WO2021218997A1 - 取代的氮杂五元环类化合物及其在药物中的应用 - Google Patents
取代的氮杂五元环类化合物及其在药物中的应用 Download PDFInfo
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- WO2021218997A1 WO2021218997A1 PCT/CN2021/090515 CN2021090515W WO2021218997A1 WO 2021218997 A1 WO2021218997 A1 WO 2021218997A1 CN 2021090515 W CN2021090515 W CN 2021090515W WO 2021218997 A1 WO2021218997 A1 WO 2021218997A1
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- Prior art keywords
- alkylene
- alkyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D207/08—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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- 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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- C07F5/02—Boron compounds
Definitions
- the invention belongs to the field of medicine, and specifically relates to substituted aza five-membered ring compounds, pharmaceutical compositions containing the compounds, and uses and methods of use in medicines.
- the compounds of the present invention are PDE4 inhibitors, which are used to treat PDE4-related diseases, such as atopic dermatitis (AD) 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 to the corresponding inactive adenosine 5-phosphate, thereby affecting various metabolic functions of the organism. 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,
- R 4 is -(CH 2 ) m -L-(CH 2 ) n -G;
- each of R x and R y is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, and 3-10 atoms.
- G is a C 3-8 cycloalkyl group, a C 6-10 aryl group, a heterocyclic group composed of 3-10 atoms, or a heteroaryl group composed of 5-10 atoms; wherein G is unsubstituted or is 1, 2, Replaced by 3 or 4 R 7;
- Each R a and R b is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, and a heterocyclic group consisting of 3-10 atoms.
- Each R d and R e are independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, and a heterocyclic group composed of 3-10 atoms.
- Each R c is independently hydrogen, deuterium, C 1-3 alkyl or C 1-3 haloalkyl;
- R is hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 1 -3 haloalkyl;
- R 5a , R 5b , R 6a and R 6b are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, C 1-3 alkyl, C 1-3 alkane Oxy, C 1-3 haloalkoxy or C 1-3 haloalkyl;
- t 1 or 2;
- n 0, 1, 2, 3 or 4;
- n 1, 2, 3, or 4.
- the compound of the present invention 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 and their prodrugs:
- each of R 1 , R 2 , R 3 , R 5a , R 5b , R 6a , R 6b , R, G, L and n has the meaning as described in the present invention.
- the compound of the present invention is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (III) , Metabolites, pharmaceutically acceptable salts and their prodrugs:
- each of R 1 , R 2 , R 3 , R 5a , R 5b , R 6a , R 6b , R, G, L and n has the meaning as described in the present invention.
- Each R 6 is independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, 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 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 Cl, -CHCl 2 , methoxy, ethoxy, n-propyloxy, methylamino, ethylamino or n-propylamino.
- each R x and R y is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C 1-4 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl group, a cyclohexyl group, -C 1-3 alkylene cyclopropyl, cyclobutyl -C 1-3 alkylene, -C 1-3 alkylene cyclopentyl, cyclohexyl, -C 1- 3 alkylene Base, phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidine Group, morpholinyl, thiomorpholinyl, tetrahydropyranyl
- G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Wherein G is unsubstituted or substituted by 1, 2, 3 or 4 R 7 ;
- each R a and R b is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 Cl,- CHCl 2 , phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piper Ridinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidiny
- the present invention provides a pharmaceutical composition comprising the compound of the present invention.
- composition of the present invention which further comprises at least one of pharmaceutically acceptable carriers, excipients, adjuvants, adjuvants and vehicles.
- composition of the present invention which further comprises an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, tylukast , 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, Tralokin
- the present invention provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine is used to prevent, treat or alleviate diseases related to phosphodiesterase type 4 .
- the disease related to type 4 phosphodiesterase is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin dependent diabetes;
- the respiratory diseases mentioned are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or Respiratory tract inflammation; among which bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;
- 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.
- the present invention provides a method for preventing, treating or alleviating a type 4 phosphodiesterase-related disease, which comprises administering to a patient an effective therapeutic amount of the compound of the present invention or the pharmaceutical composition of the present invention .
- Some of the embodiments are the method of the present invention, wherein the disease related to type 4 phosphodiesterase is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin dependent diabetes;
- the respiratory diseases mentioned are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or Respiratory tract inflammation; among which bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;
- 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.
- the present invention provides the compound of the present invention or the pharmaceutical composition of the present invention for preventing, treating or alleviating a patient's type 4 phosphodiesterase related diseases.
- the compound or pharmaceutical composition of the present invention is used to prevent, treat or alleviate a patient's type 4 phosphodiesterase-related disease, wherein the type 4 phosphodiesterase-related disease is a respiratory disease , Allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin dependent diabetes;
- the respiratory diseases mentioned are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or Respiratory tract inflammation; among which bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;
- 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) or (III).
- 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.
- 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 by one or more substituents described in the present invention, wherein the substituents are deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, amino, carboxy, azido, aryl, hetero Aryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, haloalkyl , Haloalkoxy, hydroxy-substituted alkyl, hydroxy-substituted alkoxy, amino-substituted alkyl, cyano-substituted alkyl, hydroxy-substitute
- alkyl groups contain 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in still other embodiments, the alkyl group contains 1 -4 carbon atoms; also in some embodiments, 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 some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group The group contains 1-3 carbon atoms; still in some embodiments, 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 other embodiments, the alkenyl group contains 2-6 carbon atoms; in still other embodiments, 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 other embodiments, the alkynyl group contains 2-6 carbon atoms; in still other embodiments, 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, B and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or nitrogen atoms in heterocycles
- the form where the hydrogen is substituted for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl) NR in).
- 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 some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in still other embodiments, 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-(
- alkylamino means that the two hydrogen atoms on the amino group (-NH 2 ) are independently optionally substituted by the same or different alkyl groups, including N-alkylamino or N'N-dialkylamino, Wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkylamino group contains 1-12 carbon atoms. In some embodiments, the alkylamino group contains 1-6 carbon atoms; in other embodiments, the alkylamino group contains 1-4 carbon atoms; in still other embodiments, the alkylamino group contains 1 -3 carbon atoms. The alkylamino group may be optionally substituted with one or more substituents described in this invention.
- alkylamino groups include, but are not limited to, N-methylamino (-NHCH 3 ), N-ethylamino (-NHCH 2 CH 3 ), N'N-dimethylamino (-N(CH 3 ) 2 ), N'N-diethylamino (-N(CH 2 CH 3 ) 2 ), N'N-methylethylamino N'N-methyl isopropylamino and many more.
- 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 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 Cl, -CHCl 2 , etc.
- 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 some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms; in still other embodiments, 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. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- cycloalkylalkyl 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 cycloalkane
- the group has the meaning as described in the present invention, such examples include, but are not limited to cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene Ethyl, cyclopentyl-methylene, cyclopentyl-ethylene, cyclohexyl-methylene, cyclohexyl-ethylene and the like.
- 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, phosphorus, sulfur, boron, 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-dioxanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl , Tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl , Piperazinyl
- 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.
- heterocyclylalkyl 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 meanings described in the present invention .
- examples of this include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-ylmethyl, pyrrolidin-2-ylmethyl, and Lin-4-ylmethyl and so on.
- 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.
- arylalkyl or “aryl-alkylene” can be used interchangeably, and both refer to an alkyl group substituted with one or more aryl groups, wherein the aryl and alkyl groups have those 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 aryl group refers to an alkyl group "phenylalkyl” containing C 1- 4 alkyl. Specific examples thereof include diphenylmethyl, phenylmethylene, and phenylethylene.
- the aryl group on the arylalkyl group or arylalkylene group may be further substituted with the substituents described in the present invention.
- heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-7 ring atoms, in which at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system 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.
- 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
- heteroarylalkyl or “heteroarylalkylene” can be used interchangeably, and both refer to the alkyl group being substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups have the characteristics of Within the meaning of the invention, such examples include, but are not limited to, imidazol-2-ylmethylene, furan-2-ylethylene, indol-3-ylmethylene and the like.
- 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.
- R 4 is -(CH 2 ) m -L-(CH 2 ) n -G, wherein the left and right bonds of the L group are interchangeably connected to (CH 2 ) m and (CH 2 ) n Above;
- -(CH 2 ) m -L-(CH 2 ) n -G is defined as the left end of L connected (CH 2 ) m while the right end of L is connected (CH 2 ) n , and the left end of L Connect (CH 2 ) n and connect the right end of L to (CH 2 ) m at the same time.
- 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.
- hydrate refers to the association formed by the solvent molecule being water.
- 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 pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. Generally speaking, such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxide, carbonate, bicarbonate, etc.) of Na, Ca, Mg or K, or by reacting These compounds are prepared by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
- a suitable base such as hydroxide, carbonate, bicarbonate, etc.
- non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
- a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
- 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 a new substituted aza five-membered ring compound and the use of the compound in medicine.
- the compound of the present invention or the pharmaceutical composition containing the compound, as a PDE4 inhibitor, has a good therapeutic effect on atopic dermatitis.
- 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:
- each of R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , X, X 1 and R has the meaning described in the present invention.
- R 4 is -(CH 2 ) m -L-(CH 2 ) n -G;
- each of R x and R y is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, and 3-10 atoms.
- G is C 3-8 cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 3-10 atoms or heteroaryl group composed of 5-10 atoms; wherein G is unsubsti
- Each R a and R b is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, and a heterocyclic group consisting of 3-10 atoms.
- Each R d and R e are independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, and a heterocyclic group composed of 3-10 atoms.
- Each R c is independently hydrogen, deuterium, C 1-3 alkyl or C 1-3 haloalkyl;
- R is hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 1 -3 haloalkyl;
- R 5a , R 5b , R 6a and R 6b are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, C 1-3 alkyl, C 1-3 alkane Oxy, C 1-3 haloalkoxy or C 1-3 haloalkyl;
- t 1 or 2;
- n 0, 1, 2, 3 or 4;
- n 1, 2, 3, or 4.
- the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, compound represented by formula (II), Solvates, metabolites, pharmaceutically acceptable salts or their prodrugs:
- each of R 1 , R 2 , R 3 , R 5a , R 5b , R 6a , R 6b , R, L, n, and G has the meaning described in the present invention.
- the present invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, compound represented by formula (III), Solvates, metabolites, pharmaceutically acceptable salts or their prodrugs:
- each of R 1 , R 2 , R 3 , R 5a , R 5b , R 6a , R 6b , R, G, L and n has the meaning as described in the present invention.
- the present invention relates to a compound, which is a compound represented by formula (IV) or a stereoisomer, tautomer, nitrogen oxide, hydrate, compound represented by formula (IV), Solvates, metabolites, pharmaceutically acceptable salts or their prodrugs:
- each of R 1 , R 2 , R 3 , R 5a , R 5b , R 6a , R 6b , R, L, n, and G has the meaning described in the present invention.
- the present invention relates to a compound, which is a compound represented by formula (V) or a stereoisomer, tautomer, nitrogen oxide, hydrate, compound represented by formula (V), Solvates, metabolites, pharmaceutically acceptable salts or their prodrugs:
- each of R 1 , R 2 , R 3 , R 5a , R 5b , R 6a , R 6b , R, G, L and n has the meaning as described in the present invention.
- the present invention relates to a compound, which is a compound represented by formula (VI) or a stereoisomer, tautomer, nitrogen oxide, hydrate, compound represented by formula (VI), Solvates, metabolites, pharmaceutically acceptable salts or their prodrugs:
- each of R 1 , R 2 , R 3 , R 5a , R 5b , R 6a , R 6b , R, G, L and n has the meaning as described in the present invention.
- the present invention relates to a compound, which is a compound represented by formula (VII) or a stereoisomer, tautomer, nitrogen oxide, hydrate, compound represented by formula (VII), Solvates, metabolites, pharmaceutically acceptable salts or their prodrugs:
- each of R 1 , R 2 , R 3 , R 5a , R 5b , R 6a , R 6b , R, G, L and n has the meaning as described in the present invention.
- each R 6 is independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, 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 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 ,- CH 2 CH 2 CF 3 , -CH 2 Cl, -CHCl 2 , methoxy, ethoxy, n-propyloxy, methylamino, ethylamino, or n-propylamino.
- each R x is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C 1-4 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, ring Hexyl, cyclopropyl-C 1-3 alkylene, cyclobutyl-C 1-3 alkylene, cyclopentyl-C 1-3 alkylene, cyclohexyl-C 1-3 alkylene, benzene Base, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, Linyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C
- each R y is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C 1-4 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, ring Hexyl, cyclopropyl-C 1-3 alkylene, cyclobutyl-C 1-3 alkylene, cyclopentyl-C 1-3 alkylene, cyclohexyl-C 1-3 alkylene, benzene Base, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, Linyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C
- G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Wherein G is unsubstituted or substituted by 1, 2, 3 or 4 R 7 ; wherein, each R 7 has the meaning described in the present invention.
- each R a and R b is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 Cl,- CHCl 2 , phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piper Ridinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidiny
- each R c is independently hydrogen, deuterium, C 1-3 alkyl, or C 1-3 haloalkyl.
- R is hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethyl Oxy, n-propoxy, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl or -CHCl 2 .
- R 5a , R 5b , R 6a and R 6b are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, methyl, ethyl, N-propyl, isopropyl, methoxy, ethoxy, n-propoxy, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl or -CHCl 2 .
- 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:
- Some of the embodiments are the compounds represented by formulas (I), (II), (III), (IV), (V), (VI) and (VII) of the present invention, and the pharmaceutically acceptable salt thereof is a salt Acid salt, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2- Hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamine Acid salt, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, triflate, or combinations thereof.
- a salt Acid salt hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising the formula (I), (II), (III), (IV), (V), (VI) or (VII) disclosed in the present invention The compound.
- composition of the present invention which 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, odacaterol, midistein, qi circulation, Salbutanolamine, carmoxirol, budesonide, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, rofluonide, ciclesonide, ipratropium bromide , Oxotropium bromide, tiotropium bromide, glycopyrrolate, umeclidinium bromide, vilanterol, aclidinium bromide, Benralizumab, Tralokin
- the additional therapeutic agent
- the present invention relates to the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) or its pharmaceutical composition disclosed in the present invention for preparing medicine
- the drug is used to prevent, treat or alleviate diseases related to phosphodiesterase type 4 (PDE4).
- the disease related to phosphodiesterase type 4 is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis 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), (VI) or (VII).
- 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, adsorbent, adjuvant or vehicle, and optionally, other treatments and/or Preventive ingredients.
- 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).
- any suitable route of administration can be used to provide an effective dose of the compound of the present invention to mammals, especially humans.
- oral administration rectal administration, parenteral administration, topical administration, intraocular administration, transnasal administration, transpulmonary administration, etc.
- Dosage forms include tablets, lozenges, capsules, creams, ointments, suspensions, dispersions, solutions, aerosols and the like.
- the compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered by inhalation or topical administration.
- 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 the dosage regimen, administered several times at different time intervals within a specified time period. For example, it may be administered once, twice, three or four times a day. In some embodiments, it is administered once a day. In still other embodiments, 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 a skilled person should also understand that the response of an individual patient to the dosing regimen, or when the individual patient's needs change over time, may require adjustment of an 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 dose range described in the present invention) and other pharmaceutically active agents (within the dose 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, desoxymethasone, momethasone Metaxone, Triamcinolone, Betamethasone, Alclomethasone, Dessonide, Hydrocortisone, Mepaclione;
- Anticholinergic or antimuscarinic drugs such as ipratropium bromide, oxytropium bromide, tiotropium bromide, glycopyrrolate, revatorate;
- Local calcineurin inhibitors such as tacrolimus, pimecrolimus, cyclosporine;
- Topical preparations of PDE4 inhibitors for example, apremilast, ibudilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, crexabor;
- Topical preparations of JAK kinase inhibitors such as tofacitinib, JTE-052, baritinib, and upatinib;
- Local non-steroidal anti-inflammatory drugs such as WBI-1001, MRX-6;
- Local ROR agents such as GSK2981278
- Injectable anti-IL4, IL-31, IL-22, IL-33, IL-12, IL-23, IL-17, IgE, IL-4 therapeutic drugs such as Dupilumab (Dupilumab), Lekinzumab Antibody, Nemolizumab (Nemolizumab), troroginumab, etanercept, adalimumab, infliximab, utekizumab, Secukinumab, Omar Beads (Omazumilab), CIM-331;
- Vitamin D analogs such as calcipotriol and calcitriol
- Oral retinoic acid derivatives such as alitretinoin
- Oral liver X receptor (LXR) selective agonist such as VTP-38543;
- Oral H4 receptor antagonist 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), (II), (III), (IV), (V), (VI) or (VII) is administered alone or in combination with other active ingredients for prevention and / Or treatment of 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.
- Compound (IA) can be prepared by the above synthetic route, wherein R 1 , R 2 , R 3 , X, X 1 , R 5a , R 5b , R 6a , R 6b , R, n and G have the definitions of the present invention .
- Compound (IA-1) and HOOC(CH 2 )nG undergo an esterification reaction under alkaline or acidic conditions to obtain compound (IA).
- Compound (IB) can be prepared by the above synthetic route, wherein R 1 , R 2 , R 3 , X, X 1 , R 5a , R 5b , R 6a , R 6b , R, n and G have the definitions of the present invention .
- Compound (IB-1) or its salt (such as hydrochloride, etc.) undergoes condensation reaction with HOOC(CH 2 )nG under suitable conditions to obtain compound (IB).
- Intermediate N can be prepared by an intermediate synthesis method, wherein, unless otherwise specified, R 1 and R 2 have the meanings as described in the present invention.
- the starting material N1 reacts with the material BnOH and diphenyl azide phosphate under alkaline conditions to form an amino protecting group to obtain intermediate N2, intermediate N2 is reduced by catalytic hydrogenation to obtain intermediate N3, and intermediate N3 is diazotized
- the reaction is followed by a substitution reaction with potassium iodide to obtain intermediate N; the corresponding group R 1 is removed from intermediate N under acidic conditions to obtain intermediate N4, and intermediate N4 is substituted with benzyl bromide to obtain intermediate N'.
- Benzyl (3-cyclopropylmethoxy-4-difluoromethoxy)phenyl)carbamate (145mg, 0.45mmol) was dissolved in anhydrous methanol (6mL), palladium on carbon (50mg) was added, Exclude air, pass in hydrogen, and 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%.
- the intermediate M can be prepared by the above two synthetic routes, wherein X is a halogen, and R 1 , R 2 and R 3 have the meanings as described in the present invention.
- the starting material M1 undergoes enolization under alkaline conditions (such as lithium hydroxide, potassium hydroxide, etc.) and then undergoes substitution reaction to obtain intermediate M2.
- Intermediate M2 and pinacol diborate are passed through boron under alkaline conditions.
- Compound M3, M3 and intermediate N'(Route 1) or intermediate N (Route 2) are obtained through suzuki coupling reaction to obtain intermediates M4-1 and M4-6, respectively.
- Route 1 is intermediate M4.
- the intermediate M4-2 is obtained through deprotection and salt formation reaction, and then the intermediate M4- is obtained by substitution reaction under alkaline conditions (such as triethylamine, N,N-diisopropylethylamine, etc.) 3.
- intermediate M4-4 Subsequent catalytic hydrogenation reduction is carried out to obtain intermediate M4-4, and finally the substitution reaction takes place under alkaline conditions to obtain intermediate M4-5; and the second route is that intermediate M4-6 is first catalytically hydrogenated and reduced under the action of palladium on carbon.
- Intermediate M4-7 is obtained, and the intermediate M4-8 is obtained through deprotection, and finally substituted under basic conditions (such as triethylamine, N,N-diisopropylethylamine, etc.) to obtain Intermediate M4 -9;
- M4-5 or M4-9 undergoes reduction reaction, halogenation reaction, azide reaction, hydrogenation reduction, etc. to finally obtain intermediate M.
- the synthesis method of the intermediate M is only an example of a specific synthesis method, and the synthesis method of the intermediate M referred to in the present invention should include, but is not limited to the following specific examples.
- the intermediate M in the present invention is not limited to a specific compound, and within the scope allowed by the substituents in the present invention, the same or different intermediate M will be optionally prepared in each specific embodiment.
- Example 7 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)carbamoyl)benzoic acid
- Example 8 N 1 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)-N 4 -Ethyl-N 4 -Methylterephthalamide
- Example 10 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)carbamoyl))nicotinic acid hydrochloride
- Example 12 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)carbamoyl))methylpicolinate
- Example 14 N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)-N 6 -ethyl-N 6 -picoline-2,6-dimethylamide
- Example 17 N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)-N 5 -isopropyl-N 5 -picoline-2,5-dimethylamide
- Example 18 N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)-N 5 -(4-fluorophenyl)-N 5 -picoline-2,5-dimethylamide
- Example 19 N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)-N 5 -(2-(dimethylamino)ethyl)-N 5 -picoline-2,5-dimethylamide
- Example 20 N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)-N 5 -Methyl-N 5 -(2,2,2-trifluoroethyl)pyridine-2,5-dimethylamide
- Example 21 N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)-N 5 -(cyanomethyl)-N 5 -picoline-2,5-dimethylamide
- Example 22 N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)-N 5 -(2-Amino-2-oxoethyl)-N 5 -methylpyridine-2,5-dimethylamide
- Example 23 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)amino)o-methoxybenzamide
- Step 3 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl) (Methyl) amino) o-methoxybenzamide synthesis
- Example 24 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)amino)o-methylaminobenzamide
- Step 1 Synthesis of methyl o-methylaminobenzoate
- Step 3 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl) Synthesis of (Methyl)amino)o-methylaminobenzamide
- Example 25 1-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)carbamoyl)piperidine-4-carboxylic acid
- Step 1 1-((((2R)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl) (Methyl)carbamoyl)piperidine-4-carboxylic acid methyl ester
- Step 2 1-((((2R)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl) (Methyl)carbamoyl)piperidine-4-carboxylic acid
- Step 1 Compound (S)-1-tert-butyl 2-methyl 4-((trifluoromethyl)sulfonyl)oxy-1H-pyrrole-1,2(2H,5H)-dicarboxylate synthesis
- 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)-pyrrole-1,2- Synthesis of dicarboxylic acid esters
- Step 6 Compound (2S)-tert-Butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1- Synthesis of carboxylic acid esters
- Step 7 Synthesis of compound (2S)-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride ( 11162-4)
- Step 8 Compound 1-((2S)-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1- Synthesis of ethyl ketone
- Step 9 Compound 1-((2S)-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl) Synthesis of ethyl ketone hydrochloride
- Step 10 Compound N-(((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidin-2-yl )Methyl)-2-ethoxybenzamide synthesis
- Example 38 Synthesis of N 2 -(((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- (Yl)methyl)-N 5 -ethyl-N 5 -picoline-2,5-dimethylamide
- Step 1 Compound 6-((((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)carbamoyl)Methyl nicotinate
- Step 2 Compound 6-((((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)carbamoyl)nicotinic acid
- Step 3 Compound N 2 -(((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )Methyl)-N 5 -Ethyl-N 5 -Methylpyridine-2,5-Dicarboxamide Synthesis
- Example 39 N 2 -(((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -(Yl)methyl)-N 5 -ethyl-N 5 -picoline-2,5-dimethylamide
- Step 1 Compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-di Synthesis of oxolaborane
- Step 3 (2R,4S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2 -Synthesis of dicarboxylic acid esters
- Step 5 Compound (2R,4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl Of pyrrolidine-1-carboxylic acid tert-butyl ester
- Step 6 Compound (2R,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1- Synthesis of tert-butyl carboxylate
- Step 7 Compound (2R,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride Synthesis
- Step 8 Compound 1-((2R,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine -1-yl) Synthesis of ethyl ketone
- Step 9 Compound 1-((2R,4S)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- Synthesis of 1-yl) ethyl ketone hydrochloride
- Step 10 N 2 -(((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- (Yl)methyl)-N 5 -ethyl-N 5 -methylpyridine-2,5-dimethyl amide synthesis
- Example 40 N 2 -(((2R,4R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -(Yl)methyl)-N 5 -ethyl-N 5 -picoline-2,5-dimethylamide
- Step 1 Compound (R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)-2,5-dihydro- Synthesis of 1H-pyrrole-1-carboxylic acid tert-butyl ester
- Step 2 Compound (2R, 4R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxy Synthesis of tert-butyl ester
- Step 3 Compound (2R, 4R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy) Synthesis of (methyl)pyrrolidine-1-carboxylic acid tert-butyl ester
- Step 4 Compound (2R, 4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1- Synthesis of tert-butyl carboxylate
- Step 5 Compound (2R, 4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride Synthesis
- Step 6 Compound 1-((2R,4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine Synthesis of 1-yl) ethyl ketone
- (2R, 4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (4.6g , 10.0mmol) dissolved in 20mL dichloromethane solution, under ice bath conditions, add triethylamine (0.8mL, 6.0mmol), acetyl chloride (0.1mL, 3mmol), react at room temperature for 1h, the reaction of the raw materials is complete, stop the reaction .
- Step 7 Compound 1-((2R,4R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidinyl -1-yl) Synthesis of ethyl ketone
- Step 8 Compound 1-((2R,4R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- Synthesis of 1-yl) ethyl ketone hydrochloride
- Step 9 Compound N 2 -((((2R,4R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- Synthesis of 2-yl)methyl)-N 5 -ethyl-N 5 -picoline-2,5-dimethylamide
- Example 41 N 2 -(((2S,4R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -(Yl)methyl)-N 5 -ethyl-N 5 -picoline-2,5-dimethylamide
- Step 1 Compound (2S,4R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrole Synthesis of Alkyl-1,2-Dicarboxylate
- Step 2 Compound (2S, 4R)-1-tert-butoxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine- Synthesis of 2-carboxylic acid
- Step 3 Compound (1R,4S)-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa- Synthesis of 5-azabicyclo[2.2.1]heptane-5-carboxylate
- Step 4 Compound (2S)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- Synthesis of 1H-pyrrole-2-carboxylic acid
- Step 5 Compound (2S,4R)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2- Synthesis of carboxylic acid
- Step 6 Compound (2S, 4R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1, Synthesis of 2-Dicarboxylate
- Step 7 Compound (2S,4R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine- Synthesis of 1-carboxylate
- Step 8 Compound (2S,4R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl) (Oxy) methyl) pyrrolidine-1-carboxylate synthesis
- Step 9 Compound (2S,4R)-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- Synthesis of 1-carboxylate
- Step 10 Compound (2S,4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride Synthesis of salt
- Step 11 Compound 1-(2S,4R)-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1 -The synthesis of ethyl ketone
- Step 12 Compound 1-(2S,4R)-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) Synthesis of ketone hydrochloride
- Step 13 Compound N 2 -(((2S,4R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -(Yl)methyl)-N 5 -methyl-N 5 -ethylpyridine-2,5-dimethylamide
- Example 42 N 2 -(((2S,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -(Yl)methyl)-N 5 -ethyl-N 5 -picoline-2,5-dimethylamide
- Step 1 Compound (2S)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid Synthesis
- Step 2 Compound (2S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2- Synthesis of dicarboxylic acid esters
- Step 3 Compound (2S, 4S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine- Synthesis of 1-carboxylate
- Step 4 Compound (2S, 4S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl) (Oxy) methyl) pyrrolidine-1-carboxylate synthesis
- Step 5 Compound (2S, 4S)-tert-butyl 2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrole Synthesis of alkane-1-carboxylate
- Step 6 Compound (2S, 4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride Synthesis of salt (11213-5)
- Step 7 Compound 1-(2S,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine Synthesis of -1-yl) ethyl ketone (213-6)
- Step 8 Compound 1-(2S,4S)-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) Synthesis of ketone hydrochloride
- Step 9 Compound N 2 -(((2S,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -(Yl)methyl)-N 5 -methyl N 5 -ethylpyridine-2,5-dimethylformamide
- Step 1 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of (yl)methyl)carbamoyl)nicotinate
- Step 2 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- (Yl)methyl)carbamoyl)nicotinic acid
- Step 3 N 2 -((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -(Yl)methyl)pyridine-2,5-dimethylformamide synthesis
- Example 45 N 2 -(((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxyl-4-(difluoromethoxy)phenyl)pyrrolidine-2 -(Yl)methyl)-N 5 -ethylpyridine-2,5-dimethylamide
- Example 46 N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)- N 5 -ethyl-N 5 -picoline-2,5-dimethylamide
- Step 1 Compound N 2 -((((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl) -N 5 -Ethyl-N 5 -Methylpyridine-2,5-Dicarboxamide (1245-1) Synthesis
- Step 2 N 2 -((((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl -N 5 -Ethyl-N 5 -Picoline-2,5-Dicarboxamide (DLR011245) Synthesis
- Example 48 N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methan Group) -N 5 -ethylpyridine-2,5-dimethylamide
- Step 1 N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)-N Synthesis of 5 -ethylpyridine-2,5-dimethylamide
- Step 2 N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-(isopropoxyphenyl)pyrrolidin-2-yl)methyl Yl)-N 5 -Ethylpyridine-2,5-Dicarboxamide Synthesis
- Step 1 N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)-N Synthesis of 5 -methylpyridine-2,5-dimethylamide
- Step 2 N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl) -N 5 -Methylpyridine-2,5-Diformamide Synthesis
- Step 1 ((2R,4S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2 -Yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate
- Step 3 ((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl Synthesis of 5-(ethyl(methyl)carbamoyl)picolinate
- Step 3 Lithium 5-(ethylcarbamoyl)picolinate
- Step 4 Synthesis of ((2R,2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methanol hydrochloride
- Step 6 1-((2R,2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1 -Synthesis of ethyl-1-ketone
- Step 7 ((2R,2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)5- Synthesis of (Ethylcarbamoyl) Methyl Picolinate
- Step 3 ((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)5- Synthesis of (Methylcarbamoyl) Picolinate
- Lithium 5-(methylcarbamoyl) picolinate (248mg, 1.33mmol) and 1,4-dioxane solution (0.45mL, 1.78mmol) of hydrochloric acid were dissolved in N,N-dimethylformaldehyde.
- Step 3 ((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl Synthesis of 5-carbamoylpicolinic acid
- Step 3 Compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxol Synthesis of Borane
- Step 4 (R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-1H-pyrrole-1,2(2H,5H )-Synthesis of dicarboxylic acid esters
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Abstract
本发明属于药物领域,涉及一类取代的氮杂五元环类化合物及其在药物中的应用。具体地,本发明涉及如式(I)所示的化合物,或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药;还涉及包含所述化合物的药物组合物及其用途和使用方法。特别地,本发明所述的化合物是PDE4抑制剂,用于治疗PDE4相关的疾病,例如特应性皮炎(AD)或慢性阻塞性肺病(COPD)。
Description
相关申请
本申请要求中国专利申请号为202010355360.9的优先权,该申请于2020年04月29日递交至国家知识产权局,其所有内容在此作为引用并入本文。
本发明属于药物领域,具体涉及取代的氮杂五元环类化合物、包含所述化合物的药物组合物及其在药物中的用途和使用方法。特别地,本发明所述的化合物是PDE4抑制剂,用于治疗PDE4相关的疾病,例如特应性皮炎(AD)或慢性阻塞性肺病(COPD)。
环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)是细胞内两种重要的第二信使,主要通过激活蛋白激酶A(PKA)和蛋白激酶G(PKG)途径参与能量代谢、记忆、免疫反应、视觉及嗅觉形成等生理活动,其细胞内浓度的调节主要由腺(鸟)苷酸环化酶的合成和磷酸二酯酶(PDEs)的水解作用之间的平衡决定。PDEs能特异性地以3,5-环核苷酸为底物,催化细胞内的cGMP和cAMP水解生成相应的无活性的5-磷酸腺苷,从而影响生物体的各种代谢功能。因此,抑制PDEs对引起许多细胞活性是一种很有效的途径,能影响炎症细胞和免疫细胞活化及平滑肌细胞收缩反应。
磷酸二酯酶(PDEs)迄今已报道有11个基因家族,每个家族又包括多个亚家族。PDEs分布于多个组织中,其抑制剂具有广泛的生理作用,其中PDE4、PDE7和PDE8主要特异性水解cAMP,PDE5、PDE6和PDE9特异性水解cGMP,而PDE1、PDE2、PDE3、PDE10和PDE11则对cAMP和cGMP都起作用。其中PDE4主要分布于各种炎性细胞内,其组织分布说明它与中枢神经系统和免疫系统息息相关,其抑制剂可用于治疗各种疾病,包括过敏性和炎性疾病、糖尿病、中枢神经系统疾病和疼痛。
目前,对PDE4的研究主要集中在免疫及炎症相关疾病中,世界上许多著名的制药公司都把PDE4作为慢性炎症相关疾病的靶点。PDE4抑制剂发挥抗炎作用主要通过以下几种途径:(1)抑制多种炎症介质的活性;(2)抑制细胞黏附因子的上调和表达;(3)抑制血白细胞的活化;(4)诱导细胞凋亡;(5)诱导具有抑制活性的细胞因子的生成(如白细胞介素-6);(6)诱导儿茶酚胺类物质和内源性激素的释放。第一代PDE4抑制剂主要有茶碱、咯利普兰(Rolipram)和吡拉米司特(Piclamilast)等,咯利普兰对神经系统疾病,如帕金森病、抑郁症和焦虑等都具有一定的治疗作用。但第一代PDE4抑制剂由于严重的恶心、呕吐等副作用,在临床上的应用受到了限制;第二代PDE4抑制剂有罗氟司特(Roflumilast)和西洛司特(Cilomilast)等,其中罗氟司特用于COPD的治疗,对其他炎症性疾病也有一定的治疗效果,如溃疡性结肠炎和克罗恩病。第三代PDE4抑制剂阿普斯特(Apremilast)已经用于自身免疫性疾病如银屑病的治疗,且副作用更小,病人更易耐受。WO/2000/064260披露了PDE4抑制剂Ro 20-1724 1%霜剂治疗银屑病有效。WO 2000/009504披露了另一个PDE4抑制剂CP-80633(0.5%软膏),其明显的改善了特应性皮炎的临床计分(红斑、硬结和表皮脱落)。但是,临床上仍需要更多的可以有效治疗特应性皮炎的PDE4抑制剂。
发明内容
以下仅概括说明本发明的一些方面,并不局限于此。这些方面和其他部分在后面有更完整的说明。本说明书中的所有参考文献通过整体引用于此。当本说明书的公开内容与引用文献有差异时,以本说明书的公开内容为准。
本发明提供了一类具有4型磷酸二酯酶(Phosphodiesterase-4,PDE4)抑制活性的化合物,用于制备预 防、治疗或减轻与PDE4有关的呼吸疾病、过敏、炎症、中枢神经系统疾病或非胰岛素依赖糖尿病的药物,比如慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症;其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎、闭塞性细支气管炎、过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎等;本发明化合物能够很好地抑制PDE4,同时具有优良的理化性质以及药代动力学性质。
本发明也提供了这些化合物的制备方法和包含这些化合物的药物组合物以及使用这些化合物或组合物治疗哺乳动物,尤其是人类的上述疾病的方法。
具体地说:
一方面,本发明涉及一种如式(I)所示的化合物或式(I)所示化合物的立体异构体,互变异构体,氮氧化物,水合物,溶剂化物,代谢产物,药学上可接受的盐或它们的前药,
其中:
R
1和R
2各自独立地为氢、氘、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、C
3-8环烷基、3-10个原子组成的杂环基、C
6-10芳基、5-10个原子组成的杂芳基、C
3-8环烷基-C
1-4亚烷基、C
1-6烷基-C(=O)-、C
3-8环烷基-C(=O)-、3-10个原子组成的杂环基-C
1-4亚烷基、C
6-10芳基-C
1-4亚烷基或5-10个原子组成的杂芳基-C
1-
4亚烷基;
X和X
1各自独立地为键、-O-、-S-、-N(R
c)-、-C(=O)-或-S(=O)
t-;
R
3为氢、氘、羧基、C
1-6烷基、C
1-6卤代烷基、C
2-4烯基、C
2-4炔基、C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C
3-8环烷基-C
1-4亚烷基、C
6-10芳基-C
1-4亚烷基、3-10个原子组成的杂环基-C
1-4亚烷基、5-10个原子组成的杂芳基-C
1-4亚烷基、C
1-6烷基-C(=O)-、C
1-6烷基-S(=O)
t-、C
1-6烷氧基-C(=O)-、C
3-8环烷基-C(=O)-、C
3-8环烷基-S(=O)
t-、3-10个原子组成的杂环基-C(=O)-、3-10个原子组成的杂环基-S(=O)
t-、-C(=O)-NR
dR
e、-S(=O)
t-NR
dR
e、C
6-10芳基-C(=O)-、5-10个原子组成的杂芳基-C(=O)-、C
6-10芳基-S(=O)
t-或5-10个原子组成的杂芳基-S(=O)
t-,其中R
3未被取代或被1、2、3或4个R
6所取代;
各R
6独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、C
1-4烷基、C
1-4卤代烷基、C
1-4烷氧基、C
1-4烷氨基或C
1-4烷基-C(=O)-N(R
c)-;
R
4为-(CH
2)
m-L-(CH
2)
n-G;
L为键、-O-、-S-、-NR
x-、-NR
x-C(=O)-、-NR
x-S(=O)
t-、-NR
x-C(=O)-NR
y-、-NR
x-C(=O)-O-、-S(=O)
t-、-C(=O)-或-C(=O)-O-;
优选地,L为-O-、-S-、-NR
x-、-NR
x-C(=O)-、-NR
x-S(=O)
t-、-NR
x-C(=O)-NR
y-、-NR
x-C(=O)-O-、-S(=O)
t-、-C(=O)-或-C(=O)-O-,其中,-NR
x-C(=O)-、-NR
x-S(=O)
t-、-NR
x-C(=O)-NR
y-和-NR
x-C(=O)-O-的左端分别与(CH
2)
m连接,右端分别与(CH
2)
n连接,-C(=O)-O-的右端与(CH
2)
m连接,左端与(CH
2)
n连接;
其中,各R
x和R
y独立地为氢、氘、C
1-6烷基、C
1-6卤代烷基、C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C
3-8环烷基-C
1-6亚烷基、C
6-10芳基-C
1-6亚烷基、3-10个原子组成的杂环基-C
1-6亚烷基、5-10个原子组成的杂芳基-C
1-6亚烷基、C
1-6烷基-S(=O)
t-、C
1-6烷基-C(=O)-或C
1-6烷氧基-C(=O)-C
1-6亚烷基;
G为C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基或5-10个原子组成的杂芳基;其中G未被取代或被1、2、3或4个R
7所取代;
各R
7独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、羧基、C
1-6烷基、C
1-6卤代烷基、C
1-
6烷氧基、C
1-6烷氨基、-C(=O)-NR
aR
b、-S(=O)
t-NR
aR
b、C
1-6烷基-C(=O)-N(R
c)-、C
1-6烷基-S(=O)
t-N(R
c)-、C
1-6烷氧基-C(=O)-N(R
c)-、C
1-6烷基-C(=O)-、C
1-6烷基-S(=O)
t-、C
1-6烷氧基-C(=O)-、C
1-6烷基-C(=O)-O-、C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基或5-10个原子组成的杂芳基;
各R
a和R
b独立地为氢、氘、C
1-6烷基、C
1-6卤代烷基、C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C
3-8环烷基-C
1-6亚烷基、C
6-10芳基-C
1-6亚烷基、3-10个原子组成的杂环基-C
1-6亚烷基、5-10个原子组成的杂芳基-C
1-6亚烷基、C
1-6烷基-S(=O)
t-或C
1-6烷基-C(=O)-,其中各R
a和R
b独立地未被取代或被1、2或3个选自氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、-C(=O)-NH
2、C
1-6烷氧基C(=O)-、C
1-6烷基-C(=O)-N(R
c)-、C
1-6烷基-S(=O)
t-N(R
c)-、C
1-4烷基、C
1-4卤代烷基、C
1-4烷氧基或C
1-4烷氨基的基团所取代;
各R
d和R
e独立地为氢、氘、C
1-6烷基、C
1-6卤代烷基、C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C
3-8环烷基-C
1-6亚烷基、C
6-10芳基-C
1-6亚烷基、3-10个原子组成的杂环基-C
1-6亚烷基、5-10个原子组成的杂芳基-C
1-6亚烷基、C
1-6烷基-S(=O)
t-或C
1-6烷基-C(=O)-,其中各R
d和R
e独立地未被取代或被1、2或3个选自氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、-C(=O)-NH
2、C
1-6烷氧基C(=O)-、C
1-6烷基-C(=O)-N(R
c)-、C
1-6烷基-S(=O)
t-N(R
c)-、C
1-4烷基、C
1-4卤代烷基、C
1-4烷氧基或C
1-4烷氨基的基团所取代;
各R
c独立地为氢、氘、C
1-3烷基或C
1-3卤代烷基;
R为氢、氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、C
1-3烷基、C
1-3烷氧基、C
1-3卤代烷氧基或C
1-3卤代烷基;
R
5a、R
5b、R
6a和R
6b各自独立地为氢、氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、C
1-3烷基、C
1-3烷氧基、C
1-3卤代烷氧基或C
1-3卤代烷基;
t为1或2;
n为0、1、2、3或4;
m为1、2、3或4。
其中一些实施方案是,本发明所述的化合物为式(II)所示的化合物或式(II)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐它们的前药:
其中,各R
1、R
2、R
3、R
5a、R
5b、R
6a、R
6b、R、G、L和n具有如本发明所述的含义。
其中一些实施方案是,本发明所述的化合物为式(III)所示的化合物或式(III)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐它们的前药:
其中,各R
1、R
2、R
3、R
5a、R
5b、R
6a、R
6b、R、G、L和n具有如本发明所述的含义。
其中一些实施方案是,R
1和R
2各自独立地为氢、氘、甲基、乙基、正丙基、异丙基、异丁基、-CH
2F、-CHF
2、-CF
3、-CH
2CH
2F、-CH
2CHF
2、-CH
2CF
3、-CH
2CH
2CH
2F、-CH
2CH
2CHF
2、-CH
2CH
2CF
3、-CH
2Cl、-CHCl
2、-CH=CH
2、-CH
2CH=CH
2、-C≡CH、-CH
2C≡CH、环丙基、环丁基、环戊基、环己基、环丙基亚甲基、环丙基亚乙基、环丁基亚甲基、环丁基亚乙基、环戊基亚甲基、环戊基亚乙基、环己基亚甲基、环己基亚乙基、CH
3C(=O)-、CH
3CH
2C(=O)-、CH
3CH
2CH
2C(=O)-、(CH
3)
2CHC(=O)-、环丙基-C(=O)-、环丁基-C(=O)-、环戊基-C(=O)-、环己基-C(=O)-、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C
1-3亚烷基、萘基-C
1-3亚烷基、吡啶基-C
1-3亚烷基、嘧啶基-C
1-3亚烷基、呋喃基-C
1-3亚烷基、噻吩基-C
1-3亚烷基、吡咯基-C
1-3亚烷基、吡唑基-C
1-3亚烷基、噻唑基-C
1-3亚烷基、恶唑基-C
1-3亚烷基、三氮唑基-C
1-3亚烷基、四氮唑基-C
1-3亚烷基、哌嗪基-C
1-3亚烷基、哌啶基-C
1-3亚烷基、吗啉基-C
1-3亚烷基、硫代吗啉基-C
1-3亚烷基、四氢吡喃基-C
1-3亚烷基或吡咯烷基-C
1-3亚烷基;
R
3为氢、氘、羧基、C
1-3烷基、C
1-3卤代烷基、C
2-4烯基、C
2-4炔基、CH
3-C(=O)-、CH
3CH
2-C(=O)-、CH
3CH
2CH
2-C(=O)-、(CH
3)
2CH-C(=O)-、CH
3-S(=O)
2-、CH
3CH
2-S(=O)
2-、CH
3CH
2CH
2-S(=O)
2-、(CH
3)
2CH-S(=O)
2-、CH
3-O-C(=O)-、CH
3CH
2-O-C(=O)-、CH
3CH
2CH
2-O-C(=O)-、(CH
3)
2CH-O-C(=O)-、-S(=O)
2-NH
2或-C(=O)-NH
2,其中R
3未被取代或被1、2、3或4个R
6所取代;
各R
6独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、甲基、乙基、正丙基、异丙基、-CH
2F、-CHF
2、-CF
3、-CH
2CH
2F、-CH
2CHF
2、-CH
2CF
3、-CH
2CH
2CH
2F、-CH
2CH
2CHF
2、-CH
2CH
2CF
3、-CH
2Cl、-CHCl
2、甲氧基、乙氧基、正丙基氧基、甲氨基、乙氨基或正丙基氨基。
其中一些实施方案是,各R
x和R
y独立地为氢、氘、甲基、乙基、正丙基、异丙基、C
1-4卤代烷基、环丙基、环丁基、环戊基、环己基、环丙基-C
1-3亚烷基、环丁基-C
1-3亚烷基、环戊基-C
1-3亚烷基、环己基-C
1-
3亚烷基、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C
1-3亚烷基、萘基-C
1-3亚烷基、吡啶基-C
1-3亚烷基、嘧啶基-C
1-3亚烷基、呋喃基-C
1-3亚烷基、噻吩基-C
1-3亚烷基、吡咯基-C
1-3亚烷基、吡唑基-C
1-3亚烷基、噻唑基-C
1-3亚烷基、恶唑基-C
1-3亚烷基、三氮唑基-C
1-3亚烷基、四氮唑基-C
1-3亚烷基、哌嗪基-C
1-3亚烷基、哌啶基-C
1-3亚烷基、吗啉基-C
1-3亚烷基、硫代吗啉基-C
1-3亚烷基、四氢吡喃基-C
1-3亚烷基、吡咯烷基-C
1-3亚烷基、C
1-3烷基-S(=O)
2-、C
1-3烷基-C(=O)-或C
1-3烷氧基-C(=O)-C
1-3亚烷基。
各R
7独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、羧基、C
1-4烷基、C
1-4卤代烷基、C
1-
4烷氧基、C
1-4烷氨基、-C(=O)-NR
aR
b、-S(=O)
2-NR
aR
b、C
1-4烷基-C(=O)-NH-、C
1-4烷基-S(=O)
2-NH-、C
1-4烷氧基-C(=O)-NH-、CH
3-C(=O)-、CH
3CH
2-C(=O)-、CH
3CH
2CH
2-C(=O)-、(CH
3)
2CH-C(=O)-、CH
3CH
2CH
2CH
2-C(=O)-、CH
3-S(=O)
2-、CH
3CH
2-S(=O)
2-、CH
3CH
2CH
2-S(=O)
2-、(CH
3)
2CH-S(=O)
2-、CH
3O-C(=O)-、CH
3CH
2O-C(=O)-、CH
3CH
2CH
2O-C(=O)-、(CH
3)
2CHO-C(=O)-、CH
3CH
2CH
2CH
2O-C(=O)-、CH
3-C(=O)-O-、CH
3CH
2-C(=O)-O-、CH
3CH
2CH
2-C(=O)-O-、(CH
3)
2CH-C(=O)-O-、CH
3CH
2CH
2CH
2-C(=O)-O-、环丙基、环丁基、环戊基、环己基、
其中各R
a和R
b具有如本发明所述的含义。
其中一些实施方案是,各R
a和R
b独立地为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、-CH
2F、-CHF
2、-CF
3、-CH
2CH
2F、-CH
2CHF
2、-CH
2CF
3、-CH
2CH
2CH
2F、-CH
2CH
2CHF
2、-CH
2CH
2CF
3、-CH
2Cl、-CHCl
2、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C
1-3亚烷基、萘基-C
1-3亚烷基、吡啶基-C
1-3亚烷基、嘧啶基-C
1-3亚烷基、呋喃基-C
1-3亚烷基、噻吩基-C
1-3亚烷基、吡咯基-C
1-3亚烷基、吡唑基-C
1-3亚烷基、噻唑基-C
1-3亚烷基、恶唑基-C
1-3亚烷基、三氮唑基-C
1-3亚烷基、四氮唑基-C
1-3亚烷基、哌嗪基-C
1-3亚烷基、哌啶基-C
1-3亚烷基、吗啉基-C
1-3亚烷基、硫代吗啉基-C
1-3亚烷基、四氢吡喃基-C
1-3亚烷基、吡咯烷基-C
1-3亚烷基、C
1-3烷基-S(=O)
2-或C
1-3烷基-C(=O)-;其中各R
a和R
b独立地未被取代或被1、2或3个选自氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、-C(=O)-NH
2、C
1-3烷氧基C(=O)-、C
1-3烷基-C(=O)-NH-、C
1-3烷基-S(=O)
t-NH-、甲基、乙基、正丙基、异丙基、正丁基、-CH
2F、-CHF
2、-CF
3、-CH
2CH
2F、-CH
2CHF
2、-CH
2CF
3、-CH
2CH
2CH
2F、-CH
2CH
2CHF
2、-CH
2CH
2CF
3、-CH
2Cl、-CHCl
2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、N-甲基氨基、N-乙基氨基、N’N-二甲基氨基、N’N-二乙基氨基或N’N-甲基乙基氨基的基团所取代。
另一方面,本发明提供一种药物组合物,包含本发明所述的化合物。
其中一些实施方案是,本发明所述的药物组合物,其进一步地包含药学上可接受的载体、赋形剂、附加剂、辅剂和媒介物中的至少一种。
其中一些实施方案是,本发明所述的药物组合物,其进一步地包含附加治疗剂,其中所述的附加治疗剂是:丙酮酸钠、多索茶碱、替托司特、泰鲁司特、茶碱、福莫特罗、沙美特罗、氟替卡松丙酸酯、咯利普兰、吡拉米斯特、西洛司特、茚达特罗、奥达特罗、米地司坦、齐流通、沙丁醇胺、卡莫昔罗、布地奈德、二丙酸倍氯米松、曲安奈德、氟尼缩松、糠酸莫米松、罗氟奈德、环索奈德、异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、芜地溴铵、维兰特罗、阿地溴铵、Benralizumab、Tralokinumab、瑞伐托酯、克瑞沙硼、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、地索奈德、氢化可的松、氯倍他索、卤贝他索、二氟拉松、美普克莱、他克莫司、吡美莫司、他扎罗汀、环孢素、阿普斯特、E-6005、OPA-15406、LEO-29102、DRM02、罗氟司特、异丁司特、托法替尼、JTE-052、巴瑞替尼、乌帕替尼、WBI-1001、MRX-6、GSK2981278、杜鲁单抗、来金珠单抗、尼莫利珠单抗、曲洛吉努单抗、依那西普、阿达木单抗、英夫利昔单抗、尤特可单抗、塞库吉努、奥马珠、CIM-331、戈利木单抗和聚乙二醇化赛、妥珠单抗、卡泊三醇、骨化三醇、阿利维A酸、VTP-38543、ZPL-389、阿瑞匹坦、曲地匹坦、弗维普兰特、OC-459、SUN 13834、SB-011、VTP-43742、ARN6039、TAK-828、JTE-451、PF-04965842、PF-06651600、PF-06700841、PF-06650833、GR-MD-02或它们的组合。
另一方面,本发明提供本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途,其中所述药物用于预防、治疗或减轻与4型磷酸二酯酶有关的疾病。
其中一些实施方案是,本发明所述的用途,其中所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病、肺纤维化或非胰岛素依赖糖尿病;
其中所述的呼吸疾病为:慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症;其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎;
其中所述的炎症为:过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。
另一方面,本发明提供一种预防、治疗或减轻与4型磷酸二酯酶有关的疾病的方法,其包含给予患者本发明所述的化合物或本发明所述的药物组合物的有效治疗量。
其中一些实施方案是,本发明所述的方法,其中所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病、肺纤维化或非胰岛素依赖糖尿病;
其中所述的呼吸疾病为:慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症;其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎;
其中所述的炎症为:过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。
另一方面,本发明提供本发明所述的化合物或本发明所述的药物组合物用于预防、治疗或减轻患者4型磷酸二酯酶有关的疾病。
其中一些实施方案是,本发明所述的化合物或药物组合物用于预防、治疗或减轻患者4型磷酸二酯酶有关的疾病,其中所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病、肺纤维化或非胰岛素依赖糖尿病;
其中所述的呼吸疾病为:慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管 扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症;其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎;
其中所述的炎症为:过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。
本发明另一方面涉及式(I)、(II)或(III)所示的化合物的制备、分离和纯化的方法。
前面所述内容只概述了本发明的某些方面,但并不限于这些方面。这些方面及其他方面的内容将在下面作更加具体完整的描述。
本发明详细说明书
定义和一般术语
现在详细描述本发明的某些实施方案,其实施例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案,它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到,许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术,等等),以本申请为准。
应进一步认识到,本发明的某些特征,为清楚可见,在多个独立的实施方案中进行了描述,但也可以在单个实施例中以组合形式提供。反之,本发明的各种特征,为简洁起见,在单个实施方案中进行了描述,但也可以单独或以任意适合的子组合提供。
除非另外说明,本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明,应当应用本发明所使用的下列定义。出于本发明的目的,化学元素与元素周期表CAS版,和《化学和物理手册》,第75版,1994一致。此外,有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述,其全部内容通过引用并入本发明。
除非另有说明或者上下文中有明显的冲突,本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此,本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如,“一组分”指一个或多个组分,即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象,例如也指灵长类动物(例如人类,男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中,所述受试对象是灵长类动物。在其他实施方案中,所述受试对象是人。本发明所使用的术语“患者”是指人(包括成人和儿童或者其他动物)。在一些实施方案中,“患者”是指人。
术语“包含”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
术语“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何(顺/反)异构体、阻转异构体,等等。
术语“手性”是具有与其镜像不能重叠性质的分子;而“非手性”是指与其镜像可以重叠的分子。
术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
术语“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如 电泳和色谱,例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994。
许多有机化合物以光学活性形式存在,即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时,使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号,其中(-)或l表示化合物是左旋的,前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体,这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体,当在化学反应或过程中没有立体选择性或立体特异性时,可出现这种情况。
本发明公开化合物的任何不对称原子(例如,碳等)都可以以外消旋或对映体富集的形式存在,例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中,各不对称原子在(R)-或(S)-构型方面具有至少50%对映体过量,至少60%对映体过量,至少70%对映体过量,至少80%对映体过量,至少90%对映体过量,至少95%对映体过量,或至少99%对映体过量。
依据起始物料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物,例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备,或使用常规技术拆分。如果化合物含有一个双键,取代基可能为E或Z构型;如果化合物中含有二取代的环烷基,环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体,如,通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离,如,使用手性吸附剂的高效液相色谱(HPLC)。特别地,对映异构体可以通过不对称合成制备,例如,可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Principles of Asymmetric Synthesis(2
nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972);Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(proton tautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出,本发明化合物的所有互变异构体形式都在本发明的范围之内。
像本发明所描述的,本发明的化合物可以任选地被一个或多个取代基所取代,如上面的通式化合物,或者像实施例里面特殊的例子,子类,和本发明所包含的一类化合物。
一般而言,术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明,一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不止一个 位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。
术语“任选地被……所取代”表示所述结构是未取代的或者被一个或多个本发明所述的取代基取代。本发明所述的取代基包括,但不限于,氘,氟,氯,溴,碘,氰基,羟基,氨基,羧基,叠氮基,芳基,杂芳基,烷氧基,烷氨基,烷硫基,烷基,烯基,炔基,杂环基,环烷基,巯基,硝基,芳氧基,杂芳氧基,氧代,卤代烷基,卤代烷氧基,羟基取代的烷基,羟基取代的烷氧基,氨基取代的烷基,氰基取代的烷基,羟基取代的烷基-C(=O)-,烷基-C(=O)-,烷基-O-C(=O)-,烷基-S(=O)-,烷基-S(=O)
2-,羟基取代的烷基-S(=O)-,羟基取代的烷基-S(=O)
2-,羧基烷氧基,NH
2-C(=O)-,NH
2-S(=O)
2-,芳基-亚烷基,杂芳基-亚烷基,杂环基-亚烷基,环烷基-亚烷基,等等。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换,均应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。例如,结构式“-C(=O)-N(R
pR
q)”和结构式“-C
1-6亚烷基-N(R
pR
q)”两者之间R
p的具体选项互相之间不受影响。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C
1-C
6烷基”或“C
1-6烷基”特别指独立公开的甲基、乙基、C
3烷基、C
4烷基、C
5烷基和C
6烷基。
在本发明的各部分,描述了连接取代基。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,如果该结构需要连接基团并且针对该变量的马库什基团定义列举了如“烷基”或“芳基”,则应该理解,该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”,表示含有1至20个碳原子,饱和的直链或支链一价烃基基团,其中,所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代,其中所述的取代基是,氘,氟,氯,溴,碘,氰基,羟基,氨基,羧基,叠氮基,芳基,杂芳基,烷氧基,烷氨基,烷硫基,烷基,烯基,炔基,杂环基,环烷基,巯基,硝基,芳氧基,杂芳氧基,氧代,卤代烷基,卤代烷氧基,羟基取代的烷基,羟基取代的烷氧基,氨基取代的烷基,氰基取代的烷基,羟基取代的烷基-C(=O)-,烷基-C(=O)-,烷基-O-C(=O)-,烷基-S(=O)-,烷基-S(=O)
2-,羟基取代的烷基-S(=O)-,羟基取代的烷基-S(=O)
2-,羧基烷氧基,NH
2-C(=O)-,NH
2-S(=O)
2-,芳基-亚烷基,杂芳基-亚烷基,杂环基-亚烷基,环烷基-亚烷基,等等。除非另外详细说明,烷基基团含有1-20个碳原子。在一些实施方案中,烷基基团含有1-12个碳原子;在另一些实施方案中,烷基基团含有1-6个碳原子;在又一些实施方案中,烷基基团含有1-4个碳原子;还在一些实施方案中,烷基基团含有1-3个碳原子。
烷基基团的实例包含,但并不限于,甲基(Me、-CH
3),乙基(Et、-CH
2CH
3),正丙基(n-Pr、-CH
2CH
2CH
3),异丙基(i-Pr、-CH(CH
3)
2),正丁基(n-Bu、-CH
2CH
2CH
2CH
3),异丁基(i-Bu、-CH
2CH(CH
3)
2),仲丁基(s-Bu、-CH(CH
3)CH
2CH
3),叔丁基(t-Bu、-C(CH
3)
3),正戊基(-CH
2CH
2CH
2CH
2CH
3),2-戊基(-CH(CH
3)CH
2CH
2CH
3),3-戊基(-CH(CH
2CH
3)
2),2-甲基-2-丁基(-C(CH
3)
2CH
2CH
3),3-甲基-2-丁基(-CH(CH
3)CH(CH
3)
2),3-甲基-1-丁基(-CH
2CH
2CH(CH
3)
2),2-甲基-1-丁基(-CH
2CH(CH
3)CH
2CH
3),正己基(-CH
2CH
2CH
2CH
2CH
2CH
3),2-己基(-CH(CH
3)CH
2CH
2CH
2CH
3),3-己基(-CH(CH
2CH
3)(CH
2CH
2CH
3)),2-甲基-2-戊基(-C(CH
3)
2CH
2CH
2CH
3),2,3-二甲基-2-丁基(-C(CH
3)
2CH(CH
3)
2),3,3-二甲基-2-丁基(-CH(CH
3)C(CH
3)
3),正庚基,正辛基,等等。
术语“亚烷基”表示从饱和的直链或支链烃中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明,亚烷基基团含有1-12个碳原子。在一些实施方案中,亚烷基基团含有1-6个碳原子;在另一些实施方案中,亚烷基基团含有1-4个碳原子;在又一些实施方案中,亚烷基基团含有1-3个碳原子;还在 一些实施方案中,亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH
2-),亚乙基(-CH
2CH
2-),亚丙基(-CH
2CH
2CH
2-),亚异丙基(-CH(CH
3)CH
2-)等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个不饱和位点,即有一个碳-碳sp
2双键,其中,所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代,其包括"cis"和"tans"的定位,或者"E"和"Z"的定位。在一些实施方案中,烯基基团包含2-8个碳原子;在另一些实施方案中,烯基基团包含2-6个碳原子;在又一些实施方案中,烯基基团包含2-4个碳原子。烯基基团的实例包括,但并不限于,乙烯基(-CH=CH
2)、烯丙基(-CH
2CH=CH
2)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个不饱和位点,即有一个碳-碳sp三键,其中,所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中,炔基基团包含2-8个碳原子;在另一些实施方案中,炔基基团包含2-6个碳原子;在又一些实施方案中,炔基基团包含2-4个碳原子。炔基基团的实例包括,但并不限于,乙炔基(-C≡CH)、炔丙基(-CH
2C≡CH)、1-丙炔基(-C≡C-CH
3)等等。
术语“羧基”,无论是单独使用还是和其他术语连用,如“羧烷基”,表示-CO
2H或-COOH。
术语“氘”表示单个氘原子。例如,一个氘原子取代甲基中的一个氢原子,形成单-氘代甲基(-CDH
2),两个氘原子取代甲基中的两个氢原子,形成双-氘代甲基(-CD
2H),以及三个氘原子取代甲基中的三个氢原子,形成三-氘代甲基(-CD
3)。
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。
术语“杂原子”是指O、S、N、P、B和Si,包括N、S和P任何氧化态的形式;伯、仲、叔胺和季铵盐的形式;或者杂环中氮原子上的氢被取代的形式,例如,N(像3,4-二氢-2H-吡咯基中的N),NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连,其中烷基基团具有如本发明所述的含义。除非另外详细说明,所述烷氧基基团含有1-12个碳原子。在一些实施方案中,烷氧基基团含有1-6个碳原子;在另一些实施方案中,烷氧基基团含有1-4个碳原子;在又一些实施方案中,烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氧基基团的实例包括,但并不限于,甲氧基(MeO、-OCH
3),乙氧基(EtO、-OCH
2CH
3),1-丙氧基(n-PrO、n-丙氧基、-OCH
2CH
2CH
3),2-丙氧基(i-PrO、i-丙氧基、-OCH(CH
3)
2),1-丁氧基(n-BuO、n-丁氧基、-OCH
2CH
2CH
2CH
3),2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH
2CH(CH
3)
2),2-丁氧基(s-BuO、s-丁氧基、-OCH(CH
3)CH
2CH
3),2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH
3)
3),1-戊氧基(n-戊氧基、-OCH
2CH
2CH
2CH
2CH
3),2-戊氧基(-OCH(CH
3)CH
2CH
2CH
3),3-戊氧基(-OCH(CH
2CH
3)
2),2-甲基-2-丁氧基(-OC(CH
3)
2CH
2CH
3),3-甲基-2-丁氧基(-OCH(CH
3)CH(CH
3)
2),3-甲基-l-丁氧基(-OCH
2CH
2CH(CH
3)
2),2-甲基-l-丁氧基(-OCH
2CH(CH
3)CH
2CH
3),等等。
术语“烷氨基”表示氨基(-NH
2)上的两个氢原子独立任选的被相同或不同的烷基基团所取代,包括N-烷基氨基或N’N-二烷基氨基,其中烷基基团具有如本发明所述的含义。除非另外详细说明,所述烷氨基基团含有1-12个碳原子。在一些实施方案中,烷氨基基团含有1-6个碳原子;在另一些实施方案中,烷氨基基团含有1-4个碳原子;在又一些实施方案中,烷氨基基团含有1-3个碳原子。所述烷氨基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氨基基团的实例包括,但并不限于,N-甲氨基(-NHCH
3),N-乙氨基(-NHCH
2CH
3),N’N-二甲基氨基(-N(CH
3)
2),N’N-二乙基氨基(-N(CH
2CH
3)
2),N’N-甲基乙基氨基
N’N-甲基异丙基氨基
等等。
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代,这样的实例包含,但并不限于,-CH
2F,-CHF
2,-CF
3,-CH
2CH
2F,-CH
2CHF
2,-CH
2CF
3,-CH
2CH
2CH
2F,-CH
2CH
2CHF
2,-CH
2CH
2CF
3,-CH
2Cl,-CHCl
2,等等。
术语“j-k个原子组成的”,其中各j和k独立地为任意非零的自然数,且k>j;所述“j-k”包括j、k和两者之间的任意自然数。典型地描述分子中成环原子的数目,在所述分子中成环原子的数目是j-k,所述的原子包括碳原子和/或O、N、S、P等杂原子。
术语“环烷基”表示含有3-12个碳原子的,单价或多价的饱和单环,双环或三环体系。在一些实施方案中,环烷基包含3-12个碳原子;在另一些实施方案中,环烷基包含3-8个碳原子;在又一些实施方案中,环烷基包含3-6个碳原子。所述环烷基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。环烷基的实例包括但不限于:环丙基、环丁基、环戊基、环己基,等。
术语“环烷基烷基”或“环烷基-亚烷基”可以交换使用,都是指烷基基团被一个或多个环烷基基团所取代,其中烷基基团和环烷基基团具有如本发明所述的含义,这样的实例包括,但并不限于环丙基-亚甲基、环丙基-亚乙基、环丁基-亚甲基、环丁基-亚乙基、环戊基-亚甲基、环戊基-亚乙基、环己基-亚甲基、环己基-亚乙基等。
术语“杂环基”和“杂环”在此处可交换使用,都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环,其中单环、双环或三环中不包含芳香环,且至少一个环原子选自氮、磷、硫、硼和氧原子。除非另外说明,杂环基可以是碳基或氮基,且-CH
2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括,但不限于:环氧乙烷基、氮杂环丁基,氧杂环丁基,硫杂环丁基,吡咯烷基,吡咯基,吡唑烷基,咪唑啉基,咪唑烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,二氢噻吩基,1,3-二氧环戊基,二硫环戊基,四氢吡喃基,二氢吡喃基,四氢噻喃基,哌啶基,四氢吡啶基,吗啉基,硫代吗啉基,1-氧代-硫代吗啉基,1,1-二氧代-硫代吗啉基,哌嗪基,二噁烷基,二噻烷基,噻噁烷基,高哌嗪基,高哌啶基,氧杂环庚烷基。杂环基中-CH
2-基团被-C(=O)-取代的实例包括,但不限于,2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基和3,5-二氧代哌啶基。杂环基中硫原子被氧化的实例包括,但不限于,环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“杂环基烷基”或“杂环基-亚烷基”可以交换使用,都是指杂环基取代的烷基;其中杂环基和烷基基团具有如本发明所述的含义。这样的实例包括,但并不限于硫代吗啉-4-基甲基,四氢呋喃-3-基甲基,氧杂环丁烷-3-基甲基,吡咯烷-2-基甲基,吗啉-4-基甲基等。
术语“芳基”表示含有6-14个环原子,或6-12个环原子,或6-10个环原子的单环、双环和三环的碳环体系,其中,至少一个环体系是芳香族的,其中每一个环体系包含3-7个原子组成的环,且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“芳基烷基”或“芳基-亚烷基”可以交换使用,都是指一个或多个芳基取代的烷基基团,其中所述芳基和烷基具有本发明所述的含义。其中一些实施方案是,芳基烷基基团是指“较低级的芳基烷基”基团,即芳基基团连接到C
1-6的烷基或亚烷基基团上。另外一些实施方案是,芳基烷基基团是指含C
1-
4烷基的“苯烷基”。其中具体实例包括二苯基甲基,苯基亚甲基、苯基亚乙基。芳基烷基或芳基亚烷基上的芳基可以进一步被本发明所述的取代基所取代。
术语“杂芳基”表示含有5-12个环原子,或5-10个环原子,或5-7个环原子的单环、双环和三环体系,其中至少一个环体系是芳香族的,且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含5-7 个原子组成的环,且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”,“芳杂环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在其中一些实施方案中,5-10个原子组成的杂芳基包含1,2,3或4个独立选自O,S,N或B的杂原子。
杂芳基基团的实例包括,但并不限于,呋喃基(如2-呋喃基、3-呋喃基)、咪唑基(如N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)、异噁唑基(如3-异噁唑基、4-异噁唑基、5-异噁唑基)、噁唑基(如2-噁唑基、4-噁唑基、5-噁唑基)、吡咯基(如N-吡咯基、2-吡咯基、3-吡咯基)、吡啶基(如2-吡啶基、3-吡啶基、4-吡啶基)、嘧啶基(如2-嘧啶基、4-嘧啶基、5-嘧啶基)、哒嗪基(如3-哒嗪基)、噻唑基(如2-噻唑基、4-噻唑基、5-噻唑基)、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、噻吩基(如2-噻吩基、3-噻吩基)、吡唑基(如2-吡唑基)、异噻唑基、嘧啶酮基、吡啶酮基;也包括以下的双环,但绝不限于这些双环:苯并咪唑基、苯并呋喃基、苯并四氢呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基,3-喹啉基,4-喹啉基)、
等等。
术语“杂芳基烷基”或“杂芳基亚烷基”可以交换使用,都是指烷基基团被一个或多个杂芳基所取代,其中杂芳基和烷基基团具有本发明所述的含义,这样的实例包括,但并不限于咪唑-2-基亚甲基,呋喃-2-基亚乙基,吲哚-3-基亚甲基等。
像本发明所描述的,取代基画一个键连接到中心的环上形成的环体系(如式c所示)代表取代基在该环上任何可取代的位置都可以取代。例如,式c代表取代基R可在C环上任何可能被取代的位置上单取代或多取代,如式c1~式c19所示。
像本发明所描述的,一个连接键连接到环体系上(如式d所示)代表连接键可以在环体系上任何可连接的位置与分子其余部分相连。式d代表环上任何可能连接的位置均可与分子其余部分相连,如式d1~式d5所示。
本发明中,R
4为-(CH
2)
m-L-(CH
2)
n-G,其中L基团的的左右连接键可互换地连接到(CH
2)
m和(CH
2)
n上;例如,当L为-NR
x-C(=O)-、-NR
x-S(=O)
t-、-NR
x-C(=O)-NR
y-或-NR
x-C(=O)-O-时,-(CH
2)
m-L-(CH
2)
n-G定义为L的左端连接(CH
2)
m同时L的右端连接(CH
2)
n,和L的左端连接(CH
2)
n同时L的右端连接(CH
2)
m两种情况,其中优选的方案为:当L为-NR
x-C(=O)-、-NR
x-S(=O)
t-、-NR
x-C(=O)-NR
y-或-NR
x-C(=O)-O-时,L的左端连接(CH
2)
m同时L的右端连接(CH
2)
n;另外当L为-C(=O)-O-时,-(CH
2)
m-L-(CH
2)
n-G定义为-(CH
2)
m-C(=O)-O-G和-(CH
2)
m-O-C(=O)-(CH
2)
n-G两种情况,其中,优选的方案为,当L为-C(=O)-O-时,-(CH
2)
m-L-(CH
2)
n-G定义为-(CH
2)
m-O-C(=O)-G。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式(I)或式(II)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C
1-24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基,即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献:T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定,其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化,还原,水解,酰胺化,脱酰胺作用,酯化,脱脂作用,酶裂解等等方法得到。相应地,本发明包括化合物的代谢产物,包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,如文献:S.M.Berge et al.,J.Pharmaceutical Sciences,66:1-19,1977所记载的。药学上可接受的无毒的酸形成的盐包括,但并不限于,与氨基基团反应形成的无机酸盐有盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐,和有机酸盐如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐,或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐,藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,苯甲酸盐,重硫酸盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊基丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,反丁烯二酸盐,葡庚糖酸盐,甘油磷酸盐,葡萄糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖醛酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,丙二酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,棕榈酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,硬脂酸盐,硫氰酸盐,对甲苯磺酸盐,十一酸盐,戊酸盐,等等。通过适当的碱得到的盐包括碱金属,碱土金属,铵和N
+(C
1-4烷基)
4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C
1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化 物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸,氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
术语“氮氧化物”是指当化合物含几个胺官能团时,可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是,N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514),其中例如在惰性溶剂,例如二氯甲烷中,使胺化合物与间-氯过苯甲酸(MCPBA)反应。
术语“载体”包括任何溶剂,分散介质,包衣衣料,表面活性剂,抗氧化剂,防腐剂(例如抗细菌剂、抗真菌剂),等渗剂,盐,药物稳定剂,粘合剂,赋形剂,分散剂,润滑剂,甜味剂,调味剂,着色剂,或其组合物,这些载体都是所属技术领域技术人员已知的(如Remington's Pharmaceutical Sciences,18th Ed.Mack Printing Company,1990,pp.1289-1329所述)。除了任意常规载体与活性成分不相容的情况外,涵盖其在治疗或药物组合物中的用途。
如本发明所使用的术语“治疗”任何疾病或病症,在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中,“治疗”指缓和或改善至少一种身体参数,包括可能不为患者所察觉的身体参数。在另一些实施方案中,“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中,“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言,该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应,或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地,在适当的情况中,需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如"Remington′s Pharmaceutical Sciences",第20版,Mack Publishing Company,Easton,Pa.,1985;和“药用盐手册:性质、选择和应用(Handbook of Pharmaceutical Salts:Properties,Selection,and Use)”,Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002)中可找到另外一些适宜盐的列表。
另外,本发明公开的化合物、包括它们的盐,也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO,等等)的形式得到,用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物;因此,本发明旨在包括溶剂化的和未溶剂化的形式。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构,除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,如
2H,
3H,
11C,
13C,
14C,
15N,
17O,
18O,
18F,
31P,
32P,
35S,
36Cl和
125I。
另一方面,本发明所述化合物包括同位素富集的本发明所定义的化合物,例如,其中存在放射性同位素,如
3H,
14C和
18F的那些化合物,或者其中存在非放射性同位素,如
2H和
13C。该类同位素富集的化合物可用于代谢研究(使用
14C)、反应动力学研究(使用例如
2H或
3H)、检测或成像技术,如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT),或可用于患者的放疗中。
18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)或式(II)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外,较重同位素特别是氘(即,
2H或D)的取代可提供某些治疗优点,这些优点是由代谢稳定性更高带 来的。例如,体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解,本发明中的氘被看做式(I)或式(II)所示化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘,该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5%的氘掺入)、至少4000(60%的氘掺入)、至少4500(67.5%的氘掺入),至少5000(75%的氘掺入),至少5500(82.5%的氘掺入)、至少6000(90%的氘掺入)、至少6333.3(95%的氘掺入)、至少6466.7(97%的氘掺入)、至少6600(99%的氘掺入)或至少6633.3(99.5%的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D
2O、丙酮-d
6、DMSO-d
6的那些溶剂化物。
本发明的化合物的描述
本发明涉及新的取代的氮杂五元环类化合物和所述化合物在药物方面的用途。本发明化合物或包含所述化合物的药物组合物作为PDE4抑制剂,对特应性皮炎有较好的治疗效果。
一方面,本发明涉及一种化合物,其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中,各R
1、R
2、R
3、R
4、R
5a、R
5b、R
6a、R
6b、X、X
1和R具有本发明所述的含义。
其中一些实施方案是,R
1和R
2各自独立地为氢、氘、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、C
3-8环烷基、3-10个原子组成的杂环基、C
6-10芳基、5-10个原子组成的杂芳基、C
3-8环烷基-C
1-4亚烷基、C
1-6烷基-C(=O)-、C
3-8环烷基-C(=O)-、3-10个原子组成的杂环基-C
1-4亚烷基、C
6-10芳基-C
1-4亚烷基或5-10个原子组成的杂芳基-C
1-4亚烷基;
X和X
1各自独立地为键、-O-、-S-、-N(R
c)-、-C(=O)-或-S(=O)
t-;
R
3为氢、氘、羧基、C
1-6烷基、C
1-6卤代烷基、C
2-4烯基、C
2-4炔基、C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C
3-8环烷基-C
1-4亚烷基、C
6-10芳基-C
1-4亚烷基、3-10个原子组成的杂环基-C
1-4亚烷基、5-10个原子组成的杂芳基-C
1-4亚烷基、C
1-6烷基-C(=O)-、C
1-6烷基-S(=O)
t-、C
1-6烷氧基-C(=O)-、C
3-8环烷基-C(=O)-、C
3-8环烷基-S(=O)
t-、3-10个原子组成的杂环基-C(=O)-、3-10个原子组成的杂环基-S(=O)
t-、-C(=O)-NR
dR
e、-S(=O)
t-NR
dR
e、C
6-10芳基-C(=O)-、5-10个原子组成的杂芳基-C(=O)-、C
6-10芳基-S(=O)
t-或5-10个原子组成的杂芳基-S(=O)
t-,其中R
3未被取代或被1、2、3或4个R
6所取代;
各R
6独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、C
1-4烷基、C
1-4卤代烷基、C
1-4烷氧基、C
1-4烷氨基或C
1-4烷基-C(=O)-N(R
c)-;
R
4为-(CH
2)
m-L-(CH
2)
n-G;
L为键、-O-、-S-、-NR
x-、-NR
x-C(=O)-、-NR
x-S(=O)
t-、-NR
x-C(=O)-NR
y-、-NR
x-C(=O)-O-、-S(=O)
t-、-C(=O)-、-O-C(=O)-或-C(=O)-O-;
优选地,L为-O-、-S-、-NR
x-、-NR
x-C(=O)-、-NR
x-S(=O)
t-、-NR
x-C(=O)-NR
y-、-NR
x-C(=O)-O-、-S(=O)
t-、 -C(=O)-或-C(=O)-O-,其中,-NR
x-C(=O)-、-NR
x-S(=O)
t-、-NR
x-C(=O)-NR
y-和-NR
x-C(=O)-O-的左端分别与(CH
2)
m连接,右端分别与(CH
2)
n连接,-C(=O)-O-的右端与(CH
2)
m连接,左端与(CH
2)
n连接;
其中,各R
x和R
y独立地为氢、氘、C
1-6烷基、C
1-6卤代烷基、C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C
3-8环烷基-C
1-6亚烷基、C
6-10芳基-C
1-6亚烷基、3-10个原子组成的杂环基-C
1-6亚烷基、5-10个原子组成的杂芳基-C
1-6亚烷基、C
1-6烷基-S(=O)
t-、C
1-6烷基-C(=O)-或C
1-6烷氧基-C(=O)-C
1-6亚烷基;G为C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基或5-10个原子组成的杂芳基;其中G未被取代或被1、2、3或4个R
7所取代;
各R
7独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、羧基、C
1-6烷基、C
1-6卤代烷基、C
1-
6烷氧基、C
1-6烷氨基、-C(=O)-NR
aR
b、-S(=O)
t-NR
aR
b、C
1-6烷基-C(=O)-N(R
c)-、C
1-6烷基-S(=O)
t-N(R
c)-、C
1-6烷氧基-C(=O)-N(R
c)-、C
1-6烷基-C(=O)-、C
1-6烷基-S(=O)
t-、C
1-6烷氧基-C(=O)-、C
1-6烷基-C(=O)-O-、C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基或5-10个原子组成的杂芳基;
各R
a和R
b独立地为氢、氘、C
1-6烷基、C
1-6卤代烷基、C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C
3-8环烷基-C
1-6亚烷基、C
6-10芳基-C
1-6亚烷基、3-10个原子组成的杂环基-C
1-6亚烷基、5-10个原子组成的杂芳基-C
1-6亚烷基、C
1-6烷基-S(=O)
t-或C
1-6烷基-C(=O)-,其中各R
a和R
b独立地未被取代或被1、2或3个选自氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、-C(=O)-NH
2、C
1-6烷氧基C(=O)-、C
1-6烷基-C(=O)-N(R
c)-、C
1-6烷基-S(=O)
t-N(R
c)-、C
1-4烷基、C
1-4卤代烷基、C
1-4烷氧基或C
1-4烷氨基的基团所取代;
各R
d和R
e独立地为氢、氘、C
1-6烷基、C
1-6卤代烷基、C
3-8环烷基、C
6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C
3-8环烷基-C
1-6亚烷基、C
6-10芳基-C
1-6亚烷基、3-10个原子组成的杂环基-C
1-6亚烷基、5-10个原子组成的杂芳基-C
1-6亚烷基、C
1-6烷基-S(=O)
t-或C
1-6烷基-C(=O)-,其中各R
d和R
e独立地未被取代或被1、2或3个选自氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、-C(=O)-NH
2、C
1-6烷氧基C(=O)-、C
1-6烷基-C(=O)-N(R
c)-、C
1-6烷基-S(=O)
t-N(R
c)-、C
1-4烷基、C
1-4卤代烷基、C
1-4烷氧基或C
1-4烷氨基的基团所取代;
各R
c独立地为氢、氘、C
1-3烷基或C
1-3卤代烷基;
R为氢、氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、C
1-3烷基、C
1-3烷氧基、C
1-3卤代烷氧基或C
1-3卤代烷基;
R
5a、R
5b、R
6a和R
6b各自独立地为氢、氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、C
1-3烷基、C
1-3烷氧基、C
1-3卤代烷氧基或C
1-3卤代烷基;
t为1或2;
n为0、1、2、3或4;
m为1、2、3或4。
其中一些实施方案是,本发明涉及一种化合物,其为式(II)所示的化合物或式(II)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中,各R
1、R
2、R
3、R
5a、R
5b、R
6a、R
6b、R、L、n和G具有本发明所述的含义。
其中一些实施方案是,本发明涉及一种化合物,其为式(III)所示的化合物或式(III)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中,各R
1、R
2、R
3、R
5a、R
5b、R
6a、R
6b、R、G、L和n具有如本发明所述的含义。
其中一些实施方案是,本发明涉及一种化合物,其为式(IV)所示的化合物或式(IV)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中,各R
1、R
2、R
3、R
5a、R
5b、R
6a、R
6b、R、L、n和G具有本发明所述的含义。
其中一些实施方案是,本发明涉及一种化合物,其为式(V)所示的化合物或式(V)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中,各R
1、R
2、R
3、R
5a、R
5b、R
6a、R
6b、R、G、L和n具有如本发明所述的含义。
其中一些实施方案是,本发明涉及一种化合物,其为式(VI)所示的化合物或式(VI)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中,各R
1、R
2、R
3、R
5a、R
5b、R
6a、R
6b、R、G、L和n具有如本发明所述的含义。
其中一些实施方案是,本发明涉及一种化合物,其为式(VII)所示的化合物或式(VII)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中,各R
1、R
2、R
3、R
5a、R
5b、R
6a、R
6b、R、G、L和n具有如本发明所述的含义。
其中一些实施方案是,R
1为氢、氘、甲基、乙基、正丙基、异丙基、异丁基、-CH
2F、-CHF
2、-CF
3、-CH
2CH
2F、-CH
2CHF
2、-CH
2CF
3、-CH
2CH
2CH
2F、-CH
2CH
2CHF
2、-CH
2CH
2CF
3、-CH
2Cl、-CHCl
2、-CH=CH
2、-CH
2CH=CH
2、-C≡CH、-CH
2C≡CH、环丙基、环丁基、环戊基、环己基、环丙基亚甲基、环丙基亚乙基、环丁基亚甲基、环丁基亚乙基、环戊基亚甲基、环戊基亚乙基、环己基亚甲基、环己基亚乙基、CH
3C(=O)-、CH
3CH
2C(=O)-、CH
3CH
2CH
2C(=O)-、(CH
3)
2CHC(=O)-、环丙基-C(=O)-、环丁基-C(=O)-、环戊基-C(=O)-、环己基-C(=O)-、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C
1-3亚烷基、萘基-C
1-3亚烷基、吡啶基-C
1-3亚烷基、嘧啶基-C
1-3亚烷基、呋喃基-C
1-3亚烷基、噻吩基-C
1-3亚烷基、吡咯基-C
1-3亚烷基、吡唑基-C
1-3亚烷基、噻唑基-C
1-3亚烷基、恶唑基-C
1-3亚烷基、三氮唑基-C
1-3亚烷基、四氮唑基-C
1-3亚烷基、哌嗪基-C
1-3亚烷基、哌啶基-C
1-3亚烷基、吗啉基-C
1-3亚烷基、硫代吗啉基-C
1-3亚烷基、四氢吡喃基-C
1-3亚烷基或吡咯烷基-C
1-3亚烷基。
其中一些实施方案是,R
2为氢、氘、甲基、乙基、正丙基、异丙基、异丁基、-CH
2F、-CHF
2、-CF
3、-CH
2CH
2F、-CH
2CHF
2、-CH
2CF
3、-CH
2CH
2CH
2F、-CH
2CH
2CHF
2、-CH
2CH
2CF
3、-CH
2Cl、-CHCl
2、-CH=CH
2、-CH
2CH=CH
2、-C≡CH、-CH
2C≡CH、环丙基、环丁基、环戊基、环己基、环丙基亚甲基、环丙基亚乙基、环丁基亚甲基、环丁基亚乙基、环戊基亚甲基、环戊基亚乙基、环己基亚甲基、环己基亚乙基、CH
3C(=O)-、CH
3CH
2C(=O)-、CH
3CH
2CH
2C(=O)-、(CH
3)
2CHC(=O)-、环丙基-C(=O)-、环丁基-C(=O)-、环戊基-C(=O)-、环己基-C(=O)-、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C
1-3亚烷基、萘基-C
1-3亚烷基、吡啶基-C
1-3亚烷基、嘧啶基-C
1-3亚烷基、呋喃基-C
1-3亚烷基、噻吩基-C
1-3亚烷基、吡咯基-C
1-3亚烷基、吡唑基-C
1-3亚烷基、噻唑基-C
1-3亚烷基、恶唑基-C
1-3亚烷基、三氮唑基-C
1-3亚烷基、四氮唑基-C
1-3亚烷基、哌嗪基-C
1-3亚烷基、哌啶基-C
1-3亚烷基、吗啉基-C
1-3亚烷基、硫代吗啉基-C
1-3亚烷基、四氢吡喃基-C
1-3亚烷基或吡咯烷基-C
1-3亚烷基。
其中一些实施方案是,R
3为氢、氘、羧基、C
1-3烷基、C
1-3卤代烷基、C
2-4烯基、C
2-4炔基、CH
3-C(=O)-、CH
3CH
2-C(=O)-、CH
3CH
2CH
2-C(=O)-、(CH
3)
2CH-C(=O)-、CH
3-S(=O)
2-、CH
3CH
2-S(=O)
2-、CH
3CH
2CH
2-S(=O)
2-、(CH
3)
2CH-S(=O)
2-、CH
3-O-C(=O)-、CH
3CH
2-O-C(=O)-、CH
3CH
2CH
2-O-C(=O)-、(CH
3)
2CH-O-C(=O)-、-S(=O)
2-NH
2或-C(=O)-NH
2,其中R
3未被取代或被1、2、3或4个R
6所取代。
其中一些实施方案是,各R
6独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、甲基、乙基、正丙基、异丙基、-CH
2F、-CHF
2、-CF
3、-CH
2CH
2F、-CH
2CHF
2、-CH
2CF
3、-CH
2CH
2CH
2F、-CH
2CH
2CHF
2、-CH
2CH
2CF
3、-CH
2Cl、-CHCl
2、甲氧基、乙氧基、正丙基氧基、甲氨基、乙氨基或正丙基氨基。
其中一些实施方案是,各R
x独立地为氢、氘、甲基、乙基、正丙基、异丙基、C
1-4卤代烷基、环丙基、环丁基、环戊基、环己基、环丙基-C
1-3亚烷基、环丁基-C
1-3亚烷基、环戊基-C
1-3亚烷基、环己基-C
1-3亚烷基、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C
1-3亚烷基、萘基-C
1-3亚烷基、吡啶基-C
1-3亚烷基、嘧啶基-C
1-3亚烷基、呋喃基-C
1-3亚烷基、噻吩基-C
1-3亚烷基、吡咯基-C
1-3亚烷基、吡唑基-C
1-3亚烷基、噻唑基-C
1-3亚烷基、恶唑基-C
1-3亚烷基、三氮唑基-C
1-3亚烷基、四氮唑基-C
1-3亚烷基、哌嗪基-C
1-3亚烷基、哌啶基-C
1-3亚烷基、吗啉基-C
1-3亚烷基、硫代吗啉基-C
1-3亚烷基、四氢吡喃基-C
1-3亚烷基、吡咯烷基-C
1-3亚烷基、C
1-3烷基-S(=O)
2-、C
1-3烷基-C(=O)-或C
1-3烷氧基-C(=O)-C
1-3亚烷基。
其中一些实施方案是,各R
y独立地为氢、氘、甲基、乙基、正丙基、异丙基、C
1-4卤代烷基、环丙基、环丁基、环戊基、环己基、环丙基-C
1-3亚烷基、环丁基-C
1-3亚烷基、环戊基-C
1-3亚烷基、环己基-C
1-3亚烷基、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C
1-3亚烷基、萘基-C
1-3亚烷基、吡啶基-C
1-3亚烷基、嘧啶基-C
1-3亚烷基、呋喃基-C
1-3亚烷基、噻吩基-C
1-3亚烷基、吡咯基-C
1-3亚烷基、吡唑基-C
1-3亚烷基、噻唑基-C
1-3亚烷基、恶唑基-C
1-3亚烷基、三氮唑基-C
1-3亚烷基、四氮唑基-C
1-3亚烷基、哌嗪基-C
1-3亚烷基、哌啶基-C
1-3亚烷基、吗啉基-C
1-3亚烷基、硫代吗啉基-C
1-3亚烷基、四氢吡喃基-C
1-3亚烷基、吡咯烷基-C
1-3亚烷基、C
1-3烷基-S(=O)
2-、C
1-3烷基-C(=O)-或C
1-3烷氧基-C(=O)-C
1-3亚烷基。
其中一些实施方案是,各R
7独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、羧基、C
1-4烷基、C
1-4卤代烷基、C
1-4烷氧基、C
1-4烷氨基、-C(=O)-NR
aR
b、-S(=O)
2-NR
aR
b、C
1-4烷基-C(=O)-NH-、C
1-4烷基-S(=O)
2-NH-、C
1-4烷氧基-C(=O)-NH-、CH
3-C(=O)-、CH
3CH
2-C(=O)-、CH
3CH
2CH
2-C(=O)-、(CH
3)
2CH-C(=O)-、CH
3CH
2CH
2CH
2-C(=O)-、CH
3-S(=O)
2-、CH
3CH
2-S(=O)
2-、CH
3CH
2CH
2-S(=O)
2-、(CH
3)
2CH-S(=O)
2-、CH
3O-C(=O)-、CH
3CH
2O-C(=O)-、CH
3CH
2CH
2O-C(=O)-、(CH
3)
2CHO-C(=O)-、CH
3CH
2CH
2CH
2O-C(=O)-、CH
3-C(=O)-O-、CH
3CH
2-C(=O)-O-、CH
3CH
2CH
2-C(=O)-O-、(CH
3)
2CH-C(=O)-O-、CH
3CH
2CH
2CH
2-C(=O)-O-、环丙基、环丁基、环戊基、环己基、
其中,各R
a和R
b具有本发明所述的含义。
其中一些实施方案是,各R
a和R
b独立地为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、-CH
2F、-CHF
2、-CF
3、-CH
2CH
2F、-CH
2CHF
2、-CH
2CF
3、-CH
2CH
2CH
2F、-CH
2CH
2CHF
2、-CH
2CH
2CF
3、-CH
2Cl、-CHCl
2、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C
1-3亚烷基、萘基-C
1-3亚烷基、吡啶基-C
1-3亚烷基、嘧啶基-C
1-3亚烷基、呋喃基-C
1-3亚烷基、噻吩基-C
1-3亚烷基、吡咯基-C
1-3亚烷基、吡唑基-C
1-3亚烷基、噻唑基-C
1-3亚烷基、恶唑基-C
1-3亚烷基、三氮唑基-C
1-3亚烷基、四氮唑基-C
1-3亚烷基、哌嗪基-C
1-3亚烷基、哌啶基-C
1-3亚烷基、吗啉基-C
1-3亚烷基、硫代吗啉基-C
1-3亚烷基、四氢吡喃基-C
1-3亚烷基、吡咯烷基-C
1-3亚烷基、C
1-3烷基-S(=O)
2-或C
1-3烷基-C(=O)-;其中各R
a和R
b独立地未被取代或被1、2或3个选自氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代(=O)、-C(=O)-NH
2、C
1-3烷氧基C(=O)-、C
1-3烷基-C(=O)-NH-、C
1-3烷基-S(=O)
t-NH-、甲基、乙基、正丙基、异丙基、正丁基、-CH
2F、-CHF
2、-CF
3、-CH
2CH
2F、-CH
2CHF
2、-CH
2CF
3、-CH
2CH
2CH
2F、-CH
2CH
2CHF
2、-CH
2CH
2CF
3、-CH
2Cl、-CHCl
2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、N-甲基氨基、N-乙基氨基、N’N-二甲基氨基、N’N-二乙基氨基或N’N-甲基乙基氨基的基团所取代。
其中一些实施方案是,各R
c独立地为氢、氘、C
1-3烷基或C
1-3卤代烷基。
其中一些实施方案是,R为氢、氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、-CH
2F、-CHF
2、-CF
3、-CH
2Cl或-CHCl
2。
其中一些实施方案是,R
5a、R
5b、R
6a和R
6b各自独立地为氢、氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、-CH
2F、-CHF
2、-CF
3、-CH
2Cl或-CHCl
2。
其中一些实施方案是,本发明包含但绝不限于具有下列之一结构的化合物或具有下列之一结构化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中一些实施方案是,本发明式(I)、(II)、(III)、(IV)、(V)、(VI)和(VII)所示的化合物,其药学上可接受的盐是盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、丙酮酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合。
一方面,本发明涉及一种药物组合物,所述药物组合物包含本发明公开的式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所述的化合物。
其中一些实施方案是,本发明所述的药物组合物,其进一步地包含药学上可接受的载体、赋形剂、附加剂、辅剂、媒介物或它们的任意组合。
其中一些实施方案是,本发明所述的药物组合物,进一步地包含附加治疗剂,其中所述的附加治疗剂 是:丙酮酸钠、多索茶碱、替托司特、泰鲁司特、茶碱、福莫特罗、沙美特罗、氟替卡松丙酸酯、咯利普兰、吡拉米斯特、西洛司特、茚达特罗、奥达特罗、米地司坦、齐流通、沙丁醇胺、卡莫昔罗、布地奈德、二丙酸倍氯米松、曲安奈德、氟尼缩松、糠酸莫米松、罗氟奈德、环索奈德、异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、芜地溴铵、维兰特罗、阿地溴铵、Benralizumab、Tralokinumab、瑞伐托酯、克瑞沙硼、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、地索奈德、氢化可的松、氯倍他索(clobatsol)、卤贝他索、二氟拉松、美普克莱、他克莫司、吡美莫司、他扎罗汀、环孢素、阿普斯特、E-6005、OPA-15406、LEO-29102、DRM02、罗氟司特、异丁司特、托法替尼、JTE-052、巴瑞替尼、乌帕替尼、WBI-1001、MRX-6、GSK2981278、杜鲁单抗、来金珠单抗、尼莫利珠单抗、曲洛吉努单抗、依那西普、阿达木单抗、英夫利昔单抗、尤特可单抗、塞库吉努、奥马珠、CIM-331、戈利木单抗和聚乙二醇化赛、妥珠单抗、卡泊三醇、骨化三醇、阿利维A酸、VTP-38543、ZPL-389、阿瑞匹坦、曲地匹坦、弗维普兰特、、OC-459、SUN 13834、SB-011、VTP-43742、ARN6039、TAK-828、JTE-451、PF-04965842、PF-06651600、PF-06700841、PF-06650833、GR-MD-02或它们的任意组合。
另一方面,本发明涉及本发明公开的式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示化合物或其药物组合物在制备药物中的用途,其中所述药物用于预防、治疗或减轻与4型磷酸二酯酶(PDE4)有关的疾病。
其中一些实施方案是,所述与4型磷酸二酯酶(PDE4)有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病、肺纤维化或非胰岛素依赖糖尿病。
另外一些实施方案是,所述的呼吸疾病为:慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症;其中支气管炎包括急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎;
其中所述的炎症为:过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。
本发明另一方面涉及式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物的制备、分离和纯化的方法。
本发明化合物的药物组合物、制剂和给药
本发明提供一种药物组合物,包括式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示化合物或其单独的立体异构体、异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂化物。在本发明的一个实施方式中,所述药物组合物进一步包含至少一种药学上可接受的载体、赋形剂、吸附剂、辅剂或媒介物,以及任选地,其它的治疗和/或预防成分。
合适的载体、赋形剂或吸附剂对于本领域技术人员是熟知的并且详细描述于例如Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia;Gennaro A.R.et al.,Remington:The Science and Practice of Pharmacy(2000)Lippincott,Williams&Wilkins,Philadelphia;和Rowe R.C.,Handbook of Pharmaceutical Excipients(2005)Pharmaceutical Press,Chicago中。
本发明所用“药学上可接受的赋形剂”意指与给药剂型或药物组合物一致性相关的药学上可接受的材料,混合物或溶媒。每种赋形剂在混合时必须与药物组合物的其它成分相容,以避免对患者给药时会大大降低本发明公开化合物的功效的相互作用和会导致不是药学上可接受的药物组合物的相互作用。此外,每种赋形剂必须是药学上可接受的,例如,具有足够高的纯度。
合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外,可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。例如,可选择能有助于生产均一剂型的某些药学上可接受的赋形剂。可选择能有助于生产稳定剂型的某些药学上可接受的赋形剂。可选择对患者给药时有助于携带或运输本发明化合 物从身体的一个器官或部分到身体的另一个器官或部分的某些药学上可接受的赋形剂。可选择增强患者依从性的某些药学上可接受的赋形剂。
一些合适的赋型剂实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、西黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。合适的药学上可接受的赋形剂还包括以下类型的赋形剂:溶媒、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏着剂、抗氧剂、螯合剂、渗透促进剂、pH调节剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂和助滤剂。技术人员可认识到,某些药学上可接受的赋形剂可提供不止一种功能,并提供可供选择的功能,这取决于制剂中存在多少该赋形剂和制剂中存在哪些其他赋形剂。可以采用本领域的已知方法来配制本发明化合物,以便对患者给药后能快速、持续或延缓释放出活性组份。
技术人员掌握本领域的知识和技能,以使他们能选择用于本发明的适当量的合适的药学上可接受的赋形剂。此外,存在大量技术人员可获得的资源,他们描述药学上可接受的赋形剂,并用于选择合适的药学上可接受的赋形剂。实例包括Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
在Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York中披露了用于配置药学上可接受的组合物的各种载体,和用于其制备的公知技术,这些文献各自的内容通过引用并入本发明。除任何诸如因产生任何不期望的生物作用,或以有害方式与药学上可接受组合物中的任何其它成分发生相互作用而与本发明化合物不相容的任何常用载体外,关注其应用属于本发明的范围。
合适的药学上可接受的载体取决于药物形式并且是本领域技术人员所知的。
如本发明中使用的,“药学上可接受的载体”包括任何和全部的溶剂和溶剂混合物,涂层,络合剂,固体载体,分散体介质,表面活性赋形剂,抗细菌和抗真菌药,用于药物活性物质的等渗和吸收延迟剂,和其混合物,这些同样是本领域已知的。
用于药学上可接受的载体的非限制性实例包括具有选自如下组分的那些:乳糖,明胶,糖醇(例如淀粉,甘露醇,玉米淀粉等),植物油,滑石,硬脂酸镁,胶体二氧化硅,羧甲基纤维素,微晶纤维素,十二烷硫酸钠,缓冲水溶液,共聚维酮,聚山梨酸酯,乙醇,丙二醇,聚二醇(优选地聚乙二醇,例如PEG400),
(即PEG(20),山梨糖醇一油酸酯),DMSO,水和助溶剂的混合物,例如包括醇如乙醇和/或聚二醇如聚乙二醇的水溶液,多元醇如甘油和/或聚乙二醇与脂肪酸的酯,表面活性剂如阴离子、阳离子、非离子和两性表面活性剂,络合剂如环糊精,例如α-环糊精(α-CD)或者羟丙基-β-环糊精(HP-β-CD),胆汁酸或者脂质,例如动物或者植物磷脂的盐,成胶束剂,和油如玉米油,或前面提及的两种或更多种组分的混合物。
下面提及可用于本发明的药物组合物的进一步的合适的药学上可接受的载体以及合适的添加剂的非限制性实例。
在一个实施方案中,本发明涉及本发明的药物组合物,其在水介质中形成基于脂质的药物输送系统(DDS)。所述药物组合物,除式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物中的至少一种化合物或其盐以外,还包括至少一种表面活性剂。合适的表面活性剂的非限制性实例是如上所述的。在各种实施方案中,基于脂质的药物输送系统形成以下结构:(1)脂质体(即水中层状相的分散闭合的双层组装体); (2)非层状相(例如立方体、六角形、海绵状物)的纳米颗粒;或(3)胶束,乳状液,微乳状液(即脂质和表面活性剂的简单自组装结构)。
在一些实施方案中,形成胶束、乳状液或者微乳状液的基于脂质的药物输送系统是优选的。用于形成胶束、乳状液或微乳状液的合适的表面活性剂或者表面活性剂混合物的亲水亲油平衡值(HLB-值)一般为约8-18,约10-18,或约12-16。基于脂质的药物输送系统形成自乳化药物输送系统(SEDDS)或者自微乳化药物输送系统(SMEDDS)。SEDDS和SMEDDS是油(即脂质,例如式(I)的化合物或者其盐),至少一种表面活性剂,任选地至少一种助溶剂和任选地至少一种助表面活性剂的混合物,理想地各向同性的,在温和的搅拌下当被引入水相时,其自发地乳化而形成水包油乳化剂。温和的搅拌可以例如由胃的活动性提供。
本发明公开的药物组合物使用本领域技术人员已知的技术和方法来制备。本领域一些常用方法的描述可参见Remington's Pharmaceutical Sciences(Mack Publishing Company)。
因此,另一方面,本发明涉及制备药物组合物的工艺,所述药物组合物包含本发明公开化合物和药学上可接受的赋形剂,载体,辅剂,溶媒或它们的组合,该工艺包括混合各种成分。包含本发明公开化合物的药物组合物,可以在例如环境温度和大气压下混合来制备。
本发明公开的化合物通常被配制成适合于通过所需途径对患者给药的剂型。例如,所述剂型包括那些适合于以下给药途径的剂型:(1)口服给药,例如片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、香包剂和扁囊剂;(2)胃肠外给药,例如无菌溶液剂、混悬剂和复溶粉末;(3)透皮给药,例如透皮贴片剂;(4)直肠给药,例如栓剂;(5)吸入,例如气雾剂、溶液剂和干粉剂;和(6)局部给药,例如乳膏剂、油膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。
将各种固体口服剂型用于本发明化合物的给药,例如片剂、胶囊、颗粒、锭剂和散装粉末的固体剂型。可以将本发明化合物单独给药或与本领域已知的各种药学上可接受的载体和赋形剂(例如,蔗糖、甘露醇、乳糖、淀粉)组合给药,包括但不限于助悬剂、增溶剂、缓冲剂、粘合剂、崩解剂、防腐剂、着色剂、调味剂、润滑剂等。定时释放胶囊、片剂和凝胶剂对于本发明化合物的给药也是有利的。
可以将各种外用剂型用于本发明化合物的给药,例如洗剂、软膏剂、酊剂、擦剂、醑剂、粉剂、霜剂、油剂、糊剂、硬膏剂、涂膜剂和气雾剂。局部给药还可以包括通过例如透皮贴片的方式进行的透皮给药。可以将本发明化合物单独给药或与本领域已知的各种药学上可接受的载体、稀释剂和赋形剂组合给药,包括但不限于溶剂、油性溶剂、稀释剂、安定剂、吸收延迟剂、崩散剂、乳化剂、抗氧化剂、粘合剂、结合剂、增粘剂、增溶剂、分散剂、悬乳化剂、润滑剂、吸湿剂、脂质体、微乳和β-环糊精等。
对于呼吸道疾病的治疗,优选本发明的化合物通过吸入给药。
可吸入制备物包括可吸入的粉剂、含推进剂的计量气雾剂或不含推进剂的可吸入制剂。为此,可以以粉剂(最好为微粒化形式)直接给药,或通过含有它们的喷雾溶液剂或混悬液给药。
可以向本发明的粉末化合物加入赋形剂或载体,所述赋形剂或载体通常是无毒的并且对于本发明的化合物为化学惰性的,例如乳糖或适合于改善可呼吸部分的任何其他添加剂。
包含气体推进剂例如氢氟烷烃的吸入气雾剂可以包含溶液或分散型形式的本发明化合物。推进剂驱动的制剂还可以包含其他成分,例如共溶剂、稳定剂和任选的其他赋形剂。
含本发明化合物的不含推进剂的可吸入制剂可以是在含水介质、醇类介质或含水酒精介质中的溶液或悬浮液形式,并且它们可以通过现有技术已知的喷射雾化器或超声雾化器递送,或者通过细雾雾化器(soft-mist nebulizers)例如
递送。
本发明所使用的术语“治疗有效量”是指足以显示出有益的治疗效果的各活性组分的总量。例如,给药或使体内达到平衡的足以治疗、治愈或减轻疾病的症状的量。特殊的治疗方案所需的有效量依赖于多种因 素,包括治疗的疾病,疾病的严重程度,使用的特定药物的活性,给药方式,特定药物的清除率,治疗持续时间,联合用药,年龄,体重,性别,饮食和病人的健康等。本领域关于“治疗有效量”需要考虑的其他因素的描述可参见Gilman et al.,eds.,Goodman And Gilman’s:The Pharmacological Bases of Therapeutics,8
th ed.,Pergamon Press,1990;Remington's Pharmaceutical Sciences,17
th ed.,Mack Publishing Company,Easton,Pa.,1990。
本发明的化合物的剂量取决于多种因素,包括要治疗的具体疾病、症状的严重程度、给药途径、剂量间隔频率、所用的具体化合物、化合物的效力、毒理学特征和药代动力学的特征。
可与载体材料相组合从而产生单剂量形式的活性成分的量将取决于被治疗的宿主和特定的施用方式而变化。例如,意欲涂抹施用给人的制剂可以方便地含有约5mg至约250mg/千克体重/天的活性剂,其与合适且方便的量的载体材料(可占总组合物的大约5%至大约95%)相复合。单位剂量形式一般将包含大约1mg至大约500mg的活性成分。
有利地,它们以5-250mg/千克体重/天,优选地25-150mg/千克体重/天剂量给药。
术语“给药”指给个体提供治疗有效量的药物,给药方式包括口服,舌下,静脉,皮下,经皮,肌内,皮内,鞘内,硬膜上,眼内,颅内,吸入,直肠,阴道等。给药剂型包括膏剂,洗剂,片剂,胶囊剂,丸剂,飞散性粉末剂,颗粒剂,栓剂,丹剂,锭剂,注射剂,无菌溶液或非水溶液剂,悬浮剂,乳剂,贴片剂等。活性组分与无毒的药学上可接受的载体(如葡萄糖,乳糖,阿拉伯树胶,明胶,甘露醇,淀粉糊,三硅酸镁,滑石粉,玉米淀粉,角蛋白,硅胶,土豆淀粉,尿素,右旋糖酐等)复合。
优选的给药途径会随着临床特征而变化,剂量的变化必须依赖于正在治疗的病人的情况,医生会根据个体患者来确定合适的剂量。每单位剂量的治疗有效量取决于体重,生理机能和选择的接种方案。每单位剂量的化合物是指每次给药时化合物的重量,不包括载体的重量(药物里含有载体)。
任何合适的给药途径都可用于向哺乳动物,尤其是人提供有效剂量的本发明的化合物。例如,可采用口服给药、直肠给药、非肠道给药、局部给药、经眼给药、经鼻给药、经肺给药等。剂型包括片剂、锭剂、胶囊、霜剂、膏剂、悬浮液、分散体、溶液、气雾剂等。优选地,式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物吸入给药或局部给药。
本发明提供的药物组合物可以配制成单剂量或多剂量给药。所述单剂量制剂被包装在安瓿剂、小瓶或注射器中。所述多剂量肠胃外制剂必须包含抑菌或抑真菌浓度的抗微生物剂。所有的肠胃外制剂都必须是无菌的,如本领域已知和实践的。
本发明提供的药物组合物可以与不会损害预期的治疗作用的其它活性成分共同配制,或者与补充预期的作用的物质共同配制。
在一些实施方案中,本发明的治疗方法包括对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物。本发明各实施方案包括通过对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物,来治疗本发明提及的疾病。
在一些实施方案中,本发明化合物或包含本发明化合物的药物组合物可以一次性给药,或者根据给药方案,在指定时间段内,在不同的时间间隔给药若干次。例如,每天给药一次、两次、三次或四次。在一些实施方案中,每天给药一次。在又一些实施方案中,每天给药两次。可以给药直至达到想要的治疗效果或无限期地维持想要的治疗效果。本发明化合物或包含本发明化合物的药物组合物的合适给药方案取决于该化合物的药代动力学性质,例如吸收、分布和半衰期,这些可以由技术人员测定。此外,本发明化合物或包含本发明化合物的药物组合物的合适给药方案,包括实施该方案的持续时间,取决于被治疗的疾病,被治疗疾病的严重程度、被治疗患者的年龄和身体状况、被治疗患者的医疗史、同时疗法的性质、想要的治疗效果等在技术人员知识和经验范围内的因素。这样的技术人员还应该理解,对于个体患者对给药方案 的反应,或随着时间推移个体患者需要变化时,可要求调整适宜的给药方案。
本发明化合物可以与一种或多种其它治疗剂同时,或在其之前或之后给药。本发明化合物可以与其他治疗剂通过相同或不同给药途径分别给药,或与之以同一药物组合物形式给药。这由本领域技术人员根据患者的健康、年龄、体重等身体的实际情况选择。如果配制为固定剂量,这种联用产品使用本发明的化合物(在本发明所描述的剂量范围之内)和其他药学活性剂(在其剂量范围之内)。
相应地,在一个方面,本发明包括联合用药,其包括一定数量的至少一种本发明的化合物或其可药用盐、溶剂化物、酯或前体药物和有效量的一种或多种上述附加治疗剂。
式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物可以与用于预防、治疗或减轻式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物适用的疾病或症状的其它药物联用。这些其它药物可通过其常用的途径和量与式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物同时或相继给药。当式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物与一种或多种其它药物同时使用时,含有这类其它药物以及式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物的药物单位剂型是优选的。
在各种实施方案中,本发明中所述的化合物与其它药物结合来提供用于慢性阻塞性肺病(COPD)、特应性皮炎(AD)、银屑病或其它状况的联合治疗。本发明的药物组合物包括本发明中所述的PDE4抑制剂中的至少一种和附加治疗剂,附加治疗剂的实例包括但不限于:
2-激动剂,例如沙丁醇胺、福莫特罗、沙美特罗和卡莫昔罗;
皮质类固醇类,例如布地奈德、二丙酸倍氯米松、丙酸氟替卡松、氟尼缩松、糠酸莫米松、罗氟奈德、环索奈德、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、地索奈德、氢化可的松、美普克莱;
抗胆碱能药或抗毒蕈碱药,例如异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、瑞伐托酯;
局部钙调磷酸酶抑制剂,例如他克莫司、吡美莫司、环孢素;
PDE4抑制剂的局部制剂,例如阿普斯特、异丁司特、E-6005、OPA-15406、LEO-29102、DRM02、罗氟司特、克瑞沙硼;
JAK激酶抑制剂的局部制剂,例如托法替尼、JTE-052、巴瑞替尼、乌帕替尼;
局部非甾体抗炎药物,例如WBI-1001、MRX-6;
局部ROR药剂,例如GSK2981278;
可注射抗IL4、IL-31、IL-22、IL-33、IL-12、IL-23、IL-17、IgE、IL-4治疗药物,例如杜鲁单抗(Dupilumab)、来金珠单抗、尼莫利珠单抗(Nemolizumab)、曲洛吉努单抗、依那西普、阿达木单抗、英夫利昔单抗、尤特可单抗、塞库吉努(Secukinumab)、奥马珠(Omazumilab)、CIM-331;
维生素D类似物,例如卡泊三醇、骨化三醇;
口服视黄酸衍生物,例如阿利维A酸;
口服肝X受体(LXR)选择性激动剂,例如VTP-38543;
口服H4受体拮抗剂,例如ZPL-389;
口服NK1受体拮抗剂,例如阿瑞匹坦、曲地匹坦;
口服CRTH2受体拮抗剂,例如弗维普兰特(Fevipiprant)、和OC-459;
口服糜蛋白酶抑制剂,例如SUN 13834。
优选地,给与单独的或与其他活性成分组合的式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示的化合物用于预防和/或治疗呼吸疾病或皮肤炎症疾病,例如慢性阻塞性肺病(COPD)、特应性皮炎(AD)或银屑病。
包含本发明化合物或药物组合物给药的治疗方法,进一步包括对患者进行其他抗慢性阻塞性肺病 (COPD)或特应性皮炎药物(联合治疗)的给药,其中其他抗慢性阻塞性肺病(COPD)或特应性皮炎的药物为上述附加治疗剂中的药物或它们的组合物。
本发明提供在需要这种治疗的患者中治疗肺病(例如,COPD、气喘或纤维囊肿)或炎症(例如,特应性皮炎或银屑病)的方法,该方法包括联合给予所述患者治疗有效量的至少一种式(I)或式(II)所示化合物,或其药学上可接受的盐或溶剂合物,以及至少一种选自下列的化合物:类固醇(如糖皮质激素)、钙调磷酸酶抑制剂、PDE4抑制剂、JAK激酶抑制剂、半胱氨酰基白三烯拮抗剂、非甾体抗炎药物、局部ROR药剂、抗IL4抗体、IL-31抗体、IL-22抗体、IL-33抗体、IL-12抗体、IL-23抗体、IL-17抗体、IgE抗体、IL-4抗体、维生素D类似物、肝X受体(LXR)选择性激动剂、组胺H1拮抗剂、组胺H3拮抗剂、H4受体拮抗剂、NK1受体拮抗剂、CRTH2受体拮抗剂、糜蛋白酶抑制剂、5-脂氧合酶抑制剂、β-2肾上腺素受体(adrenoceptor)激动剂、α-肾上腺素受体激动剂、蕈毒碱M1拮抗剂、蕈毒碱M3拮抗剂、蕈毒碱M2激动剂、NK3拮抗剂、LTB4拮抗剂、支气管扩张剂、PDE抑制剂。
本发明化合物和药物组合物的用途
本发明化合物或本发明的组合物中化合物的量可以有效地可探测地拮抗PDE4以治疗以下疾病:疼痛(例如,急性疼痛、急性炎性疼痛、慢性炎性疼痛和神经病性疼痛)、急性炎症、慢性炎症、银屑病关节炎、类风湿性关节炎、牛皮癣、增生性和炎性皮肤病(例如特应性皮炎、脂溢性皮炎、接触性皮炎)、哮喘、慢性阻塞性肺病(COPD)、关节炎、炎性肠道疾病、节段性回肠炎、溃疡性结肠炎、败血性休克、内毒素性休克、格兰氏阴性菌败血症、肾小球性肾炎、帕金森氏病、阿尔茨海默氏病、轻度认知损害(MCI)、抑郁症、焦虑症、急性呼吸道窘迫综合征、骨关节炎、强直性脊柱炎、多发性硬化、牙龈炎、牙周炎、搔痒症、疱疹、CNS肿瘤、间质性肺炎、过敏、结晶诱发的关节炎、急性胰腺炎、慢性胰腺炎、急性酒精性肝炎、坏死性小肠结肠炎、慢性鼻窦炎、急性呼吸窘迫综合症、肺高血压、痛风、酒精性肝病、狼疮、癌症、过敏性鼻炎、非过敏性鼻炎、自身免疫性溶血综合征、自身免疫性肝炎、自身免疫性神经病变、肝硬化、纤维化疾病、胃炎、Goodpasture氏综合征、格雷夫斯氏病、Gullain-Barre病、桥本氏甲状腺炎、HIV-相关的自身免疫性综合征和血液疾病、扁平苔癣、心肌炎(包括病毒性心肌炎)、神经病变(包括例如,IgA神经病变、细胞膜神经病变和特发性神经病变)、肾炎综合征、莱特尔氏综合征、斯耶格伦氏综合征、系统性红斑狼疮,该方法包括施于该病患有效量的至少一种式(I)、(II)或(III)所示化合物或其药学上可接受的盐或溶剂合物。
一般合成步骤
一般地,本发明的化合物可以通过本发明所描述的方法制备得到,除非有进一步的说明,其中取代基的定义如式(I)、(II)、(III)、(IV)、(V)、(VI)或(VII)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到:本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物,且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如,根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成,如适当的保护干扰基团,通过利用其他已知的试剂除了本发明所描述的,或将反应条件做一些常规的修改。另外,本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例,除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company,使用时都没有经过进一步纯化,除非其他方面表明。一般的试剂从汕头西陇化工厂,广东光华化学试剂厂,广州化学试剂厂,天津好寓宇化学品有限公司,青岛腾龙化学试剂有限公司和青岛海洋化工厂购买得到。
无水四氢呋喃,二氧六环,甲苯,乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯,石油醚,正己烷,N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明),反应瓶都塞上合适的橡皮塞,底物通过注射器打入。玻璃器皿都是干燥过的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振氢谱的测试条件是:室温条件下,布鲁克(Bruker)400MHz或600MHz的核磁仪,以CDC1
3,DMSO-d
6,CD
3OD或丙酮-d
6为溶剂(报导以ppm为单位),用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰),d(doublet,双峰),t(triplet,三重峰),q(quartet,四重峰),m(multiplet,多重峰),br(broadened,宽峰),dd(doublet of doublets,双二重峰),dt(doublet of triplets,双三重峰)。偶合常数,用赫兹(Hz)表示。
低分辨率质谱(MS)数据测定的条件是:Agilent 6120 Quadrupole HPLC-MS(柱子型号:Zorbax SB-C18,2.1x 30mm,3.5μm,6min,流速为0.6mL/min,流动相:5%-95%(含0.1%甲酸的CH
3CN)在(含0.1%甲酸的H
2O)中的比例)),在210/254nm用UV检测,用电喷雾电离模式(ESI)。
化合物纯度的表征方式为:Agilent 1260制备型高效液相色谱(Pre-HPLC)或Calesep Pump 250制备型高效液相色谱(Pre-HPLC)(柱子型号:NOVASEP,50/80mm,DAC),在210nm/254nm用UV检测。
本发明所述的各手性化合物的立体构型使用以下其中之一的分析方法进行拆分:
分析方法:
1.使用OD-H柱(厂家:大赛璐,规格:4.6×250mm,5μm),流动相条件:柱温30℃,流速1mL/min,20%乙醇,80%正己烷;
2.使用IA柱(厂家:大赛璐,规格:4.6×250mm,5μm)流动相条件:柱温40℃,流速1.0mL/min,40%乙醇,60%正己烷。下面简写词的使用贯穿本发明:
化合物(IA)的合成方案:
化合物(IA)可通过上述合成路线制备得到,其中R
1、R
2、R
3、X、X
1、R
5a、R
5b、R
6a、R
6b、R、n和G具有如本发明的定义。化合物(IA-1)与HOOC(CH
2)n-G在碱性或酸性条件下发生酯化反应得到化合物(IA)。
化合物(IB)的合成方案:
化合物(IB)可通过上述合成路线制备得到,其中R
1、R
2、R
3、X、X
1、R
5a、R
5b、R
6a、R
6b、R、n和G具有如本发明的定义。化合物(IB-1)或其盐(如盐酸盐,等)与HOOC(CH
2)n-G在合适条件下发生缩合反应得到化合物(IB)。
中间体N与中间体N’的合成方案:
中间体N可以通过中间体的合成方法制备得到,其中,除非另外说明,R
1和R
2具有如本发明所述的含义。起始物料N1与物料BnOH和叠氮磷酸二苯酯在碱性条件下发生反应,形成氨基保护基得到中间体N2,中间体N2经过催化氢化还原得到中间体N3,中间体N3经过重氮化反应,再与碘化钾发生取代反应得到中间体N;中间体N在酸性条件下脱去相应的基团R
1得到中间体N4,中间体N4与苄溴发生取代反应得到中间体N’。
中间体N与中间体N’的具体合成方法:
以下中间体N与中间体N’的具体合成方法仅为具体合成方法的举例,本发明中所指的中间体N与中间体N’的合成方法应包括,但不限于以下具体实施例。
中间体N2:(3-环丙甲氧基-4-二氟甲氧基)苯基)氨基甲酸苯甲酯的合成
将3-环丙甲氧基-4-二氟甲氧基苯甲酸(5.0g,19.4mmol)溶于甲苯(25ml)中,加入DPPA(5.0mL,23.0mmol),三乙胺(4.3mL,31.0mmol),室温下反应1h,加入苯甲醇(3.0mL,29.0mmol),加热至90℃加热反应3h。减压浓缩除去溶剂,剩余物加入水(100ml),然后用乙酸乙酯萃取(25mL×3),有机相用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=4/1),得到白色固体5.01g,产率71%。
1H NMR(600MHz,CDCl
3):δ(ppm)δ7.35-7.43(m,5H),7.09(d,J=8.6Hz,1H),6.65-6.69(m,1H),6.58(t,J
F-H=75.8Hz,1H),5.22(s,3H),3.88(s,3H),1.27-1.34(m,1H),0.58-0.73(m,2H),0.29-0.44(m,2H);
MS(ESI,pos.ion)m/z:364.10[M+H]
+.
中间体N3:(3-环丙甲氧基-4-二氟甲氧基)苯胺的合成
将(3-环丙甲氧基-4-二氟甲氧基)苯基)氨基甲酸苯甲酯(145mg,0.45mmol),溶于无水甲醇(6mL)中,加入钯炭(50mg),排除空气,通入氢气,室温反应2h。用硅藻土抽滤除去催化剂,滤液浓缩得到淡红色液体102mg,产率98%。
1H NMR(400MHz,CDCl
3):δppm 6.94(d,J=8.4Hz,1H),6.47(t,J
F-H=76.3Hz,1H),6.26(d,J=2.2Hz,1H),6.20(dd,J=8.4,2.4Hz,1H),3.80(d,J=6.8Hz,2H),1.25-1.31(m,1H),0.58-0.65(m,2H),0.30-0.35(m,2H);
MS(ESI,pos.ion)m/z:230.10[M+H]
+.
中间体N:2-(环丙甲氧基)-1-(二氟甲氧基)-4-碘苯的合成
将化合物(3-环丙甲氧基-4-二氟甲氧基)苯胺盐酸盐(17g,64.0mmol),溶于1,4-二氧六环(85mL)和水(30mL)中,搅拌均匀后降温至0℃以下,加入浓盐酸(17mL),再降温到-15℃,逐滴加入亚硝酸钠(5.3g,77.0mmol)和水(15mL)配成的溶液,继续反应40min,加入碘化钾(13.8g,83.1mmol)和水(15mL)配成的溶液,滴加完毕后,升温至0℃继续反应2h,加入水(200mL),搅拌均匀后停止反应,恢复室温后用EA萃取(200mL×2),有机相用饱和亚硫酸钠洗涤,无水硫酸钠干燥,减压浓缩,得到目标产物浅棕色液体21g,产率96%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.21-7.27(m,2H),6.89(d,J=8.1Hz,1H),6.59(t,J
F-H=75.2Hz,1H),3.84(d,J=6.9Hz,2H),1.23-1.29(m,1H),0.61-0.69(m,2H),0.32-0.40(m,2H);
GC-MS:m/z 340.0.
中间体N4:2-(二氟甲氧基)-5-碘苯酚的合成
将化合物2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(4.9g,14.0mmol)溶解在乙腈(8mL)中,加入水(10mL)和浓盐酸(10mL),80℃反应4h,加入氢氧化钠溶液调节pH=5,用乙酸乙酯萃取(5mL×3),有机相合用无水硫酸钠干燥,减压除去溶剂,浓缩液进行硅胶柱层析分离(洗脱剂:PE/EA(v/v)=5/1),得到淡黄色液体1.8g,产率44%。
1H NMR(400MHz,DMSO-d
6)δ(ppm):10.30(s,1H),7.28(d,J=2.0Hz,1H)),7.15(dd,J=8.4,2.0Hz,1H),7.02(t,J
F-H=74.7Hz,1H),6.90(d,J=8.4Hz,1H).
MS(ESI,pos.ion)m/z:286.00[M].
中间体N’:2-(苄氧基)-1-(二氟甲氧基)-4-碘苯的合成
将化合物2-(二氟甲氧基)-5-碘苯酚(3.8g,13.0mmol)和碳酸钾(5.8g,42.0mmol)加入N,N-二甲基甲酰胺(30mL)中,加入苄溴(2.5mL,21.0mmol),在100℃反应16h,过滤除去固体,滤液浓缩,加入水(50mL),用EA(25mL×3)萃取,有机相合用无水硫酸钠干燥,减压除去溶剂,浓缩液进行硅胶柱层析分 离(洗脱剂:PE/EA(v/v)=4/1),得到淡黄色液体4.8g,产率96%。
1H NMR(400MHz,DMSO-d
6)δ(ppm):7.57(d,J=1.9Hz,1H),7.45-7.47(m,2H),7.41(s,1H),7.39(d,J=3.4Hz,1H),7.33-7.37(m,2H),7.09(t,J
F-H=74.2Hz,1H),7.00(d,J=8.4Hz,1H),5.18(s,2H).
中间体M的合成方案:
中间体M可以通过上述两种合成路线制备得到,其中,X为卤素,R
1、R
2和R
3具有如本发明所述的含义。
起始物料M1在碱性(例如氢氧化锂,氢氧化钾等)条件下经烯醇化后再发生取代反应得到中间体M2,中间体M2与联硼酸频那醇酯在碱性条件下通过硼基化反应得到化合物M3,M3和中间体N’(路线一)或中间体N(路线二)通过suzuki偶联,分别得到中间体M4-1和M4-6,其中,路线一为中间体M4-1先经过脱保护与成盐反应获得中间体M4-2,再在碱性条件下(如三乙胺,N,N-二异丙基乙胺等)条件下取代反应得到中间体M4-3,随后再进行催化氢化还原得到中间体M4-4,最后再碱性条件下发生取代反应得到中间体M4-5;而路线二为中间体M4-6先在钯碳的作用下催化氢化还原得到中间体M4-7,再经过再经过脱保护得到中间体M4-8,最后在碱性(如三乙胺,N,N-二异丙基乙胺等)条件下取代反应得到中间体M4-9;M4-5或M4-9再经过还原反应、卤代反应、叠氮反应、加氢还原等最终得到中间体M。
中间体M的具体合成方法:
中间体M的合成方法仅为具体合成方法的举例,本发明中所指的中间体M的合成方法应包括,但不限于以下具体实施例。在本发明所述的中间体M不限于某一个特定的化合物,在本发明所述的取代基允许的范围内,各具体实施例将任选地制备相同或不同的中间体M。
中间体M2:(R)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)-2,5-二氢-1H-吡咯-1,2-二羧酸酯的合成
将化合物(R)-1-叔丁基2-甲基4-氧代吡咯烷-1,2-二羧酸酯(0.98g,4.0mmol)溶解在二氯甲烷(15mL)溶液中,-15℃下加入DIPEA(3.4mL,20.5mmol),三氟甲磺酸酐(1.3mL,7.7mmol),搅拌10min后,恢复室温,继续反应18h,停止反应,加入水(50mL),用二氯甲烷萃取(5mL×3),无水硫酸钠干燥,浓缩,硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=6/1)得黄色油状物1.3g,产率86%。
1H NMR(400MHz,CDCl
3)δ(ppm):5.71(dd,J=18.8,1.6Hz,1H),4.99-5.06(m,1H),4.24-4.41(m,2H),3.76(s,3H),1.42–1.47(m,9H).
MS-ESI:m/z 398.10[M+Na]
+.
中间体M3:(R)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2,5-二氢-1H-吡咯-1,2二羧酸酯的合成
将(R)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)-2,5-二氢-1H-吡咯-1,2-二羧酸酯(1.3g,3.5mmol),联硼酸频那醇酯(1.3g,5.1mmol),KOAc(1.1g,11.2mmol)和Pd(dppf)Cl
2(130mg,0.2mmol)加入干燥的1,4-二氧六环(30mL)中,氮气保护下100℃反应13h,冷却至室温,过滤,滤液中加入水(50mL),用EtOAc(5mL×3)萃取,有机相合用无水硫酸钠干燥,除去溶剂,浓缩,进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=6/1)得到淡红色液体1.05g,产率85%。
1H NMR(400MHz,CDCl
3)δ(ppm):6.33(dd,J=23.4,1.9Hz,1H),5.01-5.12(m,1H),4.26-4.40(m,2H),3.71–3.73(m,3H),1.42–1.47(m,9H),1.26(s,12H).
MS-ESI:m/z 376.15[M+Na]
+.
路线一:
化合物1-1:(R)-1-叔丁基2-甲基4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-1,2-二羧酸酯的合成
将(R)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2,5-二氢-1H-吡咯-1,2-二羧酸酯(2.1g,5.9mmol),2-(苄氧基)-1-(二氟甲氧基)-4-碘苯(5.8g,2.2mmol),磷酸钾(5.0g,24.0mmol)和Pd(dppf)Cl
2(88mg,0.12mmol)混合在干燥的1,4-二氧六环(20mL)溶液中,氮气保护下,100℃反应5h,将反应液抽滤,滤液中加入水(20mL),用EtOAc(15mL×3)萃取,有机相合用无水硫酸钠干燥,除去溶剂,浓缩,进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=4/1),得到黄褐色液体2.1g,产率74%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.37–7.44(m,5H),7.18–7.20(m,1H),7.04(s,1H),6.95–7.01(m,1H),6.60(t,J
F-H=75.0Hz,1H),6.00–6.03(m,1H),5.13–5.21(m,3H),4.54–4.67(m,2H),3.78–3.79(m,3H),1.48–1.55(m,9H).
MS-ESI:m/z 498.20[M+Na]
+.
化合物1-2:(R)-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸甲酯盐酸盐的合成
将化合物(R)-1-叔丁基-2-甲基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-1,2-二羧酸酯(2.3g,4.8mmol)溶解于二氯甲烷(5mL)中,加入HCl的乙酸乙酯溶液(4mol/L,15mL),室温反应1h,除去溶剂,得到浅黄色液体2.02g,收率100%。
1H NMR(400MHz,CD
3OD)δ(ppm):7.48–7.50(m,2H),7.33–7.43(m,4H),7.23(d,J=8.3Hz,1H),7.12(dd,J=8.3,1.9Hz,1H),6.81(t,J
F-H=74.8Hz,1H),6.45–6.46(m,1H),5.40–5.43(m,1H),5.24(s,2H),4.53–4.62(m,2H),3.93(s,3H).
MS-ESI:m/z 376.05[M+H-HCl]
+.
化合物1-3:(R)-1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸甲酯的合成
将化合物(R)-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸甲酯盐酸盐(2.0g,4.9mmol)溶解在二氯甲烷(10mL)中,加入DIPEA(4.0mL,24mmol),冷却至0℃后加入乙酰氯(1.1g,14mmol),室温搅拌3h后停止反应,加水(20mL×3)搅拌,二氯甲烷萃取(20mL×3),有机相用无水Na
2SO
4干燥,浓缩,进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=1/2),得到浅黄色液体1.8g,产率89%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.36–7.47(m,5H),7.20(d,J=8.2Hz,1H),7.05–7.06(m,1H),6.95(dd,J=8.3,1.9Hz,1H),6.61(t,J
F-H=74.8Hz,1H),6.07–6.10(m,1H),5.27–5.35(m,1H),5.17(s,2H),5.16(s,1H),4.73–4.80(m,1H),4.58–4.66(m,1H),3.83(s,1H),3.79(s,2H),2.22(s,2H),2.11(s,1H).
MS-ESI:m/z 418.60[M+H]
+.
化合物1-4:(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟苯基)吡咯烷-2-羧酸甲酯的合成
将化合物(R)-1-乙酰基-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸甲酯(4.5g,11mmol)溶于甲醇(30mL),加入10%Pd/C(450mg),通入氢气,室温反应5h,过滤,滤液浓缩得到浅褐色液体3.1g,产率87%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.10(d,J=8.3Hz,1H),6.96(d,J=1.9Hz,1H),6.79(dd,J=8.3,2.0Hz,1H),6.56(t,J
F-H=73.7Hz,1H),4.48–4.53(m,1H),3.94–3.98(m,1H),3.78(s,3H),3.63(t,J=10.5Hz,1H),3.38–3.47(m,1H),2.65–2.71(m,1H),2.14(s,3H),2.05–2.11(m,1H).
MS-ESI:m/z 330.00[M+H]
+.
化合物1-5:(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-2-羧酸甲酯的合成
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟苯基)吡咯烷-2-羧酸甲酯(1.3g,3.9mmol)溶于无水DMF(10mL),加入碳酸钾(1.8g,13mmol)和2-碘丙烷(1.5g,8.8mmol),80℃加热反应4h,减压除去溶剂,加水(50mL),用EtOAc萃取(20mL×3),有机相用无水Na
2SO
4干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=50/1),得到浅褐色液体1.5g,产率100%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.14(d,J=8.1Hz,1H),6.87(s,1H),6.83(dd,J=8.0,1.9Hz,1H),6.56(t,J
F-H=75.5Hz,1H),4.56–4.61(m,1H),4.48–4.55(m,1H),3.94–3.98(m,1H),3.79(s,3H),3.63(t,J=10.5Hz,1H),3.40–3.48(m,1H),2.65–2.72(m,1H),2.14(s,3H),2.02–2.11(m,1H),1.37(d,J=6.0Hz,6H).
MS-ESI:m/z 372.30[M+H]
+.
化合物1-6:1-((2R)-4-(4-(二氟甲氧基)-3-异丙氧苯基)-2-(羟甲基)吡咯烷-1-基)乙酮的合成
将化合物(2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-2-羧酸甲酯(560mg,1.51mmol)溶于无水THF(8mL)中,冰浴中加入硼氢化锂(320mg,15.0mmol),室温反应1h后停止,加饱和氯化钠水溶液(20mL),用EtOAc萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂得到无色液体502mg,产率96%。
1H NMR(400MHz,CD
3OD)δ(ppm):7.14(d,J=8.2Hz,1H),6.85(s,1H),6.81(dd,J=8.2,1.8Hz,1H),6.56(t,J
F-H=75.5Hz,1H),4.55–4.61(m,1H),4.23–4.29(m,1H),3.91–3.94(m,1H),3.76–3.82(m,1H),3.67–3.72(m,1H),3.44(t,J=10.8Hz,1H),2.44–2.51(m,1H),2.16(s,3H),1.65–1.74(m,1H),1.38(d,J=6.1Hz,6H).
MS-ESI:m/z 344.10[M+H]
+.
化合物1-7:1-((2R)-2-(溴甲基)-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-1-基)乙酮的合成
将化合物1-((2R)-4-(4-(二氟甲氧基)-3-异丙氧苯基)-2-(羟甲基)吡咯烷-1-基)乙酮(493mg,1.44mmol)溶于EtOAc(20mL)中,加入三乙胺(442mg,4.37mmol),冰浴中加入MsCl(333mg,2.91mmol),室温反应1h后,加入溴化锂(1.26g,14.56mmol),室温反应8h,加水(30mL),停止反应,有机相用无水硫酸钠干燥,除去溶剂得到浅黄色液体376mg,产率64%。
1H NMR(400MHz,CD
3OD):δ(ppm):7.15(d,J=8.2Hz,1H),6.94(d,J=1.4Hz,1H),6.87(dd,J=8.1,1.5 Hz,1H),6.57(t,J
F-H=75.5Hz,1H),4.56–4.62(m,1H),4.36–4.43(m,1H),4.18–4.23(m,1H),3.88–3.93(m,1H),3.68–3.71(m,1H),3.52(d,J=10.7Hz,1H),3.26–3.36(m,1H),2.51–2.62(m,1H),2.13–2.22(m,1H),2.13(s,3H),1.39(d,J=6.0Hz,6H).
MS-ESI:m/z 408.15[M+H]
+.
化合物1-8:1-((2R)-2-(叠氮甲基)-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-1-基)乙酮的合成
将化合物1-((2R)-2-(溴甲基)-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-1-基)乙酮(320mg,0.79mmol)溶于DMF(5mL),加入叠氮化钠(512mg,7.9mmol),80℃加热反应6h,冷却至室温,加水(30mL),用EtOAc萃取(10mL×3),有机相用无水Na
2SO
4干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=60/1),得到浅褐色液体223mg,产率76%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.15(d,J=8.2Hz,1H),6.91(d,J=1.5Hz,1H),6.86(dd,J=8.2,1.7Hz,1H),6.57(t,J
F-H=75.5Hz,1H),4.56–4.62(m,1H),4.28–4.34(m,1H),4.13–4.19(m,1H),3.91–3.95(m,1H),3.39–3.48(m,2H),3.38–3.41(m,1H),3.26–3.33(m,1H),2.43–2.49(m,1H),2.09–2.18(m,1H),2.13(s,3H),1.39(d,J=6.1Hz,6H).
MS-ESI:m/z 369.20[M+H]
+.
化合物1-9:1-((2R)-2-(氨甲基)-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-1-基)乙酮的合成
将化合物1-((2R)-2-(叠氮甲基)-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-1-基)乙酮(220mg,0.60mmol)溶于甲醇(8mL),加入10%Pd/C(23mg),通入氢气,室温反应3h,过滤除去催化剂,滤液浓缩得到无色液体176mg,产率86%。
1H NMR(400MHz,CD
3OD)δ(ppm):7.08–7.12(m,2H),6.95(dd,J=8.2,1.7Hz,1H),6.69(t,J
F-H=75.6Hz,1H),4.64–4.72(m,1H),4.07–4.14(m,1H),4.01–4.05(m,1H),3.46(d,J=10.8Hz,1H),2.97–3.05(m,2H),2.62–2.67(m,1H),2.48–2.55(m,1H),2.13(s,3H),1.92–2.01(m,1H),1.36(d,J=6.0Hz,6H).
MS-ESI:m/z 343.10[M+H]
+.
路线二:
化合物2-1:(R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-1,2-二羧酸酯的合成
将(R)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2,5-二氢-1H-吡咯-1,2-二羧酸酯(1.15g,3.3mmol),2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(1.1g,3.2mmol),磷酸钾(2.1g,9.9mmol)和Pd(dppf)Cl
2(120mg,0.16mmol)溶于干燥的1,4-二氧六环(15mL)中,氮气保护下100℃反应3h,将反应液抽滤,滤液中加入水(50mL),EtOAc(5mL×3)萃取,有机相合用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=8/1),得到淡红色液体1.13g,产率80%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.14(d,J=8.2Hz,1H),6.90-6.97(m,2H),6.63(t,J
F-H=75.4Hz,1H),6.00-6.03(m,1H),5.11-5.19(m,1H),4.47-4.66(m,2H),3.86-3.90(m,2H),3.76(d,J=4.0Hz,3H),1.46–1.52(m,9H),1.26-1.31(m,1H),0.61-0.70(m,2H),0.33-0.38(m,2H).
MS-ESI:m/z 462.20[M+Na]
+.
化合物2-2:(2R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯的合成
将(R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-1,2-二羧酸酯(1.1g,2.5mmol)溶于甲醇(15mL),加入Pd/C(260mg),通入氢气,室温反应7h,然后将反应液抽滤,滤液浓缩后得到黄色液体990mg,收率90%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.10(d,J=8.0Hz,1H),6.77-6.81(m,2H),6.60(t,J
F-H=74.2Hz,1H),4.30-4.40(m,1H),3.91-3.95(m,0.5H),4.02-4.06(m,0.5H),3.84-3.87(m,2H),3.76(d,J=6.7Hz,3H),3.30-3.45(m,2H),2.62-2.68(m,1H),1.99-2.07(m,1H),1.43–1.47(m,9H),1.28-1.31(m,1H),0.62-0.67(m,2H),0.33-0.37 (m,2H).
MS-ESI:m/z 464.25[M+Na]
+.
化合物2-3:(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐的合成
将化合物(2R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(990mg,2.2mmol)溶解于二氯甲烷(6mL)中,加入HCl乙酸乙酯溶液(4mol/L,8mL),室温搅拌50min,除去溶剂,得到白色固体751mg,收率98%。
1H NMR(400MHz,CD
3OD)δ(ppm):7.14(d,J=8.2Hz,1H),7.07(s,1H),6.91-6.94(m,1H),6.76(t,J
F-
H=75.5Hz,2H),4.60-4.64(m,1H),3.94(d,J=6.9Hz,2H),3.90(s,3H),3.78-3.83(m,1H),3.65-3.72(m,1H),3.33-3.39(m,1H),2.82-2.89(m,1H),2.20-2.29(m,1H),1.28-1.36(m,1H),0.63-0.66(m,2H),0.37-0.41(m,2H).
MS-ESI:m/z 342.20[M+H-HCl]
+.
化合物2-4:(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯的合成
将化合物(2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯盐酸盐(203mg,0.6mmol)溶解在二氯甲烷(5mL)中,0℃下滴加DIPEA(0.2mL,1.0mmol)和乙酰氯(0.1mL,1.0mmol),室温搅拌5h后停止反应,有机相用水(10mL×3)洗涤,无水Na
2SO
4干燥,浓缩液进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=1/1),得到浅黄色液体186mg,产率82%。
1H NMR(400MHz,CD
3OD)δ(ppm):7.11(d,J=8.2Hz,1H),7.04(s,1H),6.90-6.94(m,1H),6.74(t,J
F-
H=75.6Hz,1H),4.45-4.49(m,1H),4.08-4.12(m,1H),3.93(d,J=6.8Hz,2H),3.75(s,3H),3.50-3.64(m,2H),2.67-2.74(m,1H),2.13(s,3H),1.99-2.06(m,1H),1.27-1.33(m,1H),0.62-0.67(m,2H),0.36-0.40(m,2H).
MS-ESI:m/z 384.20[M+H]
+.
化合物2-5:1-((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-基)乙酮的合成
将化合物(2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-羧酸甲酯(800mg,2.09mmol)溶于无水四氢呋喃(8mL)中,冰浴中加入硼氢化锂(445mg,20.9mmol),室温反应4h后加入冰水(15mL),浓缩后再加入水(30mL),用EtOAc萃取(20mL×3),有机相用稀盐酸(15mL×1,1M)洗涤,用饱和氯化钠水溶液(15mL×1)洗涤,有机相用无水硫酸钠干燥,除去溶剂得到无色液体655mg,产率88%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.14(d,J=8.7Hz,1H),6.81(s,2H),6.62(t,J
F-H=75.5Hz,1H),5.57–5.59(m,1H),4.22–4.28(m,1H),3.90–3.95(m,1H),3.89(d,J=6.9Hz,2H),3.76–3.82(m,1H),3.66–3.71(m,1H),3.44(t,J=10.8Hz,1H),3.26–3.36(m,1H),2.43–2.50(m,1H),2.15(s,3H),1.65–1.74(m,1H),1.27–1.35(m,1H),0.65–0.70(m,2H),0.36–0.40(m,2H).
MS-ESI:m/z 356.25[M+H]
+.
化合物2-6:1-((2R)-2-(溴甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮的合成
将化合物1-((2R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-基)乙酮(520mg,1.46mmol)溶于EtOAc(20mL)中,加入三乙胺(525mg,5.19mmol),冰浴中加入MsCl(301mg,2.63mmol),室温反应2h后加入溴化锂(636mg,7.32mmol),室温继续反应12h,加水(30mL)停止反应,有机相用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=50/1),得到浅黄色液体146mg,产率23%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.15(d,J=8.1Hz,1H),6.90(s,1H),6.88(d,J=8.2Hz,1H),6.63(t,J
F-
H=75.6Hz,1H),4.36–4.42(m,1H),4.17–4.21(m,1H),4.05–4.10(m,1H),3.90(d,J=6.9Hz,2H),3.69–3.72(m,1H),3.52(d,J=10.7Hz,1H),3.26–3.36(m,1H),3.51–3.57(m,1H),2.15–2.24(m,1H),2.13(s,3H),1.28–1.38(m,1H),0.66–0.70(m,2H),0.36–0.41(m,2H).
MS-ESI:m/z 419.15[M+H]
+.
化合物2-7:1-((2R)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮的合成
将化合物1-((2R)-2-(溴甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(250mg,0.60mmol)溶于DMF(3mL),加入叠氮化钠(388mg,5.97mmol),90℃加热反应2.5h,冷却至室温,加水(30mL),用EtOAc萃取(10mL×3),有机相用无水Na
2SO
4干燥,减压浓缩,剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=60/1),得到浅褐色液体163mg,产率71%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.16(d,J=8.4Hz,1H),6.87(s,1H),6.85(d,J=8.2Hz,1H),6.63(t,J
F-
H=75.6Hz,1H),4.27–4.33(m,1H),4.14–4.18(m,1H),3.88–3.94(m,1H),3.91(d,J=6.9Hz,2H),3.39–3.47(m,2H),3.25–3.33(m,1H),2.42–2.48(m,1H),2.07–2.18(m,1H),2.13(s,3H),1.28–1.36(m,1H),0.66–0.71(m,2H),0.38–0.41(m,2H).
MS-ESI:m/z 381.20[M+H]
+.
化合物2-8:1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮的合成
将化合物1-((2R)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(2.7g,7.1mmol)和三苯基膦(2.4g,9.2mmol)溶于四氢呋喃/水((v/v)=3/1,40mL)混合溶剂中,50℃反应4h,减压浓缩,EtOAc萃取(10mL×3),有机相用无水Na
2SO
4干燥,减压浓缩,浓缩液进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=15/1),得到浅褐色液体1.8g,产率71%。
1H NMR(400MHz,CD
3OD)δ(ppm):7.10(d,J=8.2Hz,1H),7.08(s,1H),6.93–6.95(m,1H),6.74(t,J
F-
H=75.8Hz,1H),4.06–4.13(m,1H),4.00–4.04(m,1H),3.94(d,J=6.9Hz,2H),3.46(d,J=10.8Hz,1H),3.30–3.36(m,1H),2.95–3.05(m,2H),2.47–2.54(m,1H),2.13(s,3H),1.93–2.01(m,1H),1.29–1.35(m,1H),0.63–0.67(m,2H),0.37–0.41(m,2H).
MS-ESI:m/z 355.00[M+H]
+.
实施例1:3-((((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-2-基)甲基)氨基甲酰基)苯甲酸甲酯
将化合物1-((2R)-2-(氨甲基)-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-1-基)乙酮(40mg,0.12mmol),间苯二甲酸单甲酯(27mg,0.15mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(113mg,0.59mmol)和HOAT(30mg,0.22mmol)溶于二氯甲烷(5mL)中,降温至0℃后,加入DIPEA(90mg,0.70mmol),室温反应12h,加水(10mL),用二氯甲烷萃取(10mL×3),合并有机相,用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=50/1),得到白色粘稠物23mg,产率39%,纯度92.31%。
1H NMR(400MHz,CDCl
3)δ(ppm):8.94(br.s,1H),8.59(s,1H),8.17(d,J=7.6Hz,1H),8.07(d,J=7.7Hz,1H),7.55(t,J=7.7Hz,1H),7.15(d,J=8.2Hz,1H),6.86(s,1H),6.83(d,J=8.3Hz,1H),6.57(t,J
F-H=75.5Hz,1H),4.55–4.61(m,1H),4.37–4.43(m,1H),3.96–4.12(m,2H),3.96(s,3H),3.48(t,J=10.9Hz,1H),3.25–3.39(m,2H),2.65–2.71(m,1H),2.20(s,3H),1.82–1.91(m,1H),1.38(d,J=5.9Hz,6H).
MS-ESI:m/z 505.15[M+H]
+.
实施例2:3-((((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-2-基)甲基)氨基甲酰基)苯甲酸
将化合物3-((((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-2-基)甲基)氨基甲酰基)苯甲酸甲酯(23mg,0.045mmol)溶于THF(6mL)和水(3mL)的混合溶剂中,加入一水合氢氧化锂(10mg,0.24mmol),50℃反应1.5h后停止,加稀盐酸(1M)调节溶液pH=1,减压除去THF,剩余物用EtOAc萃取(10mL×2),有机相用无水硫酸钠干燥,除去溶剂得到浅黄色固体18mg,产率80%。
1H NMR(400MHz,CD
3OD):δ(ppm):8.53(s,1H),8.22(d,J=7.5Hz,1H),8.07(d,J=7.7Hz,1H),7.62(t,J=7.8Hz,1H),7.08(d,J=8.2Hz,1H),6.99(s,1H),6.89–6.94(m,1H),6.66(t,J
F-H=75.6Hz,1H),4.49–4.58(m,1H),4.36–4.44(m,1H),4.05–4.09(m,1H),3.72–3.90(m,2H),3.46(t,J=10.9Hz,1H),3.32–3.41(m,1H),2.53–2.60(m,1H),2.17(s,3H),1.98–2.06(m,1H),1.26(d,J=6.0Hz,6H).
MS-ESI:m/z 491.30[M+H]
+.
实施例3:N-(((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-2-基)甲基)-2-乙氧基苯甲酰胺
将化合物1-((2R)-2-(氨甲基)-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-1-基)乙酮(50mg,0.15mmol),2-乙氧基苯甲酸(37mg,0.22mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(142mg,0.74mmol)和HOAT(40mg,0.29mmol)溶于二氯甲烷(10mL)中,冷却至0℃后,加入DIPEA(116mg,0.90mmol),室温反应6h,加水(10mL),用二氯甲烷萃取(10mL×3),合并有机相,用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=50/1),得到白色粘稠物30mg,产率41%,纯度97.18%。
1H NMR(400MHz,CDCl
3)δ(ppm):8.48(br.s,1H),8.20(d,J=7.8Hz,1H),7.42–7.46(m,1H),7.07–7.10(m,2H),6.98(d,J=8.2Hz,1H),6.81(s,1H),6.77(d,J=8.3Hz,1H),6.53(t,J
F-H=75.6Hz,1H),4.41–4.48(m,1H),4.20–4.35(m,3H),3.95–4.03(m,1H),3.86–3.94(m,2H),3.39(t,J=10.7Hz,1H),3.17–3.26(m,1H),2.53–2.59(m,1H),2.14(s,3H),1.99–2.02(m,1H),1.52(t,J=6.9Hz,3H),1.27–1.31(m,6H).
MS-ESI:m/z 491.30[M+H]
+.
实施例4:4-((((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-2-基)甲基)氨基甲酰基)苯甲酸甲酯
将化合物1-((2R)-2-(氨甲基)-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-1-基)乙酮(40mg,0.12mmol),对苯二甲酸单甲酯(27mg,0.15mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(113mg,0.59mmol)和HOAT(30mg,0.22mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入DIPEA(90mg,0.70mmol),室温反应12h,加水(10mL),用二氯甲烷萃取(10mL×3),合并有机相,用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=50/1),得到白色粘稠物26mg,产率44%,纯度94.77%。
1H NMR(400MHz,CDCl
3)δ(ppm):9.05(br.s,1H),8.13(d,J=8.4Hz,2H),7.97(d,J=8.4Hz,2H),7.16(d,J=8.1Hz,1H),6.86(s,1H),6.83(d,J=8.2Hz,1H),6.57(t,J
F-H=75.4Hz,1H),4.55–4.61(m,1H),4.37–4.43(m,1H),3.97–4.13(m,2H),3.96(s,3H),3.48(t,J=10.9Hz,1H),3.26–3.36(m,2H),2.64–2.72(m,1H),2.20(s,3H),1.81–1.89(m,1H),1.39(d,J=6.0Hz,6H).
MS-ESI:m/z 505.30[M+H]
+.
实施例5:4-((((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-2-基)甲基)氨基甲酰基)苯甲酸
将化合物4-((((2R)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-2-基)甲基)氨基甲酰基)苯甲酸甲酯(20mg,0.039mmol)溶于THF(6mL)和水(3mL)的混合溶剂中,加入一水合氢氧化锂(8mg,0.19mmol),50℃反应1.5h后停止,加稀盐酸(1M)调节溶液pH=1,减压除去四氢呋喃,剩余物用EtOAc萃取(10mL×2),有机相用无水硫酸钠干燥,除去溶剂得到浅黄色固体15mg,产率77%,纯度91.92%。
1H NMR(400MHz,CD
3OD)δ(ppm):8.13(d,J=8.2Hz,2H),7.94(d,J=8.1Hz,2H),7.08(d,J=8.2Hz,1H),7.00(s,1H),6.86–6.94(m,1H),6.67(t,J
F-H=75.6Hz,1H),4.50–4.56(m,1H),4.36–4.44(m,1H),4.05–4.09(m,1H),3.70–3.88(m,2H),3.47(t,J=10.9Hz,1H),3.32–3.40(m,1H),2.54–2.61(m,1H),2.18(s,3H),1.96–2.07(m,1H),1.27(d,J=6.0Hz,6H).
MS-ESI:m/z 491.05[M+H]
+.
实施例6:4-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)苯甲酸甲酯
将化合物1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(60mg,0.17mmol),对苯二甲酸单甲酯(45mg,0.25mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(113mg,0.59mmol)和HOAT(46mg,0.36mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入DIPEA(131mg,1.01mmol),然后恢复至室温反应12h,再加入二氯甲烷(15mL),加水(10mL),用二氯甲烷萃取(10mL×3),合并有机相,用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=30/1),得到白色固体58mg,产率66%,纯度92.69%。
1H NMR(400MHz,CDCl
3)δ(ppm):9.05(br.s,1H),8.13(d,J=8.4Hz,2H),7.97(d,J=8.4Hz,2H),7.16(d,J=8.1Hz,1H),6.83(s,2H),6.63(t,J
F-H=75.5Hz,1H),4.37–4.43(m,1H),3.97–4.04(m,2H),3.96(s,3H),3.90(d,J=6.9Hz,2H),3.48(t,J=10.9Hz,1H),3.25–3.36(m,2H),2.65–2.71(m,1H),2.20(s,3H),1.81–1.90(m,1H),1.28–1.37(m,1H),0.66–0.71(m,2H),0.37–0.41(m,2H).
MS-ESI:m/z 517.30[M+H]
+.
实施例7:4-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)苯甲酸
将化合物4-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)苯甲酸甲酯(50mg,0.097mmol)溶于THF(6mL)和水(3mL)的混合溶剂中,加入一水合氢氧化锂(20mg,0.48mmol),50℃反应2h后停止,加稀盐酸(1M)调节溶液pH=1,减压除去THF,剩余物用EtOAc萃取(10mL×2),有机相用无水硫酸钠干燥,减压除去溶剂,得到白色固体48mg,产率98%,纯度94.39%。
1H NMR(400MHz,CD
3OD)δ(ppm):8.13(d,J=8.3Hz,2H),7.93(d,J=8.3Hz,2H),7.08(d,J=8.2Hz,1H),6.98(s,1H),6.89–6.91(m,1H),6.72(t,J
F-H=75.6Hz,1H),4.36–4.43(m,1H),4.04–4.10(m,1H),3.82–3.88(m,1H),3.82(d,J=6.9Hz,2H),3.69–3.74(m,1H),3.48(t,J=10.8Hz,1H),3.32–3.40(m,1H),2.54–2.61(m,1H),2.17(s,3H),1.96–2.05(m,1H),1.31–1.35(m,1H),0.59–0.63(m,2H),0.31–0.35(m,2H).
MS-ESI:m/z 503.20[M+H]
+.
实施例8:N
1-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
4-乙基-N
4-甲基对苯二甲酰胺
将化合物4-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)苯甲酸(40mg,0.08mmol),N-乙基甲基氨(14mg,0.24mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(76mg,0.40mmol)和HOAT(21mg,0.15mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入DIPEA(62mg,0.48mmol),恢复至室温继续反应12h,加水(5mL)搅拌,二氯甲烷萃取(10mL×3),合并有机相,用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=25/1),得到白色固体16mg,产率37%,纯度97.79%。
1H NMR(400MHz,CDCl
3)δ(ppm):8.96(br.s,1H),7.94(d,J=7.4Hz,2H),7.74(d,J=7.4Hz,1H),7.15(d,J=8.0Hz,1H),6.83(s,2H),6.62(t,J
F-H=75.6Hz,1H),4.36–4.43(m,1H),3.94–4.03(m,2H),3.89(d,J=6.4Hz,2H),3.55–3.65(m,1H),3.47(t,J=10.8Hz,1H),3.22–3.35(m,3H),3.09(s,2H),2.92(s,1H),2.62–2.70(m,1H),2.18(s,3H),1.77–1.90(m,1H),1.22–1.35(m,1H),1.22–1.31(m,3H),0.65–0.70(m,2H),0.35–0.40(m,2H).
MS-ESI:m/z 544.40[M+H]
+.
实施例9:6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))烟酸甲酯
将化合物1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(40mg,0.11mmol),5-(甲氧羰基)-2-吡啶羧酸甲酯(30mg,0.17mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(108mg,0.56mmol)和HOAT(30mg,0.22mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入DIPEA(87mg,0.67mmol),恢复至室温继续反应10h,加入二氯甲烷(15mL),有机相用水洗(10mL×3),有机相用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=50/1)得到浅黄色固体40mg,产率68%,纯度98.29%。
1H NMR(400MHz,CDCl
3)δ(ppm):9.24(s,1H),9.17(br.s,1H),8.46(d,J=8.1Hz,1H),8.27(d,J=8.1Hz,1H),7.11(d,J=8.1Hz,1H),6.80(s,2H),6.61(t,J
F-H=75.6Hz,1H),4.29–4.37(m,1H),3.92–4.08(m,2H),4.00(s,3H),3.84(d,J=6.9Hz,2H),3.60–3.67(m,1H),3.44(t,J=10.9Hz,1H),3.23–3.32(m,1H),2.57–2.64(m,1H),2.18(s,3H),1.92–2.03(m,1H),1.27–1.34(m,1H),0.62–0.67(m,2H),0.31–0.38(m,2H).
MS-ESI:m/z 518.30[M+H]
+.
实施例10:6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))烟酸盐酸盐
将化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))烟酸甲酯(36mg,0.070mmol)溶于THF(6mL)和水(3mL)的混合溶剂中,加入一水合氢氧化锂(14mg,0.33mmol),50℃反应2h后停止,加稀盐酸(1M)调节溶液pH=4,减压除去THF,剩余物用EtOAc萃取(10mL×2),有机相用无水硫酸钠干燥,除去溶剂得到白色固体35mg,产率97%,纯度97.13%。
1H NMR(400MHz,CD
3OD)δ(ppm):9.22(s,1H),8.52(dd,J=8.1,1.9Hz,1H),8.20(d,J=8.1Hz,1H),7.06(d,J=8.2Hz,1H),6.98(s,1H),6.87–6.90(m,1H),6.71(t,J
F-H=75.6Hz,1H),4.34–4.40(m,1H),4.02–4.06(m,1H),3.91–3.95(m,1H),3.82(d,J=6.9Hz,2H),3.69–3.74(m,1H),3.47(t,J=10.8Hz,1H),3.32–3.39(m,1H),2.53–2.59(m,1H),2.17(s,3H),1.97–2.05(m,1H),1.30–1.34(m,1H),0.59–0.63(m,2H),0.32–0.35(m,2H).
MS-ESI:m/z 504.20[M-HCl+H]
+.
实施例11:N
2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺
将化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))烟酸盐酸盐(30mg,0.06mmol),N-乙基甲基氨(10mg,0.17mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(57mg,0.30mmol)和HOAT(16mg,0.12mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入DIPEA(46mg,0.36mmol),室温反应6h,加水(50mL)搅拌,二氯甲烷萃取(10mL×3),有机相用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=24/1)得到白色固体18mg,产率55%,纯度98.84%。
1H NMR(400MHz,CDCl
3)δ(ppm):9.11(s,1H),8.67(s,1H),8.23(d,J=7.9Hz,1H),7.89(br.s,1H),7.11(d,J=7.9Hz,1H),6.81(s,2H),6.60(t,J
F-H=75.6Hz,1H),4.26–4.36(m,1H),4.00–4.08(m,1H),3.92–3.96(m,1H),3.86(d,J=6.8Hz,2H),3.59–3.67(m,2H),3.44(t,J=10.7Hz,1H),3.22–3.33(m,2H),3.12(s,1.7H),2.97(s,1.3H),2.57–2.63(m,1H),2.18(s,3H),1.92–2.01(m,1H),1.22–1.30(m,4H),0.63–0.69(m,2H),0.35–0.38(m,2H).
MS-ESI:m/z 545.30[M+H]
+.
实施例12:6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))吡啶甲酸甲酯
将化合物1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(40mg,0.11mmol),2,6-吡啶二羧酸单甲酯(30mg,0.17mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(108mg,0.56mmol)和HOAT(30mg,0.22mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入DIPEA(87mg,0.67mmol),后恢复至室温继续反应7h,加入二氯甲烷(15mL),有机相用水洗(10mL×3),有机相用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析色谱分离(洗脱剂:DCM/MeOH(v/v)=50/1),得到浅褐色固体34mg,产率58%,纯度97.59%。
1H NMR(400MHz,CDCl
3)δ(ppm):9.00(br.s,1H),8.38(d,J=7.7Hz,1H),8.25(d,J=7.7Hz,1H),8.03(tJ=7.8Hz,1H),7.09(d,J=8.7Hz,1H),6.80(s,2H),6.60(t,J
F-H=75.6Hz,1H),4.33–4.40(m,1H),4.04(s,3H),4.00–4.04(m,1H),3.93–3.97(m,1H),3.82(d,J=6.9Hz,2H),3.72–3.78(m,1H),3.48(t,J=10.8Hz,1H),3.19–3.32(m,1H),2.54–2.61(m,1H),2.20(s,3H),1.96–2.05(m,1H),1.23–1.30(m,1H),0.63–0.67(m,2H),0.33–0.36(m,2H).
MS-ESI:m/z 518.20[M+H]
+.
实施例13:6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))吡啶甲酸盐酸盐
将化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))吡啶甲酸甲酯(30mg,0.058mmol)溶于THF(6mL)和水(3mL)的混合溶剂中,加入一水合氢氧化锂(12mg,0.29mmol),50℃反应1h后冷却至室温,加稀盐酸(1M)调节溶液pH=4,减压除去THF,剩余物用EtOAc萃取(10mL×2),有机相用无水硫酸钠干燥,减压除去溶剂得到白色固体29mg,产率92%,纯度97.01%。
1H NMR(400MHz,CD
3OD)δ(ppm):8.35(d,J=7.4Hz,2H),8.19–8.23(m,1H),7.03(d,J=8.2Hz,1H),6.94(s,1H),6.85–6.88(m,1H),6.69(t,J
F-H=75.7Hz,1H),4.38–4.45(m,1H),4.01–4.05(m,1H),3.83–3.95(m,2H),3.79(d,J=6.8Hz,2H),3.44(t,J=10.8Hz,1H),3.32–3.39(m,1H),2.52–2.59(m,1H),2.29(s,0.5H),2.17(s,2.5H),2.01–2.09(m,1H),1.20–1.26(m,1H),0.59–0.62(m,2H),0.30–0.35(m,2H).
MS-ESI:m/z 504.20[M+H]
+.
实施例14:N
2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
6-乙基-N
6-甲 基吡啶-2,6-二甲酰胺
将化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))吡啶甲酸盐酸盐(30mg,0.06mmol)溶于干燥的THF(4mL)中,加入CDI(39mg,0.24mmol),60℃反应1h后,加N-乙基甲基氨(14mg,0.24mmol),继续反应6h,加水(15mL)搅拌,EtOAc萃取(5mL×3),有机相用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析色谱分离(洗脱剂:DCM/MeOH(v/v)=30/1),得到浅黄色固体14mg,产率43%,纯度98.99%。
1H NMR(400MHz,CDCl
3)δ(ppm):8.22–8.25(m,1H),7.95–7.99(m,1H),7.71–7.79(m,1H),7.09–7.12(m,1H),6.79(s,2H),6.60(t,J
F-H=75.6Hz,1H),4.27–4.35(m,1H),3.90–4.03(m,2H),3.83–3.86(m,2H),3.62–3.72(m,2H),3.35–3.44(m,2H),3.20–3.30(m,1H),3.16(s,1.5H),3.011(s,1.5H),2.52–2.60(m,1H),2.14(s,3H),1.94–2.05(m,1H),1.20(t,J=7.1Hz,3H),1.13–1.17(m,1H),0.62–0.67(m,2H),0.33–0.38(m,2H).
MS-ESI:m/z 545.20[M+H]
+.
实施例15:N-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-2-乙氧基苯甲酰胺
将2-乙氧基苯甲酸(46mg,0.28mmol)溶解在干燥的四氢呋喃(4mL)中,加入CDI(49mg,0.30mmol),室温反应1h,加入1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(60mg,0.17mmol),60℃反应6h,冷却至室温,加水(15mL),有机相用EtOAc萃取(15mL×3),合并有机相,用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=30/1),得到浅褐色固体35mg,产率41%,纯度94.40%。
1H NMR(600MHz,CDCl
3)δ(ppm):7.60(br.s,1H),7.38(t,J=7.7Hz,1H),7.09(d,J=7.1Hz,1H),7.02(t,J=7.3Hz,1H),6.93(d,J=8.2Hz,1H),6.74(s,1H),6.73(d,J=8.4Hz,1H),6.59(t,J
F-H=75.6Hz,1H),4.50–4.54(m,1H),4.10–4.14(m,2H),3.84–3.90(m,1H),3.85(d,J=6.9Hz,2H),3.56–3.65(m,1H),3.34–3.47(m,2H),3.15–3.23(m,1H),2.63–2.70(m,1H),2.03(s,3H),1.81–1.87(m,1H),1.43(t,J=6.9Hz,3H),1.29–1.36(m,1H),0.65–0.68(m,2H),0.35–0.37(m,2H).
MS-ESI:m/z 503.25[M+H]
+.
实施例16:N-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-2-乙氧基-3-氟 苯甲酰胺
将化合物1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(50mg,0.14mmol),2-乙氧基-3-氟苯甲酸(41mg,0.22mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和HOAT(29mg,0.21mmol)溶于二氯甲烷(10mL)中,冷却至0℃后,加入DIPEA(85mg,0.66mmol),恢复至室温后继续反应8h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),然后用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=30/1),得到浅褐色固体53mg,产率72%,纯度93.25%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.64(br.s,1H),7.08–7.18(m,4H),6.73–6.78(m,2H),6.59(t,J
F-H=75.6Hz,1H),4.48–4.55(m,1H),4.17–4.32(m,2H),3.82–3.91(m,1H),3.86(d,J=6.9Hz,2H),3.53–3.64(m,1H),3.37–3.47(m,2H),3.15–3.25(m,1H),2.65–2.70(m,1H),2.03(s,3H),1.81–1.94(m,1H),1.37(t,J=6.9Hz,3H),1.29–1.36(m,1H),0.64–0.69(m,2H),0.35–0.38(m,2H).
MS-ESI:m/z 521.30[M+H]
+.
实施例17:N
2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-异丙基-N
5-甲基吡啶-2,5-二甲酰胺
将化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))烟酸盐酸盐(60mg,0.12mmol),N-异丙基甲基氨(43mg,0.59mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(114mg,0.59mmol)和HOAT(32mg,0.24mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入DIPEA(77mg,0.60mmol),室温反应12h,加水(30mL),二氯甲烷萃取(10mL×3),有机相用无水硫酸钠干燥,浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=66/1),得到白色固体42mg,产率63%,纯度98.25%。
1H NMR(400MHz,CDCl
3)δ(ppm):9.10(br.s,1H),8.62(s,1H),8.21(d,J=7.9Hz,1H),7.80–7.87(m,1H),7.09(d,J=7.9Hz,1H),6.79(s,1H),6.76(d,J=8.2Hz,1H),6.58(t,J
F-H=75.6Hz,1H),4.88–5.00(m,0.4H),4.26–4.33(m,1H),3.97–4.06(m,1H),3.90–3.94(m,1H),3.80–3.87(m,0.6H),3.84(d,J=6.8Hz,2H),3.55–3.65(m,1H),3.42(t,J=10.8Hz,1H),3.20–3.29(m,1H),2.97(s,1.8H),2.79(s,1.2H),2.53–2.61(m,1H),2.16(s,3H),1.90–2.02(m,1H),1.27–1.34(m,1H),1.16–1.24(m,6H),0.62–0.66(m,2H),0.33–0.36(m,2H).
MS-ESI:m/z 559.20[M+H]
+.
实施例18:N
2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-(4-氟苯基)-N
5-甲基吡啶-2,5-二甲酰胺
将化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))烟酸盐酸盐(60mg,0.12mmol),4-氟-N-甲基苯胺(74mg,0.59mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(114mg,0.59mmol)和HOAT(32mg,0.24mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入DIPEA(78mg,0.60mmol),室温反应12h,加水(30mL),二氯甲烷萃取(10mL×3),合并有机相,用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:EtOAc(v)=100%),得到白色固体48mg,产率66%,纯度96.39%。
1H NMR(400MHz,CDCl
3)δ(ppm):8.99(br.s,1H),8.50(s,1H),7.99(d,J=7.8Hz,1H),7.68(d,J=7.4Hz,1H),6.92–7.09(m,5H),6.77(s,1H),6.76(d,J=8.2Hz,1H),6.58(t,J
F-H=75.6Hz,1H),4.20–4.27(m,1H),3.86–3.99(m,2H),3.83(d,J=6.8Hz,2H),3.49–3.56(m,1H),3.48(s,3H),3.38(t,J=10.7Hz,1H),3.17–3.27(m,1H),2.51–2.58(m,1H),2.13(s,3H),1.86–1.94(m,1H),1.23–1.32(m,1H),0.60–0.65(m,2H),0.32–0.35(m,2H).
MS-ESI:m/z 611.15[M+H]
+.
实施例19:N
2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-(2-(二甲氨基)乙基)-N
5-甲基吡啶-2,5-二甲酰胺
将化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))烟酸盐酸盐(60mg,0.12mmol),N
1,N
1,N
2-三甲基乙二胺(60mg,0.60mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(114mg,0.59mmol)和HOAT(32mg,0.24mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入DIPEA(77mg,0.60mmol),室温反应12h,加水(30mL),用二氯甲烷萃取(10mL×3),合并有机相,用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=18/1),得到白色固体42mg,产率60%,纯度97.07%。
1H NMR(400MHz,CDCl
3)δ(ppm):9.08(br.s,1H),8.67(s,1H),8.20(d,J=8.0Hz,1H),7.87–7.94(m,1H),7.09(d,J=8.0Hz,1H),6.78(s,1H),6.77(d,J=5.4Hz,1H),6.58(t,J
F-H=73.2Hz,1H),4.26–4.34(m,1H),3.98–4.04(m,1H),3.89–3.93(m,1H),3.84(d,J=6.9Hz,2H),3.66–3.74(m,1H),3.57–3.65(m,1H),3.41(t,J=10.8Hz, 1H),3.19–3.34(m,2H),3.01–3.10(m,3H),2.61–2.70(m,1H),2.54–2.61(m,1H),2.37(s,3H),2.15(s,3H),1.90–2.07(m,2H),2.04(s,3H),1.23–1.34(m,1H),0.61–0.66(m,2H),0.32–0.36(m,2H).
MS-ESI:m/z 588.50[M+H]
+.
实施例20:N
2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-甲基-N
5-(2,2,2-三氟乙基)吡啶-2,5-二甲酰胺
将化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))烟酸盐酸盐(60mg,0.12mmol),N-甲基-2,2,2-三氟乙胺盐酸盐(71mg,0.47mmol)和HOAT(33mg,0.24mmol)溶于二氯甲烷(10mL)中,冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(115mg,0.60mmol)和DIPEA(142mg,1.10mmol),室温反应4h,加水(30mL),水相用二氯甲烷萃取(10mL×2),合并有机相,用无水硫酸钠干燥,减压浓缩,浓缩液进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=54/1),得到白色固体32mg,产率44%,纯度97.31%。
1H NMR(400MHz,CDCl
3)δ(ppm):8.66(br.s,1H),7.91(s,2H),7.33(s,1H),7.09(d,J=8.2Hz,1H),6.75(d,J=7.4Hz,1H),6.76(s,1H),6.58(t,J
F-H=75.6Hz,1H),4.49–4.53(m,1H),4.16–4.29(m,1H),4.02–4.05(m,2H),3.84–3.91(m,1H),3.85(d,J=6.8Hz,2H),3.72(t,J=11.6Hz,1H),3.43–3.49(m,1H),3.10–3.23(m,4H),2.57–2.63(m,1H),2.01(s,3H),1.86–1.95(m,1H),1.25–1.36(m,1H),0.62–0.66(m,2H),0.33–0.37(m,2H).
MS(ESI,pos.ion)m/z:599.10[M+H]
+.
实施例21:N
2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-(氰甲基)-N
5-甲基吡啶-2,5-二甲酰胺
将化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))烟酸盐酸盐(80mg,0.16mmol),2-(甲基氨基)乙腈盐酸盐(71mg,0.84mmol)和HOAT(43mg,0.32mmol)溶于二氯甲烷(10mL)中,冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(155mg,0.81mmol)和DIPEA(186mg,1.44mmol),室温反应15h,加水(30mL),水相用二氯甲烷萃取(10mL×2),合并有机相,用无水硫酸钠干燥,减压浓缩,浓缩液进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=54/1),得到白色固体18mg,产率20%,纯度93.44%。
MS(ESI,pos.ion)m/z:556.40[M+H]
+.
实施例22:N
2-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-(2-氨基-2-氧代乙基)-N
5-甲基吡啶-2,5-二甲酰胺
将化合物6-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基))烟酸盐酸盐(60mg,0.12mmol),2-(甲基氨基)乙酰胺盐酸盐(50mg,0.40mmol)和HOAT(33mg,0.24mmol)溶于二氯甲烷(10mL)中,冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(115mg,0.60mmol)和DIPEA(146mg,1.13mmol),室温反应3h,冷却至室温后加水(30mL)搅拌,水相用二氯甲烷萃取(10mL×2),合并有机相,用无水硫酸钠干燥,减压浓缩,浓缩液进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=30/1),得到白色固体34mg,产率49%,纯度93.49%。
1H NMR(400MHz,CDCl
3)δ(ppm):9.16(br.s,1H),8.74(s,1H),8.24(d,J=7.5Hz,1H),7.96(d,J=7.4Hz,1H),7.09(d,J=8.0Hz,1H),6.79(s,1H),6.77(d,J=3.9Hz,1H),6.59(t,J
F-H=75.6Hz,1H),4.25–4.34(m,1H),4.15–4.24(m,1H),3.90–3.94(m,1H),3.84(d,J=6.9Hz,2H),3.55–3.62(m,1H),3.42(t,J=10.8Hz,1H),3.22–3.29(m,1H),3.11(m,3H),2.55–2.62(m,1H),2.15(s,3H),1.89–1.98(m,1H),1.62–1.67(m,2H),1.25–1.33(m,1H),0.62–0.66(m,2H),0.32–0.36(m,2H).
MS(ESI,pos.ion)m/z:574.05[M+H]
+.
实施例23:4-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基)邻甲氧基苯甲酰胺
步骤1:邻甲氧基苯甲酸甲酯的合成
向化合物水杨酸甲酯(1.02g,6.68mmol)中加入无水DMF(10mL),室温下搅拌至完全溶解,再加入碳酸钾(2.79g,19.98mmol)和碘甲烷(2.86g,20.1mmol),加热至60℃搅拌2h,停止反应,浓缩,加入水(15mL),EtOAc萃取(20mL×3),无水Na
2SO
4干燥,浓缩,硅胶柱层析分离(洗脱剂PE/EtOAc(v/v)=19:1),得黄色油状物1.12g,收率100.51%。
1H-NMR(400MHz,CDCl
3)δ(ppm):7.84-7.78(m,1H),7.52-7.46(m,1H),7.03-6.96(m,2H),3.93(s,3H),3.91(s,3H).
MS-ESI:m/z 167.20[M+H]
+.
步骤2:邻甲氧基苯甲酸的合成
向化合物邻甲氧基苯甲酸甲酯(1.11g,6.68mmol)中加入THF(12mL)和水(10mL),在室温下加入一水合氢氧化锂(0.86g,20.45mmol),室温搅拌3h,停止反应,于冰浴下加入稀盐酸(1M),调pH至5-6,浓缩,加入水(10mL),EtOAc萃取(15mL×3),无水Na
2SO
4干燥,浓缩,硅胶柱层析分离(梯度淋洗,洗脱剂DCM/MeOH(v/v)=1/0至19/1至18/1至17/1),得浅青色固体153.6mg,收率15.12%。
1H-NMR(400MHz,CD
3OD)δ(ppm):7.89-7.82(m,1H),7.60-7.52(m,1H),7.16(d,J=8.1Hz,1H),7.04(t,J=8.1Hz,1H),3.93(s,3H).
MS-ESI:m/z 153.20[M+H]
+.
步骤3:4-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基)邻甲氧基苯甲酰胺的合成
向化合物邻甲氧基苯甲酸(73.9mg,0.49mmol)中加入无水THF(8mL),室温下搅拌至溶解后加入碳酰二咪唑(86.5mg,0.52mmol),室温搅拌1h,再加入1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(93.2mg,0.26mmol),加热至60℃搅拌5h,停止反应,浓缩,加入水(15mL),EtOAc萃取(30mL×3),无水Na
2SO
4干燥,浓缩,硅胶柱层析分离(洗脱剂PE/EtOAc(v/v)=1:3),得浅褐色油状物91.1mg,收率70.9%,纯度91.93%。
1H-NMR(400MHz,CDCl
3)δ(ppm):8.24-8.14(m,1H),7.53-7.42(m,1H),7.12(s,4H),7.05–6.96(m,1H),6.60(t,J
F-H=75.5Hz,1H),4.00(s,3H),3.98–3.87(m,3H),3.86-3.76(m,3H),3.46-3.34(m,1H),2.16(s,2H),2.12–1.96(m,2H),1.38–1.18(m,4H),0.70–0.55(m,2H),0.40–0.28(m,2H).
MS-ESI:m/z 489.25[M+H]
+.
实施例24:4-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基)邻甲氨基苯甲酰胺
步骤1:邻甲氨基苯甲酸甲酯的合成
向化合物氨茴酸甲酯(1.03g,6.81mmol)中加入无水DMF(10mL),室温下搅拌至完全溶解后加入碳酸钾(2.94g,21.08mmol)以及碘甲烷(0.87g,6.1mmol),加热至60℃搅拌6h,停止反应,浓缩,加入水(15mL),EtOAc萃取(20mL×3),无水Na
2SO
4干燥,浓缩,硅胶柱层析分离(洗脱剂PE),得亮黄色油状物483mg,收率43%。
1H-NMR(400MHz,CDCl
3)δ(ppm):7.96-7.88(m,1H),7.45-7.35(m,1H),6.72-6.56(m,2H),3.87(s,3H),2.98-2.87(m,3H).
MS-ESI:m/z 166.25[M+H]
+.
步骤2:邻甲氨基苯甲酸的合成
向化合物邻甲氨基苯甲酸甲酯(247.1mg,1.50mmol)中加入THF(4mL)及水(4mL),然后加入氢氧化钾(142mg,2.53mmol),加热至60℃搅拌22h,停止反应,冰浴下加入稀盐酸(1M)调pH至2-3,浓缩,加入水(10mL),EtOAc萃取(15mL×3),无水Na
2SO
4干燥,浓缩得白色固体213.1mg,收率94.24%。
1H-NMR(400MHz,CD
3OD)δ(ppm):7.94-7.82(m,1H),7.45-7.32(m,1H),6.77-6.66(m,1H),6.62-6.51(m,1H),2.90(s,3H).
MS-ESI:m/z 152.20[M+H]
+.
步骤3:4-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基)邻甲氨基苯甲酰胺的合成
向化合物邻甲氨基苯甲酸(72.1mg,0.48mmol)中加入无水THF(8mL),室温下搅拌至完全溶解后加入碳酰二咪唑(86.9mg,0.53mmol),室温搅拌2h,之后加入1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(106.6mg,0.30mmol),加热至60℃搅拌6h,停止反应,浓缩,加入水(15mL),EtOAc萃取(30mL×3),无水Na
2SO
4干燥,浓缩,硅胶柱层析分离(洗脱剂PE:EtOAc(v/v)=1:3)得浅褐色油状物59.3mg,收率40.4%。
1H-NMR(400MHz,CDCl
3)δ(ppm):7.54-7.48(m,1H),7.37–7.30(m,1H),7.17–7.12(m,1H),6.85–6.80(m,2H),6.69–6.64(m,2H),6.63(t,J
F-H=75.5Hz,1H),4.42–4.32(m,1H),4.00–3.92(m,2H),3.90–3.86(m,2H),3.50–3.40(m,1H),3.38–3.22(m,2H),2.88(s,3H),2.70–2.60(m,1H),2.18(s,3H),2.08–1.98(m,2H),0.95–0.85(m,2H),0.72–0.64(m,2H),0.43–0.34(m,2H).
MS-ESI:m/z 488.25[M+H]
+.
实施例25:1-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)哌啶-4-甲酸
步骤1:1-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)哌啶-4-甲酸甲酯
将化合物1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(100mg,0.28mmol)溶于干燥的四氢呋喃(10mL)中,加入DIPEA(44mg,0.34mmol)和4-硝基氯甲酸苯酯(62mg,0.31mmol),室温反应1.5h,加入哌啶-4-甲酸甲酯(47mg,0.32mmol),室温反应14h,加入水(10mL),用EtOAc萃取(5mL×3),有机相用无水硫酸钠干燥,浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=30/1),得到白色固体132mg,产率49%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.14(d,J=8.7Hz,1H),7.10(d,J=5.6Hz,1H),6.81(s,2H),6.62(t,J
F-
H=75.5Hz,1H),4.24–4.30(m,1H),3.91–3.99(m,3H),3.89(d,J=7.0Hz,2H),3.70–3.75(m,1H),3.70(s,3H),3.42(t,J=11.0Hz,1H),3.13–3.28(m,2H),2.85–2.92(m,2H),2.58–2.64(m,1H),2.46–2.51(m,1H),2.15(s,3H),1.92–1.94(m,2H),1.66–1.81(m,3H),1.26–1.34(m,1H),0.65–0.70(m,2H),0.37–0.40(m,2H).
MS(ESI,pos.ion)m/z:524.20[M+H]
+.
步骤2:1-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)哌啶-4-甲酸
将化合物1-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)哌啶-4-甲酸甲酯(130mg,0.25mmol)溶于THF(3mL)和水(2mL)的混合溶剂中,再加入一水合氢氧化 锂(52mg,1.24mmol),50℃反应1.5h后停止,加稀盐酸(1M)调节溶液pH=1,减压除去THF,剩余物用二氯甲烷萃取(10mL×3),有机相用无水硫酸钠干燥,除去溶剂得到白色固体126mg,产率99%,纯度96.66%。
1H NMR(400MHz,CD
3OD)δ(ppm):7.11(d,J=8.2Hz,1H),7.02–7.03(m,1H),6.90–6.92(m,1H),6.74(t,J
F-H=75.7Hz,1H),4.59–4.68(m,2H),4.22–4.29(m,1H),4.02–4.06(m,1H),3.93–3.98(m,2H),3.93(d,J=6.8Hz,2H),3.54–3.59(m,1H),3.41–3.48(m,1H),2.92–2.98(m,2H),2.48–2.64(m,2H),2.21(s,0.8H),2.15(s,2.2H),1.89–1.94(m,3H),1.54–1.63(m,2H),1.29–1.37(m,1H),0.63–0.67(m,2H),0.37–0.41(m,2H).
MS-ESI:m/z 510.20[M+H]
+.
实施例26:N
1-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
4-乙基-N
4-甲基哌啶-1,4-二甲酰胺
将化合物1-((((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)哌啶-4-甲酸(90mg,0.18mmol),N-乙基甲基氨(68mg,1.15mmol),1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(170mg,0.89mmol)和HOAT(48mg,0.35mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入DIPEA(114mg,0.88mmol),室温反应5.5h,加水(20mL),二氯甲烷萃取(5mL×2),有机相用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=20/1),得到白色粘稠物71mg,产率73%,纯度98.69%。
1H NMR(400MHz,CDCl
3)δ(ppm):7.13(d,J=8.0Hz,1H),7.07(br.s,1H),6.81(s,2H),6.62(t,J
F-H=75.6Hz,1H),4.25–4.32(m,1H),4.05–4.12(m,2H),3.88–3.94(m,1H),3.89(d,J=6.9Hz,2H),3.67–3.75(m,1H),3.36–3.45(m,3H),3.14–3.28(m,2H),3.04(s,1.5H),2.92(s,1.5H),2.77–2.87(m,2H),2.57–2.69(m,2H),2.14(s,3H),1.68–1.82(m,5H),1.26–1.34(m,1H),1.22(t,J=6.6Hz,1.5H),1.10(t,J=6.6Hz,1.5H),0.63–0.70(m,2H),0.34–0.41(m,2H).
MS-ESI:m/z 551.10[M+H]
+.
实施例27:1-(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-3-(1-羟基-1,3-二氢苯并[c][1,2]噁硼烷-5-基)脲
将化合物2-羟基甲基-5-氨基苯硼酸半酯(47mg,0.32mmol)溶于干燥的四氢呋喃(5mL)中,加入 DIPEA(44mg,0.34mmol)和4-硝基氯甲酸苯酯(62mg,0.31mmol),室温反应3.5h,加入1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(100mg,0.28mmol),室温反应5.5h,加入水(10mL),用EtOAc萃取(5mL×3),有机相用无水硫酸钠干燥,浓缩,进行硅胶柱层析色谱分离(洗脱剂:DCM/MeOH(v/v)=30/1)得到白色固体43mg,产率28%。
1H NMR(400MHz,CD
3OD)δ(ppm):7.58–7.69(m,2H),7.05–7.14(m,3H),6.93(d,J=6.4Hz,1H),6.74(t,J
F-H=75.6Hz,1H),5.06(s,2H),4.25–4.33(m,1H),4.04–4.08(m,1H),3.89(d,J=6.7Hz,2H),3.65–3.70(m,1H),3.43–3.56(m,2H),3.29–3.40(m,1H),2.51–2.59(m,1H),2.14(s,3H),2.00–2.10(m,1H),1.23–1.34(m,1H),0.57–0.62(m,2H),0.30–0.34(m,2H).
MS(ESI,pos.ion)m/z:530.30[M+H]
+.
实施例28:1-羟基-1,3-二氢苯并[c][1,2]噁硼烷-5-基(((2R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酸酯
将化合物2-羟基甲基-5-羟基苯硼酸半酯(47mg,0.31mmol)溶于干燥的四氢呋喃(5mL)中,加入DIPEA(44mg,0.34mmol)和4-硝基氯甲酸苯酯(62mg,0.31mmol),室温反应3h,加入1-((2R)-2-(氨甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(100mg,0.28mmol),室温反应5h,加入水(10mL),用EtOAc萃取(5mL×3),有机相用无水硫酸钠干燥,浓缩,进行硅胶柱层析色谱分离(洗脱剂:DCM/MeOH(v/v)=40/1),得到白色固体28mg,产率18%,纯度99.05%。
1H NMR(400MHz,CD
3OD)δ(ppm):7.57–7.73(m,2H),7.05–7.14(m,3H),6.93(d,J=6.4Hz,1H),6.74(t,J
F-H=75.6Hz,1H),5.06(s,2H),4.25–4.33(m,1H),4.03–4.08(m,1H),3.89(d,J=6.7Hz,2H),3.66–3.71(m,1H),3.44–3.56(m,2H),3.33–3.40(m,1H),2.53–2.58(m,1H),2.14–2.23(m,3H),1.99–2.11(m,1H),1.22–1.31(m,1H),0.57–0.62(m,2H),0.30–0.34(m,2H).
MS(ESI,pos.ion)m/z:531.30[M+H]
+.
实施例37:N-(((2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-2-乙氧基苯甲酰胺
步骤1:化合物(S)-1-叔丁基2-甲基4-((三氟甲基)磺酰基)氧基-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成
将化合物(2S)-1-叔丁基氧羰基-4-氧代脯氨酸甲酯(7.75g,31.9mmol)和N,N-二异丙基乙胺(15.0mL,88.9mmol)溶解在二氯甲烷(50mL)中,在-15℃下滴加三氟甲磺酸酐(10.5mL,59.3mmol)的二氯甲烷溶液(20mL),室温搅拌2h。加入二氯甲烷(100mL)稀释,有机相用饱和食盐水(100mL×3)洗涤,用盐酸(2mol/L)调节pH=1,再用饱和碳酸氢钠溶液(100mL)洗涤,用无水硫酸钠干燥,减压浓缩液。剩余物进行硅胶柱层析分离(洗脱剂:60-90石油醚/乙酸乙酯(v/v)=10/1))得到黄色液体(11.1g,产率93%)。
1H NMR(400MHz,CDCl
3)δ(ppm):5.79–5.66(m,1H),5.09–4.97(m,1H),4.44–4.33(m,1H),4.33–4.22(m,1H),3.76(s,3H),1.47(s,4H),1.42(s,5H).
MS-ESI:m/z 320.40[M-55]
+.
步骤2:化合物(S)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成
将化合物(S)-1-叔丁基2-甲基4-((三氟甲基)磺酰基)氧基-1H-吡咯-1,2(2H,5H)-二羧酸酯(11.0g,29.3mmol),联硼酸频那醇酯(8.92g,35.1mmol),(1,1'-双(二苯基膦)二茂铁)二氯化钯二氯甲烷络合物(1.23g,1.47mmol)和醋酸钾(3.47g,35.4mmol)溶解于无水1,4-二氧六环(95mL)中,氮气保护下,100℃搅拌3h。减压浓缩,加入乙酸乙酯(200mL),用饱和食盐水洗涤(100mL x 3),用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:60-90石油醚/乙酸乙酯(v/v)=4/1)得到黄色透明液体(10.0g,产率97%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.37–6.24(m,1H),5.14–4.94(m,1H),4.36–4.22(m,2H),3.70(d,J=4.7Hz,3H),1.44(s,5H),1.39(s,4H),1.24(s,12H).
MS-ESI:m/z 216.10[M-137]
+.
步骤3:化合物(S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成
将化合物(S)-1-叔丁基2-甲基4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(8.51g,21.7mmol),3-(环丙基甲氧基)-4-(二氟甲氧基)-碘苯(8.40g,24.7mmol),(1,1'-双(二苯基膦)二茂铁)二氯化钯二氯甲烷络合物(850mg,1.02mmol)和磷酸钾(13.0g,61.2mmol)溶解于无水1,4-二氧六环(80mL)中,氮气保护下,100℃搅拌3h。减压浓缩,加入乙酸乙酯(200mL),用饱和食盐水洗涤(100mL x 3),用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:60-90石油醚/乙酸乙酯(v/v)=8/1)得到黄色液体(8.23g,产率86%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.13(d,J=8.2Hz,1H),6.99–6.86(m,2H),6.62(t,J=75.4Hz,1H),6.04–5.97(m,1H),5.19–5.08(m,1H),4.66–4.43(m,2H),3.89–3.84(m,2H),3.75(s,3H),1.51(s,3H),1.44(s,6H),1.28–1.24(m,1H),0.70–0.60(m,2H),0.39–0.31(m,2H).
MS-ESI:m/z 384.10[M-t-Bu+2H]
+.
步骤4:化合物(2S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯-1,2-二羧酸酯的合成
将化合物(S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(3.72g,8.47mmol)和10%钯碳(405mg)加入甲醇(250mL)中,氢气氛围下,搅拌12h。通过硅藻土滤去固体,减压浓缩得到黄色液体(3.49g,产率93%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.09(d,J=8.0Hz,1H),6.83–6.75(m,2H),6.59(t,J=75.6Hz,1H),4.42–4.26(m,1H),4.07–3.89(m,1H),3.88–3.81(m,2H),3.79–3.67(m,3H),3.46–3.37(m,1H),3.37–3.24(m,1H),2.71–2.57(m,1H),2.09–1.92(m,1H),1.46(s,3H),1.42(s,6H),1.31–1.21(m,1H),0.68–0.59(m,2H),0.39–0.29(m,2H).
MS-ESI:m/z 386.50[M-t-Bu+2H]
+.
步骤5:化合物(2S)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-羟甲基吡咯烷-1-羧酸酯的合成
将化合物(2S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-1,2-二羧酸酯(1.70g,3.85mmol)溶于无水四氢呋喃(20mL)中,分批加入硼氢化锂(140mg,5.78mmol)溶液,室温搅拌12h。减压除去溶剂,向剩余物加饱和食盐水(20mL),水相用乙酸乙酯萃取(50mL×3),合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:60-90石油醚/乙酸乙酯(v/v)=2/1)得无色透明液体(1.10g,产率69%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.09(d,J=8.2Hz,1H),6.78(d,J=8.2Hz,2H),6.58(t,J=76.5Hz,1H),5.16(s,1H),4.15–3.99(m,1H),3.94(s,1H),3.85(d,J=6.9Hz,2H),3.80–3.72(m,1H),3.73–3.60(m,1H),3.29–3.10(m,2H),2.47–2.29(m,1H),1.72–1.55(m,1H),1.47(s,9H),1.27–1.20(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).
MS-ESI:m/z 358.10[M-
tBu+2H]
+.
步骤6:化合物(2S)-叔丁基2-叠氮基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-羧酸酯的合成
将化合物(2S)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-羟甲基吡咯烷-1-羧酸酯(1.11g,2.68mmol)和三乙胺(750uL,5.35mmol)溶于乙酸乙酯(20mL)中,在0℃下缓慢滴入甲磺酰氯的乙酸乙酯溶液(7.3mL,3.48mmol,0.48mol/L)溶液,室温搅拌3h。滤去固体,用乙酸乙酯(10mL)洗涤,减压除去溶剂,得到黄色液体(2S)-2-甲磺酰基氧基甲基-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷(1.31g,产率99%)。
将化合物(2S)-2-甲磺酰基氧基甲基-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷(1.19g,2.42mmol)和叠氮化钠(490mg,7.31mmol)溶于无水N,N-二甲基甲酰胺(12mL)中,置于80℃下搅拌3h。减压除去N,N-二甲基甲酰胺,加入乙酸乙酯(50mL)稀释,有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:60-90石油醚/乙酸乙酯(v/v)=8/1)得黄色液体(1.05g,产率99%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.11(d,J=7.9Hz,1H),6.86–6.80(m,2H),6.60(t,J=75.7Hz,1H),4.17–3.93(m,3H),3.87(d,J=6.4Hz,2H),3.50–3.30(m,1H),3.29–3.12(m,2H),2.52–2.31(m,1H),2.10–1.95(m,1H),1.48(s,9H),1.35–1.23(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).
MS-ESI:m/z 383.20[M-t-Bu+2H]
+.
步骤7:化合物(2S)-2-叠氮基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷盐酸盐的合成(11162-4)
将化合物(2S)-叔丁基2-叠氮基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-1-羧酸酯(1.03g,2.35mmol)溶于DCM(7mL)中,注入氯化氢的二氧六环溶液(10.0mL,40.0mmol,4mol/L)溶液,室温搅拌3h。减压除去溶剂,得到褐色粘稠液体(889mg,产率99%)。
MS-ESI:m/z 339.20[M-HCl+H]
+.
步骤8:化合物1-((2S)-2-叠氮基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙基酮的合成
将化合物(2S)-2-叠氮基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷盐酸盐(880mg,2.35mmol),三乙胺(992uL,7.05mmol)溶于二氯甲烷(23mL)中,在0℃下缓慢滴入乙酰氯(251uL,3.52mmol),室温搅拌3h。加饱和食盐水(20mL),水相用二氯甲烷萃取(50mL×3),合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)=70/1)得到黄色粘稠液体(702mg,产率79%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.12(d,J=7.9Hz,1H),6.88–6.79(m,2H),6.60(t,J=75.6Hz,1H),4.32–4.23(m,1H),4.16–4.08(m,1H),3.92–3.84(m,1H),3.88(d,J=6.9Hz,2H),3.46–3.34(m,2H),3.31 –3.20(m,1H),2.48–2.37(m,1H),2.16–2.06(m,1H),2.09(s,3H),1.30–1.24(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).
MS-ESI:m/z 381.20[M+H]
+.
步骤9:化合物1-((2S)-2-氨基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙基酮盐酸盐的合成
将化合物1-((2S)-2-叠氮基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙基酮(399mg,1.05mmol),三苯基膦(3413mg,1.58mmol)溶于四氢呋喃/水(8mL,(v/v)=3/1)中,置于50℃搅拌3h。减压除去四氢呋喃,加饱和食盐水(10mL),水相用乙酸乙酯萃取(50mL×3),合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)=8/1)得到黄色粘稠液体,加入氯化氢的二氧六环溶液(1mL,4mol/L)搅拌均匀,减压除去溶剂得到黄色粘稠液体(119mg,产率29%)。
MS-ESI:m/z 355.15[M-HCl+H]
+.
步骤10:化合物N-(((2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-2-基)甲基)-2-乙氧基苯甲酰胺的合成
将化合物1-((2S)-2-氨基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙基酮盐酸盐(40mg,0.10mmol),邻乙氧基苯甲酸(18uL,0.12mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(5mL)中,在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(59mg,0.31mmol)和N,N-二异丙基乙胺(67uL,0.41mmol),室温搅拌5h。向反应液加饱和食盐水(20mL),水相用二氯甲烷萃取(50mL×3),合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)=50/1)得到黄色液体(19mg,产率37%)。
1H NMR(600MHz,CDCl
3)δ(ppm):8.45(t,J=5.6Hz,1H),8.15(dd,J=7.8,1.7Hz,1H),7.46–7.37(m,1H),7.09–7.01(m,2H),6.95(d,J=8.3Hz,1H),6.77(d,J=1.6Hz,1H),6.76–6.72(m,1H),6.56(t,J=75.7Hz,1H),4.32–4.15(m,3H),4.03–3.91(m,1H),3.91–3.81(m,2H),3.77(q,J=6.1Hz,2H),3.36(t,J=10.8Hz,1H),3.26–3.15(m,1H),2.55–2.48(m,1H),2.22(s,0.7H),2.10(s,2.3H),2.06(td,J=12.6,9.6Hz,1H),1.48(t,J=7.0Hz,3H),1.26–1.22(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).
MS-ESI:m/z 503.20[M+H]
+.
实施例38:合成N
2-(((2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺
步骤1:化合物6-((((2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)胺甲酰基)烟酸甲酯的合成
将化合物1-((2S)-2-氨基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙基酮盐酸盐(105mg,0.27mmol,参见实施例37步骤9),2,5-吡啶二羧酸-5-甲酯(56mg,0.30mmol)和N-羟基-7-氮杂 苯并三氮唑(70mg,0.51mmol)溶于二氯甲烷(10mL)中,在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(148mg,0.77mmol)和N,N-二异丙基乙胺(169uL,1.02mmol),室温搅拌5h。向反应液加饱和食盐水(20mL),水相用二氯甲烷萃取(50mL×3),合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)=70/1)得到红色液体(75mg,产率54%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.19–9.08(m,1H),8.43(dd,J=8.1,2.0Hz,1H),8.25(d,J=8.1Hz,1H),7.58–7.42(m,1H),7.09(d,J=8.2Hz,1H),6.82–6.74(m,2H),6.58(t,J=75.6Hz,1H),4.35–4.25(m,1H),4.08–4.00(m,1H),3.97(s,3H),3.95–3.88(m,1H),3.82(d,J=6.9Hz,2H),3.68–3.57(m,1H),3.42(t,J=10.8Hz,1H),3.31–3.19(m,1H),2.78–2.52(m,1H),2.16(s,3H),2.04–1.89(m,1H),1.31–1.21(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).
MS-ESI:m/z 518.35[M+H]
+.
步骤2:化合物6-((((2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)胺甲酰基)烟酸的合成
将化合物6-((((2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)胺甲酰基)烟酸甲酯(70mg,0.14mmol),氢氧化锂一水合物(11mg,0.26mmol)溶于四氢呋喃/水(6mL,(v/v)=5/1)中,室温搅拌3h。减压除去四氢呋喃,向剩余物加入乙酸乙酯(50mL)稀释,用盐酸(2mol/L)调节pH=1,用饱和食盐水(30mL×3)洗涤,用无水硫酸钠干燥,减压除去溶剂,得到白色固体(68mg,产率99%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.77(s,1H),9.50(s,1H),8.48(d,J=7.5Hz,1H),8.24(d,J=8.0Hz,1H),7.57–7.42(m,1H),7.14(d,J=8.4Hz,1H),6.84–6.77(m,2H),6.61(t,J=75.5Hz,1H),4.56–4.46(m,1H),4.05–3.95(m,2H),3.88(d,J=6.8Hz,2H),3.55–3.41(m,2H),3.31(s,1H),2.76–2.61(m,1H),2.37(s,3H),1.95–1.81(m,1H),1.34–1.22(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).
MS-ESI:m/z 504.20[M+H]
+.
步骤3:化合物N
2-(((2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺的合成
将化合物6-((((2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)胺甲酰基)烟酸(60mg,0.12mmol),N-甲基乙胺(20uL,0.23mmol)和N-羟基-7-氮杂苯并三氮唑(32mg,0.24mmol)溶于二氯甲烷(5mL)中,在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(69mg,0.36mmol)和N,N-二异丙基乙胺(78uL,0.42mmol),室温搅拌5h。向反应液加饱和食盐水(20mL),水相用二氯甲烷萃取(50mL×3),合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)=20/1)得到黄色液体(20mg,产率31%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.08(s,1H),8.64(s,1H),8.21(d,J=8.0Hz,1H),7.86(t,J=7.0Hz,1H),7.08(d,J=8.0Hz,1H),6.81–6.75(m,2H),6.58(t,J=75.5Hz,1H),4.33–4.23(m,1H),4.06–3.97(m,1H),3.91(t,J=10.3,7.0Hz,1H),3.83(d,J=6.9Hz,2H),3.65–3.55(m,2H),3.41(t,J=10.8Hz,1H),3.31–3.19(m,2H),3.09(s,1.6H),2.94(s,1.4H),2.62–2.52(m,1H),2.15(s,3H),2.01–1.90(m,1H),1.25(t,J=6.2Hz,1.5H),1.27–1.21(m,1H),1.15(t,J=6.2Hz,1.5H),0.67–0.55(m,2H),0.35–0.26(m,2H).
MS-ESI:m/z 545.20[M+H]
+.
实施例39:N
2-(((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺
步骤1:化合物2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将化合物2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(11.0g,29.43mmol),联硼酸频哪醇酯(8.96g,35.3mmol),醋酸钾(8.6g,87.6mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(Pd(dppf)Cl
2.CH
2Cl
2)(2.40g,2.94mmol)溶解在干燥的N,N-二甲基甲酰胺(80mL)溶液中,氮气保护下,100℃的环境反应2h,反应液通过硅藻土过滤后,用50mL的乙酸乙酯稀释,用饱和食盐水洗涤(50ml×2)后,合并有机相,用无水硫酸钠干燥30min,减压浓缩,通过硅胶柱层析纯化(PE/EtOAc(v/v)=10/1)得到绿色液体产物(10.01g,产率99.97%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.39(d,J=7.9Hz,1H),7.35(s,1H),7.14(d,J=7.8Hz,1H),6.67(t,J=75.6Hz,1H),3.91(d,J=7.0Hz,2H),1.34(s,12H),1.26–1.32(m,1H),0.69–0.61(m,2H),0.40–0.32(m,2H).
MS-ESI:m/z 341.15[M+H]
+.
步骤2:(R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成
将化合物2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(5g,14.7mmol),(R)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)-1H-吡咯-1,2-(2H,5H)-二羧酸酯(5.00g,13.3mmol,中间体M),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(Pd(dppf)Cl
2.CH
2Cl
2)(550mg,0.67mmol),磷酸钾(K
3PO
4)(7.60g,35.8mmol),溶解在甲苯(50mL)溶液中,氮气保护下,在50℃的油浴锅下搅拌反应8h。反应液通过硅藻土过滤后,用乙酸乙酯溶液(50ml)洗滤饼,再用饱和食盐水(50ml×2)洗涤有机相,合并有机相,并用无水硫酸钠干燥30min,减压浓缩,通过硅胶柱层析纯化(PE/EtOAc(v/v)=5/1),得到浅黄色粘稠状液体(4.60g,产率78.60%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.14(d,J=8.2Hz,1H),6.97–6.90(m,2H),6.63(t,J=75.4Hz,1H),6.05–5.98(m,1H),5.21–5.09(m,1H),4.67–4.45(m,2H),3.88(dd,J=11.6,6.9Hz,2H),3.76(d,J=4.3Hz,3H),1.52(s,3H),1.46(s,6H),1.33–1.25(m,1H),0.69–0.63(m,2H),0.34–0.39(m,2H).
MS-ESI:m/z 384.10[M-55]
+.
步骤3:(2R,4S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯的合成
将化合物(R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2-(2H,5H)-二羧酸酯(4.60g,10.5mmol),溶在甲醇溶液中(70mL),再加入10%Pd/C还原剂(140mg),用氢气置换三次后,在氢气保护、室温条件下搅拌反应3h,反应液用硅藻土过滤,减压浓缩,通过硅胶柱层析纯化(PE/EtOAc(v/v)=6/1),得到浅黄色粘稠状液体产物(4.60g,产率99.50%)。合成参考:Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2.J.Med.Chem.2014,57,9042-9064。
1H NMR(400MHz,CDCl
3)δ(ppm):7.10(d,J=8.0Hz,1H),6.81–6.78(m,2H),6.60(t,J=76.4Hz,1H),4.44–4.26(m,1H),4.07–3.90(m,1H),3.90–3.82(m,2H),3.76(d,J=6.5Hz,3H),3.47–3.37(m,1H),3.38 –3.25(m,1H),2.68–2.58(m,1H),2.10–1.95(m,1H),1.45(d,J=14.1Hz,9H),1.24–1.31(m,1H),0.71–0.59(m,2H),0.41–0.29(m,2H).
MS-ESI:m/z 386.10[M-55]
+:
步骤4:(2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-甲酸酸叔丁酯的合成
将化合物(2R,4S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(1.90g,4.301mmol)溶解在干燥四氢呋喃(15mL)溶液中,冰浴条件下加入硼氢化锂(332mg,15.6mmol),原料加完之后转移到室温反应1h。加入饱和氯化钠水溶液(30mL),用乙酸乙酯(30ml×2)萃取,有机相用无水硫酸钠干燥,减压浓缩,得到无色液体(1.80g,100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.10(d,J=8.7Hz,1H),6.84–6.78(m,2H),6.59(t,J
F-H=75.6Hz,1H),5.19(d,J=8.7Hz,1H),4.10–4.02(m,1H),4.00–3.91(m,1H),3.86(d,J=6.9Hz,2H),3.82–3.71(m,1H),3.70–3.65(m,1H),3.27–3.17(m,2H),2.44–2.33(m,1H),1.68–1.58(m,1H),1.48(s,9H),1.34–1.24(m,1H),0.67–0.62(m,2H),0.37–0.33(m,2H).
MS-ESI:m/z 358.55[M-55]
+.
步骤5:化合物(2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((甲磺酰基)氧基)甲基)吡咯烷-1-羧酸叔丁酯的合成
将化合物(2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(1.8g,4.40mmol)溶于二氯甲烷(20mL)中,加入三乙胺(880mg,8.70mmol),冰浴中加入甲磺酰氯(702mg,6.13mmol),室温反应3.5h,加水(30mL)停止反应,分离有机相,水相用二氯甲烷(30mL×2)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,得到浅黄色液体(2.1g,产率98%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.12(d,J=8.7Hz,1H),6.85–6.81(m,2H),6.62(t,J
F-H=75.7Hz,1H),4.72–4.64(m,0.5H),4.50–4.32(m,1.5H),4.25–3.13(m,1H),4.00–3.93(m,0.5H),3.89(d,J=6.9Hz,2H),3.82–3.75(m,0.5H),3.34–3.15(m,2H),3.05–3.03(m,3H),2.60–2.30(m,1H),2.21–2.04(m,1H),1.50(s,9H),1.35–1.24(m,1H),0.68–0.64(m,2H),0.40–0.35(m,2H).
MS-ESI:m/z 436.10[M-t-Bu+2H]
+.
。
步骤6:化合物(2R,4S)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-羧酸叔丁酯的合成
将化合物(2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((甲磺酰基)氧)甲基)吡咯烷-1-羧酸叔丁酯(2.1g,4.30mmol)溶于DMF(11mL),加入叠氮化钠(1.1g,17.0mmol),80℃加热反应3.5h,冷却至室温,加水(30mL),乙酸乙酯萃取(10mL×3),有机相用无水Na
2SO
4干燥,浓缩,进行硅胶柱分离(洗脱剂:PE/EtOAc(v/v)=8/1)得到无色液体(1.6g,产率88%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.11(d,J=7.9Hz,1H),6.88–6.79(m,2H),6.60(t,J
F-H=75.7Hz,1H),4.14–3.97(m,3H),3.87(d,J=6.4Hz,2H),3.44–3.33(m,1H),3.26–3.16(m,2H),2.50–2.32(m,1H),2.06–1.98(m,1H),1.48(s,9H),1.33–1.22(m,1H),0.67–0.62(m,2H),0.38–0.34(m,2H).
MS-ESI:m/z 383.60[M-55]
+.
步骤7:化合物(2R,4S)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷盐酸盐的合成
将化合物(2R,4S)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-羧酸叔丁酯(1.66g,3.79mmol)溶解于二氯甲烷(20mL)溶液中,加入3mol/L HCl的1,4-二氧六环溶液(6mL),室温搅拌2h,减压浓缩,得到无色液体(1.40g,产率99%)。
1H NMR(400MHz,CD
3OD)δ(ppm):7.15(d,J=8.2Hz,1H),7.09(d,J=1.9Hz,1H),6.94(dd,J=8.2,1.9Hz,1H),6.76(t,J=75.5Hz,1H),4.01–3.98(m,1H),3.96(d,J=6.9Hz,2H),3.94–3.91(m,1H),3.81–3.78 (m,1H),3.76–3.73(m,1H),3.65–3.59(m,1H),3.28(t,J=11.2Hz,1H),2.57–2.53(m,1H),1.99–1.94(m,1H),1.34–1.29(m,1H),0.67–0.64(m,2H),0.41–0.38(m,2H).
MS-ESI:m/z 339.15[M-HCl+H]
+.
步骤8:化合物1-((2R,4S)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮的合成
将化合物(2R,4S)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷盐酸盐(1.42g,3.79mmol)溶解在二氯甲烷(20mL)中,在冰浴中冷却,加入N,N-二异丙基乙胺(1.9g,15.0mmol)和乙酰氯(653mg,8.32mmol),室温搅拌1.5h后停止反应,加水(20mL)搅拌2min,分离有机相,有机相用无水Na
2SO
4干燥,浓缩液进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=1/1)得到浅褐色液体(1.29g,产率90%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.13(d,J=8.1Hz,1H),6.85(s,1H),6.84(d,J=7.4Hz,1H),6.61(t,J=75.6Hz,1H),4.31–4.25(m,1H),4.13(dd,J=12.4,4.7Hz,1H),3.93–3.85(m,1H),3.89(d,J=6.9Hz,2H),3.45–3.36(m,2H),3.30–3.21(m,1H),2.46–2.39(m,1H),2.15–2.06(m,1H),2.10(s,3H),1.34–1.24(m,1H),0.68–0.64(m,2H),0.38–0.35(m,2H).
MS-ESI:m/z 381.20[M+H]
+.
步骤9:化合物1-((2R,4S)-2-(氨基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮盐酸盐的合成
将化合物1-((2R,4S)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(1.2g,3.20mmol)和三苯基膦(1.1g,4.2mmol)溶于四氢呋喃/水(v/v=3/1,40mL)的混合溶剂中,50℃反应1h,减压浓缩,乙酸乙酯萃取(15mL×3),有机相用无水Na
2SO
4干燥,减压浓缩,浓缩液进行硅胶柱层析分离(洗脱剂:DCM/MeOH(v/v)=10/1)得到浅褐色液体加入HCl的1,4-二氧六环溶液(2mL,4mol/L),调节pH=1,减压浓缩,得到浅黄色固体(1.14g,产率92%)。
1H NMR(400MHz,CD
3OD)δ(ppm):7.12(d,J=8.2Hz,1H),7.09(d,J=1.5Hz,1H),6.95(d,J=1.6Hz,1H),6.75(t,J
F-H=75.7Hz,1H),4.31–4.24(m,1H),4.10–4.06(m,1H),3.95(d,J=6.9Hz,2H),3.56(d,J=10.8Hz,1H),3.46–3.37(m,1H),3.29–3.19(m,2H),2.64–2.57(m,1H),2.18(s,3H),1.98–1.90(m,1H),1.35–1.27(m,1H),0.67–0.63(m,2H),0.41–0.37(m,2H).
MS-ESI:m/z 355.10[M-HCl+H]
+.
步骤10:N
2-(((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺的合成
将化合物1-((2R,4S)-2-(氨基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮盐酸盐(660mg,1.69mmol),5-(乙基(甲基)氨基甲酰基)吡啶甲酸(452mg,2.17mmol)和1-羟基苯并三唑(342mg,2.53mmol)溶解在干燥的N,N-二甲基甲酰胺(15ml)溶液中,加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(649mg,3.39mmol),在0℃下冷却后,再加入N-甲基吗啡啉(553mg,5.47mmol),转移到室温下搅拌反应4h。加水(150mL)停止反应,用乙酸乙酯(30mL×3)萃取有机相后,用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(DCM/MeOH(v/v)=23/1),得到白色固体(632mg,产率69%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.11(s,1H),6.87(s,1H),8.23(d,J=7.9Hz,1H),7.89(br.s,1H),7.11(d,J=7.9Hz,1H),6.81(s,2H),6.60(t,J
F-H=75.6Hz,1H),4.26–4.36(m,1H),4.00–4.08(m,1H),3.92–3.96(m,1H),3.86(d,J=6.8Hz,2H),3.59–3.67(m,2H),3.44(t,J=10.7Hz,1H),3.23–3.33(m,2H),3.12(s,1.7H),2.97(s,1.3H),2.57–2.63(m,1H),2.18(s,3H),1.92–2.01(m,1H),1.13–1.36(m,4H),0.63–0.69(m,2H),0.35–0.38(m,2H).
MS-ESI:m/z 545.20[M+H]
+.
实施例40:N
2-(((2R,4R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺
步骤1:化合物(R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯的合成
将化合物(R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(4.6g,10.0mmol,实施例39步骤2)溶于50mL无水四氢呋喃溶液中,在冰浴条件下,加入硼氢化锂(507mg,13.4mmol),室温反应3h,原料反应完全,停止反应。加入冰水混合物淬灭反应,用乙酸乙酯萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:PE/EtOAc(v/v)=5/1)得到白色泡沫状固体(3.78g,产率88%,)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.13(d,J=8.2Hz,1H),6.93–7.00(m,1.25H),6.87–6.89(m,0.75H),6.63(t,J=75.4Hz,1H),6.03(s,0.3H),5.93(s,0.7H),4.89(s,0.8H),4.74(s,0.2H),4.59–4.66(m,1H),4.40–4.52(m,2H),3.89(d,J=6.9Hz,2H),3.81–3.86(m,1H),3.73–3.79(m,0.3H),3.64–3.68(m,0.7H),1.53(s,9H),1.29–1.32(m,1H),0.63–0.68(m,2H),0.35–0.38(m,2H).
MS-ESI:m/z 356.20[M-55]
+.
步骤2:化合物(2R,4R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯的合成
将化合物(R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(2.2g,5.3mmol),六氟磷酸(三环已基膦)(1,5-环辛二烯)(吡啶)合铱(Crabtrees catalyst)(0.66g,0.80mmol)溶于90mL无水二氯甲烷溶液中,在0.5Mpa氢气氛围下,室温反应72h,原料反应完全,停止反应。加入饱和食盐水300mL,用二氯甲烷萃取(50mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:PE/EtOAc(v/v)=10/1)得到黄色液体(1.75g,产率76%)。合成参考:Azacyclic FTY720 Analogues that Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in Vivo.ACS Chem.Biol.2016,11,2,409-414。
1H NMR(400MHz,CDCl
3)δ(ppm)7.09(d,J=7.9Hz,1H),6.76–6.81(m,1.75H),6.75(s,0.5H),6.59(t,J=75.7Hz,0.75H),4.15–4.23(m,1H),3.85(d,J=6.9Hz,2H),3.70–3.75(m,3H),3.30–3.46(m,2H),2.08–2.16(m,1H),1.96–2.03(m,1H),1.47(s,9H),1.27–1.30(m,1H),0.61–0.66(m,2H),0.32–0.36(m,2H).
MS-ESI:m/z 358.20[M-55]
+.
步骤3:化合物(2R,4R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((甲基磺酰基)氧基)甲基)吡咯烷-1-羧酸叔丁酯的合成
将化合物(2R,4R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(1.7g,3.9mmol)溶于30mL无水二氯甲烷溶液中,在冰浴条件下,加入甲基磺酰氯(MsCl)(1.8mL,13.0mmol),室温反应2h,原料反应完全,停止反应。加入冰水混合物淬灭反应,用二氯甲烷萃取(20mL×3),有 机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:PE/EtOAc(v/v)=5/1)得到淡黄色油状物(1.95g,产率98%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.10(d,J=7.9Hz,1H),6.77–6.79(m,2H),6.59(t,J=75.7Hz,1H),4.30–4.37(m,1H),4.17–4.26(m,1H),3.86(d,J=6.6Hz,2H),3.74–3.79(m,1H),3.40–3.50(m,1H),3.14–3.08(m,2H),3.03(s,3H),2.29–2.38(m,1H),2.14–2.19(m,1H),1.49(s,4H),1.46(s,5H),1.27–1.34(m,1H),0.62–0.66(m,2H),0.33–0.37(m,2H).
MS-ESI:m/z 436.10[M-t-Bu+2H]
+.
步骤4:化合物(2R,4R)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-羧酸叔丁酯的合成
将化合物(2R,4R)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((甲基磺酰基)氧基)甲基)吡咯烷-1-羧酸叔丁酯(1.8g,3.7mmol),叠氮化钠(716mg,11.0mmol)溶于15mL N,N-二甲基甲酰胺溶液中,在80℃加热条件下反应4h,原料反应完全,停止反应。加入100mL水,用乙酸乙酯萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:PE/EtOAc(v/v)=5/1)得到无色油状物(1.3g,产率81%)。
1H NMR(400MHz,CDCl
3)δ7.10(d,J=7.9Hz,1H),6.77–6.79(m,2H),6.59(t,J=75.7Hz,1H),4.08–4.16(m,0.6H),3.98–4.05(m,0.4H),3.86(d,J=6.2Hz,2H),3.76–3.81(m,1H),3.64–3.71(m,0.5H),3.47–3.59(m,1H),3.38–3.46(m,2H),3.27–3.32(m,0.5H),2.17–2.27(m,1H),2.07–2.15(m,1H),1.50(s,4H),1.47(s,5H),1.26–1.32(m,1H),0.62–0.67(m,2H),0.33–0.37(m,2H).
MS-ESI:m/z 383.40[M-55]
+.
步骤5:化合物(2R,4R)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷盐酸盐的合成
将化合物(2R,4R)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-羧酸叔丁酯(1.3g,2.9mmol)溶于30mL二氯甲烷溶液中,再加入盐酸1,4-二氧六环溶液(5mL),室温反应1h,原料反应完全,停止反应。减压蒸馏,除去溶剂,浓缩液得到黄色液体(1.1g,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.07(d,J=8.0Hz,1H),6.84(s,1H),6.80(d,J=8.1Hz,1H),6.57(t,J=75.5Hz,1H),4.02–4.11(m,1H),3.94–3.99(m,1H),3.85(d,J=6.9Hz,2H),3.78–3.82(m,1H),3.65(s,3H),3.25–3.36(m,1H),2.22–2.24(m,2H),1.22–1.29(m,1H),0.58–0.62(m,2H),0.30–0.34(m,2H).
MS-ESI:m/z 339.10[M-HCl+H]
+.
步骤6:化合物1-((2R,4R)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷基-1-基)乙酮的合成
将(2R,4R)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷盐酸盐(4.6g,10.0mmol)溶于20mL二氯甲烷溶液中,在冰浴条件下,加入三乙胺(0.8mL,6.0mmol),乙酰氯(0.1mL,3mmol),室温反应1h,原料反应完全,停止反应。加入饱和食盐水淬灭反应,用二氯甲烷萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:PE/EA(v/v)=2/1)得到黄色液体(1.04g,产率93%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.12(d,J=7.9Hz,1H),6.78–6.80(m,2H),6.60(t,J=75.6Hz,1H),4.38–4.41(m,1H),3.89–3.94(m,1H),3.87(d,J=6.9Hz,2H),3.76(dd,J=12.3,6.0Hz,1H),3.63–3.72(m,1H),3.47(dd,J=12.2,2.8Hz,1H),3.40(t,J=9.8Hz,1H),2.22–2.27(m,1H),2.13–2.18(m,1H),2.07(s,3H),1.29–1.35(m,1H),0.63–0.68(m,2H),0.34–0.38(m,2H).
MS-ESI:m/z 380.90[M+H]
+.
步骤7:化合物1-((2R,4R)-2-(氨基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷基-1-基)乙酮的 合成
将化合物1-((2R,4R)-2-(叠氮甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷基-1-基)乙酮(1.0g,2.63mmol)溶于30mL四氢呋喃与10mL水的混合溶剂中,然后加入三苯基膦(1.04g,4.0mmol),50℃下反应2h,原料反应完全,停止反应。加入30mL饱和食盐水,用乙酸乙酯萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:DCM/MeOH(v/v)=20/1)得到浅褐色粘稠物(0.89g,产率95%)。
MS-ESI:m/z 355.10[M+H]
+.
步骤8:化合物1-((2R,4R)-2-(氨基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮盐酸盐的合成
将化合物1-((2R,4R)-2-(氨基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷基-1-基)乙酮(0.88g,2.5mmol)溶于30mL二氯甲烷溶液中,再加入盐酸1,4-二氧六环溶液(2mL),室温反应1h,原料反应完全,停止反应。减压蒸馏,除去溶剂,浓缩液得到棕黄色固体(0.95g,产率98%)。
步骤9:化合物N
2-((((2R,4R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺的合成
将化合物1-((2R,4R)-2-(氨基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮盐酸盐(950mg,2.43mmol),5-(乙基(甲基)氨基甲酰基)吡啶甲酸(603mg,2.89mmol)和1-羟基-7-偶氮苯并三氮唑(1.12g,7.82mmol)溶于二氯甲烷(40mL)溶液中,在冰浴中冷却,依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.56g,7.72mmol)和N,N-二异丙基乙胺(1.8mL,10.0mmol),室温下反应1h,原料反应完全,停止反应,加入饱和食盐水(100mL),用二氯甲烷萃取(30mL×3),有机相用无水硫酸钠干燥,减压浓缩硅胶柱层析(洗脱剂:DCM/MeOH(v/v)=20/1)分离提纯,得暗红色固体(900mg,产率68%)。
1H NMR(400MHz,CDCl
3)δ(ppm):8.76(s,1H),8.64(s,1H),8.20(d,J=8.0Hz,1H),7.87(br.s,1H),7.11(d,J=8.0Hz,1H),6.80(s,1H),6.49(d,J=9.5Hz,1H),6.59(t,J=75.6Hz,1H),4.49–4.54(m,1H),3.90–3.95(m,1H),3.86(d,J=6.8Hz,2H),3.76–3.82(m,1H),3.55–3.72(m,4H),3.42(t,J=9.9Hz,1H),3.10(s,2H),2.95(s,1H),2.20–2.26(m,1H),2.09–2.17(m,1H),2.09(s,3H),1.30–1.34(m,1H),1.11–1.21(m,3H),0.63–0.66(m,2H),0.33–0.37(m,2H).
MS-ESI:m/z 545.25[M+H]
+.
实施例41:N
2-(((2S,4R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺
步骤1:化合物(2S,4R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-1,2-二羧酸酯的合成
将化合物2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(10.410g,26.73mmol)溶于无水四氢呋喃(62mL),冷至-20℃,滴入异丙基氯化镁-氯化锂(22mL,29.00mmol,1.3mol/L in THF),室温搅拌2h,置于-78℃搅 拌0.5h,滴入(2S)-1-叔丁基氧羰基-4-氧代脯氨酸甲酯(5.00g,20.60mmol)的无水四氢呋喃(20mL),置于-70℃搅拌2h。加入饱和氯化铵溶液(5mL)淬灭反应,加入乙酸乙酯(100mL)稀释,有机相用饱和食盐水洗涤(100mL),水相用乙酸乙酯萃取(50mL×3),合并有机相,有机相用无水无水硫酸钠干燥,浓缩得黄色液体,硅胶柱层析(洗脱剂:PE/AcOEt(v/v)=4/1)纯化得黄色透明液体(5.21g,产率55.40%)。合成参考:Synthesis of 4-cis-Phenyl-L-proline via Hydrogenolysis J.Org.Chem.2001,66,3593-3596。
1H NMR(400MHz,CDCl
3)δ(ppm):7.19(d,J=14.9Hz,1H),7.13(d,J=8.3Hz,1H),6.95(d,J=8.3Hz,1H),6.62(t,J=75.6Hz,1H),4.57–4.42(m,1H),3.95–3.84(m,3H),3.82(d,J=6.0Hz,3H),3.76–3.62(m,1H),2.68–2.58(m,1H),2.33–2.21(m,1H),1.45(d,J=8.5Hz,9H),1.28–1.24(m,1H),0.69–0.60(m,2H),0.38–0.29(m,2H).
MS-ESI:m/z 340.10[M-H
2O-Boc+2H]
+.
步骤2:化合物(2S,4R)-1-叔丁氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-2-羧酸的合成
将化合物(2S,4R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-1,2-羧酸酯(5.21g,11.38mmol),氢氧化锂一水合物(560mg,22.91mmol)溶于四氢呋喃/水(13mL,(v/v)=5/1)中,室温搅拌4h。置于冰浴冷却10min,滴入稀盐酸(4mol/L)调节pH=4,加入饱和食盐水(50mL),用乙酸乙酯(100mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,得浅褐色固体(5.15g,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.14–7.05(m,2H),6.93(d,J=8.2Hz,1H),6.61(t,J=75.6Hz,1H),4.58–4.46(m,2H),3.91–3.82(m,2H),3.82–3.70(m,1H),3.67–3.50(m,1H),2.64–2.52(m,1H),2.47(d,J=13.6Hz,1H),1.41(s,9H),1.27–1.22(m,1H),0.66–0.54(m,2H),0.39–0.25(m,2H).
MS-ESI:m/z 370.10[M-H
2O-tBu+2H]
+.
步骤3:化合物(1R,4S)-叔丁基1-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-3-氧代-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-羧酸酯的合成
将化合物(2S,4R)-1-叔丁氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-羟基吡咯烷-2-羧酸(5.10g,11.50mmol)和N,N-二异丙基乙胺(5.6mL,34.00mmol)溶于二氯甲烷(45mL)中,在0℃下缓慢滴入甲磺酰氯(1.3mL,17.00mmol),室温搅拌2h。加入二氯甲烷(100mL)稀释,有机相用水(50mL×3)洗涤,用无水硫酸钠干燥,浓缩得黄色液体,硅胶柱层析(洗脱剂:PE/AcOEt(v/v)=5/1)纯化得黄色液体(3.19g,产率65.20%)。
1H NMR(400MHz,CDCl
3):δ7.19(d,J=8.3Hz,1H),7.07(d,J=1.9Hz,1H),6.93(dd,J=8.3,2.0Hz,1H),6.64(t,J=75.2Hz,1H),4.69(br.s,1H),3.88(d,J=6.9Hz,2H),3.70–3.58(m,2H),2.42(d,J=11.9Hz,1H),2.27(d,J=10.6Hz,1H),1.47(s,9H),1.29–1.24(m,1H),0.67–0.61(m,2H),0.38–0.32(m,2H).
MS-ESI:m/z370.10[M-tBu+2H]
+.
步骤4:化合物(2S)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸的合成
将化合物(1R,4S)-叔丁基1-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-3-氧代-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-羧酸酯(3.15g,7.40mmol)溶于二氯甲烷(85mL)中,滴入三氟乙酸(5.6mL,34.00mmol)的二氯甲烷溶液(20mL),室温搅拌2.5h。有机相用水(80mL×3)洗涤,用无水硫酸钠干燥,浓缩得黄色液体,硅胶柱层析(洗脱剂:PE/AcOEt(v/v)=5/1)纯化得黄色固体(1.53g,48.50%)。
MS-ESI:m/z 370.10[M-tBu+2H]
+.
步骤5:化合物(2S,4R)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-2-羧酸的合成
将化合物(2S)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸(640 mg,1.50mmol)溶于乙醇(31mL),加入Pd/C(520mg,10%Pd,55%H
2O)和三乙胺(319uL,2.29mmol),排除空气,氢气氛围下,室温搅拌17h。把反应液通过硅藻土滤去固体,滤液减压除去溶剂得到无色透明液体(645mg,产率100%)。参考合成:Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2.J.Med.Chem.2014,57,9042-9064。
1H NMR(400MHz,CDCl
3)δ(ppm):7.03(d,J=8.1Hz,1H),6.82(d,J=9.1Hz,1H),6.77(d,J=7.4Hz,1H),6.55(t,J=75.8Hz,1H),4.25–4.19(m,1H),4.04–3.85(m,1H),3.88–3.80(m,2H),3.38(t,J=10.7Hz,1H),3.27–3.15(m,1H),2.72–2.55(m,1H),2.07–1.92(m,1H),1.41(s,9H),1.28–1.20(m,1H),0.63–0.56(m,2H),0.34–0.28(m,2H).
MS-ESI:m/z 372.05[M-t-Bu+2H]
+.
步骤6:化合物(2S,4R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯的合成
将化合物(2S,4R)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-2-羧酸(920mg,2.15mmol),甲醇(175uL,4.32mmol)和1-羟基苯并三唑(445mg,3.23mmol)溶于N,N-二甲基甲酰胺(15mL)中,在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(622mg,3.23mmol)和N-甲基吗啉(480uL,4.30mmol),室温搅拌12h。加水(50mL)稀释,反应液用乙酸乙酯(50mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:PE/AcOEt(v/v)=5/1)得到无色透明液体(764mg,产率80.39%)。
MS-ESI:m/z 386.05[M-t-Bu+2H]
+.
步骤7:化合物(2S,4R)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-羧酸酯的合成
将化合物(2S,4R)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(212-1)(760mg,1.72mmol)溶于无水四氢呋喃(7mL)中,冰浴下加入硼氢化锂(68mg,2.81mmol),室温搅拌3.5h。加入饱和氯化铵(20mL)淬灭硼氢化锂,用乙酸乙酯萃取(50mL×3),合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:PE/AcOEt(v/v)=4/1)得无色透明液体(518mg,1.25mmol,产率72.77%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.08(d,J=8.1Hz,1H),6.79(s,1H),6.78(d,J=6.7Hz,1H),6.58(t,J=75.7Hz,1H),5.18(d,J=8.2Hz,1H),4.07–4.00(m,1H),3.99–3.89(m,1H),3.85(d,J=6.9Hz,2H),3.80–3.70(m,1H),3.70–3.62(m,1H),3.28–3.12(m,2H),2.46–2.30(m,1H),1.69–1.57(m,1H),1.47(s,9H),1.28–1.23(m,1H),0.67–0.59(m,2H),0.38–0.30(m,2H).
MS-ESI:m/z 358.20[M-t-Bu+2H]
+.
步骤8:化合物(2S,4R)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((甲基磺酰基)氧基)甲基)吡咯烷-1-羧酸酯的合成
将化合物(2S,4R)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-羧酸酯(212-2)(510mg,1.23mmol)和N,N-二异丙基乙胺(612uL,3.70mmol)溶于二氯甲烷(5mL)中,在0℃下缓慢滴入甲磺酰氯(114uL,1.85mmol),室温搅拌2h。减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:PE/AcOEt(v/v)=4/1)得到黄色液体(606mg,产率99.97%)。
MS-ESI:m/z 436.10[M-t-Bu+2H]
+.
步骤9:化合物(2S,4R)-叔丁基2-叠氮基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-羧酸酯的合成
将化合物(2S,4R)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((甲基磺酰基)氧基)甲基)吡咯烷 -1-羧酸酯(590mg,1.20mmol)和叠氮化钠(241mg,3.60mmol)溶于无水N,N-二甲基甲酰胺(6mL)中,置于80℃下搅拌2h。减压除去N,N-二甲基甲酰胺,向剩余物加入乙酸乙酯(50mL)稀释,有机相用饱和食盐水(30mL×3)洗涤,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:PE/AcOEt(v/v)=5/1)得黄色液体(308mg,58.51%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.10(d,J=7.9Hz,1H),6.86–6.79(m,2H),6.59(t,J=75.7Hz,1H),4.18–3.93(m,2.6H),3.87(d,J=6.4Hz,2H),3.73–3.63(m,0.4H),3.48–3.31(m,1H),3.29–3.15(m,2H),2.50–2.31(m,1H),2.08–1.95(m,1H),1.47(s,9H),1.31–1.24(m,1H),0.67–0.62(m,2H),0.37–0.33(m,2H).
MS-ESI:m/z 383.10[M-t-Bu+2H]
+.
步骤10:化合物(2S,4R)-2-(叠氮基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷盐酸盐的合成
将化合物(2S,4R)-叔丁基2-叠氮基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-羧酸酯(270mg,0.62mmol)溶于DCM(6mL)中,注入氯化氢的二氧六环溶液(1.5mL,6.00mmol,4mol/L)溶液,室温搅拌2h。减压除去溶剂得黄色粘稠固体(230mg,产率99.66%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.11(d,J=8.1Hz,1H),6.90(s,1H),6.83(d,J=8.2Hz,1H),6.59(t,J=75.5Hz,1H),4.05–3.93(m,2H),3.87(d,J=6.9Hz,2H),3.82–3.72(m,2H),3.59–3.47(m,1H),3.45–3.32(m,1H),2.53–2.43(m,1H),2.06–1.91(m,1H),1.32–1.22(m,1H),0.69–0.57(m,2H),0.41–0.31(m,2H).
MS-ESI:m/z 339.15[M-HCl+H]
+.
步骤11:化合物1-(2S,4R)-2-叠氮基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮的合成
将化合物(2S,4R)-2-(叠氮基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷盐酸盐(220mg,0.59mmol)溶于二氯甲烷(6mL)中,在0℃下缓慢滴入三乙胺(248uL,1.76mmol)和乙酰氯(62uL,0.87mmol),室温搅拌2h。向反应液加饱和食盐水(20mL),用二氯甲烷萃取(50mL×3),合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析纯化(洗脱剂:PE/AcOEt(v/v)=1/1)得到黄色液体(180mg,产率80.61%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.11(d,J=7.9Hz,1H),6.84(s,1H),6.83–6.80(m,1H),6.60(t,J=75.6Hz,1H),4.30–4.21(m,1H),4.15–4.08(m,1H),3.92–3.88(m,1H),3.87(d,J=6.9Hz,2H),3.45–3.34(m,2H),3.30–3.20(m,1H),2.46–2.37(m,1H),2.09(s,3H),2.08–2.02(m,1H),1.31–1.25(m,1H),0.68–0.61(m,2H),0.38–0.32(m,2H).
MS-ESI:m/z 381.15[M+H]
+.
步骤12:化合物1-(2S,4R)-2-氨甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮盐酸盐的合成
将化合物1-(2S,4S)-2-叠氮基甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(180mg,0.47mmol),甲醇(5mL)中,加入钯碳(18mg,10%Pd,55%H
2O),置于室温搅拌2h。注入氯化氢的二氧六环溶液(0.5mL,2.00mmol,4mol/L)溶液,把反应液通过硅藻土滤去钯碳,减压除去溶剂得到黄色粘稠液体(185mg,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.15–7.04(m,2H),6.94–6.90(m,1H),6.73(t,J=75.7Hz,1H),4.36–4.21(m,1H),4.12–4.00(m,1H),3.93(d,J=6.2Hz,2H),3.77–3.66(m,1H),3.67–3.52(m,2H),3.46–3.32(m,1H),2.65–2.52(m,1H),2.16(s,3H),2.00–1.87(m,1H),1.32–1.24(m,1H),0.67–0.58(m,2H),0.42–0.33(m,2H).
MS-ESI:m/z 355.10[M-HCl+H]
+.
步骤13:化合物N
2-(((2S,4R)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-甲基-N
5-乙基吡啶-2,5-二甲酰胺的合成
将化合物1-(2S,4R)-2-氨甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮盐酸盐(150mg,0.38mmol),5-(乙基(甲基)氨基甲酰基)吡啶甲酸(88mg,0.42mmol)和1-羟基苯并三唑(79mg,0.57mmol)溶于N,N-二甲基甲酰胺(5mL)中,在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(111mg,0.58mmol)和N-甲基吗啉(86uL,0.77mmol),室温搅拌15h。向反应液加水(50mL)稀释,用乙酸乙酯(50mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:PE/AcOEt(v/v)=3/2)得到白色固体(118mg,产率56.45%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.08(s,1H),8.64(s,1H),8.20(d,J=8.0Hz,1H),7.86(t,J=7.0Hz,1H),7.08(d,J=8.0Hz,1H),6.81–6.76(m,2H),6.58(t,J=75.6Hz,1H),4.34–4.24(m,1H),4.05–3.97(m,1H),3.95–3.87(m,1H),3.83(d,J=6.9Hz,2H),3.66–3.46(m,2H),3.41(t,J=10.8Hz,1H),3.27–3.20(m,2H),3.09(s,1.7H),2.94(s,1.3H),2.64–2.52(m,1H),2.15(s,3H),2.00–1.92(m,1H),1.27–1.23(m,2.5H),1.18–1.10(m,1.5H),0.68–0.58(m,2H),0.39–0.30(m,2H).
MS-ESI:m/z 545.20[M+H]
+.
实施例42:N
2-(((2S,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺
步骤1:化合物(2S)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-2-羧酸的合成
将化合物(2S)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-2-羧酸(1.04g,2.45mmol,实施例41步骤4),三(三苯基膦)氯化铑(295mg,0.32mmol),三乙胺(490uL,3.52mmol),无水四氢呋喃(2mL)溶于无水乙醇(18mL)中,排除空气,在氢气(0.8MPa)氛围下,室温搅拌4天。浓缩溶剂,向剩余物加入乙酸乙酯(50mL)稀释,用稀盐酸(1mol/L)调节pH=1,分离有机相,水相用乙酸乙酯萃取(30mL×3),合并有机相,用无水硫酸钠干燥,浓缩得黄色液体,硅胶柱层析纯化(洗脱剂:PE/AcOEt(v/v)=5:1)得白色粘稠固体(843mg,产率80.45%)。合成参考:Carboxylate-Directed Highly Stereoselective Homogeneous Hydrogenation of Cyclic Olefins with Wilkinson’s Catalyst.Organic Letters.2003 Vol.5,No.9 1587-1589。
1H NMR(400MHz,CDCl
3)δ(ppm):7.15–7.06(m,1H),6.85–6.73(m,2H),6.59(t,J=75.6Hz,1H),4.56–4.30(m,1H),4.09–3.92(m,1H),3.92–3.79(m,2H),3.56–3.38(m,1H),3.39–3.23(m,1H),2.77–2.54(m,1H),2.50–2.14(m,1H),1.49–1.44(m,9H),1.33–1.18(m,1H),0.68–0.55(m,2H),0.41–0.27(m,2H).
MS-ESI:m/z 372.05[M-t-Bu+2H]
+.
步骤2:化合物(2S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯的合 成
将化合物(2S)-1-叔丁基氧羰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-吡咯烷-2-羧酸(810mg,1.90mmol),甲醇(154uL,3.80mmol)和1-羟基苯并三唑(392mg,2.84mmol)溶于N,N-二甲基甲酰胺(12mL)中,在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(548mg,2.84mmol)和N-甲基吗啉(430uL,3.80mmol),室温搅拌13h。加水(50mL)稀释,反应液用乙酸乙酯(50mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:PE/AcOEt(v/v)=5/1)得到无色透明液体(571mg,产率68.24%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.08(d,J=8.0Hz,1H),6.80–6.75(m,2H),6.58(t,J=75.6Hz,1H),4.53–4.43(m,0.3H),4.40–4.35(m,0.7H),4.04–3.91(m,1H),3.87–3.81(m,2H),3.75(s,3H),3.54–3.44(m,1H),3.43–3.36(m,0.5H),3.35–3.25(m,0.5H),2.70–2.56(m,0.3H),2.35–2.24(m,1.4H),2.07–1.93(m,0.3H),1.45–1.42(m,9H),1.29–1.22(m,1H),0.67–0.58(m,2H),0.36–0.29(m,2H).
MS-ESI:m/z 386.10[M-t-Bu+2H]
+.
步骤3:化合物(2S,4S)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-羧酸酯的合成
将化合物(2S)-1-叔丁基2-甲基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1,2-二羧酸酯(540mg,1.22mmol)溶于无水四氢呋喃(5mL)中,冰浴下加入硼氢化锂(48mg,1.98mmol),室温搅拌2h。加入饱和氯化铵(20mL)淬灭硼氢化锂,用乙酸乙酯萃取(50mL×3),合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:PE/AcOEt(v/v)=4/1)得无色透明液体(311mg,产率61.49%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.09(d,J=7.9Hz,1H),6.78(s,2H),6.58(t,J=75.7Hz,1H),4.25–4.12(m,1H),3.85(d,J=6.9Hz,2H),3.79–3.63(m,3H),3.49–3.30(m,2H),2.20–2.06(m,1H),2.06–1.96(m,1H),1.47(s,9H),1.33–1.23(m,1H),0.69–0.59(m,2H),0.39–0.31(m,2H).
MS-ESI:m/z358.10[M-t-Bu+2H]
+.
步骤4:化合物(2S,4S)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((甲基磺酰基)氧基)甲基)吡咯烷-1-羧酸酯的合成
将化合物(2S,4S)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-羧酸酯(260mg,0.63mmol)和N,N-二异丙基乙胺(324uL,1.96mmol)溶于二氯甲烷(5mL)中,在0℃下缓慢滴入甲磺酰氯(76uL,0.98mmol),室温搅拌2h。减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:PE/AcOEt(v/v)=4/1)得到黄色液体(309mg,产率99.99%)。
MS-ESI:m/z 436.10[M-t-Bu+2H]
+.
步骤5:化合物(2S,4S)-叔丁基2-(叠氮基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-羧酸酯的合成
将化合物(2S,4S)-叔丁基4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(((甲基磺酰基)氧基)甲基)吡咯烷-1-羧酸酯(320mg,0.65mmol)和叠氮化钠(131mg,1.95mmol)溶于无水N,N-二甲基甲酰胺(5mL)中,置于80℃下搅拌2h。减压旋蒸除去N,N-二甲基甲酰胺,向剩余物加入乙酸乙酯(50mL)稀释,有机相用饱和食盐水(30mL×3)洗涤,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:PE/AcOEt(v/v)=5/1)得黄色液体(189mg,产率66.20%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.10(d,J=7.9Hz,1H),6.79(s,2H),6.60(t,J=75.5Hz,1H),4.17–3.97(m,1H),3.86(d,J=6.2Hz,2H),3.79(t,J=9.1Hz,1H),3.71–3.62(m,0.5H),3.57–3.38(m,3H),3.38– 3.27(m,0.5H),2.27–2.16(m,1H),2.15–2.06(m,1H),1.50–1.47(m,9H),1.30–1.24(m,1H),0.69–0.61(m,2H),0.40–0.30(m,2H).
MS-ESI:m/z 383.15[M-t-Bu+2H]
+.
步骤6:化合物(2S,4S)-2-(叠氮基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷盐酸盐(11213-5)的合成
将化合物(2S,4S)-叔丁基2-(叠氮基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-羧酸酯(270mg,0.62mmol)溶于DCM(6mL)中,注入氯化氢的二氧六环溶液(1.5mL,6.00mmol,4mol/L)溶液,室温搅拌2h。减压除去溶剂得黄色固体(270mg,产率99.66%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.12(d,J=8.1Hz,1H),6.86(s,1H),6.82(d,J=8.2Hz,1H),6.60(t,J=75.5Hz,1H),4.13–4.02(m,1H),4.02–3.94(m,1H),3.88(d,J=6.9Hz,2H),3.86–3.81(m,1H),3.80–3.73(m,1H),3.68–3.60(m,1H),3.39–3.27(m,1H),2.29–2.23(m,1H),2.11–2.02(m,1H),1.29–1.23(m,1H),0.70–0.59(m,2H),0.42–0.32(m,2H).
MS-ESI:m/z 339.20[M-HCl+H]
+.
步骤7:化合物1-(2S,4S)-2-(叠氮基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(213-6)的合成
将化合物(2S,4S)-2-(叠氮基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷盐酸盐(220mg,0.59mmol),三乙胺(248uL,1.76mmol)溶于二氯甲烷(6mL)中,在0℃下缓慢滴入乙酰氯(62uL,0.87mmol),室温搅拌2h。向反应液加饱和食盐水(20mL),用二氯甲烷萃取(50mL×3),合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析纯化(洗脱剂:PE/AcOEt(v/v)=1/1)得到黄色液体(171mg,产率76.58%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.13(d,J=7.9Hz,1H),6.81(s,2H),6.62(t,J=75.6Hz,1H),4.44–4.37(m,1H),3.97–3.90(m,1H),3.88(d,J=6.9Hz,2H),3.79–3.74(m,1H),3.70–3.62(m,1H),3.52–3.46(m,1H),3.41(t,J=9.7Hz,1H),2.29–2.22(m,1H),2.18–2.13(m,1H),2.08(s,3H),1.33–1.26(m,1H),0.70–0.63(m,2H),0.40–0.34(m,2H).
MS-ESI:m/z 381.20[M+H]
+.
步骤8:化合物1-(2S,4S)-2-氨甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮盐酸盐的合成
将化合物1-(2S,4S)-2-(叠氮基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮(165mg,0.43mmol),甲醇(5mL)中,加入钯碳(34mg,10%Pd,55%H
2O),置于室温搅拌2h。注入氯化氢的二氧六环溶液(0.5mL,2.00mmol,4mol/L)溶液,反应液通过硅藻土过滤除去钯碳,减压浓缩,得到黄色粘稠液体(169mg,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.15–7.03(m,2H),6.96–6.88(m,1H),6.72(t,J=75.7Hz,1H),4.54–4.44(m,1H),4.09–3.97(m,1H),3.95–3.90(m,2H),3.77–3.72(m,1H),3.69–3.64(m,2H),3.59–3.53(m,1H),2.35–2.22(m,1H),2.23–2.15(m,1H),2.12(s,2.2H),2.04(s,0.8H),1.31–1.26(m,1H),0.66–0.59(m,2H),0.40–0.34(m,2H).
MS-ESI:m/z 355.25[M-HCl+H]
+.
步骤9:化合物N
2-(((2S,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-甲基N
5-乙基吡啶-2,5-二甲酰胺的合成
将化合物1-(2S,4S)-2-氨甲基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮盐酸盐(163mg,0.42mmol),5-(乙基(甲基)氨基甲酰基)吡啶甲酸(94mg,0.45mmol)和1-羟基苯并三唑(85mg,0.62 mmol)溶于N,N-二甲基甲酰胺(5mL)中,在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(118mg,0.62mmol)和N-甲基吗啉(92uL,0.82mmol),室温搅拌15h。向反应液加水(50mL)稀释,用乙酸乙酯(50mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:PE/AcOEt(v/v)=3/2)得到白色固体(110mg,产率48.43%)。
1H NMR(400MHz,CDCl
3)δ(ppm):8.81–8.71(m,1H),8.65–8.56(m,1H),8.19(d,J=8.1Hz,1H),7.85(t,J=7.4Hz,1H),7.09(d,J=8.0Hz,1H),6.82–6.76(m,2H),6.58(t,J=75.6Hz,1H),4.55–4.46(m,1H),3.95–3.87(m,1H),3.85(d,J=6.8Hz,2H),3.82–3.74(m,1H),3.72–3.50(m,3H),3.41(t,J=9.9Hz,1H),3.33–3.21(m,1H),3.09(s,1.6H),2.94(s,1.4H),2.25–2.17(m,1H),2.19–2.11(m,1H),2.08(s,3H),1.32–1.22(m,1H),1.24–1.21(m,1.5H),1.18–1.11(m,1.5H),0.67–0.59(m,2H),0.39–0.29(m,2H).
MS-ESI:m/z 545.30[M+H]
+.
实施例43:N
2-(((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)吡啶-2,5-二甲酰胺
步骤1:6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)烟酸酯的合成
将化合物1-((2R,4S)-2-(氨基甲基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-1-基)乙酮盐酸盐(1.19g,3.05mmol,实施例39步骤9)溶于二氯甲烷(24mL)溶剂中,再加入5-(甲氧羰基)吡啶甲酸(853mg,4.57mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(630mg,4.63mmol),在0℃下冷却,再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(1.75g,9.13mmol),N,N-二异丙基乙胺(DIPEA)(2.09g,16.20mmol),转移到室温下搅拌反应2h,加水(20mL)停止反应,用二氯甲烷(20mL×3)萃取后,用无水硫酸钠干燥30min,减压浓缩,通过硅胶柱层析纯化(洗脱剂:甲醇/二氯甲烷(v/v)=1/10),得到白色泡沫状物(1.01g,产率65.90%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.22(s,1H),9.13(br.s,1H),8.44(dd,J=8.1,1.7Hz,1H),8.25(d,J=8.1Hz,1H),7.09(d,J=8.0Hz,1H),6.78(s,1H),6.77(d,J=7.5Hz,1H),6.59(t,J=75.4Hz,1H),4.35–4.27(m,1H),4.07–4.00(m,1H),3.98(s,3H),3.96–3.89(m,1H),3.82(d,J=6.9Hz,2H),3.67–3.58(m,1H),3.43(t,J=10.8Hz,1H),3.31–3.20(m,1H),2.63–2.54(m,1H),2.16(s,3H),2.00–1.90(m,1H),1.23–1.32(m,1H),0.67–0.62(m,2H),0.37–0.33(m,2H).
MS-ESI:m/z 518.15[M+H]
+.
步骤2:6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)烟酸的合成
将化合物6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)烟酸酯(1.01g,1.96mmol)溶解于四氢呋喃(20mL)溶剂中,再加入氢氧化锂一水化合物(440mg,10.49mmol)及水溶液(10mL),转移到50℃温度下搅拌反应2h后,转到0℃下冷却,滴加1mol/L盐 酸,至酸性(pH=3),用乙酸乙酯(20mL×2)萃取,有机相用无水硫酸钠干燥30min,减压浓缩。得到白色固体(943mg,产率95.80%)。
1H NMR(400MHz,Chloroform-d)δ(ppm):9.77(br.s,1H),9.51(s,1H),8.48(dd,J=8.1,2.0Hz,1H),8.24(d,J=8.1Hz,1H),7.15(d,J=8.7Hz,1H),6.86–6.79(m,2H),6.62(t,J=75.5Hz,1H),4.54–4.47(m,1H),4.06–3.96(m,2H),3.88(d,J=6.9Hz,2H),3.56–3.42(m,2H),3.36–3.25(m,1H),2.75–2.65(m,1H),2.37(s,3H),1.93–1.83(m,1H),1.35–1.23(m,1H),0.69–0.65(m,2H),0.39–0.35(m,2H).
MS-ESI:m/z 504.20[M+H]
+.
步骤3:N
2-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)吡啶-2,5-二甲酰胺的合成
将化合物6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)烟酸(300mg,0.60mmol),乙胺(286mg,3.51mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(123mg,0.90mmol)溶解在干燥的四氢呋喃(20mL)溶剂中,在0℃下冷却,再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(440mg,2.30mmol),N,N-二异丙基乙胺(DIPEA)(740mg,5.73mmol),转移到室温下搅拌反应6h,停止反应,减压浓缩反应液后,加水(20mL),用乙酸乙酯(20mL×2)萃取,合并有机相,用无水硫酸钠干燥30min,减压浓缩,通过硅胶柱层析纯化(洗脱剂:甲醇/二氯甲烷(v/v)=1/10),得到白色固体(300mg,产率90.45%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.16(br.s,1H),9.05(s,1H),8.34–8.20(m,2H),7.10(d,J=8.0Hz,1H),6.79(s,1H),6.78(d,J=9.1Hz,1H),6.59(t,J=75.5Hz,1H),4.37–4.26(m,1H),4.05–3.96(m,1H),3.93(t,J=8.8Hz,1H),3.84(d,J=6.9Hz,2H),3.64–3.56(m,1H),3.43(t,J=10.8Hz,1H),3.31–3.21(m,1H),2.64–2.55(m,1H),2.16(s,3H),1.98–1.89(m,1H),1.33–1.21(m,1H),0.67–0.62(m,2H),0.37–0.33(m,2H).
MS-ESI:m/z 503.30[M+H]
+.
实施例44:N
2-(((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-甲基吡啶-2,5-二甲酰胺
将化合物6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2--2-基)甲基)氨基甲酰基)烟酸(300mg,0.60mmol),甲铵盐酸盐(270mg,4.00mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(123mg,0.90mmol)溶解在干燥的四氢呋喃(20mL)溶剂中,转移到0℃温度下,再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(360mg,1.88mmol),N,N-二异丙基乙胺(DIPEA)(769mg,5.59mmol),转移到室温下搅拌反应6h。停止反应,减压浓缩反应液后,加水(20mL)稀释,用乙酸乙酯(20mL×2)萃取,合并有机相,用无水硫酸钠干燥30min,减压浓缩,通过硅胶柱层析纯化(洗脱剂:甲醇/二氯甲烷(v/v=1/10),得到白色固体产物(300mg,产率94.15%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.11(br.s,1H),8.98(s,1H),8.22(s,2H),7.09(d,J=7.9Hz,1H),6.78(d,J=8.5Hz,2H),6.59(t,J=75.5Hz,1H),6.41(br.s,1H),4.34–4.26(m,1H),4.05–3.97(m,1H),3.96–3.89(m,1H),3.83(d,J=6.9Hz,2H),3.64–3.56(m,1H),3.43(t,J=10.8Hz,1H),3.31–3.20(m,1H),3.05(d,J=4.8Hz,3H),2.63–2.54(m,1H),2.16(s,3H),1.98–1.90(m,1H),1.31–1.22(m,1H),0.67–0.62(m,2H),0.36–0.32(m,2H).
MS-ESI:m/z 517.53[M+H]
+.
实施例45:N
2-(((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基l-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺
将化合物6-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)氨基甲酰基)烟酸(300mg,0.60mmol),乙胺(286mg,3.51mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(123mg,0.90mmol)溶解在干燥的DMF(20mL)溶剂中,转移到0中温度下,再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(440mg,2.30mmol),N,N-二异丙基乙胺(DIPEA)(740mg,5.73mmol),转移到室温下搅拌反应6h。停止反应,减压浓缩反应液后,加水(20mL)稀释,用乙酸乙酯(20mL)萃取,合并有机相,用无水硫酸钠干燥30min,减压浓缩,通过硅胶柱层析纯化(洗脱剂:甲醇/二氯甲烷(v/v)=1/10),得到白色固体产物(300mg,产率90.45%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.11(br.s,1H),8.98(s,1H),8.21(s,2H),7.09(d,J=8.0Hz,1H),6.78(d,J=8.5Hz,2H),6.59(t,J=75.6Hz,1H),6.35(br.s,1H),4.35–4.27(m,1H),4.05–3.96(m,1H),3.96–3.89(m,1H),3.83(d,J=6.9Hz,2H),3.64–3.57(m,1H),3.57–3.49(m,2H),3.43(t,J=10.8Hz,1H),3.31–3.20(m,1H),2.63–2.54(m,1H),2.16(s,3H),1.98–1.90(m,1H),1.31–1.22(m,1H),1.28(d,J=7.3Hz,3H),0.67–0.58(m,2H),0.40–0.32(m,2H).
MS-ESI:m/z 531.30[M+H]
+.
实施例46:N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺
将化合物N
2-((((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺(125mg,0.23mmol,实施例39)溶解于乙腈(3mL)溶剂中,再滴加浓盐酸(1.2g,32.91mmol),后转入到80℃温度下搅拌反应6h。冷却至室温,加水溶解沉淀物,用乙酸乙酯(300mL×3)萃取,有机相用无水硫酸钠干燥30min,减压浓缩,通过硅胶柱层析纯化(洗脱剂:二氯甲烷/甲醇=16:1),得到白色固体(74mg,产率63.30%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.11(s,1H),8.64(s,1H),8.21(d,J=8.0Hz,1H),7.87(br.s,1H),7.04(d,J=8.3Hz,1H),6.88(s,1H),6.71(d,J=7.6Hz,1H),6.53(t,J=70.3Hz,1H),4.34–4.26(m,1H),4.06–3.98(m,1H),3.95–3.88(m,1H),3.66–3.56(m,2H),3.41(t,J=10.7Hz,1H),3.31–3.19(m,2H),3.11(s,1.7H),2.95(s,1.3H),2.60–2.51(m,1H),2.16(s,3H),1.88–1.83(m,1H),1.16(t,J=7.1Hz,3H).
MS-ESI:m/z 491.15[M+H]
+.
实施例47:N
2-(((2R,4S)-1--4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基)-N
5-ethyl-N
5-甲基吡啶-2,5-二甲酰胺
步骤1:化合物N
2-((((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺(1245-1)的合成
将化合物N
2-((((2R,4S)-1-乙酰-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷基-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺(400mg,0.73mmol)溶于乙腈(6mL)中,再加入浓盐酸(3mL,36.5%),置于80℃加热条件下反应12h。反应结束,加入30mL水,用二氯甲烷萃取(20mL×3),有机相加入无水硫酸钠干燥,减压蒸馏,除去溶剂,硅胶柱层析分离提纯(DCM/MeOH(v/v)=20/1),得到白色固体(180mg,产率51%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.13–9.09(m,1H),8.64(s,1H),8.21(d,J=8.0Hz,1H),7.90–7.83(m,1H),7.04(d,J=8.3Hz,1H),6.89–6.87(m,1H),6.72–6.70(m,1H),6.53(t,J=78.3Hz,1H),6.39(s,1H),4.29(s,1H),4.06–4.00(m,1H),3.93–3.89(m,1H),3.66–3.54(m,2H),3.41(t,J=10.7Hz,1H),3.28–3.20 (m,2H),3.10(s,1.5H),2.95(s,1.5H),2.59–2.53(m,1H),2.15(s,3H),1.96–1.87(m,1H),1.26(t,J=7.1Hz,3H).
MS-ESI:m/z 491.20[M+H]
+.
步骤2:N
2-((((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺(DLR011245)的合成
将化合物N
2-((((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-基)甲基)-N
5-乙基-N
5-甲基吡啶-2,5-二甲酰胺(180mg,0.37mmol)和2-碘丙烷(94mg,0.55mmol)溶于DMF(10mL)中,再加入碳酸钾(150mg,1.11mmol),置于80℃加热条件下反应4h。反应结束,加入50mL水,用乙酸乙酯萃取(30mL×3),有机相加入无水硫酸钠干燥,减压蒸馏,除去溶剂,硅胶柱层析分离提纯(DCM/MeOH(v/v)=20/1),得到白色固体130mg,产率66%。
1H NMR(400MHz,CDCl
3)δ(ppm):9.10(s,1H),8.65(s,1H),8.22(d,J=7.9Hz,1H),7.87(s,1H),7.09(d,J=8.1Hz,1H),6.81(s,1H),6.77(d,J=8.2Hz,1H),6.52(t,J=75.5Hz,1H),4.57–4.44(m,1H),4.35–4.25(m,1H),4.07–4.00(m,1H),3.95–3.91(m,1H),3.61(d,J=7.7Hz,2H),3.42(t,J=10.7Hz,1H),3.30–3.21(m,2H),3.10(s,2H),2.95(s,1H),2.62–2.55(m,1H),2.16(s,3H),1.94(dd,J=22.3,12.0Hz,1H),1.33(dd,J=5.8,2.5Hz,6H),1.29–1.22(m,1H),1.10–1.20(m,2H).
MS-ESI:m/z 533.20[M+H]
+.
实施例48:N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺
步骤1:N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺的合成
将化合物N
2-(((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷基-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺(150mg,0.28mmol,实施例45)溶解在乙腈(5mL)溶剂中,再滴加浓盐酸(1mL),转入到80℃温度下搅拌反应8h。停止反应,冷却至室温,加入水(10mL),用乙酸乙酯(10mL×2)萃取,合并有机相,用无水硫酸钠干燥30min。减压浓缩,得到白色固体(114mg,产率85.45%)。
1H NMR(400MHz,CD
3OD)δ(ppm):9.05(s,1H),8.35–8.32(m,1H),8.17(d,J=8.1Hz,1H),7.04(d,J=8.3Hz,1H),6.90–6.89(m,1H),6.80–6.78(m,1H),6.71(t,J=75.2Hz,1H),4.44–4.31(m,2H),4.06–4.01(m,1H),3.92–3.88(m,1H),3.75–3.68(m,1H),3.49–3.42(m,3H),3.28–3.07(m,1H),2.60–2.53(m,1H),2.26(s,1H),2.17(s,2H),1.97–1.92(m,1H),1.26(t,J=7.3Hz,3H).
MS-ESI:m/z 477.20[M+H]
+.
步骤2:N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-(异丙氧基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺的合成
将化合物N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二 甲酰胺(108mg,0.23mmol)溶于N,N-二甲基甲酰胺溶剂(10mL)中,再加入无水碳酸钾(95mg,0.69mmol)及2-碘丙烷(59mg,0.35mmol),转入到80℃下搅拌反应4.5h。停止反应,冷却至室温,加入水(50mL),用乙酸乙酯(50mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥30min,通过硅胶柱层析纯化(洗脱剂:甲醇/二氯甲烷(v/v)=25%),得到浅褐色固体(100mg,产率80.69%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.14(s,1H),8.98(s,1H),8.22(s,2H),7.09(d,J=8.3Hz,1H),6.81(s,1H),6.77(d,J=8.2Hz,1H),6.53(t,J=75.6Hz,1H),6.50(br.s,1H),4.58–4.43(m,1H),4.37–4.25(m,1H),4.06–3.97(m,1H),3.97–3.87(m,1H),3.65–3.47(m,3H),3.43(t,J=10.8Hz,1H),3.31–3.19(m,1H),2.64–2.54(m,1H),2.16(s,3H),2.02–1.88(m,1H),1.40–1.29(m,6H),1.27(d,J=7.0Hz,3H).
MS-ESI:m/z 519.20[M+H]
+.
实施例49:N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基)-N
5-甲基吡啶-2,5-二甲酰胺
步骤1:N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-基)甲基)-N
5-甲基吡啶-2,5-二甲酰胺的合成
将化合物N
2-(((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基)-N
5-甲基吡啶-2,5-二甲酰胺(450mg,0.87mmol,实施例44)溶解于乙腈溶剂(10mL)中,再滴加浓盐酸(1mL),转到80℃下搅拌反应6.5h。停止反应。冷却至室温,加入50mL水,用乙酸乙酯(10mL×2)萃取,合并有机相,用无水硫酸钠干燥30min。粗产品通过硅胶柱层析纯化(洗脱剂:甲醇/二氯甲烷(v/v)=1/10),得到白色固体(285mg,产率70.84%)。
1H NMR(400MHz,CD
3OD)δ(ppm):9.06(s,1H),8.34(dd,J=8.1,1.8Hz,1H),8.18(d,J=8.1Hz,1H),7.05(d,J=8.2Hz,1H),6.90(s,1H),6.79(d,J=8.2Hz,1H),6.72(t,J=75.0Hz,1H),4.45–4.34(m,2H),4.06–4.02(m,1H),3.93–3.88(m,1H),3.77–3.68(m,1H),3.45(t,J=10.9Hz,1H),2.98(s,3H),2.61–2.54(m,1H),2.17(s,3H),2.01–1.93(m,1H).
MS-ESI:m/z 463.20[M+H]
+.
步骤2:N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧苯基)吡咯烷-2-基)甲基)-N
5-甲基吡啶-2,5-二甲酰胺的合成
将化合物N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-基)甲基)-N
5-甲基吡啶-2,5-二甲酰胺(140mg,0.3mmol)溶解在10mL的N,N-二甲酰胺溶剂中,再加入无水碳酸钾(120mg,0.9mmol)和2-碘丙烷(76mg,0.45mmol),转入到80℃下搅拌反应4h,停止反应,冷却至室温,加入水(50mL),用乙酸乙酯(50mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥30min,通过硅胶柱层析(洗脱剂:甲醇/二氯甲烷(v/v)=25%),得到浅褐色固体(91mg,产率59.86%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.13(s,1H),8.98(s,1H),8.22(s,2H),7.09(d,J=7.6Hz,1H),6.81–6.70(m,2H),6.70(s,1H),6.53(t,J=75.5Hz,1H),4.58–4.41(m,1H),4.36–4.24(m,1H),4.07–3.86(m,2H),3.67–3.52(m,1H),3.43(t,J=10.3Hz,1H),3.32–3.19(m,1H),3.04(s,3H),2.64–2.53(m,1H),2.16(s,3H),2.03–1.84(m,1H),1.37–1.26(m,6H).
MS-ESI:m/z 505.20[M+H]
+.
实施例50:N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基)吡啶-2,5-二甲酰胺
将化合物1-((2R,4S)-2-(氨基甲基)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1-基)乙酮盐酸盐(100mg,0.26mmol,实施例58步骤11)、5-氨基甲酰基吡啶甲酸(45mg,0.26mmol)和1-羟基-7-氮杂苯并三唑(71mg,0.52mmol)溶于N,N-二甲基甲酰胺(10mL)溶液中,冰浴条件下,依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(100mg,0.52mmol)和N,N-二异丙基乙胺(100mg,0.78mmol),室温下反应10h,原料反应完全,停止反应,加入饱和食盐水(50mL),用乙酸乙酯萃取(30mL×3),有机相用无水硫酸钠干燥,减压浓缩硅胶柱层析(洗脱剂:DCM/MeOH(v/v)=20/1)分离提纯,得白色固体(78mg,产率61%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.17(s,1H),9.07(s,1H),8.30(s,1H),8.24(s,1H),7.09(d,J=8.1Hz,1H),6.81(s,1H),6.77(d,J=7.8Hz,1H),6.52(t,J=75.5Hz,1H),6.18(s,1H),4.54–4.46(m,1H),4.31(s,1H),4.03–3.91(m,2H),3.66–3.56(m,1H),3.43(t,J=10.4Hz,1H),3.33–3.19(m,1H),2.65–2.55(m,1H),2.15(s,3H),1.97–1.87(m,1H),1.32(d,J=3.9Hz,6H).
MS-ESI:m/z 491.20[M+H]
+.
实施例51:((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基5-(乙基(甲基)氨基甲酰基)吡啶甲酸酯
步骤1:((2R,4S)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷基-2-基)甲基5-(乙基(甲 基)氨基甲酰基)吡啶甲酸酯的合成
将化合物(2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(380mg,0.92mmol,实施例39步骤4)溶于N,N-二甲基甲酰胺(10mL)溶剂中,再加入5-(乙基(甲基)氨基甲酰基)吡啶甲酸(211mg,1.01mmol),1-羟基苯并三唑(HOBT)(249mg,1.84mmol),在0℃下冷却,再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(353g,1.84mmol),N-甲基吗啉(NMM)(279mg,2.76mmol),转移到室温下搅拌反应16h,加水(20mL)停止反应,用乙酸乙酯(20mL×3)萃取后,合并有机相用饱和食盐水洗涤,用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(PE/EA(v/v)=1/3),得到无色油状产物(287mg,产率51.68%)。
1H NMR(400MHz,CDCl
3)δ(ppm):8.77(s,1H),8.19–8.10(m,1H),7.93–7.84(m,1H),7.12–7.05(m,1H),6.89–6.80(m,2H),6.58(t,J=75.7Hz,1H),4.77–4.53(m,2H),4.42–4.21(m,1H),4.20–3.92(m,1H),3.84(d,J=6.9Hz,2H),3.69–3.55(m,1H),3.35–3.16(m,3H),3.10(s,1.7H),2.95(s,1.3H),2.64-2.52(m,1H),2.17–1.93(m,1H),1.62(s,3H),1.56–1.36(m,9H),1.17–1.14(m,1H),0.67–0.58(m,2H),0.37–0.29(m,2H).
MS-ESI:m/z 604.30[M+H]
+.
步骤2:((2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基5-(乙基(甲基)氨基甲酰基)吡啶甲酸酯盐酸盐的合成
将化合物((2R,4S)-1-(叔丁氧羰基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷基-2-基)甲基5-(乙基(甲基)氨基甲酰基)吡啶甲酸酯(290mg,0.48mmol)溶于二氯甲烷(10mL)溶剂中,再加入盐酸的1,4-二氧六环溶液(2.4mL,9.60mmol)溶液,在室温下搅拌反应2h,停止反应,减压浓缩一次后,再加入二氯甲烷(20mL)溶解,再次减压浓缩,得到白色固体产物(241mg,92.97%)。
1H NMR(400MHz,CD
3OD)δ(ppm):8.86–8.79(m,1H),8.43–8.34(m,1H),8.26–8.13(m,1H),7.19–7.09(m,2H),7.03–6.95(m,1H),6.75(t,J=75.6Hz,1H),4.85–4.77(m,1H),4.74–4.63(m,1H),4.31–4.20(m,1H),3.93(d,J=6.9Hz,2H),3.86–3.78(m,1H),3.77–3.57(m,3H),3.50–3.39(m,1H),3.13(s,2H),3.01(s,2H),2.69–2.59(m,1H),2.18–2.04(m,1H),1.41–1.22(m,3H),1.21–1.16(m,1H),0.68–0.59(m,2H),0.41–0.33(m,2H).
MS-ESI:m/z 504.30[M-HCl+H]
+.
步骤3:((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基5-(乙基(甲基)氨基甲酰基)吡啶甲酸酯的合成
将化合物((2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基5-(乙基(甲基)氨基甲酰基)吡啶甲酸酯盐酸盐(241mg,0.48mmol)溶于二氯甲烷(10mL)溶剂中,在0℃下冷却,再加入N,N-二异丙基乙胺(DIPEA)(248mg,1.92mmol),乙酰氯(75mg,0.96mmol),转移到室温下搅拌反应1h,反应液用水(20mL×2)洗涤,并用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(DCM/MeOH(v/v)=20/1),得到浅黄色固体产物(108mg,产率41.24%)。
1H NMR(400MHz,CDCl
3)δ(ppm):8.77(s,1H),8.16(d,J=8.0Hz,1H),7.92–7.83(m,1H),7.14–7.05(m,1H),6.94–6.82(m,2H),6.59(t,J=75.6Hz,1H),4.82–4.74(m,1H),4.73–4.64(m,1H),4.63–4.51(m,1H),3.94–3.88(m,1H),3.88–3.80(m,2H),3.66–3.56(m,1H),3.51(t,J=10.8Hz,1H),3.33–3.22(m,2H),3.11(s,1.7H),2.96(s,1.3H),2.64–2.54(m,1H),2.24(s,0.6H),2.15–2.02(m,3.4H),1.34–1.21(m,3H),1.18–1.13(m,1H),0.68–0.56(m,2H),0.38–0.28(m,2H).
MS-ESI:m/z 546.20[M+H]
+.
实施例52:((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷基-2-基)甲基5-(乙基甲酰 胺基)吡啶甲酸酯
步骤1:6-(甲氧基羰基)烟酸的合成
将吡啶-2,5-二羧酸(500mg,2.99mmol)加入甲醇(10mL)中,缓慢加入浓硫酸(0.16mL,2.99mmol),在70℃下回流反应1h,冷却至室温,加入冰水(20mL),搅拌至白色固体完全析出后抽滤,固体用四氢呋喃(20mL)溶解,有机相用无水硫酸镁干燥,减压浓缩得到白色固体产物(400mg,产率73.85%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):9.20–9.11(m,1H),8.49–8.39(m,1H),8.22–8.09(m,1H),3.91(s,3H).
MS-ESI:m/z 182.10[M+H]
+.
步骤2:5-(乙基氨基甲酰基)吡啶甲酸甲酯的合成
将化合物6-(甲氧基羰基)烟酸(2.50g,13.80mmol),乙胺盐酸盐(1.35g,16.56mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(3.76g,27.60mmol)溶解在干燥的N,N-二甲基甲酰胺(30mL)溶剂中,在0℃下冷却,再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(5.29g,27.60mmol),N,N-二异丙基乙胺(DIPEA)(5.35g,41.40mmol),转移到室温下搅拌反应27h,停止反应,减压浓缩溶剂后,加水(30mL)溶解浓缩液,用二氯甲烷(30mL×2)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(DCM/MeOH(v/v)=20/1),得到白色固体(1.78g,产率61.95%)。
1H NMR(400MHz,MeOH-d
4)δ(ppm):9.07–9.02(m,1H),8.39–8.32(m,1H),8.25–8.19(m,1H),4.00(s,3H),3.51–3.42(m,2H),1.25(t,J=7.3Hz,3H).
MS-ESI:m/z 209.10[M+H]
+.
步骤3:5-(乙基氨基甲酰基)吡啶甲酸锂
将化合物5-(乙基氨基甲酰基)吡啶甲酸甲酯(1.77g,8.50mmol)溶解于四氢呋喃(16mL)溶剂中,再加入氢氧化锂一水化合物(0.37g,8.93mmol)及水溶液(2.5mL),转移到50℃温度下搅拌反应23h后,冷却至室温后抽滤,滤饼在50℃下真空干燥8h得到白色固体产物(1.55g,产率91.12%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):8.89–8.84(m,1H),8.33–8.23(m,1H),8.02(d,J=8.1Hz,1H),3.34–3.26(m,2H),1.14(t,J=7.2Hz,3H).
MS-ESI:m/z 195.20[M-Li+2H]
+.
步骤4:((2R,2S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲醇盐酸盐的合成
将化合物(2R,2S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(1.7g,4.11mmol,实施例39步骤4)溶于二氯甲烷(15mL)溶剂中,再加入盐酸的1,4-二氧六环溶液(10.3mL,41.1mmol)溶液,在室温下搅拌反应2h,停止反应,减压浓缩一次后,再加入二氯甲烷(20mL)溶解,再次减压浓缩,得到浅褐色油状产物(1.44g,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.11(d,J=8.1Hz,1H),6.89(s,1H),6.83(d,J=8.2Hz,1H),6.60(t,J=75.5Hz,1H),4.74(br.s,1H),4.11–4.03(m,1H),4.02–3.91(m,2H),3.89–3.81(m,2H),3.76(s,1H),3.62 –3.48(m,1H),3.40–3.24(m,1H),2.44–2.32(m,1H),2.17(br.s,1H),2.08–1.96(m,1H),1.32–1.25(m,1H),0.67–0.59(m,2H),0.40–0.31(m,2H).
MS-ESI:m/z 314.20[M+H]
+.
步骤5:((2R,2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)乙酸甲酯的合成
将化合物((2R,2S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲醇盐酸盐(1.44g,4.12mmol)溶于二氯甲烷(20mL)溶剂中,在0℃下冷却,再加入N,N-二异丙基乙胺(DIPEA)(2.66g,20.6mmol),乙酰氯(0.97g,12.36mmol),转移到室温下搅拌反应1h,反应液用水(20mL×2)洗涤,并用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(EA/PE(v/v)=9/1),得到黄色液体产物(1.15g,产率70.24%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.16–7.08(m,1H),6.87–6.76(m,2H),6.80–6.39(m,1H),4.39(s,2H),4.29–4.18(m,1H),3.96–3.78(m,3H),3.45–3.33(m,1H),3.33–3.13(m,1H),2.55–2.45(m,1H),2.17(s,1H),2.13–2.05(m,5H),2.01–1.87(m,1H),1.33–1.26(m,1H),0.73–0.60(m,2H),0.43–0.29(m,2H).
MS-ESI:m/z 398.20[M+H]
+.
步骤6:1-((2R,2S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-基)乙基-1-酮的合成
将化合物((2R,2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)乙酸甲酯(1.15g,2.89mmol)溶解于四氢呋喃(20mL)溶剂中,再加入氢氧化锂一水化合物(0.30g,7.23mmol)及水溶液(10mL),转移到50℃温度下搅拌反应2h后,转到0℃下冷却,滴加1M盐酸,至酸性(pH=2),用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水(30mL×2)洗涤,有机相用无水硫酸钠干燥,减压浓缩。得到褐色油状产物(1.00g,产率97.37%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.14–7.09(m,1H),6.81–6.78(m,2H),6.60(t,J=73.8Hz,1H),4.27–4.18(m,1H),3.95–3.89(m,1H),3.89–3.83(m,2H),3.82–3.74(m,1H),3.70–3.63(m,1H),3.47–3.37(m,1H),3.34–3.23(m,1H),2.48–2.40(m,1H),2.16–2.10(m,3H),1.74–1.60(m,1H),1.34–1.27(m,1H),0.69–0.62(m,2H),0.39–0.32(m,2H).
MS-ESI:m/z 356.15[M+H]
+.
步骤7:((2R,2S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)5-(乙基氨基甲酰基)吡啶甲酸甲酯的合成
将5-(乙基氨基甲酰基)吡啶甲酸锂(168mg,0.84mmol)与盐酸的1,4-二氧六环溶液(0.28mL,1mmol)溶解在溶解在N,N-二甲基甲酰胺(5mL)中,搅拌至澄清后加入1-((2R,2S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-基)乙基-1-酮(11250-3)(200mg,0.56mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(114mg,0.84mmol),在冰浴下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(268mg,1.40mmol),N,N-二异丙基乙胺(DIPEA)(325mg,2.52mmol),转移到室温下搅拌反应9h,加入水(20mL),用乙酸乙酯(20mL×2)萃取,合并有机相,用饱和食盐水(20mL×2)洗涤,用无水硫酸钠干燥有机相,浓缩拌样通过柱层析(DCM/MeOH(v/v)=15/1)得到白色固体产物(151mg,产率50.73%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.05(s,1H),8.28–8.19(m,1H),8.19–8.11(m,1H),7.14–7.05(m,1H),6.91–6.82(m,2H),6.80–6.35(m,1H),6.40(s,1H),4.82–4.72(m,1H),4.71–4.62(m,1H),4.62–4.53(m,1H),3.94–3.87(m,1H),3.85–3.74(m,2H),3.61–3.45(m,3H),3.36–3.22(m,1H),2.65–2.52(m,1H),2.23(s,0.6H),2.15–2.01(m,3.4H),1.34–1.21(m,4H),0.69–0.53(m,2H),0.39–0.21(m,2H).
MS-ESI:m/z 532.20[M+H]
+.
实施例53:((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基5-(甲基氨基甲 酰基)吡啶甲酸酯
步骤1:5-(甲基氨基甲酰基)吡啶甲酸甲酯的合成
将化合物6-(甲氧基羰基)烟酸(2.35g,12.97mmol,实施例52步骤1),甲胺盐酸盐(1.05g,15.56mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(3.76g,27.60mmol)溶解在干燥的N,N-二甲基甲酰胺(30mL)溶剂中,在0℃下冷却,再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(4.97g,25.94mmol),N,N-二异丙基乙胺(DIPEA)(5.03g,38.91mmol),转移到室温下搅拌反应17h,停止反应,减压浓缩溶剂后,加水(30mL)溶解浓缩液,用二氯甲烷(30mL×2)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(DCM/MeOH(v/v)=20/1)得到白色固体(1.50g,产率59.56%)。
1H NMR(400MHz,CD
3OD)δ(ppm):9.10–9.00(m,1H),8.42–8.32(m,1H),8.28–8.19(m,1H),4.00(s,3H),2.96(s,3H).
MS-ESI:m/z 195.10[M+H]
+.
步骤2:5-(甲基氨基甲酰基)吡啶甲酸锂的合成
将化合物5-(乙基氨基甲酰基)吡啶甲酸甲酯(250-1)(1.40g,7.21mmol)溶解于四氢呋喃(16mL)溶剂中,再加入氢氧化锂一水化合物(0.36g,8.65mmol)及水溶液(2.5mL),转移到50℃温度下搅拌反应23h后,浓缩反应液,在50℃下真空干燥8h得到白色固体产物(1.40g,产率100%)。
1H NMR(400MHz,CD
3OD)δ(ppm):8.99–8.94(m,1H),8.28–8.22(m,1H),8.12–8.06(m,1H),2.95(s,3H).
MS-ESI:m/z 181.20[M-Li+2H]
+.
步骤3:((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)5-(甲基氨基甲酰基)吡啶甲酸酯的合成
将5-(甲基氨基甲酰基)吡啶甲酸锂(248mg,1.33mmol)与盐酸的1,4-二氧六环溶液(0.45mL,1.78mmol)溶解在溶解在N,N-二甲基甲酰胺(6mL)中,搅拌至澄清后加入1-((2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-基)乙基-1-酮(315mg,0.89mmol,实施例52步骤6),1-羟基-7-氮杂苯并三氮唑(HOAT)(182mg,1.33mmol),在冰浴下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(426mg,2.23mmol),N,N-二异丙基乙胺(DIPEA)(517mg,4.00mmol),转移到室温下搅拌反应24h,加入水(20mL),用乙酸乙酯(20mL×2)萃取,合并有机相,用饱和食盐水(20mL×2)洗涤,用无水硫酸钠干燥有机相,浓缩拌样后通过柱层析(DCM/MeOH(v/v)=15/1)得到白色固体产物(206mg,产率44.72%)
1H NMR(400MHz,CDCl
3)δ(ppm):9.06(s,1H),8.30–8.21(m,1H),8.20–8.10(m,1H),7.09(d,J=8.0Hz,1H),6.91–6.80(m,2H),6.67–6.61(m,1H),6.59(t,J=75.6Hz,1H),4.78–4.73(m,1H),4.70–4.63(m,1H),4.62–4.54(m,1H),3.94–3.87(m,1H),3.81(d,J=6.9Hz,2H),3.51(t,J=10.8Hz,1H),3.35–3.24(m, 1H),3.05(d,J=4.7Hz,3H),2.63–2.53(m,1H),2.22(s,0.6H),2.14–2.02(m,1H),2.09(s,2.4H),1.27–1.22(m,1H),0.67–0.57(m,2H),0.38–0.26(m,2H).
MS-ESI:m/z 518.20[M+H]
+.
实施例54:((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基5-氨基甲酰基吡啶甲酸酯
步骤1:5-氨基甲酰基吡啶甲酸甲酯的合成
将化合物6-(甲氧基羰基)烟酸(2.50g,13.80mmol,实施例52步骤1),氯化铵(1.11g,20.70mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(3.76g,27.60mmol)溶解在N,N-二甲基甲酰胺(30mL)溶剂中,在0℃下冷却,再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(5.29g,27.60mmol),N,N-二异丙基乙胺(DIPEA)(5.35g,41.40mmol),转移到室温下搅拌反应27h,停止反应,减压浓缩溶剂后,加水(30mL)溶解浓缩液,用二氯甲烷(30mL×2)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(DCM/MeOH(v/v)=20/1),得到无色液体(1.26g,产率50.68%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):9.14–9.07(m,1H),8.43–8.35(m,1H),8.33(s,1H),8.13(d,J=8.1Hz,1H),7.78(s,1H),3.90(s,3H).
MS-ESI:m/z 181.15[M+H]
+.
步骤2:5-氨基甲酰基吡啶甲酸锂的合成
将化合物5-(乙基(甲基)氨基甲酰基)吡啶甲酸甲酯(249-1)(1.24g,6.88mmol)溶解于四氢呋喃(20mL)溶剂中,再加入氢氧化锂一水化合物(0.32g,7.57mmol)及水溶液(10mL),转移到50℃温度下搅拌反应3.5h后,减压浓缩除去溶剂,在50℃下真空干燥8h得到白色固体产物(1.18g,产率99.68%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):8.94–8.87(m,1H),8.34–8.27(m,1H),8.24(s,1H),8.01(d,J=8.1Hz,1H),7.63(s,1H).
MS-ESI:m/z 167.25[M-Li+2H]
+.
步骤3:((2R,4S)-1-乙酰基-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)吡咯烷-2-基)甲基5-氨基甲酰基吡啶甲酸的合成
将5-氨基甲酰基吡啶甲酸锂(248mg,1.44mmol)与盐酸的1,4-二氧六环溶液(0.48mL,1.92mmol)溶解在溶解在DMF(5mL)中,搅拌至澄清后加入1-((2R,4S)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-2-(羟甲基)吡咯烷-1-基)乙基-1-酮(342mg,0.96mmol,实施例52步骤6),1-羟基-7-氮杂苯并三氮唑(HOAT)(196mg,1.44mmol),在冰浴下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(460mg,2.40mmol),N,N-二异丙基乙胺(DIPEA)(558mg,4.32mmol),转移到室温下搅拌反应24h,加入水(20mL),用乙酸乙酯(20mL×2)萃取,合并有机相,用饱和食盐水(20mL×2)洗涤,用无水硫酸钠干燥有机相,浓缩拌样后通过硅胶柱层析(DCM/MeOH(v/v)=15/1)得到白色固体产物(180mg,产率37.24%)
1H NMR(400MHz,CDCl
3)δ(ppm):9.14(s,1H),8.39–8.28(m,1H),8.24–8.12(m,1H),7.21–7.01(m,1H),6.96–6.81(m,2H),6.76–6.63(m,1H),6.59(t,J=75.6Hz,1H),6.23–5.98(m,1H),4.82–4.73(m,1H),4.71–4.63(m,1H),4.62–4.46(m,1H),3.98–3.86(m,1H),3.86–3.75(m,2H),3.52(t,J=10.7Hz,1H),3.37–3.21(m,1H),2.65–2.51(m,1H),2.23(s,1H),2.15–2.02(m,3H),1.27–1.22(m,1H),0.69–0.56(m,2H),0.39–0.25(m,2H).
MS-ESI:m/z 504.20[M+H]
+.
实施例55:((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基5-(乙基(甲基)氨基甲酰基)吡啶甲酸酯
步骤1:2-(二氟甲氧基)-5-碘苯酚的合成
在250mL两口圆底烧瓶中加入2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(20.00g,58.80mmol),乙氰(80mL)溶解,再缓慢滴加浓盐酸(40mL),在氮气保护下,80℃油浴中反应12h,停止反应。冷却至室温,加入水(100mL),再加入乙酸乙酯(100mL×2)萃取,合并有机相,用无水硫酸钠干燥30min。粗产品通过硅胶柱层析纯化(洗脱剂:PE=100%),得到浅黄色油状产物(13.4g,产率79.68%)
1H NMR(400MHz,CDCl
3)δ(ppm):7.37(d,J=2.0Hz,1H),7.21(dd,J=8.5,2.1Hz,1H),6.85(d,J=8.5Hz,1H),6.51(t,J=73.1Hz,1H),5.61(s,1H).
GC-MS:m/z 285.9[M]
+.
步骤2:1-(二氟甲氧基)-4-碘-2-异丙氧基苯的合成
在250mL单口烧瓶中加入2-(二氟甲氧基)-5-碘苯酚(11.4g,39.86mmol),N,N-二甲基甲酰胺(55mL)溶解,再加入碳酸钾(16.53g,119.58mmol)和2-碘丙烷(10.16g,59.79mmol),80℃温度下搅拌反应2h,停止反应。冷却至室温,加入水(150mL),用乙酸乙酯(50mL×2)萃取,有机相再用饱和食盐水(100mL)洗一次,用无水硫酸钠干燥30min,减压浓缩,得到浅黄色油状产物(12.51g,产率95.66%)
1H NMR(400MHz,CDCl
3)δ(ppm):7.26–7.23(m,2H),6.88(d,J=8.3Hz,1H),6.52(t,J=75.2Hz,1H),4.56-4.50(m,1H),1.36(d,J=6.1Hz,6H).
GC-MS:m/z 328[M]
+.
步骤3:化合物2-(4-(二氟甲氧基)-3-异丙氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将化合物1-(二氟甲氧基)-4-碘代-2-异丙氧基苯(13.7g,41.76mmol),联硼酸频哪醇酯(11.13g,43.85mmol),醋酸钾(6.15g,62.64mmol),2-二环己基磷-2’-甲基联苯(Mephos)(1.52g,4.18mmol)和醋酸钯(470mg,2.09mmol)溶解在干燥的N,N-二甲基甲酰胺(82mL)溶液中,氮气保护下,80℃的环境反应2h,反应液冷却后,加入水(700mL)混合,乙酸乙酯萃取(40mL×3),用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(EtOAc/PE(v/v)=1/10)得到褐色液体产物(11.4g,产率83.19%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.40(s,1H),7.39(d,J=9.3Hz,1H),7.14(d,J=7.8Hz,1H),6.60(t,J
F-H=75.5Hz,1H),4.69–4.62(m,1H),1.36(d,J=6.1Hz,6H),1.34(s,12H).
GC-MS:m/z 286.10[M-(i-Pr)+H].
步骤4:(R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-异丙氧基苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成
将化合物2-(4-(二氟甲氧基)-3-异丙氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(10.58g,32.24mmol),(R)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)-1H-吡咯-1,2-(2H,5H)-二甲酸酯(11.0g,29.31mmol,中间体M2),醋酸钯(160mg,0.73mmol),2-二环己基磷-2’-甲基联苯(Mephos)(530mg,1.47mmol),N-甲基吗啡啉(NMM)(6.52g,64.48mmol),溶解在甲苯(55mL)和水(27mL)溶液中,氮气保护下,在80℃油浴中反应40min。反应液冷却后,加水(200mL×2)洗涤有机相,有机相用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(PE/EtOAc(v/v)=8/1),得到褐色液体(12.4g,产率98.98%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.40(s,1H),7.39(d,J=9.3Hz,1H),7.14(d,J=7.8Hz,1H),6.60(t,J
F-H=75.5Hz,1H),6.02–6.59(m,1H),4.69–4.62(m,1H),4.66–4.46(m,3H),3.76(d,J=4.4Hz,3H),1.52(s,3H),1.45(s,6H),1.37–1.33(m,6H).
MS-ESI:m/z 372.10[M-t-Bu+2H]
+.
步骤5:(2R,4S)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1,2-二羧酸酯的合成
将化合物(R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-异丙氧基苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(4.60g,10.5mmol),溶在甲醇溶液中(70mL),再加入10%Pd/C还原剂(140mg),用氢气置换三次后,在氢气保护、室温条件下搅拌反应3h,反应液用硅藻土过滤,减压浓缩,通过硅胶柱层析纯化(PE/EtOAc(v/v)=6/1),得到浅黄色粘稠状液体产物(4.60g,产率99.50%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.10(d,J=8.0Hz,1H),6.81–6.78(m,2H),6.60(t,J=76.4Hz,1H),4.44–4.26(m,1H),4.07–3.90(m,1H),3.90–3.82(m,2H),3.76(d,J=6.5Hz,3H),3.47–3.37(m,1H),3.38–3.25(m,1H),2.68–2.58(m,1H),2.10–1.95(m,1H),1.45(d,J=14.1Hz,9H),1.24–1.31(m,1H),0.71–0.59(m,2H),0.41–0.29(m,2H).
MS-ESI:m/z 374.20[M-t-Bu+2H]
+.
步骤6:(2R,4S)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯的合成
将化合物(2R,4S)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1,2-二羧酸酯(4.40g,10.25mmol)溶解在干燥四氢呋喃(22mL)溶液中,在-5℃中冷却,加入2mol/L硼氢化锂四氢呋喃溶液(5.13mL),原料加完之后转移到室温反应4h。加入饱和氯化钠水溶液(30mL),用乙酸乙酯(20mL×3)萃取,有机相用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(PE/EtOAc(v/v)=4/1),得到无色液体(4.10g,产率99.64%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.09(d,J=8.2Hz,1H),6.82(s,1H),6.78(d,J=8.2Hz,1H),6.53(t,J
F-H=75.6Hz,1H),5.18(d,J=8.6Hz,1H),4.57–4.51(m,1H),4.11–4.02(m,1H),4.00–3.90(m,1H),3.81–3.64(m,2H),3.27–3.17(m,2H),2.43–2.34(m,1H),1.67–1.57(m,1H),1.48(s,9H),1.35(d,J=6.1Hz,6H).
MS-ESI:m/z 346.10[M-t-Bu+2H]
+.
步骤7:化合物((2R,4S)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲醇盐酸盐的合成
将化合物(2R,4S)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(4.10g,10.21mmol)溶解于二氯甲烷(20mL)溶液中,加入4.02mol/L HCl的1,4-二氧六环溶液(15.2mL),室温搅拌3h,减压浓缩,得到浅褐色液体(3.40g,产率98.57%)。
1H NMR(400MHz,CD
3OD)δ(ppm):7.16–7.12(m,2H),6.97(dd,J=8.3,1.8Hz,1H),6.70(t,J
F-H=75.3Hz,1H),4.73–4.66(m,1H),3.98–3.88(m,2H),3.84–3.78(m,1H),3.77–3.70(m,1H),3.67–3.59(m,1H),3.30–3.24(m,1H),2.54–2.47(m,1H),2.03–1.95(m,1H),1.35(d,J=6.1Hz,6H).
MS-ESI:m/z 302.20[M-HCl+H]
+.
步骤8:化合物((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基乙酸酯的合成
将化合物((2R,4S)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲醇盐酸盐(3.40g,10.06mmol)溶解在二氯甲烷(35mL)中,在-10℃中冷却,加入N,N-二异丙基乙胺(6.50g,50.3mmol)和乙酰氯(2.21g,28.17mmol),转移到室温反应1h后停止,加水(50mL)洗有机相,分离有机相,有机相用无水Na
2SO
4干燥,减压浓缩,剩余物进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=5/3)得到褐色液体(3.80g,产率98.01%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.13–7.10(m,1H),6.84–6.78(m,2H),6.54(t,J
F-H=74.9Hz,1H),4.58–4.51(m,1H),4.44–4.35(m,2H),4.27–4.10(m,1H),3.92–3.88(m,1H),3.41–3.35(m,1H),3.31–3.15(m,1H),2.52–2.47(m,1H),2.10–2.04(m,6H),1.98–1.88(m,1H),1.37–1.34(m,6H).
MS-ESI:m/z 386.30[M+H]
+.
步骤9:化合物1-((2R,4S)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙酮的合成
将化合物((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基乙酸酯(3.80g,9.86mmol)和氢氧化锂一水合物(830mg,19.72mmol)溶于四氢呋喃/水(v/v)=2/1(45mL)的混合溶剂中,50℃反应1h,减压除去四氢呋喃,乙酸乙酯萃取(20mL×3),有机相用无水Na
2SO
4干燥,减压浓缩,得到褐色液体(3.30g,产率97.47%)。
1H NMR(400MHz,DMSO-d
6)δ(ppm):7.12–7.09(m,2H),6.98(t,J
F-H=74.9Hz,1H),6.91–6.86(m,1H),5.04–4.93(m,1H),4.71–4.61(m,1H),4.02–3.94(m,1H),3.65–3.51(m,2H),3.33–3.20(m,2H),2.39–2.33(m,1H),2.02–2.04(m,3H),1.96–1.84(m,1H),1.28(d,J=6.0Hz,6H).
MS-ESI:m/z 344.20[M+H]
+.
步骤10:((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基5-(乙基(甲基)氨基甲酰基)吡啶甲酸酯的合成
将化合物5-(乙基(甲基)氨基甲酰基)吡啶羧酸锂盐(280mg,1.32mmol)加入到干燥的N,N-二甲基甲酰胺(6ml)溶液中,加入4.02mol/L HCl的1,4-二氧六环溶液(0.44mL),加入1-((2R,4S)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙酮(302mg,0.88mmol),1-羟基-7-氮杂苯并三唑(HOAT)(180mg,1.32mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(420mg,2.20mmol),在冰浴中冷却后,加入N,N-二二异丙基乙胺(DIPEA)(510mg,3.96mmol),转移到室温下搅拌反应13h。加水(50ml)淬灭反应,用乙酸乙酯(15ml×2)萃取有机相后,用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(DCM/MeOH(v/v)=50/1),得到浅黄色固体(165mg,产率31.87%)。
1H NMR(400MHz,CDCl
3)δ(ppm):8.76(s,1H),8.15(d,J=8.0Hz,1H),7.91–7.84(m,1H),7.08(d,J=8.5Hz,1H),6.89–6.86(m,2H),6.52(t,J
F-H=75.5Hz,1H),4.81–4.65(m,2H),4.62–4.43(m,3H),3.93–4.89(m,1H),3.65–3.57(m,1H),3.51(t,J=10.8Hz,1H),3.34–3.20(m,2H),3.10(s,1.7H),2.95(s,1.3H),2.63–2.53(m,1H),2.10(s,3H),1.32–1.28(m,6H),1.27–1.14(m,3H).
MS-ESI:m/z 534.20[M+H]
+.
实施例56:((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基5-(甲基氨基甲酰基)吡啶甲酸酯
将化合物5-(甲基氨基甲酰基)吡啶羧酸锂盐(250mg,1.32mmol)加入到干燥的N,N-二甲基甲酰胺(6ml)溶液中,加入4.02mol/L HCl的1,4-二氧六环溶液(0.44mL),加入1-((2R,4S)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙酮(301mg,0.88mmol,实施例55步骤9),1-羟基-7-氮杂苯并三唑(HOAT)(180mg,1.32mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(420mg,2.20mmol),在冰浴中冷却后,加入N,N-二异丙基乙胺(DIPEA)(510mg,3.96mmol),转移到室温下搅拌反应14h。加水(50mL)淬灭反应,用乙酸乙酯(15mL×2)萃取有机相后,用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(DCM/MeOH(v/v)=25/1),得到浅黄色固体(157mg,产率34.98%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.07(s,1H),8.25(dd,J=8.1,2.0Hz,1H),8.14(d,J=8.1Hz,1H),7.08(d,J=7.9Hz,1H),6.88(s,1H),6.87–6.83(m,1H),6.78–6.67(m,1H),6.52(t,J
F-H=75.5Hz,1H),4.78–4.41(m,4H),3.94–4.88(m,1H),3.51(t,J=10.8Hz,1H),3.35–3.14(m,1H),3.04(d,J=4.7Hz,3H),2.79–2.55(m,1H),2.14–2.00(m,1H),2.09(s,3H),1.33–1.30(m,6H).
MS-ESI:m/z 506.20[M+H]
+..
实施例57:((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基5-氨基甲酰基吡啶甲酸酯
将化合物5-氨基甲酰基吡啶羧酸锂盐(220mg,1.30mmol)加入到干燥的N,N-二甲基甲酰胺(6mL)溶液中,加入4.02mol/L HCl的1,4-二氧六环溶液(0.43mL),加入1-((2R,4S)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙酮(299mg,0.87mmol,实施例55步骤9),1-羟基-7-氮杂苯并三唑(HOAT)(180mg,1.30mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(420mg,2.17mmol),在冰浴中冷却后,加入N,N-二异丙基乙胺(DIPEA)(510mg,3.92mmol),转移到室温下搅拌反应14h。加水(50mL)淬灭反应,用乙酸乙酯(15mL乙酯10萃取有机相后,用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(DCM/MeOH(v/v)=15/1),得到浅黄色固体(163mg,产率36.50%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.22(s,1H),8.38(d,J=7.0Hz,1H),8.19(d,J=6.2Hz,1H),7.09(d,J=7.9Hz,1H),6.88(s,1H),6.87(d,J=9.9Hz,1H),6.52(t,J
F-H=75.5Hz,1H),4.75–4.50(m,4H),3.97–3.88(m,1H),3.56–3.47(m,1H),2.66–2.39(m,3H),2.10(s,3H),1.31(d,J=5.8Hz,6H).
MS-ESI:m/z 492.20[M+H]
+.
实施例58:N-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基)吡啶酰胺
步骤1:化合物2-(二氟甲氧基)-5-碘苯酚的合成
将化合物2-(环丙基甲氧基)-1-(二氟甲氧基)-4-碘苯(20g,58.8mmol)溶于乙腈(80mL)中,再加入浓盐酸(48g,480.5mmol,36.5%),置于80℃加热条件下反应12h。反应结束,加入150mL水,用二氯甲烷萃取(50mL×3),有机相加入无水硫酸钠干燥,减压蒸馏,除去溶剂,硅胶柱层析分离提纯(PE/EtOAc(v/v)=100/1),得到无色液体(13.6g,产率81%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.37(d,J=2.0Hz,1H),7.21(dd,J=8.5,1.9Hz,1H),6.85(d,J=8.5Hz,1H),6.51(t,J=73.2Hz,1H),5.74(s,1H).
GC-MS(EI):m/z 285.93[M]
+.
步骤2:化合物1-(二氟甲氧基)-4-碘-2-异丙氧基苯的合成
将化合物2-(二氟甲氧基)-5-碘苯酚(13.6g,47.6mmol)和2-碘丙烷(12.1g,71.3mmol)溶于DMF(70mL)中,再加入碳酸钾(19.7g,142.7mmol),置于80℃加热条件下反应4h。反应结束,加入150mL水,用乙酸乙酯萃取(50mL×3),有机相加入无水硫酸钠干燥,减压蒸馏,除去溶剂,硅胶柱层析分离提纯(PE/EtOAc(v/v)=100/1),得到浅黄色液体(14.4g,产率92%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.26(s,1H),7.23(dd,J=8.4,1.6Hz,1H),6.88(d,J=8.3Hz,1H),6.52(t,J=75.2Hz,1H),4.56–4.50(m,1H),1.35(d,J=6.1Hz,6H).
GC-MS(EI):m/z 327.9[M]
+.
步骤3:化合物2-(4-(二氟甲氧基)-3-异丙氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将化合物1-(二氟甲氧基)-4-碘-2-异丙氧基苯(14g,42.7mmol),联硼酸频那醇酯(10.8g,42.7mmol),醋酸钾(6.3g,64.0mmol),二环己基-[2-(2-甲基苯基)苯基]膦(1.6g,4.27mmol)和醋酸钯(0.48g,2.13mmol)混合DMF(70mL)溶液中,氮气保护下80℃反应6h,停止反应,冷却至室温。向反应液加入水(250mL),用石油醚(50mL×3)萃取,有机相合用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=100/1)得到棕黄色液体(12.6g,产率90%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.40(s,1H),7.39(d,J=9.7Hz,1H),7.14(d,J=7.8Hz,1H),6.60(t,J=75.6Hz,1H),4.68–4.62(m,1H),1.36(d,J=6.1Hz,6H),1.34(s,12H).
步骤4:化合物(R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-异丙氧基苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯的合成
将化合物2-(4-(二氟甲氧基)-3-异丙氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(12g,32mmol), (R)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)1H-吡咯-1,2(2H,5H)-二羧酸酯(13g,32mmol),N-甲基吗啡啉(7.1g,70.3mmol),二环己基-[2-(2-甲基苯基)苯基]膦(0.58g,1.6mmol)和醋酸钯(0.18g,0.8mmol)混合甲苯(60mL)和水(30mL)混合溶液中,氮气保护下80℃反应1h,停止反应,冷却至室温。向反应液加入水(100mL),用乙酸乙酯(30mL×3)萃取,有机相合用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=5/1)得到黄色液体(12.6g,产率90%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.13–7.11(m,1H),6.98–6.89(m,2H),6.56(t,J=75.3Hz,1H),6.00(dd,J=12.6,1.8Hz,1H),5.19–5.10(m,1H),4.66–4.60(m,1H),4.56–4.59(m,1H),4.54–4.46(m,1H),3.76(s,1H),3.75(s,2H),1.51(s,3H),1.45(s,6H),1.36(s,3H),1.34(s,3H).
MS-ESI:m/z 328.20[M-Boc+H]
+.
步骤5:化合物(2R,4S)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1,2-二羧酸酯的合成
将化合物(R)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-异丙氧基苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(12.5g,29.2mmol),10%钯/碳(2.84g,2.92mmol)溶于190mL甲醇中,在氢气氛围下,室温反应6h,原料反应完全,停止反应。用硅藻土过滤钯碳,有机相减压浓缩得到黄色液体(10g,产率81%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.08(d,J=8.2Hz,1H),6.86–6.74(m,2H),6.52(t,J=75.6Hz,1H),4.57–4.49(m,1H),4.40–4.30(m,1H),4.06–3.91(m,1H),3.76(s,1H),3.74(s,2H),4.43–4.38(m,1H),3.35–3.26(m,1H),2.68–2.60(m,1H),2.06–1.95(m,1H),1.46(s,3H),1.42(s,6H),1.34(s,3H),1.33(s,3H).
MS-ESI:m/z 330.20[M-Boc+2H]
+.
步骤6:化合物(2R,4S)4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯的合成
将化合物(2R,4S)-1-叔丁基2-甲基4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1,2-二羧酸酯(10g,13.3mmol)溶于50mL无水四氢呋喃溶液中,在冰浴条件下,加入硼氢化锂溶液(11.6mL,2mol/L),室温反应3h,原料反应完全,停止反应。加入冰水混合物淬灭反应,用乙酸乙酯萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:PE/EtOAc(v/v)=5/1)得到无色液体(8.8g,产率94%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.09(d,J=8.2Hz,1H),6.82(s,1H),6.78(d,J=8.2Hz,1H),6.52(t,J=75.6Hz,1H),4.58–4.50(m,1H),4.05–3.95(m,2H),3.77(d,J=11.2Hz,1H),3.69–3.65(m,1H),3.26–3.16(m,2H),2.42–2.36(m,1H),1.60–1.74(m,1H),1.48(s,9H),1.35(d,J=6.1Hz,6H).
MS-ESI:m/z 346.15[M-
tBu+2H]
+.
步骤7:化合物(2R,4S)4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-((((甲基磺酰基)氧基)甲基)吡咯烷-1-羧酸叔丁酯的合成
将化合物(2R,4S)4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(7.0g,14.7mmol)和N,N-二异丙基乙胺(3.6g,27.9mmol)溶于50mL二氯甲烷溶液中,在冰浴条件下,加入甲基磺酰氯(MsCl)(2.6g,22.7mmol),室温反应2h,原料反应完全,停止反应。加入冰水混合物淬灭反应,用二氯甲烷萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,得到黄色液体(8.0g,产率96%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.09(d,J=8.2Hz,1H),6.86(s,1H),6.79(d,J=8.1Hz,1H),6.53(t,J=75.6Hz,1H),4.71–4.63(m,0.5H),4.60–4.51(m,1H),4.48–4.31(m,1.5H),4.19–4.06(m,1.5H),4.00–3.91(m,0.5H),3.30–3.12(m,2H),3.01(s,3H),2.58–2.43(m,1H),2.12–2.03(m,1H),1.52–1.47(m,9H),1.35(d,J=6.0Hz,6H).
MS-ESI:m/z 380.20[M-Boc+2H]
+.
步骤8:化合物(2R,4S)2-(叠氮甲基)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1-甲酸叔丁酯的合成
将化合物(2R,4S)4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-((((甲基磺酰基)氧基)甲基)吡咯烷-1-羧酸叔丁酯(8.0g,16.7mmol),叠氮化钠(1.6g,25.0mmol)溶于40mL N,N-二甲基甲酰胺溶液中,在80℃加热条件下反应6h,原料反应完全,停止反应。加入100mL水,用乙酸乙酯萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:PE/EA(v/v)=10/1)得到无色油状物(5.0g,产率71%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.10(d,J=8.2Hz,1H),6.86(s,1H),6.81(d,J=8.0Hz,1H),6.53(t,J=75.6Hz,1H),4.60–4.51(m,1H),4.14–3.90(m,3H),3.46–3.30(m,1H),3.26–3.17(m,2H),2.41(s,1H),2.06–1.98(m,1H),1.49(s,9H),1.36(d,J=6.0Hz,6H).
MS-ESI:m/z 327.20[M-Boc+2H]
+.
步骤9:化合物(2R,4S)-2-(叠氮甲基)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷盐酸盐的合成
将化合物(2R,4S)2-(叠氮甲基)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1-甲酸叔丁酯(4.8g,11.3mmol)溶于10mL二氯甲烷溶液中,再加入盐酸1,4-二氧六环溶液(14mL,4.01mol/L),室温反应1.5h,原料反应完全,停止反应。减压蒸馏,除去溶剂,浓缩液得到黄色液体(4.4g,产率100%)。
MS-ESI:m/z 327.20[M+H-HCl]
+.
1H NMR(400MHz,CDCl
3)δ(ppm):7.11(d,J=8.2Hz,1H),6.92(s,1H),6.83(d,J=8.2Hz,1H),6.53(t,J=75.5Hz,1H),4.63–4.53(m,1H),4.05–3.97(m,3H),3.82–3.73(m,1H),3.63–3.50(m,1H),3.45–3.33(m,1H),2.53–2.42(m,1H),2.05–1.95(m,1H),1.34(d,J=5.9Hz,6H).
MS-ESI:m/z 327.20[M+H-HCl]
+.
步骤10:化合物1-((2R,4S)-2-(叠氮甲基)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1-基)乙酮的合成
将化合物(2R,4S)-2-(叠氮甲基)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷盐酸盐(4.4g,12.1mmol)溶于20mL二氯甲烷溶液中,在冰浴条件下,加入N,N-二异丙基乙胺(6.3g,48.5mmol),乙酰氯(1.9g,24.3mmol),室温反应1h,原料反应完全,停止反应。加入饱和食盐水淬灭反应,用二氯甲烷萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:PE/EA(v/v)=1/1)得到黄色液体(4.2g,产率94%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.12(d,J=8.2Hz,1H),6.88(d,J=1.5Hz,1H),6.83(dd,J=8.2,1.7Hz,1H),6.54(t,J=75.5Hz,1H),4.56(dt,J=12.1,6.1Hz,1H),4.31–4.25(m,1H),4.13(dd,J=12.4,4.4Hz,1H),3.90(dd,J=9.6,7.7Hz,1H),3.45–3.36(m,2H),3.31–3.21(m,1H),2.47–2.37(m,1H),2.10(s,3H),2.07–2.04(m,1H),1.36(d,J=6.1Hz,6H).
MS-ESI:m/z 369.20[M+H]
+.
步骤11:化合物1-((2R,4S)-2-(氨基甲基)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1-基)乙酮盐酸盐的合成
将化合物1-((2R,4S)-2-(叠氮甲基)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1-基)乙酮(4.1g,11.1mmol)溶于40mL甲醇中,加入钯碳(0.82g,2.23mmol)和盐酸(3.6mL,4.01mol/L),1Mpa氢气氛围下室温反应2.5h,原料反应完全,停止反应。用硅藻土过滤反应液,有机相减压浓缩,除去溶剂,得到黄色固体(4.3g,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):8.68(s,2H),7.08(s,1H),6.97–6.77(m,2H),6.53(t,J=75.5Hz,1H),4.61–4.51(m,2H),4.07–3.81(m,1H),3.70–3.04(m,3H),2.82–2.55(m,1H),2.23(s,3H),2.05–1.84(m,1H),1.34(s,6H).
MS-ESI:m/z 343.20[M+H-HCl]
+.
步骤12:N-((((2R,4S)-1-乙酰-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基)吡啶酰胺的合成
将化合物1-((2R,4S)-2-(氨基甲基)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1-基)乙酮盐酸盐(200mg,0.53mmol)、2-吡啶甲酸(78mg,0.64mmol)和1-羟基-7-氮杂苯并三唑(140mg,1.1mmol)溶于二氯甲烷(10mL)溶液中,冰浴条件下,依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(200mg,1.1mmol)和N,N-二异丙基乙胺(210mg,1.6mmol),室温下反应10h,原料反应完全,停止反应,加入饱和食盐水(50mL),用二氯甲烷萃取(30mL×3),有机相用无水硫酸钠干燥,减压浓缩硅胶柱层析(洗脱剂:DCM/MeOH(v/v)=20/1)分离提纯,得白色固体(128mg,产率52%)。
1H NMR(400MHz,CDCl
3)δ(ppm):8.99(s,1H),8.62(d,J=4.4Hz,1H),8.19(d,J=7.8Hz,1H),7.85(t,J=7.7Hz,1H),7.43(dd,J=6.9,5.2Hz,1H),7.07(d,J=8.1Hz,1H),6.79(s,1H),6.77–6.75(m,1H),6.51(t,J=75.6Hz,1H),4.51–4.40(m,1H),4.35–4.28(m,1H),4.05–3.98(m,1H),3.94–3.90(m,1H),3.70–3.61(m,1H),3.42(t,J=10.8Hz,1H),3.29–3.21(m,1H),2.60–2.53(m,1H),2.16(s,3H),2.01–1.92(m,1H),1.32–1.29(m,6H).
MS-ESI:m/z 448.20[M+H]
+.
实施例59:N-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基)-2-乙氧基苯甲酰胺
将化合物1-((2R,4S)-2-(氨基甲基)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-1-基)乙酮盐酸盐(150mg,0.40mmol,实施例58步骤11)、邻乙氧基苯甲酸(80mg,0.48mmol)和1-羟基-7-氮杂苯并三唑(110mg,0.80mmol)溶于二氯甲烷(10mL)溶液中,冰浴条件下,依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(150mg,0.8mmol)和N,N-二异丙基乙胺(160mg,1.2mmol),室温下反应10h,原料反应完全,停止反应,加入饱和食盐水(50mL),用二氯甲烷萃取(30mL×3),有机相用无水硫酸钠干燥,减压浓缩硅胶柱层析(洗脱剂:DCM/MeOH(v/v)=20/1)分离提纯,得白色固体(76mg,产率39%)。
1H NMR(400MHz,CDCl
3)δ(ppm):8.46(s,1H),8.18(d,J=7.6Hz,1H),7.42(t,J=7.2Hz,1H),7.06–7.04(m,2H),6.96(d,J=8.3Hz,1H),6.79(s,1H),6.75(d,J=8.3Hz,1H),6.50(t,J=75.6Hz,1H),4.47–4.37(m,1H),4.34–4.27(m,1H),4.25–4.17(m,2H),4.05–3.95(m,1H),3.92–3.84(m,2H),3.37(t,J=10.5Hz,1H),3.27–3.18(m,1H),2.57–2.50(m,1H),2.12(s,3H),2.08–2.00(m,1H),1.50(t,J=6.9Hz,3H),1.27(dd,J=11.4,5.9Hz,6H).
MS-ESI:m/z 491.25[M+H]
+.
实施例60:((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基5-(乙基氨基甲酰基)吡啶甲酸酯
步骤1:2-(3-(苄氧基)-4-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将化合物2-(苄氧基)-1-(二氟甲氧基)-4-碘苯(10.0g,26.59mmol),联硼酸频哪醇酯(7.43g,29.25mmol),醋酸钾(5.22g,53.18mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(Pd(dppf)Cl
2.CH
2Cl
2)(2.17g,2.66mmol)溶解在N,N-二甲基甲酰胺(100mL)溶液中,在氮气保护,80℃温度下反应8h,用100mL的水稀释反应液,用乙酸乙酯萃取(100mL×3)后,合并有机相用水洗涤(100mL×3),用无水硫酸钠干燥30min,减压浓缩,通过硅胶柱层析纯化(PE/EtOAc(v/v)=10/1),得到黄色固体产物(8.90g,产率88.97%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.53–7.49(m,1H),7.48–7.31(m,6H),7.23–7.15(m,1H),6.61(t,J=75.3Hz,1H),5.16(s,2H),1.35(s,12H).
步骤2:1-(叔丁基)2-甲基(R)-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-1,2-二甲酸酯的合成
将化合物2-(3-(苄氧基)-4-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(739mg,1.96mmol),(R)-1-叔丁基2-甲基4-((((三氟甲基)磺酰基)甲氧基)-1H-吡咯-1,2(2H,5H)-二甲酸酯(700mg,1.87mmol,中间体M2),醋酸钯(21mg,0.09mmol),2-二环己基磷-2'-甲基联苯(Mephos)(68mg,0.19mmol),N-甲基吗啉(NMM)(416mg,4.11mmol)溶解在甲苯(10mL)与水(5mL)的混合溶液中,在氮气保护,80℃的油浴下搅拌反应1h,用乙酸乙酯(20mL)稀释反应液,用水(20mL×2)洗涤有机相,用无水硫酸钠干燥有机相,减压浓缩,通过硅胶柱层析纯化(PE/EtOAc=5:1),得到黄色油状产物(823mg,收率92.56%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.46–7.37(m,4H),7.37–7.30(m,1H),7.20–7.11(m,1H),7.06–7.00(m,1H),7.00–6.91(m,1H),6.58(t,J=75.0Hz,1H),6.03–5.99(m,0.4H),5.99–5.95(m,0.6H),5.20–5.07(m,3H),4.66–4.41(m,2H),3.80–3.72(m,3H),1.53(s,3H),1.46(s,6H).
MS-ESI:m/z 420.10[M-t-Bu+2H]
+.
步骤3:1-(叔丁基)2-甲基(2R,4S)-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷1,2-二甲酸酯的合成
将化合物1-(叔丁基)2-甲基(R)-4-(3-(苄氧基)-4-(二氟甲氧基)苯基)-2,5-二氢-1H-吡咯-1,2-二甲酸酯(823mg,1.73mmol)溶解在甲醇(20mL)溶剂中,再加入Pd/C(201mg,0.83mmol),氢气置换三次后,在氢气保护,室温条件下搅拌反应2h,停止反应,用硅藻土过滤,减压浓缩得到白色油状产物(670mg,产率99.98%)。
1H NMR(400MHz,CDCl3)δ(ppm):7.05(d,J=8.3Hz,1H),6.95–6.87(m,1H),6.78–6.71(m,1H),6.52(t,J=73.9Hz,1H),4.42–4.29(m,1H),4.06–3.88(m,1H),3.75(s,3H),3.45–3.35(m,1H),3.36–3.20(m,1H),2.67–2.57(m,1H),2.09–1.94(m,1H),1.51–1.36(m,9H).
MS-ESI:m/z 288.20[M-Boc+2H]
+.
步骤4:1-(叔丁基)2-甲基(2R,4S)-4-(4-(二氟甲氧基)-3-异丁氧基苯基)吡咯烷-1,2-二甲酸酯的合成
将化合物1-(叔丁基)2-甲基(2R,4S)-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷1,2-二羧酸酯(617mg,1.59 mmol)、碳酸钾(659mg,4.77mmol)、溴代异丁烷(327mg,2.39mmol)溶于N,N-二甲基甲酰胺(10mL)溶剂中,在80℃下搅拌反应3.5h。停止反应冷却至室温,加水(20mL)稀释,用乙酸乙酯(20mL×2)萃取,合并有机相用水(20mL×2)洗涤,用无水硫酸钠干燥有机相,浓缩拌样通过柱层析(PE/EtOAc(v/v)=3/1)纯化得到无色液体产物(600mg,产率85.09%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.09(d,J=8.1Hz,1H),6.85–6.74(m,2H),6.52(t,J=75.5Hz,1H),4.44–4.29(m,1H),4.07–3.86(m,1H),3.79–3.69(m,5H),3.49–3.38(m,1H),3.38–3.24(m,1H),2.70–2.58(m,1H),2.19–2.06(m,1H),2.06–1.97(m,1H),1.50–1.38(m,9H),1.04(d,J=6.7Hz,6H).
MS-ESI:m/z 344.70[M-Boc+2H]
+.
步骤5:(2R,4S)-4-(4-(二氟甲氧基)-3-异丁氧基苯基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯的合成
将化合物1-(叔丁基)2-甲基(2R,4S)-4-(4-(二氟甲氧基)-3-异丁氧基苯基)吡咯烷-1,2-二甲酸酯(561mg,1.26mmol)溶于四氢呋喃(10mL)溶剂中,冰浴下加入硼氢化锂的四氢呋喃溶液(1.26mL,2M),在室温下搅拌反应1.5h,反应液缓慢加入冰水(20mL)中,用稀盐酸(1M)调节至酸性(pH=2),用乙酸乙酯(50mL×2)萃取水相,合并有机相用饱和食盐水(25mL×2)洗涤,有机相用无水硫酸钠干燥,浓缩拌样通过柱层析(PE/EtOAc(v/v)=4/1)纯化得到无色液体产物(480mg,产率91.69%)
1H NMR(400MHz,CDCl
3)δ(ppm):7.10(d,J=7.9Hz,1H),6.84–6.74(m,2H),6.52(t,J=75.6Hz,1H),4.08–3.89(m,2H),3.82–3.72(m,3H),3.72–3.64(m,1H),3.30–3.14(m,2H),2.44–2.33(m,1H),2.19–2.07(m,1H),1.81–1.60(m,1H),1.48(s,9H),1.04(d,J=6.7Hz,6H).
MS-ESI:m/z 360.15[M-t-Bu+2H]
+.
步骤6:((2R,4S)-4-(4-(二氟甲氧基)-3-异丁氧基苯基)吡咯烷-2-基)甲醇盐酸盐的合成
将化合物(2R,4S)-4-(4-(二氟甲氧基)-3-异丁氧基苯基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(480mg,1.16mmol)溶于二氯甲烷(10mL)溶剂中,再加入盐酸的1,4-二氧六环溶液(2.9mL,4M)溶液,在室温下搅拌反应1.5h,停止反应,减压浓缩一次后,再加入二氯甲烷(20mL)溶解,再次减压浓缩,得到白色固体产物(364mg,产率89.18%)。
1H NMR(400MHz,CD
3OD)δ(ppm):7.16–7.10(m,1H),7.10–7.06(m,1H),6.97–6.89(m,1H),6.68(t,J=75.3Hz,1H),3.98–3.86(m,2H),3.84(d,J=6.4Hz,2H),3.81–3.55(m,3H),3.25(t,J=10.8Hz,1H),2.52–2.40(m,1H),2.16–2.05(m,1H),2.05–1.93(m,1H),1.06(d,J=6.7Hz,6H).
MS-ESI:m/z l316.10[M-HCl+H]
+.
步骤7:((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丁氧基苯基)吡咯烷-2-基)甲基乙酸酯
将化合物((2R,4S)-4-(4-(二氟甲氧基)-3-异丁氧基苯基)吡咯烷-2-基)甲醇盐酸盐(364mg,1.03mmol)溶于二氯甲烷(10mL)溶剂中,在0℃下冷却,再加入N,N-二异丙基乙胺(DIPEA)(666mg,5.15mmol),乙酰氯(243mg,3.09mmol),转移到室温下搅拌反应1h,反应液用水(20mL×2)洗涤,并用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(EtOAc/PE(v/v)=9/1),得到黄色液体产物(312mg,产率75.84%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.17–7.06(m,1H),6.86–6.75(m,2H),6.54(t,J=75.5Hz,1H),4.45–4.34(m,2H),4.28–4.08(m,1H),3.95–3.84(m,1H),3.81–3.73(m,2H),3.45–3.34(m,1H),3.34–3.19(m,1H),2.58–2.45(m,1H),2.20–2.05(m,7H),2.00–1.86(m,1H),1.05(d,J=6.7Hz,6H).
MS-ESI:m/z 400.15[M+H]
+.
步骤8:1-((2R,4S)-4-(4-(二氟甲氧基)-3-异丁氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙-1-酮的合成
将化合物((2R,4S)-1-乙酰-4-(4-(二氟甲氧基)-3-异丁氧基苯基)吡咯烷-2-基)甲基乙酸酯(312mg,0.78mmol)溶解于四氢呋喃(6mL)溶剂中,再加入氢氧化锂一水化合物(82mg,1.95mmol)和水(3mL),转移到50℃温度下搅拌反应2h后,转到0℃下冷却,滴加1M盐酸至酸性(pH=2),用乙酸乙酯(30 mL×3)萃取,合并有机相用饱和食盐水(30mL×2)洗涤,有机相用无水硫酸钠干燥,减压浓缩。得到黄色油状产物(280mg,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.12(d,J=8.0Hz,1H),6.83–6.74(m,2H),6.53(t,J=75.4Hz,1H),4.29–4.15(m,1H),3.95–3.85(m,1H),3.84–3.73(m,3H),3.72–3.62(m,1H),3.49–3.38(m,1H),3.36–3.21(m,1H),2.49–2.40(m,1H),2.17–2.10(m,4H),1.75–1.62(m,1H),1.05(d,J=6.7Hz,6H).
MS-ESI:m/z 358.20[M+H]
+.
步骤9:((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丁氧基苯基)吡咯烷-2-基)甲基5-(乙基氨基甲酰基)吡啶甲酸酯的合成
将5-(乙基氨基甲酰基)吡啶甲酸锂(147mg,0.73mmol)与盐酸的1,4-二氧六环溶液(0.24mL,4M)溶解在溶解在N,N-二甲基甲酰胺(5mL)溶剂中,搅拌至澄清后加入1-((2R,4S)-4-(4-(二氟甲氧基)-3-异丁氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙-1-酮(175mg,0.49mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(100mg,0.73mmol),在冰浴下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(235mg,1.40mmol),N,N-二异丙基乙胺(DIPEA)(285mg,2.21mmol),转移到室温下搅拌反应18h,加入水(20mL)稀释反应液,用乙酸乙酯(20mL×2)萃取,合并有机相,用饱和食盐水(20mL×2)洗涤,用无水硫酸钠干燥有机相,浓缩拌样通过柱层析(DCM/MeOH(v/v)=15/1)得到白色固体产物(150mg,产率57.37%,)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.13–9.03(m,1H),8.30–8.22(m,1H),8.20–8.11(m,1H),7.09(d,J=8.1Hz,1H),6.91–6.78(m,2H),6.72–6.29(m,1H),6.51–6.39(m,1H),4.82–4.63(m,2H),4.62–4.51(m,1H),3.95–3.86(m,1H),3.75–3.67(m,2H),3.60–3.44(m,3H),3.38–3.22(m,1H),2.66–2.51(m,1H),2.15–2.03(m,4H),1.34–1.20(m,4H),1.07–0.94(m,6H).
MS-ESI:m/z 534.10[M+H]
+.
实施例61:5-((3S,5R)-1-乙酰基-5-((5-(乙基氨基甲酰基)吡啶甲酰胺基)甲基)吡咯烷基-3-基)-2-(二氟甲氧基)苯基环丙基甲酸酯
将化合物N
2-((((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺(200mg,0.42mmol,实施例48步骤1)溶解在溶解在N,N-二甲基甲酰胺(10mL)溶剂中中,搅拌至澄清后加入环丙基甲酸(54mg,0.63mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(114mg,0.84mmol),在冰浴下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(161mg,0.84mmol),N,N-二异丙基乙胺(DIPEA)(217mg,1.68mmol),转移到室温下搅拌反应18h,加入水(20mL)稀释反应液,用乙酸乙酯(20mL×2)萃取,合并有机相,用饱和食盐水(20mL×2)洗涤,用无水硫酸钠干燥有机相,浓缩拌样通过柱层析(DCM/MeOH(v/v)=20/1)得到白色固体产物(150mg,产率65.58%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.08(s,1H),8.96(s,1H),8.21(s,2H),7.20–7.13(m,1H),7.11–7.04(m,1H),7.02–6.96(m,1H),6.51–6.42(m,1H),6.36(t,J=73.8Hz,1H),4.35–4.24(m,1H),4.04–3.97(m, 1H),3.97–3.89(m,1H),3.64–3.56(m,1H),3.56–3.46(m,2H),3.41(t,J=10.7Hz,1H),3.33–3.21(m,1H),2.65–2.53(m,1H),2.23(s,0.3H),2.14(s,2.7H),1.97–1.89(m,1H),1.86–1.82(m,1H),1.29–1.24(m,3H),1.21–1.14(m,2H),1.09–1.01(m,2H).
MS-ESI:m/z 545.05[M+H]
+.
实施例62:((2R,4S)-1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基5-(乙基(甲基)氨基甲酰基)吡啶甲酸酯
将化合物1-((2R,4S)-4-(3-乙氧基-4-甲氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙酮(100mg,0.34mmol,实施例64步骤11)、5-(乙基(甲基)氨基甲酰基)吡啶-2-羧酸(71mg,0.34mmol)和1-羟基-7-氮杂苯并三唑(93mg,0.68mmol)溶于二氯甲烷(10mL)溶液中,冰浴条件下,依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(130mg,0.68mmol)和N,N-二异丙基乙胺(130mg,1.02mmol),室温下反应2h,原料反应完全,停止反应,加入饱和食盐水(50mL),用二氯甲烷萃取(30mL×3),有机相用无水硫酸钠干燥,减压浓缩硅胶柱层析(洗脱剂:DCM/MeOH(v/v)=20/1)分离提纯,得白色固体(32mg,产率19%)。
1H NMR(400MHz,CDCl
3)δ(ppm):8.76(s,1H),8.14(d,J=8.0Hz,1H),7.89–7.84(m,1H),6.83–6.80(m,2H),6.79–6.77(m,1H),4.77–4.67(m,2H),4.59–4.54(m,1H),4.06–4.01(m,2H),3.93–3.85(m,1H),3.83(s,3H),3.63–3.55(m,1H),3.48(t,J=10.8Hz,1H),3.29–3.22(m,2H),3.09(s,2H),2.94(s,1H),2.59–2.52(m,1H),2.09(s,3H),2.07–2.03(m,1H),1.42(t,J=6.9Hz,3H),1.27–1.24(m,1.5H),1.16–1.13(m,1.5H).
MS-ESI:m/z 484.10[M+H]
+.
实施例63:((2R,4S)-1-乙酰基-4-(3乙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基5-(乙基氨基甲酰基)吡啶甲酸酯
将化合物5-(乙基氨基甲酰基)吡啶甲酸锂(68mg,0.34mmol)溶于DMF(10mL)中,加入盐酸的1,4-二氧六环溶液(0.17mL,4.01mmol/L),反应10min后,加入1-((2R,4S)-4-(3-乙氧基-4-甲氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙酮(100mg,0.34mmol,实施例64步骤11)和1-羟基-7-氮杂苯并三唑(93mg,0.68mmol),冰浴条件下,再依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(130mg,0.68mmol)和N,N-二异丙基乙胺(130mg,1.02mmol),室温下反应2h,原料反应完全,停止反应,加入饱和食盐水(50mL),用乙酸乙酯萃取(30mL×3),有机相用无水硫酸钠干燥,减压浓缩硅胶柱层析(洗脱剂:DCM/MeOH(v/v) =20/1)分离提纯,得白色固体(68mg,产率40%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.09(s,1H),8.25(d,J=7.9Hz,1H),8.13(d,J=8.0Hz,1H),6.82–6.80(m,2H),6.78–6.76(m,1H),6.76–6.66(m,2H),4.57–4.53(m,1H),4.05–3.99(m,2H),3.92–3.86(m,1H),3.83(s,3H),3.54–3.49(m,3H),3.30–3.21(m,1H),2.59–2.53(m,1H),2.08(s,3H),2.05–2.02(m,1H),1.41(t,J=6.8Hz,3H),1.26(t,J=7.3Hz,3H).
MS-ESI:m/z 470.10[M+H]
+.
实施例64:N
2-(((2R,4S)-1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺
步骤1:化合物3-乙氧基-4-甲氧基苯甲酸甲酯的合成
将化合物3-羟基-4-甲氧基苯甲酸甲酯(5.00g,27.45mmol),溴乙烷(4.49g,41.17mmol)和碳酸钾(11.83g,82.35mmol)混合在丙酮(25mL)中,置于60℃下反应10h,加入二氯甲烷(100mL)稀释,有机相用饱和食盐水(100mL×3)洗涤,用无水硫酸钠干燥,减压旋蒸浓缩得到黄色固体(5.23g,产率90.63%).
1H NMR(400MHz,CDCl
3):δ(ppm):7.66(dd,J=8.4,1.7Hz,1H),7.54(d,J=1.6Hz,1H),6.88(d,J=8.4Hz,1H),4.15(q,J=7.0Hz,2H),3.92(s,3H),3.88(s,3H),1.48(t,J=7.0Hz,3H).
MS-ESI:m/z 211.10[M+H]
+.
步骤2:化合物3-乙氧基-4-甲氧基苯甲酸的合成
将化合物3-乙氧基-4-甲氧基苯甲酸甲酯(10.46g,49.76mmol),氢氧化钠(3.98g,99.52mmol,乙醇(30mL),水(10mL)混合均匀,置于50℃搅拌2h。滴入稀盐酸(4mol/L)调节pH=1,加入水(100mL),搅拌(析出大量固体),过滤,所得滤饼用水(50mL×3)洗涤,真空60℃干燥12h,得白色固体(9.76g,产率97%)。
1H NMR(400MHz,CDCl
3):δ(ppm):7.77(dd,J=8.4,1.9Hz,1H),7.60(d,J=1.8Hz,1H),6.92(d,J=8.5Hz,1H),4.17(q,J=7.0Hz,2H),3.95(s,3H),1.50(t,J=7.0Hz,3H).
MS-ESI:m/z 197.15[M+H]
+.
步骤3:化合物苄基(3-乙氧基-4-甲氧基苯基)氨基甲酸酯的合成
步骤一:室温下,向两口瓶(100mL)(A瓶)加入3-乙氧基-4-甲氧基苯甲酸(9.40g,47.91mmol),三乙胺(6.30g,62.28mmol),甲苯(50mL),置于冰浴中搅拌,缓慢滴加入叠氮磷酸二苯酯(14.50g,52.70mmol),室温中搅拌2h。
步骤二:向另一个单口瓶(250mL)(B瓶)加入甲苯(50mL),苯甲醇(5.70g,52.70mmol),加热至110℃,把A瓶物料滴入B瓶中,滴毕保温搅拌2h。停止加热搅拌,冷至室温,反应液用水洗涤(100mL),再用5%氢氧化钠水溶液洗涤(100mL×3),用无水Na
2SO
4干燥,减压旋蒸浓缩得黄色固体。向粗品加入石油醚/乙酸乙酯(50mL,v/v=10/1)搅拌3h,过滤得白色固体(11.55g,产率80.00%).
1H NMR(400MHz,CDCl
3)δ(ppm):7.44–7.31(m,5H),6.85–6.72(m,2H),6.59(s,1H),5.19(s,2H),4.08(d,J=6.3Hz,2H),3.84(s,3H),1.45(t,J=7.0Hz,3H).
MS-ESI:m/z 302.10[M+H]
+.
步骤4:化合物3-乙氧基-4-甲氧基苯胺的合成
向高压釜(1L)中加入(3-乙氧基-4-甲氧基苯基)氨基甲酸酯(11.50g,38.16mmol),10%钯碳(0.61g,0.57mmol),甲醇(40mL),排除空气,通入氢气(0.5MPa),室温搅拌2h。反应液通过硅藻土过滤,滤液经减压浓缩得褐色固体(6.38g,产率100%)
1H NMR(400MHz,CDCl
3)δ(ppm):6.71(d,J=8.4Hz,1H),6.31(d,J=2.5Hz,1H),6.23(dd,J=8.4,2.6Hz,1H),4.04(q,J=7.0Hz,2H),3.79(s,3H),1.44(t,J=7.0Hz,3H).
MS-ESI:m/z 168.20[M+H]
+.
步骤5:化合物3-乙氧基-4-甲氧基碘苯的合成
将化合物3-乙氧基-4-甲氧基苯胺)(6.40g,38.28mmol),溶于1,4-二氧六环(30mL)和水(11mL)中,冷却至0℃,加入浓盐酸(9.7mL,36%aq),搅拌均匀,冷却至-15℃,逐滴加入亚硝酸钠(2.91g,42.11mmol)和水(7mL)的溶液,控制滴加温度在-15℃至-5℃之间,滴毕回温至-5℃搅拌30min后,加入碘化钾(8.26g,49.76mmol)和水(12mL)的溶液,控制滴加温度在-15℃至-5℃之间,滴毕回温至0℃下搅拌2h.加入亚硫酸氢钠(1.99g,19.14mmol)搅拌1h淬灭反应,向反应液加入石油醚(200mL),有机相用水洗涤(100mL×3),用无水Na
2SO
4干燥,减压浓缩得黄色粘稠液体。硅胶柱层析(石油醚/乙酸乙酯(v/v)=10/1)纯化得白色固体(6.24g,产率58.62%)
1H NMR(400MHz,CDCl
3)δ(ppm):7.21(dd,J=8.4,1.9Hz,1H),7.12(d,J=1.8Hz,1H),6.62(d,J=8.4Hz,1H),4.06(q,J=7.0Hz,2H),3.84(s,3H),1.46(t,J=7.0Hz,3H).
GC-MS:m/z 278.00[M]
+.
步骤6:化合物2-(3-乙氧基-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二恶唑烷的合成
将3-乙氧基-4-甲氧基碘苯(1277-6)(6.24g,22.44mmol),联硼酸频那醇酯(5.70g,22.44mmol),醋酸钾(3.30g,33.66mmol),醋酸钯(0.25g,1.12mmol),2-二环己基磷-2’-甲基联苯(Mephos)(0.82g,2.24mmol)混合在N,N-二甲基甲酰胺(36mL)中,氮气保护下80℃搅拌6h。冷却至室温,反应液中加入水(100mL),用石油醚(100mL×3)萃取反应液,合并有机相,无水硫酸钠干燥有机相,减压旋蒸浓缩得到褐色液体,硅胶柱层析(石油醚/乙酸乙酯(v/v)=10/1)纯化得黄色固体(4.85g,产率:77.70%)
1H NMR(400MHz,CDCl
3)δ(ppm):7.41(d,J=8.0Hz,1H),7.29(s,1H),6.88(d,J=8.0Hz,1H),4.15(q,J=7.0Hz,2H),3.89(s,3H),1.47(t,J=7.0Hz,3H),1.33(s,12H).
MS-ESI:m/z 279.35[M+H]
+.
步骤7:化合物(R)-1-叔丁基2-甲基4-(3-乙氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二甲酸酯的合成
将化合物2-(3-乙氧基-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(2.0g,7.19mmol),(R)-1-叔丁基2-甲基4-(((三氟甲基)磺酰基)氧基)1H-吡咯-1,2(2H,5H)-二羧酸酯(2.7g,7.19mmol),N-甲基吗啡啉(1.6g,15.82mmol),二环己基-[2-(2-甲基苯基)苯基]膦(0.13g,0.36mmol)和醋酸钯(0.04g,0.18mmol)混合甲苯(10mL)和水(5mL)混合溶液中,氮气保护下80℃反应1h,停止反应,冷却至室温。向反应液加入水(50mL),用乙酸乙酯(30mL×3)萃取,有机相合用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱层析分离(洗脱剂:PE/EtOAc(v/v)=5/1)得到黄色液体(1.1g,产率44%)。
MS-ESI:m/z 278.18[M-Boc+H]
+.
1H NMR(400MHz,CDCl
3)δ(ppm):6.93–6.88(m,2H),6.85–6.81(m,1H),5.94–5.89(m,1H),5.18–5.08(m,1H),4.66–4.47(m,2H),4.14–4.07(m,2H),3.88(s,3H),3.75(d,J=4.8Hz,3H),1.52(s,3H),1.50– 1.43(m,9H).
步骤8:化合物(2R,4S)-1-叔丁基2-甲基4-(3-乙氧基-4-甲氧基苯基)吡咯烷-1,2-二甲酸酯的合成
将化合物(R)-1-叔丁基2-甲基4-(3-乙氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二甲酸酯(2.0g,5.30mmol),钯碳(0.45g,5.30mmol)溶于35mL甲醇中,在氢气氛围下,室温反应12h,原料反应完全,停止反应。用硅藻土过滤钯碳,有机相减压浓缩得到黄色液体(1.26g,产率63%)。
MS-ESI:m/z 279.20[M-Boc+H]
+.
1H NMR(400MHz,CDCl
3)δ(ppm):6.82–6.74(m,3H),4.39–4.29(m,1H),4.11–4.05(m,2H),4.02–4.00(m,0.5H),3.95–3.89(m,0.5H),3.85(s,3H),3.76(d,J=7.0Hz,3H),3.44–3.37(m,1H),3.33–3.24(m,1H),2.66–2.57(m,1H),2.07–1.96(m,1H),1.50–1.44(m,6H),1.43(s,6H).
步骤9:化合物(2R,4S)-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯盐酸盐的合成
将化合物(2R,4S)-1-叔丁基2-甲基4-(3-乙氧基-4-甲氧基苯基)吡咯烷-1,2-二甲酸酯(1.2g,3.16mmol)溶于10mL二氯甲烷溶液中,再加入盐酸1,4-二氧六环溶液(3.94mL,4.01mol/L),室温反应1.5h,原料反应完全,停止反应。减压蒸馏,除去溶剂,浓缩液得到黄色液体(1.02g,产率100%)。
1H NMR(400MHz,CDCl
3)δ6.86(s,1H),6.79(s,2H),4.67–4.57(m,1H),4.09(q,J=6.9Hz,2H),3.90–3.78(m,1H),3.83(s,6H),3.64–3.52(m,2H),2.82–2.70(m,1H),2.28–2.17(m,1H),1.44(t,J=6.9Hz,3H).
MS-ESI:m/z280.30[M+H-HCl]
+.
步骤10:化合物(2R,4S)-1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-羧酸甲酯的合成
将化合物(2R,4S)-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯盐酸盐(1.0g,3.17mmol)溶于20mL二氯甲烷溶液中,在冰浴条件下,加入N,N-二异丙基乙胺(1.64g,12.68mmol),乙酰氯(0.50g,6.34mmol),室温反应1h,原料反应完全,停止反应。加入饱和食盐水淬灭反应,用二氯甲烷萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:DCM/MeOH(v/v)=20/1)得到黄色液体(0.95g,产率93%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.84–6.80(m,1H),6.79–6.77(m,1H),6.76–6.74(m,1H),4.46(dd,J=9.7,7.5Hz,1H),4.08(q,J=6.9Hz,2H),3.93–3.89(m,1H),3.85(s,3H),3.76(s,3H),3.59(t,J=10.5Hz,1H),3.42–3.33(m,1H),2.66–2.60(m,1H),2.10(s,3H),2.05–2.00(m,1H),1.46(t,J=7.0Hz,3H).
MS-ESI:m/z 322.20[M+H]
+.
步骤11:化合物1-((2R,4S)-4-(3-乙氧基-4-甲氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙酮的合成
将化合物(2R,4S)-1-乙酰-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-羧酸甲酯(0.50g,1.56mmol)溶于15mL四氢呋喃溶液中,在冰浴条件下,加入硼氢化锂溶液(1.17mL,2mol/L),室温反应3h,原料反应完全,停止反应。加入冰水混合物淬灭反应,用乙酸乙酯萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:PE/EtOAc(v/v)=5/1)得到无色液体(0.42g,产率92%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.84–6.82(m,1H),6.77–6.73(m,2H),4.22(dd,J=17.3,7.2Hz,1H),4.14–4.05(m,3H),3.91–3.87(m,1H),3.85(s,3H),3.77–3.74(m,1H),3.66(dd,J=11.8,7.5Hz,1H),3.41(t,J=10.8Hz,1H),3.30–3.23(m,1H),2.42(dt,J=12.8,6.5Hz,1H),2.13(s,2.5H),2.03(s,0.5H),1.46(t,J=7.0Hz,3H).
MS-ESI:m/z 294.50[M+H]
+.
步骤12:化合物((2R,4S)-1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基甲磺酸酯的合成
将化合物1-((2R,4S)-4-(3-乙氧基-4-甲氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙酮(1.35g,4.60mmol)和N,N-二异丙基乙胺(0.95g,7.36mmol)溶于15mL二氯甲烷溶液中,在冰浴条件下,加入甲基磺酰氯(MsCl)(0.69g,5.98mmol),室温反应2h,原料反应完全,停止反应。加入冰水混合物淬灭反应,用二 氯甲烷萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,得到黄色液体(1.55g,产率91%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.82–6.79(m,3H),4.43–4.38(m,1H),4.22(dd,J=10.9,5.0Hz,1H),4.11–4.07(m,2H),3.85(s,3H),3.76(dd,J=10.9,1.8Hz,1H),3.67(s,3H),3.45(t,J=10.7Hz,1H),3.27–3.21(m,1H),3.12–3.06(m,1H),2.52–2.43(m,1H),2.21–2.15(m,1H),2.12(s,3H),1.41–1.39(m,3H).
MS-ESI:m/z 372.14[M+H]
+.
步骤13:化合物1-((2R,4S)-2-(叠氮甲基)-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-1-基)乙酮的合成
将化合物((2R,4S)-1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基甲磺酸酯(1.5g,4.04mmol),叠氮化钠(0.39g,6.06mmol)溶于10mL N,N-二甲基甲酰胺溶液中,在80℃加热条件下反应3h,原料反应完全,停止反应。加入100mL水,用乙酸乙酯萃取(20mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱分离(洗脱剂:PE/EtOAc(v/v)=10/1)得到无色油状物(0.95g,产率74%)。
MS-ESI:m/z 319.20[M+H]
+.
步骤14:化合物1-((2R,4S)-2-(氨基甲基)-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-1-基)乙酮盐酸盐的合成
将化合物1-((2R,4S)-2-(叠氮甲基)-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-1-基)乙酮(0.94g,2.95mmol)溶于40mL甲醇中,加入钯碳(94.0mg,0.30mmol)和盐酸(0.96mL,4.01mol/L),1Mpa氢气氛围下室温反应5h,原料反应完全,停止反应。用硅藻土过滤反应液,有机相减压浓缩,除去溶剂,得到黄色液体(0.78g,产率80%)。
MS-ESI:m/z 293.20[M-HCl+H]
+.
步骤15N
2-((((2R,4S)-1-乙酰-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺
将化合物1-((2R,4S)-2-(氨基甲基)-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-1-基)乙酮盐酸盐(100mg,0.34mmol)、5-(乙基氨基甲酰基)吡啶-2-羧酸锂盐(68mg,0.34mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入盐酸(0.17mL,0.68mmol),反应30min后,再加入1-羟基-7-氮杂苯并三唑(93mg,0.68mmol),冰浴条件下,依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(130mg,0.68mmol)和N,N-二异丙基乙胺(130mg,1.02mmol),室温下反应4h,原料反应完全,停止反应,加入饱和食盐水(50mL),用乙酸乙酯萃取(30mL×3),有机相用无水硫酸钠干燥,减压浓缩硅胶柱层析(洗脱剂:DCM/MeOH(v/v)=20/1)分离提纯,得白色固体(68mg,产率40%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.14(s,1H),8.97(s,1H),8.24–8.20(m,1H),8.15–8.11(m,1H),7.08–7.02(m,1H),6.79–6.77(m,1H),6.73–6.69(m,2H),4.30–4.23(m,1H),4.01(dd,J=13.9,7.0Hz,2H),3.97–3.92(m,1H),3.90–3.86(m,1H),3.81(s,3H),3.58–3.52(m,1H),3.50–3.45(m,2H),3.40(t,J=10.8Hz,1H),3.25–3.16(m,1H),2.57–2.51(m,1H),2.13(s,3H),1.93–1.84(m,1H),1.40(t,J=6.9Hz,3H),1.24(t,J=7.2Hz,3H).
MS-ESI:m/z 469.60[M+H]
+.
实施例65:((2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基5-(乙基氨基甲酰基)吡啶甲酸酯
步骤1:化合物3-异丙氧基-4-甲氧基苯甲酸甲酯的合成
将化合物3-羟基-4-甲氧基苯甲酸甲酯(5.00g,27.45mmol),异丙基碘(7.00g,41.17mmol)和碳酸钾(11.83g,82.35mmol)混合在N,N-二甲基甲酰胺(25mL)中,置于80℃下搅拌10h。加入乙酸乙酯(100mL)稀释,有机相用饱和食盐水(100mL×3)洗涤,再用无水硫酸钠干燥,减压浓缩得到黄色液体(5.48g,产率89.02%).
1H NMR(400MHz,CDCl
3)δ(ppm):7.62(dd,J=8.5,1.8Hz,1H),7.53(d,J=1.7Hz,1H),6.85(d,J=8.5Hz,1H),4.60–4.54(m,1H),3.86(s,3H),3.84(s,3H),1.35(d,J=6.1Hz,6H).
MS-ESI:m/z 225.20[M+H]
+.
步骤2:化合物3-异丙氧基-4-甲氧基苯甲酸的合成
将化合物3-异丙氧基-4-甲氧基苯甲酸甲酯(11.05g,49.28mmol),氢氧化钠(3.94g,98.56mmol),乙醇(30mL),水(10mL)混合均匀,置于50℃搅拌2h。滴入稀盐酸(4mol/L)调节pH=1,加入水(100mL),搅拌(析出大量固体),过滤,所得滤饼用水(50mL×3)洗涤,真空60℃干燥12h,得白色固体(10.36g,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.76(dd,J=8.5,1.9Hz,1H),7.62(d,J=1.8Hz,1H),6.92(d,J=8.5Hz,1H),4.66–4.60(m,1H),3.93(s,3H),1.40(d,J=6.1Hz,6H).
MS-ESI:m/z 211.15[M+H]
+.
步骤3:化合物苄基(3-异丙氧基-4-甲氧基苯基)氨基甲酸酯的合成
第一步:室温下,向两口瓶(A瓶)中加入3-异丙氧基-4-甲氧基苯甲酸(10.30g,48.99mmol),三乙胺(6.44g,663.69mmol),甲苯(50ml),置于冰浴中搅拌,缓慢滴加叠氮磷酸二苯酯(DPPA)(14.83g,53.89mmol),室温中搅拌2h。
第二步:向另一个三口瓶(B瓶)加入甲苯(50mL),苯甲醇(5.83g,53.89mmol),加热至110℃,把A瓶物料滴入B瓶中,滴毕恒温搅拌2h。停止加热搅拌,冷至室温,反应液用水洗涤(100mL),再用5%氢氧化钠水溶液洗涤(100mL×3),用无水Na
2SO
4干燥,减压浓缩得黄色固体。向粗品加入石油醚/乙酸乙酯(50mL,v/v=10:1)搅拌3h,过滤得白色固体(11.34g,产率73.40%).
1H NMR(400MHz,CDCl
3)δ(ppm):7.47–7.30(m,5H),7.16(s,1H),6.86–6.72(m,2H),6.56(s,1H),5.19(s,2H),4.53(s,1H),3.82(s,3H),1.36(d,J=5.9Hz,6H).
MS-ESI:m/z 316.20[M+H]
+.
步骤4:化合物3-异丙氧基-4-甲氧基苯胺的合成
向高压釜中加入(3-异丙氧基-4-甲氧基苯基)氨基甲酸酯(11.34g,35.96mmol),10%钯碳(0.51g,0.54mmol),甲醇(40mL),置换氢气(0.5MPa),室温搅拌2h。反应液通过硅藻土过滤,收集滤液经减压浓缩得褐色固体(6.52g,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.71(d,J=8.4Hz,1H),6.33(d,J=2.4Hz,1H),6.24(dd,J=8.4,2.5Hz,1H),4.49–4.43(p,J=6.1Hz,1H),3.77(s,3H),1.34(d,J=6.1Hz,6H).
MS-ESI:m/z 182.20[M+H]
+.
步骤5:化合物3-异丙氧基-4-甲氧基碘苯的合成
将化合物3-异丙氧基-4-甲氧基苯胺(6.90g,38.07mmol),溶于1,4-二氧六环(30mL)和水(11mL)中,冷却至0℃,加入浓盐酸(9.6mL,36%aq),搅拌均匀,冷却至-15℃,逐滴加入亚硝酸钠(2.89g,41.88mmol)和水(7mL)的溶液,控制滴加温度在-15℃至-5℃之间,滴毕回温至-5℃搅拌30min后,加入碘化钾(8.22g,49.49mmol)和水(12mL)的溶液,控制滴加温度在-15℃至-5℃之间,滴毕回温至0℃下搅拌2h.加入亚硫酸氢钠(1.98g,19.04mmol)搅拌1h淬灭反应,向反应液加入石油醚(200mL),有机 相用水洗涤(100mL×3),用无水Na
2SO
4干燥,减压浓缩得黄色粘稠液体。硅胶柱层析(洗脱剂:石油醚/乙酸乙酯(v/v)=10/1)纯化得白色固体(7.83g,产率70.41%)
1H NMR(400MHz,CDCl
3)δ(ppm):7.21(dd,J=8.5,1.9Hz,1H),7.16(d,J=1.9Hz,1H),6.62(d,J=8.5Hz,1H),4.53–4.44(m,1H),3.82(s,3H),1.36(d,J=6.1Hz,6H).
GC-MS:m/z 292.0[M]
+.
步骤6:化合物2-(3-异丙氧基-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将3-异丙氧基-4-甲氧基碘苯(8.64g,26.63mmol),联硼酸频那醇酯(6.76g,26.63mmol),醋酸钾(39.2g,39.95mmol),醋酸钯(0.30g,1.33mmol),2-二环己基磷-2’-甲基联苯(Mephos)(0.97g,2.66mmol)混合在N,N-二甲基甲酰胺(48mL)中,氮气保护下80℃搅拌6h。冷却至室温,反应液中加入水(100mL),用石油醚(100mL×3)萃取反应液,合并有机相,无水硫酸钠干燥有机相,减压浓缩得到褐色液体,通过硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=10:1)纯化得黄色固体(5.04g,产率64.78%)。
1H NMR(400MHz,CDCl
3)δ(ppm):77.41(d,J=8.0Hz,1H),7.33(s,1H),6.88(d,J=8.0Hz,1H),4.67–4.56(m,1H),3.87(s,3H),1.37(d,J=6.1Hz,6H),1.33(s,12H).
MS-ESI:m/z 293.25[M+H]
+.
步骤7:化合物(R)-1-叔丁基2-甲基4-(3-异丙氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二甲酸酯的合成
将化合物(R)-1-叔丁基2-甲基4-((((三氟甲基)磺酰基)甲氧基)-1H-吡咯-1,2(2H,5H)-二甲酸酯(5.50g,14.65mmol,中间体M
2),2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(4.49g,15.38mmol),醋酸钯(82.23mg,0.37mmol),二环己基-[2-(2-甲基苯基)苯基]膦(267.00mg,0.73mmol),溶解于甲苯(30mL)溶剂中,再加入4-甲基吗啉(3.25g,32.08mmol),水(15mL),在氮气氛围下,转入到80℃搅拌反应2h,冷却至室温,加入水(100mL),用乙酸乙酯(50mL×3)萃取,有机相用无水硫酸钠干燥30min,通过硅胶柱层纯化(洗脱剂:乙酸乙酯/石油醚(v/v)=3/20),得到褐色粘稠状(5g,产率87.19%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.96–6.90(m,2H),6.85–6.82(m,1H),5.93–5.87(m,1H),5.17–5.08(m,1H),4.66–4.46(m,3H),3.85(s,3H),3.74(d,J=5.0Hz,3H),1.52(s,3H),1.45(s,6H),1.36(d,J=6.1Hz,6H).
MS-ESI:m/z
.336.05[M-t-Bu+2H]
+.
步骤8:化合物(2R,4S)-1-叔丁基2-甲基4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1,2-二甲酸酯的合成
将化合物(R)-1-叔丁基2-甲基4-(3-异丙氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(5.55g,14.18mmol)溶解于的甲醇(90mL)溶剂中,再加入钯碳(0.56mg,1.42mmol),在氢气氛围下,室温搅拌反应4h。停止反应,用硅藻土过滤,减压浓缩,得到无色粘稠状(4.45g,产率79.76%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.83–6.76(m,3H),4.53–4.46(m,1H),4.39–4.29(m,1H),4.04–3.89(m,1H),3.82(s,3H),3.75(s,3H),3.42–3.35(m,1H),3.32–3.23(m,1H),2.65–2.57(m,1H),2.06–1.95(m,1H),1.44(s,9H),1.34(d,J=6.0Hz,6H).
MS-ESI:m/z
.337.40[M-t-Bu+H]
+.
步骤9:化合物(2R,4S)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯盐酸盐的合成
将化合物(2R,4S)-1-叔丁基2-甲基4-(4-甲氧基-3-(丙氧基)苯基)吡咯烷-1,2-二羧酸酯(1.70g,4.32mmol)溶解于二氯甲烷(3mL)溶剂中,再加入氯化氢/1,4-二氧六环(9mL)溶液,加入原料完之后,在室温下搅拌反应2h。停止反应,减压浓缩一次后,再加入二氯甲烷(20mL)溶解,再次减压浓缩,得到浅黄色粘稠状物(1.27g,产率100%)
1H NMR(400MHz,CDCl
3)δ(ppm):6.84(s,1H),6.80(s,2H),4.66–4.58(m,1H),4.56–4.50(m,1H),3.83(s,3H),3.81(s,3H),3.64–3.61(m,1H),3.55–3.47(m,1H),2.82–2.73(m,1H),2.25–2.10(m,2H),1.34(d,J=4.9Hz,6H).
MS-ESI:m/z 294.36[M+H-HCl]
+.
步骤10:化合物(2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯的合成
将化合物(2R,4S)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-羧酸甲酯盐酸盐(1.7g,5.79mmol)溶解于二氯甲烷(10mL)溶剂中,转到0℃下,缓慢依次加入乙基二异丙胺(DIPEA)(2.99g,23.16mmol)及乙酰氯(0.91g,11.58mmol),转入到室温下搅拌反应2h。停止反应,反应液水洗(50mL×1),有机相用二氯甲烷(20mL)萃取一次,合并有机相,再用饱和食盐水(50mL)洗一次,分离有机相,有机相加无水硫酸钠干燥30min,减压浓缩,硅胶柱层析分离(洗脱剂:乙酸乙酯/石油醚=80%),得到浅褐色粘稠状(1.386g,产率71.37%)
1H NMR(400MHz,CDCl
3)δ(ppm):6.84–6.75(m,3H),4.54–4.43(m,2H),3.93–3.88(m,1H),3.83(s,3H),3.76(s,3H),3.58(t,J=10.5Hz,1H),3.41–3.31(m,1H),2.66–2.59(m,1H),2.10(s,3H),2.07–2.00(m,1H),1.34(d,J=6.1Hz,6H).
MS-ESI:m/z 336.35[M+H]
+.
步骤11:化合物(2R,4S)-2-(羟甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-乙酮的合成
将化合物(2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-甲酸甲酯(0.74g,2.20mmol)溶解在四氢呋喃(8mL)溶剂中,在-5℃下,滴加2mol/L氢氧化锂的四氢呋喃(95.83mg,4.4mmol)溶剂,滴加完之后,在室温下搅拌反应2h。将反应液缓慢倒入冰水混合物(50mL)中并不断搅拌,产生氢气,再加入乙酸乙酯(30mL)搅拌后,分离有机相,减压浓缩,水相用乙酸乙酯(20mL)萃取,分离有机相,溶解浓缩得到的液体,再加入乙酸乙酯(20mL)溶解完全,用饱和氯化钠(30mL)和稀盐酸调节pH=3,无水硫酸钠干燥后减压浓缩,得到无色粘稠液体(560mg,产率82.81%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.83(d,J=8.0Hz,1H),6.77(d,J=8.3Hz,2H),4.55–4.46(m,1H),4.24–4.08(m,1H),3.90–3.85(m,1H),3.82(s,3H),3.77–3.74(m,1H),3.67–3.63(m,1H),3.39(t,J=10.8Hz,1H),3.29–3.20(m,1H),2.45–2.39(m,1H),2.12(s,3H),1.69–1.61(m,1H),1.35(d,J=6.1Hz,6H).
MS-ESI:m/z 308.10[M+H]
+.
步骤12:化合物((2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基5-(乙酰胺)吡啶甲酸酯的合成 将化合物6-(乙酰胺)吡啶-3-羧酸锂(130mg,0.65mmol)溶于N,N-二甲基甲酰胺(2mL)溶剂中,加入氯化氢二氧六环溶液(36mg,0.98mmol),搅拌2min,溶液澄清后,再加入(2R,4S)-2-(羟甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-乙酮(200mg,0.65mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(130mg,0.98mmol),在0℃下冷却,加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(250mg,1.30mmol),N,N-二异丙基乙胺(DIPEA)(420mg,3.25mmol),在室温下搅拌反应12h。停止反应,停止反应,加入水(20mL),用乙酸乙酯(10mL×2)萃取,有机相再用饱和食盐水洗(20mL)一次,有机相用无水硫酸钠干燥,减压浓缩,硅胶柱层析分离(洗脱剂:甲醇/二氯甲烷(v/v)=1/20),得到浅黄色固体(83mg,产率26.10%)
1H NMR(400MHz,DMSO-d
6)δ(ppm):9.11(s,1H),8.86(s,1H),8.35(dd,J=8.1,2.2Hz,1H),8.15(d,J=8.1Hz,1H),6.89–6.85(m,3H),4.63–4.52(m,2H),4.49–4.33(m,2H),3.96(t,J=8.5Hz,1H),3.71(s,3H),3.48-3.24(m,3H),3.24–3.02(m,1H),2.67–2.41(m,2H),2.10(s,0.5H),2.00(s,2.5H),1.17–1.12(m,9H).
MS-ESI:m/z 484.10[M+H]
+.
实施例66:N
2-(((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丁氧基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺
将化合物N
2-((((2R,4S)-1-乙酰-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺(250mg,0.52mmol,实施例48步骤1)溶解在溶解在N,N-二甲基甲酰胺(10mL)溶剂中,搅拌至澄清后依次加入碳酸钾(216mg,1.56mmol)与溴代异丁烷(107mg,0.78mmol),转移到80℃油浴下搅拌反应3h,加入水(20mL)稀释反应液,用乙酸乙酯(20mL×2)萃取,合并有机相,用饱和食盐水(20mL×2)洗涤,用无水硫酸钠干燥有机相,浓缩拌样通过柱层析(DCM/MeOH(v/v)=20/1)得到白色固体产物(212mg,产率76.55%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.25–9.08(m,1H),8.98(s,1H),8.21(s,2H),7.12–7.01(m,1H),6.84–6.72(m,2H),6.52(t,J=75.5Hz,1H),6.49–6.37(m,1H),4.37–4.24(m,1H),4.07–3.97(m,1H),3.97–3.86(m,1H),3.79–3.69(m,2H),3.65–3.56(m,1H),3.56–3.48(m,2H),3.47–3.38(m,1H),3.34–3.19(m,1H),2.63–2.52(m,1H),2.24(s,0.4H),2.16(s,2.6H),2.13–2.06(m,1H),2.03–1.87(m,1H),1.27(t,J=7.2Hz,3H),1.03(d,J=6.6Hz,6H).
MS-ESI:m/z 533.10[M+H]
+.
实施例67:((2R,4S)-1-乙酰基-4-(3--4-甲氧基苯基)吡咯烷-2-基)甲基5-氨基甲酰基吡啶甲酸酯
将化合物6-酰胺吡啶-3-羧酸锂(390mg,2.28mmol)溶于N,N-二甲基甲酰胺(2mL)溶剂中,加入氯化氢二氧六环溶液(62mg,1.71mmol),搅拌2min,溶液澄清后,再加入(2R,4S)-2-(羟甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-乙酮(350mg,1.14mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(230mg,1.17mmol),在0℃下冷却,加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(440mg,2.28mmol),N,N-二异丙基乙胺(DIPEA)(740mg,5.7mmol),在室温下搅拌反应13h。停止反应,加入水(20mL),用乙酸乙酯(10mL×2)萃取,有机相再用饱和食盐水洗(20mL)一次,有机相用无水硫酸钠干燥,减压浓缩,硅胶柱层析分离(洗脱剂:甲醇/二氯甲烷(v/v)=1/20),得到浅红色固体(113mg,产率20.54%,)
1H NMR(400MHz,DMSO-d
6)δ(ppm):9.15(s,1H),8.39–8.28(m,2H),8.14(d,J=8.3Hz,1H),7.79(s,1H),6.88(s,3H),4.58(s,2H),4.53–4.25(m,2H),4.04–3.86(m,1H),3.71(s,3H),3.30–3.02(m,2H),2.69–2.43(m,1H),2.11–1.90(m,1H),2.01(s,3H),1.22–1.09(m,6H).
MS-ESI:m/z 456.20[M+H]
+.
实施例68:((2R,4S)-1-乙酰基-4-(3-乙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基5-氨基甲酰基吡啶甲酸酯
将化合物5-氨基甲酰基吡啶甲酸锂(180mg,1.02mmol)溶于DMF(10mL)中,加入盐酸的1,4-二氧六环溶液(0.34mL,4.01mmol/L),反应10min后,加入1-((2R,4S)-4-(3-乙氧基-4-甲氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙酮(200mg,0.68mmol,实施例64步骤11)和1-羟基-7-氮杂苯并三唑(190mg,1.36mmol),冰浴条件下,再依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(260mg,1.36mmol)和N,N-二异丙基乙胺(260mg,2.04mmol),室温下反应2h,原料反应完全,停止反应,加入饱和食盐水(50mL),用乙酸乙酯萃取(30mL×3),有机相用无水硫酸钠干燥,减压浓缩硅胶柱层析(洗脱剂:DCM/MeOH(v/v)=20/1)分离提纯,得白色固体(162mg,产率51%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.17(s,1H),8.32(dd,J=8.0,1.8Hz,1H),8.17(d,J=8.1Hz,1H),6.83–6.80(m,2H),6.79–6.77(m,1H),4.76–4.67(m,1.5H),4.60–4.43(m,1.5H),4.03(q,J=7.0Hz,2H),3.92–3.88(m,1H),3.84(s,3H),3.50(t,J=10.8Hz,1H),3.32–3.22(m,1H),2.61–2.54(m,1H),2.24(s,0.5H),2.10(s,2.5H),2.08–2.02(m,1H),1.42(t,J=7.0Hz,3H).
MS-ESI:m/z 442.10[M+H]
+.
实施例69:((2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基5-(甲基氨基甲酰基)吡啶甲酸酯
将化合物5-(甲基氨基甲酰基)吡啶甲酸锂溶于N,N-二甲基甲酰胺(4mL)溶剂中,加入氯化氢二氧六环溶液(130mg,3.50mmol),搅拌2min,溶液澄清后,再加入(2R,4S)-2-(羟甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-乙酮(715mg,2.33mmol,实施例65步骤11),1-羟基-7-氮杂苯并三氮唑(HOAT)(480mg,3.50mmol),在0℃下冷却,加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(890mg,4.66mmol),N,N-二异丙基乙胺(DIPEA)(1.51g,1.93mmol),再加入N,N-二甲基甲酰胺(6mL)溶剂,在30℃下搅拌反应4h。停止反应,加入水(20mL),用乙酸乙酯(10mL×2)萃取,有机相再用饱和食盐水洗(20mL)一次,有机相用无水硫酸钠干燥,减压浓缩,硅胶柱层析分离(洗脱剂:甲醇/二氯甲烷(v/v)=1/20),得到浅黄色固体(297mg,产率25.98%)
1H NMR(400MHz,DMSO-d
6)δ(ppm):9.11(s,1H),8.82(s,1H),8.35(s,1H),8.16(s,1H),6.87(s,3H),4.58(s,2H),4.52–4.23(m,2H),4.07–3.87(m,1H),3.71(s,3H),3.32–2.97(m,2H),2.83(s,3H),2.68–2.45(m,1H),2.19–1.92(m,1H),2.01(s,3H),1.30–1.03(m,6H).
MS-ESI:m/z 470.10[M+H]
+.
实施例70:((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-异丙氧基苯基)吡咯烷-2-基)甲基5-(乙基氨基甲酰基)吡啶甲酸酯
将化合物5-(乙基氨基甲酰基)吡啶羧酸锂盐(260mg,1.30mmol)加入到干燥的N,N-二甲基甲酰胺(6ml)溶液中,加入4.02mol/L HCl的1,4-二氧六环溶液(0.43mL),加入1-((2R,4S)-4-(4-(二氟甲氧基)-3-异丙氧基苯基)-2-(羟甲基)吡咯烷-1-基)乙酮(298mg,0.87mmol,实施例55步骤9),1-羟基-7-氮杂苯并三唑(HOAT)(180mg,1.30mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(420mg,2.17mmol),在冰浴中冷却后,加入N,N-二异丙基乙胺(DIPEA)(510mg,3.92mmol),转移到室温下搅拌反应16h。加水(50ml)淬灭反应,用乙酸乙酯(15mL×2)萃取有机相后,用无水硫酸钠干燥,减压浓缩,通过硅胶柱层析纯化(DCM/MeOH(v/v)=25/1),得到浅黄色固体(319mg,产率69.59%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.07(s,1H),8.25(d,J=7.6Hz,1H),8.14(d,J=8.0Hz,1H),7.08(d,J=8.0Hz,1H),6.89(s,1H),6.88–6.83(m,1H),6.65–6.55(m,1H),6.52(t,JF-H=75.5Hz,1H),4.81–4.39(m,4H),3.94–4.87(m,1H),3.57–3.47(m,3H),3.35–3.14(m,1H),2.80–2.54(m,1H),2.14–1.99(m,1H),2.22(s,3H),1.33–1.26(m,3H),1.30(d,J=6.3Hz,6H).
MS-ESI:m/z 520.30[M+H]
+.
实施例71:N
2-(((2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺
步骤1:化合物3-异丙氧基-4-甲氧基苯甲酸甲酯的合成
将化合物3-羟基-4-甲氧基苯甲酸甲酯(5.00g,27.45mmol),异丙基碘(7.00g,41.17mmol)和碳酸钾(11.83g,82.35mmol)混合在N,N-二甲基甲酰胺(25mL)中,置于80℃下搅拌10h。加入乙酸乙酯(100 mL)稀释,有机相用饱和食盐水(100mL×3)洗涤,再用无水硫酸钠干燥,减压浓缩得到黄色液体(5.48g,产率89.02%).
1H NMR(400MHz,CDCl
3)δ(ppm):7.62(dd,J=8.5,1.8Hz,1H),7.53(d,J=1.7Hz,1H),6.85(d,J=8.5Hz,1H),4.60–4.54(m,1H),3.86(s,3H),3.84(s,3H),1.35(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:225.20[M+H]
+.
步骤2:化合物3-异丙氧基-4-甲氧基苯甲酸的合成
将化合物3-异丙氧基-4-甲氧基苯甲酸甲酯(11.05g,49.28mmol),氢氧化钠(3.94g,98.56mmol),乙醇(30mL),水(10mL)混合均匀,置于50℃搅拌2h。滴入稀盐酸(4mol/L)调节pH=1,加入水(100mL),搅拌(析出大量固体),过滤,所得滤饼用水(50mL×3)洗涤,真空60℃干燥12h,得白色固体(10.36g,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.76(dd,J=8.5,1.9Hz,1H),7.62(d,J=1.8Hz,1H),6.92(d,J=8.5Hz,1H),4.66–4.60(m,1H),3.93(s,3H),1.40(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:211.15[M+H]
+.
步骤3:化合物苄基(3-异丙氧基-4-甲氧基苯基)氨基甲酸酯的合成
步骤一:室温下,向两口瓶(A瓶)中加入3-异丙氧基-4-甲氧基苯甲酸(10.30g,48.99mmol),三乙胺(6.44g,663.69mmol),甲苯(50ml),置于冰浴中搅拌,缓慢滴加叠氮磷酸二苯酯(DPPA)(14.83g,53.89mmol),室温中搅拌2h。
步骤二:向另一个三口瓶(B瓶)加入甲苯(50ml),苯甲醇(5.83g,53.89mmol),加热至110℃,把A瓶物料滴入B瓶中,滴毕恒温搅拌2h。停止加热搅拌,冷至室温,反应液用水洗涤(100mL),再用5%氢氧化钠水溶液洗涤(100mL×3),用无水Na
2SO
4干燥,减压浓缩得黄色固体。向粗品加入石油醚/乙酸乙酯(50mL,v/v=10:1)搅拌3h,过滤得白色固体(11.34g,产率73.40%).
1H NMR(400MHz,CDCl
3)δ(ppm):7.47–7.30(m,5H),7.20–7.11(m,1H),6.86–6.72(m,2H),6.56(s,1H),5.19(s,2H),3.82(s,3H),1.36(d,J=5.9Hz,6H).
MS(ESI,pos.ion)m/z:316.20[M+H]
+.
步骤4:化合物3-异丙氧基-4-甲氧基苯胺的合成
向高压釜中加入(3-异丙氧基-4-甲氧基苯基)氨基甲酸酯(11.34g,35.96mmol),10%钯碳(0.51g,0.54mmol),甲醇(40mL),置换氢气(0.5MPa),室温搅拌2h。反应液通过硅藻土过滤,收集滤液经减压浓缩得褐色固体(6.52g,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.71(d,J=8.4Hz,1H),6.33(d,J=2.4Hz,1H),6.24(dd,J=8.4,2.5Hz,1H),4.49–4.43(p,J=6.1Hz,1H),3.77(s,3H),1.34(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:182.20[M+H]
+.
步骤5:化合物3-异丙氧基-4-甲氧基碘苯的合成
将化合物3-异丙氧基-4-甲氧基苯胺(6.90g,38.07mmol),溶于1,4-二氧六环(30mL)和水(11mL)中,冷却至0℃,加入浓盐酸(9.6mL,36%aq),搅拌均匀,冷却至-15℃,逐滴加入亚硝酸钠(2.89g,41.88mmol)和水(7mL)的溶液,控制滴加温度在-15℃至-5℃之间,滴毕回温至-5℃搅拌30min后,加入碘化钾(8.22g,49.49mmol)和水(12mL)的溶液,控制滴加温度在-15℃至-5℃之间,滴毕回温至0℃下搅拌2h.加入亚硫酸氢钠(1.98g,19.04mmol)搅拌1h淬灭反应,向反应液加入石油醚(200mL),有机相用水洗涤(100mL×3),用无水Na
2SO
4干燥,减压浓缩得黄色粘稠液体。硅胶柱层析(洗脱剂:石油醚/乙酸乙酯(v/v)=10/1)纯化得白色固体(7.83g,产率70.41%)
1H NMR(400MHz,CDCl
3)δ(ppm):7.21(dd,J=8.5,1.9Hz,1H),7.16(d,J=1.9Hz,1H),6.62(d,J=8.5 Hz,1H),4.53–4.44(m,1H),3.82(s,3H),1.36(d,J=6.1Hz,6H).
GC-MS:m/z 292.0[M]
+.
步骤6:化合物2-(3-异丙氧基-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将3-异丙氧基-4-甲氧基碘苯(8.64g,26.63mmol),联硼酸频那醇酯(6.76g,26.63mmol),醋酸钾(39.2g,39.95mmol),醋酸钯(0.30g,1.33mmol),2-二环己基磷-2’-甲基联苯(Mephos)(0.97g,2.66mmol)混合在N,N-二甲基甲酰胺(48mL)中,氮气保护下80℃搅拌6h。冷却至室温,反应液中加入水(100mL),用石油醚(100mL×3)萃取反应液,合并有机相,无水硫酸钠干燥有机相,减压浓缩得到褐色液体,通过硅胶柱层析(洗脱剂:石油醚/乙酸乙酯(v/v)=10/1)纯化得黄色固体(5.04g,产率64.78%)。
1H NMR(400MHz,CDCl
3)δ(ppm):77.41(d,J=8.0Hz,1H),7.33(s,1H),6.88(d,J=8.0Hz,1H),4.67–4.56(m,1H),3.87(s,3H),1.37(d,J=6.1Hz,6H),1.33(s,12H).
MS(ESI,pos.ion)m/z:293.25[M+H]
+.
步骤7:化合物(R)-1-叔丁基2-甲基4-(3-异丙氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二甲酸酯的合成
将化合物(R)-1-叔丁基2-甲基4-((((三氟甲基)磺酰基)甲氧基)-1H-吡咯-1,2(2H,5H)-二甲酸酯(5.50g,14.65mmol,中间体M
2),2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(4.49g,15.38mmol),醋酸钯(82.23mg,0.37mmol),二环己基-[2-(2-甲基苯基)苯基]膦(267.00mg,0.73mmol),溶解于甲苯(30mL)溶剂中,再加入4-甲基吗啉(3.25g,32.08mmol),水(15mL),在氮气氛围下,转入到80℃搅拌反应2h,冷却至室温,加入水(100mL),用乙酸乙酯(50mL×3)萃取,有机相用无水硫酸钠干燥30min,通过硅胶柱层纯化(洗脱剂:乙酸乙酯/石油醚(v/v)=3/20),得到褐色粘稠状(5g,产率87.19%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.96–6.90(m,2H),6.85–6.82(m,1H),5.93–5.87(m,1H),5.17–5.08(m,1H),4.66–4.46(m,3H),3.85(s,3H),3.74(d,J=5.0Hz,3H),1.52(s,3H),1.45(s,6H),1.36(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:336.05[M-t-Bu+2H]
+.
步骤8:化合物(2R,4S)-1-叔丁基2-甲基4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1,2-二甲酸酯的合成
将化合物(R)-1-叔丁基2-甲基4-(3-异丙氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(5.55g,14.18mmol)溶解于的甲醇(90mL)溶剂中,再加入钯碳(0.56mg,1.42mmol),在氢气氛围下,室温搅拌反应4h。停止反应,用硅藻土过滤,减压浓缩,得到无色粘稠状(4.45g,产率79.76%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.83–6.76(m,3H),4.53–4.46(m,1H),4.39–4.29(m,1H),4.04–3.89(m,1H),3.82(s,3H),3.75(s,3H),3.42–3.35(m,1H),3.32–3.23(m,1H),2.65–2.57(m,1H),2.06–1.95(m,1H),1.44(s,9H),1.34(d,J=6.0Hz,6H).
MS(ESI,pos.ion)m/z:337.40[M-t-Bu+H]
+.
步骤9:化合物(2R,4S)-叔丁基2-(羟甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-甲酸酯的合成
将化合物(2R,4S)-1-叔丁基2-甲基4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1,2-二羧酸酯(3.00g,7.62mmol)溶解在四氢呋喃(10mL)中,在0℃下,加入硼氢化锂的四氢呋喃溶剂(2mol/L,0.33g,15.24mmol),转入到室温下搅拌反应2h。将反应液缓慢倒入冰水(50mL)中并不断搅拌,产生氢气,再加入乙酸乙酯(30mL)搅拌后分离有机相,减压浓缩,水相用乙酸乙酯(20mL)萃取,分离有机相,溶解浓缩得到的液体,再加入乙酸乙酯(20mL)溶解完全,用饱和氯化钠溶液(30mL)和稀盐酸调节pH=3,无水硫酸钠干燥后,减压浓缩,得到无色粘稠液体(2.95g,产率100%)
1HNMR(400MHz,CDCl
3)δ(ppm):6.83–6.81(m,1H),6.77(d,J=7.1Hz,2H),4.53–4.47(m,1H),4.06–3.93(m,2H),3.82(s,3H),3.78–3.72(m,1H),3.69–3.64(m,1H),3.23–3.13(m,2H),2.40–2.31(m,1H),1.63–1.59(m,1H),1.47(s,9H),1.35(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:310.55[M-t-Bu+2H]
+.
步骤10:化合物(2R,4S)-叔丁基4-(3-异丙氧基-4-甲氧基苯基)-2-(((甲基磺酰基)氧基)甲基)吡咯烷-1-甲酸酯的合成
将化合物(2R,4S)-叔丁基2-(羟甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-甲酸酯(2.78g,7.61mmol)溶解在二氯甲烷溶剂(15mL)中,再加入N,N-二异丙基乙胺(DIPEA)(1.57g,12.18mmol),转入到0℃下缓慢滴加甲磺酰氯(1.13g,9.89mmol),5分钟后,甲磺酰氯滴加完毕,转入到室温下搅拌反应1h。将反应液水洗(50mL)一次,再加入饱和食盐水(50mL),用稀盐酸洗调节pH=3,分离有机相,再用饱和碳酸氢钠调节pH=8,无水硫酸钠干燥后减压浓缩,得到褐色粘稠液体(3.4g,产率100%)
1HNMR(400MHz,CDCl
3)δ(ppm):6.85–6.76(m,3H),4.71–4.48(m,2H),4.47–4.32(m,1H),4.17–4.08(m,1H),4.01–3.89(m,1H),3.83(s,3H),3.27–3.12(m,2H),3.01(s,3H),2.58–2.42(m,1H),2.12–2.02(m,1H),1.48(s,9H),1.36(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:388.10[M-t-Bu+2H]
+.
步骤11:化合物(2R,4S)-叔丁基2-(叠氮甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-甲酸酯的合成
将化合物(2R,4S)-叔丁基4-(3-异丙氧基-4-甲氧基苯基)-2-(((甲基磺酰基)氧基)甲基)吡咯烷-1-甲酸酯(3.3g,7.44mmol)溶于N,N-二甲基甲酰胺溶剂(15mL)中,再加入叠氮化钠(0.63g,9.67mmol),转到80℃下搅拌反应3h。停止反应将反应液缓慢倒入水(150mL)中并不断搅拌,加入乙酸乙酯(100mL×3)萃取,合并有机相,用饱和食盐水(200mL×3)洗,无水硫酸钠干燥,减压浓缩,柱层析分离纯化(洗脱剂:乙酸乙酯/石油醚(v/v)=1/10),得到无色油状液体(1.83g,产率62.99%)
1HNMR(400MHz,CDCl
3)δ(ppm):6.85(s,1H),6.82(d,J=5.5Hz,2H),4.53–4.50(m,1H),4.12(s,1H),4.01–3.90(m,2H),3.83(s,3H),3.45–3.34(m,1H),3.26–3.13(m,2H),2.39(s,1H),2.05–1.97(m,1H),1.48(s,9H),1.36(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:335.20[M-t-Bu+2H]
+.
步骤12:化合物(2R,4S)-2-(叠氮甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷盐酸盐的合成
将化合物(2R,4S)-叔丁基2-(叠氮甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-羧酸酯(1.83g,4.69mmol)溶于二氯甲烷(5mL),再加入盐酸1,4-二氧六环溶液(0.85g,23.45mmol,5.85mL),在室温下搅拌反应2h。停止反应,减压浓缩反应液,再加入二氯甲烷(20mL)溶解,再减压浓缩,得到浅黄色粘稠状(1.53g,产率100%)
1HNMR(400MHz,CDCl
3)δ(ppm):6.88–6.78(m,3H),4.57–4.50(m,1H),4.06–3.91(m,3H),3.82(s,3H),3.80–3.71(m,1H),3.57–3.45(m,1H),3.41–3.30(m,1H),2.51–2.42(m,1H),2.03–1.91(m,1H),1.35(d,J=6.0Hz,6H).
MS(ESI,pos.ion)m/z:291.10[M-HCl+H]
+.
步骤13:化合物1-((2R,4S)-2-(叠氮甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-基)乙酮的合成
将化合物(2R,4S)-2-(叠氮甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷盐酸盐(1.53g,4.68mmol)溶于二氯甲烷(8mL)溶剂中,转到0℃下,依次加入N,N-二异丙基乙胺(DIPEA)(2.42g,18.72mmol),乙酰氯(0.73g,9.36mmol),转到室温下搅拌反应2h。反应液水(100mL)洗一次,有机相用二氯甲烷(50mL)萃取一次,合并有机相,再用饱和食盐水(100mL)洗一次,分离有机相,有机相加无水硫酸钠干燥,减压浓缩,硅胶柱层析分离(洗脱剂:乙酸乙酯/石油醚(v/v)=4/5)得到浅黄色油状(1.5g,产率96.42%)
1H NMR(400MHz,CDCl
3)δ(ppm):6.88–6.77(m,3H),4.58–4.49(m,1H),4.30–4.24(m,1H),4.14–4.10(m,1H),3.90–3.86(m,1H),3.85(s,3H),3.44–3.37(m,2H),3.28–3.18(m,1H),2.45–2.38(m,1H),2.10(s,3H),2.16–2.04(m,1H),1.37(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:333.20[M+H]
+.
步骤14:化合物1-((2R,4S)-2-(氨基甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-基)乙酮盐酸盐的合成
将化合物1-((2R,4S)-2-(叠氮甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-基)乙酮(1.5g,4.51mmol)溶于甲醇(15mL)溶剂中,再加入还原剂钯碳(0.15g,0.41mmol)及盐酸1,4-二氧六环(0.21g,5.86mmol,1.46mL),在1Mpa氢气氛围中,室温搅拌反应3h。将反应液用硅藻土过滤,滤液减压浓缩得黄色泡沫状固体(1.47g,95.05%)
1H NMR(400MHz,CDCl
3)δ(ppm):6.89–6.71(m,3H),4.63–4.20(m,3H),3.95–3.81(m,1H),3.82(s,3H),3.56–3.12(m,3H),2.73–2.46(m,1H),2.26–2.09(m,3H),1.94–1.77(m,1H),1.36(d,J=6.1Hz,6H).
MS(ESI,pos.ion)m/z:307.20[M+H-HCl]
+.
步骤15:化合物N
2-(((2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺的合成
将化合物6-(乙酰胺)吡啶-3-羧酸锂(220mg,1.09mmol)溶于N,N-二甲基甲酰胺(5mL)溶剂中,转到0℃下,加入氯化氢1,4-二氧六环溶液(40mg,1.09mmol),搅拌2min,溶液澄清后,转入到室温,再加入1-((2R,4S)-2-(氨基甲基)-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-1-基)乙酮盐酸盐(250mg,0.73mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(150mg,1.09mmol),在0℃下冷却,加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI)(420mg,2.19mmol),N,N-二异丙基乙胺(DIPEA)(570mg,4.38mmol),在室温下搅拌反应15h。停止反应,停止反应,加入水(20mL),用乙酸乙酯(10mL×2)萃取,有机相再用饱和食盐水洗(20mL)一次,有机相用无水硫酸钠干燥,减压浓缩,硅胶柱层析分离(洗脱剂:甲醇/二氯甲烷(v/v)=1/20),得到白色固体(219mg,产率:58.79%)
1H NMR(400MHz,CDCl
3)δ(ppm):9.18(s,1H),8.98–8.92(m,1H),8.20(s,2H),6.82–6.68(m,3H),6.59(s,1H),4.56–4.37(m,1H),4.36–4.20(m,1H),4.09–3.85(m,2H),3.81(s,3H),3.66–3.44(m,3H),3.43–3.32(m,1H),3.28–3.10(m,1H),2.15(s,3H),2.00–1.75(m,2H),1.31(d,J=6.1Hz,6H),1.25(d,J=7.5Hz,3H).
MS(ESI,pos.ion)m/z:483.25[M+H]
+.
实施例72:((2R,4S)-1-乙酰基-4-(3-异丙氧基-4-甲氧基苯基)吡咯烷-2-基)甲基5-(乙基氨基甲酰基)吡啶甲酸酯
步骤1:化合物3-异丁氧基-4-甲氧基苯甲酸甲酯的合成
将化合物3-羟基-4-甲氧基苯甲酸甲酯(10.00g,54.89mmol),溴代异丁烷(11.28g,82.34mmol)和碳酸钾(22.76g,164.67mmol)混合在N,N-二甲基甲酰胺(50mL)中,置于80℃下搅拌10h.加入乙酸乙酯(200mL)稀释,有机相用饱和食盐水(100mL×3)洗涤,用无水硫酸钠干燥,减压浓缩得到黄色液体(11.06 g,产率84.56%).
1H NMR(400MHz,CDCl
3)δ(ppm):7.64(dd,J=8.4,1.8Hz,1H),7.52(d,J=1.7Hz,1H),6.86(d,J=8.4Hz,1H),3.90(s,3H),3.87(s,3H),3.80(d,J=6.8Hz,2H),2.20–2.12(m,1H),1.03(d,J=6.7Hz,6H).
MS(ESI,pos.ion)m/z:239.50[M+H]
+.
步骤2:化合物3-异丁氧基-4-甲氧基苯甲酸的合成
将化合物3-异丁氧基-4-甲氧基苯甲酸甲酯(11.00g,46.16mmol),氢氧化钠(3.69g,92.32mmol),乙醇(30mL),水(10mL)混合均匀,置于50℃搅拌2h。滴入稀盐酸(4mol/L)调节pH=1,加入水(100mL),搅拌析出大量固体,过滤,所得滤饼用水(50mL×3)洗涤,真空60℃干燥12h,得绿色固体(10.35g,产率100%)。
1H NMR(400MHz,CDCl
3)δ(ppm):7.76(dd,J=8.4,1.9Hz,1H),7.59(d,J=1.8Hz,1H),6.91(d,J=8.5Hz,1H),3.94(s,3H),3.83(d,J=6.8Hz,2H),2.24–2.14(m,1H),1.05(d,J=6.7Hz,6H).
MS(ESI,pos.ion)m/z:225.50[M+H]
+.
步骤3:化合物苄基(3-异丁氧基-4-甲氧基苯基)氨基甲酸酯的合成
步骤一:室温下,向两口瓶(100mL)(A瓶)加入3-异丁氧基-4-甲氧基苯甲酸(10.35g,46.15mmol),三乙胺(6.07g,59.99mmol),甲苯(50ml),置于冰浴中搅拌,缓慢滴加入叠氮磷酸二苯酯(13.97g,50.77mmol),室温中搅拌2h。
步骤二:向另一个单口瓶(250mL)(B瓶)加入甲苯(50mL),苯甲醇(5.49g,50.77mmol),加热至110℃,把A瓶物料滴入B瓶中,滴毕保温搅拌2h。停止加热搅拌,冷至室温,反应液用水洗涤(100mL),再用5%氢氧化钠水溶液洗涤(100mL×3),用无水硫酸钠干燥,减压浓缩得黄色固体。向粗品加入石油醚/乙酸乙酯(50mL,v/v=10/1)搅拌3h,过滤得白色固体(10.98g,产率72.23%).
1H NMR(400MHz,CDCl
3)δ(ppm):7.46–7.37(m,5H),7.24–7.12(m,1H),6.82(d,J=8.5Hz,1H),6.75(d,J=8.3Hz,1H),6.61(br.s,1H),5.22(s,2H),3.85(s,3H),3.78(d,J=6.4Hz,2H),2.23–2.11(m,1H),1.05(d,J=6.7Hz,6H).
MS(ESI,pos.ion)m/z:330.20[M+H]
+.
步骤4:化合物3-异丁氧基-4-甲氧基苯胺的合成
向高压釜(250m L)中加入(3-异丁氧基-4-甲氧基苯基)氨基甲酸酯(10.90g,33.09mmol),10%钯碳(0.53g,0.50mmol),甲醇(50mL),排去空气,通入氢气(0.5MPa),室温搅拌2h。把反应液通过硅藻土过滤,收集滤液经减压浓缩得褐色固体(4.05g,产率62.68%)
1H NMR(400MHz,CDCl
3)δ(ppm):6.71(d,J=8.4Hz,1H),6.32(d,J=2.5Hz,1H),6.23(dd,J=8.4,2.6Hz,1H),3.78(s,3H),3.70(d,J=6.8Hz,2H),2.17–2.09(m,1H),1.01(d,J=6.7Hz,6H).
MS(ESI,pos.ion)m/z:196.45[M+H]
+.
步骤5:化合物3-异丁氧基-4-甲氧基碘苯的合成
将化合物3-异丁氧基-4-甲氧基苯胺(4.05g,20.74mmol),溶于1,4-二氧六环(30mL)和水(11mL)中,冷却至0℃,加入浓盐酸(5.3mL,36%浓度),搅拌均匀,冷却至-15℃,逐滴加入亚硝酸钠(1.57g,22.81mmol)和水(7mL)的溶液,控制滴加温度在-15℃至-5℃之间,滴加完毕后,升温至-5℃搅拌30min后,加入碘化钾(4.48g,26.96mmol)和水(12mL)的溶液,控制滴加温度在-15℃至-5℃之间,滴加完毕后,升温至0℃下搅拌2h.加入亚硫酸氢钠(1.08g,10.37mmol)搅拌1h淬灭反应,向反应液加入石油醚(200mL),有机相用水洗涤(100mL×3),用无水硫酸钠干燥,减压浓缩得黄色粘稠液体。硅胶柱层析(石油醚/乙酸乙酯(v/v)=10/1)纯化得白色固体(3.62g,产率56.97%)
1H NMR(400MHz,CDCl
3)δ(ppm):7.20(dd,J=8.4,1.9Hz,1H),7.12(d,J=1.8Hz,1H),6.62(d,J=8.4Hz,1H),3.83(s,3H),3.72(d,J=6.8Hz,2H),2.20–2.10(m,1H),1.03(d,J=6.7Hz,6H).
GC-MS(EI):306.0[M]
+.
步骤6:化合物2-(3-异丁氧基-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的合成
将3-异丁氧基-4-甲氧基碘苯(3.60g,11.76mmol),联硼酸频那醇酯(2.99g,11.76mmol),醋酸钾(1.73g,17.64mmol),醋酸钯(0.13g,0.59mmol),2-二环己基磷-2’-甲基联苯(Mephos)(0.43g,1.18mmol)混合在N,N-二甲基甲酰胺(48mL)中,氮气保护下80℃搅拌6h。冷却至室温,反应液中加入水(100mL),用石油醚(100mL×3)萃取反应液,合并有机相,无水硫酸钠干燥有机相,减压浓缩得到褐色液体,硅胶柱层析(石油醚/乙酸乙酯(v/v)=10/1)纯化得黄色液体(2.16g,产率59.98%)
1H NMR(400MHz,CDCl
3)δ(ppm):7.41(d,J=8.0Hz,1H),7.28(s,1H),6.88(d,J=8.0Hz,1H),3.88(s,3H),3.81(d,J=6.8Hz,2H),2.22–2.12(m,1H),1.34(s,12H),1.04(d,J=6.7Hz,6H).
MS(ESI,pos.ion)m/z:307.60[M+H]
+.
步骤7:化合物(R)-1-叔丁基2-甲基4-(3-异丁氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二甲酸酯的合成
将化合物2-(3-异丁氧基-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧环戊硼烷(2.10g,6.86mmol),(R)-1-叔丁基2-甲基4(((三氟甲基)磺酰基)氧基)-1H-吡咯-1,2(2H,5H)-二羧酸酯(2.57g,6.86mmol),醋酸钯(39mg,0.17mmol),2-二环己基磷-2’-甲基联苯(Mephos)(130mg,0.34mmol)和N-甲基吗啉(1.53g,15.09mmol)溶解于甲苯(10mL)和水(5mL)中,氮气保护下,80℃搅拌1h。减压浓缩,加入水(100mL),用乙酸乙酯(100mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,进行硅胶柱层析分离(洗脱剂:60-90石油醚/乙酸乙酯(v/v)=5/1)得到黄色液体(2.15g,产率77.22%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.92(s,1H),6.90–6.85(m,1H),6.85–6.79(m,1H),5.94–5.88(m,1H),5.20–5.06(m,1H),4.66–4.47(m,2H),3.86(s,3H),3.80–3.71(m,5H),2.21–2.11(m,1H),1.52(s,3H),1.45(s,6H),1.03(d,J=6.7Hz,6H).
MS(ESI,pos.ion)m/z:350.15[M-t-Bu+2H]
+.
步骤8:化合物(2R,4S)-1-叔丁基2-甲基4-(3-异丁氧基-4-甲氧基苯基)吡咯烷-1,2-二甲酸酯的合成
将化合物(R)-1-叔丁基2-甲基4-(3-异丁氧基-4-甲氧基苯基)-1H-吡咯-1,2(2H,5H)-二甲酸酯(2.14g,5.28mmol)和10%钯碳(200mg)加入甲醇(30mL)中,氢气氛围下(1atm),搅拌12h。通过硅藻土滤去固体,减压浓缩得到无色透明液体(2.02g,产率93.88%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.81(d,J=8.0Hz,1H),6.78–6.74(m,1H),6.74–6.71(m,1H),4.41–4.28(m,1H),4.06–3.88(m,1H),3.83(s,3H),3.78–3.71(m,5H),3.45–3.35(m,1H),3.35–3.22(m,1H),2.68–2.57(m,1H),2.21–2.10(m,1H),2.08–1.97(m,1H),1.43(s,9H),1.03(d,J=6.6Hz,6H).
MS(ESI,pos.ion)m/z:352.20[M-t-Bu+2H]
+.
步骤9:化合物(2R,4S)-1-叔丁基2-羟甲基-4-(3-异丁氧基-4-甲氧基苯基)吡咯烷-1-甲酸酯的合成
将化合物(2R,4S)-1-叔丁基2-甲基4-(3-异丁氧基-4-甲氧基苯基)吡咯烷-1,2-二甲酸酯(2.02g,4.96mmol)溶于无水四氢呋喃(5mL)中,置于冰浴搅拌0.5h,滴加入硼氢化锂(2.5mL,4.96mmol,2mol/L in THF)溶液,室温搅拌4h。加入饱和氯化铵溶液(50mL)淬灭反应,向剩余物加入乙酸乙酯(100mL)稀释,用饱和氯化铵溶液(100mL×2)洗涤,用盐酸(4mol/L)调节pH=3,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:60-90石油醚/乙酸乙酯(v/v)=3/1)得无色透明粘稠固体(1.70g,产率90.32%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.82(d,J=8.1Hz,1H),6.75(d,J=8.3Hz,1H),6.73(s,1H),4.09–4.01(m,1H),4.00–3.91(m,1H),3.84(s,3H),3.80–3.76(m,1H),3.75(d,J=6.8Hz,2H),3.71–3.65(m,1H), 3.24–3.13(m,2H),2.41–2.32(m,1H),2.21–2.09(m,1H),1.71–1.61(m,1H),1.48(s,9H),1.04(d,J=6.7Hz,6H).
MS(ESI,pos.ion)m/z:324.20[M-t-Bu+2H]
+.
步骤10:化合物((2R,4S)-4-(3-异丁氧基-4-甲氧基苯基)吡咯烷-2-基)甲醇盐酸盐的合成
将化合物(2R,4S)-1-叔丁基2-羟甲基-4-(3-异丁氧基-4-甲氧基苯基)吡咯烷-1-甲酸酯(1.50g,3.95mmol)溶于DCM(1mL)中,注入氯化氢的二氧六环溶液(5.0mL,20.0mmol,4mol/L)溶液,室温搅拌3h。减压除去溶剂,得到黄色固体(1.10g,99.68%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.95–6.71(m,3H),4.08–4.01(m,1H),3.99–3.89(m,1H),3.80(s,2H),3.74(d,J=6.7Hz,2H),3.68(s,3H),3.55–3.43(m,1H),3.37–3.16(m,1H),2.41–2.30(m,1H),2.18–2.08(m,1H),2.06–1.95(m,1H),1.01(d,J=6.6Hz,6H).
MS(ESI,pos.ion)m/z:280.30[M-HCl+H]
+.
步骤11:化合物1-((2R,4S)-2-羟甲基-4-(3-异丁氧基-4-甲氧基苯基)吡咯烷-1-基)乙基酮的合成
将化合物((2R,4S)-4-(3-异丁氧基-4-甲氧基苯基)吡咯烷-2-基)甲醇盐酸盐(1.09g,3.90mmol),三乙胺(2.02g,15.60mmol)溶于二氯甲烷(5mL)中,在0℃下缓慢滴入乙酰氯(610mg,7.80mmol),室温搅拌2h。加入二氯甲烷(50mL),反应液用水洗涤(50mL×2),用无水硫酸钠干燥,减压浓缩得黄色液体(1.15g,3.16mmol).将前述黄色液体(1.15g,3.16mmol),氢氧化锂一水合物(199mg,4.74mmol),四氢呋喃(6mL),水(2mL)混合均匀,置于50℃搅拌2h。加入饱和食盐水(20mL),滴入稀盐酸(4mol/L)调节pH=1,用乙酸乙酯(50mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压除去溶剂得到黄色液体(938mg,产率92.35%)。
1H NMR(400MHz,CDCl
3)δ(ppm):6.82(d,J=8.2Hz,1H),6.74(d,J=8.3Hz,1H),6.72(s,1H),4.27–4.16(m,1H),3.92–3.85(m,1H),3.83(s,3H),3.78–3.73(m,1H),3.74(d,J=6.6Hz,2H),3.70–3.61(m,1H),3.40(t,J=10.8Hz,1H),3.31–3.19(m,1H),2.46–2.35(m,1H),2.18–2.09(m,1H),2.12(s,3H),1.72–1.60(m,1H),1.03(d,J=6.7Hz,6H).
MS(ESI,pos.ion)m/z:322.20[M+H]
+.
步骤12:化合物((2R,4S)-1-乙酰基-4-(3-异丁氧基-4-甲氧基苯基)吡咯烷-2-基)甲基5-(乙基氨基甲酰基)吡啶甲酸酯的合成
将化合物1-((2R,4S)-2-羟甲基-4-(3-异丁氧基-4-甲氧基苯基)吡咯烷-1-基)乙基酮(151mg,0.47mmol),5-(乙基胺甲酰基)吡啶酸(183mg,0.94mmol)和N-羟基-7-氮杂苯并三氮唑(160mg,1.17mmol)溶于N,N-二甲基甲酰胺(5mL)中,在冰浴中加入1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(270mg,1.41mmol)和N,N-二异丙基乙胺(243,1.88mmol),室温搅拌15h。向反应液加二氯甲烷萃取(100mL),有机相用水(50mL×3)洗涤,用无水硫酸钠干燥,减压除去溶剂,剩余物进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)=20/1)得到白色固体(80mg,产率34.21%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.07(s,1H),8.24(d,J=7.0Hz,1H),8.13(d,J=8.0Hz,1H),6.86–6.74(m,3H),6.71–6.59(m,1H),4.77–4.65(m,2H),4.60–4.54(m,1H),3.95–3.85(m,1H),3.82(s,3H),3.71(d,J=6.6Hz,2H),3.57–3.45(m,3H),3.32–3.21(m,1H),2.62–2.50(m,1H),2.15–1.98(m,2H),2.09(s,3H),1.27(t,J=7.1Hz,3H),1.00(d,J=6.6Hz,6H).
MS(ESI,pos.ion)m/z:498.25[M+H]
+.
实施例73:5-((3S,5R)-1-乙酰基-5-((5-(乙基氨基甲酰基)吡啶甲酰胺基)甲基)吡咯烷-3-基)-2-(二氟甲氧基)苯基异丁酸酯
将化合物N
2-((((2R,4S)-1-乙酰基-4-(4-(二氟甲氧基)-3-羟基苯基)吡咯烷-2-基)甲基)-N
5-乙基吡啶-2,5-二甲酰胺(214mg,0.45mmol,实施例48步骤1)溶解在溶解在N,N-二甲基甲酰胺(10mL)溶剂中中,搅拌至澄清后加入异丁酸(59mg,0.68mmol),1-羟基-7-氮杂苯并三氮唑(HOAT)(123mg,0.90mmol),在冰浴下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(173mg,0.90mmol),N,N-二异丙基乙胺(DIPEA)(233mg,1.80mmol),转移到室温下搅拌反应21h,加入水(20mL)稀释反应液,用乙酸乙酯(20mL×2)萃取,合并有机相,用饱和食盐水(20mL×2)洗涤,用无水硫酸钠干燥有机相,浓缩拌样通过柱层析(DCM/MeOH(v/v)=20/1)得到白色固体产物(200mg,产率81.32%)。
1H NMR(400MHz,CDCl
3)δ(ppm):9.12–9.05(m,1H),8.96(s,1H),8.21(s,2H),7.20–7.12(m,1H),7.10–7.03(m,1H),7.00–6.95(m,1H),6.43(s,1H),6.35(t,J=73.9Hz,1H),4.34–4.25(m,1H),4.04–3.97(m,1H),3.97–3.89(m,1H),3.65–3.56(m,1H),3.55–3.47(m,2H),3.46–3.38(m,1H),3.33–3.22(m,1H),2.89–2.77(m,1H),2.65–2.54(m,1H),2.23(s,0.4H),2.15(s,2.6H),2.01–1.87(m,1H),1.31(d,J=7.0Hz,6H),1.27(t,J=7.3Hz,3H).
MS(ESI,pos.ion)m/z:547.15[M+H]
+.
生物试验
生物实施例
本发明采用以下方法对本发明化合物进行生物试验:(1)采用BPS生产试剂盒(BPS,Cat.No.60343),按照制造商提供的说明书,采用荧光偏振方法检测化合物对PDE4B2酶抑制作用。(2)将PDE4B2酶浓度配制为83.33pg/μL,终浓度为27.78pg/μL;底物FAM-Cyclic-3’,5’-AMP浓度配制为300nM,反应终浓度为100nM,酶及底物稀释液均使用试剂盒自带缓冲液PDE Assay buffer;Binding Agent利用试剂盒自带Binding Agent Diluent进行100倍稀释,备用。反应体系如表1所示。
表1化合物对PDE4B2酶IC
50检测体系
采用384孔板进行检测,实验设置受试样品孔、阳性对照孔、阴性对照孔及空白孔,每个样品利用双复孔检测10个浓度下对PDE4B2酶浓度的抑制作用,利用PDE4B2酶及FAM-Cyclic-3’,5’-AMP底物反应 孔作为阳性对照,FAM-Cyclic-3’,5’-AMP底物孔作为阴性对照,缓冲液孔作为空白对照。各孔按表1顺序加入相应样品、酶、底物及缓冲液后,25℃恒温箱孵育1h,然后每孔加入已配置好的Binding Agent 15μL,并于25℃恒温振荡器振摇1h后,利用PHER Astar FS多功能酶标仪(BMG)在FP485/525波长处进行检测。利用Graph Pad Prism 5软件对化合物不同浓度下对PDE4B2酶抑制作用进行作图,计算IC
50。
按照上述方法测定本发明化合物对PDE4B2酶的抑制作用,发现本发明化合物对PDE4B2酶具有抑制作用,其IC
50值小于1μM;进一步发现,本发明部分化合物的对PDE4B2酶的抑制作用的IC
50值小于500nM;更进一步发现,本发明部分化合物的对PDE4B2酶的抑制作用的IC
50值小于200nM。具体地,本发明部分化合物对PDE4B2酶抑制作用的测定结果参见表2。
表2本发明部分化合物对PDE4B2酶抑制作用的测定结果
结论:实验证明,本发明化合物在体外对PDE4B2酶普遍具有较高的抑制作用。
本发明化合物对PMA诱导急性特应性皮炎小鼠模型
取雌性ICR小鼠,体重26-28g,动物适应性饲养7天后,随机分为正常组、模型组和各化合物组,正常组4只,其余每组10只。除正常组小鼠外,其余小鼠用20μL浓度为0.25mg/mL的PMA溶液(溶于无水乙醇)涂抹于右耳造模,正常组涂抹相应溶媒。各化合物组在造模前30min进行第一次给药和造模后15min进行第二次给药,各组动物耳部涂抹20μL浓度为15mg/mL受试药物溶液[乙醇:丙酮=1:1(v/v)],正常组、模型组动物涂抹相应溶媒。在第二次给药6小时后处死动物,每只动物剪下右耳用8mm打耳器 在固定位置获取耳片并进行称重,随后液氮保存耳片,然后加入500μL生理盐水用匀浆机匀浆,离心后取上清,检测上清中的IL-1β和IL-6浓度并归一化蛋白浓度。
具体结果见表3~7:本发明化合物对PMA诱导急性特应性皮炎小鼠耳厚度、耳重量以及耳部炎症因子分泌的影响(Mean±SEM,动物数据N=4 or N=10)
表3化合物对小鼠耳厚度以及耳重量的影响(Mean±Sem)
续表
表4化合物对小鼠耳厚度、耳重量以及炎症因子的影响(Mean±Sem)
续表
表5化合物对小鼠耳厚度、耳重量以及炎症因子的影响(Mean±Sem)
续表
表6化合物对小鼠耳厚度、耳重量以及炎症因子的影响(Mean±Sem)
续表
表7.化合物对小鼠耳厚度、耳重量以及炎症因子的影响(Mean±Sem)
续表
(注:*P<0.05,**P<0.01,vs.模型组;)
由上述实验结果可知,与模型组比较,本发明的化合物均能显著地降低PMA诱导的急性特应性皮炎小鼠耳厚度和耳重量以及耳部炎症因子IL-1β和IL-6的分泌(P<0.05)。
本发明化合物对OXA诱导慢性特应性皮炎小鼠模型
选取雄性Balb/c小鼠,体重24-26g,动物适应性饲养7天后,除正常组外,其余动物在Day 0和Day 1用40μL 1%的OXA溶液(溶于丙酮)涂于小鼠双耳致敏,在Day 7和Day 8用40μL 0.5%的OXA溶液涂于小鼠双耳重复致敏,正常组涂抹相应溶媒。从Day 12开始,除正常组外,其余动物用20μl 0.5%的OXA溶液涂于小鼠右耳进行激发,每周两次,正常组涂抹相应溶媒,每次激发24h后测量右耳厚度。除正常组外,其余动物在第13天根据耳厚度的结果随机分为模型组和各化合物组,正常组5只,其余每组10只。在Day 14开始给药,每天两次,各给药组动物耳部涂抹20μL浓度为15mg/mL受试药物溶液[乙醇:丙酮=1:1(v/v)],正常组、模型组动物涂抹相应溶媒。Day 29测量耳厚度后处死,每只动物剪下右耳用8mm打耳器在固定位置获取耳片并进行称重,随后液氮保存耳片,然后加入500μL生理盐水用匀浆机匀浆,离心后取上清,检测上清中的IL-1β、IL-4、IL-5、IL-6和TNF-α浓度并归一化蛋白浓度。
结果可知,与模型组比较,本发明的化合物从Day 20开始到给药结束均能显著的降低OXA诱导慢性特应性皮炎小鼠耳厚度和终点耳重量以及耳部炎症因子IL-1β、IL-4、IL-5、IL-6和TNF-α的分泌(P<0.01);
对于本领域技术人员显而易见的是,本发明内容并不限于前述说明性实施例,而且可以体现在其它具体形式中而又不偏离其实质特性。因此,预期各实施例在所有方面都被视作说明性的且非限制性的,应参照所附权利要求书,而不是前述实施例,因此,在所附权利要求书等同内容的含义和范围内的所有变化都包括在本发明中。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
最后,需要注意的是,还有其他方式用来实施本发明。相应地,本发明的实施例是将作为例证进行说明,但并不限于本发明所描述的内容,还可能是在本发明范围内所作的修改或在权利要求中所添加的等同内容。本发明所引用的所有出版物或专利都将作为本发明的参考文献。
Claims (16)
- 一种化合物,其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:其中:R 1和R 2各自独立地为氢、氘、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-10个原子组成的杂环基、C 6-10芳基、5-10个原子组成的杂芳基、C 3-8环烷基-C 1-4亚烷基、C 1-6烷基-C(=O)-、C 3-8环烷基-C(=O)-、3-10个原子组成的杂环基-C 1-4亚烷基、C 6-10芳基-C 1-4亚烷基或5-10个原子组成的杂芳基-C 1- 4亚烷基;X和X 1各自独立地为键、-O-、-S-、-N(R c)-、-C(=O)-或-S(=O) t-;R 3为氢、氘、羧基、C 1-6烷基、C 1-6卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、C 6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C 3-8环烷基-C 1-4亚烷基、C 6-10芳基-C 1-4亚烷基、3-10个原子组成的杂环基-C 1-4亚烷基、5-10个原子组成的杂芳基-C 1-4亚烷基、C 1-6烷基-C(=O)-、C 1-6烷基-S(=O) t-、C 1-6烷氧基-C(=O)-、C 3-8环烷基-C(=O)-、C 3-8环烷基-S(=O) t-、3-10个原子组成的杂环基-C(=O)-、3-10个原子组成的杂环基-S(=O) t-、-C(=O)-NR dR e、-S(=O) t-NR dR e、C 6-10芳基-C(=O)-、5-10个原子组成的杂芳基-C(=O)-、C 6-10芳基-S(=O) t-或5-10个原子组成的杂芳基-S(=O) t-,其中R 3未被取代或被1、2、3或4个R 6所取代;各R 6独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氨基或C 1-4烷基-C(=O)-N(R c)-;R 4为-(CH 2) m-L-(CH 2) n-G;L为键、-O-、-S-、-NR x-、-NR x-C(=O)-、-NR x-S(=O) t-、-NR x-C(=O)-NR y-、-NR x-C(=O)-O-、-S(=O) t-、-C(=O)-或-C(=O)-O-;其中,各R x和R y独立地为氢、氘、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、C 6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C 3-8环烷基-C 1-6亚烷基、C 6-10芳基-C 1-6亚烷基、3-10个原子组成的杂环基-C 1-6亚烷基、5-10个原子组成的杂芳基-C 1-6亚烷基、C 1-6烷基-S(=O) t-、C 1-6烷基-C(=O)-或C 1-6烷氧基-C(=O)-C 1-6亚烷基;G为C 3-8环烷基、C 6-10芳基、3-10个原子组成的杂环基或5-10个原子组成的杂芳基;其中G未被取 代或被1、2、3或4个R 7所取代;各R 7独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、羧基、C 1-6烷基、C 1-6卤代烷基、C 1- 6烷氧基、C 1-6烷氨基、-C(=O)-NR aR b、-S(=O) t-NR aR b、C 1-6烷基-C(=O)-N(R c)-、C 1-6烷基-S(=O) t-N(R c)-、C 1-6烷氧基-C(=O)-N(R c)-、C 1-6烷基-C(=O)-、C 1-6烷基-S(=O) t-、C 1-6烷氧基-C(=O)-、C 1-6烷基-C(=O)-O-、C 3-8环烷基、C 6-10芳基、3-10个原子组成的杂环基或5-10个原子组成的杂芳基;各R a和R b独立地为氢、氘、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、C 6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C 3-8环烷基-C 1-6亚烷基、C 6-10芳基-C 1-6亚烷基、3-10个原子组成的杂环基-C 1-6亚烷基、5-10个原子组成的杂芳基-C 1-6亚烷基、C 1-6烷基-S(=O) t-或C 1-6烷基-C(=O)-,其中各R a和R b独立地未被取代或被1、2或3个选自氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、-C(=O)-NH 2、C 1-6烷氧基C(=O)-、C 1-6烷基-C(=O)-N(R c)-、C 1-6烷基-S(=O) t-N(R c)-、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4烷氨基的基团所取代;各R d和R e独立地为氢、氘、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基、C 6-10芳基、3-10个原子组成的杂环基、5-10个原子组成的杂芳基、C 3-8环烷基-C 1-6亚烷基、C 6-10芳基-C 1-6亚烷基、3-10个原子组成的杂环基-C 1-6亚烷基、5-10个原子组成的杂芳基-C 1-6亚烷基、C 1-6烷基-S(=O) t-或C 1-6烷基-C(=O)-,其中各R d和R e独立地未被取代或被1、2或3个选自氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、-C(=O)-NH 2、C 1-6烷氧基C(=O)-、C 1-6烷基-C(=O)-N(R c)-、C 1-6烷基-S(=O) t-N(R c)-、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4烷氨基的基团所取代;各R c独立地为氢、氘、C 1-3烷基或C 1-3卤代烷基;R为氢、氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、C 1-3烷基、C 1-3烷氧基、C 1-3卤代烷氧基或C 1-3卤代烷基;R 5a、R 5b、R 6a和R 6b各自独立地为氢、氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、C 1-3烷基、C 1-3烷氧基、C 1-3卤代烷氧基或C 1-3卤代烷基;t为1或2;n为0、1、2、3或4;m为1、2、3或4。
- 根据权利要求1-3任意一项所述的化合物,其中:R 1和R 2各自独立地为氢、氘、甲基、乙基、正丙基、异丙基、异丁基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CH 2Cl、-CHCl 2、-CH=CH 2、-CH 2CH=CH 2、-C=CH、-CH 2C=CH、环丙基、环丁基、环戊基、环己基、环丙基亚甲基、环丙基亚乙基、环丁基亚甲基、环丁基亚乙基、环戊基亚甲基、环戊基亚乙基、环己基亚甲基、环己基亚乙基、CH 3C(=O)-、CH 3CH 2C(=O)-、CH 3CH 2CH 2C(=O)-、(CH 3) 2CHC(=O)-、环丙基-C(=O)-、环丁基-C(=O)-、环戊基-C(=O)-、环己基-C(=O)-、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C 1-3亚烷基、萘基-C 1-3亚烷基、吡啶基-C 1-3亚烷基、嘧啶基-C 1-3亚烷基、呋喃基-C 1-3亚烷基、噻吩基-C 1-3亚烷基、吡咯基-C 1-3亚烷基、吡唑基-C 1-3亚烷基、噻唑基-C 1-3亚烷基、恶唑基-C 1-3亚烷基、三氮唑基-C 1-3亚烷基、四氮唑基-C 1-3亚烷基、哌嗪基-C 1-3亚烷基、哌啶基-C 1-3亚烷基、吗啉基-C 1-3亚烷基、硫代吗啉基-C 1-3亚烷基、四氢吡喃基-C 1-3亚烷基或吡咯烷基-C 1-3亚烷基;R 3为氢、氘、羧基、C 1-3烷基、C 1-3卤代烷基、C 2-4烯基、C 2-4炔基、CH 3-C(=O)-、CH 3CH 2-C(=O)-、CH 3CH 2CH 2-C(=O)-、(CH 3) 2CH-C(=O)-、CH 3-S(=O) 2-、CH 3CH 2-S(=O) 2-、CH 3CH 2CH 2-S(=O) 2-、(CH 3) 2CH-S(=O) 2-、CH 3-O-C(=O)-、CH 3CH 2-O-C(=O)-、CH 3CH 2CH 2-O-C(=O)-、(CH 3) 2CH-O-C(=O)-、-S(=O) 2-NH 2或-C(=O)-NH 2,其中R 3未被取代或被1、2、3或4个R 6所取代;各R 6独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、甲基、乙基、正丙基、异丙基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CH 2Cl、 -CHCl 2、甲氧基、乙氧基、正丙基氧基、甲氨基、乙氨基或正丙基氨基。
- 根据权利要求1-4任意一项所述的化合物,其中:各R x和R y独立地为氢、氘、甲基、乙基、正丙基、异丙基、C 1-4卤代烷基、环丙基、环丁基、环戊基、环己基、环丙基-C 1-3亚烷基、环丁基-C 1-3亚烷基、环戊基-C 1-3亚烷基、环己基-C 1-3亚烷基、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C 1-3亚烷基、萘基-C 1-3亚烷基、吡啶基-C 1-3亚烷基、嘧啶基-C 1-3亚烷基、呋喃基-C 1-3亚烷基、噻吩基-C 1-3亚烷基、吡咯基-C 1-3亚烷基、吡唑基-C 1-3亚烷基、噻唑基-C 1-3亚烷基、恶唑基-C 1-3亚烷基、三氮唑基-C 1-3亚烷基、四氮唑基-C 1-3亚烷基、哌嗪基-C 1-3亚烷基、哌啶基-C 1-3亚烷基、吗啉基-C 1-3亚烷基、硫代吗啉基-C 1-3亚烷基、四氢吡喃基-C 1-3亚烷基、吡咯烷基-C 1-3亚烷基、C 1-3烷基-S(=O) 2-、C 1-3烷基-C(=O)-或C 1-3烷氧基-C(=O)-C 1-3亚烷基。
- 根据权利要求1-5任意一项所述的化合物,其中:各R 7独立地为氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、羧基、C 1-4烷基、C 1-4卤代烷基、C 1- 4烷氧基、C 1-4烷氨基、-C(=O)-NR aR b、-S(=O) 2-NR aR b、C 1-4烷基-C(=O)-NH-、C 1-4烷基-S(=O) 2-NH-、C 1-4烷氧基-C(=O)-NH-、CH 3-C(=O)-、CH 3CH 2-C(=O)-、CH 3CH 2CH 2-C(=O)-、(CH 3) 2CH-C(=O)-、CH 3CH 2CH 2CH 2-C(=O)-、CH 3-S(=O) 2-、CH 3CH 2-S(=O) 2-、CH 3CH 2CH 2-S(=O) 2-、(CH 3) 2CH-S(=O) 2-、CH 3O-C(=O)-、CH 3CH 2O-C(=O)-、CH 3CH 2CH 2O-C(=O)-、(CH 3) 2CHO-C(=O)-、CH 3CH 2CH 2CH 2O-C(=O)-、CH 3-C(=O)-O-、CH 3CH 2-C(=O)-O-、CH 3CH 2CH 2-C(=O)-O-、(CH 3) 2CH-C(=O)-O-、CH 3CH 2CH 2CH 2-C(=O)-O-、环丙基、环丁基、环戊基、环己基、
- 根据权利要求1-6任意一项所述的化合物,其中:各R a和R b独立地为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CH 2Cl、-CHCl 2、苯基、萘基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、恶唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、苯基-C 1-3亚烷基、萘基-C 1-3亚烷基、吡啶基-C 1-3亚烷基、嘧啶基-C 1-3亚烷基、呋喃基-C 1-3亚烷基、噻吩基-C 1-3亚烷基、吡咯基-C 1-3亚烷基、吡唑基-C 1-3亚烷基、噻唑基-C 1-3亚烷基、恶唑基-C 1-3亚烷基、三氮唑基-C 1-3亚烷基、四氮唑基-C 1-3亚烷基、哌嗪基-C 1-3亚烷基、哌啶基-C 1-3亚烷基、吗啉基-C 1-3亚烷基、硫代吗啉基-C 1-3亚烷基、四氢吡喃基-C 1-3亚烷基、吡咯烷基-C 1- 3亚烷基、C 1-3烷基-S(=O) 2-或C 1-3烷基-C(=O)-;其中各R a和R b独立地未被取代或被1、2或3个选自氘、-F、-Cl、-Br、-I、羟基、氨基、氰基、氧代、-C(=O)-NH 2、C 1-3烷氧基C(=O)-、C 1-3烷基-C(=O)-NH-、C 1- 3烷基-S(=O) t-NH-、甲基、乙基、正丙基、异丙基、正丁基、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CHF 2、-CH 2CF 3、-CH 2CH 2CH 2F、-CH 2CH 2CHF 2、-CH 2CH 2CF 3、-CH 2Cl、-CHCl 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、N-甲基氨基、N-乙基氨基、N’N-二甲基氨基、N’N-二乙基氨基或N’N-甲基乙基氨基的基团所取代。
- 一种药物组合物,包含权利要求1-8任意一项所述的化合物,任选地,其进一步地包含药学上可接受的载体、赋形剂、附加剂、辅剂和媒介物中的至少一种。
- 根据权利要求9所述的药物组合物,其进一步地包含附加治疗剂,其中所述的附加治疗剂是:丙酮酸钠、多索茶碱、替托司特、泰鲁司特、茶碱、福莫特罗、沙美特罗、氟替卡松丙酸酯、咯利普兰、吡拉米斯特、西洛司特、茚达特罗、奥达特罗、米地司坦、齐流通、沙丁醇胺、卡莫昔罗、布地奈德、二丙酸倍氯米松、曲安奈德、氟尼缩松、糠酸莫米松、罗氟奈德、环索奈德、异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、芜地溴铵、维兰特罗、阿地溴铵、Benralizumab、Tralokinumab、瑞伐托酯、克瑞沙硼、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、地索奈德、氢化可的松、氯倍他索、 卤贝他索、二氟拉松、美普克莱、他克莫司、吡美莫司、他扎罗汀、环孢素、阿普斯特、E-6005、OPA-15406、LEO-29102、DRM02、罗氟司特、异丁司特、托法替尼、JTE-052、巴瑞替尼、乌帕替尼、WBI-1001、MRX-6、GSK2981278、杜鲁单抗、来金珠单抗、尼莫利珠单抗、曲洛吉努单抗、依那西普、阿达木单抗、英夫利昔单抗、尤特可单抗、塞库吉努、奥马珠、CIM-331、戈利木单抗和聚乙二醇化赛、妥珠单抗、卡泊三醇、骨化三醇、阿利维A酸、VTP-38543、ZPL-389、阿瑞匹坦、曲地匹坦、弗维普兰特、OC-459、SUN13834、SB-011、VTP-43742、ARN6039、TAK-828、JTE-451、PF-04965842、PF-06651600、PF-06700841、PF-06650833、GR-MD-02或它们的组合。
- 权利要求1-8任意一项所述的化合物或权利要求9-10任意一项所述的药物组合物在制备药物中的用途,其中所述药物用于预防、治疗或减轻与4型磷酸二酯酶有关的疾病。
- 根据权利要求11所述的用途,其中所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病、肺纤维化或非胰岛素依赖糖尿病;其中所述的呼吸疾病为:慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症;其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎;其中所述的炎症为:过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。
- 一种预防、治疗或减轻与4型磷酸二酯酶有关的疾病的方法,其包含给予患者权利要求1-8任意一项所述的化合物或权利要求9-10任意一项所述的药物组合物的有效治疗量。
- 根据权利要求13所述的方法,其中所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病、肺纤维化或非胰岛素依赖糖尿病;其中所述的呼吸疾病为:慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症;其中支气管炎为急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎;其中所述的炎症为:过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。
- 根据权利要求1-8任意一项所述的化合物或权利要求9-10任意一项所述的药物组合物用于预防、治疗或减轻患者4型磷酸二酯酶有关的疾病。
- 根据权利要求15所述的化合物或药物组合物,其中所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病、肺纤维化或非胰岛素依赖糖尿病;其中所述的呼吸疾病为:慢性阻塞性肺疾病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症;其中支气管炎为急性支 气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎;其中所述的炎症为:过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。
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