨基)乙基)-6-(羟甲基)-N-甲基吡啶酰胺(45mg,0.19mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(207mg,1.08mmol)和N-羟基-7-氮杂苯并三氮唑(44mg,0.32mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入N,N-二异丙基乙胺(83mg,0.64mmol)，室温反应9h，加二氯甲烷(15mL)，有机相水洗(20mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝24/1)，得到白色粘稠固体47mg，收率49％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (60mg, 0.16mmol) , N-(2-(dimethylamino)ethyl)-6-(hydroxymethyl)-N-picolineamide (45mg, 0.19mmol), 1-ethyl-(3-dimethylaminopropyl) ) Carbodiimide hydrochloride (207mg, 1.08mmol) and N-hydroxy-7-azabenzotriazole (44mg, 0.32mmol) dissolved in dichloromethane (10mL), cooled to 0°C, Add N,N-diisopropylethylamine (83mg, 0.64mmol), react at room temperature for 9h, add dichloromethane (15mL), wash the organic phase with water (20mL×2), dry the organic phase with anhydrous sodium sulfate, and reduce pressure After concentration, the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=24/1) to obtain 47 mg of a white viscous solid with a yield of 49%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.78–7.83(m,1H),7.50–7.57(m,2H),7.12(d,J＝8.7Hz,1H),6.82(s,1H),6.78–6.2(m,1H),6.61(t,J F-H＝75.5Hz,1H),5.23–5.45(m,2H),4.56–4.60(m,1H),3.93–3.98(m,1H),3.86(d,J＝6.9Hz,2H),3.60–3.70(m,2H),3.41–3.51(m,2H),3.11(s,1.5H),3.06(s,1.5H),2.67–2.72(m,2H),2.55–2.61(m,1H),2.39(s,3H),2.18–2.26(m,1H),2.14(s,3H),2.12(s,3H),1.25–1.36(m,1H),0.63–0.67(m,2H),0.33–0.37(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.78–7.83(m,1H), 7.50–7.57(m,2H), 7.12(d,J=8.7Hz,1H), 6.82(s,1H) ,6.78–6.2(m,1H),6.61(t,J FH =75.5Hz,1H), 5.23–5.45(m,2H), 4.56–4.60(m,1H), 3.93–3.98(m,1H), 3.86(d,J=6.9Hz,2H), 3.60–3.70(m, 2H), 3.41–3.51(m, 2H), 3.11(s, 1.5H), 3.06(s, 1.5H), 2.67–2.72( m, 2H), 2.55-2.61(m, 1H), 2.39(s, 3H), 2.18-2.26(m, 1H), 2.14(s, 3H), 2.12(s, 3H), 1.25-1.36(m, 1H), 0.63-0.67 (m, 2H), 0.33-0.37 (m, 2H).
MS(ESI,pos.ion)m/z:589.30[M+H] +. MS(ESI,pos.ion)m/z:589.30[M+H] + .
实施例125：化合物(2R)-(6-(甲基(丙基)氨甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 125: Compound (2R)-(6-(methyl(propyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000187
Figure PCTCN2021090489-appb-000187
步骤1：化合物6-(甲基(丙基)氨基甲酰基)-2-吡啶甲酸甲酯的合成Step 1: Synthesis of compound 6-(methyl(propyl)carbamoyl)-2-picolinate methyl ester
取化合物吡啶二羧酸单甲酯(1.00g,5.5mmol)于50mL单口瓶，加入35mL二氯甲烷，搅拌，溶解，再室温加入N,N-甲基丙基胺(0.70g,9.4mmol)以及N-羟基-7-氮杂苯并三氮唑(1.50g,11mmol)，之后冰浴下依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(3.23g,16.7mmol)和N,N-二异丙基乙胺(5.73g,44mmol)，最后室温搅拌7h，停止反应，水洗3次(30mL×3)，无水Na 2SO 4干燥，浓缩，进行硅胶柱层析分离(梯度洗脱,洗脱剂：石油醚/乙酸乙酯(v/v)＝3:1,2:1)，得到淡黄色油状物1.21g，收率92.8％。 Take the compound monomethyl dipicolinate (1.00g, 5.5mmol) in a 50mL single-neck flask, add 35mL of dichloromethane, stir and dissolve, and then add N,N-methylpropylamine (0.70g, 9.4mmol) at room temperature And N-hydroxy-7-azabenzotriazole (1.50g, 11mmol), then add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride one by one under ice bath (3.23g, 16.7mmol) and N,N-diisopropylethylamine (5.73g, 44mmol), finally stirred at room temperature for 7h, stopped the reaction, washed 3 times with water (30mL×3), dried with anhydrous Na 2 SO 4 , Concentrate and perform silica gel column chromatography separation (gradient elution, eluent: petroleum ether/ethyl acetate (v/v)=3:1, 2:1) to obtain 1.21 g of light yellow oil, yield 92.8% .
1H-NMR(400MHz,CDCl 3)δ(ppm):8.17(t,J＝8.1Hz,1H),7.96(t,J＝8.0Hz,1H),7.85(t,J＝8.1Hz,1H),4.03(s,3H),3.53(t,J＝8.1Hz,1H),3.41(t,J＝8.1Hz,1H),3.12(d,J＝8.1Hz,3H),1.80–1.70(m,2H),1.01(t,J＝8.1Hz,1H),0.81(t,J＝8.1Hz,2H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.17 (t, J = 8.1 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.85 (t, J = 8.1 Hz, 1H) ,4.03(s,3H),3.53(t,J=8.1Hz,1H),3.41(t,J=8.1Hz,1H),3.12(d,J=8.1Hz,3H),1.80–1.70(m, 2H), 1.01 (t, J = 8.1 Hz, 1H), 0.81 (t, J = 8.1 Hz, 2H).
MS(ESI,pos.ion)m/z:237.20[M+H] +. MS(ESI,pos.ion)m/z:237.20[M+H] + .
步骤2：化合物6-羟甲基-N,N-甲基丙基-2-吡啶甲酰胺的合成Step 2: Synthesis of compound 6-hydroxymethyl-N,N-methylpropyl-2-pyridinecarboxamide
取化合物6-(甲基(丙基)氨基甲酰基)-2-吡啶甲酸甲酯(0.60g,2.5mmol)于100mL单口瓶，加入10mL无水四氢呋喃，之后冰浴下加入硼氢化锂(0.15g,6.9mmol)，室温搅拌5h，停止反应，冰浴下加入20mL饱和氯化钠溶液，乙酸乙酯萃取(15mL×3)，无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(梯度洗脱,洗脱剂：石油醚/乙酸乙酯(v/v)＝1:1,1:2)，得到浅青色油状物290mg，收率55％。Take compound 6-(methyl(propyl)carbamoyl)-2-picolinate methyl ester (0.60g, 2.5mmol) in a 100mL single-necked flask, add 10mL anhydrous tetrahydrofuran, then add lithium borohydride (0.15 g, 6.9mmol), stir at room temperature for 5h, stop the reaction, add 20mL saturated sodium chloride solution under ice bath, extract with ethyl acetate (15mL×3), dry with anhydrous sodium sulfate, concentrate, and conduct silica gel column chromatography separation (gradient Elution, eluent: petroleum ether/ethyl acetate (v/v)=1:1, 1:2) to obtain 290 mg of light cyan oil with a yield of 55%.
1H-NMR(400MHz,CDCl 3)δ(ppm):7.79(t,J＝8.1Hz,1H),7.49(t,J＝8.0Hz,1H),7.32(t,J＝8.1Hz,1H),4.79(s,2H),3.54(t,J＝8.1Hz,1H),3.28(t,J＝8.1Hz,1H),3.12(s,2H),3.01(s,1H),1.8-1.6(m,2H),1.01(t,J＝8.1Hz,1H),0.80(t,J＝8.1Hz,2H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.79 (t, J = 8.1 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H) ,4.79(s,2H),3.54(t,J=8.1Hz,1H), 3.28(t,J=8.1Hz,1H),3.12(s,2H),3.01(s,1H),1.8-1.6( m, 2H), 1.01 (t, J = 8.1 Hz, 1H), 0.80 (t, J = 8.1 Hz, 2H).
MS(ESI,pos.ion)m/z:209.20[M+H] +. MS(ESI,pos.ion)m/z:209.20[M+H] + .
步骤3：化合物(2R)-(6-(甲基(丙基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯的合成Step 3: Compound (2R)-(6-(methyl(propyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
取化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(120mg,0.32mmol)于50mL单口瓶，加入10mL二氯甲烷，搅拌，溶解，在室温加入6-羟甲基-N,N-甲基丙基-2-吡啶甲酰胺(80mg，0.40mmol)以及N-羟基-7-氮杂苯并三氮唑(80mg,0.60mmol)，之后冰浴下依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(210mg，1.10mmol)和N,N-二异丙基乙胺(300mg,2.30mmol)，最后室温搅拌5.5h，停止反应，水洗3次(30mL×3)，无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(梯度洗脱,洗脱剂：二氯甲烷/甲醇(v/v)＝7:1,6:1)，得淡黄色油状物147.6mg，收率81％。Take compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120mg, 0.32mmol) In a 50mL single-neck flask, add 10mL of dichloromethane, stir and dissolve, add 6-hydroxymethyl-N,N-methylpropyl-2-pyridinecarboxamide (80mg, 0.40mmol) and N-hydroxy-7 at room temperature -Azabenzotriazole (80mg, 0.60mmol), followed by 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (210mg, 1.10mmol) under ice bath And N,N-diisopropylethylamine (300mg, 2.30mmol), and finally stirred at room temperature for 5.5h, stop the reaction, wash 3 times (30mL×3) with water, dry with anhydrous sodium sulfate, concentrate, and separate by silica gel column chromatography (Gradient elution, eluent: dichloromethane/methanol (v/v)=7:1, 6:1) to obtain 147.6 mg of pale yellow oil, with a yield of 81%.
1H-NMR(400MHz,CDCl 3)δ(ppm):7.87-7.76(m,1H),7.58-7.50(m,2H),7.18-7.10(m,1H),6.88-6.83(m,2H),6.67(t,J F-H＝75.6Hz,1H),5.47-5.42(m,1H),5.34-5.28(m,2H),4.65-4.56(m,1H),3.98(t,J＝8.0Hz,1H),3.92-3.85(m,2H),3.65(t,J＝8.1Hz,1H),3.55-3.40(m,2H),3.33-3.25(m,1H),3.15-3.06(m,2H),3.02-2.97(m,1H),2.78-2.68(m,1H),2.18-2.12(m,3H),1.36-1.24(m,3H),0.99(t,J＝8.0Hz,1H),0.79(t,J＝8.0Hz,2H),0.71-0.64(m,2H),0.41-0.33(m,2H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.87-7.76 (m, 1H), 7.58-7.50 (m, 2H), 7.18-7.10 (m, 1H), 6.88-6.83 (m, 2H) ,6.67(t,J FH =75.6Hz,1H),5.47-5.42(m,1H),5.34-5.28(m,2H),4.65-4.56(m,1H),3.98(t,J=8.0Hz, 1H),3.92-3.85(m,2H),3.65(t,J=8.1Hz,1H),3.55-3.40(m,2H),3.33-3.25(m,1H),3.15-3.06(m,2H) ,3.02-2.97(m,1H),2.78-2.68(m,1H),2.18-2.12(m,3H),1.36-1.24(m,3H),0.99(t,J=8.0Hz,1H),0.79 (t,J=8.0Hz,2H),0.71-0.64(m,2H),0.41-0.33(m,2H).
MS(ESI,pos.ion)m/z:560.20[M+H] +. MS(ESI,pos.ion)m/z:560.20[M+H] + .
实施例126：化合物(2R)-(6-二甲基氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 126: The compound (2R)-(6-dimethylcarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-(di (Fluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000188
Figure PCTCN2021090489-appb-000188
步骤1：化合物6-(二甲基氨基甲酰基)-2-吡啶甲酸甲酯的合成Step 1: Synthesis of compound 6-(dimethylcarbamoyl)-2-picolinate methyl ester
取化合物吡啶二羧酸单甲酯(1.02g,5.63mmol)于100mL单口瓶，加入40mL二氯甲烷，搅拌，溶解，再室温加入盐酸二甲胺(2.49g,9.4mmol)以及N-羟基-7-氮杂苯并三氮唑(1.50g,11mmol)，之后冰浴下依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(3.23g,16.7mmol)和N,N-二异丙基乙胺(5.73g,44mmol)，最后室温搅拌5h，停止反应，水洗3次(30mL×3)，无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(梯度洗脱,洗脱剂：石油醚/乙酸乙酯(v/v)＝2:1,1:1)，得到淡黄色油状物1.05g，收率89.6％。Take the compound monomethyl dipicolinate (1.02g, 5.63mmol) in a 100mL single-neck flask, add 40mL of dichloromethane, stir and dissolve, and then add dimethylamine hydrochloride (2.49g, 9.4mmol) and N-hydroxy- 7-azabenzotriazole (1.50g, 11mmol), and then add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (3.23g, 16.7 mmol) and N,N-diisopropylethylamine (5.73g, 44mmol), finally stirred at room temperature for 5h, the reaction was stopped, washed with water 3 times (30mL×3), dried with anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography After separation (gradient elution, eluent: petroleum ether/ethyl acetate (v/v)=2:1, 1:1), 1.05 g of light yellow oil was obtained, with a yield of 89.6%.
1H-NMR(400MHz,CDCl 3)δ(ppm):8.22-8.17(m,1H),7.98(t,J＝8.0Hz,1H),7.90-7.85(m,1H),4.03(s,3H),3.19-3.13(m,5H),3.02-2.88(m,1H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.22-8.17 (m, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.90-7.85 (m, 1H), 4.03 (s, 3H) ), 3.19-3.13 (m, 5H), 3.02-2.88 (m, 1H).
MS(ESI,pos.ion)m/z:209.10[M+H] +. MS(ESI,pos.ion)m/z:209.10[M+H] + .
步骤2：化合物6-羟甲基-N,N-二甲基-2-吡啶甲酰胺的合成Step 2: Synthesis of compound 6-hydroxymethyl-N,N-dimethyl-2-pyridinecarboxamide
取化合物6-(二甲基氨基甲酰基)-2-吡啶甲酸甲酯(0.52g,2.5mmol)于25mL单口瓶，加入6mL无水四氢呋喃，之后冰浴下加入硼氢化锂(0.11g,5.0mmol)，室温搅拌3h，停止反应，冰浴下加入20mL饱和氯化钠溶液，乙酸乙酯萃取(15mL×3)，无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(梯度洗脱,洗脱剂：DCM/MeOH(v/v)＝39:1,6:1)，得到白色固体260mg，收率58％。Take compound 6-(dimethylcarbamoyl)-2-picolinate methyl ester (0.52g, 2.5mmol) in a 25mL single-necked flask, add 6mL of anhydrous tetrahydrofuran, then add lithium borohydride (0.11g, 5.0 mmol), stir at room temperature for 3h, stop the reaction, add 20mL saturated sodium chloride solution under ice bath, extract with ethyl acetate (15mL×3), dry with anhydrous sodium sulfate, concentrate, and perform silica gel column chromatography (gradient elution, Eluent: DCM/MeOH (v/v)=39:1, 6:1) to obtain 260 mg of white solid with a yield of 58%.
1H-NMR(400MHz,CDCl 3)δ(ppm):7.81(t,J＝8.1Hz,1H),7.55-7.50(m,1H),7.37-7.30(m,1H),4.80(s,2H),3.17(s,3H),3.07(s,1H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.81 (t, J = 8.1 Hz, 1H), 7.55-7.50 (m, 1H), 7.37-7.30 (m, 1H), 4.80 (s, 2H) ), 3.17(s, 3H), 3.07(s, 1H).
MS(ESI,pos.ion)m/z:181.25[M+H] +. MS(ESI,pos.ion)m/z:181.25[M+H] + .
步骤3：化合物(2R)-(6-(二甲基)氨甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯的合成Step 3: Compound (2R)-(6-(dimethyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-( Synthesis of difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
取化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(120mg,0.32mmol)于25mL单口瓶，加入11mL二氯甲烷，搅拌，溶解，再室温加入6-羟甲基-N,N-二甲基-2-吡啶甲酰胺(60mg,0.33mmol)以及N-羟基-7-氮杂苯并三氮唑(90mg,0.65mmol)，之后冰浴下依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(200mg,1.03mmol)和N,N-二异丙基乙胺(400mg,3.03mmol)，最后室温搅拌17h，停止反应，水洗3次(30mL×3)，无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(梯度洗脱，洗脱剂：二氯甲烷/甲醇(v/v)＝11:1,10:1,9:1)，得到淡黄色油状物78.9mg，收率44.6％。Take compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120mg, 0.32mmol) In a 25mL single-neck flask, add 11mL of dichloromethane, stir and dissolve, and add 6-hydroxymethyl-N,N-dimethyl-2-pyridinecarboxamide (60mg, 0.33mmol) and N-hydroxy-7- Azabenzotriazole (90mg, 0.65mmol), followed by the addition of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (200mg, 1.03mmol) and N,N-Diisopropylethylamine (400mg, 3.03mmol), finally stirred at room temperature for 17h, stopped the reaction, washed 3 times with water (30mL×3), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (gradient Elution, eluent: dichloromethane/methanol (v/v) = 11:1, 10:1, 9:1) to obtain 78.9 mg of pale yellow oil with a yield of 44.6%.
1H-NMR(400MHz,CDCl 3)δ(ppm):7.84(t,J＝8.1Hz,1H),7.61-7.52(m,2H),7.18-7.12(m,1H),6.88-6.83(m,2H),6.63(t,J F-H＝75.6Hz,1H),5.47-5.42(m,1H),5.34-5.28(m,2H),4.65-4.56(m,1H),4.02-3.96(m,1H),3.92-3.85(m,2H),3.68-3.62(m,1H),3.13(s,3H),3.06(s,3H),2.18-2.12(m,3H),2.04-2.00(m,1H),0.94-0.85(m,2H),0.71-0.64(m,2H),0.41-0.33(m,2H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.84 (t, J = 8.1 Hz, 1H), 7.61-7.52 (m, 2H), 7.18-7.12 (m, 1H), 6.88-6.83 (m ,2H),6.63(t,J FH =75.6Hz,1H),5.47-5.42(m,1H),5.34-5.28(m,2H),4.65-4.56(m,1H),4.02-3.96(m, 1H), 3.92-3.85 (m, 2H), 3.68-3.62 (m, 1H), 3.13 (s, 3H), 3.06 (s, 3H), 2.18-2.12 (m, 3H), 2.04-2.00 (m, 1H), 0.94-0.85 (m, 2H), 0.71-0.64 (m, 2H), 0.41-0.33 (m, 2H).
MS(ESI,pos.ion)m/z:532.20[M+H] +. MS(ESI,pos.ion)m/z:532.20[M+H] + .
实施例127：化合物(2R)-(6-((氰甲基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 127: Compound (2R)-(6-((cyanomethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000189
Figure PCTCN2021090489-appb-000189
步骤1：化合物2-(甲基氨基)乙腈盐酸盐的合成Step 1: Synthesis of compound 2-(methylamino)acetonitrile hydrochloride
将化合物叔丁基(氰甲基)(甲基)氨基甲酸酯(300mg,0.066mmol)溶解在二氯甲烷(5mL)溶液中，加入HCl的乙酸乙酯溶液(4M,8mL)，室温反应30min，减压浓缩，得到浅褐色固体176mg，收率93％。The compound tert-butyl (cyanomethyl) (methyl) carbamate (300mg, 0.066mmol) was dissolved in dichloromethane (5mL) solution, HCl in ethyl acetate solution (4M, 8mL) was added, and reacted at room temperature After 30 minutes, it was concentrated under reduced pressure to obtain 176 mg of light brown solid with a yield of 93%.
1H NMR(400MHz,CD 3OD)δ(ppm):4.34(s,1H),3.84(s,1H),2.87(s,1.5H),2.75(s,1.5H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 4.34 (s, 1H), 3.84 (s, 1H), 2.87 (s, 1.5H), 2.75 (s, 1.5H).
MS(ESI,pos.ion)m/z:70.10[M-HCl+H] +. MS(ESI,pos.ion)m/z:70.10[M-HCl+H] + .
步骤2：化合物6-((氰甲基)(甲基)氨基甲酰基)吡啶甲酸甲酯的合成Step 2: Synthesis of compound methyl 6-((cyanomethyl)(methyl)carbamoyl)picolinate
将化合物2,6-吡啶二羧酸单甲酯(300mg,1.66mmol)，2-(甲基氨基)乙腈盐酸盐(172mg,1.61mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(634mg,3.31mmol)和N-羟基-7-氮杂苯并三氮唑(333mg,2.45mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入N,N-二异丙基乙胺(624mg,4.83mmol)，室温反应6h，加水(20mL×2)洗，分离有机相，用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分 离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到浅褐色液体121mg，收率31％。The compound 2,6-pyridinedicarboxylic acid monomethyl ester (300mg, 1.66mmol), 2-(methylamino)acetonitrile hydrochloride (172mg, 1.61mmol), 1-ethyl-(3-dimethylamino) Propyl) carbodiimide hydrochloride (634mg, 3.31mmol) and N-hydroxy-7-azabenzotriazole (333mg, 2.45mmol) were dissolved in dichloromethane (10mL) and cooled to 0 ℃, add N,N-diisopropylethylamine (624mg, 4.83mmol), react at room temperature for 6h, add water (20mL×2) to wash, separate the organic phase, dry with anhydrous sodium sulfate, concentrate under reduced pressure, concentrate Separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 121 mg of light brown liquid with a yield of 31%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.24–8.27(m,1H),8.16–8.18(m,0.5H),7.99–8.07(m,1.5H),4.95(s,0.8H),4.52(s,1.2H),4.03(s,3H),3.38(s,1.8H),3.29(s,1.2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.24-8.27 (m, 1H), 8.16-8.18 (m, 0.5H), 7.99-8.07 (m, 1.5H), 4.95 (s, 0.8H) , 4.52(s,1.2H), 4.03(s,3H), 3.38(s,1.8H), 3.29(s,1.2H).
MS(ESI,pos.ion)m/z:234.05[M+H] +. MS(ESI,pos.ion)m/z:234.05[M+H] + .
步骤3：化合物N-(氰甲基)-6-(羟甲基)-N-甲基吡啶酰胺的合成Step 3: Synthesis of compound N-(cyanomethyl)-6-(hydroxymethyl)-N-picolinamide
将化合物6-((氰甲基)(甲基)氨基甲酰基)吡啶甲酸甲酯(115mg,0.49mmol)溶于甲醇(5mL)中，冰浴下加入硼氢化钠(149mg,3.94mmol)，室温反应2.5h后停止，减压浓缩，浓缩液进行硅胶柱分离(洗脱剂：二氯甲烷/甲醇(v/v)＝15/1)，得到无色液体29mg，收率28％。Compound 6-((cyanomethyl)(methyl)carbamoyl)picolinate (115mg, 0.49mmol) was dissolved in methanol (5mL), sodium borohydride (149mg, 3.94mmol) was added under ice bath, The reaction was stopped after 2.5 hours at room temperature, concentrated under reduced pressure, and the concentrated solution was separated on a silica gel column (eluent: dichloromethane/methanol (v/v)=15/1) to obtain 29 mg of a colorless liquid with a yield of 28%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.86–7.91(m,1H),7.81(d,J＝7.5,Hz,0.4H),7.67(d,J＝7.6,Hz,0.6H),7.44(t,J＝8.6,Hz,1H),4.85(d,J＝13.0,Hz,2H),4.55(d,J＝8.5,Hz,2H),3.32(br.s,1H),3.28(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.86–7.91 (m, 1H), 7.81 (d, J = 7.5, Hz, 0.4H), 7.67 (d, J = 7.6, Hz, 0.6H) ,7.44(t,J＝8.6,Hz,1H),4.85(d,J＝13.0,Hz,2H),4.55(d,J＝8.5,Hz,2H),3.32(br.s,1H),3.28 (s,3H).
MS(ESI,pos.ion)m/z:206.20[M+H] +. MS(ESI,pos.ion)m/z:206.20[M+H] + .
步骤4：化合物(2R)-(6-((氰甲基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯的合成Step 4: Compound (2R)-(6-((cyanomethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(50mg,0.14mmol)，N-(氰甲基)-6-(羟甲基)-N-甲基吡啶酰胺(23mg,0.11mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(107mg,0.56mmol)和N-羟基-7-氮杂苯并三氮唑(32mg,0.24mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入N,N-二异丙基乙胺(78mg,0.60mmol)，室温反应14h，加水(15mL)搅拌5min，二氯甲烷萃取(10mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝54/1)，得到浅褐色粘稠固体16mg，收率25％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (50mg, 0.14mmol) , N-(cyanomethyl)-6-(hydroxymethyl)-N-picolineamide (23mg, 0.11mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Hydrochloride (107mg, 0.56mmol) and N-hydroxy-7-azabenzotriazole (32mg, 0.24mmol) were dissolved in dichloromethane (10mL), cooled to 0℃, added N,N-di Isopropylethylamine (78mg, 0.60mmol), react at room temperature for 14h, add water (15mL) and stir for 5min, extract with dichloromethane (10mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the concentrated solution to silica gel It was separated by column chromatography (eluent: dichloromethane/methanol (v/v)=54/1) to obtain 16 mg of a light brown viscous solid with a yield of 25%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.82–7.94(m,1.5H),7.58–7.70(m,1.5H),7.12(d,J＝7.6Hz,1H),6.82(s,2H),6.61(t,J F-H＝75.5Hz,1H),5.43–5.51(m,1H),5.22–5.30(m,1H),4.56–4.76(m,2H),4.43–4.51(m,1H),3.90–3.99(m,1H),3.86(d,J＝6.0Hz,2H),3.60–3.65(m,1H),3.37–3.51(m,1H),3.24(d,J＝11.4Hz,3H),2.66–2.77(m,1H),2.11(s,3H),1.97–2.05(m,1H),1.25–1.35(m,1H),0.57–0.69(m,2H),0.30–0.38(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.82–7.94(m,1.5H), 7.58–7.70(m,1.5H), 7.12(d,J=7.6Hz,1H), 6.82(s, 2H),6.61(t,J FH =75.5Hz,1H),5.43-5.51(m,1H),5.22-5.30(m,1H),4.56-4.76(m,2H),4.43-4.51(m,1H) ), 3.90–3.99(m,1H), 3.86(d,J=6.0Hz,2H), 3.60–3.65(m,1H), 3.37–3.51(m,1H), 3.24(d,J=11.4Hz, 3H), 2.66–2.77(m, 1H), 2.11(s, 3H), 1.97–2.05(m, 1H), 1.25–1.35(m, 1H), 0.57–0.69(m, 2H), 0.30–0.38( m,2H).
MS(ESI,pos.ion)m/z:557.20[M+H] +. MS(ESI,pos.ion)m/z:557.20[M+H] + .
实施例128：化合物(2R)-(6-((2-甲氧基乙基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 128: The compound (2R)-(6-((2-methoxyethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclo (Propylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000190
Figure PCTCN2021090489-appb-000190
步骤1：化合物6-((2-甲氧基乙基)氨基甲酰基)吡啶甲酸甲酯的合成Step 1: Synthesis of compound methyl 6-((2-methoxyethyl)carbamoyl)picolinate
将化合物2,6-吡啶二羧酸单甲酯(500mg,2.76mmol)，2-甲氧基乙胺(402mg,5.35mmol)溶于二氯甲烷(20mL)中，加入N-羟基-7-氮杂苯并三氮唑(563mg,4.14mmol)，在冰浴中加加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.1g,5.70mmol)和N,N-二异丙基乙胺(890mg,6.89mmol)，室温反应5h，有机相用水洗(20mL×2)，用无水硫酸钠干燥有机相，减压浓缩，剩余物用硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到白色固体598mg，收率91％。The compound 2,6-pyridinedicarboxylic acid monomethyl ester (500mg, 2.76mmol), 2-methoxyethylamine (402mg, 5.35mmol) were dissolved in dichloromethane (20mL), and N-hydroxy-7- Azabenzotriazole (563mg, 4.14mmol), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.1g, 5.70mmol) in an ice bath React with N,N-diisopropylethylamine (890mg, 6.89mmol) at room temperature for 5h, wash the organic phase with water (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column for the remainder Chromatographic separation (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 598 mg of white solid with a yield of 91%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.42(br.s,1H),8.39(d,J＝7.8Hz,1H),8.23(d,J＝7.8Hz,1H), 8.01(t,J＝7.8Hz,1H),4.02(s,3H),3.69–3.73(m,2H),3.61(t,J＝5.2Hz,2H),3.41(s,3H). 1 H NMR(400MHz, CD 3 OD)δ(ppm): 8.42(br.s,1H), 8.39(d,J=7.8Hz,1H), 8.23(d,J=7.8Hz,1H), 8.01( t,J=7.8Hz,1H),4.02(s,3H),3.69–3.73(m,2H),3.61(t,J=5.2Hz,2H),3.41(s,3H).
MS(ESI,pos.ion)m/z:239.10[M-HCl+H] +. MS(ESI,pos.ion)m/z:239.10[M-HCl+H] + .
步骤2：化合物6-((2-甲氧基乙基)(甲基)氨基甲酰基)吡啶甲酸甲酯的合成Step 2: Synthesis of compound methyl 6-((2-methoxyethyl)(methyl)carbamoyl)picolinate
将化合物6-((2-甲氧基乙基)氨基甲酰基)吡啶甲酸甲酯(585mg,2.46mmol)溶于无水N,N-二甲基甲酰胺(8mL)中，在冰浴中加入60％氢化钠(128mg,3.20mmol)，室温反应1h后加入碘甲烷(1.1g,7.70mmol)，60℃反应8h后停止反应，减压除去溶剂，加水(20mL)，水相用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到浅褐色固体199mg，收率32％。The compound 6-((2-methoxyethyl)carbamoyl)picolinate (585mg, 2.46mmol) was dissolved in anhydrous N,N-dimethylformamide (8mL) and placed in an ice bath Add 60% sodium hydride (128mg, 3.20mmol), react at room temperature for 1 hour and then add methyl iodide (1.1g, 7.70mmol), react at 60°C for 8 hours, stop the reaction, remove the solvent under reduced pressure, add water (20mL), and use ethyl acetate for the aqueous phase Ester extraction (10mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/ 1) Obtain 199 mg of light brown solid with a yield of 32%.
MS(ESI,pos.ion)m/z:253.10[M+H] +. MS(ESI,pos.ion)m/z:253.10[M+H] + .
步骤3：化合物6-(羟甲基)-N-(2-甲氧乙基)-N-甲基吡啶酰胺的合成Step 3: Synthesis of compound 6-(hydroxymethyl)-N-(2-methoxyethyl)-N-picolineamide
将化合物6-((2-甲氧基乙基)(甲基)氨基甲酰基)吡啶甲酸甲酯(195mg,0.77mmol)溶于甲醇(5mL)中，冰浴中加入硼氢化钠(233mg，6.16mmol)，室温反应3.5h后停止，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)，得到无色液体162mg，收率93％。The compound 6-((2-methoxyethyl)(methyl)carbamoyl)picolinate (195mg, 0.77mmol) was dissolved in methanol (5mL), and sodium borohydride (233mg, 6.16mmol), the reaction was stopped after 3.5h at room temperature, concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=50/1) to obtain 162mg of colorless liquid. The yield was 93%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.76–7.80(m,1H),7.56(d,J＝7.6Hz,0.6H),7.50(d,J＝7.6Hz,0.4H),7.28–7.31(m,1H),4.77(s,2H),3.68–3.76(m,2H),3.57–3.61(m,2H),3.40(s,1.4H),3.30(s,1.6H),3.16(s,1.4H),3.10(s,1.6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.76-7.80 (m, 1H), 7.56 (d, J = 7.6 Hz, 0.6H), 7.50 (d, J = 7.6 Hz, 0.4H), 7.28 --7.31(m,1H),4.77(s,2H), 3.68–3.76(m,2H), 3.57–3.61(m,2H), 3.40(s,1.4H), 3.30(s,1.6H), 3.16 (s,1.4H), 3.10(s,1.6H).
MS(ESI,pos.ion)m/z:225.20[M+H] +. MS(ESI,pos.ion)m/z:225.20[M+H] + .
步骤4：化合物(2R)-(6-((2-甲氧基乙基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯的合成Step 4: Compound (2R)-(6-((2-methoxyethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropyl) Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(107mg,0.29mmol)，6-(羟甲基)-N-(2-甲氧基乙基)-N-甲基吡啶酰胺(11029-1)(50mg,0.22mmol)溶于二氯甲烷(10mL)中，加入N-羟基-7-氮杂苯并三氮唑(61mg,0.45mmol)，在冰浴中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(214mg,1.12mmol)和N,N-二异丙基乙胺(144mg,1.11mmol)，室温反应6h，加水(20mL)搅拌5min，二氯甲烷萃取(5mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝54/1)，得到浅褐色粘稠固体78mg，收率60％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (107mg, 0.29mmol) , 6-(hydroxymethyl)-N-(2-methoxyethyl)-N-picolineamide (11029-1) (50mg, 0.22mmol) was dissolved in dichloromethane (10mL), and N -Hydroxy-7-azabenzotriazole (61mg, 0.45mmol), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (214mg, 1.12mmol) and N,N-diisopropylethylamine (144mg, 1.11mmol), react at room temperature for 6h, add water (20mL) and stir for 5min, extract with dichloromethane (5mL×2), dry the organic phase with anhydrous sodium sulfate It was concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=54/1) to obtain 78 mg of light brown viscous solid with a yield of 60%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.81(t,J＝7.6Hz,1H),7.49–7.56(m,2H),7.12(d,J＝8.3Hz,1H),6.82(s,1H),6.78–6.81(m,1H),6.60(t,J F-H＝75.5Hz,1H),5.24–5.44(m,2H),4.56–4.61(m,1H),3.93–3.98(m,1H),3.86(d,J＝6.9Hz,2H),3.65–3.72(m,2H),3.62(t,J＝10.4Hz,1H),3.50–3.58(m,2H),3.39–3.49(m,1H),3.37(s,1.5H),3.25(s,1.5H),3.13(s,1.5H),3.08(s,1.5H),2.67–2.74(m,1H),2.06–2.14(m,1H),2.12(s,3H),1.25–1.36(m,1H),0.62–0.67(m,2H),0.33–0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.81 (t, J = 7.6 Hz, 1H), 7.49-7.56 (m, 2H), 7.12 (d, J = 8.3 Hz, 1H), 6.82 (s ,1H),6.78–6.81(m,1H),6.60(t,J FH =75.5Hz,1H), 5.24–5.44(m,2H),4.56–4.61(m,1H),3.93-3.98(m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.65–3.72 (m, 2H), 3.62 (t, J = 10.4 Hz, 1H), 3.50–3.58 (m, 2H), 3.39–3.49 (m ,1H), 3.37(s, 1.5H), 3.25(s, 1.5H), 3.13(s, 1.5H), 3.08(s, 1.5H), 2.67–2.74(m, 1H), 2.06–2.14(m ,1H), 2.12(s,3H), 1.25-1.36(m,1H), 0.62-0.67(m,2H), 0.33-0.37(m,2H).
MS(ESI,pos.ion)m/z:576.20[M+H] +. MS(ESI,pos.ion)m/z:576.20[M+H] + .
实施例129：化合物(2R)-(6-(甲基(2,2,2-三氟乙基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 129: Compound (2R)-(6-(methyl(2,2,2-trifluoroethyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000191
Figure PCTCN2021090489-appb-000191
步骤1：化合物6-(甲基(2,2,2-三氟乙基)氨基甲酰基)吡啶甲酸甲酯的合成Step 1: Synthesis of compound methyl 6-(methyl(2,2,2-trifluoroethyl)carbamoyl)picolinate
将化合物2,6-吡啶二羧酸单甲酯(400mg,2.21mmol)，N-甲基-2,2,2-三氟乙胺盐酸盐(330mg,2.21mmol)溶于二氯甲烷(15mL)中，加入N-羟基-7-氮杂苯并三氮唑(450mg,3.31mmol)，在冰浴中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(846mg,4.41mmol)和N,N-二异丙基乙胺(999mg,7.73mmol)，室温反应3.5h，有机相用水洗(20mL×2)，用无水硫酸钠干燥有机相，减压浓缩，剩余物用硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/1)，得到无色液体436mg，收率71％。The compound 2,6-pyridinedicarboxylic acid monomethyl ester (400mg, 2.21mmol), N-methyl-2,2,2-trifluoroethylamine hydrochloride (330mg, 2.21mmol) were dissolved in dichloromethane ( 15mL), add N-hydroxy-7-azabenzotriazole (450mg, 3.31mmol), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide in an ice bath Hydrochloride (846mg, 4.41mmol) and N,N-diisopropylethylamine (999mg, 7.73mmol), react at room temperature for 3.5h, wash the organic phase with water (20mL×2), dry the organic phase with anhydrous sodium sulfate After concentration under reduced pressure, the residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 436 mg of colorless liquid with a yield of 71%.
1H NMR(400MHz,CD 3OD)δ(ppm):8.19–8.21(m,1H),7.89–8.01(m,2H),4.62(q,J＝7.5,Hz,1.2H),4.21(q,J＝9.0,Hz,0.8H),4.01(s,3H),3.30(s,1.3H),3.25(s,1.7H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 8.19-8.21 (m, 1H), 7.89-8.01 (m, 2H), 4.62 (q, J = 7.5, Hz, 1.2H), 4.21 (q ,J=9.0,Hz,0.8H),4.01(s,3H), 3.30(s,1.3H), 3.25(s,1.7H).
MS(ESI,pos.ion)m/z:277.20[M+H] +. MS(ESI,pos.ion)m/z:277.20[M+H] + .
步骤2：化合物6-(羟甲基)-N-甲基N-(2,2,2-三氟乙基)-吡啶酰胺的合成Step 2: Synthesis of compound 6-(hydroxymethyl)-N-methyl N-(2,2,2-trifluoroethyl)-pyridine amide
将化合物6-(甲基(2,2,2-三氟乙基)氨基甲酰基)吡啶甲酸甲酯(430mg,1.56mmol)溶于甲醇(5mL)中，冰浴中加入硼氢化钠(294mg，7.78mmol)，室温反应1.5h后停止，减压浓缩，浓缩液进行硅胶柱分离(洗脱剂：二氯甲烷/甲醇(v/v)＝66/1)，得到无色液体310mg，收率80％。The compound 6-(methyl(2,2,2-trifluoroethyl)carbamoyl)methyl picolinate (430mg, 1.56mmol) was dissolved in methanol (5mL), and sodium borohydride (294mg , 7.78mmol), the reaction was stopped after 1.5h at room temperature, concentrated under reduced pressure, and the concentrated solution was separated on a silica gel column (eluent: dichloromethane/methanol (v/v)=66/1) to obtain 310mg of colorless liquid. The rate is 80%.
H NMR(400MHz,CDCl 3)δ(ppm):7.80–7.85(m,1H),7.55–7.64(m,1H),7.37(d,J＝8.8,Hz,1H),4.79(d,J＝4.3,Hz,2H),4.32(q,J＝8.6,Hz,1H),4.22(q,J＝8.9,Hz,1H),3.24(s,1.5H),3.19(s,1.5H). H NMR (400MHz, CDCl 3 ) δ (ppm): 7.80-7.85 (m, 1H), 7.55-7.64 (m, 1H), 7.37 (d, J = 8.8, Hz, 1H), 4.79 (d, J = 4.3, Hz, 2H), 4.32 (q, J = 8.6, Hz, 1H), 4.22 (q, J = 8.9, Hz, 1H), 3.24 (s, 1.5H), 3.19 (s, 1.5H).
MS(ESI,pos.ion)m/z:249.20[M+H] +. MS(ESI,pos.ion)m/z:249.20[M+H] + .
步骤3：化合物(2R)-(6-(甲基(2,2,2-三氟乙基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯的合成Step 3: Compound (2R)-(6-(methyl(2,2,2-trifluoroethyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclo Synthesis of propylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(97mg,0.26mmol)，6-(羟甲基)-N-甲基-N-(2,2,2-三氟乙基)-吡啶酰胺(50mg,0.20mmol)溶于二氯甲烷(10mL)中，加入N-羟基-7-氮杂苯并三氮唑(61mg,0.45mmol)，在冰浴中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(214mg,1.12mmol)和N,N-二异丙基乙胺(144mg,1.11mmol)，室温反应11h，加水(20mL)搅拌5min，二氯甲烷萃取(5mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝54/1)，得到浅褐色粘稠固体68mg，收率56％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (97mg, 0.26mmol) , 6-(Hydroxymethyl)-N-methyl-N-(2,2,2-trifluoroethyl)-pyridine amide (50mg, 0.20mmol) was dissolved in dichloromethane (10mL), and N- Hydroxy-7-azabenzotriazole (61mg, 0.45mmol), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (214mg, 1.12 mmol) and N,N-diisopropylethylamine (144mg, 1.11mmol), react at room temperature for 11h, add water (20mL) and stir for 5min, extract with dichloromethane (5mL×2), dry the organic phase with anhydrous sodium sulfate, It was concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=54/1) to obtain 68 mg of a light brown viscous solid with a yield of 56%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.83–7.88(m,1H),7.69–7.71(m,0.5H),7.55–7.59(m,1.5H),7.12(d,J＝8.5Hz,1H),6.82(s,1H),6.75–6.81(m,1H),6.60(t,J F-H＝75.5Hz,1H),5.38–5.46(m,1H),5.22–5.29(m,15H),4.56–4.60(m,1H),4.42–4.48(m,1H),4.15–4.22(m,1H),3.93–3.98(m,1H),3.86(d,J＝6.9Hz,2H),3.63(t,J＝10.4Hz,1H),3.39–3.49(m,1H),3.19–3.21(m,3H),2.66–2.74(m,1H),2.05–2.14(m,1H),2.12(s,3H),1.25–1.36(m,1H),0.63–0.67(m,2H),0.33–0.37(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.83–7.88(m,1H), 7.69–7.71(m,0.5H), 7.55–7.59(m,1.5H), 7.12(d,J=8.5 Hz, 1H), 6.82 (s, 1H), 6.75-6.81 (m, 1H), 6.60 (t, J FH = 75.5 Hz, 1H), 5.38-5.46 (m, 1H), 5.22-5.29 (m, 15H) ), 4.56–4.60(m,1H), 4.42–4.48(m,1H), 4.15–4.22(m,1H), 3.93–3.98(m,1H), 3.86(d,J=6.9Hz,2H), 3.63(t,J=10.4Hz,1H), 3.39–3.49(m,1H), 3.19–3.21(m,3H), 2.66–2.74(m,1H), 2.05–2.14(m,1H), 2.12( s, 3H), 1.25-1.36 (m, 1H), 0.63-0.67 (m, 2H), 0.33-0.37 (m, 2H).
MS(ESI,pos.ion)m/z:600.20[M+H] +. MS(ESI,pos.ion)m/z:600.20[M+H] + .
实施例130：化合物(2R)-(6-(吗啉-4-羰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 130: Compound (2R)-(6-(morpholin-4-carbonyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-( (Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000192
Figure PCTCN2021090489-appb-000192
步骤1：化合物6-(吗啉-4-羰基)-2-吡啶甲酸甲酯的合成Step 1: Synthesis of compound 6-(morpholine-4-carbonyl)-2-picolinate methyl ester
取化合物吡啶二羧酸单甲酯(1.04g,5.74mmol)于50mL单口瓶，加入32mL二氯甲烷，搅拌，溶解， 在室温加入吗啉(0.82g,9.4mmol)以及N-羟基-7-氮杂苯并三氮唑(1.50g,10.8mmol)，之后冰浴下依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(3.21g,16.6mmol)和N,N-二异丙基乙胺(5.78g,44.6mmol)，最后室温搅拌3h，停止反应，水洗(30mL×3)，无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(梯度洗脱,洗脱剂：石油醚/乙酸乙酯(v/v)＝2:1,1:1)，得白色固体1.30g，收率90.4％。Take the compound monomethyl dipicolinate (1.04g, 5.74mmol) in a 50mL single-neck flask, add 32mL of dichloromethane, stir and dissolve, add morpholine (0.82g, 9.4mmol) and N-hydroxy-7- Azabenzotriazole (1.50g, 10.8mmol), followed by the addition of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (3.21g, 16.6mmol) under ice bath ) And N,N-diisopropylethylamine (5.78g, 44.6mmol), finally stirred at room temperature for 3h, stopped the reaction, washed with water (30mL×3), dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography ( Gradient elution, eluent: petroleum ether/ethyl acetate (v/v)=2:1, 1:1) to obtain 1.30 g of white solid, with a yield of 90.4%.
1H-NMR(400MHz,CDCl 3)δ(ppm):8.23-8.18(m,1H),8.00(t,J＝8.0Hz,1H),7.96-7.91(m,1H),4.03(s,3H),3.85(s,4H),3.75(s,4H). 1 H-NMR(400MHz, CDCl 3 )δ(ppm): 8.23-8.18(m,1H),8.00(t,J=8.0Hz,1H),7.96-7.91(m,1H),4.03(s,3H) ), 3.85(s, 4H), 3.75(s, 4H).
MS(ESI,pos.ion)m/z:251.10[M+H] +. MS(ESI,pos.ion)m/z:251.10[M+H] + .
步骤2：化合物(6-(羟甲基)吡啶基-2-基)(吗啉基)甲酮的合成Step 2: Synthesis of compound (6-(hydroxymethyl)pyridin-2-yl)(morpholinyl)methanone
取化合物6-(吗啉-4-羰基)-2-吡啶甲酸甲酯(0.71g,2.8mmol)于100mL单口瓶，加入6mL无水四氢呋喃，之后冰浴下加入硼氢化锂(0.14g,6.4mmol)，室温搅拌5h，停止反应，冰浴下加入20mL饱和NaCl溶液，乙酸乙酯萃取(15mL×3)，无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(梯度洗脱,洗脱剂：二氯甲烷/甲醇(v/v)＝12:1,11:1)，得白色固体209mg，收率33％。Take compound 6-(morpholine-4-carbonyl)-2-picolinate methyl ester (0.71g, 2.8mmol) in a 100mL single-necked flask, add 6mL anhydrous tetrahydrofuran, then add lithium borohydride (0.14g, 6.4 mmol), stirring at room temperature for 5h, stop the reaction, add 20mL saturated NaCl solution under ice bath, extract with ethyl acetate (15mL×3), dry with anhydrous sodium sulfate, concentrate, and perform silica gel column chromatography (gradient elution, elution Reagent: dichloromethane/methanol (v/v)=12:1, 11:1) to obtain 209 mg of white solid with a yield of 33%.
MS(ESI,pos.ion)m/z:223.10[M+H] +. MS(ESI,pos.ion)m/z:223.10[M+H] + .
步骤3：化合物(2R)-(6-(吗啉-4-羰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯的合成Step 3: Compound (2R)-(6-(morpholin-4-carbonyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-(di Synthesis of (fluoromethoxy)phenyl)pyrrolidine-2-carboxylate
取化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(96.9mg,0.26mmol)于25mL单口瓶，加入10mL二氯甲烷，搅拌，溶解，再室温加入6-羟甲基-N,N-甲基丙基-2-吡啶甲酰胺(69.6mg,0.31mmol)以及N-羟基-7-氮杂苯并三氮唑(77.1mg,0.56mmol)，之后冰浴下依次加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(159.0mg,0.82mmol)和N,N-二异丙基乙胺(285.0mg,2.20mmol)，最后室温搅拌6h，停止反应，水洗(30mL×3)，无水硫酸钠干燥，浓缩，进行硅胶柱层析分离(梯度洗脱,洗脱剂：二氯甲烷/甲醇(v/v)＝7:1,6:1)，得淡黄色油状物78.1mg，收率51.9％。Take compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (96.9mg, 0.26mmol ) In a 25mL single-neck flask, add 10mL of dichloromethane, stir and dissolve, and then add 6-hydroxymethyl-N,N-methylpropyl-2-pyridinecarboxamide (69.6mg, 0.31mmol) and N-hydroxyl at room temperature -7-azabenzotriazole (77.1mg, 0.56mmol), and then add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (159.0mg ,0.82mmol) and N,N-diisopropylethylamine (285.0mg, 2.20mmol), and finally stirred at room temperature for 6h, stop the reaction, wash with water (30mL×3), dry with anhydrous sodium sulfate, concentrate, and perform silica gel column layer Analytical separation (gradient elution, eluent: dichloromethane/methanol (v/v)=7:1, 6:1), 78.1 mg of pale yellow oily substance was obtained, with a yield of 51.9%.
1H-NMR(400MHz,CDCl 3)δ(ppm):7.89-7.82(m,1H),7.62-7.58(m,1H),7.57-7.54(m,1H),7.18-7.14(m,1H),6.88-6.83(m,2H),6.64(t,J F-H＝75.6Hz,1H),5.47-5.42(m,1H),5.28-5.24(m,1H),4.64-4.58(m,1H),4.02-3.97(m,1H),3.92-3.86(m,2H),3.84-3.76(m,4H),3.72-3.67(m,2H),3.65-3.60(m,2H),2.76-2.71(m,1H),2.27-2.23(m,1H),2.15(s,2H),2.07-2.01(m,2H),0.93-0.87(m,2H),0.71-0.67(m,2H),0.40-0.35(m,2H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.89-7.82 (m, 1H), 7.62-7.58 (m, 1H), 7.57-7.54 (m, 1H), 7.18-7.14 (m, 1H) , 6.88-6.83 (m, 2H), 6.64 (t, J FH = 75.6Hz, 1H), 5.47-5.42 (m, 1H), 5.28-5.24 (m, 1H), 4.64-4.58 (m, 1H), 4.02-3.97(m,1H),3.92-3.86(m,2H),3.84-3.76(m,4H),3.72-3.67(m,2H),3.65-3.60(m,2H),2.76-2.71(m ,1H),2.27-2.23(m,1H),2.15(s,2H),2.07-2.01(m,2H),0.93-0.87(m,2H),0.71-0.67(m,2H),0.40-0.35 (m,2H).
MS(ESI,pos.ion)m/z:574.60[M+H] +. MS(ESI,pos.ion)m/z:574.60[M+H] + .
实施例131：化合物(2R)-(6-(环己基(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 131: Compound (2R)-(6-(cyclohexyl(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000193
Figure PCTCN2021090489-appb-000193
步骤1：化合物6-(环己基(甲基)氨基甲酰基)吡啶甲酸甲酯的合成Step 1: Synthesis of compound methyl 6-(cyclohexyl(methyl)carbamoyl)picolinate
将化合物2,6-吡啶二羧酸单甲酯(500mg,2.76mmol)，N-甲基环己胺(374mg,3.30mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.30g,6.80mmol)和N-羟基-7-氮杂苯并三氮唑(753mg,5.53mmol)溶于二氯甲烷(20mL)中，冷却至0℃，加入N,N-二异丙基乙胺(1.5mL,8.10mmol)，室温反应17.5h，加水洗(20mL×2)有机相，分离有机相，用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗 脱剂：石油醚/乙酸乙酯(v/v)＝3/2)，得到浅褐色液体754mg，收率98％。The compound 2,6-pyridinedicarboxylic acid monomethyl ester (500mg, 2.76mmol), N-methylcyclohexylamine (374mg, 3.30mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Diimide hydrochloride (1.30g, 6.80mmol) and N-hydroxy-7-azabenzotriazole (753mg, 5.53mmol) were dissolved in dichloromethane (20mL), cooled to 0℃, and added N,N-Diisopropylethylamine (1.5mL, 8.10mmol), react at room temperature for 17.5h, wash the organic phase with water (20mL×2), separate the organic phase, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and concentrate Perform silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/2) to obtain 754 mg of light brown liquid with a yield of 98%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.17(t,J＝8.8Hz,1H),7.93–7.98(m,1H),7.78–7.85(m,1H),4.50–4.58(m,0.4H),4.02(s,1.2H),4.01(s,1.8H),3.63–3.70(m,0.6H),3.03(s,1.8H),2.93(s,1.2H),1.78–1.97(m,4H),1.46–1.49(m,4H),1.09–1.17(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.17 (t, J = 8.8Hz, 1H), 7.93-7.98 (m, 1H), 7.78-7.85 (m, 1H), 4.50-4.58 (m, 0.4H), 4.02(s, 1.2H), 4.01(s, 1.8H), 3.63-3.70(m, 0.6H), 3.03(s, 1.8H), 2.93(s, 1.2H), 1.78-1.97( m,4H),1.46-1.49(m,4H),1.09-1.17(m,2H).
MS(ESI,pos.ion)m/z:277.20[M+H] +. MS(ESI,pos.ion)m/z:277.20[M+H] + .
步骤2：化合物N-环己基-6-(羟甲基)-N-甲基吡啶酰胺的合成Step 2: Synthesis of compound N-cyclohexyl-6-(hydroxymethyl)-N-picolineamide
将化合物6-(环己基(甲基)氨基甲酰基)吡啶甲酸甲酯(750mg,2.71mmol)溶于四氢呋喃(10mL)中，冰浴下加入硼氢化锂(117mg,5.50mmol)，室温反应2.5h后停止，加入饱和氯化钠水溶液(30mL)，乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，减压浓缩，得到白色固体632mg，收率93％。The compound 6-(cyclohexyl(methyl)carbamoyl) methyl picolinate (750mg, 2.71mmol) was dissolved in tetrahydrofuran (10mL), lithium borohydride (117mg, 5.50mmol) was added under ice bath, and the reaction was carried out at room temperature for 2.5 Stop after h, add saturated sodium chloride aqueous solution (30 mL), extract with ethyl acetate (20 mL×3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 632 mg of white solid with a yield of 93%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.97(t,J＝7.8Hz,1H),7.62–7.66(m,1H),7.41(d,J＝7.6Hz,1H),4.72–4.73(m,2H),3.36–3.42(m,0.6H),3.01(s,1.8H),2.82(s,1.2H),2.58–2.65(m,0.4H),1.76–1.93(m,4H),1.42–1.67(m,4H),1.06–1.21(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.97 (t, J = 7.8Hz, 1H), 7.62-7.66 (m, 1H), 7.41 (d, J = 7.6 Hz, 1H), 4.72- 4.73(m,2H), 3.36-3.42(m,0.6H), 3.01(s,1.8H), 2.82(s,1.2H), 2.58-2.65(m,0.4H), 1.76-1.93(m,4H) ), 1.42-1.67 (m, 4H), 1.06-1.21 (m, 2H).
MS(ESI,pos.ion)m/z:249.30[M+H] +. MS(ESI,pos.ion)m/z:249.30[M+H] + .
步骤3：化合物(2R)-(6-(环己基(甲基)氨基甲酰基)吡啶-2-基)甲基-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯的合成Step 3: Compound (2R)-(6-(cyclohexyl(methyl)carbamoyl)pyridin-2-yl)methyl-1-acetyl-4-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(80mg,0.22mmol)，N-环己基-6-(羟甲基)-N-甲基吡啶酰胺(53mg,0.21mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(207mg,1.08mmol)和N-羟基-7-氮杂苯并三氮唑(60mg,0.44mmol)溶于二氯甲烷(8mL)中，冷却至0℃，加入N,N-二异丙基乙胺(167mg,1.29mmol)，室温反应13h，加二氯甲烷(15mL)，有机相水洗(20mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)，得到白色粘稠固体83mg，收率64％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (80mg, 0.22mmol) , N-cyclohexyl-6-(hydroxymethyl)-N-picolinamide (53mg, 0.21mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (207mg, 1.08mmol) and N-hydroxy-7-azabenzotriazole (60mg, 0.44mmol) dissolved in dichloromethane (8mL), cooled to 0℃, added N,N-diisopropyl Ethylamine (167mg, 1.29mmol), react at room temperature for 13h, add dichloromethane (15mL), wash the organic phase with water (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and subject the concentrate to silica gel column chromatography After separation (eluent: dichloromethane/methanol (v/v)=50/1), 83 mg of a white viscous solid was obtained with a yield of 64%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.80–7.85(m,1H),7.45–7.55(m,2H),7.15(d,J＝8.4Hz,1H),6.85(s,1H),6.80–6.84(m,1H),6.63(t,J F-H＝75.5Hz,1H),5.25–5.46(m,2H),4.59–4.64(m,1H),3.95–4.01(m,1H),3.89(d,J＝6.7Hz,2H),3.63–3.68(m,1H),3.40–3.54(m,2H),3.00(s,1.8H),2.83(s,1.2H),.70–2.77(m,1H),2.10–2.17(m,1H),2.15(s,3H),1.73–1.87(m,4H),1.46–1.58(m,4H),1.28–1.31(m,1H),1.05–1.16(m,2H),0.65–0.69(m,2H),0.36–0.40(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.80-7.85(m,1H),7.45-7.55(m,2H), 7.15(d,J=8.4Hz,1H), 6.85(s,1H) ,6.80–6.84(m,1H),6.63(t,J FH =75.5Hz,1H), 5.25–5.46(m,2H),4.59–4.64(m,1H),3.95–4.01(m,1H), 3.89(d,J=6.7Hz,2H),3.63–3.68(m,1H), 3.40–3.54(m,2H), 3.00(s,1.8H), 2.83(s,1.2H),.70–2.77 (m,1H), 2.10–2.17(m,1H), 2.15(s,3H), 1.73–1.87(m,4H), 1.46–1.58(m,4H), 1.28–1.31(m,1H), 1.05 --1.16 (m, 2H), 0.65 - 0.69 (m, 2H), 0.36 - 0.40 (m, 2H).
MS(ESI,pos.ion)m/z:600.30[M+H] +. MS(ESI,pos.ion)m/z:600.30[M+H] + .
实施例132：化合物(2R)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 132: Compound (2R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy) -4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000194
Figure PCTCN2021090489-appb-000194
步骤1：化合物6-(甲基(对甲苯基)氨基甲酰基)吡啶甲酸甲酯的合成Step 1: Synthesis of compound methyl 6-(methyl(p-tolyl)carbamoyl)picolinate
将化合物2,6-吡啶二羧酸单甲酯(500mg,2.76mmol)，N-甲基-4-甲基苯胺(402mg,3.32mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.30g,6.80mmol)和N-羟基-7-氮杂苯并三氮唑(753mg,5.53mmol)溶于二氯甲烷(20mL)中，冷却至0℃，加入N,N-二异丙基乙胺(1.10g,8.51mmol)，室温反应 17h，加水洗(20mL×2)有机相，分离有机相，用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝3/2)，得到浅褐色液体761mg，收率97％。The compound 2,6-pyridinedicarboxylate monomethyl ester (500mg, 2.76mmol), N-methyl-4-methylaniline (402mg, 3.32mmol), 1-ethyl-(3-dimethylaminopropyl) Base) carbodiimide hydrochloride (1.30g, 6.80mmol) and N-hydroxy-7-azabenzotriazole (753mg, 5.53mmol) dissolved in dichloromethane (20mL), cooled to 0 ℃, add N,N-diisopropylethylamine (1.10g, 8.51mmol), react at room temperature for 17h, wash the organic phase with water (20mL×2), separate the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrated solution was separated by silica gel column (eluent: petroleum ether/ethyl acetate (v/v)=3/2) to obtain 761 mg of light brown liquid with a yield of 97%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.97(d,J＝7.5Hz,1H),7.73(t,J＝8.8Hz,1H),7.57(d,J＝7.4Hz,1H),6.96–7.01(m,4H),3.92(s,3H),3.51(s,3H),2.26(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.97 (d, J = 7.5 Hz, 1H), 7.73 (t, J = 8.8 Hz, 1H), 7.57 (d, J = 7.4 Hz, 1H), 6.96--7.01(m,4H), 3.92(s,3H), 3.51(s,3H), 2.26(s,3H).
MS(ESI,pos.ion)m/z:285.20[M+H] +. MS(ESI,pos.ion)m/z:285.20[M+H] + .
步骤2：化合物6-(羟甲基)-N-甲基-N-(对甲苯基)吡啶酰胺的合成Step 2: Synthesis of compound 6-(hydroxymethyl)-N-methyl-N-(p-tolyl)pyridine amide
将化合物6-(甲基(对甲苯基)氨基甲酰基)吡啶甲酸甲酯(680mg,2.39mmol)溶于甲醇(8mL)中，冰浴中加入硼氢化钠(271mg，7.16mmol)，室温反应3h后停止，加入饱和氯化钠水溶液(30mL)，乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/4)，得到白色固体171mg，收率27％。The compound 6-(methyl(p-tolyl)carbamoyl)picolinate (680mg, 2.39mmol) was dissolved in methanol (8mL), sodium borohydride (271mg, 7.16mmol) was added to the ice bath, and the reaction was carried out at room temperature. Stop after 3h, add saturated sodium chloride aqueous solution (30mL), extract with ethyl acetate (20mL×3), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the concentrated solution by silica gel column chromatography (eluent: Petroleum ether/ethyl acetate (v/v) = 1/4) to obtain 171 mg of white solid with a yield of 27%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.58–7.67(m,2H),6.97–7.07(m,5H),4.49(s,2H),3.52(s,3H),2.85(br.s,1H),2.30(s,3H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.58-7.67 (m, 2H), 6.97-7.07 (m, 5H), 4.49 (s, 2H), 3.52 (s, 3H), 2.85 (br .s,1H),2.30(s,3H).
MS(ESI,pos.ion)m/z:257.20[M+H] +. MS(ESI,pos.ion)m/z:257.20[M+H] + .
步骤3：化合物(2R)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯的合成Step 3: Compound (2R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(80mg,0.22mmol)，6-(羟甲基)-N-甲基-N-(对甲苯基)吡啶酰胺(52mg,0.22mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(207mg,1.08mmol)和N-羟基-7-氮杂苯并三氮唑(58mg,0.43mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入N,N-二异丙基乙胺(141mg,1.09mmol)，室温反应9h，加二氯甲烷(15mL)，有机相水洗(20mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/2)，得到白色粘稠固体87mg，收率65％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (80mg, 0.22mmol) , 6-(Hydroxymethyl)-N-methyl-N-(p-tolyl)pyridine amide (52mg, 0.22mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Hydrochloride (207mg, 1.08mmol) and N-hydroxy-7-azabenzotriazole (58mg, 0.43mmol) were dissolved in dichloromethane (10mL), cooled to 0℃, added N,N-di Isopropylethylamine (141mg, 1.09mmol), react at room temperature for 9h, add dichloromethane (15mL), wash the organic phase with water (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the concentrated solution to silica gel Column chromatography separation (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) to obtain 87 mg of a white viscous solid with a yield of 65%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.54–7.66(m,1H),7.31–7.40(m,1H),7.22–7.28(m,1H),7.14(d,J＝8.3Hz,1H),6.93–6.99(m,4H),6.84(s,1H),6.82(d,J＝3.9Hz,1H),6.62(t,J F-H＝75.5Hz,1H),5.04–5.24(m,2H),4.55–4.59(m,1H),3.95–3.99(m,1H),3.88(d,J＝6.9Hz,2H),3.63(t,J＝10.5Hz,1H),3.39–3.52(m,1H),3.48(s,3H),2.68–2.74(m,1H),2.27(s,3H),2.13(s,3H),2.03–2.11(m,1H),1.27–1.35(m,1H),0.65–0.69(m,2H),0.36–0.39(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.54–7.66(m,1H), 7.31–7.40(m,1H), 7.22–7.28(m,1H), 7.14(d,J=8.3Hz, 1H), 6.93–6.99 (m, 4H), 6.84 (s, 1H), 6.82 (d, J = 3.9 Hz, 1H), 6.62 (t, J FH = 75.5 Hz, 1H), 5.04–5.24 (m, 2H), 4.55–4.59 (m, 1H), 3.95–3.99 (m, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.63 (t, J = 10.5 Hz, 1H), 3.39–3.52 (m ,1H),3 ), 0.65--0.69 (m, 2H), 0.36--0.39 (m, 2H).
MS(ESI,pos.ion)m/z:608.50[M+H] +. MS(ESI,pos.ion)m/z:608.50[M+H] + .
实施例133：化合物(2R)-(6-((4-氟苯基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 133: Compound (2R)-(6-((4-Fluorophenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropyl) Methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000195
Figure PCTCN2021090489-appb-000195
步骤1：化合物6-羟甲基吡啶-2-羧酸甲酯的合成Step 1: Synthesis of compound 6-hydroxymethylpyridine-2-carboxylic acid methyl ester
将化合物2,6-吡啶二羧酸单甲酯(1.0g,5.5mmol)溶解在无水四氢呋喃(10mL)溶液中，加入N,N-羰基二咪唑(1.1g,6.8mmol)，50℃加热反应1h后停止，冷却至室温，加入硼氢化钠(320mg,8.4mmol)，室温反应2.5h，加入水(25mL)淬灭反应，用乙酸乙酯萃取(30mL×6)，无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/4)，得无色液体704mg，收率76％。Dissolve the compound 2,6-pyridinedicarboxylic acid monomethyl ester (1.0g, 5.5mmol) in anhydrous tetrahydrofuran (10mL) solution, add N,N-carbonyldiimidazole (1.1g, 6.8mmol), and heat at 50℃ The reaction was stopped after 1h, cooled to room temperature, sodium borohydride (320mg, 8.4mmol) was added, reacted at room temperature for 2.5h, water (25mL) was added to quench the reaction, extracted with ethyl acetate (30mL×6), dried with anhydrous sodium sulfate It was concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/4) to obtain 704 mg of colorless liquid, with a yield of 76%.
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.00(t,J＝7.7Hz,1H),7.94(t,J＝8.3Hz,1H),7.72(d,J＝7.7Hz,1H),4.62(s,2H),3.88(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.00 (t, J = 7.7 Hz, 1H), 7.94 (t, J = 8.3 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H ), 4.62(s, 2H), 3.88(s, 3H).
MS(ESI,pos.ion)m/z:168.20[M+H] +. MS(ESI,pos.ion)m/z:168.20[M+H] + .
步骤2：化合物6-(((叔丁基二甲基硅基)氧基)甲基)吡啶甲酸甲酯的合成Step 2: Synthesis of compound methyl 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinate
将化合物6-羟甲基吡啶-2-羧酸甲酯(700mg,4.19mmol)溶解在二氯甲烷(10mL)溶液中，加入三乙胺(639mg,6.31mmol)，冰浴中加入叔丁基二甲硅基三氟甲磺酸酯(1.3g,4.90mmol)，室温反应3h，停止反应，水洗有机相(20mL×2)，无水硫酸钠干燥，减压浓缩，进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝10/1)，得无色液体744mg，收率63％。The compound 6-hydroxymethylpyridine-2-carboxylic acid methyl ester (700mg, 4.19mmol) was dissolved in dichloromethane (10mL) solution, triethylamine (639mg, 6.31mmol) was added, and tert-butyl was added to the ice bath Dimethylsilyl trifluoromethanesulfonate (1.3g, 4.90mmol), react at room temperature for 3h, stop the reaction, wash the organic phase (20mL×2) with water, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography for separation (Eluent: petroleum ether/ethyl acetate (v/v)=10/1) to obtain 744 mg of colorless liquid, with a yield of 63%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.02(d,J＝7.7Hz,1H),7.88(t,J＝7.8Hz,1H),7.76(d,J＝7.8Hz,1H),4.96(s,2H),4.02(s,3H),0.98(s,9H),0.14(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.02 (d, J = 7.7 Hz, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 4.96(s, 2H), 4.02(s, 3H), 0.98(s, 9H), 0.14(s, 6H).
MS(ESI,pos.ion)m/z:282.20[M+H] +. MS(ESI,pos.ion)m/z:282.20[M+H] + .
步骤3：化合物6-(((叔丁基二甲基硅基)氧基)甲基)吡啶甲酸的合成Step 3: Synthesis of compound 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinic acid
将化合物6-(((叔丁基二甲基硅基)氧基)甲基)吡啶甲酸甲酯(740mg,2.63mmol)溶于四氢呋喃(5mL)和水(5mL)的混合溶剂中，加入一水合氢氧化锂(220mg,5.24mmol)，60℃反应45min后停止，加稀盐酸调节溶液pH＝6，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到白色固体232mg，收率33％。The compound 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinate (740mg, 2.63mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (5mL), and one Lithium hydroxide hydrate (220mg, 5.24mmol), the reaction was stopped at 60°C for 45 minutes, diluted hydrochloric acid was added to adjust the pH of the solution to 6, extracted with ethyl acetate (20mL×3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain White solid 232mg, yield 33%.
MS(ESI,pos.ion)m/z:268.20[M+H] +. MS(ESI,pos.ion)m/z:268.20[M+H] + .
步骤4：化合物6-(((叔丁基二甲基硅基)氧基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺的合成Step 4: Synthesis of compound 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(4-fluorophenyl)-N-picolineamide
将化合物6-(((叔丁基二甲基硅基)氧基)甲基)吡啶甲酸(200mg,0.75mmol)，4-氟-N-甲基苯胺(134mg,0.99mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(716mg,3.74mmol)和N-羟基-7-氮杂苯并三氮唑(203mg,1.49mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入N,N-二异丙基乙胺(280mg,2.17mmol)，室温反应10h，加入二氯甲烷(15mL)，加水洗有机相(20mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4/1)，得到浅褐色液体113mg，收率44％。The compound 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinic acid (200mg, 0.75mmol), 4-fluoro-N-methylaniline (134mg, 0.99mmol), 1-ethyl -(3-Dimethylaminopropyl) carbodiimide hydrochloride (716mg, 3.74mmol) and N-hydroxy-7-azabenzotriazole (203mg, 1.49mmol) dissolved in dichloromethane In methane (10mL), cool to 0℃, add N,N-diisopropylethylamine (280mg, 2.17mmol), react at room temperature for 10h, add dichloromethane (15mL), add water to wash the organic phase (20mL×2) The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain 113 mg of light brown liquid. The yield was 44%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.60–7.69(m,1H),7.34–7.40(m,2H),6.99–7.12(m,2H),6.86–6.95(m,2H),4.55(s,2H),3.50(s,3H),0.94(s,9H),0.07(s,6H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.60-7.69(m,1H), 7.34-7.40(m,2H), 6.99-7.12(m,2H), 6.86-6.95(m,2H), 4.55(s, 2H), 3.50(s, 3H), 0.94(s, 9H), 0.07(s, 6H).
MS(ESI,pos.ion)m/z:375.20[M+H] +. MS(ESI,pos.ion)m/z:375.20[M+H] + .
步骤5：化合物N-(4-氟苯基)-6-(羟甲基)-N-甲基吡啶酰胺的合成Step 5: Synthesis of compound N-(4-fluorophenyl)-6-(hydroxymethyl)-N-picolineamide
将化合物6-(((叔丁基二甲基硅基)氧基)甲基)-N-(4-氟苯基)-N-甲基吡啶酰胺(107mg,0.29mmol)溶于四氢呋喃(5mL)中，加入3mol/L四丁基氟化铵的四氢呋喃溶液(1.5mL)，室温反应2h，加入饱和氯化钠(5mL)，乙酸乙酯萃取(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：乙酸乙酯(v)＝100％)，得到白色固体68mg，收率91％。The compound 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(4-fluorophenyl)-N-picolineamide (107mg, 0.29mmol) was dissolved in tetrahydrofuran (5mL ), add 3mol/L tetrabutylammonium fluoride solution in tetrahydrofuran (1.5mL), react at room temperature for 2h, add saturated sodium chloride (5mL), extract with ethyl acetate (15mL×2), and use anhydrous sulfuric acid for the organic phase After drying with sodium and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate (v) = 100%) to obtain 68 mg of a white solid with a yield of 91%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.67–7.71(m,1H),7.59–7.61(m,1H),7.04–7.13(m,3H),6.94–6.98(m,2H),4.52(s,2H),3.52(s,3H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.67-7.71(m,1H), 7.59-7.61(m,1H), 7.04-7.13(m,3H), 6.94-6.98(m,2H), 4.52(s,2H),3.52(s,3H).
MS(ESI,pos.ion)m/z:261.20[M+H] +. MS(ESI,pos.ion)m/z:261.20[M+H] + .
步骤6：化合物(2R)-(6-((4-氟苯基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯的合成Step 6: Compound (2R)-(6-((4-fluorophenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(51mg,0.14mmol)，N-(4-氟苯基)-6-(羟甲基)-N-甲基吡啶酰胺(35mg,0.14mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(260mg,1.36mmol)和N-羟基-7-氮杂苯并三氮唑(55mg,0.40mmol)溶于二氯甲烷(10mL)中，冷却 至0℃，加入N,N-二异丙基乙胺(174mg,1.35mmol)，室温反应10h，加入二氯甲烷(15mL)，加水洗有机相(20mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝30/1)，得到59mg白色粘稠固体，收率70％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (51mg, 0.14mmol) , N-(4-fluorophenyl)-6-(hydroxymethyl)-N-picolineamide (35mg, 0.14mmol), 1-ethyl-(3-dimethylaminopropyl) carbonyl Imine hydrochloride (260mg, 1.36mmol) and N-hydroxy-7-azabenzotriazole (55mg, 0.40mmol) were dissolved in dichloromethane (10mL), cooled to 0℃, added N,N -Diisopropylethylamine (174mg, 1.35mmol), react at room temperature for 10h, add dichloromethane (15mL), add water to wash the organic phase (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and remain The product was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=30/1) to obtain 59 mg of white viscous solid with a yield of 70%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.59–7.68(m,1H),7.31–7.43(m,2H),7.12(d,J＝8.0Hz,1H),6.97–7.05(m,2H),6.84–6.93(m,2H),6.82(s,1H),6.77–6.81(m,1H),6.60(t,J F-H＝75.5Hz,1H),5.10–5.21(m,1H),4.90–5.02(m,1H),4.51–4.55(m,1H),3.92–3.97(m,1H),3.86(d,J＝6.8Hz,2H),3.61(t,J＝10.4Hz,1H),3.46(s,3H),3.39–3.50(m,1H),2.64–2.71(m,1H),2.11(s,3H),2.01–2.11(m,1H),1.25–1.34(m,1H),0.62–0.67(m,2H),0.34–0.38(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.59–7.68(m,1H), 7.31–7.43(m,2H), 7.12(d,J=8.0Hz,1H), 6.97–7.05(m, 2H), 6.84–6.93(m, 2H), 6.82(s, 1H), 6.77–6.81(m, 1H), 6.60(t, J FH = 75.5Hz, 1H), 5.10–5.21(m, 1H), 4.90–5.02(m,1H),4.51–4.55(m,1H),3.92–3.97(m,1H), 3.86(d,J=6.8Hz,2H),3.61(t,J=10.4Hz,1H) , 3.46 (s, 3H), 3.39-3.50 (m, 1H), 2.64-2.71 (m, 1H), 2.11 (s, 3H), 2.01-2.11 (m, 1H), 1.25-1.34 (m, 1H) , 0.62-0.67 (m, 2H), 0.34-0.38 (m, 2H).
MS(ESI,pos.ion)m/z:612.20[M+H] +. MS(ESI,pos.ion)m/z:612.20[M+H] + .
实施例134：化合物(2R)-(3-(氨基甲酰基)苄基)1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 134: Compound (2R)-(3-(carbamoyl)benzyl)1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl )Pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000196
Figure PCTCN2021090489-appb-000196
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(150mg,0.41mmol)，3-(羟甲基)苯甲酰胺(74mg,0.49mmol)和N-羟基-7-氮杂苯并三氮唑(111mg,0.82mmol)溶于二氯甲烷(8mL)和N,N-二甲基甲酰胺(1mL)中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(234mg,1.22mmol)和N,N-二异丙基乙胺(210mg,1.62mmol)，室温反应5h，减压浓缩除去溶剂，加水(30mL)，用乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝35/1)，得到白色固体137mg，收率67％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150mg, 0.41mmol) , 3-(hydroxymethyl)benzamide (74mg, 0.49mmol) and N-hydroxy-7-azabenzotriazole (111mg, 0.82mmol) were dissolved in dichloromethane (8mL) and N,N- To dimethylformamide (1mL), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (234mg, 1.22mmol) and N,N-diisopropylethyl Amine (210mg, 1.62mmol), react at room temperature for 5h, concentrate under reduced pressure to remove the solvent, add water (30mL), extract with ethyl acetate (10mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and carry out the residue Separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=35/1) to obtain 137 mg of white solid with a yield of 67%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.98(s,1H),7.89–7.95(m,1H),7.35–7.47(m,2H),7.12(d,J＝7.3Hz,1H),6.78–6.89(m,2H),6.60(t,J F-H＝75.4Hz,1H),5.55(d,J＝13.0Hz,1H),5.12(d,J＝13.1Hz,1H),4.54–4.63(m,1H),3.92–3.99(m,1H),3.86(d,J＝6.0Hz,2H),3.60–3.66(m,1H),3.39–3.50(m,1H),2.65–2.76(m,1H),2.05–2.17(m,1H),2.10(s,3H),1.21–1.32(m,1H),0.56–0.69(m,2H),0.26–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.98 (s, 1H), 7.89-7.95 (m, 1H), 7.35-7.47 (m, 2H), 7.12 (d, J = 7.3 Hz, 1H) ,6.78–6.89(m,2H),6.60(t,J FH =75.4Hz,1H),5.55(d,J=13.0Hz,1H), 5.12(d,J=13.1Hz,1H),4.54–4.63 (m,1H), 3.92–3.99(m,1H), 3.86(d,J=6.0Hz,2H), 3.60–3.66(m,1H), 3.39–3.50(m,1H), 2.65–2.76(m ,1H), 2.05--2.17(m,1H), 2.10(s,3H), 1.21--1.32(m,1H), 0.56--0.69(m,2H), 0.26--0.39(m,2H).
MS(ESI,pos.ion)m/z:503.15[M+H] +. MS(ESI,pos.ion)m/z:503.15[M+H] + .
实施例135：化合物(2R)-(6-(氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 135: Compound (2R)-(6-(carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethyl (Oxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000197
Figure PCTCN2021090489-appb-000197
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(150mg,0.41mmol)，6-(羟甲基)吡啶酰胺(74mg,0.49mmol)和N-羟基-7-氮杂苯并三氮唑(110mg,0.81mmol)溶于二氯甲烷 (8mL)和N,N-二甲基甲酰胺(1mL)中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(233mg,1.22mmol)和N,N-二异丙基乙胺(209mg,1.62mmol)，室温反应5h，减压浓缩除去溶剂，加水(30mL)，用乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝35/1)，得到白色固体112mg，收率55％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150mg, 0.41mmol) , 6-(hydroxymethyl) pyridine amide (74mg, 0.49mmol) and N-hydroxy-7-azabenzotriazole (110mg, 0.81mmol) dissolved in dichloromethane (8mL) and N,N-di To methylformamide (1mL), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (233mg, 1.22mmol) and N,N-diisopropylethylamine (209mg, 1.62mmol), react at room temperature for 5h, concentrate under reduced pressure to remove the solvent, add water (30mL), extract with ethyl acetate (10mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the residue to silica gel It was separated by column chromatography (eluent: dichloromethane/methanol (v/v)=35/1) to obtain 112 mg of white solid with a yield of 55%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.11(d,J＝7.3Hz,1H),8.07(br.s,1H),7.85–7.89(m,1H),7.56(d,J＝7.4Hz,1H),7.11(d,J＝7.9Hz,1H),6.76–6.88(m,2H),6.60(t,J F-H＝75.5Hz,1H),5.48(d,J＝13.7Hz,1H),5.22(d,J＝13.7Hz,1H),4.59–4.63(m,1H),3.95–3.99(m,1H),3.85(d,J＝6.6Hz,2H),3.61–3.66(m,1H),3.39–3.50(m,1H),2.67–2.77(m,1H),2.05–2.17(m,1H),2.12(s,3H),1.21–1.32(m,1H),0.59–0.68(m,2H),0.28–0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.11 (d, J = 7.3 Hz, 1H), 8.07 (br.s, 1H), 7.85-7.89 (m, 1H), 7.56 (d, J = 7.4Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.76-6.88 (m, 2H), 6.60 (t, J FH = 75.5 Hz, 1H), 5.48 (d, J = 13.7 Hz, 1H ),5.22(d,J=13.7Hz,1H),4.59-4.63(m,1H),3.95-3.99(m,1H), 3.85(d,J=6.6Hz,2H),3.61-3.66(m, 1H), 3.39-3.50(m, 1H), 2.67-2.77(m, 1H), 2.05--2.17(m, 1H), 2.12(s, 3H), 1.21--1.32(m, 1H), 0.59-0.68( m,2H),0.28--0.37(m,2H).
MS(ESI,pos.ion)m/z:504.10[M+H] +. MS(ESI,pos.ion)m/z:504.10[M+H] + .
实施例136：化合物(2R)-(3-氧代异吲哚-5-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 136: Compound (2R)-(3-oxoisoindol-5-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) (Yl)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000198
Figure PCTCN2021090489-appb-000198
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(150mg,0.41mmol)，6-(羟甲基)异吲哚-1-酮(99mg,0.61mmol)和N-羟基-7-氮杂苯并三氮唑(110mg,0.81mmol)溶于二氯甲烷(8mL)和N,N-二甲基甲酰胺(1mL)中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(233mg,1.22mmol)和N,N-二异丙基乙胺(209mg,1.62mmol)，室温反应6h，减压浓缩除去溶剂，加水(30mL)，用乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝35/1)，得到白色固体19mg，收率9％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150mg, 0.41mmol) , 6-(hydroxymethyl) isoindol-1-one (99mg, 0.61mmol) and N-hydroxy-7-azabenzotriazole (110mg, 0.81mmol) dissolved in dichloromethane (8mL) and In N,N-dimethylformamide (1mL), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (233mg, 1.22mmol) and N,N-di Isopropylethylamine (209mg, 1.62mmol), react at room temperature for 6h, concentrate under reduced pressure to remove the solvent, add water (30mL), extract with ethyl acetate (10mL×2), dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure The residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=35/1) to obtain 19 mg of white solid with a yield of 9%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.85(s,1H),7.59(d,J＝7.9Hz,1H),7.47(d,J＝7.8Hz,1H),7.25–7.21(m,1H),7.10(d,J＝8.0Hz,1H),6.80(s,1H),6.79(d,J＝7.7Hz,1H),6.59(t,J F-H＝75.5Hz,1H),5.29(s,2H),4.52–4.56(m,1H),4.45(s,2H),3.92–3.96(m,1H),3.85(d,J＝6.9Hz,2H),3.59–3.65(m,1H),3.37–3.46(m,1H),2.64–2.71(m,1H),2.12(s,3H),1.99–2.08(m,1H),1.25–1.33(m,1H),0.61–0.66(m,2H),0.32–0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.85 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.25-7.21 (m ,1H),7.10(d,J=8.0Hz,1H),6.80(s,1H),6.79(d,J=7.7Hz,1H),6.59(t,J FH =75.5Hz,1H),5.29( s,2H),4.52–4.56(m,1H),4.45(s,2H),3.92–3.96(m,1H), 3.85(d,J=6.9Hz,2H),3.59–3.65(m,1H) , 3.37–3.46(m,1H), 2.64–2.71(m,1H), 2.12(s,3H), 1.99–2.08(m,1H), 1.25–1.33(m,1H), 0.61–0.66(m, 2H), 0.32--0.37 (m, 2H).
MS(ESI,pos.ion)m/z:515.20[M+H] +. MS(ESI,pos.ion)m/z:515.20[M+H] + .
实施例137：化合物(2R)-(1-氧代异吲哚-5-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 137: Compound (2R)-(1-oxoisoindol-5-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) (Yl)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000199
Figure PCTCN2021090489-appb-000199
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(200mg,0.54mmol)和5-(羟甲基)异吲哚-1-酮(220mg,1.35mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入N-羟基-7-氮杂苯并三氮唑(147mg,1.08mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(312mg,1.63mmol)和N,N-二异丙基乙胺(201mg,1.56mmol)，室温反应11h，减压浓缩除去溶剂，加水(30mL)，用乙酸乙酯萃取(20mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝25/1)，得到白色固体129mg，收率46％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (200mg, 0.54mmol) And 5-(hydroxymethyl) isoindol-1-one (220mg, 1.35mmol) dissolved in N,N-dimethylformamide (5mL), add N-hydroxy-7-azabenzotriazide Azole (147mg, 1.08mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (312mg, 1.63mmol) and N,N-diisopropylethylamine (201mg , 1.56mmol), react at room temperature for 11h, concentrate under reduced pressure to remove the solvent, add water (30mL), extract with ethyl acetate (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the residue to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=25/1) to obtain 129 mg of white solid with a yield of 46%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.86(d,J＝6.8Hz,1H),7.52(s,1H),7.43–7.47(m,1H),7.11(d,J＝7.7Hz,1H),6.81(s,1H),6.80(d,J＝7.5Hz,1H),6.60(t,J F-H＝75.6Hz,1H),5.24–5.36(m,2H),4.50–4.59(m,1H),4.47(s,2H),3.90–3.99(m,1H),3.85(d,J＝6.5Hz,2H),3.57–3.66(m,1H),3.37–3.50(m,1H),2.63–2.74(m,1H),2.13(s,3H),2.00–2.08(m,1H),1.25–1.33(m,1H),0.60–0.69(m,2H),0.30–0.39(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.86(d,J=6.8Hz,1H),7.52(s,1H),7.43-7.47(m,1H),7.11(d,J=7.7Hz ,1H),6.81(s,1H),6.80(d,J=7.5Hz,1H),6.60(t,J FH =75.6Hz,1H),5.24-5.36(m,2H),4.50-4.59(m ,1H),4.47(s,2H),3.90–3.99(m,1H), 3.85(d,J=6.5Hz,2H),3.57–3.66(m,1H), 3.37–3.50(m,1H), 2.63–2.74(m,1H), 2.13(s,3H), 2.00–2.08(m,1H), 1.25–1.33(m,1H), 0.60–0.69(m,2H), 0.30–0.39(m,2H) ).
MS(ESI,pos.ion)m/z:515.10[M+H] +. MS(ESI,pos.ion)m/z:515.10[M+H] + .
实施例138：化合物(2R)-(1-羟基-1,3-二氢苯并[c][1,2]噁硼烷-5-基)1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 138: Compound (2R)-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxboran-5-yl)1-acetyl-4-(3-(cyclo (Propylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000200
Figure PCTCN2021090489-appb-000200
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(100mg,0.27mmol)，2-羟基甲基-5-羟基苯硼酸半酯(48mg,0.32mmol)溶于干燥的N,N-二甲基甲酰胺(5mL)中，加入N-羟基-7-氮杂苯并三氮唑(73mg,0.54mmol)，在冰浴中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(259mg,1.35mmol)和N,N-二异丙基乙胺(174mg,1.35mmol)，室温反应5h，加水(20mL)搅拌5min，乙酸乙酯萃取(10mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝54/1)，得到白色固体42mg，收率31％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100mg, 0.27mmol) , 2-Hydroxymethyl-5-hydroxyphenylboronic acid half ester (48mg, 0.32mmol) was dissolved in dry N,N-dimethylformamide (5mL), and N-hydroxy-7-azabenzotriazole was added Nitrozazole (73mg, 0.54mmol), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (259mg, 1.35mmol) and N,N-diiso in an ice bath Propylethylamine (174mg, 1.35mmol), react at room temperature for 5h, add water (20mL) and stir for 5min, extract with ethyl acetate (10mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the concentrated solution to silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v)=54/1) to obtain 42 mg of white solid with a yield of 31%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.70(s,1H),7.18(s,1H),7.14(d,J＝8.1Hz,1H),7.11(d,J＝7.8Hz,1H),7.09(s,1H),6.97(d,J＝7.9Hz,1H),6.76(t,J F-H＝75.6Hz,1H),5.08(s,2H),4.68–4.71(m,1H),4.15–4.18(m,1H),3.94(d,J＝6.7Hz,2H),3.71(t,J＝10.2Hz,1H),3.61–3.68(m,1H),2.86–2.90(m,1H),2.22–2.28(m,1H),2.19(s,3H),1.31–1.38(m,1H),0.61–0.66(m,2H),0.37–0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.70 (s, 1H), 7.18 (s, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H ), 7.09 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.76 (t, J FH = 75.6 Hz, 1H), 5.08 (s, 2H), 4.68–4.71 (m, 1H), 4.15–4.18 (m, 1H), 3.94 (d, J = 6.7 Hz, 2H), 3.71 (t, J = 10.2 Hz, 1H), 3.61–3.68 (m, 1H), 2.86–2.90 (m, 1H) ,2.22-2.28(m,1H),2.19(s,3H),1.31-1.38(m,1H),0.61-0.66(m,2H),0.37-0.40(m,2H).
MS(ESI,pos.ion)m/z:502.10[M+H] +. MS(ESI,pos.ion)m/z:502.10[M+H] + .
实施例139：化合物(2R)-(3-氧代异吲哚-5-基)1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 139: Compound (2R)-(3-oxoisoindol-5-yl)1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl) pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000201
Figure PCTCN2021090489-appb-000201
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(200mg,0.54mmol)， 5-羟基异吲哚-1-酮(96mg,0.64mmol)和N-羟基-7-氮杂苯并三氮唑(149mg,1.09mmol)溶于二氯甲烷(12mL)和N,N-二甲基甲酰胺(4mL)中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(313mg,1.63mmol)和N,N-二异丙基乙胺(282mg,2.18mmol)，室温反应5h，减压浓缩除去溶剂，加水(40mL)，用乙酸乙酯萃取(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝35/1)，得到白色固体163mg，收率60％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (200mg, 0.54mmol) , 5-Hydroxyisoindole-1-one (96mg, 0.64mmol) and N-hydroxy-7-azabenzotriazole (149mg, 1.09mmol) were dissolved in dichloromethane (12mL) and N,N- To dimethylformamide (4mL), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (313mg, 1.63mmol) and N,N-diisopropylethyl Amine (282mg, 2.18mmol), react at room temperature for 5h, concentrate under reduced pressure to remove the solvent, add water (40mL), extract with ethyl acetate (15mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and carry out the residue Separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=35/1) to obtain 163 mg of white solid with a yield of 60%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.60(s,1H),7.43–7.48(m,2H),7.24–7.34(m,1H),7.16(d,J＝6.0Hz,1H),6.80–6.94(m,2H),6.64(t,J＝75.3Hz,1H),4.64–4.80(m,1H),4.46(s,2H),3.96–4.09(m,1H),3.89(d,J＝4.6Hz,2H),3.63–3.74(m,1H),3.46–3.60(m,1H),2.77–2.92(m,1H),2.17–2.32(m,1H),2.16(s,3H),1.26–1.38(m,1H),0.59–0.71(m,2H),0.31–0.44(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.60 (s, 1H), 7.43-7.48 (m, 2H), 7.24-7.34 (m, 1H), 7.16 (d, J = 6.0 Hz, 1H) ,6.80–6.94(m,2H),6.64(t,J=75.3Hz,1H), 4.64–4.80(m,1H), 4.46(s,2H), 3.96–4.09(m,1H), 3.89(d ,J=4.6Hz,2H),3.63–3.74(m,1H), 3.46–3.60(m,1H), 2.77–2.92(m,1H), 2.17–2.32(m,1H), 2.16(s,3H) ), 1.26--1.38(m,1H), 0.59--0.71(m,2H), 0.31--0.44(m,2H).
MS(ESI,pos.ion)m/z:501.10[M+H] +. MS(ESI,pos.ion)m/z:501.10[M+H] + .
实施例140：化合物(2R)-(2-甲基-1-氧代异吲哚-5-基)1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯和Example 140: The compound (2R)-(2-methyl-1-oxoisoindol-5-yl) 1-acetyl-4-(3-(cyclopropylmethoxy)-4-(two (Fluoromethoxy) phenyl) pyrrolidine-2-carboxylate and
实施例141：化合物(2R)-(2,3-二甲基-1-氧代异吲哚-5-基)1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 141: Compound (2R)-(2,3-Dimethyl-1-oxoisoindol-5-yl)1-acetyl-4-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
实施例140：
Figure PCTCN2021090489-appb-000202
和实施例141：
Figure PCTCN2021090489-appb-000203
Example 140:
Figure PCTCN2021090489-appb-000202
And Example 141:
Figure PCTCN2021090489-appb-000203
步骤1：化合物5-(苄氧基)异吲哚-1-酮的合成Step 1: Synthesis of compound 5-(benzyloxy)isoindol-1-one
将5-羟基异吲哚-1-酮(400mg,2.68mmol)和碳酸钾(741mg,5.36mmol)混合，加入无水N,N-二甲基甲酰胺(5mL)溶液和苄溴(688mg,4.02mmol)，80℃反应4h，冷却至室温，加入水(60mL)析出白色固体，抽滤，滤饼干燥，得到白色固体536mg，收率84％。Mix 5-hydroxyisoindole-1-one (400mg, 2.68mmol) and potassium carbonate (741mg, 5.36mmol), add anhydrous N,N-dimethylformamide (5mL) solution and benzyl bromide (688mg, 4.02mmol), reacted at 80°C for 4h, cooled to room temperature, added water (60mL) to precipitate a white solid, filtered with suction, and dried the filter cake to obtain 536mg of a white solid with a yield of 84%.
1H NMR(400MHz,d 6-DMSO)δ(ppm):8.32(br.s,1H),7.58(d,J＝8.4Hz,1H),7.46–7.47(m,2H),7.38–7.42(m,2H),7.32–7.36(m,1H),7.21(s,1H),7.09(dd,J＝8.4,2.0Hz,1H),5.18(s,2H),4.31(s,2H). 1 H NMR (400MHz, d 6 -DMSO) δ (ppm): 8.32 (br.s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.46-7.47 (m, 2H), 7.38-7.42 ( m, 2H), 7.32–7.36 (m, 1H), 7.21 (s, 1H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 5.18 (s, 2H), 4.31 (s, 2H).
MS(ESI,pos.ion)m/z:240.10[M+H] +. MS(ESI,pos.ion)m/z:240.10[M+H] + .
步骤2：化合物5-(苄氧基)-2-甲基异吲哚-1-酮和5-(苄氧基)-2,3-二甲基异吲哚-1-酮的合成Step 2: Synthesis of compounds 5-(benzyloxy)-2-methylisoindol-1-one and 5-(benzyloxy)-2,3-dimethylisoindol-1-one
将5-(苄氧基)异吲哚-1-酮(400mg,1.67mmol)溶解在无水二甲基亚风(5mL)溶液中，在冰浴中冷却，加入60％氢化钠(133mg,3.33mmol)反应30min，再加入碘甲烷(475mg,3.33mmol)反应4h，加入水(60mL)淬灭反应，用二氯甲烷(10mL×2)萃取，有机相合用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝40/1)，得到混合物浅黄色液体414mg，总收率95％。Dissolve 5-(benzyloxy) isoindol-1-one (400mg, 1.67mmol) in anhydrous dimethyl arson (5mL) solution, cool in an ice bath, and add 60% sodium hydride (133mg, 3.33mmol) react for 30min, then add methyl iodide (475mg, 3.33mmol) to react for 4h, add water (60mL) to quench the reaction, extract with dichloromethane (10mL×2), dry the organic phase with anhydrous sodium sulfate, remove the solvent The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 414 mg of the mixture as a pale yellow liquid, with a total yield of 95%.
步骤3：化合物5-羟基-2-甲基异吲哚-1-酮和5-羟基-2,3-二甲基异吲哚-1-酮的合成Step 3: Synthesis of compounds 5-hydroxy-2-methylisoindol-1-one and 5-hydroxy-2,3-dimethylisoindol-1-one
将化合物5-(苄氧基)-2-甲基异吲哚-1-酮(11136-1-2)和5-(苄氧基)-2,3-二甲基异吲哚-1-酮(11154-1-2)的混合物(675mg)溶于甲醇(8mL)，加入Pd/C(200mg,0.3g/g)，通入氢气室温反应1h，然后将反应液抽滤，滤液浓缩，经过高效液相色谱分离得到5-羟基-2-甲基异吲哚-1-酮(11136-1)白色固体153mg和5-羟基-2,3-二甲基异吲哚-1-酮(11154-1)白色固体72mg。The compounds 5-(benzyloxy)-2-methyl isoindole-1-one (11136-1-2) and 5-(benzyloxy)-2,3-dimethyl isoindole-1- A mixture of ketones (11154-1-2) (675mg) was dissolved in methanol (8mL), Pd/C (200mg, 0.3g/g) was added, and hydrogen was introduced to react at room temperature for 1 hour, then the reaction solution was filtered with suction, and the filtrate was concentrated. After separation by high performance liquid chromatography, 5-hydroxy-2-methylisoindol-1-one (11136-1) white solid 153mg and 5-hydroxy-2,3-dimethylisoindol-1-one (11136-1) 11154-1) 72 mg of white solid.
化合物5-羟基-2-甲基异吲哚-1-酮： 1H NMR(400MHz,d 6-DMSO)δ(ppm):10.07(br.s,1H),7.46(d,J＝8.2Hz,1H),6.90(s,1H),6.84(d,J＝8.2Hz,1H),4.33(s,2H),3.01(s,3H). Compound 5-hydroxy-2-methyl isoindol-1-one: 1 H NMR (400MHz, d 6 -DMSO) δ (ppm): 10.07 (br.s, 1H), 7.46 (d, J = 8.2 Hz ,1H),6.90(s,1H),6.84(d,J=8.2Hz,1H),4.33(s,2H),3.01(s,3H).
MS(ESI,pos.ion)m/z:164.10[M+H] +. MS(ESI,pos.ion)m/z:164.10[M+H] + .
化合物5-羟基-2,3-二甲基异吲哚-1-酮： 1H NMR(400MHz,d 6-DMSO)δ(ppm):10.09(br.s,1H),7.45(d,J＝8.2Hz,1H),6.91(s,1H),6.84(d,J＝8.2Hz,1H),4.42(q,J＝6.6Hz,1H),2.95(s,3H),1.37(d,J＝6.7Hz,3H). Compound 5-hydroxy-2,3-dimethyl isoindol-1-one: 1 H NMR (400MHz, d 6 -DMSO) δ (ppm): 10.09 (br.s, 1H), 7.45 (d, J =8.2Hz,1H),6.91(s,1H),6.84(d,J=8.2Hz,1H), 4.42(q,J=6.6Hz,1H),2.95(s,3H),1.37(d,J ＝6.7Hz, 3H).
MS(ESI,pos.ion)m/z:178.10[M+H] +. MS(ESI,pos.ion)m/z:178.10[M+H] + .
步骤4：化合物(2R)-(2-甲基-1-氧代异吲哚-5-基)1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯(实施例140)的合成Step 4: Compound (2R)-(2-methyl-1-oxoisoindol-5-yl)1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoro (Methoxy) phenyl) pyrrolidine-2-carboxylate (Example 140) synthesis
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(120mg,0.32mmol)和5-羟基-2-甲基异吲哚-1-酮(58mg,0.36mmol)溶于二氯甲烷(4mL)和N,N-二甲基甲酰胺(2mL)中，加入N-羟基-7-氮杂苯并三氮唑(89mg,0.65mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(187mg,0.98mmol)和N,N-二异丙基乙胺(169mg,1.31mmol)，室温反应11h，减压浓缩除去溶剂，加水(20mL)，用乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝35/1)，得到白色固体132mg，收率79％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120mg, 0.32mmol) And 5-hydroxy-2-methyl isoindol-1-one (58mg, 0.36mmol) dissolved in dichloromethane (4mL) and N,N-dimethylformamide (2mL), add N-hydroxy- 7-azabenzotriazole (89mg, 0.65mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (187mg, 0.98mmol) and N,N- Diisopropylethylamine (169mg, 1.31mmol), reacted at room temperature for 11h, concentrated under reduced pressure to remove the solvent, added water (20mL), extracted with ethyl acetate (10mL×2), the organic phase was dried over anhydrous sodium sulfate and reduced under reduced pressure After concentration, the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=35/1) to obtain 132 mg of white solid with a yield of 79%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.83(d,J＝6.9Hz,1H),7.29(s,1H),7.09–7.22(m,2H),6.78–6.90(m,2H),6.61(t,J F-H＝75.6Hz,1H),4.61–4.72(m,1H),4.35(s,2H),3.95–4.05(m,1H),3.87(d,J＝5.7Hz,2H),3.62–3.75(m,1H),3.46–3.59(m,1H),3.18(s,3H),2.74–2.87(m,1H),2.16–2.28(m,1H),2.15(s,3H),1.21–1.32(m,1H),0.56–0.69(m,2H),0.27–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.83 (d, J = 6.9 Hz, 1H), 7.29 (s, 1H), 7.09-7.22 (m, 2H), 6.78-6.90 (m, 2H) ,6.61(t,J FH =75.6Hz,1H), 4.61–4.72(m,1H), 4.35(s,2H), 3.95–4.05(m,1H), 3.87(d,J=5.7Hz,2H) ,3.62–3.75(m,1H), 3.46–3.59(m,1H), 3.18(s,3H), 2.74–2.87(m,1H), 2.16–2.28(m,1H), 2.15(s,3H) ,1.21--1.32(m,1H), 0.56--0.69(m,2H), 0.27--0.39(m,2H).
MS(ESI,pos.ion)m/z:515.25[M+H] +. MS(ESI,pos.ion)m/z:515.25[M+H] + .
步骤5：化合物(2R)-(2,3-二甲基-1-氧代异吲哚-5-基)1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯(实施例141)的合成Step 5: Compound (2R)-(2,3-Dimethyl-1-oxoisoindol-5-yl)1-acetyl-4-(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)pyrrolidine-2-carboxylate (Example 141)
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(120mg,0.32mmol)和5-羟基-2,3-二甲基异吲哚-1-酮(63mg,0.36mmol)溶于二氯甲烷(4mL)和N,N-二甲基甲酰胺(2mL)中，加入N-羟基-7-氮杂苯并三氮唑(89mg,0.65mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(187mg,0.98mmol)和N,N-二异丙基乙胺(169mg,1.31mmol)，室温反应11h，减压浓缩除去溶剂，加水(20mL)，用乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝35/1)，得到白色固体137mg，收率80％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120mg, 0.32mmol) And 5-hydroxy-2,3-dimethylisoindol-1-one (63mg, 0.36mmol) dissolved in dichloromethane (4mL) and N,N-dimethylformamide (2mL), add N -Hydroxy-7-azabenzotriazole (89mg, 0.65mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (187mg, 0.98mmol) and N ,N-Diisopropylethylamine (169mg, 1.31mmol), react at room temperature for 11h, concentrate under reduced pressure to remove the solvent, add water (20mL), extract with ethyl acetate (10mL×2), and dry the organic phase with anhydrous sodium sulfate After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=35/1) to obtain 137 mg of white solid with a yield of 80%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.82(d,J＝7.7Hz,1H),7.26(s,1H),7.16–7.21(m,1H),7.15(d,J＝9.0Hz,1H),6.80–6.90(m,2H),6.62(t,J F-H＝75.6Hz,1H),4.66–4.69(m,1H),4.37–4.47(m,1H),3.96–4.05(m,1H),3.87(d,J＝6.4Hz,2H),3.65–3.75(m,1H),3.48–3.59(m,1H),3.11(s,3H),2.77–2.88(m,1H),2.16–2.28(m,1H),2.16(s,3H),1.47(d,J＝5.9Hz,3H),1.21–1.32(m,1H),0.60–0.69(m,2H),0.30–0.41(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.82(d,J=7.7Hz,1H),7.26(s,1H),7.16-7.21(m,1H),7.15(d,J=9.0Hz ,1H),6.80–6.90(m,2H),6.62(t,J FH =75.6Hz,1H),4.66–4.69(m,1H),4.37–4.47(m,1H),3.96–4.05(m, 1H), 3.87(d,J=6.4Hz,2H), 3.65–3.75(m,1H), 3.48–3.59(m,1H), 3.11(s,3H), 2.77–2.88(m,1H), 2.16 –2.28(m,1H),2.16(s,3H),1.47(d,J=5.9Hz,3H),1.21–1.32(m,1H),0.60–0.69(m,2H),0.30–0.41(m ,2H).
MS(ESI,pos.ion)m/z:529.30[M+H] +. MS(ESI,pos.ion)m/z:529.30[M+H] + .
实施例142：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((6-氟吡啶-2-基)甲基)吡咯烷-2-甲酰胺Example 142: The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((6-fluoropyridine- 2-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000204
Figure PCTCN2021090489-appb-000204
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(203mg,0.55mmol)，(6-氟吡啶-2-基)甲胺二盐酸盐(162mg,0.81mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(521mg,2.72mmol)和N-羟基-7-氮杂苯并三氮唑(149mg,1.09mmol)溶于二氯甲烷(5mL)中，0℃条件下向此溶液中滴加N,N-二异丙基乙胺(0.7mL,4.0mmol)，室温反应16h，加水洗(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)，得到浅黄色固体163mg，收率62％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (203mg, 0.55mmol) , (6-Fluoropyridin-2-yl) methylamine dihydrochloride (162mg, 0.81mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (521mg, 2.72mmol) and N-hydroxy-7-azabenzotriazole (149mg, 1.09mmol) dissolved in dichloromethane (5mL), add N,N-diisopropyl to this solution dropwise at 0℃ Ethylethylamine (0.7mL, 4.0mmol), react at room temperature for 16h, wash with water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and apply the concentrated solution to silica gel column layer Analyze and separate (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 163 mg of light yellow solid with a yield of 62%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.75–7.81(m,1H),7.24(d,J＝5.4Hz,1H),7.12(d,J＝8.1Hz,1H),6.90(s,1H),6.81–6.87(m,2H),6.62(t,J F-H＝75.6Hz,1H),4.54–4.63(m,3H),3.94–3.98(m,1H),3.88(d,J＝6.9Hz,2H),3.57(t,J＝10.7Hz,1H),3.30–3.42(m,1H),2.54–2.62(m,1H),2.42–2.51(m,1H),2.16(s,3H),1.24–1.33(m,1H),0.64–0.69(m,2H),0.35–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.75-7.81 (m, 1H), 7.24 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.90 (s ,1H),6.81–6.87(m,2H),6.62(t,J FH =75.6Hz,1H),4.54–4.63(m,3H),3.94–3.98(m,1H),3.88(d,J= 6.9Hz,2H),3.57(t,J=10.7Hz,1H), 3.30–3.42(m,1H), 2.54–2.62(m,1H),2.42–2.51(m,1H), 2.16(s,3H) ), 1.24-1.33 (m, 1H), 0.64--0.69 (m, 2H), 0.35--0.39 (m, 2H).
MS(ESI,pos.ion)m/z:478.30[M+H] +. MS(ESI,pos.ion)m/z:478.30[M+H] + .
实施例143：化合物(6-(乙基(甲基)氨基甲酰基)吡啶-2-基)甲基(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 143: Compound (6-(ethyl(methyl)carbamoyl)pyridin-2-yl)methyl(2R)-1-acetyl-4-(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000205
Figure PCTCN2021090489-appb-000205
步骤1：化合物6-(乙基(甲基)氨基甲酰基)吡啶甲酸甲酯的合成Step 1: Synthesis of compound 6-(ethyl(methyl)carbamoyl)picolinate methyl ester
将化合物2,6-吡啶二羧酸单甲酯(500mg,2.76mmol)，N-乙基甲基胺(327mg,5.53mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(2.65g,13.8mmol)和N-羟基-7-氮杂苯并三氮唑(750mg,5.51mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入N,N-二异丙基乙胺(2.1g,16.0mmol)，室温反应5h，加水(20mL)，用二氯甲烷萃取(15mL×3)，有机相用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝2/1)，得到浅褐色液体592mg，收率96％。The compound 2,6-pyridinedicarboxylic acid monomethyl ester (500mg, 2.76mmol), N-ethylmethylamine (327mg, 5.53mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Diimide hydrochloride (2.65g, 13.8mmol) and N-hydroxy-7-azabenzotriazole (750mg, 5.51mmol) were dissolved in dichloromethane (10mL), cooled to 0℃, and added N,N-Diisopropylethylamine (2.1g, 16.0mmol), react at room temperature for 5h, add water (20mL), extract with dichloromethane (15mL×3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure The concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 592 mg of light brown liquid with a yield of 96%.
1H NMR(400MHz,CDCl 3)δ(ppm):8.16–8.19(m,1H),7.96(t,J＝7.8Hz,1H),7.85(t,J＝6.3Hz,1H),4.02(s,3H),3.25–3.30(m,2H),3.11–3.12(m,3H),1.24–1.28(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.16–8.19 (m, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.85 (t, J = 6.3 Hz, 1H), 4.02 (s ,3H), 3.25–3.30(m,2H), 3.11–3.12(m,3H), 1.24–1.28(m,3H).
MS(ESI,pos.ion)m/z:223.20[M+H] +. MS(ESI,pos.ion)m/z:223.20[M+H] + .
步骤2：化合物N-乙基-6-(羟甲基)-N-甲基吡啶酰胺的合成Step 2: Synthesis of compound N-ethyl-6-(hydroxymethyl)-N-picolineamide
将化合物6-(乙基(甲基)氨基甲酰基)吡啶甲酸甲酯(370mg,1.66mmol)溶于四氢呋喃(6mL)中，冰浴下加入硼氢化锂(354mg,16.6mmol)，室温反应1h后停止，加入饱和氯化钠水溶液(10mL)，乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：二氯 甲烷/甲醇(v/v)＝30/1)，得到浅黄色液体116mg，收率36％。Compound 6-(ethyl(methyl)carbamoyl)picolinic acid methyl ester (370mg, 1.66mmol) was dissolved in tetrahydrofuran (6mL), lithium borohydride (354mg, 16.6mmol) was added under ice bath, and reacted at room temperature for 1h After stopping, add saturated sodium chloride aqueous solution (10mL), extract with ethyl acetate (10mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the concentrated solution by silica gel column chromatography (eluent: two Chloromethane/methanol (v/v)=30/1) to obtain 116 mg of light yellow liquid with a yield of 36%.
1H NMR(400MHz,d 6-DMSO)δ(ppm):7.90(d,J＝7.7Hz,1H),7.53(d,J＝7.7Hz,1H),7.36(d,J＝7.6Hz,1H),5.49(t,J＝5.9Hz,1H),4.56–4.58(m,2H),3.47(q,J＝0.8Hz,1H),3.22(q,J＝1.2Hz,1H),2.96(s,1.7H),2.88(s,1.3H),1.14(t,J＝7.1Hz,1.2H),1.08(t,J＝7.0Hz,1.8H). 1 H NMR (400MHz, d 6 -DMSO) δ (ppm): 7.90 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H ), 5.49 (t, J = 5.9 Hz, 1H), 4.56–4.58 (m, 2H), 3.47 (q, J = 0.8 Hz, 1H), 3.22 (q, J = 1.2 Hz, 1H), 2.96 (s ,1.7H), 2.88 (s, 1.3H), 1.14 (t, J = 7.1Hz, 1.2H), 1.08 (t, J = 7.0Hz, 1.8H).
MS(ESI,pos.ion)m/z:195.20[M+H] +. MS(ESI,pos.ion)m/z:195.20[M+H] + .
步骤3：化合物(6-(乙基(甲基)氨基甲酰基)吡啶-2-基)甲基(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯的合成Step 3: Compound (6-(ethyl(methyl)carbamoyl)pyridin-2-yl)methyl(2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate synthesis
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(70mg,0.19mmol)，N-乙基-6-(羟甲基)-N-甲基吡啶酰胺(52mg,0.27mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(181mg,0.94mmol)和N-羟基-7-氮杂苯并三氮唑(51mg,0.37mmol)溶于二氯甲烷(5mL)中，冷却至0℃，加入N,N-二异丙基乙胺(146mg,0.13mmol)，室温反应12h，加水(15mL)，用二氯甲烷萃取(5mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝25/1)，得到浅黄色粘稠固体216mg，收率49％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (70mg, 0.19mmol) , N-ethyl-6-(hydroxymethyl)-N-picolineamide (52mg, 0.27mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (181mg, 0.94mmol) and N-hydroxy-7-azabenzotriazole (51mg, 0.37mmol) dissolved in dichloromethane (5mL), cooled to 0℃, added N,N-diisopropyl Ethylamine (146mg, 0.13mmol), react at room temperature for 12h, add water (15mL), extract with dichloromethane (5mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v)=25/1) to obtain 216 mg of light yellow viscous solid with a yield of 49%.
1H NMR(400MHz,CDCl 3)δ(ppm):7.84(t,J＝7.7Hz,1H),7.51–7.55(m,2H),7.15(d,J＝8.6Hz,1H),6.84(s,1H),6.80–6.84(m,1H),6.63(t,J F-H＝71.5Hz,1H),5.26–5.47(m,2H),4.59–4.64(m,1H),3.96–4.01(m,1H),3.88(d,J＝6.9Hz,2H),3.56–3.68(m,2H),3.41–3.52(m,1H),3.33–3.40(m,1H),3.09(s,1.8H),3.01(s,1.2H),2.70–2.77(m,1H),2.15(s,3H),2.06–1.15(m,1H),1.25–1.34(m,1H),1.17–1.26(m,3H),0.65–0.69(m,2H),0.35–0.38(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.84 (t, J = 7.7 Hz, 1H), 7.51-7.55 (m, 2H), 7.15 (d, J = 8.6 Hz, 1H), 6.84 (s ,1H),6.80–6.84(m,1H),6.63(t,J FH =71.5Hz,1H), 5.26–5.47(m,2H),4.59–4.64(m,1H),3.96–4.01(m, 1H), 3.88(d,J=6.9Hz,2H),3.56–3.68(m,2H),3.41–3.52(m,1H),3.33–3.40(m,1H),3.09(s,1.8H), 3.01(s,1.2H), 2.70–2.77(m,1H), 2.15(s,3H), 2.06–1.15(m,1H), 1.25–1.34(m,1H), 1.17–1.26(m,3H) , 0.65--0.69 (m, 2H), 0.35--0.38 (m, 2H).
MS(ESI,pos.ion)m/z:546.30[M+H] +. MS(ESI,pos.ion)m/z:546.30[M+H] + .
实施例144：化合物(2R)-1-异吲哚酮-5-基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯Example 144: Compound (2R)-1-isoindolinone-5-yl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000206
Figure PCTCN2021090489-appb-000206
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(128mg,0.35mmol)，5-羟基异吲哚-1-酮(61mg,0.41mmol)和N-羟基-7-氮杂苯并三氮唑(91mg,0.67mmol)溶于N,N-二甲基甲酰胺(15mL)中，冷却至0℃，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(186mg,0.97mmol)和N,N-二异丙基乙胺(127mg,1.29mmol)，室温反应7h，减压浓缩除去溶剂，加水(20mL)，用乙酸乙酯萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：DCM/MeOH(v/v)＝35/1)，得到浅褐色固体59mg，收率34％。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (128mg, 0.35mmol) , 5-Hydroxyisoindole-1-one (61mg, 0.41mmol) and N-hydroxy-7-azabenzotriazole (91mg, 0.67mmol) dissolved in N,N-dimethylformamide (15mL ), cool to 0°C, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (186mg, 0.97mmol) and N,N-diisopropylethylamine ( 127mg, 1.29mmol), react at room temperature for 7h, concentrate under reduced pressure to remove the solvent, add water (20mL), extract with ethyl acetate (10mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the residue to a silica gel column Chromatographic separation (eluent: DCM/MeOH(v/v)=35/1) gave 59 mg of light brown solid with a yield of 34%.
1H NMR(400MHz,CD 3OD)δ(ppm):7.83(d,J＝8.3Hz,1H),7.33(s,1H),7.23(d,J＝8.3Hz,1H),7.15(d,J＝8.2Hz,1H),7.07(s,1H),6.96–6.99(m,1H),6.76(t,J F-H＝74.9Hz,1H),4.50(s,2H),4.14–4.18(m,1H),3.90(d,J＝7.0Hz,2H),3.62–3.77(m,3H),2.85–2.93(m,1H),2.19–2.28(m,1H),2.20(s,3H),1.21–1.28(m,1H),0.59–0.63(m,2H),0.30–0.34(m,2H). 1 H NMR (400MHz, CD 3 OD) δ (ppm): 7.83 (d, J = 8.3 Hz, 1H), 7.33 (s, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.15 (d, J = 8.2Hz, 1H), 7.07 (s, 1H), 6.96-6.99 (m, 1H), 6.76 (t, J FH = 74.9 Hz, 1H), 4.50 (s, 2H), 4.14-4.18 (m, 1H), 3.90(d,J=7.0Hz,2H),3.62–3.77(m,3H), 2.85–2.93(m,1H), 2.19–2.28(m,1H), 2.20(s,3H), 1.21 --1.28(m,1H),0.59-0.63(m,2H),0.30-0.34(m,2H).
MS-ESI:m/z 501.05[M+H] +. MS-ESI: m/z 501.05[M+H] + .
实施例145：1-羟基-1,3-二氢苯并[c][1,2]氧杂环戊硼烷-5-基(2R)-1-乙酰基-4-(6-乙氧基吡啶-3-基)吡咯烷-2- 甲酸酯Example 145: 1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl(2R)-1-acetyl-4-(6-ethoxy Pyridin-3-yl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000207
Figure PCTCN2021090489-appb-000207
步骤1:化合物2-乙氧基-5-碘吡啶的合成Step 1: Synthesis of compound 2-ethoxy-5-iodopyridine
往封管中加入2-羟基-5-碘吡啶(1.50g，4.00mmol)，无水碳酸钾(1.90g,14.0mmol)，DMF(12ml)，在室温下搅拌30min后，加入碘乙烷(3g,19.2mmol)，80℃下搅拌反应12h。加入乙酸乙酯(100mL)稀释，用饱和氯化铵溶液洗涤有机相(40mL)，用无水硫酸钠干燥有机相，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯(v/v)＝4/1)得到黄色固体(1.00g,产率59％)。Add 2-hydroxy-5-iodopyridine (1.50g, 4.00mmol), anhydrous potassium carbonate (1.90g, 14.0mmol), DMF (12ml) to the sealed tube. After stirring for 30min at room temperature, add iodoethane ( 3g, 19.2mmol), the reaction was stirred at 80°C for 12h. Add ethyl acetate (100mL) to dilute, wash the organic phase (40mL) with saturated ammonium chloride solution, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: Petroleum ether/ethyl acetate (v/v)=4/1) to obtain a yellow solid (1.00 g, yield 59%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.50(d,J＝2.3Hz,1H),7.41(dd,J＝9.5,2.5Hz,1H),6.39(d,J＝9.5Hz,1H),3.95(q,J＝7.2Hz,2H),1.35(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.50 (d, J = 2.3 Hz, 1H), 7.41 (dd, J = 9.5, 2.5 Hz, 1H), 6.39 (d, J = 9.5 Hz, 1H ), 3.95(q,J=7.2Hz,2H),1.35(t,J=7.2Hz,3H).
MS(ESI,pos.ion)m/z:250.00[M+H] +. MS(ESI,pos.ion)m/z:250.00[M+H] + .
步骤2:化合物1-叔丁基2-甲基(R)-4-(6-乙氧基吡啶-3-基)-1H-吡咯-1,2-(2H,5H)-二甲酸酯的合成Step 2: Compound 1-tert-butyl 2-methyl(R)-4-(6-ethoxypyridin-3-yl)-1H-pyrrole-1,2-(2H,5H)-dicarboxylate Synthesis
将(R)-1-叔丁基-2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(2.00g,4.40mmol)，2-乙氧基-5-碘吡啶(1.00g,4.00mmol)，磷酸钾(3.40g,16.1mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl 2)(147mg,0.20mmol)混合在干燥的1,4-二氧六环(10mL)溶液中，氮气保护下100℃反应22h，冷却至室温后抽滤，滤液中加入水(50mL)，用乙酸乙酯(15mL×3)萃取，有机相合并后用无水硫酸钠干燥，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯(v/v)＝1/4)得到黄色液体(0.80g,产率57％)。 Add (R)-1-tert-butyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrrole-1,2(2H,5H)-dicarboxylate (2.00g, 4.40mmol), 2-ethoxy-5-iodopyridine (1.00g, 4.00mmol), potassium phosphate (3.40g, 16.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 ) (147mg, 0.20mmol) mixed in dry 1,4-dioxane In the ring (10mL) solution, react at 100°C for 22h under nitrogen protection, cool to room temperature and filter with suction. Add water (50mL) to the filtrate, extract with ethyl acetate (15mL×3), and combine the organic phases with anhydrous sodium sulfate After drying, concentrating under reduced pressure to remove the solvent, the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/4) to obtain a yellow liquid (0.80 g, yield 57%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.46(dd,J＝9.5,2.6Hz,1H),7.14–7.20(m,1H),6.58(d,J＝9.5Hz,1H),5.79–5.88(m,1H),5.04–5.16(m,1H),4.35–4.56(m,2H),3.94–4.03(m,2H),3.75(d,J＝3.9Hz,3H),1.52(s,3H),1.45(s,6H),1.32–1.39(m,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.46 (dd, J = 9.5, 2.6 Hz, 1H), 7.14-7.20 (m, 1H), 6.58 (d, J = 9.5 Hz, 1H), 5.79 –5.88(m,1H),5.04–5.16(m,1H), 4.35–4.56(m,2H), 3.94–4.03(m,2H), 3.75(d,J=3.9Hz,3H), 1.52(s ,3H),1.45(s,6H),1.32--1.39(m,3H).
MS(ESI,pos.ion)m/z:349.65[M+H] +. MS(ESI,pos.ion)m/z:349.65[M+H] + .
步骤3:化合物1-(叔丁基)2-甲基(2R)-4-(6-乙氧基吡啶-3-基)吡咯烷-1,2-二甲酸酯的合成Step 3: Synthesis of compound 1-(tert-butyl)2-methyl(2R)-4-(6-ethoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate
将化合物1-叔丁基2-甲基(R)-4-(6-乙氧基吡啶-3-基)-1H-吡咯-1,2-(2H,5H)-二甲酸酯(0.8g,2.3mmol)溶于甲醇(15mL)，加入Pd/C(80mg,0.10g/g)，通入氢气，室温反应23h，过滤除去催化剂，滤液浓缩得到黄色油状物(639mg,产率79％)。The compound 1-tert-butyl 2-methyl(R)-4-(6-ethoxypyridin-3-yl)-1H-pyrrole-1,2-(2H,5H)-dicarboxylate (0.8 g, 2.3mmol) was dissolved in methanol (15mL), Pd/C (80mg, 0.10g/g) was added, hydrogen was added, and the reaction was at room temperature for 23h. The catalyst was removed by filtration. The filtrate was concentrated to obtain a yellow oil (639mg, yield 79%). ).
1H NMR(400MHz,CDCl 3):δ(ppm)7.19–7.26(m,1H),7.08–7.12(m,1H),6.56(d,J＝9.4Hz,1H),4.27–4.40(m,1H),3.91–3.99(m,0.5H),3.95(q,J＝7.2Hz,2H),3.82–3.89(m,0.5H),3.75(d,J＝6.3Hz,3H),3.27–3.38(m,1H),3.05–3.17(m,1H),2.51–2.63(m,1H),1.84–1.98(m,1H),1.38–1.49(m,9H),1.34(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ(ppm) 7.19–7.26(m,1H), 7.08–7.12(m,1H), 6.56(d,J=9.4Hz,1H), 4.27–4.40(m, 1H), 3.91–3.99(m,0.5H), 3.95(q,J=7.2Hz,2H), 3.82–3.89(m,0.5H), 3.75(d,J=6.3Hz,3H), 3.27–3.38 (m,1H),3.05–3.17(m,1H),2.51–2.63(m,1H),1.84–1.98(m,1H),1.38–1.49(m,9H),1.34(t,J=7.2Hz ,3H).
MS(ESI,pos.ion)m/z:351.20[M+H] +. MS(ESI,pos.ion)m/z:351.20[M+H] + .
步骤4:化合物(2R)-4-(6-乙氧基吡啶-3-基)吡咯烷-2-甲酸甲酯盐酸盐的合成Step 4: Synthesis of compound (2R)-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物1-(叔丁基)2-甲基(2R)-4-(6-乙氧基吡啶-3-基)吡咯烷-1,2-二甲酸酯(0.64g,1.80mmol)溶解于二氯甲烷(6mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(8mL)，室温搅拌50min，减压浓缩除 去溶剂，得到浅黄色固体(585mg,产率100％)。Dissolve compound 1-(tert-butyl)2-methyl(2R)-4-(6-ethoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate (0.64g, 1.80mmol) Add 4 mol/L HCl ethyl acetate solution (8 mL) to the dichloromethane (6 mL) solution, stir at room temperature for 50 min, and concentrate under reduced pressure to remove the solvent to obtain a pale yellow solid (585 mg, yield 100%).
1H NMR(400MHz,CD 3OD):δ(ppm)7.83–7.89(m,1H),7.70–7.76(m,1H),6.74(d,J＝9.2Hz,1H),4.61(dd,J＝10.5,7.5Hz,1H),4.11(q,J＝7.1Hz,2H),3.88(s,3H),3.72–3.80(m,1H),3.53–3.67(m,1H),3.27–3.34(m,1H),2.75–2.86(m,1H),2.20(q,J＝12.0Hz,1H),1.37(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.83-7.89 (m, 1H), 7.70-7.76 (m, 1H), 6.74 (d, J = 9.2 Hz, 1H), 4.61 (dd, J = 10.5, 7.5 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.72-3.80 (m, 1H), 3.53-3.67 (m, 1H), 3.27-3.34 ( m, 1H), 2.75–2.86 (m, 1H), 2.20 (q, J = 12.0 Hz, 1H), 1.37 (t, J = 7.2 Hz, 3H).
MS(ESI,pos.ion)m/z:251.20[M+H-HCl] +. MS(ESI,pos.ion)m/z:251.20[M+H-HCl] + .
步骤5:化合物(2R)-1-乙酰基-4-(6-乙氧基吡啶-3-基)吡咯烷-2-甲酸甲酯的合成Step 5: Synthesis of compound (2R)-1-acetyl-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(2R)-4-(6-乙氧基吡啶-3-基)吡咯烷-2-甲酸甲酯盐酸盐(520mg,1.80mmol)溶解在二氯甲烷(8mL)中，加入N,N-二异丙基乙胺(1.89mL,10.9mmol)，冷却至0℃，加入乙酰氯(0.39mL,5.4mmol)，室温搅拌3h后停止反应，加水(15mL)，二氯甲烷萃取(10mL×3)，合并有机相用无水硫酸钠干燥，减压浓缩除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝20/1)得到褐色液体(378mg,71％)。Compound (2R)-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (520mg, 1.80mmol) was dissolved in dichloromethane (8mL), and N, N-Diisopropylethylamine (1.89mL, 10.9mmol), cooled to 0°C, added acetyl chloride (0.39mL, 5.4mmol), stirred at room temperature for 3h and then stopped the reaction, added water (15mL), extracted with dichloromethane (10mL ×3), the combined organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain brown Liquid (378mg, 71%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.28(d,J＝2.6Hz,1H),7.12–7.17(m,1H),6.58(d,J＝9.3Hz,1H),4.42–4.51(m,1H),3.91–4.02(m,2H),3.83–3.91(m,1H),3.73–3.79(m,3H),3.52(t,J＝10.4Hz,1H),3.15–3.27(m,1H),2.53–2.63(m,1H),2.11(s,3H),1.89–1.97(m,1H),1.33–1.38(m,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.28 (d, J = 2.6 Hz, 1H), 7.12-7.17 (m, 1H), 6.58 (d, J = 9.3 Hz, 1H), 4.42-4.51 (m,1H),3.91-4.02(m,2H),3.83-3.91(m,1H),3.73-3.79(m,3H),3.52(t,J=10.4Hz,1H),3.15-3.27(m ,1H), 2.53-2.63(m,1H), 2.11(s,3H), 1.89-1.97(m,1H), 1.33-1.38(m,3H).
MS(ESI,pos.ion)m/z:293.15[M+H] +. MS(ESI,pos.ion)m/z:293.15[M+H] + .
步骤6:(2R)-1-乙酰基-4-(6-乙氧基吡啶-3-基)吡咯烷-2-甲酸的合成Step 6: Synthesis of (2R)-1-acetyl-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid
将化合物(2R)-1-乙酰基-4-(6-乙氧基吡啶-3-基)吡咯烷-2-羧酸甲酯(350mg,1.20mmol)溶于四氢呋喃(6mL)和水(3mL)的混合溶剂中，再加入一水合氢氧化锂(100mg,2.40mmol)，50℃反应1.5h后停止，加稀盐酸调节溶液Ph＝1，减压浓缩除去溶剂，进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝8/1)得到白色固体(375mg,99％)。The compound (2R)-1-acetyl-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid methyl ester (350mg, 1.20mmol) was dissolved in tetrahydrofuran (6mL) and water (3mL ), add lithium hydroxide monohydrate (100mg, 2.40mmol), and stop the reaction at 50°C for 1.5h, add dilute hydrochloric acid to adjust the solution Ph=1, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v)=8/1) to obtain a white solid (375 mg, 99%).
1H NMR(400MHz,CD 3OD):δ(ppm)7.60–7.64(m,2H),6.55(d,J＝9.0Hz,1H),4.32(dd,J＝16.9,8.0Hz,1H),4.10–4.16(m,0.6H),4.03(q,J＝7.1Hz,2H),3.93–3.98(m,0.4H),3.51–3.58(m,0.4H),3.25–3.33(m,0.6H),3.09–3.24(m,1H),2.57–2.79(m,1H),2.10(s,1H),2.01(s,2H),1.83–1.98(m,1H),1.33(t,J＝7.1Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.60-7.64 (m, 2H), 6.55 (d, J = 9.0 Hz, 1H), 4.32 (dd, J = 16.9, 8.0 Hz, 1H), 4.10–4.16(m,0.6H), 4.03(q,J=7.1Hz,2H), 3.93–3.98(m,0.4H), 3.51–3.58(m,0.4H), 3.25–3.33(m,0.6H) ), 3.09–3.24(m,1H), 2.57–2.79(m,1H),2.10(s,1H),2.01(s,2H),1.83–1.98(m,1H),1.33(t,J=7.1 Hz, 3H).
MS(ESI,pos.ion)m/z:279.25[M+H] +. MS(ESI,pos.ion)m/z:279.25[M+H] + .
步骤7:1-羟基-1,3-二氢苯并[c][1,2]氧杂环戊硼烷-5-基(2R)-1-乙酰基-4-(6-乙氧基吡啶-3-基)吡咯烷-2-甲酸酯的合成Step 7: 1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl(2R)-1-acetyl-4-(6-ethoxy) Synthesis of pyridin-3-yl)pyrrolidine-2-carboxylate
将化合物(2R)-1-乙酰基-4-(6-乙氧基吡啶-3-基)吡咯烷-2-甲酸(200mg,0.64mmol)，2-羟基甲基-5-羟基苯硼酸半酯(114mg,0.76mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入N-羟基-7-氮杂苯并三氮唑(265mg,1.91mmol)，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(365mg,1.91mmol)和N,N-二异丙基乙胺(494mg,3.81mmol)，室温反应23h，加水(20mL)搅拌5min，二氯甲烷萃取(5mL×2)，用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝15/1)，得到白色固体(100mg,产率56％)。The compound (2R)-1-acetyl-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid (200mg, 0.64mmol), 2-hydroxymethyl-5-hydroxyphenylboronic acid half Ester (114mg, 0.76mmol) was dissolved in N,N-dimethylformamide (10mL), N-hydroxy-7-azabenzotriazole (265mg, 1.91mmol) was added, and 1 was added in an ice bath -Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (365mg, 1.91mmol) and N,N-diisopropylethylamine (494mg, 3.81mmol), react at room temperature for 23h, Add water (20mL) and stir for 5min, extract with dichloromethane (5mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the concentrated solution by silica gel column chromatography (eluent: dichloromethane/methanol (v /v)=15/1) to obtain a white solid (100mg, yield 56%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.75(d,J＝8.0Hz,1H),7.32(dd,J＝9.4,2.5Hz,1H),7.18–7.23(m,1H),7.11(s,1H),7.06(d,J＝7.9Hz,1H),6.63(d,J＝9.4Hz,1H),5.03(s,2H),4.63–4.72(m,1H),3.90–4.03(m,3H),3.60(t,J＝10.4Hz,1H),3.25–3.39(m,1H),2.68–2.82(m,1H),2.16(s,3H),2.09–2.13(m,1H),1.33(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.75 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 9.4, 2.5 Hz, 1H), 7.18-7.23 (m, 1H), 7.11 (s, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 9.4 Hz, 1H), 5.03 (s, 2H), 4.63-4.72 (m, 1H), 3.90-4.03 ( m,3H), 3.60(t,J=10.4Hz,1H), 3.25–3.39(m,1H), 2.68–2.82(m,1H), 2.16(s,3H), 2.09–2.13(m,1H) ,1.33(t,J=7.2Hz,3H).
MS(ESI,pos.ion)m/z:m/z:411.10[M+H] +. MS(ESI,pos.ion)m/z:m/z:411.10[M+H] + .
实施例146：(6-(乙基(甲基)氨基甲酰基)吡啶-2-基)甲基(2R)-1-乙酰基-4-(6-乙氧基吡啶-3-基)吡咯烷-2-甲酸酯Example 146: (6-(Ethyl(methyl)carbamoyl)pyridin-2-yl)methyl(2R)-1-acetyl-4-(6-ethoxypyridin-3-yl)pyrrole Alkyl-2-carboxylate
Figure PCTCN2021090489-appb-000208
Figure PCTCN2021090489-appb-000208
将化合物(2R)-1-乙酰基-4-(6-乙氧基吡啶-3-基)吡咯烷-2-甲酸(100mg,0.36mmol，实施例145步骤6)，N-乙基-6-(羟基甲基)-N-甲基吡啶酰胺(74mg,0.38mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入N-羟基-7-氮杂苯并三氮唑(132mg,0.95mmol)，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(184mg,0.95mmol)和N,N-二异丙基乙胺(247mg,1.90mmol)，室温反应23h，减压浓缩除去溶剂，加水(10mL)搅拌5min，二氯甲烷萃取(20mL×2)，合并有机相用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体(60mg,产率：42％)。The compound (2R)-1-acetyl-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid (100mg, 0.36mmol, Example 145 step 6), N-ethyl-6 -(Hydroxymethyl)-N-picolineamide (74mg, 0.38mmol) was dissolved in N,N-dimethylformamide (5mL), and N-hydroxy-7-azabenzotriazole ( 132mg, 0.95mmol), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (184mg, 0.95mmol) and N,N-diisopropylethyl in an ice bath Amine (247mg, 1.90mmol), react at room temperature for 23h, concentrate under reduced pressure to remove the solvent, add water (10mL) and stir for 5min, extract with dichloromethane (20mL×2), combine the organic phases and dry with anhydrous sodium sulfate, concentrate under reduced pressure, and concentrate The liquid was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain a white solid (60 mg, yield: 42%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.77–7.85(m,1H),7.45–7.54(m,2H),7.23–7.26(m,1H),7.15–7.18(m,1H),6.58(d,J＝9.4Hz,1H),5.36–5.44(m,1H),5.21–5.31(m,1H),4.52–4.62(m,1H),3.93–4.04(m,2H),3.83–3.92(m,1H),3.48–3.62(m,2H),3.29–3.37(m,1H),3.19–3.28(m,1H),3.07(s,2H),2.98(s,1H),2.56–2.69(m,1H),2.11(s,3H),2.00–2.05(m,1H),1.34(t,J＝7.1Hz,3H),1.20–1.23(m,1H),1.12–1.19(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.77-7.85 (m, 1H), 7.45-7.54 (m, 2H), 7.23-7.26 (m, 1H), 7.15-7.18 (m, 1H), 6.58(d,J=9.4Hz,1H), 5.36–5.44(m,1H), 5.21–5.31(m,1H), 4.52–4.62(m,1H), 3.93–4.04(m,2H), 3.83– 3.92 (m, 1H), 3.48 - 3.62 (m, 2H), 3.29 - 3.37 (m, 1H), 3.19 - 3.28 (m, 1H), 3.07 (s, 2H), 2.98 (s, 1H), 2.56 - 2.69 (m, 1H), 2.11 (s, 3H), 2.00-2.05 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.20-1.23 (m, 1H), 1.12-1.19 (m, 2H).
MS(ESI,pos.ion)m/z:455.20[M+H] +. MS(ESI,pos.ion)m/z:455.20[M+H] + .
实施例147：(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(1-氧代异吲哚啉-5-基)吡咯烷-2-甲酰胺Example 147: (2S)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-oxoisoindole (Lin-5-yl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000209
Figure PCTCN2021090489-appb-000209
将化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(151mg,0.41mmol，实施例18步骤1)，5-氨基异吲哚啉-1-酮(89mg,0.60mmol)和N-羟基-7-氮杂苯并三氮唑(110mg,0.81mmol)溶于二氯甲烷/无水N,N-二甲基甲酰胺(8mL,(v/v)＝3/1)中，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(243mg,1.26mmol)和N,N-二异丙基乙胺(268uL,1.62mmol)，室温搅拌3h。加饱和食盐水(20mL)，水相用二氯甲烷萃取(50mL×3)，合并有机相，用无水硫酸钠干燥，减压除去溶剂，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)得到黄白色固体(161mg,79％,HPLC 98.44％)。The compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (151mg, 0.41mmol, implementation Example 18 Step 1), 5-aminoisoindolin-1-one (89mg, 0.60mmol) and N-hydroxy-7-azabenzotriazole (110mg, 0.81mmol) dissolved in dichloromethane/none In water N,N-dimethylformamide (8mL, (v/v)=3/1), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in an ice bath Hydrochloride (243mg, 1.26mmol) and N,N-diisopropylethylamine (268uL, 1.62mmol) were stirred at room temperature for 3h. Saturated brine (20mL) was added, the aqueous phase was extracted with dichloromethane (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: Dichloromethane/methanol (v/v)=50/1) to obtain a yellow-white solid (161 mg, 79%, HPLC 98.44%).
1H NMR(600MHz,CDCl 3):δ(ppm)10.25(s,1H),8.93(s,1H),8.11(s,1H),7.43(d,J＝8.1Hz,1H),7.11(d,J＝8.1Hz,1H),6.92(d,J＝8.0Hz,1H),6.89(s,1H),6.84(d,J＝8.2Hz,1H),6.60(t,J＝75.6Hz,1H),4.76(t,J＝7.4Hz,1H),4.30–4.16(m,2H),4.07–3.96(m,1H),3.86(d,J＝6.9Hz,2H),3.72(t,J＝9.9Hz,1H),3.48–3.36(m,1H),2.73–2.61(m,1H),2.37–2.27(m,1H),2.24(s,3H),1.30–1.21(m,1H),0.67–0.60(m,2H),0.38–0.30(m,2H). 1 H NMR (600MHz, CDCl 3 ): δ (ppm) 10.25 (s, 1H), 8.93 (s, 1H), 8.11 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.11 (d ,J=8.1Hz,1H), 6.92(d,J=8.0Hz,1H), 6.89(s,1H), 6.84(d,J=8.2Hz,1H), 6.60(t,J=75.6Hz,1H ), 4.76 (t, J = 7.4 Hz, 1H), 4.30-4.16 (m, 2H), 4.07-3.96 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.72 (t, J = 9.9Hz, 1H), 3.48–3.36(m, 1H), 2.73–2.61(m, 1H), 2.37–2.27(m, 1H), 2.24(s, 3H), 1.30–1.21(m, 1H), 0.67 -0.60(m,2H),0.38-0.30(m,2H).
MS(ESI,pos.ion)m/z:500.20[M+H] +. MS(ESI,pos.ion)m/z:500.20[M+H] + .
实施例148：(6-(甲基(p-甲苯基)氨基甲酰基)吡啶-2-基)甲基(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 148: (6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl(2S)-1-acetyl-4-(3-(cyclopropylmethoxy) -4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000210
Figure PCTCN2021090489-appb-000210
将化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(107mg,0.29mmol，实施例18步骤1)，6-羟甲基-N-甲基-N-对甲苯基-吡啶甲酰胺(90mg,0.35mmol)和N-羟基-7-氮杂苯并三氮唑(74mg,0.54mmol)溶于二氯甲烷(10mL)中，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(157mg,81mmol)和N,N-二异丙基乙胺(179uL,1.08mmol)，室温搅拌3h。加饱和食盐水(20mL)，水相用二氯甲烷萃取(50mL×3)，合并有机相，用无水硫酸钠干燥，减压除去溶剂，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)得到白色固体(80mg,产率79％)。The compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (107 mg, 0.29 mmol, Example 18 Step 1), 6-hydroxymethyl-N-methyl-N-p-tolyl-picolinamide (90mg, 0.35mmol) and N-hydroxy-7-azabenzotriazole (74mg, 0.54mmol) was dissolved in dichloromethane (10mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (157mg, 81mmol) and N, N -Diisopropylethylamine (179uL, 1.08mmol), stirred at room temperature for 3h. Saturated brine (20 mL) was added, the aqueous phase was extracted with dichloromethane (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: Dichloromethane/methanol (v/v)=50/1) to obtain a white solid (80 mg, yield 79%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.57(s,1H),7.38–7.18(m,2H),7.11(d,J＝8.1Hz,1H),7.03–6.86(m,4H),6.84–6.76(m,2H),6.60(t,J＝75.5Hz,1H),5.25–4.98(m,2H),4.59–1.49(m,1H),3.94(t,J＝8.0Hz,1H),3.85(d,J＝6.8Hz,2H),3.61(t,J＝10.1Hz,1H),3.51–3.34(m,4H),2.74–2.64(m,1H),2.25(s,3H),2.11(s,3H),2.16–2.02(m,1H),1.33–1.21(m,1H),0.69–0.58(m,2H),0.41–0.28(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.57 (s, 1H), 7.38-7.18 (m, 2H), 7.11 (d, J = 8.1 Hz, 1H), 7.03-6.86 (m, 4H) ,6.84-6.76(m,2H),6.60(t,J=75.5Hz,1H),5.25-4.98(m,2H),4.59-1.49(m,1H),3.94(t,J=8.0Hz,1H ), 3.85(d,J=6.8Hz,2H),3.61(t,J=10.1Hz,1H),3.51–3.34(m,4H),2.74–2.64(m,1H),2.25(s,3H) , 2.11 (s, 3H), 2.16-2.02 (m, 1H), 1.33-1.21 (m, 1H), 0.69-0.58 (m, 2H), 0.41-0.28 (m, 2H).
MS(ESI,pos.ion)m/z:608.20[M+H] +. MS(ESI,pos.ion)m/z:608.20[M+H] + .
实施例149：(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((3-氧代异吲哚啉-5-基)甲基)吡咯烷-2-甲酰胺Example 149: (2S)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((3-oxoisoindyl) (Dolin-5-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000211
Figure PCTCN2021090489-appb-000211
将化合物(2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸(86mg,0.23mmol)，6-氨甲基异吲哚啉-1-酮(53mg,0.33mmol)和N-羟基-7-氮杂苯并三氮唑(73mg,0.54mmol)溶于于二氯甲烷/无水N,N-二甲基甲酰胺(8mL,(v/v)＝1/1)中，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(157mg,81mmol)和N,N-二异丙基乙胺(179uL,1.08mmol)，室温搅拌3h。加饱和食盐水(20mL)，水相用二氯甲烷萃取(50mL×3)，合并有机相，用无水硫酸钠干燥，减压除去溶剂，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝20/1)得到白色固体(66mg,产率55％)。The compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (86mg, 0.23mmol) , 6-Aminomethyl isoindolin-1-one (53mg, 0.33mmol) and N-hydroxy-7-azabenzotriazole (73mg, 0.54mmol) dissolved in dichloromethane/anhydrous N , N-dimethylformamide (8mL, (v/v)=1/1), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in an ice bath Salt (157mg, 81mmol) and N,N-diisopropylethylamine (179uL, 1.08mmol), stirred at room temperature for 3h. Saturated brine (20mL) was added, the aqueous phase was extracted with dichloromethane (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: Dichloromethane/methanol (v/v)=20/1) to obtain a white solid (66 mg, yield 55%).
1H NMR(600MHz,CDCl 3):δ(ppm)8.51(d,J＝7.2Hz,1H),7.98(s,1H),7.50–7.47(m,2H),7.27(d,J＝8.3Hz,1H),7.11(d,J＝8.1Hz,1H),6.90(d,J＝1.7Hz,1H),6.85(dd,J＝8.2,1.8Hz,1H),6.61(t,J＝75.6Hz,1H),5.05–4.98(m,1H),4.68(t,J＝8.4Hz,1H),4.13(d,J＝17.3Hz,1H),3.99–3.93(m,1H),3.92(d,J＝7.7Hz,1H),3.87(d,J＝6.9Hz,2H),3.86–3.83(m,1H),3.70(t,J＝10.7Hz,1H),3.39–3.31(m,1H),2.67–2.62(m,1H),2.37–2.30(m,1H),2.15(s,3H),1.30–1.24(m,1H),0.66–0.62(m,2H),0.37–0.33(m,2H). 1 H NMR (600MHz, CDCl 3 ): δ (ppm) 8.51 (d, J = 7.2Hz, 1H), 7.98 (s, 1H), 7.50-7.47 (m, 2H), 7.27 (d, J = 8.3Hz) ,1H),7.11(d,J＝8.1Hz,1H), 6.90(d,J＝1.7Hz,1H), 6.85(dd,J＝8.2,1.8Hz,1H),6.61(t,J＝75.6Hz ,1H),5.05–4.98(m,1H),4.68(t,J=8.4Hz,1H), 4.13(d,J=17.3Hz,1H),3.99–3.93(m,1H),3.92(d, J = 7.7 Hz, 1H), 3.87 (d, J = 6.9 Hz, 2H), 3.86–3.83 (m, 1H), 3.70 (t, J = 10.7 Hz, 1H), 3.39–3.31 (m, 1H), 2.67–2.62(m,1H), 2.37–2.30(m,1H), 2.15(s,3H), 1.30–1.24(m,1H), 0.66–0.62(m,2H), 0.37–0.33(m,2H) ).
MS(ESI,pos.ion)m/z:514.20[M+H] +. MS(ESI,pos.ion)m/z:514.20[M+H] + .
实施例150：(2R,4R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(1-氧代异吲哚啉-5-基)吡咯烷-2-甲酰胺Example 150: (2R,4R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-oxoiso Indolin-5-yl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000212
Figure PCTCN2021090489-appb-000212
步骤1：化合物(2R,4S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-1,2-二甲酸酯的合成Step 1: Compound (2R, 4S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrole Synthesis of Alkyl-1,2-Dicarboxylate
将化合物2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(5.0g,14.7mmol)溶解在无水四氢呋喃(40mL)溶液中，氮气保护下冷却至-78℃，加入1.3mol/L异丙基氯化镁-氯化锂的四氢呋喃溶液(16mL,20.8mmol)，反应1.5h，缓慢加入N-Boc-4-氧代-D-脯氨酸甲酯(3.5g,14.0mmol)的无水四氢呋喃(20mL)溶液，-78℃下继续反应4h后停止，依次加入饱和氯化铵水溶液(70mL)和水(30mL)，用乙酸乙酯萃取(35mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：PE/EtOAc(v/v)＝3/1)得浅褐色油状物(2.9g,产率43％)。合成参考：Synthesis of 4-cis-Phenyl-L-proline via Hydrogenolysis J.Org.Chem.2001,66,3593-3596。The compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (5.0g, 14.7mmol) was dissolved in anhydrous tetrahydrofuran (40mL) solution and cooled to -78℃, add 1.3mol/L isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution (16mL, 20.8mmol), react for 1.5h, slowly add N-Boc-4-oxo-D-proline methyl ester ( 3.5g, 14.0mmol) in anhydrous tetrahydrofuran (20mL) solution, continue the reaction at -78℃ for 4h and then stop, add saturated ammonium chloride aqueous solution (70mL) and water (30mL) successively, and extract with ethyl acetate (35mL×2 ), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: PE/EtOAc(v/v)=3/1) to obtain a light brown oil (2.9 g, yield 43%). Synthesis reference: Synthesis of 4-cis-Phenyl-L-proline via Hydrogenolysis J.Org.Chem.2001,66,3593-3596.
1H NMR(400MHz,CDCl 3):δ(ppm)6.84–7.23(m,1H),7.19–7.22(m,1H),7.12(d,J＝8.3Hz,1H),7.02–7.07(m,1H),5.56(d,J＝8.7Hz,1H),4.38–4.45(m,1H),3.89(d,J＝6.9Hz,2H),3.64–3.66(m,3H),3.55–3.60(m,2H),2.62–2.69(m,1H),2.18–2.25(m,1H),1.37–1.41(m,9H),1.19–1.28(m,1H),0.55–0.59(m,2H),0.32–0.36(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 6.84–7.23 (m, 1H), 7.19–7.22 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.02–7.07 (m, 1H), 5.56(d,J=8.7Hz,1H), 4.38–4.45(m,1H), 3.89(d,J=6.9Hz,2H), 3.64–3.66(m,3H),3.55–3.60(m ,2H),2.62–2.69(m,1H),2.18–2.25(m,1H),1.37–1.41(m,9H),1.19–1.28(m,1H),0.55–0.59(m,2H),0.32 –0.36(m,2H).
MS(ESI,pos.ion)m/z:384.15[M-H 2O-t-Bu+2H] +. MS(ESI,pos.ion)m/z:384.15[MH 2 Ot-Bu+2H] + .
步骤2：化合物(2R,4S)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-2-甲酸的合成Step 2: Compound (2R, 4S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrole Synthesis of alkane-2-carboxylic acid
将化合物(2R,4S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-1,2-二甲酸酯(770mg,1.68mmol)溶于四氢呋喃(10mL)和水(10mL)的混合溶剂中，加入一水合氢氧化锂(285mg，6.79mmol)，室温反应1.5h后停止，加盐酸调节溶液pH＝4，再用乙酸乙酯萃取(20mL×3),有机相用无水硫酸钠干燥,减压浓缩，得到白色固体(741mg,产率99％)。The compound (2R, 4S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine- 1,2-Dicarboxylate (770mg, 1.68mmol) was dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (10mL), lithium hydroxide monohydrate (285mg, 6.79mmol) was added, and the reaction was stopped at room temperature for 1.5 hours. The pH of the solution was adjusted to 4 by adding hydrochloric acid, and then extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid (741 mg, yield 99%).
1H NMR(400MHz,CD 3OD):δ(ppm)7.23(s,1H),7.06–7.14(m,2H),6.76(t,J F-H＝75.6Hz,1H),4.45–4.53(m,1H),3.94(d,J＝6.6Hz,2H),3.67–3.76(m,2H),2.73–2.79(m,1H),2.42–2.45(m,1H),1.48–1.50(m,9H),1.24–1.35(m,1H),0.60–0.68(m,2H),0.34–0.42(m,2H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.23 (s, 1H), 7.06-7.14 (m, 2H), 6.76 (t, J FH = 75.6 Hz, 1H), 4.45-4.53 (m, 1H), 3.94(d,J=6.6Hz,2H), 3.67–3.76(m,2H), 2.73–2.79(m,1H), 2.42–2.45(m,1H), 1.48–1.50(m,9H) , 1.24--1.35(m,1H), 0.60--0.68(m,2H), 0.34--0.42(m,2H).
MS(ESI,pos.ion)m/z:466.10[M+Na] +. MS(ESI,pos.ion)m/z:466.10[M+Na] + .
步骤3：化合物(1S,4R)-叔丁基1-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-3-氧代-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-甲酸酯的合成Step 3: Compound (1S,4R)-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa- Synthesis of 5-azabicyclo[2.2.1]heptane-5-carboxylate
将(2R,4S)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-2-甲酸(817mg,1.84mmol)溶解在二氯甲烷(25mL)溶液中，加入N,N-二异丙基乙胺(717mg,5.55mmol)，在冰浴中冷却，加入甲磺酰氯(317mg,2.77mmol)，室温反应3h，加入水(30mL)洗有机相，分离有机相，水相用二氯甲烷萃取(5mL×2)，合并有机相合，用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：PE/EtOAc(v/v)＝6/1)得到浅黄色液体(681mg,产率87％)。(2R,4S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine-2 -Formic acid (817mg, 1.84mmol) was dissolved in dichloromethane (25mL) solution, added N,N-diisopropylethylamine (717mg, 5.55mmol), cooled in an ice bath, added methanesulfonyl chloride (317mg, 2.77mmol), react at room temperature for 3h, add water (30mL) to wash the organic phase, separate the organic phase, extract the aqueous phase with dichloromethane (5mL×2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and concentrate The liquid was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=6/1) to obtain a pale yellow liquid (681 mg, yield 87%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.24(d,J＝8.3Hz,1H),7.10(d,J＝1.9Hz,1H),6.96(dd,J＝8.3,2.0Hz,1H),6.67(t,J F-H＝75.2Hz,1H),4.66–4.82(m,1H),3.91(d,J＝6.9Hz,2H),3.62–3.75(m,2H),2.43–2.46(m,1H),2.29–2.32(m,1H),1.51(s,9H),1.26–1.37(m,1H),0.66–0.71(m,2H),0.37–0.41(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.24 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.96 (dd, J = 8.3, 2.0 Hz, 1H ),6.67(t,J FH =75.2Hz,1H),4.66-4.82(m,1H),3.91(d,J=6.9Hz,2H),3.62-3.75(m,2H),2.43-2.46(m ,1H), 2.29–2.32(m,1H), 1.51(s,9H), 1.26–1.37(m,1H), 0.66–0.71(m,2H), 0.37–0.41(m,2H).
MS(ESI,pos.ion)m/z:448.10[M+Na] +. MS(ESI,pos.ion)m/z:448.10[M+Na] + .
步骤4：化合物(R)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-甲酸的合成Step 4: Compound (R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro Synthesis of -1H-pyrrole-2-carboxylic acid
将化合物(1S,4R)-叔丁基1-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-3-氧代-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-甲酸酯(1.4g,3.29mmol)溶于二氯甲烷(50mL)，加入三氟乙酸(TFA)(824mg,7.23mmol)，室温反应2h，加入水(40mL)洗有机相，分离有机相，用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：PE/EtOAc(v/v)＝1/2)得到浅褐色固体(1.2g,产率86％)。The compound (1S, 4R)-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa-5- Azabicyclo[2.2.1]heptane-5-carboxylate (1.4g, 3.29mmol) was dissolved in dichloromethane (50mL), trifluoroacetic acid (TFA) (824mg, 7.23mmol) was added and reacted at room temperature for 2h, Water (40mL) was added to wash the organic phase, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (eluent: PE/EtOAc(v/v)=1/2) A light brown solid (1.2 g, yield 86%) was obtained.
1H NMR(400MHz,CD 3OD):δ(ppm)7.16–7.20(m,1H),7.14(d,J＝8.3Hz,1H),7.01–7.06(m,1H),6.79(t,J F-H＝75.4Hz,1H),6.24–6.29(m,1H),5.06–5.12(m,1H),4.51–4.62(m,2H),3.96(d,J＝6.8Hz,2H),1.49–1.54(m,9H),1.24–1.37(m,1H),0.62–0.67(m,2H),0.38–0.42(m,2H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.16-7.20 (m, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.01-7.06 (m, 1H), 6.79 (t, J FH = 75.4 Hz, 1H), 6.24–6.29 (m, 1H), 5.06–5.12 (m, 1H), 4.51–4.62 (m, 2H), 3.96 (d, J = 6.8 Hz, 2H), 1.49–1.54 (m,9H), 1.24--1.37(m,1H), 0.62--0.67(m,2H), 0.38--0.42(m,2H).
MS(ESI,pos.ion)m/z:370.10[M-t-Bu+2H] +. MS(ESI,pos.ion)m/z:370.10[Mt-Bu+2H] + .
步骤5：化合物(2R,4R)-1-(叔丁氧羰基)-4-(3-(环丙甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸的合成Step 5: Compound (2R, 4R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid Synthesis
将化合物(R)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-甲酸(1.6g,3.80mmol)溶于乙醇(27mL)和无水四氢呋喃(3mL)，加入三苯基膦氯化铑(452mg,0.49mmol)和三乙胺(572mg,5.65mmol)，通入氢气0.5MPa压力下室温反应3天，然后将反应液浓缩，加水(27mL)，加稀盐酸调节pH＝1，用乙酸乙酯萃取(30mL×3)，合并有机相合，用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂：PE/EtOAc(v/v)＝1/1)得到浅黄色液体(1.2g,产率75％,4R:4S＝4:1)，经过手性柱拆分得到(2R,4R)-1-(叔丁氧羰基)-4-(3-(环丙甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸。合成参考：Carboxylate-Directed Highly Stereoselective Homogeneous Hydrogenation of Cyclic Olefins with Wilkinson’s Catalyst.Organic Letters.2003 Vol.5,No.9 1587-1589。The compound (R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H -Pyrrole-2-carboxylic acid (1.6g, 3.80mmol) dissolved in ethanol (27mL) and anhydrous tetrahydrofuran (3mL), add triphenylphosphine rhodium chloride (452mg, 0.49mmol) and triethylamine (572mg, 5.65mmol) ), reacted at room temperature with hydrogen gas at 0.5MPa pressure for 3 days, then concentrated the reaction solution, added water (27mL), added dilute hydrochloric acid to adjust pH=1, extracted with ethyl acetate (30mL×3), combined the organic phases, and used It was dried over sodium sulfate, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (eluent: PE/EtOAc(v/v)=1/1) to obtain a pale yellow liquid (1.2g, yield 75%, 4R: 4S=4:1), after chiral column resolution, (2R, 4R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) )Phenyl)pyrrolidine-2-carboxylic acid. Synthesis reference: Carboxylate-Directed Highly Stereoselective Homogeneous Hydrogenation of Cyclic Olefins with Wilkinson’s Catalyst Organic Letters. 2003 Vol. 5, No. 9 1587-1589.
1H NMR(400MHz,CD 3OD):δ(ppm)7.10(d,J＝8.2Hz,1H),7.00–7.03(m,1H),6.86–6.90(m,1H),6.73(t,J F-H＝75.7Hz,1H),4.38–4.46(m,1H),3.89–3.97(m,1H),3.92(d,J＝6.9Hz,2H),3.49–3.57(m,1H),3.35–3.41(m,1H),2.43–2.51(m,1H),2.32–2.39(m,1H),1.46–1.49(m,9H),1.26–1.35(m,1H),0.61–0.66(m,2H),0.36–0.40(m,2H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.10 (d, J = 8.2 Hz, 1H), 7.00-7.03 (m, 1H), 6.86-6.90 (m, 1H), 6.73 (t, J FH = 75.7Hz, 1H), 4.38–4.46 (m, 1H), 3.89–3.97 (m, 1H), 3.92 (d, J = 6.9 Hz, 2H), 3.49–3.57 (m, 1H), 3.35–3.41 (m,1H), 2.43-2.51(m,1H), 2.32-2.39(m,1H), 1.46-1.49(m,9H), 1.26-1.35(m,1H), 0.61-0.66(m,2H) ,0.36--0.40(m,2H).
MS(ESI,pos.ion)m/z:372.10[M-t-Bu+2H] +. MS(ESI,pos.ion)m/z:372.10[Mt-Bu+2H] + .
步骤6：化合物(2R,4R)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-((1-氧代异吲哚啉-5-基)氨基甲酰基)吡咯烷-1-甲酸酯的合成Step 6: Compound (2R, 4R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((1-oxoisoindyl) Synthesis of Dolin-5-yl)carbamoyl)pyrrolidine-1-carboxylate
将化合物(2R,4R)-1-(叔丁氧羰基)-4-(3-(环丙甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(120mg,0.28mmol)，5-氨基异吲哚-1-酮(50mg,0.34mmol)和N-羟基-7-氮杂苯并三氮唑(76mg,0.56mmol)溶于二氯甲烷(12mL)和无水DMF(4mL)中，加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(167mg,0.87mmol) 和N,N-二异丙基乙胺(169mg,1.31mmol)，室温反应10h，减压浓缩，剩余物加水(20mL)，用乙酸乙酯萃取(20mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)＝23/1)得到白色固体(83mg,产率53％)。The compound (2R, 4R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120mg , 0.28mmol), 5-aminoisoindol-1-one (50mg, 0.34mmol) and N-hydroxy-7-azabenzotriazole (76mg, 0.56mmol) dissolved in dichloromethane (12mL) and To anhydrous DMF (4mL), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (167mg, 0.87mmol) and N,N-diisopropylethylamine ( 169mg, 1.31mmol), react at room temperature for 10h, concentrate under reduced pressure, add water (20mL) to the residue, extract with ethyl acetate (20mL×2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and carry out the residue Separation by silica gel column chromatography (eluent: DCM/MeOH(v/v)=23/1) gave a white solid (83mg, yield 53%).
化合物11178-3:MS(ESI,pos.ion)m/z:558.20[M+H] +. Compound 11178-3: MS (ESI, pos.ion) m/z: 558.20[M+H] + .
步骤7：化合物(2R,4R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(1-氧代异吲哚啉-5-基)吡咯烷-2-甲酰胺盐酸盐的合成Step 7: Compound (2R, 4R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-oxoisoindoline-5 -Yl) pyrrolidine-2-carboxamide hydrochloride synthesis
将化合物(2R,4R)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-((1-氧代异吲哚啉-5-基)氨基甲酰基)吡咯烷-1-甲酸酯(11178-3)(83mg,0.15mmol)溶解于二氯甲烷(4mL)溶液中，加入4mol/L HCl的1,4-二氧六环溶液(1.5mL)，室温搅拌2h，除去溶剂，得到白色固体(74mg,产率100％)。The compound (2R, 4R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((1-oxoisoindoline) -5-yl)carbamoyl)pyrrolidine-1-carboxylate (11178-3) (83mg, 0.15mmol) dissolved in dichloromethane (4mL) solution, add 4mol/L HCl 1,4-bis The oxane solution (1.5 mL) was stirred at room temperature for 2 h, and the solvent was removed to obtain a white solid (74 mg, yield 100%).
步骤8：化合物(2R,4R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(1-氧代异吲哚啉-5-基)吡咯烷-2-甲酰胺的合成Step 8: Compound (2R, 4R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-oxoiso Synthesis of indolin-5-yl)pyrrolidine-2-carboxamide
将化合物(2R,4R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(1-氧代异吲哚啉-5-基)吡咯烷-2-甲酰胺盐酸盐(73mg,0.15mmol)溶解在二氯甲烷(8mL)中，在冰浴中冷却，加入N,N-二异丙基乙胺(191mg,1.48mmol)和乙酰氯(59mg,0.75mmol)，室温搅拌1h后停止反应，加水(20mL)搅拌2min，分离有机相，水相用二氯甲烷萃取(10mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：DCM/MeOH(v/v)＝35/1)得到褐色固体(27mg,产率36％)。The compound (2R, 4R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-oxoisoindolin-5-yl ) Pyrrolidine-2-carboxamide hydrochloride (73mg, 0.15mmol) was dissolved in dichloromethane (8mL), cooled in an ice bath, and N,N-diisopropylethylamine (191mg, 1.48mmol) was added And acetyl chloride (59mg, 0.75mmol), stirred at room temperature for 1h, then stop the reaction, add water (20mL) and stir for 2min, separate the organic phase, extract the aqueous phase with dichloromethane (10mL×2), combine the organic phases, and use anhydrous sodium sulfate After drying and concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: DCM/MeOH(v/v)=35/1) to obtain a brown solid (27 mg, yield 36%).
1H NMR(400MHz,CDCl 3):δ(ppm)10.18(br.s,1H),8.08(s,1H),7.46–7.58(m,1H),7.14(d,J＝7.4Hz,1H),7.01–7.10(m,1H),6.86–6.91(m,2H),6.62(t,J F-H＝75.6Hz,1H),4.72–4.89(m,1H),4.20–4.35(m,2H),3.96–4.10(m,1H),3.88(d,J＝5.5Hz,2H),3.61–3.74(m,1H),3.32–3.53(m,1H),2.59–2.74(m,1H),2.37–2.53(m,1H),2.26(s,3H),1.23–1.34(m,1H),0.60–0.71(m,2H),0.31–0.41(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 10.18 (br.s, 1H), 8.08 (s, 1H), 7.46-7.58 (m, 1H), 7.14 (d, J = 7.4 Hz, 1H) ,7.01–7.10(m,1H), 6.86–6.91(m,2H), 6.62(t,J FH = 75.6Hz,1H), 4.72–4.89(m,1H), 4.20–4.35(m,2H), 3.96–4.10(m,1H), 3.88(d,J=5.5Hz,2H), 3.61–3.74(m,1H), 3.32–3.53(m,1H), 2.59–2.74(m,1H), 2.37– 2.53(m,1H), 2.26(s,3H), 1.23-1.34(m,1H), 0.60-0.71(m,2H), 0.31-0.41(m,2H).
MS(ESI,pos.ion)m/z:500.05[M+H] +. MS(ESI,pos.ion)m/z:500.05[M+H] + .
实施例151：(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(1-氧代异吲哚啉-5-基)吡咯烷-2-甲酰胺Example 151: (2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-oxoiso Indolin-5-yl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000213
Figure PCTCN2021090489-appb-000213
步骤1：化合物(2R,4S)-1-(叔丁氧羰基)-4-(3-(环丙甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸的合成Step 1: Compound (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid Synthesis
将化合物(R)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-甲酸(500mg,1.18mmol，实施例150步骤4)溶于乙醇(27mL)，加入Pd/C(400mg)和三乙胺(178mg,1.76mmol)，通入氢气室温反应12h，然后将反应液抽滤，滤液浓缩得到浅褐色液体(483mg,产率96％)。合成参考：Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2.J.Med.Chem.2014,57,9042-9064。The compound (R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H -Pyrrole-2-carboxylic acid (500mg, 1.18mmol, step 4 of Example 150) was dissolved in ethanol (27mL), Pd/C (400mg) and triethylamine (178mg, 1.76mmol) were added, and hydrogen was introduced to react at room temperature for 12h, Then the reaction liquid was suction filtered, and the filtrate was concentrated to obtain a light brown liquid (483 mg, yield 96%). Synthesis reference: Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2. J. Med. Chem. 2014, 57, 9042-9064.
1H NMR(400MHz,CD 3OD):δ(ppm)7.07–7.09(m,2H),6.89–6.92(m,1H),6.73(t,J F-H＝75.8Hz,1H),4.19–4.25(m,1H),3.89–3.97(m,1H),3.98(d,J＝6.9Hz,2H),3.44(d,J＝10.6Hz,1H),3.32–3.38(m,1H),2.61–2.68(m,1H),1.98–2.07(m,1H),1.48(s,9H),1.28–1.34(m,1H),0.61–0.66(m,2H),0.37–0.41(m, 2H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.07-7.09 (m, 2H), 6.89-6.92 (m, 1H), 6.73 (t, J FH = 75.8Hz, 1H), 4.19-4.25 ( m, 1H), 3.89–3.97 (m, 1H), 3.98 (d, J = 6.9 Hz, 2H), 3.44 (d, J = 10.6 Hz, 1H), 3.32–3.38 (m, 1H), 2.61–2.68 (m,1H), 1.98-2.07(m,1H), 1.48(s,9H), 1.28-1.34(m,1H), 0.61-0.66(m,2H), 0.37-0.41(m, 2H).
MS(ESI,pos.ion)m/z:372.10[M-t-Bu+2H] +. MS(ESI,pos.ion)m/z:372.10[Mt-Bu+2H] + .
步骤2：化合物(2R,4S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯的合成Step 2: Compound (2R, 4S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1, Synthesis of 2-Dicarboxylate
将化合物(2R,4S)-1-(叔丁氧羰基)-4-(3-(环丙甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(280mg,0.66mmol)，甲醇(106mg,3.31mmol)和N-羟基-7-氮杂苯并三氮唑(178mg,1.31mmol)溶于二氯甲烷(8mL)中，加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(503mg,2.62mmol)和N,N-二异丙基乙胺(339mg,2.62mmol)，室温反应8h，加水(20mL)停止反应，用二氯甲烷萃取(5mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)＝5/1)得到无色液体(165mg,产率57％)。The compound (2R, 4S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (280mg , 0.66mmol), methanol (106mg, 3.31mmol) and N-hydroxy-7-azabenzotriazole (178mg, 1.31mmol) dissolved in dichloromethane (8mL), add 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (503mg, 2.62mmol) and N,N-diisopropylethylamine (339mg, 2.62mmol), react at room temperature for 8h, add water (20mL) to stop the reaction , Extracted with dichloromethane (5mL×2), combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: PE/EtOAc(v/v)=5 /1) A colorless liquid (165 mg, yield 57%) was obtained.
1H NMR(400MHz,CDCl 3):δppm 7.10(d,J＝7.9Hz,1H),6.77–6.81(m,2H),6.59(t,J F-H＝75.6Hz,1H),4.30–4.40(m,1H),4.02–4.06(m,0.6H),3.91–3.95(m,0.4H),3.84–3.86(m,2H),3.76(d,J＝7.1Hz,3H),3.38–3.44(m,1H),3.26–3.36(m,1H),2.61–2.68(m,1H),1.96–2.07(m,1H),1.43–1.46(m,9H),1.25–1.33(m,1H),0.62–0.67(m,2H),0.33–0.38(m,2H). 1 H NMR (400MHz, CDCl 3 ): δppm 7.10 (d, J = 7.9 Hz, 1H), 6.77-6.81 (m, 2H), 6.59 (t, J FH = 75.6 Hz, 1H), 4.30-4.40 (m ,1H),4.02–4.06(m,0.6H),3.91–3.95(m,0.4H), 3.84–3.86(m,2H), 3.76(d,J=7.1Hz,3H), 3.38–3.44(m ,1H), 3.26–3.36(m,1H), 2.61–2.68(m,1H), 1.96–2.07(m,1H), 1.43–1.46(m,9H),1.25–1.33(m,1H), 0.62 -0.67(m,2H),0.33-0.38(m,2H).
MS(ESI,pos.ion)m/z:386.40[M-t-Bu+2H] +. MS(ESI,pos.ion)m/z:386.40[Mt-Bu+2H] + .
步骤3：化合物(2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸甲酯盐酸盐的合成Step 3: Synthesis of compound (2R,4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R,4S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯(11179-3)(4.03g,9.13mmol)溶解于二氯甲烷(50mL)溶液中，加入3mol/L HCl的1,4-二氧六环溶液(20mL)，室温搅拌4.5h，除去溶剂，得到浅黄色固体(3.5g,100％)。The compound (2R, 4S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2- Diformate (11179-3) (4.03g, 9.13mmol) was dissolved in dichloromethane (50mL) solution, added 3mol/L HCl 1,4-dioxane solution (20mL), stirred at room temperature for 4.5h , The solvent was removed to obtain a pale yellow solid (3.5 g, 100%).
1H NMR(400MHz,CD 3OD)δ:(ppm)7.14(d,J＝8.2Hz,1H),7.09(d,J＝1.8Hz,1H),6.93(dd,J＝8.3,1.8Hz,1H),6.76(t,J F-H＝75.5Hz,1H),4.61–4.65(m,1H),3.94(d,J＝6.9Hz,2H),3.90(s,3H),3.79–3.83(m,1H),3.64–3.74(m,1H),3.37(t,J＝11.1Hz,1H),2.82–2.89(m,1H),2.20–2.29(m,1H),1.27–1.35(m,1H),0.63–0.68(m,2H),0.37–0.41(m,2H). 1 H NMR (400MHz, CD 3 OD) δ: (ppm) 7.14 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 8.3, 1.8 Hz, 1H), 6.76(t, J FH = 75.5Hz, 1H), 4.61–4.65(m, 1H), 3.94(d, J = 6.9Hz, 2H), 3.90(s, 3H), 3.79–3.83(m, 1H), 3.64–3.74(m,1H), 3.37(t,J=11.1Hz,1H), 2.82–2.89(m,1H), 2.20–2.29(m,1H), 1.27–1.35(m,1H) ,0.63-0.68(m,2H),0.37-0.41(m,2H).
MS(ESI,pos.ion)m/z:342.15[M+H-HCl] +. MS(ESI,pos.ion)m/z:342.15[M+H-HCl] + .
步骤4：化合物(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸甲酯的合成Step 4: Compound (2R, 4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester synthesis
将化合物(2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸甲酯盐酸盐(3.5g,9.30mmol)溶解在二氯甲烷(50mL)中，在冰浴中冷却，加入N,N-二异丙基乙胺(6.0g,46.0mmol)和乙酰氯(2.2g,28.0mmol)，室温搅拌2.5h后停止反应，加水(50mL)搅拌2min，分离有机相，水相用二氯甲烷萃取(20mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：PE/EtOAc(v/v)＝1/3)得到褐色液体(3.4g,96％)。The compound (2R, 4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (3.5g, 9.30 mmol) was dissolved in dichloromethane (50mL), cooled in an ice bath, added N,N-diisopropylethylamine (6.0g, 46.0mmol) and acetyl chloride (2.2g, 28.0mmol), stirred at room temperature for 2.5 After h, stop the reaction, add water (50mL) and stir for 2min, separate the organic phase, extract the aqueous phase with dichloromethane (20mL×2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the residue to silica gel column layer Analyze and separate (eluent: PE/EtOAc (v/v) = 1/3) to obtain a brown liquid (3.4 g, 96%).
1H NMR(400MHz,CD 3OD):δ(ppm)7.09–7.13(m,1H),6.82(s,1H),6.78–6.81(m,1H),6.60(t,J F-H＝75.5Hz,1H),4.45–4.49(m,1H),3.91–3.95(m,1H),3.84–3.87(m,2H),3.77(s,3H),3.60(t,J＝10.4Hz,1H),3.36–3.45(m,1H),2.62–2.68(m,1H),2.11(s,2.5H),2.02–2.06(m,1H),1.98(s,0.5H),1.24–1.33(m,1H),0.63–0.68(m,2H),0.34–0.37(m,2H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.09–7.13 (m, 1H), 6.82 (s, 1H), 6.78–6.81 (m, 1H), 6.60 (t, J FH = 75.5 Hz, 1H), 4.45–4.49(m,1H), 3.91–3.95(m,1H), 3.84–3.87(m,2H), 3.77(s,3H), 3.60(t,J=10.4Hz,1H), 3.36 --3.45(m,1H),2.62–2.68(m,1H),2.11(s,2.5H),2.02–2.06(m,1H),1.98(s,0.5H),1.24–1.33(m,1H) , 0.63-0.68 (m, 2H), 0.34--0.37 (m, 2H).
MS(ESI,pos.ion)m/z:384.10[M+H] +. MS(ESI,pos.ion)m/z:384.10[M+H] + .
步骤5：化合物(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸的合成Step 5: Synthesis of compound (2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid
将化合物(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯(11179-5)(3.4g,8.90mmol)溶于四氢呋喃(40mL)和水(20mL)的混合溶剂中，再加入一水合氢氧化锂(1.1mg，26.0mmol)，50℃反应1h后停止，冰浴中冷却，加入稀盐酸调节溶液pH＝1，减压除去四氢呋喃，再用乙酸乙酯萃取(25mL×3),合并有机相，用无水硫酸钠干燥,减压浓缩，得到浅黄色固体(3.3g,100％)。The compound (2R, 4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (11179 -5) (3.4g, 8.90mmol) was dissolved in a mixed solvent of tetrahydrofuran (40mL) and water (20mL), and then lithium hydroxide monohydrate (1.1mg, 26.0mmol) was added, and the reaction was stopped at 50°C for 1 hour, and ice bath After cooling, add dilute hydrochloric acid to adjust the pH of the solution to 1, remove tetrahydrofuran under reduced pressure, and extract with ethyl acetate (25mL×3). Combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a pale yellow solid (3.3 g, 100%).
1H NMR(400MHz,CD 3OD):δ(ppm)7.09–7.12(m,1H),7.01–7.05(m,1H),6.87–6.93(m,1H),6.54–6.90(m,1H),4.64–4.68(m,0.2H),4.43–4.47(m,0.8H),4.22–4.26(m,0.2H),4.08–4.12(m,0.8H),3.91–3.94(m,2H),3.57–3.63(m,1H),3.47–3.55(m,1H),2.88–2.95(m,0.2H),2.71–2.78(m,0.8H),2.14(s,2.5H),2.00–2.08(m,1H),2.02(s,0.5H),1.26–1.33(m,1H),0.62–0.67(m,2H),0.37–0.41(m,2H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.09-7.12 (m, 1H), 7.01-7.05 (m, 1H), 6.87-6.93 (m, 1H), 6.54-6.90 (m, 1H) , 4.64–4.68(m,0.2H), 4.43–4.47(m,0.8H), 4.22–4.26(m,0.2H), 4.08–4.12(m,0.8H), 3.91–3.94(m,2H), 3.57–3.63(m,1H), 3.47–3.55(m,1H), 2.88–2.95(m,0.2H), 2.71–2.78(m,0.8H), 2.14(s,2.5H), 2.00–2.08( m, 1H), 2.02 (s, 0.5H), 1.26-1.33 (m, 1H), 0.62-0.67 (m, 2H), 0.37-0.41 (m, 2H).
MS(ESI,pos.ion)m/z:370.20[M+H] +. MS(ESI,pos.ion)m/z:370.20[M+H] + .
步骤6：化合物(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(1-氧代异吲哚啉-5-基)吡咯烷-2-甲酰胺的合成Step 6: Compound (2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-oxoiso Synthesis of indolin-5-yl)pyrrolidine-2-carboxamide
将化合物(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(120mg,0.32mmol)，5-氨基异吲哚-1-酮(57mg,0.38mmol)和N-羟基-7-氮杂苯并三氮唑(88mg,0.65mmol)溶于DCM(12mL)和DMF(4mL)中，加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(187mg,0.98mmol)和N,N-二异丙基乙胺(169mg,1.31mmol)，室温反应8h，减压浓缩除去溶剂，加水(20mL)，用乙酸乙酯萃取(20mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)＝17/1)得到浅黄色固体(122mg,产率75％)。The compound (2R, 4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120mg, 0.32mmol ), 5-aminoisoindole-1-one (57mg, 0.38mmol) and N-hydroxy-7-azabenzotriazole (88mg, 0.65mmol) dissolved in DCM (12mL) and DMF (4mL) , Add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (187mg, 0.98mmol) and N,N-diisopropylethylamine (169mg, 1.31mmol) at room temperature React for 8h, concentrate under reduced pressure to remove the solvent, add water (20mL), extract with ethyl acetate (20mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the residue by silica gel column chromatography (eluent :DCM/MeOH(v/v)=17/1) to obtain a pale yellow solid (122mg, yield 75%).
1H NMR(400MHz,CDCl 3):δ(ppm)10.20(br.s,1H),8.35(br.s,1H),8.08(s,1H),7.44–7.58(m,1H),7.12(d,J＝7.5Hz,1H),6.97–7.06(m,1H),6.90(s,1H),6.85(d,J＝7.4Hz,1H),6.61(t,J F-H＝75.6Hz,1H),4.70–4.87(m,1H),4.18–4.35(m,2H),3.96–4.09(m,1H),3.87(d,J＝6.6Hz,2H),3.63–3.76(m,1H),3.36–3.53(m,1H),2.59–2.76(m,1H),2.32–2.47(m,1H),2.24(s,3H),1.23–1.34(m,1H),0.57–0.71(m,2H),0.28–0.41(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 10.20 (br.s, 1H), 8.35 (br.s, 1H), 8.08 (s, 1H), 7.44-7.58 (m, 1H), 7.12 ( d,J=7.5Hz,1H),6.97–7.06(m,1H),6.90(s,1H),6.85(d,J=7.4Hz,1H),6.61(t,J FH =75.6Hz,1H) ,4.70–4.87(m,1H),4.18–4.35(m,2H), 3.96–4.09(m,1H), 3.87(d,J=6.6Hz,2H),3.63–3.76(m,1H), 3.36 --3.53(m,1H), 2.59–2.76(m,1H), 2.32–2.47(m,1H), 2.24(s,3H), 1.23–1.34(m,1H), 0.57–0.71(m,2H) ,0.28--0.41(m,2H).
MS(ESI,pos.ion)m/z:498.50[M-H] -. MS(ESI,pos.ion)m/z:498.50[MH] - .
实施例152：(2R,4S)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 152: (2R,4S)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000214
Figure PCTCN2021090489-appb-000214
步骤1：化合物(2R,4S)-1-叔丁基2-((6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯的合成Step 1: Compound (2R,4S)-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropyl) Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate
将化合物(2R,4S)-1-(叔丁氧羰基)-4-(3-(环丙甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(298mg,0.70mmol，实施151步骤1)，6-(羟甲基)-N-甲基-N-(对甲基苯基)吡啶酰胺(179mg,0.70mmol)和1-羟基苯并三唑(142mg,1.05mmol)溶于干燥的DMF(5mL)中，加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(201mg,1.05mmol)和N-甲基吗啡啉(142mg,1.40mmol)，室温反应17h，加水(30mL)停止反应，用乙酸乙酯萃取(15mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)＝1/1)得到白色粘稠固体(285mg,产率61％)。The compound (2R, 4S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (298mg , 0.70mmol, implement 151 step 1), 6-(hydroxymethyl)-N-methyl-N-(p-methylphenyl)pyridine amide (179mg, 0.70mmol) and 1-hydroxybenzotriazole (142mg , 1.05mmol) dissolved in dry DMF (5mL), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (201mg, 1.05mmol) and N-methylmorphine Morpholine (142mg, 1.40mmol), react at room temperature for 17h, add water (30mL) to stop the reaction, extract with ethyl acetate (15mL×2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the residue to a silica gel column Chromatographic separation (eluent: PE/EtOAc (v/v)=1/1) gave a white viscous solid (285 mg, yield 61%).
1H NMR(400MHz,CDCl 3):δppm 7.49–7.62(m,1H),7.22–7.33(m,1H),7.13–7.19(m,1H),7.09(d,J＝7.9Hz,1H),6.86–7.03(m,4H),6.78–6.83(m,2H),6.59(t,J F-H＝75.6Hz,1H),5.19–4.97(m,2H),4.37–4.48(m,1H),4.05–4.09(m,0.5H),3.92–3.96(m,0.5H),3.82–3.86(m,2H),3.46(s,3H),3.26–3.44(m,2H), 2.62–2.74(m,1H),2.25(s,3H),1.97–2.10(m,1H),1.37(s,4.5H),1.45(s,4.5H),1.24–1.31(m,1H),0.60–0.68(m,2H),0.31–0.38(m,2H). 1 H NMR (400MHz, CDCl 3 ): δppm 7.49–7.62(m,1H), 7.22–7.33(m,1H), 7.13–7.19(m,1H), 7.09(d,J=7.9Hz,1H), 6.86–7.03(m,4H), 6.78–6.83(m,2H), 6.59(t,J FH ＝75.6Hz,1H), 5.19–4.97(m,2H), 4.37–4.48(m,1H),4.05 --4.09(m,0.5H), 3.92–3.96(m,0.5H), 3.82–3.86(m,2H), 3.46(s,3H), 3.26–3.44(m,2H), 2.62–2.74(m, 1H), 2.25 (s, 3H), 1.97 - 2.10 (m, 1H), 1.37 (s, 4.5H), 1.45 (s, 4.5H), 1.24 - 1.31 (m, 1H), 0.60 - 0.68 (m, 2H), 0.31--0.38 (m, 2H).
MS(ESI,pos.ion)m/z:666.30[M+H] +. MS(ESI,pos.ion)m/z:666.30[M+H] + .
步骤2：化合物(2R,4S)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐的合成Step 2: Compound (2R,4S)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-( Synthesis of difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride
将化合物(2R,4S)-1-叔丁基2-((6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯(1184-6)(280mg,0.42mmol)溶解于二氯甲烷(12mL)溶液中，加入4mol/L HCl的1,4-二氧六环溶液(5mL)，室温搅拌3h，减压浓缩除去溶剂，得到浅黄色固体(297mg,100％，含有溶剂)。The compound (2R, 4S)-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethyl) (Oxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (1184-6) (280mg, 0.42mmol) was dissolved in dichloromethane (12mL) solution and added 4mol/L HCl 1,4-dioxane solution (5mL), stirred at room temperature for 3h, concentrated under reduced pressure to remove the solvent to obtain a pale yellow solid (297mg, 100%, containing solvent).
1H NMR(400MHz,CD 3OD)δ:(ppm)7.76–7.85(m,1H),7.46–7.52(m,1H),7.29–7.36(m,1H),7.09–7.16(m,2H),7.00–7.08(m,4H),6.94–6.97(m,1H),6.75(t,J F-H＝75.6Hz,1H),5.29–5.39(m,2H),4.73–4.78(m,1H),3.95(d,J＝6.8Hz,2H),3.82–3.87(m,1H),3.71–3.78(m,1H),3.36–3.47(m,1H),3.45(s,3H),2.87–2.95(m,1H),2.30–2.43(m,1H),2.24(s,3H),1.26–1.38(m,1H),0.61–0.68(m,2H),0.35–0.42(m,2H). 1 H NMR (400MHz, CD 3 OD) δ: (ppm) 7.76-7.85 (m, 1H), 7.46-7.52 (m, 1H), 7.29-7.36 (m, 1H), 7.09-7.16 (m, 2H) ,7.00–7.08(m,4H), 6.94–6.97(m,1H), 6.75(t,J FH = 75.6Hz,1H), 5.29–5.39(m,2H), 4.73–4.78(m,1H), 3.95(d,J=6.8Hz,2H), 3.82–3.87(m,1H), 3.71–3.78(m,1H), 3.36–3.47(m,1H), 3.45(s,3H), 2.87–2.95( m,1H), 2.30--2.43(m,1H), 2.24(s,3H), 1.26--1.38(m,1H), 0.61--0.68(m,2H), 0.35--0.42(m,2H).
MS(ESI,pos.ion)m/z:566.20[M+H-HCl] +. MS(ESI,pos.ion)m/z:566.20[M+H-HCl] + .
步骤3：化合物(2R,4S)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯的合成Step 3: Compound (2R,4S)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R,4S)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐(253mg,0.42mmol)溶解在二氯甲烷(8mL)中，在冰浴中冷却，加入N,N-二异丙基乙胺(269mg,2.08mmol)和乙酰氯(82mg,1.05mmol)，室温搅拌4h后停止反应，加水(30mL)搅拌2min，分离有机相，水相用二氯甲烷萃取(5mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：DCM/MeOH(v/v)＝23/1)得到白色固体(184mg,产率72％)。The compound (2R, 4S)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride (253mg, 0.42mmol) was dissolved in dichloromethane (8mL), cooled in an ice bath, and N,N-diisopropylethyl was added Amine (269mg, 2.08mmol) and acetyl chloride (82mg, 1.05mmol) were stirred at room temperature for 4h and the reaction was stopped. Water (30mL) was added and stirred for 2min. The organic phase was separated. The aqueous phase was extracted with dichloromethane (5mL×2), and the organic The phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM/MeOH(v/v)=23/1) to obtain a white solid (184mg, yield 72%) .
1H NMR(400MHz,CDCl 3):δ(ppm)7.50–7.64(m,1H),7.27–7.38(m,1H),7.20–7.27(m,1H),7.08–7.13(m,1H),6.86–7.05(m,4H),6.82(s,1H),6.80(d,J＝3.9Hz,1H),6.60(t,J F-H＝75.5Hz,1H),5.01–5.22(m,2H),4.53–4.57(m,1H),3.92–3.97(m,1H),3.86(d,J＝6.9Hz,2H),3.61(t,J＝10.4Hz,1H),3.46(s,3H),3.37–3.45(m,1H),2.66–2.72(m,1H),2.25(s,3H),2.11(s,3H),2.04–2.09(m,1H),1.24–1.34(m,1H),0.63–0.67(m,2H),0.34–0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.50--7.64 (m, 1H), 7.27--7.38 (m, 1H), 7.20--7.27 (m, 1H), 7.08-7.13 (m, 1H), 6.86–7.05(m,4H), 6.82(s,1H), 6.80(d,J=3.9Hz,1H), 6.60(t,J FH =75.5Hz,1H), 5.01–5.22(m,2H), 4.53–4.57(m,1H), 3.92–3.97(m,1H), 3.86(d,J=6.9Hz,2H), 3.61(t,J=10.4Hz,1H), 3.46(s,3H), 3.37 --3.45(m,1H),2.66-2.72(m,1H),2.25(s,3H),2.11(s,3H),2.04-2.09(m,1H),1.24-1.34(m,1H),0.63 –0.67(m,2H),0.34–0.37(m,2H).
MS(ESI,pos.ion)m/z:608.30[M+H] +. MS(ESI,pos.ion)m/z:608.30[M+H] + .
实施例153：(3-异吲哚啉-5-基)甲基(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 153: (3-Isoindolin-5-yl)methyl(2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) (Yl)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000215
Figure PCTCN2021090489-appb-000215
将化合物(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(200mg,0.54 mmol，实施例151步骤5)，6-(羟甲基)异吲哚-1-酮(221mg,1.35mmol)和N-羟基-7-氮杂苯并三氮唑(146mg,1.08mmol)溶于无水DMF(8mL)中，加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(311mg,1.62mmol)，加入N,N-二异丙基乙胺(279mg,2.16mmol)，室温反应11h，减压浓缩除去溶剂，加水(40mL)，用乙酸乙酯萃取(25mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)＝17/1)得到白色固体(176mg,产率63％)。The compound (2R, 4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (200mg, 0.54 mmol , Example 151 step 5), 6-(hydroxymethyl) isoindol-1-one (221 mg, 1.35 mmol) and N-hydroxy-7-azabenzotriazole (146 mg, 1.08 mmol) were dissolved in To anhydrous DMF (8mL), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (311mg, 1.62mmol), add N,N-diisopropylethylamine (279mg, 2.16mmol), react at room temperature for 11h, concentrate under reduced pressure to remove the solvent, add water (40mL), extract with ethyl acetate (25mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the residue to silica gel Column chromatography separation (eluent: DCM/MeOH(v/v)=17/1) gave a white solid (176mg, yield 63%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.85(s,1H),7.59(d,J＝6.3Hz,1H),7.47(d,J＝5.7Hz,1H),7.14(br.s,1H),7.10(d,J＝6.7Hz,1H),6.80(s,1H),6.72–6.80(m,1H),6.59(t,J F-H＝75.7Hz,1H),5.29(s,2H),4.49–4.59(m,1H),4.45(s,2H),3.89–3.99(m,1H),3.85(d,J＝4.3Hz,2H),3.55–3.66(m,1H),3.35–3.48(m,1H),2.60–2.74(m,1H),2.12(s,3H),1.99–2.08(m,1H),1.25–1.33(m,1H),0.58–0.69(m,2H),0.27–0.41(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.85 (s, 1H), 7.59 (d, J = 6.3 Hz, 1H), 7.47 (d, J = 5.7 Hz, 1H), 7.14 (br.s ,1H),7.10(d,J=6.7Hz,1H),6.80(s,1H),6.72-6.80(m,1H),6.59(t,J FH =75.7Hz,1H),5.29(s,2H ), 4.49–4.59(m,1H), 4.45(s,2H), 3.89–3.99(m,1H), 3.85(d,J=4.3Hz,2H),3.55–3.66(m,1H), 3.35– 3.48(m,1H), 2.60-2.74(m,1H), 2.12(s,3H), 1.99-2.08(m,1H), 1.25-1.33(m,1H), 0.58-0.69(m,2H), 0.27--0.41 (m, 2H).
MS(ESI,pos.ion)m/z:515.20[M+H] +. MS(ESI,pos.ion)m/z:515.20[M+H] + .
实施例154：(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((3-氧代异吲哚啉-5-基)甲基)吡咯烷-2-甲酰胺Example 154: (2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((3-oxo Isoindolin-5-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000216
Figure PCTCN2021090489-appb-000216
将化合物(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(120mg,0.32mmol，实施例151步骤5)，6-(氨甲基)异吲哚-1-酮(58mg,0.36mmol)和N-羟基-7-氮杂苯并三氮唑(89mg,0.65mmol)溶于无水DMF(4mL)和二氯甲烷(2mL)中，加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(188mg,0.98mmol)，加入N,N-二异丙基乙胺(167mg,1.29mmol)，室温反应14h，减压浓缩除去溶剂，加水(20mL)，用乙酸乙酯萃取(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)＝15/1)得到白色固体(113mg,产率68％)。The compound (2R, 4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120mg, 0.32mmol , Example 151 step 5), 6-(aminomethyl) isoindol-1-one (58mg, 0.36mmol) and N-hydroxy-7-azabenzotriazole (89mg, 0.65mmol) were dissolved in To dry DMF (4mL) and dichloromethane (2mL), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (188mg, 0.98mmol), add N, N -Diisopropylethylamine (167mg, 1.29mmol), react at room temperature for 14h, concentrate under reduced pressure to remove the solvent, add water (20mL), extract with ethyl acetate (15mL×2), dry the organic phase with anhydrous sodium sulfate, reduce After pressure concentration, the residue was subjected to silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain a white solid (113 mg, yield 68%).
1H NMR(400MHz,CDCl 3):δ(ppm)8.42(br.s,1H),7.84(br.s,1H),7.45–7.56(m,2H),7.25–7.34(m,1H),7.12(d,J＝8.0Hz,1H),6.90(s,1H),6.85(d,J＝7.9Hz,1H),6.61(t,J F-H＝75.7Hz,1H),4.93–4.99(m,1H),4.62–4.74(m,1H),4.10–4.20(m,1H),3.99–4.07(m,1H),3.89–3.97(m,2H),3.88(d,J＝6.8Hz,2H),3.62–3.74(m,1H),3.28–3.41(m,1H),2.59–2.69(m,1H),2.29–2.44(m,1H),2.15(s,3H),1.21–1.36(m,1H),0.59–0.69(m,2H),0.31–0.42(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 8.42 (br.s, 1H), 7.84 (br.s, 1H), 7.45-7.56 (m, 2H), 7.25-7.34 (m, 1H), 7.12(d,J=8.0Hz,1H),6.90(s,1H),6.85(d,J=7.9Hz,1H),6.61(t,J FH =75.7Hz,1H),4.93-4.99(m, 1H), 4.62–4.74(m,1H), 4.10–4.20(m,1H), 3.99–4.07(m,1H), 3.89–3.97(m,2H), 3.88(d,J=6.8Hz,2H) ,3.62–3.74(m,1H), 3.28–3.41(m,1H), 2.59–2.69(m,1H), 2.29–2.44(m,1H), 2.15(s,3H), 1.21–1.36(m, 1H), 0.59-0.69 (m, 2H), 0.31-0.42 (m, 2H).
MS(ESI,pos.ion)m/z:514.20[M+H] +. MS(ESI,pos.ion)m/z:514.20[M+H] + .
实施例155：(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((1-氧代异吲哚啉-5-基)甲基)吡咯烷-2-甲酰胺Example 155: (2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((1-oxo Isoindolin-5-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000217
Figure PCTCN2021090489-appb-000217
将化合物(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(120mg,0.32mmol，实施例151步骤5)，5-(氨甲基)异吲哚-1-酮(52mg,0.32mmol)和N-羟基-7-氮杂苯并三氮唑(89mg,0.65mmol)溶于无水DMF(8mL)中，加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(188mg,0.98mmol)，加入N,N-二异丙基乙胺(167mg,1.29mmol)，室温反应18h，减压浓缩除去溶剂，加水(20mL)，用乙酸乙酯萃取(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)＝15/1)得到白色固体(70mg,产率49％)。The compound (2R, 4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120mg, 0.32mmol , Example 151 step 5), 5-(aminomethyl) isoindol-1-one (52mg, 0.32mmol) and N-hydroxy-7-azabenzotriazole (89mg, 0.65mmol) were dissolved in To anhydrous DMF (8mL), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188mg, 0.98mmol), add N,N-diisopropylethylamine (167mg, 1.29mmol), react at room temperature for 18h, concentrate under reduced pressure to remove the solvent, add water (20mL), extract with ethyl acetate (15mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and apply the residue to silica gel Column chromatography separation (eluent: DCM/MeOH(v/v)=15/1) to obtain a white solid (70mg, yield 49%).
1H NMR(400MHz,CDCl 3):δ(ppm)8.10(br.s,1H),7.78(br.s,1H),7.38–7.44(m,1H),7.33(s,1H),7.29(d,J＝7.2Hz,1H),7.11(d,J＝8.0Hz,1H),6.91(s,1H),6.86(d,J＝7.9Hz,1H),6.61(t,J F-H＝75.6Hz,1H),4.70–4.88(m,2H),4.08–4.23(m,1H),4.19(s,2H),3.90–3.97(m,1H),3.87(d,J＝6.8Hz,2H),3.65–3.73(m,1H),3.27–3.42(m,1H),2.56–2.68(m,1H),2.34–2.45(m,1H),2.15(s,3H),1.21–1.36(m,1H),0.59–0.69(m,2H),0.29–0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 8.10 (br.s, 1H), 7.78 (br.s, 1H), 7.38-7.44 (m, 1H), 7.33 (s, 1H), 7.29 ( d,J=7.2Hz,1H), 7.11(d,J=8.0Hz,1H), 6.91(s,1H), 6.86(d,J=7.9Hz,1H), 6.61(t,J FH ＝75.6Hz ,1H),4.70–4.88(m,2H),4.08–4.23(m,1H),4.19(s,2H),3.90–3.97(m,1H), 3.87(d,J=6.8Hz,2H), 3.65–3.73(m,1H), 3.27–3.42(m,1H), 2.56–2.68(m,1H), 2.34–2.45(m,1H), 2.15(s,3H), 1.21–1.36(m,1H) ), 0.59-0.69 (m, 2H), 0.29-0.40 (m, 2H).
MS(ESI,pos.ion)m/z:514.20[M+H] +. MS(ESI,pos.ion)m/z:514.20[M+H] + .
实施例156：(2R,4R)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 156: (2R,4R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000218
Figure PCTCN2021090489-appb-000218
步骤1：化合物(2R,4R)-1-叔丁基2-((6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯的合成Step 1: Compound (2R, 4R)-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropyl) Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate
将化合物(2R,4R)-1-(叔丁氧羰基)-4-(3-(环丙甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(900mg,2.11mmol，实施例150步骤5)，6-(羟甲基)-N-甲基-N-(对甲基苯基)吡啶酰胺(50mg,0.34mmol)和1-羟基苯并三唑(426mg,3.15mmol)溶于干燥的DMF(8mL)中，加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(605mg,3.16mmol)，冰浴中加入N–甲基吗啡啉(426mg,4.21mmol)，室温反应10h，加水(130mL)，用乙酸乙酯萃取(25mL×3)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:DCM/EtOAc(v/v)＝10/1)得到浅褐色固体(983mg,产率70％)。The compound (2R, 4R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (900mg , 2.11mmol, Example 150 step 5), 6-(hydroxymethyl)-N-methyl-N-(p-methylphenyl)pyridine amide (50mg, 0.34mmol) and 1-hydroxybenzotriazole ( 426mg, 3.15mmol) was dissolved in dry DMF (8mL), added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (605mg, 3.16mmol), added to the ice bath N-Methylmorpholine (426mg, 4.21mmol), react at room temperature for 10h, add water (130mL), extract with ethyl acetate (25mL×3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and leave the residue Perform silica gel column chromatography (eluent: DCM/EtOAc (v/v)=10/1) to obtain a light brown solid (983 mg, yield 70%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.49–7.61(m,1H),7.13–7.32(m,2H),7.09(d,J＝7.8Hz,1H), 6.86–7.01(m,4H),6.76–6.81(m,2H),6.59(t,J F-H＝75.6Hz,1H),4.99–5.18(m,2H),4.37–4.48(m,1H),4.05–4.09(m,0.5H),3.92–3.96(m,0.5H),3.82–3.86(m,2H),3.46(s,3H),3.28–3.44(m,2H),2.64–2.73(m,1H),2.28–2.41(m,0.5H),2.24(s,3H),1.99–2.11(m,0.5H),1.37–1.45(m,9H),1.22–1.33(m,1H),0.61–0.67(m,2H),0.31–0.39(m,2H). 1 H NMR(400MHz, CDCl 3 ): δ(ppm)7.49–7.61(m,1H), 7.13–7.32(m,2H), 7.09(d,J=7.8Hz,1H), 6.86–7.01(m, 4H), 6.76–6.81(m, 2H), 6.59(t, J FH = 75.6Hz, 1H), 4.99–5.18(m, 2H), 4.37–4.48(m, 1H), 4.05–4.09(m, 0.5 H), 3.92–3.96(m,0.5H), 3.82–3.86(m,2H), 3.46(s,3H), 3.28–3.44(m,2H), 2.64–2.73(m,1H), 2.28–2.41 (m,0.5H),2.24(s,3H),1.99–2.11(m,0.5H),1.37–1.45(m,9H),1.22–1.33(m,1H),0.61–0.67(m,2H) ,0.31--0.39(m,2H).
MS(ESI,pos.ion)m/z:666.30[M+H] +. MS(ESI,pos.ion)m/z:666.30[M+H] + .
步骤2：化合物(2R,4R)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐的合成Step 2: Compound (2R, 4R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-( Synthesis of difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride
将化合物(2R,4R)-1-叔丁基2-((6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯(880mg,1.32mmol)溶解于二氯甲烷(12mL)溶液中，加入4mol/L HCl的1,4-二氧六环溶液(5mL)，室温搅拌1h，除去溶剂，得到浅黄色固体(817mg,产率100％)。The compound (2R, 4R)-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethyl) (Oxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (880mg, 1.32mmol) dissolved in dichloromethane (12mL) solution, add 4mol/L HCl The 1,4-dioxane solution (5 mL) was stirred at room temperature for 1 h, and the solvent was removed to obtain a pale yellow solid (817 mg, yield 100%).
步骤3：化合物(2R,4R)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯的合成Step 3: Compound (2R, 4R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R,4R)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐(795mg,1.32mmol)溶解在二氯甲烷(15mL)中，在冰浴中冷却，加入N,N-二异丙基乙胺(682mg,5.28mmol)和乙酰氯(259mg,3.30mmol)，室温搅拌3h后停止反应，加水(20mL)搅拌2min，分离有机相，水相用二氯甲烷萃取(10mL×2)，合并有机相，用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂：DCM/MeOH(v/v)＝23/1)和制备纯化得到白色固体(614mg,产率77％，手性HPLC纯度2R4R:23.43％,2R4S:75.35％)。再进行手性制备得到白色固体(83mg)。The compound (2R, 4R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy) phenyl) pyrrolidine-2-carboxylate hydrochloride (795 mg, 1.32 mmol) was dissolved in dichloromethane (15 mL), cooled in an ice bath, and N,N-diisopropyl ethyl was added Amine (682mg, 5.28mmol) and acetyl chloride (259mg, 3.30mmol) were stirred at room temperature for 3h and the reaction was stopped. Water (20mL) was added and stirred for 2min. The organic phase was separated. The aqueous phase was extracted with dichloromethane (10mL×2), and the organic Phase, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: DCM/MeOH(v/v)=23/1) and preparation and purification to obtain a white solid (614mg, yield 77%, chiral HPLC purity 2R4R: 23.43%, 2R4S: 75.35%). Chiral preparation was performed to obtain a white solid (83 mg).
1H NMR(400MHz,CDCl 3):δ(ppm)7.55–7.65(m,1H),7.22–7.35(m,2H),7.12–7.16(m,1H),6.87–7.05(m,4H),6.79–6.83(m,2H),6.63(t,J F-H＝75.6Hz,1H),5.02–5.25(m,2H),4.79(d,J＝8.1Hz,0.8H),4.61(d,J＝8.4Hz,0.2H),4.05–4.09(m,1H),3.86–3.90(m,2H),3.63–3.72(m,1H),3.49–3.53(m,1H),3.47(s,3H),2.34–2.47(m,2H),2.27(s,3H),2.13(s,2.5H),2.04(s,0.5H),1.22–1.35(m,1H),0.65–0.70(m,2H),0.35–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.55-7.65 (m, 1H), 7.22-7.35 (m, 2H), 7.12-7.16 (m, 1H), 6.87-7.05 (m, 4H), 6.79–6.83 (m, 2H), 6.63 (t, J FH = 75.6 Hz, 1H), 5.02–5.25 (m, 2H), 4.79 (d, J = 8.1 Hz, 0.8H), 4.61 (d, J = 8.4Hz, 0.2H), 4.05-4.09 (m, 1H), 3.86-3.90 (m, 2H), 3.63-3.72 (m, 1H), 3.49-3.53 (m, 1H), 3.47 (s, 3H), 2.34–2.47(m,2H), 2.27(s,3H), 2.13(s,2.5H), 2.04(s,0.5H), 1.22–1.35(m,1H), 0.65–0.70(m,2H), 0.35--0.39 (m, 2H).
MS(ESI,pos.ion)m/z:608.25[M+H] +. MS(ESI,pos.ion)m/z:608.25[M+H] + .
实施例157：(2S,4S)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 157: (2S,4S)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000219
Figure PCTCN2021090489-appb-000219
步骤1：化合物(2S,4R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-1,2-二甲酸酯的合成Step 1: Compound (2S,4R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrole Synthesis of Alkyl-1,2-Dicarboxylate
将化合物2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(10.410g,26.73mmol)溶于无水四氢呋喃(62mL),冷至-20℃,滴入异丙基氯化镁-氯化锂(22mL,29.00mmol,1.3mol/L的四氢呋喃溶液)，室温搅拌2h,置于-78℃搅拌0.5h,滴入(2S)-1-叔丁基氧羰基-4-氧代脯氨酸甲酯(5.00g,20.60mmol)的无水四氢呋喃(20mL),置于-70℃搅拌2h。加入饱和氯化铵溶液(5mL)淬灭反应,加入乙酸乙酯(100mL)稀释，有机相 用饱和食盐水洗涤(100mL),水相用乙酸乙酯萃取(50mL×3)，合并有机相，有机相用无水无水硫酸钠干燥，浓缩得黄色液体,硅胶柱层析(洗脱剂：PE/AcOEt(v/v)＝4/1)纯化得黄色透明液体(5.21g,产率55.40％)。合成参考：Synthesis of 4-cis-Phenyl-L-proline via Hydrogenolysis J.Org.Chem.2001,66,3593-3596。Dissolve the compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (10.410g, 26.73mmol) in anhydrous tetrahydrofuran (62mL), cool to -20℃, drop Add isopropylmagnesium chloride-lithium chloride (22mL, 29.00mmol, 1.3mol/L tetrahydrofuran solution), stir at room temperature for 2h, place at -78℃ and stir for 0.5h, add dropwise (2S)-1-tert-butyloxycarbonyl -4-oxoproline methyl ester (5.00g, 20.60mmol) in anhydrous tetrahydrofuran (20mL), placed at -70°C and stirred for 2h. The reaction was quenched by adding saturated ammonium chloride solution (5 mL), diluted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (100 mL), the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phases were combined. The organic phase was dried with anhydrous anhydrous sodium sulfate and concentrated to obtain a yellow liquid, which was purified by silica gel column chromatography (eluent: PE/AcOEt(v/v)=4/1) to obtain a yellow transparent liquid (5.21g, yield 55.40) %). Synthesis reference: Synthesis of 4-cis-Phenyl-L-proline via Hydrogenolysis J.Org.Chem.2001,66,3593-3596.
1H NMR(400MHz,CDCl 3):δ(ppm)7.19(d,J＝14.9Hz,1H),7.13(d,J＝8.3Hz,1H),6.95(d,J＝8.3Hz,1H),6.62(t,J＝75.6Hz,1H),4.57–4.42(m,1H),3.95–3.84(m,3H),3.82(d,J＝6.0Hz,3H),3.76–3.62(m,1H),2.68–2.58(m,1H),2.33–2.21(m,1H),1.45(d,J＝8.5Hz,9H),1.28–1.24(m,1H),0.69–0.60(m,2H),0.38–0.29(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.19 (d, J = 14.9 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.62(t,J=75.6Hz,1H), 4.57–4.42(m,1H), 3.95–3.84(m,3H), 3.82(d,J=6.0Hz,3H), 3.76–3.62(m,1H) ,2.68–2.58(m,1H),2.33–2.21(m,1H),1.45(d,J=8.5Hz,9H),1.28–1.24(m,1H),0.69–0.60(m,2H),0.38 –0.29(m,2H).
MS(ESI,pos.ion)m/z:340.10[M-H 2O-Boc+2H] +. MS(ESI,pos.ion)m/z:340.10[MH 2 O-Boc+2H] + .
步骤2：化合物(2S,4R)-1-叔丁氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-2-甲酸的合成Step 2: Compound (2S, 4R)-1-tert-butoxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine- Synthesis of 2-formic acid
将化合物(2S,4R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-1,2-二甲酸酯(5.21g,11.38mmol)，氢氧化锂一水合物(560mg,22.91mmol)溶于四氢呋喃/水(13mL,(v/v)＝5/1)中，室温搅拌4h。置于冰浴冷却10min,滴入稀盐酸(4mol/L)调节pH＝4,加入饱和食盐水(50mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压浓缩，得浅褐色固体(5.15g,产率100％)。The compound (2S, 4R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine- 1,2-Dicarboxylate (5.21g, 11.38mmol), lithium hydroxide monohydrate (560mg, 22.91mmol) dissolved in tetrahydrofuran/water (13mL, (v/v)=5/1), stirred at room temperature 4h. Place in an ice bath to cool for 10 minutes, add dilute hydrochloric acid (4mol/L) to adjust pH=4, add saturated brine (50mL), extract with ethyl acetate (100mL×3), combine the organic phases, and dry with anhydrous sodium sulfate And concentrated under reduced pressure to obtain a light brown solid (5.15 g, yield 100%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.14–7.05(m,2H),6.93(d,J＝8.2Hz,1H),6.61(t,J＝75.6Hz,1H),4.58–4.46(m,2H),3.91–3.82(m,2H),3.82–3.70(m,1H),3.67–3.50(m,1H),2.64–2.52(m,1H),2.47(d,J＝13.6Hz,1H),1.41(s,9H),1.27–1.22(m,1H),0.66–0.54(m,2H),0.39–0.25(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.14-7.05 (m, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.61 (t, J = 75.6 Hz, 1H), 4.58-4.46 (m,2H), 3.91–3.82(m,2H), 3.82–3.70(m,1H), 3.67–3.50(m,1H), 2.64–2.52(m,1H), 2.47(d,J=13.6Hz) ,1H),1.41(s,9H),1.27-1.22(m,1H),0.66-0.54(m,2H),0.39-0.25(m,2H).
MS(ESI,pos.ion)m/z:370.10[M-H 2O-tBu+2H] +. MS(ESI,pos.ion)m/z:370.10[MH 2 O-tBu+2H] + .
步骤3：化合物(1R,4S)-叔丁基1-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-3-氧代-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-甲酸酯的合成Step 3: Compound (1R,4S)-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa- Synthesis of 5-azabicyclo[2.2.1]heptane-5-carboxylate
将化合物(2S,4R)-1-叔丁氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-2-甲酸(5.10g,11.50mmol)和N,N-二异丙基乙胺(5.6mL,34.00mmol)溶于二氯甲烷(45mL)中，在0℃下缓慢滴入甲磺酰氯(1.3mL,17.00mmol)，室温搅拌2h。加入二氯甲烷(100mL)稀释，有机相用水(50mL×3)洗涤,用无水硫酸钠干燥，浓缩得黄色液体,硅胶柱层析(洗脱剂：PE/AcOEt(v/v)＝5/1)纯化得黄色液体(3.19g,产率65.20％)。The compound (2S, 4R)-1-tert-butoxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine-2- Formic acid (5.10g, 11.50mmol) and N,N-diisopropylethylamine (5.6mL, 34.00mmol) were dissolved in dichloromethane (45mL), and methanesulfonyl chloride (1.3mL, 17.00mmol), stirred at room temperature for 2h. Dilute with dichloromethane (100mL), wash the organic phase with water (50mL×3), dry with anhydrous sodium sulfate, and concentrate to obtain a yellow liquid. Silica gel column chromatography (eluent: PE/AcOEt(v/v)=5 /1) Purified to obtain a yellow liquid (3.19g, yield 65.20%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.19(d,J＝8.3Hz,1H),7.07(d,J＝1.9Hz,1H),6.93(dd,J＝8.3,2.0Hz,1H),6.64(t,J＝75.2Hz,1H),4.69(br.s,1H),3.88(d,J＝6.9Hz,2H),3.70–3.58(m,2H),2.42(d,J＝11.9Hz,1H),2.27(d,J＝10.6Hz,1H),1.47(s,9H),1.29–1.24(m,1H),0.67–0.61(m,2H),0.38–0.32(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.19 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.93 (dd, J = 8.3, 2.0 Hz, 1H ), 6.64 (t, J = 75.2 Hz, 1H), 4.69 (br.s, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.70-3.58 (m, 2H), 2.42 (d, J = 11.9Hz, 1H), 2.27 (d, J = 10.6Hz, 1H), 1.47 (s, 9H), 1.29-1.24 (m, 1H), 0.67-0.61 (m, 2H), 0.38-0.32 (m, 2H) ).
MS(ESI,pos.ion)m/z:370.10[M-t-Bu+2H] +. MS(ESI,pos.ion)m/z:370.10[Mt-Bu+2H] + .
步骤4：化合物(2S)-1-(叔丁基氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-甲酸的合成Step 4: Compound (2S)-1-(tert-butyloxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-di Synthesis of Hydrogen-1H-pyrrole-2-carboxylic acid
将化合物(1R,4S)-叔丁基1-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-3-氧代-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-甲酸酯(3.15g,7.40mmol)溶于二氯甲烷(85mL)中,滴入三氟乙酸(5.6mL,34.00mmol)的二氯甲烷溶液(20mL),室温搅拌2.5h。有机相用水(80mL×3)洗涤,用无水硫酸钠干燥，浓缩得黄色液体,硅胶柱层析(洗脱剂：PE/AcOEt(v/v)＝5/1)纯化得黄色固体(1.53g,产率48.50％)。The compound (1R, 4S)-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa-5- Azabicyclo[2.2.1]heptane-5-carboxylate (3.15g, 7.40mmol) was dissolved in dichloromethane (85mL), and trifluoroacetic acid (5.6mL, 34.00mmol) in dichloromethane was added dropwise (20mL), stirred at room temperature for 2.5h. The organic phase was washed with water (80mL×3), dried with anhydrous sodium sulfate, concentrated to obtain a yellow liquid, and purified by silica gel column chromatography (eluent: PE/AcOEt(v/v)=5/1) to obtain a yellow solid (1.53 g, yield 48.50%).
MS(ESI,pos.ion)m/z:370.10[M-t-Bu+2H] +. MS(ESI,pos.ion)m/z:370.10[Mt-Bu+2H] + .
步骤5：化合物(2S)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-2-甲酸的合成Step 5: Compound (2S)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid synthesis
将化合物(2S)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-甲酸(1.04g,2.45mmol)，三(三苯基膦)氯化铑(295mg,0.32mmol)，三乙胺(490uL,3.52mmol)，无水四氢呋喃(2mL)溶于无水乙醇(18mL)中，排除空气,在氢气(0.8MPa)氛围下，室温搅拌4天。浓缩溶剂， 向剩余物加入乙酸乙酯(50mL)稀释，用稀盐酸(1M/L)调节pH＝1，分离有机相，水相用乙酸乙酯萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，浓缩得黄色液体，硅胶柱层析纯化(洗脱剂：PE/AcOEt(v/v)＝5/1)得白色粘稠固体(843mg,80.45％)。合成参考：Carboxylate-Directed Highly Stereoselective Homogeneous Hydrogenation of Cyclic Olefins with Wilkinson’s Catalyst.Organic Letters.2003 Vol.5,No.9 1587-1589。The compound (2S)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H- Pyrrole-2-carboxylic acid (1.04g, 2.45mmol), tris(triphenylphosphine) rhodium chloride (295mg, 0.32mmol), triethylamine (490uL, 3.52mmol), anhydrous tetrahydrofuran (2mL) dissolved in anhydrous In ethanol (18 mL), the air was removed, and the mixture was stirred at room temperature for 4 days under a hydrogen (0.8 MPa) atmosphere. The solvent was concentrated, ethyl acetate (50mL) was added to the residue to dilute, the pH=1 was adjusted with dilute hydrochloric acid (1M/L), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30mL×3), the organic phases were combined and used It was dried with anhydrous sodium sulfate and concentrated to obtain a yellow liquid, and purified by silica gel column chromatography (eluent: PE/AcOEt(v/v)=5/1) to obtain a white viscous solid (843 mg, 80.45%). Synthesis reference: Carboxylate-Directed Highly Stereoselective Homogeneous Hydrogenation of Cyclic Olefins with Wilkinson’s Catalyst Organic Letters. 2003 Vol. 5, No. 9 1587-1589.
1H NMR(400MHz,CDCl 3):δ(ppm)7.15–7.06(m,1H),6.85–6.73(m,2H),6.59(t,J＝75.6Hz,1H),4.56–4.30(m,1H),4.09–3.92(m,1H),3.92–3.79(m,2H),3.56–3.38(m,1H),3.39–3.23(m,1H),2.77–2.54(m,1H),2.50–2.14(m,1H),1.49–1.44(m,9H),1.33–1.18(m,1H),0.68–0.55(m,2H),0.41–0.27(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.15-7.06 (m, 1H), 6.85-6.73 (m, 2H), 6.59 (t, J = 75.6 Hz, 1H), 4.56-4.30 (m, 1H), 4.09--3.92(m,1H), 3.92--3.79(m,2H), 3.56--3.38(m,1H), 3.39--3.23(m,1H), 2.77--2.54(m,1H), 2.50-- 2.14 (m, 1H), 1.49-1.44 (m, 9H), 1.33-1.18 (m, 1H), 0.68-0.55 (m, 2H), 0.41-0.27 (m, 2H).
MS(ESI,pos.ion)m/z:372.05[M-t-Bu+2H] +. MS(ESI,pos.ion)m/z:372.05[Mt-Bu+2H] + .
步骤6：化合物(2S)-1-叔丁基2-((6-(甲基(对甲苯基)氨甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯的合成Step 6: Compound (2S)-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate
将化合物(2S)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-2-甲酸(840mg,1.97mmol)，6-羟甲基-N-甲基-N-对甲苯基-吡啶甲酰胺(554mg,2.16mmol)和1-羟基苯并三唑(406mg,2.94mmol)溶于N,N-二甲基甲酰胺(15mL)中，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(568mg,2.95mmol)和N-甲基吗啉(440uL,3.90mmol)，室温搅拌18h。加水(100mL)稀释，有机相用二氯甲烷(50mL×3)萃取，用无水硫酸钠干燥，减压除去溶剂，剩余物进行硅胶柱层析分离(洗脱剂：60-90石油醚/乙酸乙酯(v/v)＝3/2)得到白色固体(940mg,71.85％)。Compound (2S)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid (840mg, 1.97mmol), 6-hydroxymethyl-N-methyl-N-p-tolyl-picolinamide (554mg, 2.16mmol) and 1-hydroxybenzotriazole (406mg, 2.94mmol) dissolved in N, N- In dimethylformamide (15mL), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (568mg, 2.95mmol) and N-methyl in an ice bath Morpholine (440uL, 3.90mmol), stirred at room temperature for 18h. Dilute with water (100mL), extract the organic phase with dichloromethane (50mL×3), dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate the residue by silica gel column chromatography (eluent: 60-90 petroleum ether/ Ethyl acetate (v/v)=3/2) to obtain a white solid (940 mg, 71.85%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.60–7.48(m,1H),7.30–7.12(m,2H),7.07(d,J＝8.0Hz,1H),7.00–6.83(m,4H),6.80–6.74(m,2H),6.56(t,J＝75.7Hz,1H),5.18–4.96(m,2H),4.60–4.33(m,1H),4.02–3.88(m,1H),3.86–3.78(m,2H),3.53–3.45(m,1H),3.42(s,3H),3.40–3.29(m,1H),2.42–2.26(m,2H),2.22(s,3H),1.43(s,5H),1.36(s,4H),1.27–1.23(m,1H),0.65–0.58(m,2H),0.35–0.28(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.60-7.48 (m, 1H), 7.30-7.12 (m, 2H), 7.07 (d, J=8.0Hz, 1H), 7.00-6.83 (m, 4H), 6.80–6.74(m,2H), 6.56(t,J=75.7Hz,1H), 5.18–4.96(m,2H), 4.60–4.33(m,1H), 4.02–3.88(m,1H) , 3.86–3.78(m,2H),3.53–3.45(m,1H),3.42(s,3H),3.40–3.29(m,1H),2.42–2.26(m,2H),2.22(s,3H) ,1.43(s,5H),1.36(s,4H),1.27-1.23(m,1H),0.65-0.58(m,2H),0.35-0.28(m,2H).
MS(ESI,pos.ion)m/z:666.10[M+H] +. MS(ESI,pos.ion)m/z:666.10[M+H] + .
步骤7：化合物(2S)-(6-(甲基(对甲苯基)氨甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐的合成Step 7: Compound (2S)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of (Methoxy) Phenyl) Pyrrolidine-2-carboxylate Hydrochloride
将化合物(2S)-1-叔丁基2-((6-(甲基(对甲苯基)氨甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯(940mg,1.41mmol)溶于二氯甲烷(14mL)中，注入氯化氢的二氧六环溶液(3.5mL,14mmol,4mol/L)溶液，室温搅拌3h。减压除去溶剂，得到黄色泡沫状固体(850mg,99.88％)。The compound (2S)-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy) -4-(Difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (940mg, 1.41mmol) was dissolved in dichloromethane (14mL), and a dioxane solution of hydrogen chloride (3.5 mL, 14mmol, 4mol/L) solution, stirred at room temperature for 3h. The solvent was removed under reduced pressure to obtain a yellow foamy solid (850mg, 99.88%).
1H NMR(400MHz,CDCl 3):δ(ppm)8.28–8.05(m,1H),7.86–7.69(m,2H),7.25–7.11(m,2H),7.11–6.95(m,4H),6.93–6.78(m,1H),6.56(t,J＝75.6Hz,1H),5.90–5.56(m,1H),5.19–4.82(m,1H),4.09–3.93(m,1H),3.93–3.80(m,2H),3.80–3.70(m,1H),3.66–3.62(m,1H),3.62–3.56(m,1H),3.44(s,3H),2.85–2.67(m,1H),2.53–2.34(m,1H),2.30–2.12(m,3H),1.28–1.17(m,1H),0.64–0.49(m,2H),0.38–0.25(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 8.28-8.05 (m, 1H), 7.86-7.69 (m, 2H), 7.25-7.11 (m, 2H), 7.11-6.95 (m, 4H), 6.93–6.78(m,1H), 6.56(t,J=75.6Hz,1H), 5.90–5.56(m,1H), 5.19–4.82(m,1H), 4.09–3.93(m,1H), 3.93– 3.80 (m, 2H), 3.80-3.70 (m, 1H), 3.66-3.62 (m, 1H), 3.62-3.56 (m, 1H), 3.44 (s, 3H), 2.85-2.67 (m, 1H), 2.53–2.34(m,1H), 2.30–2.12(m,3H), 1.28–1.17(m,1H), 0.64–0.49(m,2H), 0.38–0.25(m,2H).
MS(ESI,pos.ion)m/z:566.10[M-HCl+H] +. MS(ESI,pos.ion)m/z:566.10[M-HCl+H] + .
步骤8：化合物(2S,4S)-(6-(甲基(对甲苯基)氨甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯的合成Step 8: Compound (2S, 4S)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2S)-((6-(甲基(对甲苯基)氨甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸酯盐酸盐(850mg,1.41mmol)，三乙胺(596uL,4.23mmol)溶于二氯甲烷(14mL)中，在0℃下缓慢滴入乙酰氯(151uL,2.12mmol),室温搅拌2h。加入二氯甲烷(50mL)，有机相用饱和食盐水 (30mL×3)洗涤，用无水硫酸钠干燥，减压除去溶剂，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝50:1)得到黄色粘稠液体(690mg,80.44％,(2S,4S):(2S,4R)＝63:23),手性制备拆分得白色固体(144mg,16.78％,(2S,4S)＝100％)。The compound (2S)-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethyl (Oxy) phenyl) pyrrolidine-2-carboxylate hydrochloride (850mg, 1.41mmol), triethylamine (596uL, 4.23mmol) dissolved in dichloromethane (14mL), slowly dripped at 0℃ Acetyl chloride (151uL, 2.12mmol), stirred at room temperature for 2h. Dichloromethane (50mL) was added, the organic phase was washed with saturated brine (30mL×3), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was subjected to silica gel Column chromatography separation (eluent: dichloromethane/methanol (v/v) = 50:1) to obtain a yellow viscous liquid (690 mg, 80.44%, (2S, 4S): (2S, 4R) = 63:23 ), chiral preparation and resolution gave a white solid (144mg, 16.78%, (2S, 4S)=100%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.56(br.s,1H),7.31–7.17(m,2H),7.11(d,J＝8.2Hz,1H),7.02–6.85(m,4H),6.83–6.74(m,2H),6.59(t,J＝75.6Hz,1H),5.23–5.00(m,2H),4.75(d,J＝8.2Hz,1H),4.10–3.99(m,1H),3.86(d,J＝6.9Hz,2H),3.70–3.58(m,1H),3.52–3.44(m,1H),3.43(s,3H),2.45–2.37(m,1H),2.37–2.27(m,1H),2.24(s,3H),2.10(s,2.5H),2.00(s,0.5H),1.28–1.24(m,1H),0.68–0.59(m,2H),0.38–0.30(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.56 (br.s, 1H), 7.31-7.17 (m, 2H), 7.11 (d, J = 8.2 Hz, 1H), 7.02-6.85 (m, 4H), 6.83–6.74(m,2H), 6.59(t,J=75.6Hz,1H), 5.23–5.00(m,2H), 4.75(d,J=8.2Hz,1H), 4.10–3.99(m ,1H), 3.86(d,J=6.9Hz,2H),3.70–3.58(m,1H),3.52–3.44(m,1H),3.43(s,3H),2.45–2.37(m,1H), 2.37–2.27(m,1H), 2.24(s,3H), 2.10(s,2.5H), 2.00(s,0.5H), 1.28–1.24(m,1H), 0.68–0.59(m,2H), 0.38-0.30 (m, 2H).
MS(ESI,pos.ion)m/z:608.20[M+H] +. MS(ESI,pos.ion)m/z:608.20[M+H] + .
实施例158：(2S,4R)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 158: (2S,4R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000220
Figure PCTCN2021090489-appb-000220
步骤1：化合物(2S,4R)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-2-甲酸的合成Step 1: Compound (2S,4R)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2- Synthesis of formic acid
将化合物(2S)-1-(叔丁基氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-甲酸(640mg,1.50mmol，实施例157步骤4)溶于乙醇(31mL)，加入Pd/C(520mg,10％Pd,55％H 2O)和三乙胺(319uL,2.29mmol)，排除空气，氢气氛围下，室温搅拌17h。把反应液通过硅藻土滤去固体，滤液减压除去溶剂得到无色透明液体(645mg,产率100％)。合成参考：Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2.J.Med.Chem.2014,57,9042-9064。 The compound (2S)-1-(tert-butyloxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H-pyrrole-2-carboxylic acid (640mg, 1.50mmol, step 4 of Example 157) was dissolved in ethanol (31mL), Pd/C (520mg, 10% Pd, 55% H 2 O) and triethylamine (319uL, 2.29mmol), excluding air, and stirring at room temperature for 17h under a hydrogen atmosphere. The reaction solution was filtered through Celite to remove solids, and the filtrate was decompressed to remove the solvent to obtain a colorless and transparent liquid (645 mg, yield 100%). Synthesis reference: Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2.J.Med.Chem.2014,57,9042-9064.
1H NMR(400MHz,CDCl 3):δ(ppm)7.03(d,J＝8.1Hz,1H),6.82(d,J＝9.1Hz,1H),6.77(d,J＝7.4Hz,1H),6.55(t,J＝75.8Hz,1H),4.25–4.19(m,1H),4.04–3.84(m,1H),3.88–3.80(m,2H),3.38(t,J＝10.7Hz,1H),3.27–3.15(m,1H),2.72–2.55(m,1H),2.07–1.92(m,1H),1.41(s,9H),1.29–1.18(m,1H),0.63–0.56(m,2H),0.34–0.28(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.03 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 9.1 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.55(t,J=75.8Hz,1H), 4.25–4.19(m,1H), 4.04–3.84(m,1H), 3.88–3.80(m,2H), 3.38(t,J=10.7Hz,1H) , 3.27–3.15(m,1H), 2.72–2.55(m,1H), 2.07–1.92(m,1H), 1.41(s,9H), 1.29–1.18(m,1H), 0.63–0.56(m, 2H), 0.34-0.28 (m, 2H).
MS(ESI,pos.ion)m/z:372.05[M-t-Bu+2H] +. MS(ESI,pos.ion)m/z:372.05[Mt-Bu+2H] + .
步骤2：化合物(2S,4R)-1-叔丁基2-((6-(甲基(对甲苯基)氨甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯的合成Step 2: Compound (2S,4R)-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropyl) Synthesis of methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate
将化合物(2S,4R)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-2-甲酸(600mg,1.40mmol)，6-羟甲基-N-甲基-N-对甲苯基-吡啶甲酰胺(396mg,1.55mmol)和1-羟基苯并三唑(290mg,2.10mmol)溶于N,N-二甲基甲酰胺(10mL)中，在冰浴中冷却，加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(405mg,2.10mmol)和N-甲基吗啉(310uL,2.80mmol)，室温搅拌21h。加水(50mL)稀释，有机相用二氯甲烷(50mL×3)萃取，用无水硫酸钠干燥，减压除去溶剂，剩余物进行硅胶柱层析分离(洗脱剂：60-90石油醚/乙酸乙酯(v/v)＝3/2)得到白色固体(650.0mg,0.98mmol,产率69.55％)。The compound (2S, 4R)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid ( 600mg, 1.40mmol), 6-hydroxymethyl-N-methyl-N-p-tolyl-pyridinecarboxamide (396mg, 1.55mmol) and 1-hydroxybenzotriazole (290mg, 2.10mmol) dissolved in N, In N-dimethylformamide (10mL), cool in an ice bath, add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (405mg, 2.10mmol) and N -Methylmorpholine (310uL, 2.80mmol), stirred at room temperature for 21h. Dilute with water (50mL), extract the organic phase with dichloromethane (50mL×3), dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate the residue by silica gel column chromatography (eluent: 60-90 petroleum ether/ Ethyl acetate (v/v)=3/2) to obtain a white solid (650.0 mg, 0.98 mmol, yield 69.55%).
1H NMR(400MHz,CDCl 3):δ(ppm))7.62–7.47(m,1H),7.32–7.22(m,1H),7.19–7.06(m,1H),7.08(d,J＝8.0Hz,1H),7.02–6.85(m,4H),6.81–6.77(m,2H),6.58(t,J＝75.6Hz,1H),5.19–4.97(m,2H),4.49 –4.33(m,1H),4.08–3.89(m,1H),3.85–3.82(m,2H),3.45(s,3H),3.42–3.35(m,1H),3.35–3.27(m,1H),2.73–2.62(m,1H),2.10–1.97(m,1H),2.03(s,3H),1.45(s,4H),1.36(s,5H),1.25–1.23(m,1H),0.66–0.60(m,2H),0.37–0.31(m,2H). 1 H NMR(400MHz, CDCl 3 ): δ(ppm)) 7.62–7.47(m,1H), 7.32–7.22(m,1H), 7.19–7.06(m,1H), 7.08(d,J=8.0Hz ,1H),7.02–6.85(m,4H), 6.81–6.77(m,2H), 6.58(t,J=75.6Hz,1H), 5.19–4.97(m,2H), 4.49 –4.33(m,1H ), 4.08–3.89(m,1H), 3.85–3.82(m,2H), 3.45(s,3H), 3.42–3.35(m,1H), 3.35–3.27(m,1H), 2.73–2.62(m ,1H),2.10-1.97(m,1H),2.03(s,3H),1.45(s,4H),1.36(s,5H),1.25-1.23(m,1H),0.66-0.60(m,2H) ), 0.37--0.31 (m, 2H).
MS(ESI,pos.ion)m/z:666.30[M+H] +. MS(ESI,pos.ion)m/z:666.30[M+H] + .
步骤3：化合物(2S,4R)-(6-(甲基(对甲苯基)氨甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐的合成Step 3: Compound (2S,4R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-( Synthesis of difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride
将化合物(2S,4R)-1-叔丁基2-((6-(甲基(对甲苯基)氨甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(11195-2)(600mg,0.90mmol)溶于二氯甲烷(10mL)中，注入氯化氢的二氧六环溶液(2.5mL,10.0mmol,4mol/L)溶液，室温搅拌2h。减压除去溶剂，得到褐色粘稠液体(542mg,99.88％)。The compound (2S, 4R)-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (11195-2) (600mg, 0.90mmol) dissolved in dichloromethane (10mL) and injected with hydrogen chloride Dioxane solution (2.5 mL, 10.0 mmol, 4 mol/L) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to obtain a brown viscous liquid (542 mg, 99.88%).
1H NMR(400MHz,CDCl 3):δ(ppm)8.02–7.82(m,1H),7.27–7.15(m,1H),7.10–6.95(m,5H),6.92–6.79(m,3H),6.57(t,J＝75.7Hz,1H),5.62–5.49(m,2H),4.95–4.75(m,1H),3.90–3.85(m,2H),3.85–3.79(m,1H),3.74–3.68(m,1H),3.64–3.56(m,1H),3.46–3.36(m,3H),2.82–2.66(m,1H),2.51–2.35(m,1H),2.19(s,3H),1.26–1.20(m,1H),0.61–0.53(m,2H),0.35–0.25(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 8.02-7.82 (m, 1H), 7.27-7.15 (m, 1H), 7.10-6.95 (m, 5H), 6.92-6.79 (m, 3H), 6.57(t,J=75.7Hz,1H), 5.62–5.49(m,2H), 4.95–4.75(m,1H), 3.90–3.85(m,2H), 3.85–3.79(m,1H), 3.74– 3.68(m,1H), 3.64–3.56(m,1H), 3.46–3.36(m,3H), 2.82–2.66(m,1H), 2.51–2.35(m,1H), 2.19(s,3H), 1.26--1.20(m,1H), 0.61--0.53(m,2H), 0.35--0.25(m,2H).
MS(ESI,pos.ion)m/z:566.15[M-HCl+H] +. MS(ESI,pos.ion)m/z:566.15[M-HCl+H] + .
步骤4：化合物(2S,4R)-(6-(甲基(对甲苯基)氨甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯的合成Step 4: Compound (2S,4R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2S,4R)-((6-(甲基(对甲苯基)氨甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐(500mg,0.83mmol)，三乙胺(351uL,2.49mmol)溶于二氯甲烷(8mL)中，在0℃下缓慢滴入乙酰氯(89uL,1.25mmol),室温搅拌2h。加入二氯甲烷(50mL)，有机相用饱和食盐水(30mL×3)洗涤，用无水硫酸钠干燥，减压除去溶剂，剩余物进行硅胶柱层析分离(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)得到黄色粘稠液体(333mg,66.00％)。The compound (2S,4R)-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(two (Fluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride (500mg, 0.83mmol), triethylamine (351uL, 2.49mmol) dissolved in dichloromethane (8mL), slowly at 0℃ Acetyl chloride (89uL, 1.25mmol) was added dropwise and stirred at room temperature for 2h. Dichloromethane (50mL) was added, the organic phase was washed with saturated brine (30mL×3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue Perform silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=50/1) to obtain a yellow viscous liquid (333 mg, 66.00%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.68–7.47(m,1H),7.36–7.28(m,1H),7.25–7.18(m,1H),7.14–7.04(m,1H),7.03–6.84(m,4H),6.81(s,1H),6.79–6.75(m,1H),6.58(t,J＝75.5Hz,1H),5.20–5.00(m,2H),4.53(t,J＝8.5Hz,1H),3.97–3.88(m,1H),3.84(d,J＝6.9Hz,2H),3.60(t,J＝10.5Hz,1H),3.44(s,3H),3.41–3.29(m,1H),2.72–2.61(m,1H),2.23(s,3H),2.09(s,3H),2.07–2.03(m,1H),1.27–1.22(m,1H),0.65–0.61(m,2H),0.35–0.32(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.68-7.47 (m, 1H), 7.36-7.28 (m, 1H), 7.25-7.18 (m, 1H), 7.14-7.04 (m, 1H), 7.03–6.84(m,4H),6.81(s,1H),6.79–6.75(m,1H),6.58(t,J=75.5Hz,1H),5.20–5.00(m,2H),4.53(t, J = 8.5Hz, 1H), 3.97–3.88 (m, 1H), 3.84 (d, J = 6.9 Hz, 2H), 3.60 (t, J = 10.5 Hz, 1H), 3.44 (s, 3H), 3.41– 3.29(m,1H), 2.72--2.61(m,1H), 2.23(s,3H), 2.09(s,3H), 2.07--2.03(m,1H), 1.27--1.22(m,1H), 0.65-- 0.61 (m, 2H), 0.35-0.32 (m, 2H).
MS(ESI,pos.ion)m/z:608.20[M+H] +. MS(ESI,pos.ion)m/z:608.20[M+H] + .
实施例159：(2-甲基-3-氧代异吲哚啉-5-基)甲基(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 159: (2-Methyl-3-oxoisoindolin-5-yl)methyl(2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000221
Figure PCTCN2021090489-appb-000221
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酸(100mg,0.27mmol，实施例1步骤7)，6-(羟甲基)-2-甲基异吲哚-1-酮(50mg,0.28mmol)溶于二氯甲烷(10mL)中， 加入N-羟基-7-氮杂苯并三氮唑(113mg,0.81mmol)，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(157mg,0.81mmol)和N,N-二异丙基乙胺(141mg,1.09mmol)，室温反应22h，加水(10mL)搅拌5min，二氯甲烷萃取(20mL×2)，合并有机相后用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝1/1)，得到白色固体(40mg,产率28％)。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100mg, 0.27mmol, Example 1 Step 7), 6-(hydroxymethyl)-2-methylisoindol-1-one (50mg, 0.28mmol) was dissolved in dichloromethane (10mL), and N-hydroxy-7-nitrogen was added Heterobenzotriazole (113mg, 0.81mmol), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (157mg, 0.81mmol) and N, in an ice bath N-Diisopropylethylamine (141mg, 1.09mmol), react at room temperature for 22h, add water (10mL) and stir for 5min, extract with dichloromethane (20mL×2), combine the organic phases and dry the organic phase with anhydrous sodium sulfate. After pressure concentration, the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 1/1) to obtain a white solid (40 mg, yield 28%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.82(s,1H),7.51–7.58(m,1H),7.39–7.48(m,1H),7.10(d,J＝7.9Hz,1H),6.75–6.84(m,2H),6.59(t,J＝75.6Hz,1H),5.23–5.34(m,2H),4.47–4.60(m,1H),4.30–4.42(m,2H),3.90–4.00(m,1H),3.79–3.89(m,2H),3.61(t,J＝10.1Hz,1H),3.34–3.51(m,1H),3.15–3.29(m,3H),2.59–2.74(m,1H),2.12(s,2.6H),1.95–2.06(m,1H),1.92(s,0.4H),1.22–1.26(m,1H),0.59–0.71(m,2H),0.29–0.41(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.82 (s, 1H), 7.51-7.58 (m, 1H), 7.39-7.48 (m, 1H), 7.10 (d, J = 7.9 Hz, 1H) ,6.75–6.84(m,2H),6.59(t,J=75.6Hz,1H), 5.23–5.34(m,2H), 4.47–4.60(m,1H), 4.30–4.42(m,2H),3.90 –4.00(m,1H),3.79–3.89(m,2H),3.61(t,J=10.1Hz,1H), 3.34–3.51(m,1H), 3.15–3.29(m,3H), 2.59–2.74 (m,1H),2.12(s,2.6H),1.95-2.06(m,1H),1.92(s,0.4H),1.22-1.26(m,1H),0.59-0.71(m,2H),0.29 –0.41(m,2H).
MS(ESI,pos.ion)m/z:529.20[M+H] +. MS(ESI,pos.ion)m/z:529.20[M+H] + .
实施例160：(1,2-二甲基-3-氧代异吲哚啉-5-基)甲基(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 160: (1,2-Dimethyl-3-oxoisoindolin-5-yl)methyl(2R)-1-acetyl-4-(3-(cyclopropylmethoxy) -4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000222
Figure PCTCN2021090489-appb-000222
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(100mg,0.27mmol，实施例1步骤7)，6-(羟甲基)-2,3-二甲基异吲哚-1-酮(50mg,0.28mmol)溶于二氯甲烷(10mL)中，加入N-羟基-7-氮杂苯并三氮唑(113mg,0.81mmol)，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(157mg,0.81mmol)和N,N-二异丙基乙胺(141mg,1.09mmol)，室温反应20h，加水(10mL)搅拌5min，二氯甲烷萃取(20mL×2)，合并有机相后用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝1/1)，得到白色固体(40mg,27％,HPLC纯度84.31％)。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100mg, 0.27mmol, implementation Example 1 Step 7), 6-(hydroxymethyl)-2,3-dimethylisoindol-1-one (50mg, 0.28mmol) was dissolved in dichloromethane (10mL), and N-hydroxy-7 was added -Azabenzotriazole (113mg, 0.81mmol), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (157mg, 0.81mmol) and N,N-Diisopropylethylamine (141mg, 1.09mmol), react at room temperature for 20h, add water (10mL) and stir for 5min, extract with dichloromethane (20mL×2), combine the organic phases and dry the organic phase with anhydrous sodium sulfate It was concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=1/1) to obtain a white solid (40 mg, 27%, HPLC purity 84.31%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.80(s,1H),7.52–7.59(m,1H),7.41(d,J＝7.7Hz,1H),7.10(d,J＝7.9Hz,1H),6.73–6.83(m,2H),6.59(t,J＝75.5Hz,1H),5.22–5.30(m,2H),4.49–4.58(m,1H),4.39–4.48(m,1H),3.89–3.97(m,1H),3.80–3.89(m,2H),3.57–3.65(m,1H),3.35–3.46(m,1H),3.11(s,2.6H),3.02(s,0.4H),2.62–2.72(m,1H),2.12(s,2.6H),1.97–2.08(m,1H),1.92(s,0.4H),1.43–1.50(m,3H),1.22–1.25(m,1H),0.60–0.68(m,2H),0.31–0.38(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.80 (s, 1H), 7.52-7.59 (m, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.9 Hz ,1H),6.73-6.83(m,2H),6.59(t,J=75.5Hz,1H),5.22-5.30(m,2H),4.49-4.58(m,1H),4.39-4.48(m,1H ), 3.89–3.97(m,1H), 3.80–3.89(m,2H), 3.57–3.65(m,1H), 3.35–3.46(m,1H), 3.11(s,2.6H), 3.02(s, 0.4H), 2.62-2.72 (m, 1H), 2.12 (s, 2.6H), 1.97-2.08 (m, 1H), 1.92 (s, 0.4H), 1.43--1.50 (m, 3H), 1.22-1.25 (m,1H), 0.60--0.68(m,2H), 0.31--0.38(m,2H).
MS(ESI,pos.ion)m/z:543.20[M+H] +. MS(ESI,pos.ion)m/z:543.20[M+H] + .
实施例161：(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((2-甲基-3-氧代异吲哚啉-5-基)甲基)吡咯烷-2-甲酰胺Example 161: (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((2-methyl-3 -Oxoisoindolin-5-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000223
Figure PCTCN2021090489-appb-000223
步骤1：化合物(2R)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-((((2-甲基-3-氧代异吲哚啉-5-基)甲基)氨基甲酰基)吡咯烷-1-羧酸酯的合成Step 1: Compound (2R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((((2-methyl-3 -Oxoisoindolin-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate
将化合物(2R)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(150mg,0.35mmol)，6-(氨基甲基)-2-甲基异吲哚-1-酮(64mg,0.36mmol，中间体13)溶于N,N’-二甲基甲酰胺(6mL)中，加入N-羟基-7-氮杂苯并三氮唑(146mg,1.05mmol)，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(203mg,1.05mmol)和N,N-二异丙基乙胺(182mg,1.41mmol)，室温反应6h，加水(10mL)搅拌5min，二氯甲烷萃取(20mL×2)，合并有机相后用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝20/1)，得到白色固体(157mg,产率76％)。Compound (2R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150mg, 0.35mmol), 6-(aminomethyl)-2-methylisoindol-1-one (64mg, 0.36mmol, Intermediate 13) was dissolved in N,N'-dimethylformamide (6mL), Add N-hydroxy-7-azabenzotriazole (146mg, 1.05mmol), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 203mg, 1.05mmol) and N,N-diisopropylethylamine (182mg, 1.41mmol), react at room temperature for 6h, add water (10mL) and stir for 5min, extract with dichloromethane (20mL×2), combine the organic phases and use The organic phase was dried with sodium sulfate and concentrated under reduced pressure. The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain a white solid (157mg, yield 76%) ).
1H NMR(600MHz,CD 3OD):δ(ppm)7.67–7.73(m,1H),7.55–7.63(m,1H),7.47–7.54(m,1H),7.05–7.10(m,1H),7.03(s,1H),6.85–6.90(m,1H),6.71(t,J＝75.8Hz,1H),4.55–4.62(m,1H),4.47(s,2H),4.38–4.45(m,1H),4.26–4.35(m,1H),3.94–3.99(m,1H),3.90(d,J＝6.6Hz,2H),3.34–3.47(m,2H),3.18(s,3H),2.59–2.69(m,1H),2.03–2.06(m,1H),1.47(s,3H),1.34(s,6H),1.22–1.28(m,1H),0.58–0.65(m,2H),0.33–0.40(m,2H). 1 H NMR (600MHz, CD 3 OD): δ (ppm) 7.67-7.73 (m, 1H), 7.55-7.63 (m, 1H), 7.47-7.54 (m, 1H), 7.05-7.10 (m, 1H) ,7.03(s,1H),6.85-6.90(m,1H),6.71(t,J=75.8Hz,1H),4.55-4.62(m,1H),4.47(s,2H),4.38-4.45(m ,1H), 4.26–4.35(m,1H), 3.94–3.99(m,1H), 3.90(d,J=6.6Hz,2H), 3.34–3.47(m,2H), 3.18(s,3H), 2.59–2.69(m,1H), 2.03–2.06(m,1H), 1.47(s,3H), 1.34(s,6H), 1.22–1.28(m,1H), 0.58–0.65(m,2H), 0.33-0.40 (m, 2H).
MS(ESI,pos.ion)m/z:486.25[M-Boc+2H] +. MS(ESI,pos.ion)m/z:486.25[M-Boc+2H] + .
步骤2：化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(((2-甲基-3-氧代异吲哚啉-5-基)甲基)吡咯烷-2-甲酰胺盐酸盐的合成Step 2: Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(((2-methyl-3-oxoiso Synthesis of indolin-5-yl)methyl)pyrrolidine-2-carboxamide hydrochloride
将化合物(2R)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-((((2-甲基-3-氧代异吲哚啉-5-基)甲基)氨基甲酰基)吡咯烷-1-羧酸酯(11204-1)(150mg,0.26mmol)溶解于二氯甲烷(10mL)溶液中，加入4mol/L HCl的二氧六环溶液(5mL)，室温搅拌50min，减压浓缩除去溶剂，得到白色固体(134mg,100％)。The compound (2R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((((2-methyl-3-oxy Substitute isoindolin-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (11204-1) (150mg, 0.26mmol) was dissolved in dichloromethane (10mL) solution, and 4mol/ L HCl in dioxane solution (5 mL), stirred at room temperature for 50 min, and concentrated under reduced pressure to remove the solvent to obtain a white solid (134 mg, 100%).
1H NMR(600MHz,CD 3OD):δ(ppm)7.69(s,1H),7.51–7.58(m,2H),7.10(d,J＝8.2Hz,1H),7.05(d,J＝1.5Hz,1H),6.87–6.92(m,1H),6.73(t,J＝75.5Hz,1H),4.57(d,J＝3.6Hz,2H),4.48(s,2H),4.43–4.47(m,1H),3.90(d,J＝6.8Hz,2H),3.75–3.80(m,1H),3.56–3.60(m,1H),3.34–3.40(m,1H),3.19(s,3H),2.83–2.90(m,1H),2.09–2.17(m,1H),1.24–1.29(m,1H),0.60–0.66(m,2H),0.34–0.39(m,2H). 1 H NMR (600MHz, CD 3 OD): δ (ppm) 7.69 (s, 1H), 7.51-7.58 (m, 2H), 7.10 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.87–6.92 (m, 1H), 6.73 (t, J = 75.5 Hz, 1H), 4.57 (d, J = 3.6 Hz, 2H), 4.48 (s, 2H), 4.43–4.47 (m ,1H),3.90(d,J=6.8Hz,2H),3.75–3.80(m,1H),3.56–3.60(m,1H),3.34–3.40(m,1H),3.19(s,3H), 2.83–2.90(m,1H), 2.09–2.17(m,1H), 1.24–1.29(m,1H), 0.60–0.66(m,2H), 0.34–0.39(m,2H).
MS(ESI,pos.ion)m/z:486.75[M-HCl+H] +. MS(ESI,pos.ion)m/z:486.75[M-HCl+H] + .
步骤3：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(((2-甲基-3-氧代异吲哚啉-5-基)甲基)吡咯烷-2-甲酰胺的合成Step 3: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(((2-methyl- Synthesis of 3-oxoisoindolin-5-yl)methyl)pyrrolidine-2-carboxamide
将化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-(((2-甲基-3-氧代异吲哚啉-5-基)甲基)吡咯烷-2-甲酰胺盐酸盐(134mg,0.26mmol)溶解在二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(167mg,1.28mmol)，冷却至0℃，加入乙酰氯(59mg,0.76mmol)，室温搅拌1h后停止反应，加水(10mL)淬灭反应，二氯甲烷萃取(40mL×2)，有机相用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝20/1)得到白色固体(100mg,产率74％)。The compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(((2-methyl-3-oxoisoindole) Lin-5-yl)methyl)pyrrolidine-2-carboxamide hydrochloride (134mg, 0.26mmol) was dissolved in dichloromethane (10mL), and N,N-diisopropylethylamine (167mg, 1.28 mmol), cool to 0°C, add acetyl chloride (59mg, 0.76mmol), stir at room temperature for 1h, then stop the reaction, add water (10mL) to quench the reaction, extract with dichloromethane (40mL×2), and use anhydrous sodium sulfate for the organic phase After drying and concentration under reduced pressure, the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain a white solid (100 mg, yield 74%).
1H NMR(600MHz,CD 3OD):δ(ppm)7.66–7.70(m,1H),7.61(d,J＝7.6Hz,1H),7.50–7.55(m,1H), 7.03–7.12(m,2H),6.88–6.94(m,1H),6.72(t,J＝75.7Hz,1H),4.54–4.60(m,1H),4.51(s,2H),4.47(s,2H),4.04–4.10(m,1H),3.86–3.95(m,2H),3.58–3.67(m,1H),3.43–3.53(m,1H),3.19(s,3H),2.60–2.71(m,1H),2.13(s,2.4H),2.00–2.09(m,1H),1.91(s,0.6H),1.23–1.28(m,1H),0.58–0.66(m,2H),0.32–0.40(m,2H). 1 H NMR(600MHz, CD 3 OD): δ(ppm) 7.66–7.70(m,1H), 7.61(d,J=7.6Hz,1H), 7.50–7.55(m,1H), 7.03–7.12(m ,2H),6.88–6.94(m,1H),6.72(t,J=75.7Hz,1H),4.54–4.60(m,1H),4.51(s,2H),4.47(s,2H),4.04– 4.10(m,1H), 3.86–3.95(m,2H), 3.58–3.67(m,1H), 3.43–3.53(m,1H), 3.19(s,3H), 2.60–2.71(m,1H), 2.13(s,2.4H),2.00-2.09(m,1H),1.91(s,0.6H),1.23-1.28(m,1H),0.58-0.66(m,2H),0.32-0.40(m,2H) ).
MS(ESI,pos.ion)m/z:528.20[M+H] +. MS(ESI,pos.ion)m/z:528.20[M+H] + .
实施例162：(2R)-(2-甲基-1-氧代异吲哚啉-5-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 162: (2R)-(2-methyl-1-oxoisoindolin-5-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000224
Figure PCTCN2021090489-appb-000224
步骤1：化合物(2R)-1-叔丁基2-(((2-甲基-1-氧代异吲哚啉-5-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯的合成Step 1: Compound (2R)-1-tert-butyl 2-(((2-methyl-1-oxoisoindolin-5-yl)methyl)4-(3-(cyclopropylmethoxy Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate
将化合物(2R)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(150mg,0.35mmol，实施例1步骤4)，5-(羟甲基)-2-甲基异吲哚-1-酮(64mg,0.36mmol)溶于N,N’-二甲基甲酰胺(6mL)中，加入N-羟基-7-氮杂苯并三氮唑(146mg,1.05mmol)，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(203mg,1.05mmol)和N,N-二异丙基乙胺(182mg,1.41mmol)，室温反应6h，加水(10mL)搅拌5min，二氯甲烷萃取(20mL×2)，合并有机相后用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯(v/v)＝1/1)，得到无色液体(130mg,产率63％)。Compound (2R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150mg, 0.35mmol, Example 1 step 4), 5-(hydroxymethyl)-2-methylisoindol-1-one (64mg, 0.36mmol) dissolved in N,N'-dimethylformamide (6mL) Add N-hydroxy-7-azabenzotriazole (146mg, 1.05mmol), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in an ice bath Salt (203mg, 1.05mmol) and N,N-diisopropylethylamine (182mg, 1.41mmol), react at room temperature for 6h, add water (10mL) and stir for 5min, extract with dichloromethane (20mL×2), combine the organic phases The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain a colorless liquid (130mg, The yield is 63%).
1H NMR(600MHz,CDCl 3):δ(ppm)7.78–7.85(m,1H),7.41–7.47(m,2H),7.08(d,J＝8.1Hz,1H),6.73–6.82(m,2H),6.59(t,J＝75.6Hz,1H),5.32–5.38(m,1H),5.19–5.24(m,1H),4.42–4.49(m,1H),4.34–4.38(m,2H),3.90–3.97(m,1H),3.83(t,J＝6.8Hz,2H),3.39–3.47(m,1H),3.29–3.38(m,1H),3.16–3.24(m,3H),2.63–2.72(m,1H),1.97–2.05(m,1H),1.46(s,4H),1.35(s,5H),1.23–1.25(m,1H),0.61–0.67(m,2H),0.31–0.38(m,2H). 1 H NMR (600MHz, CDCl 3 ): δ (ppm) 7.78-7.85 (m, 1H), 7.41-7.47 (m, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.73-6.82 (m, 2H), 6.59(t,J=75.6Hz,1H), 5.32–5.38(m,1H), 5.19–5.24(m,1H), 4.42–4.49(m,1H), 4.34–4.38(m,2H) ,3.90–3.97(m,1H), 3.83(t,J=6.8Hz,2H), 3.39–3.47(m,1H), 3.29–3.38(m,1H), 3.16–3.24(m,3H), 2.63 --2.72(m,1H),1.97-2.05(m,1H),1.46(s,4H),1.35(s,5H),1.23-1.25(m,1H),0.61-0.67(m,2H),0.31 –0.38(m,2H).
MS(ESI,pos.ion)m/z:531.40[M-t-Bu+2H] +. MS(ESI,pos.ion)m/z:531.40[Mt-Bu+2H] + .
步骤2：化合物(2R)-(2-甲基-1-氧代异吲哚啉-5-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐的合成Step 2: Compound (2R)-(2-methyl-1-oxoisoindolin-5-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) (Yl)phenyl)pyrrolidine-2-carboxylate hydrochloride
将化合物(2R)-1-叔丁基2-(((2-甲基-1-氧代异吲哚啉-5-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯(120mg,0.20mmol)溶解于二氯甲烷(10mL)溶液中，加入4mol/L HCl的二氧六环溶液(5mL)，室温搅拌50min，减压浓缩除去溶剂，得到白色固体(107mg,100％)。The compound (2R)-1-tert-butyl 2-(((2-methyl-1-oxoisoindolin-5-yl)methyl)4-(3-(cyclopropylmethoxy) -4-(Difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (120mg, 0.20mmol) was dissolved in dichloromethane (10mL) solution, and 4mol/L HCl dioxane was added The ring solution (5 mL) was stirred at room temperature for 50 min, and concentrated under reduced pressure to remove the solvent to obtain a white solid (107 mg, 100%).
1H NMR(600MHz,CD 3OD):δ(ppm)7.76(d,J＝7.7Hz,1H),7.62(s,1H),7.56(d,J＝7.8Hz,1H),7.10(d,J＝8.1Hz,1H),7.02(s,1H),6.84–6.88(m,1H),6.73(t,J＝75.6Hz,1H),5.49(s,0.5H),5.43(s,1.5H),4.65–4.70(m,1H),4.50(s,2H),3.90(d,J＝6.8Hz,2H),3.76–3.82(m,1H),3.59(d,J＝4.6Hz,1H),3.37(t,J＝11.1Hz,1H),3.20(s,3H),2.84–2.90(m,1H),2.18–2.26(m,1H),1.27–1.30(m,1H),0.59–0.66(m,2H),0.31–0.40(m,2H). 1 H NMR (600MHz, CD 3 OD): δ (ppm) 7.76 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 8.1Hz, 1H), 7.02 (s, 1H), 6.84-6.88 (m, 1H), 6.73 (t, J = 75.6 Hz, 1H), 5.49 (s, 0.5H), 5.43 (s, 1.5H) ), 4.65–4.70(m,1H),4.50(s,2H),3.90(d,J=6.8Hz,2H),3.76–3.82(m,1H),3.59(d,J=4.6Hz,1H) , 3.37(t,J=11.1Hz,1H), 3.20(s,3H), 2.84–2.90(m,1H), 2.18–2.26(m,1H), 1.27–1.30(m,1H), 0.59–0.66 (m,2H),0.31-0.40(m,2H).
MS(ESI,pos.ion)m/z:487.20[M-HCl+H] +. MS(ESI,pos.ion)m/z:487.20[M-HCl+H] + .
步骤3：化合物(2R)-(2-甲基-1-氧代异吲哚啉-5-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯的合成Step 3: Compound (2R)-(2-methyl-1-oxoisoindolin-5-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R)-(2-甲基-1-氧代异吲哚啉-5-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐(107mg,0.20mmol)溶解在二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(133mg,1.03mmol)，冷却至0℃，加入乙酰氯(48mg,0.60mmol)，室温搅拌1h后停止反应，加水(10mL)，二氯甲烷萃取(40mL×2)，有机相用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝20/1)得到白色固体(70mg,产率65％)。The compound (2R)-(2-methyl-1-oxoisoindolin-5-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)pyrrolidine-2-carboxylate hydrochloride (107mg, 0.20mmol) was dissolved in dichloromethane (10mL), N,N-diisopropylethylamine (133mg, 1.03mmol) was added and cooled to At 0°C, add acetyl chloride (48mg, 0.60mmol), stir at room temperature for 1h and stop the reaction, add water (10mL), extract with dichloromethane (40mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and concentrate. Perform silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain a white solid (70 mg, yield 65%).
1H NMR(600MHz,CD 3OD):δ(ppm)7.74(d,J＝7.8Hz,1H),7.58(s,1H),7.50(d,J＝7.9Hz,1H),7.08(d,J＝8.2Hz,1H),7.01(s,1H),6.87(d,J＝8.1Hz,1H),6.72(t,J＝75.6Hz,1H),5.22–5.37(m,2H),4.52–4.57(m,1H),4.49(s,2H),4.07–4.13(m,1H),3.89(d,J＝6.9Hz,2H),3.61(t,J＝10.4Hz,1H),3.49–3.58(m,1H),3.19(s,3H),2.69–2.77(m,1H),2.13(s,2.5H),1.97–2.06(m,1H),1.94(s,0.5H),1.22–1.28(m,1H),0.58–0.65(m,2H),0.32–0.39(m,2H). 1 H NMR (600MHz, CD 3 OD): δ (ppm) 7.74 (d, J = 7.8Hz, 1H), 7.58 (s, 1H), 7.50 (d, J = 7.9Hz, 1H), 7.08 (d, J = 8.2Hz, 1H), 7.01 (s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.72 (t, J = 75.6 Hz, 1H), 5.22-5.37 (m, 2H), 4.52- 4.57 (m, 1H), 4.49 (s, 2H), 4.07–4.13 (m, 1H), 3.89 (d, J = 6.9 Hz, 2H), 3.61 (t, J = 10.4 Hz, 1H), 3.49–3.58 (m,1H),3.19(s,3H),2.69-2.77(m,1H),2.13(s,2.5H),1.97-2.06(m,1H),1.94(s,0.5H),1.22-1.28 (m,1H),0.58-0.65(m,2H),0.32-0.39(m,2H).
MS(ESI,pos.ion)m/z:529.20[M+H] +. MS(ESI,pos.ion)m/z:529.20[M+H] + .
实施例163：(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((2-甲基-1-氧代异吲哚啉-5-基)甲基)吡咯烷-2-甲酰胺Example 163: (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((2-methyl-1 -Oxoisoindolin-5-yl)methyl)pyrrolidine-2-carboxamide
Figure PCTCN2021090489-appb-000225
Figure PCTCN2021090489-appb-000225
步骤1：化合物(2R)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((2-甲基-1-氧代异吲哚啉-5-基)甲基)氨基甲酰基)吡咯烷-1-甲酸酯的合成Step 1: Compound (2R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((2-methyl-1- Synthesis of oxoisoindolin-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate
将化合物(2R)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(150mg,0.35mmol，实施例1步骤4)，5-(氨基甲基)-2-甲基异吲哚-1-酮(64mg,0.36mmol，中间体14)溶于N,N’-二甲基甲酰胺(6mL)中，加入N-羟基-7-氮杂苯并三氮唑(146mg,1.05mmol)，在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(203mg,1.05mmol)和N,N-二异丙基乙胺(182mg,1.41mmol)，室温反应6h，加水(10mL)搅拌5min，二氯甲烷萃取(20mL×2)，合并有机相后用无水硫酸钠干燥有机相，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯(v/v)＝1/4)，得到白色固体(100mg,产率49％)。Compound (2R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150mg, 0.35mmol, Example 1 step 4), 5-(aminomethyl)-2-methylisoindol-1-one (64mg, 0.36mmol, Intermediate 14) was dissolved in N,N'-dimethylform To the amide (6mL), add N-hydroxy-7-azabenzotriazole (146mg, 1.05mmol), and add 1-ethyl-3-(3-dimethylaminopropyl) carbon dioxide in an ice bath Imine hydrochloride (203mg, 1.05mmol) and N,N-diisopropylethylamine (182mg, 1.41mmol), react at room temperature for 6h, add water (10mL) and stir for 5min, extract with dichloromethane (20mL×2), After the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain a white solid (100mg, yield 49%).
1H NMR(600MHz,CD 3OD):δ(ppm)7.66–7.73(m,1H),7.50–7.59(m,1H),7.47(d,J＝7.8Hz,1H),7.07(d,J＝8.2Hz,1H),7.03(s,1H),6.86–6.92(m,1H),6.71(t,J＝75.7Hz,1H),4.54–4.61(m,2H),4.47(s,2H),4.28–4.38(m,1H),3.94–4.01(m,1H),3.90(d,J＝6.8Hz,2H),3.35–3.49(m,2H),3.18(s,3H),2.59–2.69(m,1H),1.99–2.07(m,1H),1.49(s,3H),1.34(s,6H),1.23–1.28(m,1H),0.57–0.67(m,2H),0.31–0.41(m,2H). 1 H NMR(600MHz, CD 3 OD): δ(ppm) 7.66–7.73(m,1H), 7.50–7.59(m,1H), 7.47(d,J=7.8Hz,1H), 7.07(d,J ＝8.2Hz,1H),7.03(s,1H),6.86-6.92(m,1H),6.71(t,J=75.7Hz,1H),4.54-4.61(m,2H),4.47(s,2H) , 4.28–4.38(m,1H), 3.94–4.01(m,1H), 3.90(d,J=6.8Hz,2H), 3.35–3.49(m,2H), 3.18(s,3H), 2.59–2.69 (m,1H),1.99-2.07(m,1H),1.49(s,3H),1.34(s,6H),1.23-1.28(m,1H),0.57-0.67(m,2H),0.31-0.41 (m,2H).
MS(ESI,pos.ion)m/z:586.25[M+H] +. MS(ESI,pos.ion)m/z:586.25[M+H] + .
步骤2：化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((2-甲基-1-氧代异吲哚啉-5-基)甲基)吡咯烷-2-甲酰胺盐酸盐的合成Step 2: Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((2-methyl-1-oxoisoindyl) Synthesis of (dolin-5-yl)methyl)pyrrolidine-2-carboxamide hydrochloride
将化合物(2R)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((2-甲基-1-氧代异吲哚啉-5-基)甲基)氨基甲酰基)吡咯烷-1-甲酸酯(100mg,0.17mmol)溶解于二氯甲烷(10mL)溶液中，加入4mol/L HCl的二氧六环溶液(5mL)，室温搅拌50min，减压浓缩除去溶剂，得到白色固体(90mg,100％)。The compound (2R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((2-methyl-1-oxo) Isoindolin-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (100mg, 0.17mmol) was dissolved in dichloromethane (10mL) solution, and 4mol/L HCl dioxane was added The ring solution (5 mL) was stirred at room temperature for 50 min, and concentrated under reduced pressure to remove the solvent to obtain a white solid (90 mg, 100%).
1H NMR(600MHz,CD 3OD):δ(ppm)7.74(d,J＝7.8Hz,1H),7.53(s,1H),7.47(d,J＝7.8Hz,1H),7.13(d,J＝8.2Hz,1H),7.06(d,J＝1.8Hz,1H),6.89–6.93(m,1H),6.76(t,J＝75.5Hz,1H),4.57–4.62(m,2H),4.50(s,2H),4.44–4.48(m,1H),3.90–3.94(m,2H),3.75–3.78(m,1H),3.58–3.62(m,1H),3.36–3.43(m,1H),3.21(s,3H),2.85–2.91(m,1H),2.09–2.16(m,1H),1.26–1.29(m,1H),0.61–0.69(m,2H),0.34–0.41(m,2H). 1 H NMR (600MHz, CD 3 OD): δ (ppm) 7.74 (d, J = 7.8Hz, 1H), 7.53 (s, 1H), 7.47 (d, J = 7.8Hz, 1H), 7.13 (d, J=8.2Hz,1H), 7.06(d,J=1.8Hz,1H), 6.89–6.93(m,1H), 6.76(t,J=75.5Hz,1H), 4.57–4.62(m,2H), 4.50 (s, 2H), 4.44-4.48 (m, 1H), 3.90-3.94 (m, 2H), 3.75-3.78 (m, 1H), 3.58-3.62 (m, 1H), 3.36-3.43 (m, 1H) ), 3.21(s, 3H), 2.85–2.91(m, 1H), 2.09–2.16(m, 1H), 1.26–1.29(m, 1H), 0.61–0.69(m, 2H), 0.34–0.41(m ,2H).
MS(ESI,pos.ion)m/z:486.35[M-HCl+H] +. MS(ESI,pos.ion)m/z:486.35[M-HCl+H] + .
步骤3：化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((2-甲基-1-氧代异吲哚啉-5-基)甲基)吡咯烷-2-甲酰胺的合成Step 3: Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((2-methyl-1 -Oxoisoindolin-5-yl)methyl)pyrrolidine-2-carboxamide
将化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-N-((2-甲基-1-氧代异吲哚-5-基)甲基)吡咯烷-2-甲酰胺盐酸盐(90mg,0.17mmol)溶解在二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(113mg,0.87mmol)，冷却至0℃，加入乙酰氯(44mg,0.56mmol)，室温搅拌1h后停止反应，加水(10mL)，二氯甲烷萃取(40mL×2)，有机相用无水硫酸钠干燥，减压浓缩，浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)＝20/1)得到白色固体(75mg,产率82％)。The compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-((2-methyl-1-oxoisoindole- 5-yl)methyl)pyrrolidine-2-carboxamide hydrochloride (90mg, 0.17mmol) was dissolved in dichloromethane (10mL), and N,N-diisopropylethylamine (113mg, 0.87mmol) was added , Cooled to 0℃, added acetyl chloride (44mg, 0.56mmol), stirred at room temperature for 1h and then stopped the reaction, added water (10mL), extracted with dichloromethane (40mL×2), dried the organic phase with anhydrous sodium sulfate, and concentrated under reduced pressure The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain a white solid (75 mg, yield 82%).
1H NMR(600MHz,CD 3OD):δ(ppm)7.68–7.73(m,1H),7.55(s,1H),7.44–7.49(m,1H),7.04–7.12(m,2H),6.89–6.93(m,1H),6.73(t,J＝75.7Hz,1H),4.57–4.65(m,1H),4.48(s,2H),4.47(s,1H),4.43–4.46(m,1H),4.06–4.12(m,1H),3.85–3.94(m,2H),3.63(t,J＝10.6Hz,1H),3.44–3.53(m,1H),3.18(s,3H),2.62–2.70(m,1H),2.14(s,3H),2.02–2.09(m,1H),1.25–1.29(m,1H),0.59–0.66(m,2H),0.33–0.39(m,2H). 1 H NMR (600MHz, CD 3 OD): δ (ppm) 7.68-7.73 (m, 1H), 7.55 (s, 1H), 7.44-7.49 (m, 1H), 7.04-7.12 (m, 2H), 6.89 –6.93(m,1H),6.73(t,J=75.7Hz,1H),4.57–4.65(m,1H), 4.48(s,2H), 4.47(s,1H), 4.43–4.46(m,1H) ), 4.06–4.12(m, 1H), 3.85–3.94(m, 2H), 3.63(t, J = 10.6Hz, 1H), 3.44–3.53(m, 1H), 3.18(s, 3H), 2.62– 2.70(m,1H), 2.14(s,3H), 2.02-2.09(m,1H), 1.25-1.29(m,1H), 0.59-0.66(m,2H), 0.33-0.39(m,2H).
MS(ESI,pos.ion)m/z:528.40[M+H] +. MS(ESI,pos.ion)m/z:528.40[M+H] + .
实施例164：(2R)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-甲酰基吡咯烷-2-甲酸酯Example 164: (2R)-(6-(Methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoro (Methoxy)phenyl)-1-formylpyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000226
Figure PCTCN2021090489-appb-000226
步骤1：化合物(2R)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸的合成Step 1: Compound (2R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid synthesis
将化合物(2R)-1-叔丁基2-甲基4-(3-(环丙甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(2.4g,5.4mmol，实施例1步骤4)溶于四氢呋喃(20mL)和水(10mL)的混合溶剂中，再加入一水合氢氧化锂(688mg，16.4mmol)，室温反应5h后停止，加盐酸调节溶液pH＝4，减压除去四氢呋喃，用乙酸乙酯萃取(30mL×3)，有机相用无水硫酸钠干燥，除去溶剂得到无色粘稠固体(2.3g,产率99％)。The compound (2R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylic acid The ester (2.4g, 5.4mmol, step 4 of Example 1) was dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), then lithium hydroxide monohydrate (688mg, 16.4mmol) was added, and the reaction was stopped at room temperature for 5 hours. Add hydrochloric acid to adjust the solution pH=4, remove tetrahydrofuran under reduced pressure, extract with ethyl acetate (30mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent to obtain a colorless viscous solid (2.3g, yield 99%) .
1H NMR(400MHz,CD 3OD):δ(ppm)7.10(d,J＝8.2Hz,1H),7.03(s,1H),6.89(d,J＝8.1Hz,1H),6.73(t,J F-H＝75.5Hz,1H),4.31–4.37(m,1H),3.92–3.99(m,1H),3.92(d,J＝6.9Hz,2H),3.35–3.47(m,2H),2.69–2.76(m,1H),1.97–2.09(m,1H),1.46–1.49(m,9H),1.24–1.34(m,1H),0.62–0.66(m,2H),0.37– 0.41(m,2H). 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.10 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.73 (t, J FH = 75.5Hz, 1H), 4.31–4.37 (m, 1H), 3.92–3.99 (m, 1H), 3.92 (d, J = 6.9 Hz, 2H), 3.35–3.47 (m, 2H), 2.69– 2.76(m,1H),1.97-2.09(m,1H),1.46-1.49(m,9H),1.24-1.34(m,1H),0.62-0.66(m,2H),0.37-0.41(m,2H) ).
MS(ESI,pos.ion)m/z:450.20[M+Na] +. MS(ESI,pos.ion)m/z:450.20[M+Na] + .
步骤2：化合物(2R)-1-叔丁基2-((6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯的合成Step 2: Compound (2R)-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethyl) Synthesis of oxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate
将化合物(2R)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(1.10g,2.60mmol)和6-(羟甲基)-N-甲基-N-(对甲基苯基)吡啶酰胺(690mg,0.70mmol)溶于二氯甲烷(30mL)中，加入N-羟基-7-氮杂苯并三氮唑(700mg,5.14mmol)和1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(1.50g,7.80mmol)，冰浴下加入N,N-二异丙基乙胺(1.3g,10.0mmol)，室温反应12h，加水(30mL)，用二氯甲烷萃取(10mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)＝2/1)得到白色粘稠固体(1.1g,62％)。The compound (2R)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (1.10g , 2.60mmol) and 6-(hydroxymethyl)-N-methyl-N-(p-methylphenyl)pyridine amide (690mg, 0.70mmol) were dissolved in dichloromethane (30mL), and N-hydroxy- 7-azabenzotriazole (700mg, 5.14mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.50g, 7.80mmol) under ice bath Add N,N-diisopropylethylamine (1.3g, 10.0mmol), react at room temperature for 12h, add water (30mL), extract with dichloromethane (10mL×2), dry the organic phase with anhydrous sodium sulfate, and reduce pressure After concentration, the residue was subjected to silica gel column chromatography (eluent: PE/EtOAc (v/v)=2/1) to obtain a white viscous solid (1.1 g, 62%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.49–7.61(m,1H),7.13–7.32(m,2H),7.09(d,J＝7.9Hz,1H),6.86–7.03(m,4H),6.76–6.81(m,2H),6.59(t,J F-H＝75.6Hz,1H),4.99–5.18(m,2H),4.37–4.48(m,1H),4.05–4.09(m,0.5H),3.92–3.96(m,0.5H),3.82–3.86(m,2H),3.46(s,3H),3.28–3.44(m,2H),2.63–2.75(m,1H),2.25(s,3H),1.99–2.10(m,1H),1.37–1.45(m,9H),1.22–1.33(m,1H),0.61–0.67(m,2H),0.32–0.37(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.49-7.61 (m, 1H), 7.13-7.32 (m, 2H), 7.09 (d, J = 7.9 Hz, 1H), 6.86-7.03 (m, 4H), 6.76–6.81(m, 2H), 6.59(t, J FH = 75.6Hz, 1H), 4.99–5.18(m, 2H), 4.37–4.48(m, 1H), 4.05–4.09(m, 0.5 H), 3.92-3.96(m, 0.5H), 3.82-3.86(m, 2H), 3.46(s, 3H), 3.28-3.44(m, 2H), 2.63-2.75(m, 1H), 2.25(s ,3H),1.99--2.10(m,1H), 1.37-1.45(m,9H), 1.22-1.33(m,1H), 0.61-0.67(m,2H), 0.32-0.37(m,2H).
MS(ESI,pos.ion)m/z:666.30[M+H] +. MS(ESI,pos.ion)m/z:666.30[M+H] + .
步骤3：化合物(2R)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐的合成Step 3: Compound (2R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of (Methoxy) Phenyl) Pyrrolidine-2-carboxylate Hydrochloride
将化合物(2R)-1-叔丁基2-((6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯(1.1g,2.70mmol)溶解于二氯甲烷(15mL)溶液中，加入4mol/L HCl的乙酸乙酯溶液(5mL)，室温搅拌1.5h，减压除去溶剂，得到浅黄色固体(1.0g,100％)。The compound (2R)-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethoxy) )-4-(Difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (1.1g, 2.70mmol) was dissolved in dichloromethane (15mL) solution, and 4mol/L HCl in acetic acid was added The ethyl ester solution (5 mL) was stirred at room temperature for 1.5 h, and the solvent was removed under reduced pressure to obtain a pale yellow solid (1.0 g, 100%).
1H NMR(400MHz,CD 3OD)δ:(ppm)7.76–7.85(m,1H),7.46–7.52(m,1H),7.29–7.36(m,1H),7.09–7.16(m,2H),7.00–7.08(m,4H),6.94–6.97(m,1H),6.75(t,J F-H＝75.6Hz,1H),5.29–5.39(m,2H),4.73–4.78(m,1H),3.95(d,J＝6.8Hz,2H),3.82–3.87(m,1H),3.71–3.78(m,1H),3.36–3.47(m,1H),3.45(s,3H),2.87–2.95(m,1H),2.30–2.43(m,1H),2.24(s,3H),1.26–1.38(m,1H),0.61–0.68(m,2H),0.35–0.42(m,2H). 1 H NMR (400MHz, CD 3 OD) δ: (ppm) 7.76-7.85 (m, 1H), 7.46-7.52 (m, 1H), 7.29-7.36 (m, 1H), 7.09-7.16 (m, 2H) ,7.00–7.08(m,4H), 6.94–6.97(m,1H), 6.75(t,J FH = 75.6Hz,1H), 5.29–5.39(m,2H), 4.73–4.78(m,1H), 3.95(d,J=6.8Hz,2H), 3.82–3.87(m,1H), 3.71–3.78(m,1H), 3.36–3.47(m,1H), 3.45(s,3H), 2.87–2.95( m,1H), 2.30--2.43(m,1H), 2.24(s,3H), 1.26--1.38(m,1H), 0.61--0.68(m,2H), 0.35--0.42(m,2H).
MS(ESI,pos.ion)m/z:566.20[M+H-HCl] +. MS(ESI,pos.ion)m/z:566.20[M+H-HCl] + .
步骤4：化合物(2R)-(6-(甲基(对甲基苯基)氨基甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1-甲酰基吡咯烷-2-甲酸酯的合成Step 4: Compound (2R)-(6-(methyl(p-methylphenyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-( Synthesis of difluoromethoxy)phenyl)-1-formylpyrrolidine-2-carboxylate
将化合物(2R)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐(100mg,0.17mmol)和N-羟基-7-氮杂苯并三氮唑(45mg,0.33mmol)溶于二氯甲烷(8mL)中，加入甲酸(45mg,0.98mmol)，冰浴下加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(127mg,0.66mmol)和N,N-二异丙基乙胺(306mg,2.37mmol)，室温反应2h，加水(20mL)搅拌2min，用二氯甲烷萃取(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)＝15/1)得到白色粘稠固体(73mg,产率74％)。The compound (2R)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) (Yl)phenyl)pyrrolidine-2-carboxylate hydrochloride (100mg, 0.17mmol) and N-hydroxy-7-azabenzotriazole (45mg, 0.33mmol) dissolved in dichloromethane (8mL) In, formic acid (45mg, 0.98mmol) was added, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (127mg, 0.66mmol) and N,N-bis Isopropylethylamine (306mg, 2.37mmol), react at room temperature for 2h, add water (20mL) and stir for 2min, extract with dichloromethane (15mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and carry out the residue Separation by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) gave a white viscous solid (73mg, yield 74%).
1H NMR(400MHz,CDCl 3):δ(ppm)8.35(s,1H),7.55–7.63(m,1H),7.23–7.33(m,1H),7.12–7.16(m,1H),6.89–7.04(m,4H),6.79–6.84(m,2H),6.49–6.75(m,1H),5.07–5.22(m,2H),4.57–4.65(m,1H),4.26–4.31(m,0.2H),4.06–4.09(m,0.8H),3.86–3.89(m,2H),3.60–3.64(m,1H),3.49(s,3H),3.36–3.41(m,1H),2.77–2.86(m,1H),2.27(s,3H),2.11–2.17(m,1H),1.28–1.36(m,1H),0.66–0.69(m,2H),0.36–0.40(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 8.35 (s, 1H), 7.55-7.63 (m, 1H), 7.23-7.33 (m, 1H), 7.12-7.16 (m, 1H), 6.89- 7.04(m,4H), 6.79-6.84(m,2H), 6.49-6.75(m,1H), 5.07-5.22(m,2H), 4.57-4.65(m,1H), 4.26-4.31(m,0.2 H), 4.06–4.09(m,0.8H), 3.86–3.89(m,2H), 3.60–3.64(m,1H), 3.49(s,3H), 3.36–3.41(m,1H), 2.77–2.86 (m, 1H), 2.27 (s, 3H), 2.11 - 2.17 (m, 1H), 1.28 - 1.36 (m, 1H), 0.66 - 0.69 (m, 2H), 0.36 - 0.40 (m, 2H).
MS(ESI,pos.ion)m/z:594.20[M+H] +. MS(ESI,pos.ion)m/z:594.20[M+H] + .
实施例165：2-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)异吲哚啉-5-甲酰胺Example 165: 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl)iso Indoline-5-carboxamide
Figure PCTCN2021090489-appb-000227
Figure PCTCN2021090489-appb-000227
步骤1：化合物2-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)异吲哚-5-甲酸甲酯的合成Step 1: Compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl) iso Synthesis of indole-5-methyl carboxylate
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(300mg,0.81mmol，实施例1步骤7)和异吲哚-5-羧酸甲酯(220mg,0.89mmol)溶于DMF(8mL)中，加入N-羟基-7-氮杂苯并三氮唑(221mg,1.62mmol)和1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(467mg,2.44mmol)，冰浴下加入N,N-二异丙基乙胺(419mg,3.24mmol)，室温反应5h，加水(20mL)，用乙酸乙酯萃取(5mL×2)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)＝35/1)得到浅褐色固体(397mg,产率93％)。The compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (300mg, 0.81mmol, implementation Example 1 Step 7) and isoindole-5-carboxylic acid methyl ester (220mg, 0.89mmol) were dissolved in DMF (8mL), and N-hydroxy-7-azabenzotriazole (221mg, 1.62mmol) was added. And 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (467mg, 2.44mmol), add N,N-diisopropylethylamine (419mg, 3.24mmol) under ice bath ), react at room temperature for 5h, add water (20mL), extract with ethyl acetate (5mL×2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the residue by silica gel column chromatography (eluent: DCM/ MeOH (v/v)=35/1) to obtain a light brown solid (397 mg, yield 93%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.95–8.02(m,2H),7.32–7.39(m,1H),7.14(d,J＝8.1Hz,1H),6.94(s,1H),6.87–6.90(m,1H),6.63(t,J F-H＝75.6Hz,1H),5.41(t,J＝13.8Hz,1H),4.75–5.01(m,4H),3.93–3.99(m,1H),3.95(s,3H),3.89(d,J＝6.9Hz,2H),3.76(t,J＝10.7Hz,1H),3.38–3.50(m,1H),2.58–2.67(m,1H),2.22–2.35(m,1H),2.14(s,3H),1.28–1.35(m,1H),0.64–0.69(m,2H),0.35–0.39(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.95-8.02 (m, 2H), 7.32-7.39 (m, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H) ,6.87–6.90(m,1H),6.63(t,J FH =75.6Hz,1H), 5.41(t,J=13.8Hz,1H), 4.75–5.01(m,4H),3.93-3.99(m, 1H), 3.95 (s, 3H), 3.89 (d, J = 6.9 Hz, 2H), 3.76 (t, J = 10.7 Hz, 1H), 3.38-3.50 (m, 1H), 2.58-2.67 (m, 1H ), 2.22-2.35 (m, 1H), 2.14 (s, 3H), 1.28-1.35 (m, 1H), 0.64-0.69 (m, 2H), 0.35-0.39 (m, 2H).
MS(ESI,pos.ion)m/z:529.15[M+H] +. MS(ESI,pos.ion)m/z:529.15[M+H] + .
步骤2：化合物2-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)异吲哚啉-5-甲酸的合成Step 2: Compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl) iso Synthesis of indoline-5-carboxylic acid
将化合物2-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)异吲哚-5-羧酸甲酯(11208-1)(340mg,0.64mmol)溶于四氢呋喃(10mL)和水(5mL)的混合溶剂中，加入一水合氢氧化锂(135mg，3.22mmol)，50℃反应30min后停止，加盐酸调节溶液pH＝2，再用乙酸乙酯萃取(10mL×3),有机相用无水硫酸钠干燥,除去溶剂得到白色固体(309mg,93％)。The compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl)isoindole Methyl-5-carboxylate (11208-1) (340mg, 0.64mmol) was dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (5mL), and lithium hydroxide monohydrate (135mg, 3.22mmol) was added and reacted at 50℃ Stop after 30 minutes, add hydrochloric acid to adjust the pH of the solution to 2, then extract with ethyl acetate (10 mL×3), dry the organic phase with anhydrous sodium sulfate, remove the solvent to obtain a white solid (309 mg, 93%).
1H NMR(600MHz,CD 3OD):δ(ppm)8.03(s,1H),8.02(d,J＝7.9Hz,1H),7.47(t,J＝7.5Hz,1H),7.13(s,1H),7.12(d,J＝8.4Hz,1H),6.95–6.96(m,1H),6.75(t,J F-H＝75.7Hz,1H),5.27–5.31(m,1H),5.02–5.06(m,1H),4.90–4.94(m,1H),4.80–4.85(m,2H),4.10–4.14(m,1H),3.92–3.95(m,2H),3.69(t,J＝10.7Hz,1H),3.53–3.60(m,1H),2.75–2.80(m,1H),2.14(s,3H),2.05–2.13(m,1H),1.29–1.36(m,1H),0.64–0.67(m,2H),0.38–0.41(m,2H). 1 H NMR (600MHz, CD 3 OD): δ (ppm) 8.03 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.13 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.95-6.96 (m, 1H), 6.75 (t, J FH = 75.7 Hz, 1H), 5.27-5.31 (m, 1H), 5.02-5.06 ( m,1H), 4.90–4.94(m,1H), 4.80–4.85(m,2H), 4.10–4.14(m,1H), 3.92–3.95(m,2H), 3.69(t,J=10.7Hz, 1H), 3.53–3.60(m,1H), 2.75–2.80(m,1H), 2.14(s,3H), 2.05–2.13(m,1H), 1.29–1.36(m,1H), 0.64–0.67( m,2H),0.38--0.41(m,2H).
MS(ESI,pos.ion)m/z:515.15[M+H] +. MS(ESI,pos.ion)m/z:515.15[M+H] + .
步骤3：化合物2-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)异吲哚啉-5-甲酰胺的合成Step 3: Compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl) iso Synthesis of indoline-5-carboxamide
将化合物2-((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)异吲哚-5-羧酸(90mg,0.17mmol)和氯化铵(930mg,1.74mmol)溶于无水DMF(5mL)中，加入N-羟基-7-氮杂苯并三氮唑(35mg,0.26mmol)和1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(467mg,2.44mmol)，冰浴下加入N,N- 二异丙基乙胺(134mg,0.70mmol)，室温反应17h，减压浓缩，加水(40mL)搅拌2min，用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸钠干燥，减压浓缩，剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)＝8/1)得到白色固体(78mg,87％，HPLC纯度98.12％)。The compound 2-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl)isoindole -5-carboxylic acid (90mg, 0.17mmol) and ammonium chloride (930mg, 1.74mmol) dissolved in anhydrous DMF (5mL), add N-hydroxy-7-azabenzotriazole (35mg, 0.26mmol) ) And 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (467mg, 2.44mmol), add N,N-diisopropylethylamine (134mg, 0.70 mmol), react at room temperature for 17h, concentrate under reduced pressure, add water (40mL) and stir for 2min, extract with ethyl acetate (10mL×3), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the residue by silica gel column chromatography (Eluent: DCM/MeOH(v/v)=8/1) to obtain a white solid (78mg, 87%, HPLC purity 98.12%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.21–7.79(m,2H),7.30–7.34(m,1H),7.13(d,J＝8.1Hz,1H),6.92(s,1H),6.88(d,J＝8.1Hz,1H),6.63(t,J F-H＝75.6Hz,1H),5.37(t,J＝15.2Hz,1H),4.91–4.96(m,1H),4.83–4.88(m,1H),4.74–4.79(m,2H),3.96–3.99(m,1H),3.89(d,J＝6.9Hz,2H),3.73(t,J＝10.6Hz,1H),3.40–3.48(m,1H),2.59–2.66(m,1H),2.22–2.30(m,1H),2.13(s,3H),1.28–1.32(m,1H),0.65–0.68(m,2H),0.36–0.39(m,2H). 1 H NMR(400MHz, CDCl 3 ): δ(ppm) 7.21–7.79(m,2H), 7.30–7.34(m,1H), 7.13(d,J=8.1Hz,1H), 6.92(s,1H) ,6.88(d,J=8.1Hz,1H),6.63(t,J FH =75.6Hz,1H),5.37(t,J=15.2Hz,1H),4.91-4.96(m,1H),4.83-4.88 (m, 1H), 4.74–4.79 (m, 2H), 3.96–3.99 (m, 1H), 3.89 (d, J = 6.9 Hz, 2H), 3.73 (t, J = 10.6 Hz, 1H), 3.40– 3.48(m,1H), 2.59–2.66(m,1H), 2.22–2.30(m,1H), 2.13(s,3H), 1.28–1.32(m,1H), 0.65–0.68(m,2H), 0.36--0.39 (m, 2H).
MS(ESI,pos.ion)m/z:514.20[M+H] +. MS(ESI,pos.ion)m/z:514.20[M+H] + .
实施例166：(2R,4S)-(6-(对甲苯基氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 166: (2R,4S)-(6-(p-tolylcarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000228
Figure PCTCN2021090489-appb-000228
步骤1：(2R,4S)-1-叔丁基2-((6-(对甲苯基氨基甲酰基)吡啶-2-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯的合成Step 1: (2R,4S)-1-tert-butyl 2-((6-(p-tolylcarbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethoxy) Synthesis of -4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate
将化合物(2R,4S)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(400mg,0.94mmol，实施例151步骤1)，6-(羟甲基)-N-(对甲苯基)吡啶甲酸酰胺(280mg,1.2mmol)及1-羟基苯并三唑(189mg,1.4mmol)溶解在N,N-二甲基甲酰胺(10mL)溶液中，在0℃下冷却后，再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(360mg,1.9mmol)，N-甲基吗啡啉(NMM)(190mg,1.9mmol)，转移到室温下搅拌反应18h。加水(50mL)停止反应，用乙酸乙酯(20mL×3)萃取有机相后，用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：石油醚/EtOAc(v/v)＝4/1)，得到浅褐色油状产物(320mg,52.47％)。The compound (2R, 4S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid ( 400mg, 0.94mmol, Example 151 step 1), 6-(hydroxymethyl)-N-(p-tolyl)picolinic acid amide (280mg, 1.2mmol) and 1-hydroxybenzotriazole (189mg, 1.4mmol) Dissolved in N,N-dimethylformamide (10mL) solution, after cooling at 0°C, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) ( 360mg, 1.9mmol), N-methylmorpholine (NMM) (190mg, 1.9mmol), transferred to room temperature and stirred for 18h. Water (50mL) was added to stop the reaction, and the organic phase was extracted with ethyl acetate (20mL×3), dried over anhydrous sodium sulfate for 30min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/EtOAc (v /v)=4/1), a light brown oily product (320 mg, 52.47%) was obtained.
1H NMR(400MHz,CDCl 3)δ9.85(d,J＝24.1Hz,1H),8.24(dd,J＝14.0,7.7Hz,1H),8.02–7.87(m,1H),7.69–7.51(m,3H),7.18(dd,J＝8.6,3.1Hz,2H),7.07(dd,J＝8.0,5.5Hz,1H),6.83–6.76(m,2H),6.76–6.37(m,1H),5.52–5.27(m,2H),4.60–4.43(m,1H),4.13(m,1H),3.82(t,J＝7.2Hz,2H),3.51–3.30(m,2H),2.81–2.68(m,1H),2.35(s,3H),2.18–2.00(m,1H),1.43(d,J＝22.5Hz,9H),1.30-1.22(m,1H),0.67-0.61(m,2H),0.36-0.32(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 9.85 (d, J = 24.1 Hz, 1H), 8.24 (dd, J = 14.0, 7.7 Hz, 1H), 8.02-7.87 (m, 1H), 7.69-7.51 ( m, 3H), 7.18 (dd, J = 8.6, 3.1 Hz, 2H), 7.07 (dd, J = 8.0, 5.5 Hz, 1H), 6.83-6.76 (m, 2H), 6.76-6.37 (m, 1H) ,5.52–5.27(m,2H),4.60–4.43(m,1H),4.13(m,1H), 3.82(t,J=7.2Hz,2H),3.51–3.30(m,2H),2.81–2.68 (m,1H),2.35(s,3H),2.18-2.00(m,1H),1.43(d,J=22.5Hz,9H),1.30-1.22(m,1H),0.67-0.61(m,2H ), 0.36-0.32 (m, 2H).
MS(ESI,pos.ion)m/z:652.30[M+H] +. MS(ESI,pos.ion)m/z:652.30[M+H] + .
步骤2：(2R,4S)-(6-(对甲苯基氨甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐的合成Step 2: (2R,4S)-(6-(p-tolylcarbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) )Phenyl) pyrrolidine-2-carboxylate hydrochloride synthesis
将化合物(2R,4S)-1-叔丁基2-((6-(对甲苯基氨甲酰基)吡啶-2-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(320mg,0.49mmol)溶解在二氯甲烷(5mL)溶液中，再加入1,4-二氧六环盐酸溶液(1.5mL,6.0mmol)，在室温下搅拌反应1h。停止反应，减压浓缩一次后，再加入二氯甲烷溶液(20mL)溶解，再次减压浓缩，得到浅褐色油状粗产物(340mg,100.00％)。The compound (2R, 4S)-1-tert-butyl 2-((6-(p-tolylcarbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (320mg, 0.49mmol) was dissolved in dichloromethane (5mL), and 1,4-dioxane was added Hydrochloric acid solution (1.5 mL, 6.0 mmol), stirred at room temperature for 1 h. The reaction was stopped, and after concentration under reduced pressure once, dichloromethane solution (20 mL) was added to dissolve, and concentrated under reduced pressure again to obtain a light brown oily crude product (340 mg, 100.00%).
1H NMR(400MHz,CD 3OD)δ8.18(d,J＝7.7Hz,1H),8.09(t,J＝7.8Hz,1H),8.00(s,1H),7.73(d,J＝7.8Hz,1H),7.59(d,J＝8.4Hz,2H),7.17(d,J＝8.3Hz,2H),7.06(d,J＝8.2Hz,1H),7.02(d,J＝2.1Hz,1H),6.86(dd,J＝8.2,2.1Hz,1H),6.72(t,J＝75.5Hz,1H),5.66–5.44(m,2H),3.90–3.84(m,2H),3.82–3.71(m,2H),3.64–3.58(m,1H),3.39(t,J＝11.0Hz,1H),3.05-2.96(m,1H),2.88(s,3H),2.37-2.29(m,1H),1.32-1.22(m,1H),0.69–0.59(m,2H),0.38-0.34(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 8.18 (d, J = 7.7 Hz, 1H), 8.09 (t, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.86(dd,J=8.2,2.1Hz,1H), 6.72(t,J=75.5Hz,1H), 5.66–5.44(m,2H), 3.90–3.84(m,2H), 3.82–3.71 (m, 2H), 3.64–3.58 (m, 1H), 3.39 (t, J = 11.0 Hz, 1H), 3.05-2.96 (m, 1H), 2.88 (s, 3H), 2.37-2.29 (m, 1H) ), 1.32-1.22 (m, 1H), 0.69-0.59 (m, 2H), 0.38-0.34 (m, 2H).
MS(ESI,pos.ion)m/z:552.25[M+H] +. MS(ESI,pos.ion)m/z:552.25[M+H] + .
步骤3：(2R,4S)-(6-(对甲苯甲氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯的合成Step 3: (2R,4S)-(6-(p-tolylcarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-( Synthesis of difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R,4S)-(6-(对甲苯基氨甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯盐酸盐(320mg,0.58mmol)溶解在二氯甲烷(8.0mL)溶液中，在0℃下冷却，加入N,N-二异丙基乙胺(DIPEA)(340mL,2.6mmol)和乙酰氯(114mg,1.45mmol)，转移到室温下搅拌反应3h。加水(25mL)停止反应，分离有机相，水相用二氯甲烷(25mL×2)萃取，有机相用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：石油醚/EtOAc(v/v)＝3/7)，得到白色粘稠固体(150mg,产率41.40％)。The compound (2R, 4S)-(6-(p-tolylcarbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)pyrrolidine-2-carboxylate hydrochloride (320mg, 0.58mmol) was dissolved in dichloromethane (8.0mL) solution, cooled at 0℃, and N,N-diisopropylethylamine ( DIPEA) (340 mL, 2.6 mmol) and acetyl chloride (114 mg, 1.45 mmol) were transferred to room temperature and stirred for 3 h. Add water (25mL) to stop the reaction, separate the organic phase, extract the aqueous phase with dichloromethane (25mL×2), dry the organic phase with anhydrous sodium sulfate for 30min, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: petroleum Ether/EtOAc (v/v)=3/7) to obtain a white viscous solid (150 mg, yield 41.40%).
1H NMR(400MHz,CDCl 3)δ9.97(s,1H),8.23(d,J＝7.7Hz,1H),7.93(t,J＝7.8Hz,1H),7.67(d,J＝8.4Hz,2H),7.62(d,J＝7.8Hz,1H),7.17(d,J＝8.1Hz,2H),7.10(d,J＝8.1Hz,1H),6.84–6.78(m,2H),6.60(t,J＝75.5Hz,1H),5.50(d,J＝13.7Hz,1H),5.33(d,J＝13.6Hz,1H),4.66–4.59(m,1H),4.01–3.93(m,1H),3.84(d,J＝6.9Hz,2H),3.64(t,J＝10.4Hz,1H),3.52–3.40(m,1H),2.78–2.69(m,1H),2.34(s,3H),2.17–2.07(m,1H),2.12(s,3H),1.32–1.22(m,1H),0.69–0.61(m,2H),0.41-0.33(m,2H). 1 H NMR(400MHz,CDCl 3 )δ9.97(s,1H), 8.23(d,J=7.7Hz,1H), 7.93(t,J=7.8Hz,1H), 7.67(d,J=8.4Hz , 2H), 7.62 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 1H), 6.84-6.78 (m, 2H), 6.60 (t,J=75.5Hz,1H), 5.50(d,J=13.7Hz,1H), 5.33(d,J=13.6Hz,1H), 4.66–4.59(m,1H), 4.01–3.93(m, 1H), 3.84 (d, J = 6.9 Hz, 2H), 3.64 (t, J = 10.4 Hz, 1H), 3.52-3.40 (m, 1H), 2.78-2.69 (m, 1H), 2.34 (s, 3H) ), 2.17-2.07(m, 1H), 2.12(s, 3H), 1.32-1.22(m, 1H), 0.69-0.61(m, 2H), 0.41-0.33(m, 2H).
MS(ESI,pos.ion)m/z:593.05[M] +. MS(ESI,pos.ion)m/z:593.05[M] + .
实施例167：(2R,4S)-(6-(甲基氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 167: (2R,4S)-(6-(methylcarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-( (Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000229
Figure PCTCN2021090489-appb-000229
步骤1：(2R,4S)-1-叔丁基2-((6-(甲基氨基甲酰基)吡啶-2-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯的合成Step 1: (2R,4S)-1-tert-butyl 2-((6-(methylcarbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate
将化合物(2R,4S)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(400mg,0.94mmol，实施例151步骤1)，6-(羟甲基)-N-甲基吡啶甲酰胺(188mg,1.1mmol，中间体16)，1-羟基苯并三唑(190mg,1.4mmol)溶解在N,N-二甲基甲酰胺(10mL)溶液中，在0℃下冷却，再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(358mg,1.9mmol)，N-甲基吗啡啉(NMM)(190mg,1.9mmol)，转移到室温下搅拌反应14h。加水(50mL)停止，用乙酸乙酯(20mL×3)萃取有机相后，用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：石油醚/EtOAc(v/v)＝4/1)，得到浅褐色油状物(530mg,产率98.39％)。The compound (2R, 4S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid ( 400mg, 0.94mmol, Example 151 step 1), 6-(hydroxymethyl)-N-picolinamide (188mg, 1.1mmol, Intermediate 16), 1-hydroxybenzotriazole (190mg, 1.4mmol ) Was dissolved in N,N-dimethylformamide (10mL) solution, cooled at 0°C, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) ( 358mg, 1.9mmol), N-methylmorpholine (NMM) (190mg, 1.9mmol), transferred to room temperature and stirred for 14h. Add water (50mL) to stop, extract the organic phase with ethyl acetate (20mL×3), dry with anhydrous sodium sulfate for 30min, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: petroleum ether/EtOAc (v/ v)=4/1), a light brown oil (530mg, yield 98.39%) was obtained.
1H NMR(400MHz,CDCl 3)δ8.39(m,1H),7.92–7.82(m,1H),7.55–7.48(m,1H),7.11(d,J＝8.1Hz,1H),6.81(d,J＝10.4Hz,2H),6.61(t,J＝75.6Hz,1H),5.43–5.27(m,1H),4.60–4.42(m,1H),4.12–3.95(m,1H),3.85(t,J＝7.8Hz,2H),3.51–3.28(m,2H),3.05–3.00(m,3H),2.82–2.70(m,1H),2.15–1.99(m,2H),1.52–1.44(s,6H),1.39(s,3H),1.27–1.21(s,1H),0.66–0.61(m,2H),0.36–0.31(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.39 (m, 1H), 7.92-7.82 (m, 1H), 7.55-7.48 (m, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.81 ( d, J = 10.4 Hz, 2H), 6.61 (t, J = 75.6 Hz, 1H), 5.43–5.27 (m, 1H), 4.60–4.42 (m, 1H), 4.12–3.95 (m, 1H), 3.85 (t,J=7.8Hz,2H),3.51–3.28(m,2H),3.05–3.00(m,3H), 2.82–2.70(m,1H), 2.15–1.99(m,2H), 1.52–1.44 (s, 6H), 1.39 (s, 3H), 1.27 - 1.21 (s, 1H), 0.66 - 0.61 (m, 2H), 0.36 - 0.31 (m, 2H).
MS(ESI,pos.ion)m/z:576.20[M+H] +. MS(ESI,pos.ion)m/z:576.20[M+H] + .
步骤2：(2R,4S)-(6-(甲基氨基甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸盐酸盐的合成Step 2: (2R,4S)-(6-(methylcarbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)pyrrolidine-2-carboxylate hydrochloride
将化合物(2R,4S)-1-叔丁基2-((6-(甲基氨基甲酰基)吡啶-2-基)甲基)4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二甲酸酯(530mg,0.92mmol)溶解在二氯甲烷(5mL)溶液中，再加入1,4-二氧六环盐酸溶液(2.5mL,10.0mmol)，在室温下搅拌反应1h。减压浓缩一次后，再加入二氯甲烷溶液(20mL)溶解，再次减压浓缩，得到浅褐色油状粗产物(435mg,产率92.27％)The compound (2R, 4S)-1-tert-butyl 2-((6-(methylcarbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (530mg, 0.92mmol) was dissolved in dichloromethane (5mL) solution, and 1,4-dioxane hydrochloric acid was added The solution (2.5 mL, 10.0 mmol) was stirred at room temperature for 1 h. After concentrating under reduced pressure once, adding dichloromethane solution (20 mL) to dissolve, and concentrating under reduced pressure again to obtain a light brown oily crude product (435 mg, yield 92.27%)
1H NMR(400MHz,CD 3OD)δ7.97–7.90(m,1H),7.90–7.84(m,2H),7.06–6.99(m,1H),6.95(s,1H),6.83–6.77(m,1H),6.64(t,J＝75.6Hz,1H),5.38(d,J＝6.6Hz,2H),3.85–3.77(m,2H),3.74–3.53(m,4H),3.32–3.20(m,1H),2.83(s,3H),2.24–2.05(m,1H),1.14–1.25(m,1H),0.55–0.51(m,2H),0.30–0.24(m,2H). 1 H NMR (400MHz, CD 3 OD) δ 7.97-7.90 (m, 1H), 7.90-7.84 (m, 2H), 7.06-6.99 (m, 1H), 6.95 (s, 1H), 6.83-6.77 ( m, 1H), 6.64 (t, J = 75.6 Hz, 1H), 5.38 (d, J = 6.6 Hz, 2H), 3.85–3.77 (m, 2H), 3.74–3.53 (m, 4H), 3.32–3.20 (m,1H), 2.83(s,3H), 2.24-2.05(m,1H), 1.14-1.25(m,1H), 0.55-0.51(m,2H), 0.30-0.24(m,2H).
MS(ESI,pos.ion)m/z:476.20[M+H] +. MS(ESI,pos.ion)m/z:476.20[M+H] + .
步骤3：(2R,4S)-(6-(甲基氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯的合成Step 3: (2R,4S)-(6-(methylcarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-(di Synthesis of (fluoromethoxy)phenyl)pyrrolidine-2-carboxylate
将化合物(2R,4S)-(6-(甲基氨基甲酰基)吡啶-2-基)甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸盐酸盐(435mg,0.91mmol)溶解在二氯甲(8mL)烷溶液中，在0℃下冷却，加入N,N-二异丙基乙胺(DIPEA)(550mL,4.3mmol)及乙酰氯(200mg,2.3mmol)，转移到室温下搅拌反应2h。加水(25mL)停止反应，分离有机相，水相用二氯甲烷(25mL×2)萃取，有机相用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇(v/v)＝50/1)，得到浅褐色油状物(133mg,产率27.73％)。The compound (2R, 4S)-(6-(methylcarbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)pyrrolidine-2-carboxylate (435mg, 0.91mmol) was dissolved in dichloromethane (8mL) alkane solution, cooled at 0℃, and N,N-diisopropylethylamine (DIPEA) was added (550mL, 4.3mmol) and acetyl chloride (200mg, 2.3mmol), transferred to room temperature and stirred for 2h. Add water (25mL) to stop the reaction, separate the organic phase, extract the aqueous phase with dichloromethane (25mL×2), dry the organic phase with anhydrous sodium sulfate for 30min, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: two Chloromethane/methanol (v/v)=50/1) to obtain a light brown oil (133 mg, yield 27.73%).
1H NMR(400MHz,CDCl 3)δ8.34(br.s,1H),8.13(d,J＝7.7Hz,1H),7.86(t,J＝7.8Hz,1H),7.51(d,J＝7.8Hz,1H),7.13(d,J＝8.7Hz,1H),6.87–6.79(m,2H),6.61(t,J＝75.5Hz,1H),5.52(d,J＝13.8Hz,1H),5.20(d,J＝13.8Hz,1H),4.65–4.61(m,1H),400–3.96(m,1H),3.86(d,J＝6.9Hz,2H),3.65(t,J＝10.4Hz,1H),3.52–3.39(m,1H),3.03(d,J＝5.0Hz,3H),2.79–2.69(m,1H),2.14(s,3H),2.11–1.96(m,1H),1.33–1.22(m,1H),0.69–0.63(m,2H),0.36(m,2H). 1 H NMR(400MHz, CDCl 3 )δ8.34(br.s,1H), 8.13(d,J=7.7Hz,1H), 7.86(t,J=7.8Hz,1H), 7.51(d,J= 7.8Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.87–6.79 (m, 2H), 6.61 (t, J = 75.5 Hz, 1H), 5.52 (d, J = 13.8 Hz, 1H) , 5.20 (d, J = 13.8 Hz, 1H), 4.65–4.61 (m, 1H), 400–3.96 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.65 (t, J = 10.4 Hz,1H),3.52–3.39(m,1H),3.03(d,J=5.0Hz,3H),2.79–2.69(m,1H),2.14(s,3H),2.11–1.96(m,1H) ,1.33-1.22(m,1H),0.69-0.63(m,2H),0.36(m,2H).
MS(ESI,pos.ion)m/z:518.20[M+H] +. MS(ESI,pos.ion)m/z:518.20[M+H] + .
实施例168：6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)氧基)甲基)吡啶甲酸Example 168: 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carbonyl)oxy)methyl)picolinic acid
Figure PCTCN2021090489-appb-000230
Figure PCTCN2021090489-appb-000230
步骤1：叔丁基6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)氧基)甲基) 吡啶甲酸酯的合成Step 1: tert-Butyl 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine -2-Carbonyl)oxy)methyl)picolinate
将化合物(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(540mg,1.46mmol，实施例151步骤5)溶于N,N-二甲酰胺(15mL)溶剂中，再加入6-(羟甲基)吡啶甲酸叔丁酯(374mg,1.79mmol，中间体17)，1-羟基苯并三唑(HOBT)(300mg,2.22mmol)，转移到0℃下，再加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDCI)(637mg,3.32mmol)，N-甲基吗啡啉(NMM)(370mg,3.66mmol)，加入原料完之后，转移到室温下搅拌反应17h。加水(50mL)停止反应，再用乙酸乙酯(20mL×3)萃取有机相后，有机相用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯(v/v)＝1/4)，得到浅褐色油状物(590mg,产率71.99％)。The compound (2R, 4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (540mg, 1.46mmol , Example 151 step 5) was dissolved in N,N-dimethylamide (15mL) solvent, and 6-(hydroxymethyl)picolinate tert-butyl ester (374mg, 1.79mmol, intermediate 17) was added, 1-hydroxyl Benzotriazole (HOBT) (300mg, 2.22mmol), transfer to 0℃, and then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (637mg, 3.32) mmol), N-methylmorpholine (NMM) (370 mg, 3.66 mmol), after adding the raw materials, the mixture was transferred to room temperature and stirred for 17 hours. Water (50mL) was added to stop the reaction, and then the organic phase was extracted with ethyl acetate (20mL×3). The organic phase was dried over anhydrous sodium sulfate for 30min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/ Ethyl acetate (v/v) = 1/4) to obtain a light brown oil (590 mg, yield 71.99%).
1H NMR(400MHz,CDCl 3)δ7.94(d,J＝7.8Hz,1H),7.84(t,J＝7.8Hz,1H),7.66(d,J＝7.7Hz,1H),7.12(d,J＝8.7Hz,1H),6.85–6.80(m,2H),6.61(d,J＝75.5Hz,1H),5.56–5.33(m,2H),4.64–4.57(m,1H),4.01–3.91(m,1H),3.88–3.82(m,2H),3.63(t,J＝10.5Hz,1H),3.51–3.42(m,1H),2.79–2.68(m,1H),2.19–2.10(m,1H),2.13(s,3H),1.61(s,9H),1.34–1.24(m,1H),0.68–0.63(m,2H),0.38–0.34(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.94 (d, J = 7.8Hz, 1H), 7.84 (t, J = 7.8Hz, 1H), 7.66 (d, J = 7.7Hz, 1H), 7.12 (d ,J=8.7Hz,1H), 6.85–6.80(m,2H), 6.61(d,J=75.5Hz,1H), 5.56–5.33(m,2H), 4.64–4.57(m,1H),4.01– 3.91(m,1H),3.88–3.82(m,2H),3.63(t,J=10.5Hz,1H),3.51–3.42(m,1H),2.79–2.68(m,1H),2.19–2.10( m, 1H), 2.13 (s, 3H), 1.61 (s, 9H), 1.34-1.24 (m, 1H), 0.68-0.63 (m, 2H), 0.38-0.34 (m, 2H).
MS(ESI,pos.ion)m/z:561.30[M+H] +. MS(ESI,pos.ion)m/z:561.30[M+H] + .
步骤2：6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)氧基)甲基)吡啶甲酸的合成Step 2: 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of carbonyl)oxy)methyl)picolinic acid
将化合物叔丁基6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基氧基)甲基]吡啶甲酸酯(620mg,1.11mmol)溶解在二氯甲烷(20mL)溶剂中，再滴加三氟乙酸(4.59g,40.62mmol)，在室温下搅拌反应11h。停止反应，通过HPLC制备纯化，得到白色粘稠固体(210mg,产率34.84％)。The compound tert-butyl 6-(((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 2-Carbonyloxy)methyl]picolinate (620mg, 1.11mmol) was dissolved in dichloromethane (20mL) solvent, then trifluoroacetic acid (4.59g, 40.62mmol) was added dropwise, and the reaction was stirred at room temperature for 11h The reaction was stopped and purified by HPLC preparation to obtain a white viscous solid (210 mg, yield 34.84%).
1H NMR(400MHz,CDCl 3)δ8.16(d,J＝7.6Hz,1H),7.96(t,J＝7.8Hz,1H),7.65(d,J＝7.8Hz,1H),7.14(d,J＝8.7Hz,1H),6.84(s,1H),6.83(d,J＝6.4Hz,1H),6.62(t,J＝75.5Hz,1H),5.57(d,J＝14.1Hz,1H),5.29(d,J＝8.7Hz,1H),4.66–4.59(m,1H),3.99(t,J＝8.6Hz,1H),3.87(d,J＝6.9Hz,2H),3.65(t,J＝10.5Hz,1H),3.54–3.43(m,1H),2.79–2.69(m,1H),2.19–2.09(m,1H),2.16(s,3H),1.35–1.21(m,1H),0.69–0.64(m,2H),0.38–0.34(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 8.16 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.14 (d ,J=8.7Hz,1H), 6.84(s,1H), 6.83(d,J=6.4Hz,1H), 6.62(t,J=75.5Hz,1H), 5.57(d,J=14.1Hz,1H ), 5.29 (d, J = 8.7 Hz, 1H), 4.66–4.59 (m, 1H), 3.99 (t, J = 8.6 Hz, 1H), 3.87 (d, J = 6.9 Hz, 2H), 3.65 (t ,J=10.5Hz,1H),3.54–3.43(m,1H), 2.79–2.69(m,1H), 2.19–2.09(m,1H), 2.16(s,3H), 1.35–1.21(m,1H) ), 0.69-0.64 (m, 2H), 0.38-0.34 (m, 2H).
MS(ESI,pos.ion)m/z:505.10[M+H] +. MS(ESI,pos.ion)m/z:505.10[M+H] + .
实施例169：(2R,4S)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酸酯Example 169: (2R,4S)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(4-(difluoromethoxy) -3-Hydroxyphenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000231
Figure PCTCN2021090489-appb-000231
步骤1：6-((((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-羰基)氧基)甲基)吡啶甲酸的合成Step 1: 6-((((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carbonyl)oxy)methyl ) Synthesis of picolinic acid
将化合物叔丁基6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羰基)氧基)甲基)吡啶甲酸酯(185mg,0.33mmol，实施例168步骤1)溶于二氯甲烷(5.5mL)溶剂中，再加入溴化锌(74mg,0.33mmol)，在室温下搅拌反应23.5h。加入水(20mL)，搅拌2分钟，分离有机相，水相再加入二氯甲烷溶剂(20mL×2)萃取，合并有机相，并用无水硫酸钠干燥30min，通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇(v/v)＝10/1)，得到白色固体(22mg,产率14.80％)The compound tert-butyl 6-(((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 2-Carbonyl)oxy)methyl)picolinate (185mg, 0.33mmol, step 1 of Example 168) was dissolved in dichloromethane (5.5mL) solvent, and zinc bromide (74mg, 0.33mmol) was added, The reaction was stirred at room temperature for 23.5h. Add water (20mL), stir for 2 minutes, separate the organic phase, add dichloromethane solvent (20mL×2) to the aqueous phase for extraction, combine the organic phases, dry with anhydrous sodium sulfate for 30min, and purify by silica gel column chromatography (elution Reagent: dichloromethane/methanol (v/v)=10/1) to obtain a white solid (22mg, yield 14.80%)
MS(ESI,pos.ion)m/z:451.20[M+H] +. MS(ESI,pos.ion)m/z:451.20[M+H] + .
步骤2：(2R,4S)-(6-(甲基(对甲苯基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-甲酸酯的合成Step 2: (2R,4S)-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(4-(difluoromethoxy)- Synthesis of 3-hydroxyphenyl)pyrrolidine-2-carboxylate
将化合物6-((((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-羰基)氧基)甲基)吡啶甲酸(100mg,0.22mmol)，N-甲基-对甲基苯胺(40mg,0.33mmol)，溶于二氯甲烷溶剂(5mL)中，再加入1-羟基苯并三唑(HOBT)(148mg,1.1mmol)，在0℃下冷却，加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDCI)(126mg,0.66mmol)，N,N-二异丙基乙胺(DIPEA)(142mg,1.1mmol)。原料加入完之后，转移到室温下搅拌反应7h。加水停止反应，用二氯甲烷(100mL×2)萃取，有机相用无水硫酸钠干燥30min，减压浓缩，通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇(v/v)＝16/1)，得到白色固体产物(40mg,产率28.50％)The compound 6-(((((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carbonyl)oxy)methyl) Picolinic acid (100mg, 0.22mmol), N-methyl-p-methylaniline (40mg, 0.33mmol), dissolved in dichloromethane solvent (5mL), then add 1-hydroxybenzotriazole (HOBT) (148mg , 1.1mmol), cooled at 0°C, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (126mg, 0.66mmol), N,N-diisopropyl Ethylamine (DIPEA) (142 mg, 1.1 mmol). After the raw materials were added, the mixture was transferred to room temperature and stirred for 7 hours. Add water to stop the reaction, extract with dichloromethane (100mL×2), dry the organic phase with anhydrous sodium sulfate for 30min, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) =16/1) to obtain a white solid product (40mg, yield 28.50%)
1H NMR(400MHz,CDCl 3)δ7.51(s,1H),7.13–7.02(m,3H),7.01–6.96(m,2H),6.94–6.86(m,2H),6.83–6.64(m,2H),6.61(t,J＝74.7Hz,1H),5.33(d,J＝13.8Hz,1H),4.97(d,J＝13.2Hz,1H),4.61–4.52(m,1H),3.91(t,J＝8.8Hz,1H),3.55–3.48(m,3H),3.44–3.33(m,1H),2.69–2.57(m,1H),2.25(s,3H),2.17–2.084(m,1H),2.10(s,3H),1.37–1.267(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.51 (s, 1H), 7.13-7.02 (m, 3H), 7.01-6.96 (m, 2H), 6.94-6.86 (m, 2H), 6.83-6.64 (m , 2H), 6.61 (t, J = 74.7 Hz, 1H), 5.33 (d, J = 13.8 Hz, 1H), 4.97 (d, J = 13.2 Hz, 1H), 4.61–4.52 (m, 1H), 3.91 (t,J=8.8Hz,1H),3.55–3.48(m,3H),3.44–3.33(m,1H),2.69–2.57(m,1H),2.25(s,3H),2.17–2.084(m ,1H), 2.10 (s, 3H), 1.37-1.267 (m, 1H).
MS(ESI,pos.ion)m/z:554.20[M+H] +. MS(ESI,pos.ion)m/z:554.20[M+H] + .
实施例170：(6-((4-羟基苯基)(甲基)氨基甲酰基)吡啶-2-基)甲基(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸酯Example 170: (6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridin-2-yl)methyl(2R,4S)-1-acetyl-4-(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000232
Figure PCTCN2021090489-appb-000232
将化合物(2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-甲酸(300mg,0.81mmol，实施例151步骤5)，6-(羟甲基)-N-(4-羟苯基)-N-甲基吡啶酰胺(250mg,0.97mmol，中间体18)和1-羟基苯并三唑(130mg,0.97mmol)溶解在干燥的N,N-二甲基甲酰胺(5ml)溶液中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(190mg,0.97mmol)和N-甲基吗啡啉(NMM)(120mg,1.22mmol)，转移到室温下搅拌反应16h。加水(30mL)停止反应，用乙酸乙酯(10ml×3)萃取有机相后，用无水硫酸钠干燥，减压浓缩，通过硅胶柱层析纯化(MeOH/DCM(v/v)＝1/50)，得到白色固体(36mg,产率6.98％)。The compound (2R, 4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (300mg, 0.81mmol , Example 151 step 5), 6-(hydroxymethyl)-N-(4-hydroxyphenyl)-N-picolineamide (250mg, 0.97mmol, Intermediate 18) and 1-hydroxybenzotriazole (130mg, 0.97mmol) was dissolved in dry N,N-dimethylformamide (5ml) solution, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) ( 190mg, 0.97mmol) and N-methylmorpholine (NMM) (120mg, 1.22mmol) were transferred to room temperature and stirred for 16h. The reaction was stopped by adding water (30mL), the organic phase was extracted with ethyl acetate (10ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH/DCM(v/v)=1/ 50) to obtain a white solid (36 mg, yield 6.98%).
1H NMR(400MHz,CDCl 3):δ(ppm)9.46(s,1H),7.69(t,J＝7.2Hz,1H),7.28–7.21(m,2H),7.12(d,J＝8.1Hz,1H),7.07(s,1H),7.02(t,J F-H＝74.9Hz,1H),6.94–6.84(m,3H),6.60–6.51(m,2H),5.01(s,2H),4.47–4.36(m,1H),4.14–4.05(m,1H),3.90(d,J＝6.3Hz,2H),3.58–3.40(m,2H),3.28(s,3H),2.75–2.65(m,1H),2.03(s,3H),2.02–1.91(m,1H),1.29–1.17(m,1H),0.62–0.51(m,2H),0.38–0.26(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 9.46 (s, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.28-7.21 (m, 2H), 7.12 (d, J = 8.1 Hz ,1H),7.07(s,1H),7.02(t,J FH =74.9Hz,1H),6.94-6.84(m,3H),6.60-6.51(m,2H),5.01(s,2H),4.47 –4.36(m,1H), 4.14–4.05(m,1H), 3.90(d,J=6.3Hz,2H), 3.58–3.40(m,2H), 3.28(s,3H), 2.75–2.65(m ,1H),2.03(s,3H),2.02–1.91(m,1H), 1.29–1.17(m,1H), 0.62–0.51(m,2H), 0.38–0.26(m,2H).
MS(ESI,pos.ion)m/z:610.15[M+H] +.. MS(ESI,pos.ion)m/z:610.15[M+H] + ..
实施例171：(2R,4S)-(6-((4-羟基苯基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸酯Example 171: (2R,4S)-(6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-ethoxy -4-Methoxyphenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000233
Figure PCTCN2021090489-appb-000233
步骤1：化合物3-乙氧基-4-甲氧基苯甲酸甲酯的合成Step 1: Synthesis of compound 3-ethoxy-4-methoxybenzoic acid methyl ester
将化合物3-羟基-4-甲氧基苯甲酸甲酯(5.00g,27.45mmol),溴乙烷(4.49g,41.17mmol)和碳酸钾(11.83g,82.35mmol)混合在丙酮(25mL)中,置于60℃下反应10h，加入二氯甲烷(100mL)稀释，有机相用饱和食盐水(100mL×3)洗涤，用无水硫酸钠干燥，减压旋蒸浓缩得到黄色固体(5.23g,产率90.63％).The compound 3-hydroxy-4-methoxybenzoic acid methyl ester (5.00g, 27.45mmol), bromoethane (4.49g, 41.17mmol) and potassium carbonate (11.83g, 82.35mmol) were mixed in acetone (25mL) Place the reaction at 60°C for 10h, add dichloromethane (100mL) to dilute, wash the organic phase with saturated brine (100mL×3), dry with anhydrous sodium sulfate, and concentrate by rotary evaporation under reduced pressure to obtain a yellow solid (5.23g, The yield is 90.63%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.66(dd,J＝8.4,1.7Hz,1H),7.54(d,J＝1.6Hz,1H),6.88(d,J＝8.4Hz,1H),4.15(q,J＝7.0Hz,2H),3.92(s,3H),3.88(s,3H),1.48(t,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.66 (dd, J = 8.4, 1.7 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H ), 4.15(q,J=7.0Hz,2H), 3.92(s,3H), 3.88(s,3H), 1.48(t,J=7.0Hz,3H).
MS(ESI,pos.ion)m/z:211.10[M+H] +. MS(ESI,pos.ion)m/z:211.10[M+H] + .
步骤2：化合物3-乙氧基-4-甲氧基苯甲酸的合成Step 2: Synthesis of compound 3-ethoxy-4-methoxybenzoic acid
将化合物3-乙氧基-4-甲氧基苯甲酸甲酯(10.46g,49.76mmol),氢氧化钠(3.98g,99.52mmol，乙醇(30mL)，水(10mL)混合均匀，置于50℃搅拌2h。滴入稀盐酸(4M/L)调节pH＝1，加入水(100mL)，搅拌(析出大量固体)，过滤，所得滤饼用水(50mL×3)洗涤，真空60℃干燥12h，得白色固体(9.76g,产率97％)。Combine the compound 3-ethoxy-4-methoxybenzoic acid methyl ester (10.46g, 49.76mmol), sodium hydroxide (3.98g, 99.52mmol, ethanol (30mL), water (10mL), mix well, place in 50 Stir for 2h at °C. Add dilute hydrochloric acid (4M/L) to adjust pH=1, add water (100mL), stir (a large amount of solids are deposited), filter, wash the resulting filter cake with water (50mL×3), and dry at 60°C for 12h. A white solid (9.76 g, 97% yield) was obtained.
1H NMR(400MHz,CDCl 3):δ(ppm)7.77(dd,J＝8.4,1.9Hz,1H),7.60(d,J＝1.8Hz,1H),6.92(d,J＝8.5Hz,1H),4.17(q,J＝7.0Hz,2H),3.95(s,3H),1.50(t,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.77 (dd, J = 8.4, 1.9 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H ), 4.17 (q, J = 7.0 Hz, 2H), 3.95 (s, 3H), 1.50 (t, J = 7.0 Hz, 3H).
MS(ESI,pos.ion)m/z:197.15[M+H] +. MS(ESI,pos.ion)m/z:197.15[M+H] + .
步骤3：化合物苄基(3-乙氧基-4-甲氧基苯基)氨基甲酸酯的合成Step 3: Synthesis of compound benzyl (3-ethoxy-4-methoxyphenyl) carbamate
步骤一：室温下，向两口瓶(100mL)(A瓶)加入3-乙氧基-4-甲氧基苯甲酸(9.40g,47.91mmol)，三乙胺(6.30g,62.28mmol)，甲苯(50mL)，置于冰浴中搅拌，缓慢滴加入叠氮磷酸二苯酯(14.50g,52.70mmol)，室温中搅拌2h。Step 1: At room temperature, add 3-ethoxy-4-methoxybenzoic acid (9.40g, 47.91mmol), triethylamine (6.30g, 62.28mmol), toluene to a two-necked flask (100mL) (Bottle A) (50 mL), place in an ice bath and stir, slowly add diphenyl azide phosphate (14.50 g, 52.70 mmol) dropwise, and stir at room temperature for 2 h.
步骤二：向另一个单口瓶(250mL)(B瓶)加入甲苯(50mL)，苯甲醇(5.70g,52.70mmol)，加热至110℃，把A瓶物料滴入B瓶中，滴毕保温搅拌2h。停止加热搅拌，冷至室温,反应液用水洗涤(100mL)，再用5％氢氧化钠水溶液洗涤(100mL×3)，用无水Na 2SO 4干燥，减压旋蒸浓缩得黄色固体。向粗品加入石油醚/乙酸乙酯(50mL,v/v＝10/1)搅拌3h,过滤得白色固体(11.55g,产率80.00％). Step 2: Add toluene (50mL), benzyl alcohol (5.70g, 52.70mmol) to another single-mouth bottle (250mL) (Bottle B), heat to 110°C, drop the material from Bottle A into Bottle B, and keep stirring after dripping 2h. Stop heating and stirring, and cool to room temperature. The reaction solution was washed with water (100 mL), then washed with 5% sodium hydroxide aqueous solution (100 mL×3), dried with anhydrous Na 2 SO 4 , and concentrated by rotary evaporation under reduced pressure to obtain a yellow solid. Petroleum ether/ethyl acetate (50mL, v/v=10/1) was added to the crude product, stirred for 3h, and filtered to obtain a white solid (11.55g, yield 80.00%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.44–7.31(m,5H),6.85–6.72(m,2H),6.59(s,1H),5.19(s,2H),4.08(d,J＝6.3Hz,2H),3.84(s,3H),1.45(t,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.44-7.31 (m, 5H), 6.85-6.72 (m, 2H), 6.59 (s, 1H), 5.19 (s, 2H), 4.08 (d, J = 6.3Hz, 2H), 3.84 (s, 3H), 1.45 (t, J = 7.0Hz, 3H).
MS(ESI,pos.ion)m/z:302.10[M+H] +. MS(ESI,pos.ion)m/z:302.10[M+H] + .
步骤4：化合物3-乙氧基-4-甲氧基苯胺的合成Step 4: Synthesis of compound 3-ethoxy-4-methoxyaniline
向高压釜(1L)中加入苄基(3-乙氧基-4-甲氧基苯基)氨基甲酸酯(11.50g,38.16mmol),10％钯碳(0.61g,0.57mmol),甲醇(40mL)，排除空气，通入氢气(0.5MPa)，室温搅拌2h。反应液通过硅藻土过滤，滤液经减压浓缩得褐色固体(6.38g,产率100％)Add benzyl (3-ethoxy-4-methoxyphenyl) carbamate (11.50g, 38.16mmol), 10% palladium on carbon (0.61g, 0.57mmol), methanol to the autoclave (1L) (40mL), remove the air, pass in hydrogen (0.5MPa), and stir at room temperature for 2h. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a brown solid (6.38g, yield 100%)
1H NMR(400MHz,CDCl 3):δ(ppm)6.71(d,J＝8.4Hz,1H),6.31(d,J＝2.5Hz,1H),6.23(dd,J＝8.4,2.6Hz,1H),4.04(q,J＝7.0Hz,2H),3.79(s,3H),1.44(t,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 6.71 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 6.23 (dd, J = 8.4, 2.6 Hz, 1H ), 4.04 (q, J = 7.0Hz, 2H), 3.79 (s, 3H), 1.44 (t, J = 7.0Hz, 3H).
MS(ESI,pos.ion)m/z:168.20[M+H] +. MS(ESI,pos.ion)m/z:168.20[M+H] + .
步骤5：化合物3-乙氧基-4-甲氧基碘苯的合成Step 5: Synthesis of compound 3-ethoxy-4-methoxy iodobenzene
将化合物3-乙氧基-4-甲氧基苯胺(6.40g,38.28mmol)，溶于1,4-二氧六环(30mL)和水(11mL)中，冷却至0℃，加入浓盐酸(9.7mL,36％aq)，搅拌均匀，冷却至-15℃，逐滴加入亚硝酸钠(2.91g,42.11mmol)和水(7mL)的溶液，控制滴加温度在-15℃至-5℃之间，滴毕回温至-5℃搅拌30min后，加入碘化钾(8.26g,49.76mmol)和水(12mL)的溶液，控制滴加温度在-15℃至-5℃之间，滴毕回温至0℃下搅拌2h.加入亚硫酸氢钠(1.99g,19.14mmol)搅拌1h淬灭反应，向反应液加入石油醚(200mL)，有机相用水洗涤(100mL×3)，用无水Na 2SO4干燥，减压浓缩得黄色粘稠液体。硅胶柱层析(石油醚/乙酸乙酯(v/v)＝10/1)纯化得白色固体(6.24g,产率58.62％) The compound 3-ethoxy-4-methoxyaniline (6.40g, 38.28mmol) was dissolved in 1,4-dioxane (30mL) and water (11mL), cooled to 0℃, and concentrated hydrochloric acid was added (9.7mL, 36% aq), stir well, cool to -15°C, add a solution of sodium nitrite (2.91g, 42.11mmol) and water (7mL) dropwise, control the temperature of the dropwise addition at -15°C to -5 After dropping temperature to -5°C and stirring for 30 minutes, add a solution of potassium iodide (8.26g, 49.76mmol) and water (12mL), control the temperature of dropping between -15°C and -5°C, and then add the solution of potassium iodide (8.26g, 49.76mmol) and water (12mL). Warm to 0℃ and stir for 2h. Add sodium bisulfite (1.99g, 19.14mmol) and stir for 1h to quench the reaction, add petroleum ether (200mL) to the reaction solution, wash the organic phase with water (100mL×3), and use anhydrous Dry over Na 2 SO 4 and concentrate under reduced pressure to obtain a yellow viscous liquid. Purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) to obtain a white solid (6.24 g, yield 58.62%)
1H NMR(400MHz,CDCl 3):δ(ppm)7.21(dd,J＝8.4,1.9Hz,1H),7.12(d,J＝1.8Hz,1H),6.62(d,J＝8.4Hz,1H),4.06(q,J＝7.0Hz,2H),3.84(s,3H),1.46(t,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.21 (dd, J = 8.4, 1.9 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H ), 4.06(q,J=7.0Hz,2H), 3.84(s,3H), 1.46(t,J=7.0Hz,3H).
GC-MS:m/z 278.00[M] +. GC-MS: m/z 278.00[M] + .
步骤6：化合物2-(3-乙氧基-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二恶唑烷的合成Step 6: Synthesis of compound 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxazolidine
将3-乙氧基-4-甲氧基碘苯(1277-6)(6.24g,22.44mmol)，联硼酸频那醇酯(5.70g,22.44mmol)，醋酸钾(3.30g,33.66mmol)，醋酸钯(0.25g,1.12mmol),2-二环己基磷-2’-甲基联苯(Mephos)(0.82g,2.24mmol)混合在N,N-二甲基甲酰胺(36mL)中，氮气保护下80℃搅拌6h。冷却至室温，反应液中加入水(100mL)，用石油醚(100mL×3)萃取反应液，合并有机相，无水硫酸钠干燥有机相，减压旋蒸浓缩得到褐色液体，硅胶柱层析(石油醚/乙酸乙酯(v/v)＝10/1)纯化得黄色固体(4.85g,产率：77.70％)Combine 3-ethoxy-4-methoxy iodobenzene (1277-6) (6.24g, 22.44mmol), pinacol diborate (5.70g, 22.44mmol), potassium acetate (3.30g, 33.66mmol) , Palladium acetate (0.25g, 1.12mmol), 2-Dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) (0.82g, 2.24mmol) mixed in N,N-dimethylformamide (36mL) , Stir at 80°C for 6h under nitrogen protection. Cool to room temperature, add water (100mL) to the reaction solution, extract the reaction solution with petroleum ether (100mL×3), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, and concentrate by rotary evaporation under reduced pressure to obtain a brown liquid. Silica gel column chromatography (Petroleum ether/ethyl acetate (v/v)=10/1) purified to obtain a yellow solid (4.85g, yield: 77.70%)
1H NMR(400MHz,CDCl 3):δ(ppm)7.41(d,J＝8.0Hz,1H),7.29(s,1H),6.88(d,J＝8.0Hz,1H),4.15(q,J＝7.0Hz,2H),3.89(s,3H),1.47(t,J＝7.0Hz,3H),1.33(s,12H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.41 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.15 (q, J =7.0Hz,2H),3.89(s,3H),1.47(t,J=7.0Hz,3H),1.33(s,12H).
MS(ESI,pos.ion)m/z:279.35[M+H] +. MS(ESI,pos.ion)m/z:279.35[M+H] + .
步骤7：化合物(R)-1-叔丁基2-甲基4-(3-乙氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二甲酸酯的合成Step 7: Compound (R)-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl)-1H-pyrrole-1,2(2H,5H)-dimethyl Synthesis of acid esters
将化合物2-(3-乙氧基-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(2.0g,7.19mmol)，(R)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)1H-吡咯-1,2(2H,5H)-二羧酸酯(2.7g,7.19mmol)，N-甲基吗啡啉(1.6g,15.82mmol)，二环己基-[2-(2-甲基苯基)苯基]膦(0.13g,0.36mmol)和醋酸钯(0.04g,0.18mmol)混合甲苯(10mL)和水(5mL)混合溶液中，氮气保护下80℃反应1h，停止反应，冷却至室温。向反应液加入水(50mL)，用乙酸乙酯(30mL×3)萃取，有机相合用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱层析分离(洗脱剂：PE/EtOAc(v/v)＝5/1)得到黄色液体(1.1g,产率44％)。The compound 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.0g, 7.19mmol) , (R)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)1H-pyrrole-1,2(2H,5H)-dicarboxylate (2.7g , 7.19mmol), N-methylmorpholine (1.6g, 15.82mmol), dicyclohexyl-[2-(2-methylphenyl)phenyl]phosphine (0.13g, 0.36mmol) and palladium acetate (0.04 g, 0.18mmol) mixed toluene (10mL) and water (5mL) in a mixed solution, reacted at 80°C for 1h under nitrogen protection, stopped the reaction, and cooled to room temperature. Water (50mL) was added to the reaction solution, extracted with ethyl acetate (30mL×3), the organic phase was combined and dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: PE/EtOAc (v /v)=5/1) A yellow liquid (1.1g, yield 44%) was obtained.
MS(ESI,pos.ion)m/z:278.18[M-Boc+2H] +. MS(ESI,pos.ion)m/z:278.18[M-Boc+2H] + .
1H NMR(400MHz,CDCl 3)δ(ppm)6.93–6.88(m,2H),6.85–6.81(m,1H),5.94–5.89(m,1H),5.18–5.08(m,1H),4.66–4.47(m,2H),4.14–4.07(m,2H),3.88(s,3H),3.75(d,J＝4.8Hz,3H),1.52(s,3H),1.50–1.43(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 6.93-6.88 (m, 2H), 6.85-6.81 (m, 1H), 5.94-5.89 (m, 1H), 5.18-5.08 (m, 1H), 4.66 –4.47(m,2H),4.14–4.07(m,2H),3.88(s,3H), 3.75(d,J=4.8Hz,3H),1.52(s,3H),1.50–1.43(m,9H ).
步骤8：化合物(2R,4S)-1-叔丁基2-甲基4-(3-乙氧基-4-甲氧基苯基)吡咯烷-1,2-二甲酸酯的合成Step 8: Synthesis of compound (2R, 4S)-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate
将化合物(R)-1-叔丁基2-甲基4-(3-乙氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二甲酸酯(2.0g,5.30mmol)，钯碳(0.45g,5.30mmol)溶于35mL甲醇中，在氢气氛围下，室温反应12h，原料反应完全，停止反应。用硅藻土过滤钯碳，有机相减压浓缩得到黄色液体(1.26g,产率63％)。The compound (R)-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (2.0g, 5.30mmol), palladium on carbon (0.45g, 5.30mmol) was dissolved in 35mL of methanol, and reacted for 12h at room temperature under a hydrogen atmosphere. The reaction of the raw materials was complete and the reaction was stopped. The palladium-carbon was filtered through diatomaceous earth, and the organic phase was concentrated under reduced pressure to obtain a yellow liquid (1.26 g, yield 63%).
MS(ESI,pos.ion)m/z:280.20[M-Boc+2H] +. MS(ESI,pos.ion)m/z:280.20[M-Boc+2H] + .
1H NMR(400MHz,CDCl 3)δ(ppm)6.82–6.74(m,3H),4.39–4.29(m,1H),4.11–4.05(m,2H),4.02–4.00(m,0.5H),3.95–3.89(m,0.5H),3.85(s,3H),3.76(d,J＝7.0Hz,3H),3.44–3.37(m,1H),3.33–3.24(m,1H),2.66–2.57(m,1H),2.07–1.96(m,1H),1.50–1.44(m,6H),1.43(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 6.82-6.74 (m, 3H), 4.39-4.29 (m, 1H), 4.11-4.05 (m, 2H), 4.02-4.00 (m, 0.5H), 3.95–3.89(m,0.5H), 3.85(s,3H), 3.76(d,J=7.0Hz,3H), 3.44–3.37(m,1H), 3.33–3.24(m,1H), 2.66–2.57 (m,1H), 2.07-1.96(m,1H), 1.50-1.44(m,6H), 1.43(s,6H).
步骤9：化合物(2R,4S)-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯盐酸盐的合成Step 9: Synthesis of compound (2R,4S)-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R,4S)-1-叔丁基2-甲基4-(3-乙氧基-4-甲氧基苯基)吡咯烷-1,2-二甲酸酯(1.2g,3.16mmol)溶于10mL二氯甲烷溶液中，再加入盐酸1,4-二氧六环溶液(3.94mL,4.01mol/L)，室温反应1.5h，原料反应完全，停止反应。减压蒸馏，除去溶剂，浓缩液得到黄色液体(1.02g,产率100％)。The compound (2R, 4S)-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (1.2g, 3.16 mmol) was dissolved in 10 mL of dichloromethane solution, and then 1,4-dioxane hydrochloride solution (3.94 mL, 4.01 mol/L) was added, and the reaction was carried out at room temperature for 1.5 hours. The reaction of the raw materials was completed and the reaction was stopped. Distill under reduced pressure to remove the solvent and concentrate the solution to obtain a yellow liquid (1.02 g, yield 100%).
MS(ESI,pos.ion)m/z:280.30[M+H-HCl] +. MS(ESI,pos.ion)m/z:280.30[M+H-HCl] + .
1H NMR(400MHz,CDCl 3)δ(ppm)6.86(s,1H),6.79(s,2H),4.67–4.57(m,1H),4.09(q,J＝6.9Hz,2H),3.90–3.78(m,1H),3.83(s,6H),3.64–3.52(m,2H),2.82–2.70(m,1H),2.28–2.17(m,1H),1.44(t,J＝6.9Hz,3H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 6.86(s,1H), 6.79(s,2H), 4.67–4.57(m,1H), 4.09(q,J=6.9Hz,2H), 3.90– 3.78(m,1H), 3.83(s,6H), 3.64–3.52(m,2H), 2.82–2.70(m,1H), 2.28–2.17(m,1H), 1.44(t,J=6.9Hz, 3H).
MS(ESI,pos.ion)m/z:280.30[M+H-HCl] +. MS(ESI,pos.ion)m/z:280.30[M+H-HCl] + .
步骤10：化合物(2R,4S)-1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯的合成Step 10: Synthesis of compound (2R, 4S)-1-acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(2R,4S)-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯盐酸盐(1.0g,3.17mmol)溶于20mL二氯甲烷溶液中，在冰浴条件下，加入N,N-二异丙基乙胺(1.64g,12.68mmol)，乙酰氯(0.50g,6.34mmol)，室温反应1h，原料反应完全，停止反应。加入饱和食盐水淬灭反应，用二氯甲烷萃取(20mL×3)，有机相用无水硫酸钠干燥，除去溶剂，浓缩液进行硅胶柱分离(洗脱剂：DCM/MeOH(v/v)＝20/1)得到黄色液体(0.95g,产率93％)。The compound (2R, 4S)-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0g, 3.17mmol) was dissolved in 20mL dichloromethane solution In an ice bath, add N,N-diisopropylethylamine (1.64g, 12.68mmol), acetyl chloride (0.50g, 6.34mmol), and react at room temperature for 1 hour. The reaction of the raw materials is complete and the reaction is stopped. The reaction was quenched by adding saturated brine, extracted with dichloromethane (20mL×3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated on a silica gel column (eluent: DCM/MeOH(v/v) =20/1) A yellow liquid (0.95g, yield 93%) was obtained.
1H NMR(400MHz,CDCl 3)δ(ppm)6.84–6.80(m,1H),6.79–6.77(m,1H),6.76–6.74(m,1H),4.46(dd,J＝9.7,7.5Hz,1H),4.08(q,J＝6.9Hz,2H),3.93–3.89(m,1H),3.85(s,3H),3.76(s,3H),3.59(t,J＝10.5Hz,1H),3.42–3.33(m,1H),2.66–2.60(m,1H),2.10(s,3H),2.05–2.00(m,1H),1.46(t,J＝7.0Hz,3H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 6.84–6.80(m,1H), 6.79–6.77(m,1H), 6.76–6.74(m,1H), 4.46(dd,J=9.7,7.5Hz ,1H),4.08(q,J=6.9Hz,2H),3.93-3.89(m,1H),3.85(s,3H),3.76(s,3H),3.59(t,J=10.5Hz,1H) ,3.42–3.33(m,1H), 2.66–2.60(m,1H), 2.10(s,3H), 2.05–2.00(m,1H), 1.46(t,J=7.0Hz,3H).
MS(ESI,pos.ion)m/z:322.20[M+H] +. MS(ESI,pos.ion)m/z:322.20[M+H] + .
步骤11：化合物(2R,4S)-1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸的合成Step 11: Synthesis of compound (2R,4S)-1-acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid
将化合物(2R,4S)-1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯溶于四氢呋喃(8mL)和水(4mL)的混合溶剂中，加入氢氧化锂(59mg,2.48mmol)，置于50℃加热条件下反应1.5h。原料反应完全，停止反应，加入饱和食盐水(30mL)，用稀盐酸调节pH＝3，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，减压浓缩，得黄色固体(320mg,产率84％)。The compound (2R, 4S)-1-acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester was dissolved in tetrahydrofuran (8mL) and water (4mL). In the mixed solvent, lithium hydroxide (59 mg, 2.48 mmol) was added, and the mixture was heated at 50° C. to react for 1.5 hours. The reaction of the raw materials was completed, the reaction was stopped, saturated brine (30mL) was added, the pH was adjusted to 3 with dilute hydrochloric acid, extracted with ethyl acetate (20mL×3), the organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid (320mg, yield 84%).
1H NMR(400MHz,CDCl 3)δ(ppm)6.85–6.81(m,1H),6.80(s,1H),6.78–6.76(m,1H),4.58(t,J＝8.6Hz,1H),4.13–4.07(m,2H),3.96–3.92(m,1H),3.86(s,3H),3.54(t,J＝10.6Hz,1H),3.39–3.31(m,1H),2.69–2.62(m,1H),2.39–2.30(m,1H),2.18(s,3H),1.47(t,J＝7.0Hz,3H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 6.85–6.81(m,1H), 6.80(s,1H), 6.78–6.76(m,1H), 4.58(t,J=8.6Hz,1H), 4.13–4.07(m,2H), 3.96–3.92(m,1H), 3.86(s,3H), 3.54(t, J=10.6Hz, 1H), 3.39–3.31(m,1H), 2.69–2.62( m,1H), 2.39-2.30(m,1H), 2.18(s,3H), 1.47(t,J=7.0Hz,3H).
MS(ESI,pos.ion)m/z:308.15[M+H] +. MS(ESI,pos.ion)m/z:308.15[M+H] + .
步骤12：化合物(2R,4S)-(6-((4-((叔丁基二甲基硅烷基)氧基)苯基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸酯的合成Step 12: Compound (2R,4S)-(6-((4-((tert-butyldimethylsilyl)oxy)phenyl)(methyl)carbamoyl)pyridin-2-yl)methyl Synthesis of 1-acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylate
将化合物(2R,4S)-1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸(140mg,0.44mmol)、N-(4-((叔丁基二甲基硅烷基)氧基)苯基)-6-(羟甲基)-N-甲基吡啶甲酰胺(150mg,0.40mmol)和1-羟基-7-氮杂苯并三唑(110mg,0.80mmol)溶于二氯甲烷(20mL)溶液中，冰浴条件下，依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(150mg,0.80mmol)和N,N-二异丙基乙胺(160mg,1.20mmol)，室温下反应18h，原料反应完全，停止反应，加入饱和食盐水(50mL)，用二氯甲烷萃取(30mL×3)，有机相用无水硫酸钠干燥，减压浓缩硅胶柱层析(洗脱剂：PE/EtOAc(v/v)＝1/1)分离提纯，得淡黄色液体(200mg,产率76％)。The compound (2R, 4S)-1-acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid (140mg, 0.44mmol), N-(4-(( (Tert-Butyldimethylsilyl)oxy)phenyl)-6-(hydroxymethyl)-N-picolinamide (150mg, 0.40mmol) and 1-hydroxy-7-azabenzotriazole (110mg, 0.80mmol) dissolved in dichloromethane (20mL) solution, under ice bath conditions, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150mg, 0.80mmol) and N,N-diisopropylethylamine (160mg, 1.20mmol), reacted at room temperature for 18h, the reaction of the raw materials was complete, the reaction was stopped, saturated brine (50mL) was added, and the mixture was extracted with dichloromethane (30mL×3 ), the organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to separate and purify to obtain a pale yellow liquid (200 mg, yield 76%) ).
1H NMR(400MHz,CDCl 3)δ(ppm)7.58–7.55(m,1H),7.33(d,J＝8.2Hz,1H),7.22(d,J＝6.7Hz,1H),6.91–6.89(m,2H),6.84–6.79(m,2H),6.77–6.76(m,1H),6.63(d,J＝7.9Hz,2H),5.26–5.23(m,1H),5.07–5.03(m,1H),4.56–4.52(m,1H),4.14–4.05(m,3H),3.95–3.90(m,1H),3.86(s,3H),3.60(t,J＝10.5Hz,1H),3.46(s,3H),3.40–3.37(m,1H),2.70–2.64(m,1H),2.11(s,3H),1.46(t,J＝7.0Hz,3H),0.93(s,9H), 0.13(s,6H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.58–7.55(m,1H), 7.33(d,J=8.2Hz,1H), 7.22(d,J=6.7Hz,1H), 6.91–6.89( m,2H), 6.84–6.79(m,2H), 6.77–6.76(m,1H), 6.63(d,J=7.9Hz,2H), 5.26–5.23(m,1H),5.07–5.03(m, 1H), 4.56–4.52(m,1H), 4.14–4.05(m,3H), 3.95–3.90(m,1H), 3.86(s,3H), 3.60(t,J=10.5Hz,1H), 3.46 (s,3H), 3.40–3.37(m,1H), 2.70–2.64(m,1H), 2.11(s,3H), 1.46(t,J=7.0Hz,3H), 0.93(s,9H), 0.13(s,6H).
MS(ESI,pos.ion)m/z:662.20[M+H] +. MS(ESI,pos.ion)m/z:662.20[M+H] + .
步骤13：(2R,4S)-(6-((4-羟基苯基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸酯的合成Step 13: (2R,4S)-(6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-ethoxy- Synthesis of 4-methoxyphenyl)pyrrolidine-2-carboxylate
将化合物(2R,4S)-(6-((4-((叔丁基二甲基硅烷基)氧基)苯基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸酯(200mg,0.30mmol)溶于四氢呋喃(10mL)中，加入四丁基氟化铵溶液(0.60mL,1.0mmol/L)，室温反应1h。原料反应完全，停止反应，加入饱和食盐水(30mL)，用乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，减压浓缩硅胶柱层析(洗脱剂：DCM/MeOH(v/v)＝20/1)分离提纯，得白色固体(136mg,产率82％)。The compound (2R, 4S)-(6-((4-((tert-butyldimethylsilyl)oxy)phenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1- Acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylate (200mg, 0.30mmol) was dissolved in tetrahydrofuran (10mL), and tetrabutylammonium fluoride solution was added (0.60mL, 1.0mmol/L), react at room temperature for 1h. The reaction of the raw materials was complete, the reaction was stopped, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography (eluent: DCM/MeOH) (v/v)=20/1) After separation and purification, a white solid (136mg, yield 82%) was obtained.
1H NMR(400MHz,CDCl 3)δ(ppm)7.54(t,J＝7.7Hz,1H),7.36(d,J＝7.7Hz,1H),7.22(d,J＝7.6Hz,1H),6.88–6.84(m,2H),6.82–6.77(m,2H),6.76–6.74(m,1H),6.72–6.66(m,2H),5.11–5.06(m,1H),4.96–4.93(m,1H),4.55(t,J＝8.6Hz,1H),4.08(q,J＝7.0Hz,2H),3.96–3.91(m,1H),3.85(s,3H),3.62(t,J＝10.5Hz,1H),3.46(s,3H),3.41–3.37(m,1H),2.72–2.66(m,1H),2.14(s,3H),2.08–2.01(m,1H),1.46(t,J＝7.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.54 (t, J = 7.7 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.88 --6.84(m,2H), 6.82–6.77(m,2H), 6.76–6.74(m,1H), 6.72–6.66(m,2H), 5.11–5.06(m,1H), 4.96–4.93(m, 1H),4.55(t,J=8.6Hz,1H),4.08(q,J=7.0Hz,2H),3.96-3.91(m,1H),3.85(s,3H),3.62(t,J=10.5 Hz, 1H), 3.46 (s, 3H), 3.41-3.37 (m, 1H), 2.72-2.66 (m, 1H), 2.14 (s, 3H), 2.08-2.01 (m, 1H), 1.46 (t, J=7.0Hz, 3H).
MS(ESI,pos.ion)m/z:548.70[M+H] +. MS(ESI,pos.ion)m/z:548.70[M+H] + .
实施例172：(2R,4S)-(6-((4-羟基苯基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-甲酸酯Example 172: (2R,4S)-(6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-isopropoxy 4-methoxyphenyl)pyrrolidine-2-carboxylate
Figure PCTCN2021090489-appb-000234
Figure PCTCN2021090489-appb-000234
步骤1：化合物3-异丙氧基-4-甲氧基苯甲酸甲酯的合成Step 1: Synthesis of compound 3-isopropoxy-4-methoxybenzoic acid methyl ester
将化合物3-羟基-4-甲氧基苯甲酸甲酯(5.00g,27.45mmol)，异丙基碘(7.00g,41.17mmol)和碳酸钾(11.83g,82.35mmol)混合在N,N-二甲基甲酰胺(25mL)中，置于80℃下搅拌10h。加入乙酸乙酯(100mL)稀释，有机相用饱和食盐水(100mL×3)洗涤，再用无水硫酸钠干燥，减压浓缩得到黄色液体(5.48g,产率89.02％).The compound 3-hydroxy-4-methoxybenzoic acid methyl ester (5.00g, 27.45mmol), isopropyl iodide (7.00g, 41.17mmol) and potassium carbonate (11.83g, 82.35mmol) were mixed in N, N- In dimethylformamide (25 mL), place the mixture at 80° C. and stir for 10 h. Add ethyl acetate (100mL) to dilute, the organic phase was washed with saturated brine (100mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow liquid (5.48g, yield 89.02%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.62(dd,J＝8.5,1.8Hz,1H),7.53(d,J＝1.7Hz,1H),6.85(d,J＝8.5Hz,1H),4.60–4.54(m,1H),3.86(s,3H),3.84(s,3H),1.35(d,J＝6.1Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.62 (dd, J = 8.5, 1.8 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H ), 4.60–4.54(m,1H), 3.86(s,3H), 3.84(s,3H), 1.35(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:225.20[M+H] +. MS(ESI,pos.ion)m/z:225.20[M+H] + .
步骤2：化合物3-异丙氧基-4-甲氧基苯甲酸的合成Step 2: Synthesis of compound 3-isopropoxy-4-methoxybenzoic acid
将化合物3-异丙氧基-4-甲氧基苯甲酸甲酯(11.05g,49.28mmol)，氢氧化钠(3.94g,98.56mmol)，乙醇(30mL)，水(10mL)混合均匀，置于50℃搅拌2h。滴入稀盐酸(4M/L)调节pH＝1，加入水(100mL)，搅拌(析出大量固体)，过滤，所得滤饼用水(50mL×3)洗涤，真空60℃干燥12h，得白色固体(10.36g,产率100％)。The compound 3-isopropoxy-4-methoxybenzoic acid methyl ester (11.05g, 49.28mmol), sodium hydroxide (3.94g, 98.56mmol), ethanol (30mL), water (10mL) were mixed uniformly, set Stir at 50°C for 2h. Dilute hydrochloric acid (4M/L) was added dropwise to adjust pH=1, water (100mL) was added, stirred (a large amount of solids precipitated), filtered, and the resulting filter cake was washed with water (50mL×3) and dried under vacuum at 60°C for 12h to obtain a white solid ( 10.36g, yield 100%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.76(dd,J＝8.5,1.9Hz,1H),7.62(d,J＝1.8Hz,1H),6.92(d,J＝8.5Hz,1H),4.66–4.60(m,1H),3.93(s,3H),1.40(d,J＝6.1Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.76 (dd, J = 8.5, 1.9 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H ), 4.66–4.60(m,1H),3.93(s,3H), 1.40(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:211.15[M+H] +. MS(ESI,pos.ion)m/z:211.15[M+H] + .
步骤3：化合物苄基(3-异丙氧基-4-甲氧基苯基)氨基甲酸酯的合成Step 3: Synthesis of compound benzyl (3-isopropoxy-4-methoxyphenyl) carbamate
步骤一：室温下，向两口瓶(A瓶)中加入3-异丙氧基-4-甲氧基苯甲酸(10.30g,48.99mmol)，三乙胺(6.44g,663.69mmol)，甲苯(50ml)，置于冰浴中搅拌，缓慢滴加叠氮磷酸二苯酯(DPPA)(14.83g,53.89mmol)，室温中搅拌2h。Step 1: At room temperature, add 3-isopropoxy-4-methoxybenzoic acid (10.30g, 48.99mmol), triethylamine (6.44g, 663.69mmol), toluene ( 50ml), placed in an ice bath and stirred, slowly added dropwise diphenyl azide phosphate (DPPA) (14.83g, 53.89mmol), and stirred at room temperature for 2h.
步骤二：向另一个三口瓶(B瓶)加入甲苯(50ml)，苯甲醇(5.83g,53.89mmol)，加热至110℃，把A瓶物料滴入B瓶中，滴毕恒温搅拌2h。停止加热搅拌，冷至室温，反应液用水洗涤(100mL)，再用5％氢氧化钠水溶液洗涤(100mL×3)，用无水Na 2SO 4干燥，减压浓缩得黄色固体。向粗品加入石油醚/乙酸乙酯(50mL,v/v＝10:1)搅拌3h,过滤得白色固体(11.34g,产率73.40％). Step 2: Add toluene (50ml) and benzyl alcohol (5.83g, 53.89mmol) to another three-necked flask (Bottle B), heat to 110°C, drop the material from Bottle A into Bottle B, and stir at constant temperature for 2h after dropping. Stop heating and stirring and cool to room temperature. The reaction solution was washed with water (100 mL), then washed with 5% sodium hydroxide aqueous solution (100 mL×3), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to obtain a yellow solid. Petroleum ether/ethyl acetate (50mL, v/v=10:1) was added to the crude product, stirred for 3h, and filtered to obtain a white solid (11.34g, yield 73.40%).
1H NMR(400MHz,CDCl 3):δ(ppm)7.47–7.30(m,5H),7.20–7.11(m,1H),6.86–6.72(m,2H),6.56(s,1H),5.19(s,2H),3.82(s,3H),1.36(d,J＝5.9Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.47--7.30 (m, 5H), 7.20 - 7.11 (m, 1H), 6.86 - 6.72 (m, 2H), 6.56 (s, 1H), 5.19 ( s, 2H), 3.82 (s, 3H), 1.36 (d, J = 5.9 Hz, 6H).
MS(ESI,pos.ion)m/z:316.20[M+H] +. MS(ESI,pos.ion)m/z:316.20[M+H] + .
步骤4：化合物3-异丙氧基-4-甲氧基苯胺的合成Step 4: Synthesis of compound 3-isopropoxy-4-methoxyaniline
向高压釜中加入苄基(3-异丙氧基-4-甲氧基苯基)氨基甲酸酯(11.34g,35.96mmol)，10％钯碳(0.51g,0.54mmol)，甲醇(40mL)，置换氢气(0.5MPa)，室温搅拌2h。反应液通过硅藻土过滤，收集滤液经减压浓缩得褐色固体(6.52g,产率100％)。To the autoclave was added benzyl (3-isopropoxy-4-methoxyphenyl) carbamate (11.34g, 35.96mmol), 10% palladium on carbon (0.51g, 0.54mmol), methanol (40mL ), replacing hydrogen (0.5MPa), stirring at room temperature for 2h. The reaction solution was filtered through Celite, and the filtrate was collected and concentrated under reduced pressure to obtain a brown solid (6.52 g, yield 100%).
1H NMR(400MHz,CDCl 3):δ(ppm)6.71(d,J＝8.4Hz,1H),6.33(d,J＝2.4Hz,1H),6.24(dd,J＝8.4,2.5Hz,1H),4.49–4.43(p,J＝6.1Hz,1H),3.77(s,3H),1.34(d,J＝6.1Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 6.71 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 6.24 (dd, J = 8.4, 2.5 Hz, 1H ), 4.49-4.43 (p, J = 6.1Hz, 1H), 3.77 (s, 3H), 1.34 (d, J = 6.1Hz, 6H).
MS(ESI,pos.ion)m/z:182.20[M+H] +. MS(ESI,pos.ion)m/z:182.20[M+H] + .
步骤5：化合物3-异丙氧基-4-甲氧基碘苯的合成Step 5: Synthesis of compound 3-isopropoxy-4-methoxy iodobenzene
将化合物3-异丙氧基-4-甲氧基苯胺(6.90g,38.07mmol)，溶于1,4-二氧六环(30mL)和水(11mL)中，冷却至0℃，加入浓盐酸(9.6mL,36％aq)，搅拌均匀，冷却至-15℃，逐滴加入亚硝酸钠(2.89g,41.88mmol)和水(7mL)的溶液，控制滴加温度在-15℃至-5℃之间，滴毕回温至-5℃搅拌30min后，加入碘化钾(8.22g,49.49mmol)和水(12mL)的溶液，控制滴加温度在-15℃至-5℃之间，滴毕回温至0℃下搅拌2h.加入亚硫酸氢钠(1.98g,19.04mmol)搅拌1h淬灭反应，向反应液加入石油醚(200mL)，有机相用水洗涤(100mL×3)，用无水Na 2SO 4干燥，减压浓缩得黄色粘稠液体。硅胶柱层析(洗脱剂:石油醚/乙酸乙酯(v/v)＝10/1)纯化得白色固体(7.83g,产率70.41％) The compound 3-isopropoxy-4-methoxyaniline (6.90g, 38.07mmol) was dissolved in 1,4-dioxane (30mL) and water (11mL), cooled to 0°C, and concentrated Hydrochloric acid (9.6mL, 36% aq), stir evenly, cool to -15°C, add a solution of sodium nitrite (2.89g, 41.88mmol) and water (7mL) dropwise, control the temperature of the dropwise addition at -15°C to- At 5℃, after dripping and warming to -5℃ and stirring for 30min, add a solution of potassium iodide (8.22g, 49.49mmol) and water (12mL), control the dripping temperature between -15℃ and -5℃, and drop After warming to 0℃ and stirring for 2h. Add sodium bisulfite (1.98g, 19.04mmol) and stir for 1h to quench the reaction. Petroleum ether (200mL) was added to the reaction solution, and the organic phase was washed with water (100mL×3). Water was dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a yellow viscous liquid. Purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1) to obtain a white solid (7.83 g, yield 70.41%)
1H NMR(400MHz,CDCl 3):δ(ppm)7.21(dd,J＝8.5,1.9Hz,1H),7.16(d,J＝1.9Hz,1H),6.62(d,J＝8.5Hz,1H),4.53–4.44(m,1H),3.82(s,3H),1.36(d,J＝6.1Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 7.21 (dd, J = 8.5, 1.9 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H ),4.53-4.44(m,1H),3.82(s,3H),1.36(d,J=6.1Hz,6H).
GC-MS:m/z 292.0[M] +. GC-MS: m/z 292.0[M] + .
步骤6：化合物2-(3-异丙氧基-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成Step 6: Synthesis of compound 2-(3-isopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
将3-异丙氧基-4-甲氧基碘苯(8.64g,26.63mmol)，联硼酸频那醇酯(6.76g,26.63mmol)，醋酸钾(39.2g,39.95mmol)，醋酸钯(0.30g,1.33mmol)，2-二环己基磷-2’-甲基联苯(Mephos)(0.97g,2.66mmol)混合在N,N-二甲基甲酰胺(48mL)中，氮气保护下80℃搅拌6h。冷却至室温，反应液中加入水(100mL)，用石油醚(100mL×3)萃取反应液，合并有机相，无水硫酸钠干燥有机相，减压浓缩得到褐色液体，通过硅胶柱层析(洗脱剂：石油醚/乙酸乙酯(v/v)＝10/1)纯化得黄色固体(5.04g,产率64.78％)。Combine 3-isopropoxy-4-methoxy iodobenzene (8.64g, 26.63mmol), pinacol diborate (6.76g, 26.63mmol), potassium acetate (39.2g, 39.95mmol), palladium acetate ( 0.30g, 1.33mmol), 2-Dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) (0.97g, 2.66mmol) mixed in N,N-dimethylformamide (48mL) under nitrogen protection Stir at 80°C for 6h. Cool to room temperature, add water (100mL) to the reaction solution, extract the reaction solution with petroleum ether (100mL×3), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to obtain a brown liquid, and pass it through silica gel column chromatography ( Eluent: petroleum ether/ethyl acetate (v/v)=10/1) purified to obtain a yellow solid (5.04 g, yield 64.78%).
1H NMR(400MHz,CDCl 3):δ(ppm)77.41(d,J＝8.0Hz,1H),7.33(s,1H),6.88(d,J＝8.0Hz,1H),4.67–4.56(m,1H),3.87(s,3H),1.37(d,J＝6.1Hz,6H),1.33(s,12H). 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 77.41 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.67-4.56 (m ,1H),3.87(s,3H),1.37(d,J=6.1Hz,6H),1.33(s,12H).
MS(ESI,pos.ion)m/z:293.25[M+H] +. MS(ESI,pos.ion)m/z:293.25[M+H] + .
步骤7：化合物(R)-1-叔丁基2-甲基4-(3-异丙氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二甲酸酯的合 成Step 7: Compound (R)-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)-1H-pyrrole-1,2(2H,5H)-di Synthesis of formate
将化合物(R)-1-叔丁基2-甲基4-((((三氟甲基)磺酰基)甲氧基)-1H-吡咯-1,2(2H,5H)-二甲酸酯(5.50g,14.65mmol，中间体M 2)，2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(4.49g,15.38mmol)，醋酸钯(82.23mg,0.37mmol)，二环己基-[2-(2-甲基苯基)苯基]膦(267.00mg,0.73mmol)，溶解于甲苯(30mL)溶剂中，再加入4-甲基吗啉(3.25g,32.08mmol)，水(15mL)，在氮气氛围下，转入到80℃搅拌反应2h，冷却至室温，加入水(100mL)，用乙酸乙酯(50mL×3)萃取，有机相用无水硫酸钠干燥30min，通过硅胶柱层纯化(洗脱剂:乙酸乙酯/石油醚(v/v)＝3/20)，得到褐色粘稠状(5g,产率87.19％)。 The compound (R)-1-tert-butyl 2-methyl 4-((((trifluoromethyl)sulfonyl)methoxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylic acid Ester (5.50g, 14.65mmol, intermediate M 2 ), 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetra Methyl-1,3,2-dioxolane (4.49g, 15.38mmol), palladium acetate (82.23mg, 0.37mmol), dicyclohexyl-[2-(2-methylphenyl)benzene Base] phosphine (267.00mg, 0.73mmol), dissolved in toluene (30mL) solvent, then add 4-methylmorpholine (3.25g, 32.08mmol), water (15mL), under nitrogen atmosphere, transferred to 80 The reaction was stirred at ℃ for 2h, cooled to room temperature, water (100mL) was added, extracted with ethyl acetate (50mL×3), the organic phase was dried over anhydrous sodium sulfate for 30min, and purified by silica gel column (eluent: ethyl acetate/ Petroleum ether (v/v)=3/20) to obtain a brown viscous form (5g, yield 87.19%).
1H NMR(400MHz,CDCl 3)δ(ppm)6.96–6.90(m,2H),6.85–6.82(m,1H),5.93–5.87(m,1H),5.17–5.08(m,1H),4.66–4.46(m,3H),3.85(s,3H),3.74(d,J＝5.0Hz,3H),1.52(s,3H),1.45(s,6H),1.36(d,J＝6.1Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 6.96-6.90 (m, 2H), 6.85-6.82 (m, 1H), 5.93-5.87 (m, 1H), 5.17-5.08 (m, 1H), 4.66 –4.46(m,3H),3.85(s,3H),3.74(d,J=5.0Hz,3H),1.52(s,3H),1.45(s,6H),1.36(d,J=6.1Hz, 6H).
MS(ESI,pos.ion)m/z:336.05[M-t-Bu+2H] +. MS(ESI,pos.ion)m/z:336.05[Mt-Bu+2H] + .
步骤8：化合物(2R,4S)-1-叔丁基2-甲基4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1,2-二甲酸酯的合成Step 8: Synthesis of compound (2R, 4S)-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate
将化合物(R)-1-叔丁基2-甲基4-(3-异丙氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(5.55g,14.18mmol)溶解于的甲醇(90mL)溶剂中，再加入钯碳(0.56mg,1.42mmol)，在氢气氛围下，室温搅拌反应4h。停止反应，用硅藻土过滤，减压浓缩，得到无色粘稠状(4.45g,产率79.76％)。The compound (R)-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylic acid The ester (5.55 g, 14.18 mmol) was dissolved in methanol (90 mL) solvent, and palladium on carbon (0.56 mg, 1.42 mmol) was added, and the reaction was stirred at room temperature for 4 h under a hydrogen atmosphere. The reaction was stopped, filtered with celite, and concentrated under reduced pressure to obtain a colorless viscous form (4.45 g, yield 79.76%).
1H NMR(400MHz,CDCl 3)δ(ppm)6.83–6.76(m,3H),4.53–4.46(m,1H),4.39–4.29(m,1H),4.04–3.89(m,1H),3.82(s,3H),3.75(s,3H),3.42–3.35(m,1H),3.32–3.23(m,1H),2.65–2.57(m,1H),2.06–1.95(m,1H),1.44(s,9H),1.34(d,J＝6.0Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 6.83-6.76 (m, 3H), 4.53-4.46 (m, 1H), 4.39-4.29 (m, 1H), 4.04--3.89 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.42--3.35 (m, 1H), 3.32--3.23 (m, 1H), 2.65--2.57 (m, 1H), 2.06--1.95 (m, 1H), 1.44 (s,9H),1.34(d,J=6.0Hz,6H).
MS(ESI,pos.ion)m/z:337.40[M-t-Bu+H] +. MS(ESI,pos.ion)m/z:337.40[Mt-Bu+H] + .
步骤9：化合物(2R,4S)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯盐酸盐的合成Step 9: Synthesis of compound (2R,4S)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride
将化合物(2R,4S)-1-叔丁基2-甲基4-(4-甲氧基-3-(丙氧基)苯基)吡咯烷-1,2-二羧酸酯(1.70g,4.32mmol)溶解于二氯甲烷(3mL)溶剂中，再加入氯化氢/1,4-二氧六环(9mL)溶液,加入原料完之后，在室温下搅拌反应2h。停止反应，减压浓缩一次后，再加入二氯甲烷(20mL)溶解，再次减压浓缩，得到浅黄色粘稠状物(1.27g,产率100％)The compound (2R, 4S)-1-tert-butyl 2-methyl 4-(4-methoxy-3-(propoxy)phenyl)pyrrolidine-1,2-dicarboxylate (1.70g , 4.32mmol) was dissolved in dichloromethane (3mL) solvent, and then hydrogen chloride/1,4-dioxane (9mL) solution was added. After adding the raw materials, the reaction was stirred at room temperature for 2h. The reaction was stopped, and after concentration under reduced pressure once, dichloromethane (20 mL) was added to dissolve, and concentrated under reduced pressure again to obtain a pale yellow viscous substance (1.27 g, yield 100%)
1H NMR(400MHz,CDCl 3)δ(ppm)6.84(s,1H),6.80(s,2H),4.66–4.58(m,1H),4.56–4.50(m,1H),3.83(s,3H),3.81(s,3H),3.64–3.61(m,1H),3.55–3.47(m,1H),2.82–2.73(m,1H),2.25–2.10(m,2H),1.34(d,J＝4.9Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 6.84 (s, 1H), 6.80 (s, 2H), 4.66-4.58 (m, 1H), 4.56-4.50 (m, 1H), 3.83 (s, 3H) ), 3.81(s, 3H), 3.64-3.61(m, 1H), 3.55-3.47(m, 1H), 2.82-2.73(m, 1H), 2.25--2.10(m, 2H), 1.34(d, J =4.9Hz, 6H).
MS(ESI,pos.ion)m/z:294.30[M+H-HCl] +. MS(ESI,pos.ion)m/z:294.30[M+H-HCl] + .
步骤10：化合物(2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯的合成Step 10: Synthesis of compound (2R, 4S)-1-acetyl-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester
将化合物(2R,4S)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-羧酸甲酯盐酸盐(1.7g,5.79mmol)溶解于二氯甲烷(10mL)溶剂中，在冰浴中冷却，缓慢依次加入乙基二异丙胺(DIPEA)(2.99g,23.16mmol)及乙酰氯(0.91g,11.58mmol)，转入到室温下搅拌反应2h。停止反应，反应液水洗(50mL×1)，有机相用二氯甲烷(20mL)萃取一次，合并有机相，再用饱和食盐水(50mL)洗一次，分离有机相，有机相加无水硫酸钠干燥30min，减压浓缩，硅胶柱层析分离(洗脱剂：乙酸乙酯/石油醚＝80％)，得到浅褐色粘稠状(1.386g,产率71.37％)The compound (2R, 4S)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.7g, 5.79mmol) was dissolved in dichloromethane (10mL) in the solvent, cool in an ice bath, slowly add ethyldiisopropylamine (DIPEA) (2.99g, 23.16mmol) and acetyl chloride (0.91g, 11.58mmol) in sequence, then transfer to room temperature and stir for 2h. The reaction was stopped, the reaction solution was washed with water (50mL×1), the organic phase was extracted once with dichloromethane (20mL), the organic phases were combined, and then washed with saturated brine (50mL), the organic phase was separated, and the organic phase was added with anhydrous sodium sulfate Dry for 30 min, concentrate under reduced pressure, and separate by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 80%) to obtain a light brown viscous form (1.386 g, yield 71.37%)
1H NMR(400MHz,CDCl 3)δ(ppm)6.84–6.75(m,3H),4.54–4.43(m,2H),3.93–3.88(m,1H),3.83(s,3H),3.76(s,3H),3.58(t,J＝10.5Hz,1H),3.41–3.31(m,1H),2.66–2.59(m,1H),2.10(s,3H),2.07–2.00(m,1H),1.34(d,J＝6.1Hz,6H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 6.84-6.75(m,3H), 4.54-4.43(m,2H), 3.93-3.88(m,1H), 3.83(s,3H), 3.76(s ,3H),3.58(t,J=10.5Hz,1H),3.41-3.31(m,1H),2.66-2.59(m,1H),2.10(s,3H),2.07-2.00(m,1H), 1.34(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:336.35[M+H] +. MS(ESI,pos.ion)m/z:336.35[M+H] + .
步骤11：化合物(2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-甲酸的合成Step 11: Synthesis of compound (2R,4S)-1-acetyl-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid
将化合物(2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯(0.62g,1.86mmol)，水合氢氧化锂(0.16g,3.72mmol)溶于四氢呋喃(5mL)及水(2.5mL)，在50℃下搅拌反3h。停止反应，在-5℃中冷却，滴加稀盐酸(0.5M/L)，调节pH＝2，加入饱和食盐水(50mL×2)洗涤，分离有机相，无水硫酸钠干燥30min，减压浓缩，得到浅黄色固体(561mg,产率93.85％)The compound (2R, 4S)-1-acetyl-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester (0.62g, 1.86mmol), hydrated with hydrogen Lithium (0.16g, 3.72mmol) was dissolved in tetrahydrofuran (5mL) and water (2.5mL), and stirred at 50°C for 3h. Stop the reaction, cool at -5°C, add dilute hydrochloric acid (0.5M/L) dropwise, adjust pH=2, add saturated brine (50mL×2) to wash, separate the organic phase, dry with anhydrous sodium sulfate for 30min, reduce pressure Concentrate to obtain a light yellow solid (561mg, yield 93.85%)
1H NMR(400MHz,DMSO-d 6)δ6.91–6.85(m,2H),6.84–6.78(m,1H),4.59–4.50(m,2H),4.23–4.19(m,1H),4.06–4.00(m,1H),3.72(s,3H),3.30–3.18(m,1H),2.67–2.58(m,1H),2.00(s,3H),1.91–1.78(m,2H),1.24(d,J＝6.0Hz,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ 6.91-6.85 (m, 2H), 6.84-6.78 (m, 1H), 4.59-4.50 (m, 2H), 4.23-4.19 (m, 1H), 4.06 --4.00 (m, 1H), 3.72 (s, 3H), 3.30-3.18 (m, 1H), 2.67-2.58 (m, 1H), 2.00 (s, 3H), 1.91-1.78 (m, 2H), 1.24 (d,J=6.0Hz,6H).
MS(ESI,pos.ion)m/z:322.20[M+H] +. MS(ESI,pos.ion)m/z:322.20[M+H] + .
步骤12：化合物(2R,4S)-(6-((4-羟基苯基)(甲基)氨基甲酰基)吡啶-2-基)甲基1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-甲酸酯的合成Step 12: Compound (2R,4S)-(6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-isopropoxy Of 4-methoxyphenyl)pyrrolidine-2-carboxylate
将化合物(2R,4S)-1-乙酰基-4-(4-甲氧基-3-(丙-2-基氧基)苯基)吡咯烷-2-甲酸(151.04mg,0.47mmol)，6-(羟甲基)-N-(4-羟苯基)-N-甲基吡啶-2-羧酰胺(145.66mg,0.56mmol)，N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(135.15mg,0.7mmol)，1-羟基苯并三唑(76.21mg,0.56mmol)，4-甲基吗啉(76.06mg,0.75mmol)，溶解在二氯甲烷(5mL)溶剂中，在室温下搅拌反应5h。停止反应，加入水(20mL)，用乙酸乙酯(10mL×2)萃取，有机相再用饱和食盐水洗(20mL)一次，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱剂：甲醇/二氯甲烷(v/v)＝5％)，得到白色固体(30mg,产率13.06％)The compound (2R, 4S)-1-acetyl-4-(4-methoxy-3-(prop-2-yloxy)phenyl)pyrrolidine-2-carboxylic acid (151.04mg, 0.47mmol), 6-(Hydroxymethyl)-N-(4-hydroxyphenyl)-N-methylpyridine-2-carboxamide (145.66mg, 0.56mmol), N-(3-dimethylaminopropyl)-N '-Ethylcarbodiimide hydrochloride (135.15mg, 0.7mmol), 1-hydroxybenzotriazole (76.21mg, 0.56mmol), 4-methylmorpholine (76.06mg, 0.75mmol), dissolved in In dichloromethane (5mL) solvent, the reaction was stirred at room temperature for 5h. The reaction was stopped, water (20mL) was added, extracted with ethyl acetate (10mL×2), the organic phase was washed with saturated brine (20mL) once, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (Eluent: methanol/dichloromethane (v/v)=5%) to obtain a white solid (30mg, yield 13.06%)
1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),7.69(t,J＝8.0Hz,1H),7.27–7.21(m,2H),6.94–6.86(m,4H),6.85–6.79(m,1H),6.55(d,J＝8.2Hz,2H),5.09–4.95(m,2H),4.57–4.49(m,1H),4.43–4.35(m,1H),4.09–4.02(m,1H),3.72(s,3H),3.29(s,3H),3.50–3.40(m,2H),2.03(s,3H),1.99–1.85(m,2H),1.22(d,J＝5.9Hz,6H). 1 H NMR(400MHz,DMSO-d 6 )δ9.46(s,1H), 7.69(t,J=8.0Hz,1H), 7.27–7.21(m,2H), 6.94–6.86(m,4H), 6.85–6.79(m,1H),6.55(d,J=8.2Hz,2H),5.09–4.95(m,2H),4.57–4.49(m,1H),4.43–4.35(m,1H),4.09– 4.02(m,1H), 3.72(s,3H), 3.29(s,3H), 3.50--3.40(m,2H),2.03(s,3H),1.99--1.85(m,2H),1.22(d, J=5.9Hz, 6H).
MS(ESI,pos.ion)m/z:562.50[M+H] +. MS(ESI,pos.ion)m/z:562.50[M+H] + .
生物试验Biological test
生物实施例1：本发明化合物对PDE4B2酶抑制作用的测定Biological Example 1: Determination of the inhibitory effect of the compound of the present invention on PDE4B2 enzyme
1.实验方法1. Experimental method
本发明采用以下方法对本发明化合物进行生物试验：(1)采用BPS生产试剂盒(BPS，Cat.No.60343)，按照制造商提供的说明书，采用荧光偏振方法检测化合物对PDE4B2酶抑制作用。(2)将PDE4B2酶浓度配制为83.33pg/μL，终浓度为27.78pg/μL；底物FAM-Cyclic-3’,5’-AMP浓度配制为300nM，反应终浓度为100nM，酶及底物稀释液均使用试剂盒自带缓冲液PDE Assay buffer；Binding Agent利用试剂盒自带Binding Agent Diluent进行100倍稀释，备用。反应体系如表1所示。The present invention uses the following methods to conduct biological tests on the compounds of the present invention: (1) Using a BPS production kit (BPS, Cat. No. 60343), according to the instructions provided by the manufacturer, using a fluorescence polarization method to detect the inhibitory effect of the compound on the PDE4B2 enzyme. (2) Prepare the PDE4B2 enzyme concentration to 83.33pg/μL, the final concentration is 27.78pg/μL; the substrate FAM-Cyclic-3', 5'-AMP concentration is formulated to 300nM, the final reaction concentration is 100nM, enzyme and substrate The diluents are all diluted with the PDE Assay buffer that comes with the kit; the Binding Agent uses the Binding Agent Diluent that comes with the kit to dilute 100 times for use. The reaction system is shown in Table 1.
表1化合物对PDE4B2酶IC 50检测体系 Table 1 Compounds to PDE4B2 enzyme IC 50 detection system
Figure PCTCN2021090489-appb-000235
Figure PCTCN2021090489-appb-000235
采用384孔板进行检测，实验设置受试样品孔、阳性对照孔、阴性对照孔及空白孔，每个样品利用双复孔检测10个浓度下对PDE4B2酶浓度的抑制作用，利用PDE4B2酶及FAM-Cyclic-3’,5’-AMP底物反应孔作为阳性对照，FAM-Cyclic-3’,5’-AMP底物孔作为阴性对照，缓冲液孔作为空白对照。各孔按表1顺序加入相应样品、酶、底物及缓冲液后，25℃恒温箱孵育1h，然后每孔加入已配置好的Binding Agent 15μL，并于25℃恒温振荡器振摇1h后，利用PHER Astar FS多功能酶标仪(BMG)在FP485/525波长处进行检测。利用Graph Pad Prism 5软件对化合物不同浓度下对PDE4B2酶抑制作用进行作图，计算IC 50。 A 384-well plate was used for detection. The experiment was set up with test sample wells, positive control wells, negative control wells and blank wells. Each sample was used to detect the inhibitory effect on the PDE4B2 enzyme concentration at 10 concentrations, using PDE4B2 enzyme and The FAM-Cyclic-3',5'-AMP substrate reaction well was used as a positive control, the FAM-Cyclic-3',5'-AMP substrate well was used as a negative control, and the buffer well was used as a blank control. After adding the corresponding samples, enzymes, substrates and buffers to each well in the order of Table 1, incubate for 1 hour at 25°C, then add 15μL of the configured Binding Agent to each well, and shake at a constant temperature oscillator at 25°C for 1 hour. Use PHER Astar FS multi-function microplate reader (BMG) to detect at FP485/525 wavelength. Graph Pad Prism 5 software using different concentrations of compound was plotted against enzyme inhibition PDE4B2 calculated IC 50.
2.实验结果2. Experimental results
按照上述方法测定本发明实施例提供的化合物对PDE4B2酶的抑制作用，发现本发明化合物对PDE4B2酶具有抑制作用，其IC 50值小于1μM；进一步发现，本发明部分实施例化合物的对PDE4B2酶的抑制作用的IC 50值小于500nM；更进一步发现，本发明部分实施例化合物的对PDE4B2酶的抑制作用的IC 50值小于200nM。具体地，本发明部分实施例化合物对PDE4B2酶抑制作用的测定结果参见表2。 According to the above method, the inhibitory effect of the compounds provided in the examples of the present invention on PDE4B2 enzyme was determined, and it was found that the compounds of the present invention have an inhibitory effect on PDE4B2 enzyme, with an IC 50 value of less than 1 μM; The IC 50 value of the inhibitory effect is less than 500 nM; it is further found that the IC 50 value of the inhibitory effect on the PDE4B2 enzyme of some of the example compounds of the present invention is less than 200 nM. Specifically, see Table 2 for the determination results of the inhibitory effect of some of the example compounds of the present invention on the PDE4B2 enzyme.
表2本发明部分化合物对PDE4B2酶抑制作用的测定结果Table 2 Results of determination of the inhibitory effect of some compounds of the present invention on PDE4B2 enzyme
实施例编号Example number IC 50(nM) IC 50 (nM) 实施例编号Example number IC 50(nM) IC 50 (nM)
实施例3Example 3 15.215.2 实施例78Example 78 2.32.3
实施例4Example 4 12.412.4 实施例79Example 79 40.6740.67
实施例11Example 11 59.759.7 实施例80Example 80 59.5759.57
实施例13Example 13 6.56.5 实施例81Example 81 1.001.00
实施例14Example 14 15.7115.71 实施例82Example 82 1.681.68
实施例15Example 15 17.7417.74 实施例83Example 83 5.785.78
实施例16Example 16 18.3718.37 实施例84Example 84 43.543.5
实施例18Example 18 29.1029.10 实施例85Example 85 10.4410.44
实施例19Example 19 10.9210.92 实施例86Example 86 0.730.73
实施例20Example 20 24.4624.46 实施例87Example 87 4.584.58
实施例22Example 22 8.968.96 实施例89Example 89 9.869.86
实施例23Example 23 211.7211.7 实施例90Example 90 5.005.00
实施例24Example 24 13.0513.05 实施例91Example 91 1.481.48
实施例25Example 25 7.087.08 实施例92Example 92 9.159.15
实施例26Example 26 13.0513.05 实施例93Example 93 1.681.68
实施例27Example 27 11.9311.93 实施例94Example 94 34.4234.42
实施例28Example 28 26.0826.08 实施例95Example 95 16.3216.32
实施例29Example 29 13.3613.36 实施例96Example 96 5.895.89
实施例31Example 31 77.2077.20 实施例98Example 98 5.625.62
实施例33Example 33 61.5561.55 实施例99Example 99 22.722.7
实施例34Example 34 7.777.77 实施例100Example 100 0.420.42
实施例35Example 35 4.254.25 实施例101Example 101 1.871.87
实施例36Example 36 5.655.65 实施例102Example 102 0.940.94
实施例37Example 37 5.035.03 实施例103Example 103 12.5412.54
实施例38Example 38 19.8619.86 实施例106Example 106 0.20.2
实施例39Example 39 2.842.84 实施例107Example 107 0.480.48
实施例40Example 40 4.454.45 实施例108Example 108 26.9726.97
实施例41Example 41 53.6753.67 实施例109Example 109 124.9124.9
实施例43Example 43 42.3742.37 实施例110Example 110 1.661.66
实施例44Example 44 77.6877.68 实施例111Example 111 1.711.71
实施例编号Example number IC 50(nM) IC 50 (nM) 实施例编号Example number IC 50(nM) IC 50 (nM)
实施例46Example 46 22.1822.18 实施例114Example 114 47.4847.48
实施例47Example 47 33.5933.59 实施例115Example 115 69.3769.37
实施例48Example 48 46.5446.54 实施例117Example 117 19.6919.69
实施例49Example 49 8.658.65 实施例120Example 120 49.8449.84
实施例50Example 50 11.3611.36 实施例121Example 121 34.0934.09
实施例51Example 51 48.8348.83 实施例122Example 122 9.869.86
实施例52Example 52 3.013.01 实施例123Example 123 13.213.2
实施例53Example 53 0.1880.188 实施例124Example 124 0.330.33
实施例54Example 54 2.592.59 实施例125Example 125 4.914.91
实施例55Example 55 5.775.77 实施例126Example 126 17.8917.89
实施例56Example 56 6.426.42 实施例127Example 127 14.6614.66
实施例57Example 57 42.8442.84 实施例128Example 128 5.935.93
实施例58Example 58 15.7815.78 实施例129Example 129 15.0815.08
实施例59Example 59 6.126.12 实施例130Example 130 23.0723.07
实施例60Example 60 24.9824.98 实施例131Example 131 0.420.42
实施例61Example 61 53.9653.96 实施例132Example 132 0.450.45
实施例62Example 62 12.2912.29 实施例133Example 133 0.490.49
实施例63Example 63 14.2614.26 实施例134Example 134 10.7210.72
实施例64Example 64 0.960.96 实施例135Example 135 16.7416.74
实施例65Example 65 0.570.57 实施例136Example 136 3.113.11
实施例66Example 66 0.730.73 实施例137Example 137 11.1111.11
实施例67Example 67 2.242.24 实施例138Example 138 45.9645.96
实施例68Example 68 17.2617.26 实施例139Example 139 51.2751.27
实施例69Example 69 11.9211.92 实施例140Example 140 35.2935.29
实施例70Example 70 0.960.96 实施例141Example 141 55.5755.57
实施例71Example 71 10.6510.65 实施例142Example 142 29.3629.36
实施例74Example 74 0.370.37 实施例143Example 143 10.010.0
实施例76Example 76 1.591.59 实施例144Example 144 79.8679.86
实施例77Example 77 0.940.94 // //
实施例148Example 148 29.0829.08 实施例160Example 160 24.2324.23
实施例151Example 151 12.7912.79 实施例162Example 162 43.543.5
实施例152Example 152 0.990.99 实施例164Example 164 10.3810.38
实施例153Example 153 3.433.43 实施例167Example 167 28.9428.94
实施例154Example 154 5.875.87 实施例168Example 168 16.3516.35
实施例155Example 155 2.912.91 实施例170Example 170 2.162.16
实施例156Example 156 4.714.71 实施例171Example 171 6.586.58
实施例158Example 158 66.9166.91 实施例172Example 172 23.2723.27
实施例159Example 159 40.7440.74 // //
3.实验结论3. Experimental conclusion
实验证明，本发明化合物在体外对PDE4B2酶普遍具有较高的抑制作用；特别是表2中的化合物，它们在对PDE4B2酶的体外抑制筛选实验中表现出显著的抑制活性。Experiments have proved that the compounds of the present invention generally have a higher inhibitory effect on PDE4B2 enzyme in vitro; especially the compounds in Table 2 show significant inhibitory activity in the in vitro inhibition screening experiment on PDE4B2 enzyme.
生物实施例2：本发明化合物对PMA诱导急性特应性皮炎小鼠模型Biological Example 2: The compound of the present invention has an effect on a mouse model of PMA-induced acute atopic dermatitis
1.试验方法1. Test method
选取雌性ICR小鼠，体重26-28g，动物适应性饲养7天后，随机分为正常组、模型组、和各化合物组，正常组4只，其余每组10只。除正常组小鼠外，其余小鼠用20μL浓度为0.25mg/mL的PMA(Phorbol 12-myristate 13-acetate，佛波酯)溶液(溶于无水乙醇)涂抹于右耳造模，正常组涂抹相应溶媒。各化合物组在造模前30min进行第一次给药和造模后15min进行第二次给药，各组动物耳部涂抹20μL浓度为15mg/mL受试药物溶液[乙醇:丙酮＝1:1(v/v)]，正常组、模型组动物涂抹相应溶媒。在第二次给药6小时后处死动物，每只动物剪下右耳用8mm打耳器在固定位置获取耳片并进行称重，随后液氮保存耳片，然后加入500μL生理盐水用匀浆机匀浆，离心后取上清液，检测上清液中的IL-1β和IL-6浓度并用归一化法计算蛋白浓度。Select female ICR mice, weighing 26-28g, and after the animals are adaptively reared for 7 days, they are randomly divided into normal group, model group, and each compound group. There are 4 normal groups and 10 in each group. Except for the mice in the normal group, the other mice were smeared on the right ear with 20 μL of PMA (Phorbol 12-myristate 13-acetate, phorbol ester) solution (dissolved in absolute ethanol) at a concentration of 0.25 mg/mL. The normal group Apply the corresponding solvent. Each compound group was given the first dose 30 minutes before modeling and the second dose 15 minutes after modeling. The ears of each group of animals were smeared with 20 μL of the test drug solution at a concentration of 15 mg/mL [ethanol:acetone=1:1 (v/v)], apply the corresponding solvent to the animals in the normal group and model group. The animals were sacrificed 6 hours after the second administration. Each animal cut off the right ear and used an 8mm ear punch to obtain the ear piece at a fixed position and weigh it. Then the ear piece was stored in liquid nitrogen, and then 500μL of normal saline was added for homogenization. Machine homogenate, centrifuge and take the supernatant, detect the concentration of IL-1β and IL-6 in the supernatant and calculate the protein concentration by normalization method.
2.实验结果2. Experimental results
表3～9为本发明化合物对PMA诱导急性特应性皮炎小鼠耳厚度、耳重量以及耳部炎症因子分泌的影响(Mean±SEM，动物数量N＝4 or N＝10，与模型组相比，*表示P<0.05，**表示P<0.01)。Tables 3 to 9 show the effects of the compounds of the present invention on ear thickness, ear weight, and ear inflammatory factor secretion in PMA-induced acute atopic dermatitis mice (Mean±SEM, number of animals N=4 or N=10, similar to the model group Ratio, * means P<0.05, ** means P<0.01).
表3.化合物对小鼠耳厚度以及耳重量的影响(Mean±Sem)Table 3. Effects of compounds on mouse ear thickness and ear weight (Mean±Sem)
Figure PCTCN2021090489-appb-000236
Figure PCTCN2021090489-appb-000236
表4.化合物对小鼠耳厚度、耳重量以及炎症因子的影响(Mean±Sem)Table 4. Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean±Sem)
Figure PCTCN2021090489-appb-000237
Figure PCTCN2021090489-appb-000237
续表Continued
Figure PCTCN2021090489-appb-000238
Figure PCTCN2021090489-appb-000238
Figure PCTCN2021090489-appb-000239
Figure PCTCN2021090489-appb-000239
表5.化合物对小鼠耳厚度、耳重量以及炎症因子的影响(Mean±Sem)Table 5. Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean±Sem)
Figure PCTCN2021090489-appb-000240
Figure PCTCN2021090489-appb-000240
续表Continued
Figure PCTCN2021090489-appb-000241
Figure PCTCN2021090489-appb-000241
表6.化合物对小鼠耳厚度、耳重量以及炎症因子的影响(Mean±Sem)Table 6. Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean±Sem)
Figure PCTCN2021090489-appb-000242
Figure PCTCN2021090489-appb-000242
续表Continued
Figure PCTCN2021090489-appb-000243
Figure PCTCN2021090489-appb-000243
表7.化合物对小鼠耳厚度、耳重量以及炎症因子的影响(Mean±Sem)Table 7. Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean±Sem)
Figure PCTCN2021090489-appb-000244
Figure PCTCN2021090489-appb-000244
Figure PCTCN2021090489-appb-000245
Figure PCTCN2021090489-appb-000245
续表Continued
Figure PCTCN2021090489-appb-000246
Figure PCTCN2021090489-appb-000246
表8.化合物对小鼠耳厚度、耳重量以及炎症因子的影响(Mean±Sem)Table 8. Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean±Sem)
Figure PCTCN2021090489-appb-000247
Figure PCTCN2021090489-appb-000247
续表Continued
Figure PCTCN2021090489-appb-000248
Figure PCTCN2021090489-appb-000248
表9.化合物对小鼠耳厚度、耳重量以及炎症因子的影响(Mean±Sem)Table 9. Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean±Sem)
Figure PCTCN2021090489-appb-000249
Figure PCTCN2021090489-appb-000249
续表Continued
Figure PCTCN2021090489-appb-000250
Figure PCTCN2021090489-appb-000250
Figure PCTCN2021090489-appb-000251
Figure PCTCN2021090489-appb-000251
3.实验结论3. Experimental conclusion
由上述实验结果可知，与模型组比较，本发明的化合物均能显著地降低PMA诱导的急性特应性皮炎小鼠耳厚度和耳重量以及耳部炎症因子IL-1β和IL-6的分泌(P<0.05)。It can be seen from the above experimental results that, compared with the model group, the compounds of the present invention can significantly reduce the ear thickness and ear weight of PMA-induced acute atopic dermatitis mice and the secretion of ear inflammatory factors IL-1β and IL-6 ( P<0.05).
生物实施例3：本发明化合物对OXA诱导慢性特应性皮炎小鼠模型Biological Example 3: The compound of the present invention has an effect on a mouse model of chronic atopic dermatitis induced by OXA
1.实验方法1. Experimental method
选取雄性Balb/c小鼠，体重24-26g，动物适应性饲养7天后，除正常组外，其余动物在第0天和第一天用40μL 1％的OXA溶液(溶于丙酮)涂于小鼠双耳致敏，在第7天和第8天用40μL 0.5％的OXA溶液涂于小鼠双耳重复致敏，正常组涂抹相应溶媒。从第12天开始，除正常组外，其余动物用20μl 0.5％的OXA溶液涂于小鼠右耳进行激发，每周两次，正常组涂抹相应溶媒，每次激发24h后测量右耳厚度。除正常组外，其余动物在第13天根据耳厚度的结果随机分为模型组和各化合物组，正常组5只，其余每组10只。在第14天开始给药，每天两次，各给药组动物耳部涂抹20μL浓度为15mg/mL受试药物溶液[乙醇:丙酮＝1:1(v/v)]，正常组、模型组动物涂抹相应溶媒。第29天测量耳厚度后处死，每只动物剪下右耳用8mm打耳器在固定位置获取耳片并进行称重，随后液氮保存耳片，然后加入500μL生理盐水用匀浆机匀浆，离心后取上清，检测上清中的IL-1β、IL-4、IL-5、IL-6和TNF-α浓度并用归一化法计算蛋白浓度。Select male Balb/c mice with a body weight of 24-26g. After the animals are adaptively reared for 7 days, except for the normal group, the rest of the animals are coated with 40 μL 1% OXA solution (dissolved in acetone) on day 0 and day 1. The mice were sensitized to both ears, and 40 μL 0.5% OXA solution was applied to the mice's ears on the 7th and 8th day to repeat the sensitization, and the normal group was smeared with the corresponding solvent. From the 12th day, except for the normal group, other animals were challenged with 20μl 0.5% OXA solution applied to the right ear of the mouse, twice a week, the normal group was smeared with the corresponding solvent, and the thickness of the right ear was measured after each challenge for 24 hours. Except for the normal group, the other animals were randomly divided into the model group and each compound group according to the results of ear thickness on the 13th day, with 5 in the normal group and 10 in each group. Start the administration on the 14th day, twice a day, apply 20μL of 15mg/mL test drug solution [ethanol:acetone=1:1(v/v)] to the ears of animals in each administration group, normal group and model group Apply the corresponding solvent to the animal. On the 29th day, the ear thickness was measured and then sacrificed. Each animal cut off the right ear and used an 8mm ear punch to obtain the ear piece at a fixed position and weigh it. Then the ear piece was stored in liquid nitrogen, and then 500μL of saline was added to homogenize with a homogenizer After centrifugation, the supernatant was taken, and the concentration of IL-1β, IL-4, IL-5, IL-6 and TNF-α in the supernatant was detected and the protein concentration was calculated by the normalization method.
2.实验结果2. Experimental results
由结果可知，与模型组比较，本发明的化合物从第20天开始到给药结束均能显著的降低OXA诱导慢性特应性皮炎小鼠耳厚度和终点耳重量以及耳部炎症因子IL-1β、IL-4、IL-5、IL-6和TNF-α的分泌(P<0.01)。It can be seen from the results that compared with the model group, the compound of the present invention can significantly reduce the ear thickness and end-point ear weight of OXA-induced chronic atopic dermatitis mice and the ear inflammation factor IL-1β from day 20 to the end of administration. , IL-4, IL-5, IL-6 and TNF-α secretion (P<0.01).
对于本领域技术人员显而易见的是，本发明内容并不限于前述说明性实施例，而且可以体现在其它具体形式中而又不偏离其实质特性。因此，预期各实施例在所有方面都被视作说明性的且非限制性的，应参照所附权利要求书，而不是前述实施例，因此，在所附权利要求书等同内容的含义和范围内的所有变化都包括在本发明中。It is obvious to those skilled in the art that the content of the present invention is not limited to the foregoing illustrative embodiments, and may be embodied in other specific forms without departing from its essential characteristics. Therefore, each embodiment is expected to be regarded as illustrative and non-restrictive in all aspects, and the appended claims should be referred to instead of the foregoing embodiments. Therefore, the meaning and scope of equivalent content of the appended claims should be referred to. All changes within are included in the present invention.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。In the description of this specification, descriptions with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples" or "some examples" etc. mean the specific features described in conjunction with the embodiment or example, The structure, material or feature is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above-mentioned terms do not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics can be combined in any one or more embodiments or examples in a suitable manner.
最后，需要注意的是，还有其他方式用来实施本发明。相应地，本发明的实施例是将作为例证进行说明，但并不限于本发明所描述的内容，还可能是在本发明范围内所作的修改或在权利要求中所添加的等同内容。本发明所引用的所有出版物或专利都将作为本发明的参考文献。Finally, it should be noted that there are other ways to implement the present invention. Correspondingly, the embodiments of the present invention will be described as examples, but are not limited to the content described in the present invention, and may also be modifications made within the scope of the present invention or equivalent content added in the claims. All publications or patents cited in the present invention will serve as references in the present invention.

Claims (24)

  1. 一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：A compound that is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable compound represented by formula (I) Accepted salts or their prodrugs:
    Figure PCTCN2021090489-appb-100001
    Figure PCTCN2021090489-appb-100001
    其中：in:
    X为CH或N；X is CH or N;
    Y为-(CH 2) m-C(＝O)-NH-(CR mR n) p-或-(CH 2) m-C(＝O)-O-(CR mR n) p-； Y is -(CH 2 ) m -C(=O)-NH-(CR m R n ) p -or -(CH 2 ) m -C(=O)-O-(CR m R n ) p -;
    A环为C 6-10芳基或5-10个原子组成的杂芳基； Ring A is a C 6-10 aryl group or a heteroaryl group composed of 5-10 atoms;
    R 1为氢、氘、-OR a或-NR cR d； R 1 is hydrogen, deuterium, -OR a or -NR c R d ;
    R 2为C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、C 3-6环烷基-C 1-4烷基、5-7个原子组成的杂环基或(5-7个原子组成的杂环基)-C 1-4烷基；或 R 2 is a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyl group-C 1-4 alkyl group, a heterocyclic group composed of 5-7 atoms Cyclic group or (heterocyclic group consisting of 5-7 atoms) -C 1-4 alkyl; or
    R 2与R a和其相连的原子共同形成5-7个原子组成的杂环基，所述的5-7个原子组成的杂环基任选地被选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、C 1-4烷基、C 1-4烷氧基或卤代C 1-4烷基的取代基所取代； And R a and R 2 which together form a 5-7 atom heterocyclic group of atoms, said heterocyclic group consisting of 5-7 atoms optionally substituted selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl substituents;
    R 3为氢、氘、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 1-6烷基-C(＝O)-、HC(＝O)-、C 1-6烷基-O-C(＝O)-、C 1-6烷基-S(＝O) 2-或C 1-6烷基-C(＝NH)-，其中所述的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 1-6烷基-C(＝O)-、C 1-6烷基-O-C(＝O)-、C 1-6烷基-S(＝O) 2-和C 1-6烷基-C(＝NH)-各自独立任选地被1、2或3个选自氘、F、Cl、Br、I、-OH、-CN或-NH 2的取代基所取代； R 3 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-C(=O)-, HC(=O)-, C 1-6 alkyl-OC(=O)-, C 1-6 alkyl-S(=O) 2 -or C 1-6 alkyl-C(=NH)-, Wherein said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-C(=O)-, C 1- 6 alkyl-OC(=O)-, C 1-6 alkyl-S(=O) 2 -and C 1-6 alkyl-C(=NH)- each independently optionally by 1, 2 or 3 Substituted by a substituent selected from deuterium, F, Cl, Br, I, -OH, -CN or -NH 2;
    R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8和R 9各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、C 1-4烷基-C(＝O)-或C 1-4烷基-S(＝O) 2-； R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 and R 9 are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 ,- NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, C 1-4 alkyl-C(=O)- or C 1-4 alkyl -S(=O) 2 -;
    R a为氢、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基或5-10个原子组成的杂芳基，其中所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或5-10个原子组成的杂环基的取代基所取代； R a is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclic group composed of 5-10 atoms, C 6- 10 aryl groups or heteroaryl groups composed of 5-10 atoms, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, 5- 10-atom heterocyclic group, C 6-10 aryl group and 5-10 atom heteroaryl group are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 5-10 atoms Substituted by the substituent of the cyclic group;
    各R b独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基-OC(＝O)-、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-8环烷基-C 1-6烷基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基、5-10个原子组成的杂芳基、-NR eC(＝O)C 1-6烷基、-NR eR f、-S(＝O) 2-NR eR f、-C(＝O)-NR eR f或-C 1-6烷基-NR eR f，其中所述的C 1-6烷基、C 1-6烷氧基、C 3-8环烷基-C 1-6烷基、C 3-8环烷基、5-10个原子组成的杂环基、C 6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-6烷基、C 1-6烷氨基或C 1-6烷氧基的取代基所取代； Each R b is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, oxo, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkyl-OC(=O)-, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-S(=O) 2 -, C 3-8 cycloalkane -C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 heterocyclic group, C 6-10 aryl, 5-10 heteroaryl, -NR e C (=O)C 1-6 alkyl, -NR e R f , -S(=O) 2 -NR e R f , -C(=O)-NR e R f or -C 1-6 alkyl- NR e R f , wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 A heterocyclic group composed of three atoms, a C 6-10 aryl group and a heteroaryl group composed of 5-10 atoms are each independently optionally selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-6 alkyl, C 1-6 alkylamino or C 1-6 alkoxy substituents;
    R c和R d各自独立地为氢、-OH、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基-C 1-4烷基、C 3-6环烷基、5-7个原子组成的杂环基、(5-7个原子组成的杂环基)-C 1-4烷基、C 1-4烷基-C(＝O)-或C 1-4烷基-S(＝O) 2-； R c and R d are each independently hydrogen, -OH, C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 ring Alkyl group, heterocyclic group composed of 5-7 atoms, (heterocyclic group composed of 5-7 atoms) -C 1-4 alkyl, C 1-4 alkyl -C(=O)-or C 1 -4 alkyl-S(=O) 2 -;
    R e和R f各自独立地为氢、C 1-6烷基、C 1-6烷基-OC(＝O)-、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-8环 烷基、C 6-10芳基、5-10个原子组成的杂环基、5-10个原子组成的杂芳基、11-15个原子组成的杂芳基、C 3-8环烷基-C 1-6烷基、C 6-10芳基-C 1-6烷基、(5-10个原子组成的杂环基)-C 1-6烷基、(5-10个原子组成的杂芳基)-C 1-6烷基或-C 1-6烷基-NR gR j；或者R e和R f与它们相连的N原子一起形成4-7个原子组成的杂环基；其中所述的R e、R f和4-7个原子组成的杂环基各自独立任选地被1、2、3或4个R h所取代； R e and R f are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl-OC(=O)-, C 1-6 alkyl-C(=O)-, C 1-6 Alkyl-S(=O) 2 -, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 heterocyclic group, 5-10 heteroaryl, 11- Heteroaryl composed of 15 atoms, C 3-8 cycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl, (heterocyclic group composed of 5-10 atoms) -C 1-6 alkyl group, (heteroaryl group consisting of 5-10 atoms) -C 1-6 alkyl group or -C 1-6 alkyl group -NR g R j ; or R e and R f are connected to them The N atoms together form a heterocyclic group consisting of 4-7 atoms; wherein said R e , R f and a heterocyclic group consisting of 4-7 atoms are each independently optionally substituted by 1, 2, 3 or 4 Replaced by R h;
    各R h独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基或C 1-4烷氧基； Each R h is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy or C 1 -4 alkoxy;
    R g和R j各自独立地为氢、C 1-4烷基、C 1-4烷基-OC(＝O)-、C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 2-、C 3-6环烷基、C 6-10芳基、5-6个原子组成的杂环基或5-6个原子组成的杂芳基； R g and R j are each independently hydrogen, C 1-4 alkyl, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-C(=O)-, C 1-4 Alkyl-S(=O) 2 -, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 5-6 atoms or heteroaryl group consisting of 5-6 atoms;
    R m和R n各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、C 1-4烷基、卤代C 1-4烷基或-C(＝O)NH 2； R m and R n are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , C 1-4 alkyl, halo C 1-4 alkyl, or -C( =O)NH 2 ;
    各n独立地为0、1、2、3或4；Each n is independently 0, 1, 2, 3, or 4;
    m和p各自独立地为0、1、2或3。m and p are each independently 0, 1, 2, or 3.
  2. 根据权利要求1所述的化合物，其中A环为苯基、萘基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、吲哚基、异吲哚基、
    Figure PCTCN2021090489-appb-100002
    Figure PCTCN2021090489-appb-100003
    The compound according to claim 1, wherein the A ring is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazole Group, oxazolyl, indolyl, isoindolyl,
    Figure PCTCN2021090489-appb-100002
    Figure PCTCN2021090489-appb-100003
  3. 根据权利要求1或2所述的化合物，其中R 3为氢、氘、C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 1-4烷基-C(＝O)-、HC(＝O)-、C 1-4烷基-O-C(＝O)-、C 1-4烷基-S(＝O) 2-或C 1-4烷基-C(＝NH)-，其中所述的C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 1-4烷基-C(＝O)-、C 1-4烷基-O-C(＝O)-、C 1-4烷基-S(＝O) 2-和C 1-4烷基-C(＝NH)-各自独立任选地被1、2或3个选自氘、F、Cl、Br、I、-OH、-CN或-NH 2的取代基所取代。 The compound according to claim 1 or 2, wherein R 3 is hydrogen, deuterium, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1 -4 alkyl-C(=O)-, HC(=O)-, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-S(=O) 2 -or C 1 -4 alkyl-C(=NH)-, wherein said C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkane Group -C(=O)-, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-S(=O) 2 -and C 1-4 alkyl-C(=NH) - each independently is optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH 2 to a substituent group.
  4. 根据权利要求1-3任意一项所述的化合物，其中R a为氢、氘、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基，其中所述的C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、苯基和5-6个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或5-6个原子组成的杂环基的取代基所取代。 The compound of any one of claims 1-3, wherein R a is hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, , Heterocyclic group composed of 5-6 atoms, phenyl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group , C 3-6 cycloalkyl group, 5-6 atom heterocyclic group, phenyl group and 5-6 atom heteroaryl group are each independently optionally selected from deuterium , F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 5 It is substituted by a substituent of a heterocyclic group consisting of -6 atoms.
  5. 根据权利要求1-4任意一项所述的化合物，其中各R b独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、氧代、C 1-4烷基、C 1-4烷氧基、C 1-4烷基-OC(＝O)-、C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 2-、C 3-6环烷基-C 1-4烷基、C 3-6环烷基、5-6个原子组成的杂环基、苯基、5-6个原子组成的杂芳基、-NR eC(＝O)C 1-4烷基、-NR eR f、-S(＝O) 2-NR eR f、-C(＝O)-NR eR f或-C 1-4烷基-NR eR f，其中所述的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基-C 1-4烷基、C 3-6环烷基、苯基、5-6个原子组成的杂环基和5-6个原子组成的杂芳基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、C 1-4烷基、C 1-4烷氨基或C 1-4烷氧基的取代基所取代。 The compound according to any one of claims 1-4, wherein each R b is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, oxo , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-OC(=O)-, C 1-4 alkyl-C(=O)-, C 1-4 alkyl -S(=O) 2 -, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclic group composed of 5-6 atoms, phenyl, 5-6 Heteroaryl group composed of atoms, -NR e C(=O)C 1-4 alkyl, -NR e R f , -S(=O) 2 -NR e R f , -C(=O)-NR e R f or -C 1-4 alkyl-NR e R f , wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 cycloalkyl group, phenyl group, heterocyclic group composed of 5-6 atoms and heteroaryl group composed of 5-6 atoms are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, C 1-4 alkyl, C 1-4 alkylamino or C 1-4 alkoxy substituents replace.
  6. 根据权利要求1-5任意一项所述的化合物，其中R e和R f各自独立地为氢、C 1-4烷基、C 1-4烷基-OC(＝O)-、C 1-4烷基-C(＝O)-、C 1-4烷基-S(＝O) 2-、C 3-6环烷基、C 6-10芳基、5-7个原子组成的杂环基、5-7个原子组成的杂芳基、14-15个原子组成的杂芳基、C 3-6环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、(5-7个原子组成的杂环基)-C 1-4烷基、(5-7个原子组成的杂芳基)-C 1-4烷基或-C 1-4烷基-NR gR j；或者R e和R f与它们相连的N原子 一起形成4-6个原子组成的杂环基；其中所述的R e、R f和4-6个原子组成的杂环基各自独立任选地被1、2、3或4个R h所取代。 The compound according to any one of claims 1-5, wherein R e and R f are each independently hydrogen, C 1-4 alkyl, C 1-4 alkyl-OC(=O)-, C 1- 4 alkyl-C(=O)-, C 1-4 alkyl-S(=O) 2 -, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclic ring composed of 5-7 atoms Group, heteroaryl group consisting of 5-7 atoms, heteroaryl group consisting of 14-15 atoms, C 3-6 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 Alkyl group, (heterocyclic group consisting of 5-7 atoms) -C 1-4 alkyl, (heteroaryl group consisting of 5-7 atoms) -C 1-4 alkyl or -C 1-4 alkyl heterocyclic R e, R f, and 4-6 atoms wherein said composition; 4-6 forming atoms, or a heterocyclic group consisting of R e and R f N atom to which they are attached together; -NR g R j Each of the groups is independently optionally substituted with 1, 2, 3, or 4 R h .
  7. 根据权利要求1-6任意一项所述的化合物，其中R 2为甲基、乙基、正丙基、异丙基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CF 2CH 2CH 3、-CH 2Cl、-CHCl 2、环丙基、环丁基、环戊基、环己基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、四氢吡喃基甲基、四氢呋喃基甲基或吡咯烷基甲基；或 The compound according to any one of claims 1-6, wherein R 2 is methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, piperazine , Piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl or pyrrolidinylmethyl; or
    R 2与R a和其相连的原子共同形成1,3-二氧杂环戊烯、1,3-二氧杂环己烯、2.3-二氢-1,4,2-二噁嗪烯或1,5,3-二氧氮杂环庚烯，所述的1,3-二氧杂环戊烯、1,3-二氧杂环己烯、2.3-二氢-1,4,2-二噁嗪烯或1,5,3-二氧氮杂环庚烯独立任选地被选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CHF 2、-CF 3、-CH 2CHF 2、-CH 2CF 3或-CF 2CH 3的取代基所取代。 R 2 and R a and the atoms to which they are connected together form 1,3-dioxolene, 1,3-dioxolene, 2.3-dihydro-1,4,2-dioxazinene or 1,5,3-dioxazepine, the 1,3-dioxole, 1,3-dioxene, 2.3-dihydro-1,4,2- Dioxazine or 1,5,3-dioxazepin is independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl , N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF 3 or -CF 2 CH 3 substituents.
  8. 根据权利要求1-7任意一项所述的化合物，其中R 3为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、HC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-O-C(＝O)-、乙基-O-C(＝O)-、正丙基-O-C(＝O)-、异丙基-O-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、甲基-C(＝NH)-、乙基-C(＝NH)-、正丙基-C(＝NH)-或异丙基-C(＝NH)-； The compound according to any one of claims 1-7, wherein R 3 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl Group, methoxy, ethoxy, n-propoxy, isopropoxy, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, HC( =O)-, methyl-C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl- OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-S(=O) 2 -, Ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -, isopropyl-S(=O) 2 -, methyl-C(=NH)-, ethyl-C( =NH)-, n-propyl-C(=NH)- or isopropyl-C(=NH)-;
    其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-O-C(＝O)-、乙基-O-C(＝O)-、正丙基-O-C(＝O)-、异丙基-O-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、甲基-C(＝NH)-、乙基-C(＝NH)-、正丙基-C(＝NH)-和异丙基-C(＝NH)-各自独立任选地被1、2或3个选自氘、F、Cl、Br、I、-OH、-CN或-NH 2的取代基所取代。 Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy Base, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, methyl-C(=O)-, ethyl-C(=O)-, N-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O )-, isopropyl-OC(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -, isopropyl Base -S(=O) 2 -, methyl-C(=NH)-, ethyl-C(=NH)-, n-propyl-C(=NH)- and isopropyl-C(=NH) - each independently is optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH 2 to a substituent group.
  9. 根据权利要求1-8任意一项所述的化合物，其中R 4、R 5a、R 5b、R 6、R 7a、R 7b、R 8和R 9各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CF 2CH 2CH 3、-CH 2Cl、-CHCl 2、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-或异丙基-S(＝O) 2-。 The compound according to any one of claims 1-8, wherein R 4 , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 and R 9 are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropyl Oxy, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , methyl-C(=O)-, ethyl-C(=O )-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl -S(=O) 2 -or isopropyl-S(=O) 2 -.
  10. 根据权利要求1-9任意一项所述的化合物，其中R a为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基或噁唑基； Compound according to any one of claims 1-9, wherein R a is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl Base, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piper Ridinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrole Group, pyrazolyl, imidazolyl, thiazolyl or oxazolyl;
    其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、乙烯基、1-丙烯基、2-丙烯基、乙炔基、1-丙炔基、3-丙炔基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基和噁唑基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基或吡咯烷基的取代基所取代。 The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl , Tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl and oxazolyl each independently Optionally by 1, 2, 3 or 4 selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, n-propyl, Isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, sulfur Substituted by morpholinyl, tetrahydropyranyl, tetrahydrofuranyl or pyrrolidinyl substituents.
  11. 根据权利要求1-10任意一项所述的化合物，其中各R b独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、 -NO 2、-COOH、氧代、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、甲基-OC(＝O)-、乙基-OC(＝O)-、正丙基-OC(＝O)-、异丙基-OC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、环丙基甲基、环丙基乙基、环丙基正丙基、环丙基异丙基、环丁基甲基、环戊基甲基、环己基甲基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、-NR eC(＝O)甲基、-NR eC(＝O)乙基、-NR eC(＝O)正丙基、-NR eC(＝O)异丙基、-NR eR f、-S(＝O) 2-NR eR f、-C(＝O)-NR eR f、-甲基-NR eR f、-乙基-NR eR f、-正丙基-NR eR f或-异丙基-NR eR f； The compound according to any one of claims 1-10, wherein each R b is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, oxo , Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl -OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)- , Ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(= O) 2 -, n-propyl-S(=O) 2 -, isopropyl-S(=O) 2 -, cyclopropylmethyl, cyclopropylethyl, cyclopropyl n-propyl, cyclopropyl Isopropyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorph Linyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazole Group, oxazolyl, -NR e C(=O) methyl, -NR e C(=O) ethyl, -NR e C(=O) n-propyl, -NR e C(=O) isopropyl , -NR e R f , -S(=O) 2 -NR e R f , -C(=O)-NR e R f , -methyl-NR e R f , -ethyl-NR e R f , -N-propyl-NR e R f or -isopropyl-NR e R f ;
    其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基甲基、环丙基乙基、环丙基正丙基、环丙基异丙基、环丁基甲基、环戊基甲基、环己基甲基、环丙基、环丁基、环戊基、环己基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基和噁唑基各自独立任选地被1、2、3或4个选自氘、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-COOH、甲基、乙基、正丙基、异丙基、甲氨基、二甲氨基、甲氧基、乙氧基、正丙氧基或异丙氧基的取代基所取代。 Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy Cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl n-propyl, cyclopropyl isopropyl, cyclobutyl methyl, cyclopentyl methyl, cyclohexyl methyl, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazine Group, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl and oxazolyl are each independently optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, methylamino, dimethylamino, methoxy, ethoxy, N-propoxy or isopropoxy substituents.
  12. 根据权利要求1-11任意一项所述的化合物，其中R c和R d各自独立地为氢、-OH、甲基、乙基、正丙基、异丙基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CF 2CH 2CH 3、-CH 2Cl、-CHCl 2、环丙基甲基、环丙基乙基、环丁基甲基、环戊基甲基、环己基甲基、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-或异丙基-S(＝O) 2-。 The compound according to any one of claims 1-11, wherein R c and Rd are each independently hydrogen, -OH, methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CF 2 CH 2 CH 3 , -CH 2 Cl, -CHCl 2 , cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, Methyl-C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -or isopropyl-S(=O) 2 -.
  13. 根据权利要求1-12任意一项所述的化合物，其中R e和R f各自独立地为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲基-OC(＝O)-、乙基-OC(＝O)-、正丙基-OC(＝O)-、异丙基-OC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、异丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、环丙基、环丁基、环戊基、环己基、苯基、萘基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、环丙基甲基、环丙基乙基、环丙基正丙基、环丙基异丙基、环丁基甲基、环戊基甲基、环己基甲基、苯甲基、苯乙基、5-7个原子组成的杂环基-C 1-4烷基、吡啶基甲基、嘧啶基甲基、呋喃基甲基、噻吩基甲基、吡咯基甲基、吡唑基甲基、咪唑基甲基、噻唑基甲基、噁唑基甲基、-甲基-NR gR j、-乙基-NR gR j、-正丙基-NR gR j、-异丙基-NR gR j或
    Figure PCTCN2021090489-appb-100004
    The compound according to any one of claims 1-12, wherein R e and R f are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Group, tert-butyl, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl -C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) 2- , Ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -, isopropyl-S(=O) 2 -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Phenyl, naphthyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazine Base, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, cyclopropylmethyl, cyclopropylethyl, cyclopropyl n-propyl, cyclopropyl isopropyl , Cyclobutyl methyl, cyclopentyl methyl, cyclohexyl methyl, benzyl, phenethyl, 5-7 atoms heterocyclic group -C 1-4 alkyl, pyridyl methyl, pyrimidinyl methyl Group, furyl methyl, thienyl methyl, pyrrolyl methyl, pyrazolyl methyl, imidazolyl methyl, thiazolyl methyl, oxazolyl methyl, -methyl -NR g R j , -ethyl -NR g R j , -n-propyl-NR g R j , -isopropyl-NR g R j or
    Figure PCTCN2021090489-appb-100004
    或者R e和R f与它们相连的N原子一起形成氮杂环丁基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基或哌嗪基； Or R e and R f together with the N atom to which they are connected form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
    其中所述的R e、R f、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基和哌嗪基各自独立任选地被1、2、3或4个R h所取代。 Wherein said R e , R f , azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently optionally substituted by 1, 2, 3 or 4 Replaced by R h.
  14. 根据权利要求1-13任意一项所述的化合物，其中各R h独立地为氘、F、Cl、Br、I、-OH、-CN、-NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、三氟甲氧基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基； The compound according to any one of claims 1-13, wherein each R h is independently deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl, n-propyl , Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, N-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
    R g和R j各自独立地为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲基-OC(＝O)-、乙基-OC(＝O)-、正丙基-OC(＝O)-、异丙基-OC(＝O)-、甲基-C(＝O)-、乙基-C(＝O)-、正丙基-C(＝O)-、甲基-S(＝O) 2-、乙基-S(＝O) 2-、正丙基-S(＝O) 2-、异丙基-S(＝O) 2-、异丙基-C(＝O)-、环丙基、环丁基、环戊基、环己基、苯 基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、四氢呋喃基、吡咯烷基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噻唑基或噁唑基； R g and R j are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl-OC(=O)- , Ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, ethyl-C(=O) )-, n-propyl-C(=O)-, methyl-S(=O) 2 -, ethyl-S(=O) 2 -, n-propyl-S(=O) 2 -, isopropyl Base -S(=O) 2 -, isopropyl-C(=O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, piperazinyl, piperidinyl, morpholinyl , Thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, Thiazolyl or oxazolyl;
    R m和R n各自独立地为氢、氘、F、Cl、Br、I、-OH、-CN、-NH 2、甲基、乙基、正丙基、异丙基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CF 2CH 3、-CH 2Cl、-CHCl 2或-C(＝O)NH 2。 R m and R n are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 Cl, -CHCl 2 or -C(=O)NH 2 .
  15. 根据权利要求1-14任意一项所述的化合物，其为式(II)或(III)所示的化合物，或式(II)或(III)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：The compound according to any one of claims 1-14, which is a compound represented by formula (II) or (III), or a stereoisomer or tautomer of a compound represented by formula (II) or (III) Constructs, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs:
    Figure PCTCN2021090489-appb-100005
    Figure PCTCN2021090489-appb-100005
  16. 一种化合物，其为具有下列之一结构的化合物或具有下列之一结构化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药：A compound that is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable compound of one of the following structures Salts or their prodrugs:
    Figure PCTCN2021090489-appb-100006
    Figure PCTCN2021090489-appb-100006
    Figure PCTCN2021090489-appb-100007
    Figure PCTCN2021090489-appb-100007
    Figure PCTCN2021090489-appb-100008
    Figure PCTCN2021090489-appb-100008
    Figure PCTCN2021090489-appb-100009
    Figure PCTCN2021090489-appb-100009
    Figure PCTCN2021090489-appb-100010
    Figure PCTCN2021090489-appb-100010
    Figure PCTCN2021090489-appb-100011
    Figure PCTCN2021090489-appb-100011
    Figure PCTCN2021090489-appb-100012
    Figure PCTCN2021090489-appb-100012
    Figure PCTCN2021090489-appb-100013
    Figure PCTCN2021090489-appb-100013
    Figure PCTCN2021090489-appb-100014
    Figure PCTCN2021090489-appb-100014
    Figure PCTCN2021090489-appb-100015
    Figure PCTCN2021090489-appb-100015
    Figure PCTCN2021090489-appb-100016
    Figure PCTCN2021090489-appb-100016
    Figure PCTCN2021090489-appb-100017
    Figure PCTCN2021090489-appb-100017
    Figure PCTCN2021090489-appb-100018
    Figure PCTCN2021090489-appb-100018
    Figure PCTCN2021090489-appb-100019
    Figure PCTCN2021090489-appb-100019
    Figure PCTCN2021090489-appb-100020
    Figure PCTCN2021090489-appb-100020
    Figure PCTCN2021090489-appb-100021
    Figure PCTCN2021090489-appb-100021
    Figure PCTCN2021090489-appb-100022
    Figure PCTCN2021090489-appb-100022
    Figure PCTCN2021090489-appb-100023
    Figure PCTCN2021090489-appb-100023
  17. 一种药物组合物，包含权利要求1-16任意一项所述的化合物，其进一步地包含药学上可接受的载体、赋形剂、附加剂、辅剂或媒介物中的至少一种。A pharmaceutical composition comprising the compound of any one of claims 1-16, which further comprises at least one of a pharmaceutically acceptable carrier, excipient, adjuvant, adjuvant or vehicle.
  18. 根据权利要求17所述的药物组合物，其进一步地包含附加治疗剂，其中所述的附加治疗剂是：丙酮酸钠、多索茶碱、替托司特、泰鲁司特、茶碱、福莫特罗、沙美特罗、氟替卡松丙酸酯、咯利普兰、吡拉米斯特、西洛司特、茚达特罗、奥达特罗、米地司坦、齐流通、沙丁醇胺、卡莫昔罗、布地奈德、二丙酸倍氯米松、氟尼缩松、罗氟奈德、环索奈德、异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、芜地溴铵、维兰特罗、阿地溴铵、Benralizumab、Tralokinumab、瑞伐托酯、克瑞沙硼、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、曲安奈德、地索奈德、氢化可的松、氯倍他索、卤贝他索、糠酸莫米松、二氟拉松、美普克莱、他克莫司、吡美莫司、他扎罗汀、环孢素、阿普斯特、E-6005、OPA-15406、LEO-29102、DRM02、罗氟司特、异丁司特、托法替尼、JTE-052、巴瑞替尼、乌帕替尼、WBI-1001、MRX-6、GSK2981278、杜鲁单抗、来金珠单抗、尼莫利珠单抗、曲洛吉努单抗、依那西普、阿达木单抗、英夫利 昔单抗、尤特可单抗、塞库吉努、奥马珠、CIM-331、戈利木单抗和聚乙二醇化赛、妥珠单抗、卡泊三醇、骨化三醇、阿利维A酸、VTP-38543、ZPL-389、阿瑞匹坦、曲地匹坦、弗维普兰特、OC-459、SUN 13834、SB-011、VTP-43742、ARN6039、TAK-828、JTE-451、PF-04965842、PF-06651600、PF-06700841、PF-06650833、GR-MD-02或它们的组合。The pharmaceutical composition according to claim 17, further comprising an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, telukast, theophylline, Formoterol, salmeterol, fluticasone propionate, rolipram, piramistrol, cilomilast, indacaterol, odacaterol, midistein, qi circulation, salbutanol Amines, carmoxirol, budesonide, beclomethasone dipropionate, flunisolide, rofluonide, ciclesonide, ipratropium bromide, oxotropium bromide, tiotropium bromide, grating Methylpyrrolate, umeclidinium, vilanterol, aclidinium bromide, Benralizumab, Tralokinumab, Revatroxate, Cresaboron, Fluocinolone Acetate, Dexamethasone, Mometasone, Triamcinolone , Betamethasone, Alclomethasone, Triamcinolone Acetonide, Dessonide, Hydrocortisone, Clobetasol, Halobetasol, Mometasone Furoate, Diflurazone, Meplaxil, Taco Moss, pimecrolimus, tazarotene, cyclosporine, apremilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, ibudilast, tofacitinib , JTE-052, Baritinib, Upatinib, WBI-1001, MRX-6, GSK2981278, Duluzumab, Lekinizumab, Nimolizumab, Traloginumab, Etanercept, Adalimumab, Infliximab, Utecomumab, Secugenu, Omazu, CIM-331, Golimumab and Pegylation, Tuzumab , Calcipotriol, Calcitriol, Aliretinoin, VTP-38543, ZPL-389, Aprepitant, Tridipitan, Fuviplante, OC-459, SUN 13834, SB-011 VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02 or their combination.
  19. 权利要求1-16任意一项所述的化合物或权利要求17-18所述的药物组合物在制备药物中的用途，其中所述药物用于预防、治疗或减轻与4型磷酸二酯酶有关的疾病。The use of the compound of any one of claims 1-16 or the pharmaceutical composition of claims 17-18 in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate the type 4 phosphodiesterase related Disease.
  20. 根据权利要求19所述的用途，其中所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病或非胰岛素依赖糖尿病；The use according to claim 19, wherein the disease related to type 4 phosphodiesterase is respiratory disease, allergy, inflammation, central nervous system disease or non-insulin dependent diabetes;
    其中所述的呼吸疾病为：慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症；其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎；The respiratory diseases mentioned are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or Respiratory tract inflammation; among which bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;
    其中所述的炎症为：过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。The inflammation mentioned is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatic Arthritis or psoriatic arthritis.
  21. 一种预防、治疗或减轻与4型磷酸二酯酶有关的疾病的方法，其包含给予患者权利要求1-16任意一项所述的化合物或权利要求17-18任意一项所述的药物组合物的有效治疗量。A method for preventing, treating or alleviating diseases related to type 4 phosphodiesterase, which comprises administering to a patient the compound of any one of claims 1-16 or the drug combination of any one of claims 17-18 The effective therapeutic amount of the substance.
  22. 根据权利要求21所述的方法，其中所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病或非胰岛素依赖糖尿病；The method according to claim 21, wherein the disease related to type 4 phosphodiesterase is respiratory disease, allergy, inflammation, central nervous system disease or non-insulin dependent diabetes;
    其中所述的呼吸疾病为：慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症；其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎；The respiratory diseases mentioned are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or Respiratory tract inflammation; among which bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;
    其中所述的炎症为：过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。The inflammation mentioned is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatic Arthritis or psoriatic arthritis.
  23. 根据权利要求1-16任意一项所述的化合物或权利要求17-18任意一项所述的药物组合物用于预防、治疗或减轻患者4型磷酸二酯酶有关的疾病。The compound according to any one of claims 1-16 or the pharmaceutical composition according to any one of claims 17-18 is used to prevent, treat or alleviate a patient's type 4 phosphodiesterase related diseases.
  24. 根据权利要求23所述的化合物或组合物，其中所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病或非胰岛素依赖糖尿病；The compound or composition according to claim 23, wherein the disease related to type 4 phosphodiesterase is respiratory disease, allergy, inflammation, central nervous system disease or non-insulin dependent diabetes;
    其中所述的呼吸疾病为：慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症；其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎；The respiratory diseases mentioned are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or Respiratory tract inflammation; among which bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;
    其中所述的炎症为：过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。The inflammation mentioned is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatic Arthritis or psoriatic arthritis.
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