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WO2021218992A1 - Composé pyrrolidine substitué et son utilisation en médecine - Google Patents

Composé pyrrolidine substitué et son utilisation en médecine Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
alkyl
methyl
group
ethyl
isopropyl
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PCT/CN2021/090489
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English (en)
Chinese (zh)
Inventor
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/fr

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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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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
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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

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Abstract

L'invention concerne un composé pyrrolidine substitué et son utilisation en médecine. En particulier, l'invention concerne un composé pyrrolidine substitué ou un stéréoisomère, un tautomère, un oxyde d'azote, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable de celui-ci ou un promédicament de celui-ci, et une composition pharmaceutique contenant le composé susmentionné. L'invention concerne également l'utilisation du composé susmentionné ou de la composition pharmaceutique de celui-ci dans la préparation d'un médicament, le médicament étant utilisé pour traiter des maladies liées à PDE4, telles que la dermatite atopique (AD) ou la bronchopneumopathie chronique obstructive (BPCO).
PCT/CN2021/090489 2020-04-29 2021-04-28 Composé pyrrolidine substitué et son utilisation en médecine WO2021218992A1 (fr)

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