WO2021036953A1 - 苯基吡咯烷类化合物 - Google Patents

苯基吡咯烷类化合物 Download PDF

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WO2021036953A1
WO2021036953A1 PCT/CN2020/110622 CN2020110622W WO2021036953A1 WO 2021036953 A1 WO2021036953 A1 WO 2021036953A1 CN 2020110622 W CN2020110622 W CN 2020110622W WO 2021036953 A1 WO2021036953 A1 WO 2021036953A1
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group
diseases
compound
pde4
membered
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French (fr)
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张学军
李莉娥
沈洁
付强强
孙红娜
叶大炳
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湖北生物医药产业技术研究院有限公司
人福医药集团股份公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a novel phenylpyrrolidine compound, its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, its preparation method, and pharmaceutical compositions containing them as well as PDE4 inhibitors
  • the purpose of the agent is to a novel phenylpyrrolidine compound, its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, its preparation method, and pharmaceutical compositions containing them as well as PDE4 inhibitors The purpose of the agent.
  • Phosphodiesterase (abbreviated as PDE), or more precisely 3', 5'-cyclic nucleotide phosphodiesterase, is the second messenger cAMP (cyclic adenosine acid) and cGMP (cyclic guanosine acid) Hydrolysis to 5'-AMP (5'-adenosine monophosphate) and 5'-GMP (5'-guanosine monophosphate) enzymes.
  • PDE4 is the most important regulator of cAMP expressed in immune and inflammatory cells such as neutrophils, macrophages and T-lymphocytes (Z.
  • PDE4 can regulate the inflammation of inflammatory cells by regulating pro-inflammatory cytokines (such as TNF ⁇ , IL-2, IFN- ⁇ , GM-CSF and LTB4) reaction. Inhibition of PDE4 can effectively treat asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, inflammatory bowel diseases such as Crohn's disease (Crohn's disease), atopic dermatitis (AD) and other inflammations Sexual disease.
  • COPD chronic obstructive pulmonary disease
  • rheumatoid arthritis rheumatoid arthritis
  • atopic dermatitis inflammatory bowel diseases such as Crohn's disease (Crohn's disease)
  • AD atopic dermatitis
  • PDE4 includes PDE4A, PDE4B, PDE4C, PDE4D and other subtypes. Inhibition of PDE4D can cause side effects such as vomiting, and selective inhibition of PDE4B can improve the occurrence of side effects of vomiting (Osamu Suzuki et al., J Pharmacol Sci 123, 219-226, 2013).
  • cyclic nucleotides are important second messengers for regulating smooth muscle contractility.
  • Cyclic nucleotide phosphodiesterase (PDE) hydrolyzes cyclic nucleotides and is important in regulating the level of cyclic nucleotides in cells and the duration of action. Compounds that inhibit PDE increase the cellular level of cyclic nucleotides, thereby relaxing many types of smooth muscle. Studies have shown that phosphodiesterase 4 (PDE4) can specifically hydrolyze cAMP, and it is abundantly expressed in the bladder.
  • PCT patent application WO2016040083A1 discloses some azetidinyloxyphenylpyrrolidine compounds, which can be used as PDE4 inhibitors to treat overactive bladder (OAB) and related symptoms, such as frequent urination and urgency, and others Alleviation of illness.
  • OAB overactive bladder
  • the inventors of the present invention have synthesized a novel compound that can inhibit the activity of PDE4B and PDE4D.
  • the compound can be used to prepare PDE4 inhibitors with novel structure, excellent efficacy, high bioavailability, and good druggability.
  • PDE4 inhibitors can be used to inhibit the activity of PDE4 and up-regulate the level of cAMP in immune and inflammatory cells, thereby Reduce the release of pro-inflammatory cytokines, which in turn reduces the inflammatory response.
  • the compounds provided by the present invention can effectively treat diseases and disorders related to PDE4, including but not limited to inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritis diseases, skin inflammatory diseases, inflammatory diseases Intestinal diseases and diseases related to smooth muscle contractility.
  • the present invention provides a compound which is a compound represented by general formula (A-1) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or a compound represented by general formula (A-1) Prodrug:
  • R 1 is selected H, unsubstituted or optionally substituted by at least one R a group of the following: C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 6 - C 20 aryl, 5-20 membered heteroaryl;
  • Each of said at least one of R a same or different and are independently selected from F, Cl, Br, I, OH, CN, O, NO 2, unsubstituted or optionally substituted by at least one R b is a group of the following Group: -NH 2 , C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 6 -C 20 aryl, C 6 -C 20 aryloxy, 5-20 membered hetero Aryl, 5-20 membered heteroaryloxy;
  • R 2 is selected from the following groups H, unsubstituted or optionally substituted with at least one R c : C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclic group, C 6- C 20 aryl, 5-20 membered heteroaryl;
  • R 1 is not methyl, ethyl, or isopropyl.
  • the inventors through a large number of experimental explorations, synthesized a new type of compound of general formula (A-1), and found that the compound can inhibit the activity of PDE4 subtypes PDE4D and PDE4B. Since PDE4 can specifically hydrolyze cAMP in cells, the compounds of the present invention can increase the level of cAMP in immune and inflammatory cells by inhibiting the activity of PDE4, thereby reducing pro-inflammatory cytokines (such as TNF ⁇ , IL-2, The release of IFN- ⁇ , GM-CSF and LTB4, etc.), which in turn reduces the inflammatory response.
  • pro-inflammatory cytokines such as TNF ⁇ , IL-2, The release of IFN- ⁇ , GM-CSF and LTB4, etc.
  • the compounds of the present invention can be used to regulate the level and duration of action of cAMP in cells by inhibiting the activity of PDE4, and then relax various types of smooth muscle.
  • the compound of the general formula (A-1) of the present invention can be used to treat diseases and disorders related to PDE4, including but not limited to inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritis Diseases, skin inflammatory diseases, inflammatory bowel disease, and diseases related to smooth muscle contractility.
  • the present invention provides a compound represented by general formula (A), its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
  • R 1 is selected from H, unsubstituted or optionally substituted with one or more substituents R a following groups: C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 20 aryl, 5-20 membered heteroaryl;
  • R 1 is not methyl, ethyl, or isopropyl.
  • R 1 is selected from a C 1 -C 10 alkyl group that is unsubstituted or optionally substituted with at least one Ra , C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclic group;
  • R 2 is selected from the group consisting of H, unsubstituted or optionally substituted with at least one R c : C 1 -C 10 alkyl, C 3- C 10 cycloalkyl, 3-10 membered heterocyclic group;
  • R 2 is selected from the group consisting of H, unsubstituted or optionally substituted with at least one R c : C 1 -C 10 alkyl, C 3- C 10 cycloalkyl;
  • R 2 is selected from the group consisting of H, unsubstituted or optionally substituted with at least one R c : C 1 -C 5 alkyl, C 3- C 5 cycloalkyl;
  • R 2 is selected from the group consisting of H, unsubstituted or optionally substituted with at least one R c : C 1 -C 5 alkyl, C 3- C 5 cycloalkyl;
  • Each of the at least one R c is the same or different and is independently selected from F, Cl, Br, and I, respectively.
  • the compound is selected from one of the following structures:
  • novel compounds provided by the present invention can inhibit the activity of PDE4 subtypes PDE4B and PDE4D.
  • inhibition of PDE4D can cause side effects such as vomiting
  • compounds 001, 003, 004, 005 and 006 can selectively inhibit the activity of PDE4B, thereby effectively improving the occurrence of side effects such as vomiting.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (A-1) and/or (A) or its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.
  • the pharmaceutical composition further includes pharmaceutically acceptable excipients, such as pharmaceutically acceptable carriers, diluents or excipients.
  • the compounds provided by the present invention are used to prepare drugs in various dosage forms, which are administered to subjects in a therapeutically effective amount. After the drugs are absorbed by the subjects, they can increase intracellular cAMP levels, thereby affecting the pro-inflammatory cytokine levels. Release and smooth muscle state, thereby treating or ameliorating diseases related to PDE4.
  • the pharmaceutical composition further comprises one or more other therapeutic agents.
  • the other therapeutic agents have similar functions to the compounds of the present invention, and can be used to treat diseases related to PDE4.
  • the present invention relates to suitable pharmaceutically acceptable salts of compounds represented by general formula (A-1) or (A), including but not limited to hydrochloride, hydrobromide, sulfate or hydrogen sulfate, phosphate or Hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate Acid salt or p-toluenesulfonate.
  • any of the compounds of the present invention mentioned herein include pharmaceutically acceptable salts, solvates, or combinations thereof.
  • the present invention also includes other salts. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used in the identification, characterization or purification of the compounds of the present invention.
  • the present invention relates to the compound represented by the general formula (A-1) or (A), its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, in the preparation of therapeutics and phosphodiesterase -4 (PDE4) Use in medicines related to diseases.
  • the disease related to phosphodiesterase-4 is selected from the group consisting of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritic diseases, skin inflammatory diseases, Inflammatory bowel disease and diseases related to smooth muscle contractility.
  • the allergic disease is selected from asthma, chronic bronchitis, chronic obstructive pneumonia, allergic rhinitis, adult respiratory distress syndrome.
  • the skin inflammatory disease is selected from idiopathic dermatitis, psoriasis or urticaria.
  • the arthritis disease is selected from rheumatoid arthritis, osteoarthritis, gouty arthritis or spondylitis.
  • the inflammatory bowel disease is selected from ulcerative colitis or Crohn's disease.
  • the disease related to smooth muscle contractility is selected from overactive bladder and related symptoms, such as frequent urination and urgency.
  • the present invention also provides the use of the compound represented by the general formula (A-1) or (A), its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, and prodrugs in the treatment of diseases related to PDE4.
  • the diseases related to PDE4 are selected from the group consisting of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritic diseases, skin inflammatory diseases, inflammatory bowel diseases, and Diseases related to smooth muscle contractility.
  • the diseases related to PDE4 are selected from asthma, chronic bronchitis, chronic obstructive pneumonia, allergic rhinitis, adult respiratory distress syndrome, idiopathic dermatitis, psoriasis, urticaria, Rheumatoid arthritis, osteoarthritis, gouty arthritis or spondylitis, ulcerative colitis, Crohn’s disease, overactive bladder.
  • the present invention also provides a method for treating diseases related to PDE4 by administering the pharmaceutical composition to patients suffering from diseases related to PDE4.
  • the diseases related to PDE4 are selected from the group consisting of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection, arthritic diseases, skin inflammatory diseases, inflammatory bowel diseases, and Diseases related to smooth muscle contractility.
  • the diseases related to PDE4 are selected from asthma, chronic bronchitis, chronic obstructive pneumonia, allergic rhinitis, adult respiratory distress syndrome, idiopathic dermatitis, psoriasis, urticaria, Rheumatoid arthritis, osteoarthritis, gouty arthritis or spondylitis, ulcerative colitis, Crohn’s disease, overactive bladder.
  • the present invention also relates to a method for treating diseases related to phosphodiesterase-4 (PDE4), which comprises administering to a patient a therapeutically effective dose of a pharmaceutical preparation containing the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • PDE4 phosphodiesterase-4
  • salts derived from inorganic bases include, but are not limited to, metal salts formed by Al, Ca, Li, Mg, K, Na, and Zn; salts derived from organic bases include, but are not limited to, salts of primary, secondary or tertiary amines, including Naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins, such as ammonium, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, Dimethylethanolamine, 2-Dimethylaminoethanol, 2-Diethylaminoethanol, Dicyclohexylamine, Caffeine, Procaine, Choline, Betaine, Benminicillin, Ethylenediamine, Glucosamine, Organic salts
  • stereoisomer refers to the isomers produced by the different arrangements of atoms in the molecule in space, including cis and trans isomers, enantiomers, diastereomers and conformational isomers.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more mutually convertible species.
  • Proton shift tautomers result from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in an equilibrium form. An attempt to separate a single tautomer usually produces a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties of the molecule.
  • the ketone type is dominant; in phenol, the enol type is dominant.
  • the present invention encompasses all tautomeric forms of the compound.
  • pharmaceutical composition means a mixture of one or more of the compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically/pharmaceutically acceptable Carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the compound to the organism, which is conducive to the absorption of the active ingredient and thus the biological activity.
  • solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces.
  • solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted into a biologically active compound under physiological conditions or by solvolysis.
  • the prodrug of the present invention is prepared by modifying the functional group in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • Prodrugs include compounds formed by connecting a hydroxyl group or amino group to any group in the compound of the present invention. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form a free hydroxyl group and a free group, respectively. The amino group.
  • C 1 -C 10 alkyl should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-d
  • C 2 -C 10 alkynyl should be understood to preferably mean a linear or branched monovalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 Or 10 carbon atoms.
  • C 3 -C 10 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3-10 carbon atoms. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as decalin ring.
  • C 3 -C 6 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which has 3 to 6 carbon atoms.
  • heterocyclic group means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclic group may include but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or trithiaalkyl; or a 7-membered ring, such as diazacycloheptanyl.
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5, 5-membered ring, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5, 6-membered bicyclic ring, such as hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing the nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadi Azinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
  • the heterocyclic group is non-aromatic.
  • C 6 -C 20 aryl should be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6-20 carbon atoms.
  • a ring having 6 carbon atoms such as phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or having 10
  • a ring with three carbon atoms such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or a ring with 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or Is a ring with 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6 -C 20 aryloxy group means that it is connected to at least one oxy group "-O-" on the basis of the aforementioned "C 6 -C 20 aryl group”.
  • 5-20 membered heteroaryl should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5-20 ring atoms and containing 1-5 independently selected from N, O And S heteroatoms, for example "5-14 membered heteroaryl”.
  • the term “5-14 membered heteroaryl” should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and it contains 1-5, preferably 1-3 heteroatoms each independently selected from the group consisting of N, O and S, in addition in each case Can be benzo-fused.
  • the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, thio-4H-pyrazolyl, etc.
  • 5-20 membered heteroaryloxy group refers to the connection with at least one oxy group "-O-" on the basis of the aforementioned "5-20 membered heteroaryl group”.
  • excipients refers to pharmaceutically acceptable inert ingredients.
  • Non-limiting examples of the types of the term “excipient” include binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical preparation, that is, make the preparation more suitable for direct compression by increasing fluidity and/or adhesion.
  • Examples of typical "pharmaceutically acceptable carriers” suitable for the above formulations are: sugars, such as lactose, sucrose, mannitol, and sorbitol; starches, such as corn starch, tapioca starch, and potato starch; cellulose and its derivatives Substances, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid ; Alkaline earth metal stearates, such as magnesium stearate and calcium stearate; stearic acid; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants ; Glycol polymers; fatty alcohols; and grain hydrolyzed solids and other non-toxic compatible fillers
  • the present invention also relates to a method for preparing the compound of general formula (A) of the present invention, which method comprises:
  • R 1 is defined as described above;
  • X is halogen, such as Cl, Br, I, etc.;
  • the structure of formula (IV) is Wherein, the compound of formula (I) is coupled with azetidin-3-ol or its salt under catalyst conditions to obtain the compound of formula (II); the compound of formula (II) is reacted with methylsulfonyl chloride to obtain the compound of formula (III) ) Compound, the compound of formula (III) further undergoes a nucleophilic substitution reaction with the compound of formula (IV) to obtain the compound of formula (V), and the compound of formula (V) removes the protective agent under acidic conditions to obtain the target compound (A).
  • the synthetic route and preparation method of formula (IV) refer to the synthetic methods disclosed in patent applications WO2001047905A1, CN106795137A and the journal documents Nichols, P.J.; DeMattei, J.A. Org. Lett. 2006, 8, 1495-1498.
  • the synthetic route and preparation method of the compound of general formula (A-1) provided by the present invention are similar to the aforementioned method of preparing the compound of general formula (A), except that the starting materials during synthesis are different, that is, the above-mentioned formula (I) The compounds are different.
  • Figure 1 shows the clinical scores of the G1, G2, G3 and G4 groups in the mouse CIA arthritis model experiment
  • Figure 2 shows the AUC inhibition rate of the clinical scores in the G2, G3 and G4 groups in the mouse CIA arthritis model experiment.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • N equivalent concentration, for example, 1N hydrochloric acid means 1mol/L hydrochloric acid solution
  • PE Petroleum ether
  • Ms methylsulfonyl
  • LPS Lipopolysaccharide, lipopolysaccharide (endotoxin)
  • PBMC peripheral blood mononuclear cells
  • TNF ⁇ tumor necrosis factor ⁇
  • PBS phosphate buffered saline
  • FBS fetal bovine serum
  • IC 50 The half inhibition concentration refers to the concentration at which half of the maximum inhibition effect is reached.
  • the third step ((3S,4S)-4-(3-((1-(5-cyclopropoxypyridin-2-yl)azetidinyl)oxy)-4-methoxyphenyl)- 3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl)((S)-2,2-dimethyl-1,3-dioxolane-4 -Yl) ketone (001D) synthesis
  • the fourth step (S)-1-((3S,4S)-4-(3-((1-(5-cyclopropoxypyridin-2-yl)azetidin-3-yl)oxy )-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)3-methylpyrrolidin-1-yl)-2,3-dihydroxypropane-1-one (target compound 001 ) Synthesis (target compound 001) synthesis
  • Dibromohydantoin (50.5g, 176.4mmol) was added to 300mL DCM at room temperature, cooled to -78°C, 70% pyridine hydrofluoric acid solution (400mL, 3136.8mmol) was added at low temperature, and stirred for 45min. Slowly drip O-(6-bromo-2-methylpyridin-3-yl) methyl mercaptothiocarbonate (005C) (10.9g, 39.2mmol) in 100mL DCM solution, and slowly warm up to -5 after dripping °C, stir for 1.5h.
  • Step 5 Synthesis of 1-(6-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidine-3-yl methanesulfonate (005F)
  • the sixth step ((S)-2,2-dimethyl-1,3-dioxolane-4-yl)((3S,4S)-3-((R)-1-hydroxyethyl Yl)-4-(4-methoxy-3-((1-(6-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy (Yl)phenyl)-3-methylpyrrolidin-1-yl)methanone (005G)
  • the seventh step (S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-( (1-(6-Methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidine-1- Base) synthesis of propan-1-one (005)
  • Dibromohydantoin (37.0g, 129.5mmol) was added to 300mL DCM at room temperature, cooled to -78°C, 60% pyridine hydrofluoric acid solution (368mL, 2473.6mmol) was added at low temperature, and stirred for 45min. Slowly drip O-(6-bromo-4-methylpyridin-3-yl) S-methyl dithiocarbonate (006C) (8.0g, 28.7mmol) in 100mL DCM solution, and slowly heat up after dripping To -5°C, stir for 1.5h.
  • Step 5 Synthesis of 1-(4-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl methanesulfonate (006F)
  • the seventh step (S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-( (1-(4-Methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl ) Synthesis of propan-1-one (006)
  • the inhibitory activity of the positive control compound and the compounds 001-006 provided by the present invention on PDE4B and PDE4D can be detected by using the PDE-Glo Phosphodiesterase Assay Kit (promega, V1361). To put it simply, first prepare a 10mM concentrated stock solution of the compound to be tested in DMSO solvent, and then dilute it into a 10 ⁇ working solution with the Reaction buffer provided by the kit. Operate on ice, use Reaction buffer to dilute PDE4B enzyme (Enzo Life Sciences, BML-SE522-0020) to a concentration of 1ng/ ⁇ L, and PDE4D enzyme (Enzo Life Sciences, BML-SE523-0020) to a concentration of 4ng/ ⁇ L .
  • Table 1 shows the inhibitory activity of the positive control compound, the compounds 001 to 006 provided by the present invention, on PDE4B and PDE4D determined by the enzyme activity experiment.
  • Example 8 LPS induces human PBMC to secrete TNF ⁇ model test
  • PBMC extraction process obtain fresh human peripheral blood concentrate, draw 1 unit of human peripheral blood concentrate (concentrated from 200cc peripheral blood), add 0.9% normal saline to a total volume of 120ml, and mix well. Take a 50ml centrifuge tube, add 15ml Lymphoprep TM separately , hold the centrifuge tube at an angle of about 45 degrees, draw 30ml of the diluted concentrated blood, carefully and slowly adhere to the wall, so that the diluted blood overlaps the layering solution, avoiding dilution The blood mixes into the separation liquid or breaks through the liquid surface of the separation liquid. The ratio of Lymphoprep TM to diluted blood is 1:2.
  • centrifuge tube Place the centrifuge tube in a horizontal centrifuge (eppendorf, 5810R), and centrifuge at 800g for 20 minutes at 20°C, with the rising speed set to 1, and the falling speed set to 0. Carefully remove the centrifuge tube. Directly insert the Pasteur pipette deep into the albuginea layer to absorb PBMC. Add 3 times the volume of 0.9% saline or PBS (without calcium and magnesium), gently pipetting to mix. After mixing, centrifuge at 250g for 10 min at 20°C to remove the platelets remaining in the cell suspension, remove the supernatant, and suspend the cell pellet in 20ml PBS, and count by trypan blue staining.
  • PBMC screening process Centrifuge the PBMC obtained in step 1, remove PBS, and then resuspend the count in complete medium (RPMI1640+10%FBS+1%P/S). The cells were inserted at 5 ⁇ 10 4/ well and 100 ⁇ L/well. The compound to be screened is formulated to 4 ⁇ at the final concentration. Add 50 ⁇ L/well to the cells. Pre-incubate for 30 minutes in advance. At the same time, set a control well without adding compound. The final concentration of LPS for stimulation is 10ng/ml, prepared as 4 ⁇ , and added to the cells at 50 ⁇ l/well. At the same time, set the control wells without adding LPS wells. Continue to incubate the cells and collect 10% supernatant for detection at 24h. The collected supernatant was tested according to Invitrogen's Human TNF ⁇ kit (REF: 88-7346-88).
  • the inhibitory activity of the positive control compound, the compounds 001 to 006 provided by the present invention, on LPS-induced TNF ⁇ secretion from human PBMC was determined according to the above method.
  • Test compound IC 50 (nM) Positive control group 3.32 001 0.96 002 1.45 003 1.67 004 5.32 005 0.63 006 0.50
  • the experimental results show that, compared with the positive control group, the compounds 001 ⁇ 003 and 005, 006 of the present invention have better inhibitory activity of human PBMC secreting TNF ⁇ , can better inhibit the secretion of inflammatory factor TNF ⁇ in human PBMC, and have more prominent The anti-inflammatory effect.
  • Compound 004 has an inhibitory activity on the secretion of TNF ⁇ from human PBMC, which is equivalent to that of the positive control group, and can also inhibit the secretion of the inflammatory factor TNF ⁇ in human PBMC, and has an anti-inflammatory effect.
  • mice Take 18 Balb/c mice, age: 6-8 weeks, randomly assigned to blank group, model group and administration group, orally orally give vehicle (blank group, model group) or 50mg/kg compound (given The drug group, the positive control group was given a dose of 100 mg/kg).
  • vehicle the positive control group was given a dose of 100 mg/kg.
  • PBS blank group
  • 1 mg/kg LPS model group and administration group
  • the mouse TNF ⁇ detection kit (Mouse TNF ⁇ ELISA kit: Biolegend, Cat: 430904) was used to detect the serum TNF ⁇ level.
  • the compound's release inhibitory activity on TNF ⁇ was calculated based on the serum TNF ⁇ level.
  • Compound inhibitory activity % ⁇ 1-(administration group TNF ⁇ concentration-blank group TNF ⁇ concentration)/(model group TNF ⁇ concentration-blank group TNF ⁇ concentration) ⁇ 100
  • mice 9 male CD-1 mice, 20-25g, fasted overnight, orally administered 10 mg/kg by gavage. Three mice were taken at each time point of blood collection, and a total of 9 mice were taken alternately before the administration and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after the administration. The blood sample was centrifuged at 8000 rpm for 6 minutes at 4°C, and the plasma was collected and stored at -20°C.
  • the experimental results showed that, compared with the compounds in the positive control group, the compounds 001 and 002 of the present invention showed better plasma exposure. Both Cmax and AUC0-t were better than those in the positive control group. Cmax was about twice that of the positive control group. The exposure amount AUC0-t is about 3 times that of the positive control; the compound of the present invention has excellent pharmacokinetic properties.
  • acetic acid Dilute 2N acetic acid to 100mM, filter with 0.22 micron filter membrane, and store at 4°C.
  • bovine type II collagen solution dissolve bovine type II collagen (CII) in 100 mM acetic acid solution and store at 4°C overnight. The final concentration of collagen is 8 mg/mL.
  • Preparation of emulsion Mix the CII solution stored overnight with an equal volume of complete Freund's adjuvant, use a high-speed homogenizer, and homogenize on ice at 30,000 revolutions per minute for approximately 60 minutes, until the solution forms a stable emulsion.
  • mice induced by arthritis were randomly grouped according to their body weight, so that the average body weight of each group was consistent, and they were randomly divided into 4 treatment groups for administration, with 10 mice in each group.
  • G1 is a normal mouse without any treatment; G2 group was given a blank vehicle; G3 and G4 groups were given a compound (positive control compound and compound 002), at a dose of 30 mg/kg, twice a day for a total of 21 days.
  • the volume of intragastric administration is 10 mL/kg.
  • the mice After boosting the immunity, observe the mouse disease every day.
  • the clinical score is based on the different degree of the disease (redness, joint deformation) according to the standard of 0-4 points, the highest score for each limb is 4 points, and each animal The maximum score is 16 points. Score at least three times a week.
  • Inhibition rate% 1-(administration group AUC/blank vehicle group AUC)*100%
  • the experimental data is expressed by Mean ⁇ SEM, and the clinical score is expressed by One-way ANOVA. P ⁇ 0.05 is considered as a significant difference.
  • Figure 1 and Figure 2 show the results of the clinical score and the AUC inhibition rate of the clinical score for each group
  • Table 6 shows the results of the clinical score and the AUC inhibition rate of the clinical score at the end of the experiment.

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Abstract

本发明提供了苯基吡咯烷类化合物，即通式(A-1)或(A)所示化合物，以提供结构新颖、药效优良、生物利用度高、成药性好的PDE4抑制剂，用于有效治疗PDE4相关的疾病、病症，包括但不限于炎性疾病、变应性疾病、自身免疫性疾病、移植排斥反应、关节炎性疾病、皮肤炎性疾病、炎症性肠病以及与平滑肌收缩性相关的疾病等。 (A-1) (A)

Description

苯基吡咯烷类化合物
优先权信息
本申请请求于2019年8月23日向中国国家知识产权局提交的、专利申请号为201910787733.7、申请名称为“苯基吡咯烷类化合物”的中国专利申请的优先权，并且其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种新型的苯基吡咯烷类化合物，及其立体异构体、水合物、溶剂化物、药学可接受的盐或前药、其制备方法以及含有它们的药物组合物以及作为PDE4抑制剂的用途。
背景技术
磷酸二酯酶(缩写为PDE)，或更精确地为3'，5'-环核苷酸磷酸二酯酶，是催化第二信使cAMP(环腺苷酸)和cGMP(环鸟苷酸)水解为5'-AMP(5'-腺苷一磷酸)和5'-GMP(5'-鸟苷一磷酸)的酶。在至今已鉴别出的11种磷酸二酯酶中，其中PDE4、PDE7和PDE8对于cAMP有特异性。PDE4是免疫和炎性细胞如嗜中性粒细胞、巨噬细胞和T-淋巴细胞中表达的cAMP的最重要的调节剂(Z.Huang,Current Med Chem,13,2006,第3253-3262页)。由于cAMP为炎性反应调节的关键性第二信使，已发现PDE4可以通过调节促炎细胞因子(例如TNFα、IL-2、IFN-γ、GM-CSF和LTB4)来调节炎性细胞的炎性反应。抑制PDE4能有效治疗哮喘、慢性阻塞性肺病(COPD)、类风湿性关节炎、特应性皮炎、炎性肠病如克罗恩氏病(Crohn’s disease)、特应性皮炎(AD)等炎性疾病。PDE4包括PDE4A、PDE4B、PDE4C、PDE4D等多种亚型，抑制PDE4D会导致呕吐等副反应，选择性的抑制PDE4B能改善呕吐副作用的发生(Osamu Suzuki等,J Pharmacol Sci 123,219-226,2013)。
此外，环核苷酸(cAMP和cGMP)为调节平滑肌收缩性的重要的第二信使。环核苷酸磷酸二酯酶(PDE)水解环核苷酸，并且在调节细胞内环核苷酸的水平以及作用的持续时间中是重要的。抑制PDE的化合物提升了环核苷酸的细胞水平，从而松弛多种类型的平滑肌。研究显示，磷酸二酯酶4(PDE4)可特异性水解cAMP，并且其在膀胱中大量表达。PCT专利申请WO2016040083A1公开了一些氮杂环丁烷基氧基苯基吡咯烷类化合物，其作为PDE4的抑制剂可用于治疗膀胱过度活动症(OAB)及其相关症状，例如尿 频和尿急和其他病症的缓解。
尽管目前对炎性疾病、变应性疾病、自身免疫性疾病等疾病的治疗取得了一定的进展，但仍有大量的患者需要更优、更有效的临床治疗药物和方案。
发明内容
本发明的发明人合成了一种新型化合物，该化合物能够抑制PDE4B和PDE4D的活性。鉴于此，利用该化合物可制备结构新颖、药效优良、生物利用度高、成药性好的PDE4抑制剂，利用PDE4抑制剂抑制PDE4的活性，以上调免疫和炎性细胞中cAMP的水平，从而降低促炎细胞因子的释放，继而降低炎性反应。本发明提供的化合物可有效治疗与PDE4相关的疾病、病症，包括但不限于炎性疾病、变应性疾病、自身免疫性疾病、移植排斥反应、关节炎性疾病、皮肤炎性疾病、炎症性肠病以及与平滑肌收缩性相关的疾病等。
本发明提供一种化合物，所述化合物为通式(A-1)所示化合物或者通式(A-1)所示化合物的立体异构体、水合物、溶剂化物、药学可接受的盐或前药：
Figure PCTCN2020110622-appb-000001
其中，
R 1选自H、无取代或任选被至少一个R a取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 6-C 20芳基、5-20元杂芳基；
所述至少一个R a的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、无取代或任选被至少一个R b取代的下列基团：-NH 2、C 1-C 10烷基、C 1-C 10烷氧基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 10环烷基、C 3-C 10环烷基氧基、3-10元杂环基、3-10元杂环基氧基、C 6-C 20芳基、C 6-C 20芳基氧基、5-20元杂芳基、5-20元杂芳基氧基；
所述至少一个R b的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、或下列基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 20芳基、5-20元杂芳基；
R 2选自H、无取代或任选被至少一个R c取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 6-C 20芳基、5-20元杂芳基；
所述至少一个R c的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、CN、 ＝O、NO 2、NH 2，
前提是，当R 2为H时，R 1不为甲基、乙基、异丙基。
发明人通过大量的实验探索，合成一种新型的通式(A-1)的化合物，且发现该化合物可抑制PDE4的亚型PDE4D和PDE4B的活性。由于PDE4可特异性水解细胞中的cAMP，因此，利用本发明化合物，通过抑制PDE4的活性，可上调免疫和炎性细胞中cAMP的水平，从而降低促炎细胞因子(如TNFα、IL-2、IFN-γ、GM-CSF和LTB4等)的释放，继而降低炎性反应。另一方面，由于cAMP是调节平滑肌收缩性的重要的第二信使，利用本发明中化合物通过抑制PDE4的活性，以调节细胞内cAMP的水平和作用持续时间，继而松弛多种类型的平滑肌。鉴于此，本发明中通式(A-1)的化合物可用于治疗与PDE4相关的疾病、病症，包括但不限于炎性疾病、变应性疾病、自身免疫性疾病、移植排斥反应、关节炎性疾病、皮肤炎性疾病、炎症性肠病以及与平滑肌收缩性相关的疾病等。
本发明提供一种通式(A)所示化合物，其立体异构体、水合物、溶剂化物、药学可接受的盐或前药：
Figure PCTCN2020110622-appb-000002
其中R 1选自H、无取代或任选被一个或多个R a取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 6-C 20芳基、5-20元杂芳基；
每一个R a相同或不同，彼此独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、无取代或任选被一个或多个R b取代的下列基团：-NH 2、C 1-C 10烷基、C 1-C 10烷氧基、C 2-C 10烯基、C 2-C 10烯氧基、C 2-C 10炔基、C 2-C 10炔氧基、C 3-C 10环烷基、C 3-C 10环烷基氧基、3-10元杂环基、3-10元杂环基氧基、C 6-C 20芳基、C 6-C 20芳基氧基、5-20元杂芳基、5-20元杂芳基氧基；
每一个R b相同或不同，各自独立选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、或下列基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 20芳基、5-20元杂芳基；
其中R 1不为甲基、乙基、异丙基。
根据本发明的实施例，一种通式(A)所示的化合物、其立体异构体、水合物、溶剂化物、药学可接受的盐或前药：
Figure PCTCN2020110622-appb-000003
R 1选自无取代或任选被一个或多个R a取代C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基；R a相同或不同，各自独立选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、或下列基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基；优选地，R a选自F；其中R 1不为甲基、乙基、异丙基。
根据本发明的实施例，在通式(A-1)或(A)中，R 1选自无取代或任选被至少一个R a取代的C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基；
所述至少一个R a的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、或下列基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基。
根据本发明的实施例，在通式(A-1)中，R 2选自H、无取代或任选被至少一个R c取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基；
所述至少一个R c的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2。
根据本发明的实施例，在通式(A-1)中，R 2选自H、无取代或任选被至少一个R c取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基；
所述至少一个R c的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、＝O。
根据本发明的实施例，在通式(A-1)中，R 2选自H、无取代或任选被至少一个R c取代的以下基团：C 1-C 5烷基、C 3-C 5环烷基；
所述至少一个R c的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、＝O。
根据本发明的实施例，在通式(A-1)中，R 2选自H、无取代或任选被至少一个R c取代的以下基团：C 1-C 5烷基、C 3-C 5环烷基；
所述至少一个R c的每一个相同或不同并且分别独立地选自F、Cl、Br、I。
本发明的优选方案，所述化合物选自如下结构之一：
Figure PCTCN2020110622-appb-000004
Figure PCTCN2020110622-appb-000005
本发明提供的新型化合物，例如前述的001、002、003、004、005以及006，能够抑制PDE4的亚型PDE4B和PDE4D的活性。并且，由于抑制PDE4D会导致呕吐等副反应，化合物001、003、004、005以及006能够选择性抑制PDE4B的活性，从而有效改善呕吐等副作用的发生。
本发明还提供药物组合物，其包含式(A-1)和/或(A)所示化合物或其立体异构体、水合物、溶剂化物、药学可接受的盐或前药。
根据本发明的实施例，所述药物组合物还进一步包括药学上可接受的辅料，例如药学上可接受的载体、稀释剂或赋形剂。
利用本发明提供的化合物制成各种剂型的药品，将其以治疗有效量施用于受试者，该药物被受试者吸收后，能够通过上调细胞内cAMP水平，继而影响促炎细胞因子的释放和平滑肌的状态，从而治疗或改善与PDE4相关的疾病。
根据本发明的实施例，所述药物组合物进一步包含一种或多种其他治疗剂。其中，所述其他治疗剂与本发明的化合物的功能类似，均可用于治疗与PDE4相关疾病。
本发明涉及通式(A-1)或(A)所示化合物的合适的药学上可接受的盐，包括但不限于盐酸盐、氢溴酸盐、硫酸盐或硫酸氢盐、磷酸盐或磷酸氢盐、乙酸盐、苯甲酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡糖酸盐、甲磺酸盐、苯磺酸盐或对甲苯磺酸盐。根据前文所述，任何本文中提到的本发明化合物均包括其药学上可接受的盐、溶剂合物或它们的组合。
除了本发明化合物的药学可接受的盐外，本发明还包括其他盐。它们可以在化合物纯化中或在制备其它药学上可接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
进一步，本发明涉及通式(A-1)或(A)所示的化合物、其立体异构体、水合物、溶 剂化物、药学可接受的盐、前药，在制备治疗与磷酸二酯酶-4(PDE4)有关疾病的药物中的用途。
本发明的优选方案，其中与磷酸二酯酶-4(PDE4)有关的疾病选自炎性疾病、变应性疾病、自身免疫性疾病、移植排斥反应、关节炎性疾病、皮肤炎性疾病、炎症性肠病以及与平滑肌收缩性相关的疾病。
本发明的优选方案，其中变应性疾病选自哮喘、慢性支气管炎、慢性阻塞性肺炎、变应性鼻炎、成人呼吸窘迫综合征。
本发明的优选方案，其中皮肤炎性疾病选自特发性皮炎、银屑病或荨麻疹。
本发明的优选方案，其中关节炎性疾病选自类风湿性关节炎、骨关节炎、痛风性关节炎或脊椎炎。
本发明的优选方案，其中炎症性肠病选自溃疡性结肠炎或克罗恩病。
本发明的优选方案，其中与平滑肌收缩性相关的疾病选自膀胱过度活动症及其相关症状，例如尿频和尿急。
本发明还提供通式(A-1)或(A)所示的化合物、其立体异构体、水合物、溶剂化物、药学可接受的盐、前药在治疗与PDE4相关疾病中的用途。
本发明的优选方案，其中所述的与PDE4相关疾病选自炎性疾病、变应性疾病、自身免疫性疾病、移植排斥反应、关节炎性疾病、皮肤炎性疾病、炎症性肠病以及与平滑肌收缩性相关的疾病。
本发明的优选方案，其中所述的与PDE4相关疾病选自哮喘、慢性支气管炎、慢性阻塞性肺炎、变应性鼻炎、成人呼吸窘迫综合征、特发性皮炎、银屑病、荨麻疹、类风湿性关节炎、骨关节炎、痛风性关节炎或脊椎炎、溃疡性结肠炎、克罗恩病、膀胱过度活动症。
本发明还提供一种治疗与PDE4相关疾病的方法，向患有与PDE4相关疾病的患者施用所述的药物组合物。
本发明的优选方案，其中所述的与PDE4相关疾病选自炎性疾病、变应性疾病、自身免疫性疾病、移植排斥反应、关节炎性疾病、皮肤炎性疾病、炎症性肠病以及与平滑肌收缩性相关的疾病。
本发明的优选方案，其中所述的与PDE4相关疾病选自哮喘、慢性支气管炎、慢性阻塞性肺炎、变应性鼻炎、成人呼吸窘迫综合征、特发性皮炎、银屑病、荨麻疹、类风湿性关节炎、骨关节炎、痛风性关节炎或脊椎炎、溃疡性结肠炎、克罗恩病、膀胱过度活动症。
本发明还涉及治疗与磷酸二酯酶-4(PDE4)有关的疾病方法，该方法包括向患者施用治疗有效剂量的包含本发明所述化合物或其药学上可接受的盐的药物制剂。
术语定义和说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。衍生自无机碱的盐包括但不限于Al、Ca、Li、Mg、K、Na和Zn形成的金属盐；衍生自有机碱的盐包括但不限于伯胺、仲胺或叔胺的盐，包括天然存在的取代或未取代的胺、环胺和碱性离子交换树脂，例如铵、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶或聚胺树脂形成的有机盐；衍生自无机酸和有机酸的盐包括但不限于硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、赖氨酸、精氨酸、门冬氨酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸等形成的有机盐。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“药物组合物”表示一种或多种本发明所述化合物或其生理学/药学上可接受的盐 或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药，利于活性成分的吸收进而发挥生物活性。
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。
术语“C 1-C 10烷基”应理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等；“C 1-C 6烷基”应理解为表示具有1、2、3、4、5、6个碳原子的直链或支链饱和一价烃基。
术语“C 2-C 10炔基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子。
术语“C 3-C 10环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3-10个碳原子。如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。术语“C 3-C 6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3-6个碳原子。
术语“3-10元杂环基”意指饱和的一价单环或双环烃环，其包含1-5个，优选1-3个选自N、O和S的杂原子。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5- 二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。
术语“C 6-C 20芳基”应理解为优选表示具有6-20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环。特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者具有13个碳原子的环(“C 13芳基”)，例如芴基，或者是具有14个碳原子的环(“C 14芳基”)，例如蒽基。
术语“C 6-C 20芳基氧基”是指在前述“C 6-C 20芳基”的基础上与至少一个氧基“-O-”相连。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5-20个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各自独立选自N、O和S的杂原子，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
术语“5-20元杂芳基氧基”是指在前述“5-20元杂芳基”的基础上与至少一个氧基“-O-”相连。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类的非限制性实例包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的“药学上可接受的载体”的实例为：糖类，例如乳糖、蔗糖、甘露醇和山梨醇；淀粉类，例如玉米淀粉、木薯淀粉和土豆淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和甲基纤维素；磷酸钙类，例如磷酸二钙和磷酸三钙；硫酸钠；硫酸钙；聚乙烯吡咯烷酮；聚乙烯醇；硬脂酸；硬脂酸碱土金属盐，例如硬脂酸镁和硬脂酸钙；硬脂酸；植物 油类，例如花生油、棉籽油、芝麻油、橄榄油和玉米油；非离子、阳离子和负离子表面活性剂；乙二醇聚合物；脂肪醇类；和谷物水解固形物以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。
本发明还涉及一种制备本发明通式(A)化合物的方法，该方法包括：
Figure PCTCN2020110622-appb-000006
其中R 1的定义如上文所述；X为卤素，如Cl、Br、I等；式(IV)的结构为
Figure PCTCN2020110622-appb-000007
其中，式(I)化合物在催化剂条件下与氮杂环丁基-3-醇或其盐发生偶联反应得到式(II)化合物；式(II)化合物与甲基磺酰氯反应得到式(III)化合物，式(III)化合物进一步与式(IV)化合物发生亲核取代反应得到式(V)化合物，式(V)化合物在酸性条件下脱去保护剂得到目标化合物(A)。
式(IV)的合成路线和制备方法参考专利申请WO2001047905A1、CN106795137A以及期刊文献Nichols，P.J.；DeMattei，J.A.Org.Lett.2006，8，1495-1498所公开的合成方法。
本发明提供的通式为(A-1)化合物的合成路线和制备方法与前述制备通式(A)的化合物的方法类似，区别仅在于合成时的起始原料不同，即上述式(I)化合物不同。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1显示了小鼠CIA关节炎模型实验中G1、G2、G3及G4组临床评分；
图2显示了小鼠CIA关节炎模型实验中G2、G3及G4组临床评分AUC抑制率。
发明详细描述
以下实施例详细说明发明的技术方案，但本发明的保护范围包括但不限于此。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。
本发明的缩写定义如下：
CuI：碘化亚铜
DCM：二氯甲烷
DMF：N,N-二甲基甲酰胺
DMSO：二甲基亚砜
EA：乙酸乙酯
Et 3N：三乙胺
N：当量浓度，例如1N盐酸表示1mol/L盐酸溶液
PE：石油醚
除非作出相反的指示，本文例举的化合物使用ChemBioDraw Ultra 13.0命名和编号。Ms：甲磺酰基；LPS：Lipopolysaccharide，脂多糖(内毒素)；PBMC：外周血单核细胞；TNFα：肿瘤坏死因子α；PBS：磷酸盐缓冲液；FBS：胎牛血清；“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
本发明以下实施例中所用的阳性对照组化合物的结构式为
Figure PCTCN2020110622-appb-000008
阳性对照组化合物
参考专利WO2014159012A1制备方法制备得到阳性对照组化合物，该化合物可作为 PDE4的抑制剂，用于治疗与PDE4相关的疾病。
LC-MS,M/Z(ESI):486[M+1]。
实施例
实施例1：目标化合物001的制备
(S)-1-((3S,4S)-4-(3-((1-(5-环丙氧基吡啶-2-基)氮杂环丁基-3-基)氧)-4-甲氧苯基)-3-((R)-1-羟乙基)-3-甲基吡咯烷-1-基)-2,3-二羟基丙烷-1-酮
(S)-1-((3S,4S)-4-(3-((1-(5-cyclopropoxypyridin-2-yl)azetidin-3-yl)oxy)-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl)-2,3-dihydroxypropan-1-one
Figure PCTCN2020110622-appb-000009
目标化合物001的合成路线如下所示：
Figure PCTCN2020110622-appb-000010
第一步：1-(5-环丙氧基吡啶-2-基)氮杂环丁基-3-醇(001B)的合成
1-(5-cyclopropoxypyridin-2-yl)azetidin-3-ol
Figure PCTCN2020110622-appb-000011
将2-溴-5-环丙氧基吡啶(001A)(1.6g，7.47mmol)溶入到20mL DMSO中，加入氮杂环丁基-3-醇盐酸盐(2.03g，18.6mmol)，碘化亚铜(284mg，1.49mmol)，L-脯氨酸(343mg， 2.98mmol)，碳酸钾(3.09g，22.41mmol)，加热至90℃，在氮气保护下，搅拌过夜。冷却至室温，加入水(300mL)稀释，用乙酸乙酯(100mL×3)萃取，合并有机相，有机相用饱和食盐水(100mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:1)得化合物1-(5-环丙氧基吡啶-2-基)氮杂环丁基-3-醇(001B)，为淡黄色固体(650mg，产率42.4％)。
第二步：1-(5-环丙氧基吡啶-2-基)氮杂环丁基-3-甲基磺酸酯(001C)的合成
1-(5-cyclopropoxypyridin-2-yl)azetidin-3-yl methanesulfonate
Figure PCTCN2020110622-appb-000012
将1-(5-环丙氧基吡啶-2-基)氮杂环丁基-3-醇(001B)(650mg，3.16mmol)，溶入到二氯甲烷(15mL)中，加入三乙胺(638mg，6.32mmol)，冷却至0℃，加入甲基磺酰氯(540mg，4.73mmol)，室温搅拌2h。加入二氯甲烷(60mL)稀释，用水(60mL×3)洗，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:1)得化合物1-(5-环丙氧基吡啶-2-基)氮杂环丁基-3-甲基磺酸酯(001C)，为淡黄色固体(460mg，产率51.3％)。
第三步：((3S,4S)-4-(3-((1-(5-环丙氧基吡啶-2-基)氮杂环丁基)氧)-4-甲氧苯基)-3-((R)-1-羟乙基)-3-甲基吡咯烷-1-基)((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲酮(001D)的合成
((3S,4S)-4-(3-((1-(5-cyclopropoxypyridin-2-yl)azetidin-3-yl)oxy)-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl)((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methanone
Figure PCTCN2020110622-appb-000013
将化合物((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)((3S，4S)(3-4-羟基-4-甲氧基苯基)-(3-(R)-1-羟乙基)-3-甲基吡咯烷-1-基)甲酮(化合物IV)(380mg，1mmol)溶入DMF(5mL)，加入磷酸钾(466mg，2.50mmol)，加热至90℃并搅拌0.5h，冷却至40℃，加入1-(5-环丙氧基吡啶-2-基)氮杂环丁基-3-甲基磺酸酯(001C)(460mg，2.50mmol)，加热至90℃，搅拌过夜。冷却至室温，加入水(60mL)稀释，用乙酸乙酯(60mL×3)萃取，合并有机相，有机相用饱和食盐水(60mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留 物用硅胶柱纯化(石油醚:乙酸乙酯(V/V)＝2:1)得到化合物((3S,4S)-4-(3-((1-(5-环丙氧基吡啶-2-基)氮杂环丁基)氧)-4-甲氧苯基)-3-((R)-1-羟乙基)-3-甲基吡咯烷-1-基)((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲酮(001D)，为白色固体(350mg，产率61.7％)。
第四步：(S)-1-((3S,4S)-4-(3-((1-(5-环丙氧基吡啶-2-基)氮杂环丁基-3-基)氧)-4-甲氧苯基)-3-((R)-1-羟乙基)3-甲基吡咯烷-1-基)-2,3-二羟基丙烷-1-酮(目标化合物001)的合成(目标化合物001)的合成
(S)-1-((3S,4S)-4-(3-((1-(5-cyclopropoxypyridin-2-yl)azetidin-3-yl)oxy)-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl)-2,3-dihydroxypropan-1-one
Figure PCTCN2020110622-appb-000014
将((3S,4S)-4-(3-((1-(5-环丙氧基吡啶-2-基)氮杂环丁基)氧)-4-甲氧苯基)-3-((R)-1-羟乙基)-3-甲基吡咯烷-1-基)((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲酮(001D)(350mg，0.62mmol)溶于四氢呋喃(10mL)，加入1N盐酸(8mL)，室温搅拌过夜。加入饱和碳酸氢钠水溶液，调节pH至8～9，用乙酸乙酯(25mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(纯乙酸乙酯)，得到化合物(S)-1-((3S,4S)-4-(3-((1-(5-环丙氧基吡啶-2-基)氮杂环丁基-3-基)氧)-4-甲氧苯基)-3-((R)-1-羟乙基)3-甲基吡咯烷-1-基)-2,3-二羟基丙烷-1-酮(目标化合物001)，为白色固体(230mg，70.6％)。
1H NMR(400MHz,DMSO-d6)δ7.86-7.85(m,1H),7.80-7.77(m,1H),7.70-6.97(dd,1H),6.93-6.88(m,2H),6.72-6.71(m,1H),6.47(s,3H),5.19-5.16(m,1H),4.62-4.59(m,2H),4.30-4.24(m,1H),4.21-4.14(m,2H),3.97-3.94(m,2H),3.77(s,3H),3.74-3.45(m,6H),3.39-3.34(m,1H),1.04(d,3H),0.82-0.78(m,2H),0.71-0.68(m,2H),0.66(d,3H).
LC-MS,M/Z(ESI):528.2(M+1).
实施例2：目标化合物002的制备
(S)-2,3-二羟基-1-((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧)苯基)-3-甲基吡咯烷-1-基)丙烷-1-酮
(S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-((1-(5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl)propan-1-one
Figure PCTCN2020110622-appb-000015
以2-溴-5-(三氟甲氧基)吡啶(002A)为起始原料，参考实施例1的制备方法制备得到目标化合物002。
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.62(d,1H),6.93(dd,1H),6.89(d,1H),6.69(d,1H),6.54(d,1H),5.17-5.10(m,1H),4.88(s,2H),4.77(s,1H),4.42(dd,2H),4.24(d,1H),3.97-3.91(m,3H),3.75(s,3H),3.74-3.45(m,6H),1.02(d,3H),0.64(d,3H).
LC-MS,M/Z(ESI):556.2(M+1).
实施例3：目标化合物003的制备
(S)-1-((3S,4S)-4-(3-((1-(5-环丁氧基吡啶-2-基)氮杂环丁基-3-基)氧)-4-甲氧苯基)-3-((R)-1-羟乙基)-3-甲基吡咯烷-1-基)-2,3-二羟基丙烷-1-酮
(S)-1-((3S,4S)-4-(3-((1-(5-cyclobutoxypyridin-2-yl)azetidin-3-yl)oxy)-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl)-2,3-dihydroxypropan-1-one
Figure PCTCN2020110622-appb-000016
以2-溴-5-环丁基氧基吡啶(003A)为起始原料，参考实施例1的制备方法制备得到目标化合物003。
1H NMR(400MHz,DMSO-d6)δ7.75(d,1H),7.20-7.16(m,1H),6.95(dd,1H),6.87-6.85(m,1H),6.68(s,1H),6.44(d,1H),5.10-5.08(m,1H),4.92-4.83(m,2H),4.76-4.71(m,1H),4.61-4.55(m,1H),4.31-4.21(m,3H),3.95-3.91(m,1H),3.82-3.80(m,2H),3.75(s,3H),3.74-3.45(m,6H),2.51-2.33(m,3H),2.02-1.97(m,2H),1.76-1.74(m,1H),1.65-1.56(m,1H),1.02(d,3H),0.64(d,3H).
LC-MS,M/Z(ESI):542.2(M+1).
实施例4：目标化合物004的制备
(S)-2,3-二羟基-1-((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(5-(氧杂环丁基-3-基氧)吡啶-2-基)氮杂环丁基-3-基)氧)苯基)-3-甲基吡咯烷-1-基)丙烷-1-酮
(S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-((1-(5-(oxetan-3-yloxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl)propan-1-one
以2-溴-5-(氧杂环丁基-3-基氧基)吡啶(004A)为起始原料，参考实施例1的制备方法制备得到目标化合物004。
Figure PCTCN2020110622-appb-000017
1H NMR(400MHz,DMSO-d6)δ7.70(d,1H),7.19-7.16(m,1H),6.93(dd,1H),6.87-6.85(m,1H),6.68(s,1H),6.46(d,1H),5.23-5.17(m,1H),5.11-5.08(m,1H),4.92-4.85(m,4H),4.76-4.71(m,1H),4.54-4.51(m,2H),4.32-4.23(m,3H),3.93-3.91(m,1H),3.84-3.78(m,2H),3.75(s,3H),3.68-3.45(m,6H),3.19-3.16(m,1H),1.01(d,3H),0.64(d,3H).
LC-MS,M/Z(ESI):544.3(M+1).
实施例5：目标化合物005的制备
(S)-2,3-二羟基-1-((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧)苯基)-3-甲基吡咯烷-1-基)丙烷-1-酮
(S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-((1-(6-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl)propan-1-one
Figure PCTCN2020110622-appb-000018
Figure PCTCN2020110622-appb-000019
第一步：O-(6-溴-2-甲基吡啶-3-基)硫代碳酰氯(005B)的合成
O-(6-bromo-2-methylpyridin-3-yl)carbonochloridothioate(005B)
Figure PCTCN2020110622-appb-000020
0℃下将2-溴-5-羟基-6-甲基吡啶(005A)(30.0g，160.4mmol)加入到210mL 5％的NaOH溶液中，加入二氯硫化碳(20.0g，173.9mmol)的120mL氯仿溶液，0℃下搅拌2h。升至室温，用氯仿(120mL×3)萃取，合并有机相，有机相用饱和食盐水(50mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，得标题化合物粗品淡黄色液体O-(6-溴-2-甲基吡啶-3-基)硫代碳酰氯(005B)(45.2g粗品)。
第二步：O-(6-溴-2-甲基吡啶-3-基)甲巯基硫代碳酸酯(005C)的合成
O-(6-bromo-2-methylpyridin-3-yl)S-methyl carbonodithioate
Figure PCTCN2020110622-appb-000021
室温下将O-(6-溴-2-甲基吡啶-3-基)硫代碳酰氯(005B)(45.2g,160.4mmol)加入到200mL氯仿中，加入甲硫醇钠(12.4g,177.1mmol)，室温搅拌72h。加入水(200mL)稀释，用氯仿(120mL×3)萃取，合并有机相，有机相用饱和食盐水(50mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(PE:EA＝10:1)得标题化合物淡黄色液 体O-(6-溴-2-甲基吡啶-3-基)甲巯基硫代碳酸酯(005C)(15.8g，两步产率35.6％)。
第三步：6-溴-2-甲基-3-(三氟甲氧基)吡啶(005D)的合成
6-bromo-2-methyl-3-(trifluoromethoxy)pyridine(005D)
Figure PCTCN2020110622-appb-000022
室温下将二溴海因(50.5g,176.4mmol)加入到300mL DCM中，冷却至-78℃，低温下加入70％吡啶氢氟酸溶液(400mL,3136.8mmol)，搅拌45min。将O-(6-溴-2-甲基吡啶-3-基)甲巯基硫代碳酸酯(005C)(10.9g,39.2mmol)的100mL DCM溶液缓慢滴入，滴完后缓慢升温至-5℃，搅拌1.5h。将反应液倒入500mL冷的饱和NaHCO 3溶液中，用NaOH调节pH＝10～12，用DCM(200mL×3)萃取，合并有机相，有机相用饱和食盐水(200mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(PE:EA＝10:1)得标题化合物淡黄色液体6-溴-2-甲基-3-(三氟甲氧基)吡啶(005D)(7.0g，产率69.7％)。
LC-MS,M/Z(ESI):256.3(M+1).
第四步：1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-醇(005E)的合成
1-(6-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-ol(005E)
Figure PCTCN2020110622-appb-000023
室温下将6-溴-2-甲基-3-(三氟甲氧基)吡啶(005D)(2.56g,10.0mmol)加入到30mL DMSO中，加入氮杂环丁基-3-醇盐酸盐(1.65g,15.0mmol)、碘化亚铜(190mg,1.0mmol)，L-脯氨酸(1.27g,11.0mmol)以及磷酸钾(4.24g,20.0mmol)，加热至110℃，搅拌过夜。冷却至室温，加入水(150mL)稀释，用乙酸乙酯(50mL×3)萃取，合并有机相，有机相用饱和食盐水(50mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(PE:EA＝2:1)得标题化合物淡黄色固体1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-醇(005E)(1.0g，产率40.3％)。
LC-MS,M/Z(ESI):249.4(M+1).
第五步：1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁烷-3-基甲磺酸酯(005F)的合成
1-(6-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl methanesulfonate(005F)
Figure PCTCN2020110622-appb-000024
室温下将1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-醇(005E)(140mg,0.56mmol)，加入到3mL二氯甲烷中，加入三乙胺(171mg,1.69mmol)，加入甲基磺酰氯(97mg,0.85mmol)，搅拌2h。加入二氯甲烷(10mL)稀释，用水(10mL×3)洗，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(PE:EA＝2:1)得标题化合物淡黄色固体1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁烷-3-基甲磺酸酯(005F)(150mg，产率81.5％)。
LC-MS,M/Z(ESI):327.2(M+1).
第六步：((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁烷-3-基)氧基)苯基)-3-甲基吡咯烷-1-基)甲酮(005G)的合成
((S)-2,2-dimethyl-1,3-dioxolan-4-yl)((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-((1-(6-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl)methanone(005G)
Figure PCTCN2020110622-appb-000025
将化合物((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)((3S,4S)(3-羟基-4-甲氧基苯基)-(3-(R)-1-羟乙基)-3-甲基吡咯烷-1-基)甲酮(1.30g,3.37mmol)加入DMF(20mL)中，加入磷酸钾(1.40g,6.74mmol)，加入1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-甲基磺酸酯(005F)(1.10g,3.37mmol)，加热至110℃，搅拌过夜。冷却至室温，加入水(60mL)稀释，用乙酸乙酯(60mL×3)萃取，合并有机相，有机相用饱和食盐水(60mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱纯化(PE:EA＝2:1)得标题化合物淡黄色固体((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁烷-3-基)氧基)苯基)-3-甲基吡咯烷-1-基)甲酮(005G)(1.40g，产率68.1％)。
LC-MS,M/Z(ESI):610.3(M+1).
第七步：(S)-2,3-二羟基-1-((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧基)苯基)-3-甲基吡咯烷-1-基)丙烷-1-酮(005)的合成
(S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-((1-(6-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl)propan-1-one(005)
Figure PCTCN2020110622-appb-000026
将((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧)苯基)-3-甲基吡咯烷-1-基)甲酮(005G)(400mg,0.66mmol)溶于四氢呋喃(10mL)，加入2N盐酸(2mL)，室温搅拌过夜。加入饱和碳酸氢钠水溶液，调节pH＝8～9，用乙酸乙酯(25mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(纯EA)，得标题化合物白色固体(S)-2,3-二羟基-1-((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(6-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧基)苯基)-3-甲基吡咯烷-1-基)丙烷-1-酮(005)(340mg，产率90.9％)。
1H NMR(400MHz,DMSO-d6)δ7.59(d,1H),6.96(dd,1H),6.88(d,1H),6.68(s,1H),6.37(d,1H),5.12(d,1H),4.92(b,2H),4.41(t,2H),4.26-4.22(m,1H),3.94-3.91(m,3H),3.75(s,3H),3.74-3.48(m,8H),2.31(s,3H),1.02(d,3H),0.64(s,3H).
LC-MS,M/Z(ESI):570.3(M+1).
实施例6：目标化合物006的制备
(S)-2,3-二羟基-1-((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧)苯基)-3-甲基吡咯烷-1-基)丙烷-1-酮
(S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-((1-(4-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl)propan-1-one
Figure PCTCN2020110622-appb-000027
Figure PCTCN2020110622-appb-000028
第一步：O-(6-溴-4-甲基吡啶-3-基)硫代碳酰氯(006B)的合成
O-(6-bromo-4-methylpyridin-3-yl)carbonochloridothioate(006B)
Figure PCTCN2020110622-appb-000029
0℃下将6-溴-3-羟基-4-甲基吡啶(006A)(13.5g,71.8mmol)加入到95mL 5％的NaOH溶液中，加入二氯硫化碳(9.1g,173.9mmol)的55mL氯仿溶液，0℃下搅拌2h。升至室温，用氯仿(120mL×3)萃取，合并有机相，有机相用饱和食盐水(50mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，得标题化合物粗品淡黄色液体O-(6-溴-2-甲基吡啶-3-基)硫代碳酰氯(006B)(20.0g粗品直接用于下一步)。
第二步：O-(6-溴-4-甲基吡啶-3-基)甲巯基硫代碳酸酯(006C)的合成
O-(6-bromo-4-methylpyridin-3-yl)S-methyl carbonodithioate(006C)
Figure PCTCN2020110622-appb-000030
室温下将上一步粗品O-(6-溴-4-甲基吡啶-3-基)硫代碳酰氯(006B)(20.0g,71.8mmol)加入到100mL氯仿中，加入甲硫醇钠(5.5g,78.9mmol)，室温搅拌72h。加入水(100mL)稀释，用氯仿(50mL×3)萃取，合并有机相，有机相用饱和食盐水(50mL×2)洗涤，分液，有机相用 无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(PE:EA＝10:1)得标题化合物淡黄色液体O-(6-溴-4-甲基吡啶-3-基)甲巯基硫代碳酸酯(006C)(10.0g,两步产率50.1％)。
第三步：6-溴-4-甲基-3-(三氟甲氧基)吡啶(006D)的合成
6-bromo-4-methyl-3-(trifluoromethoxy)pyridine(006D)
Figure PCTCN2020110622-appb-000031
室温下将二溴海因(37.0g,129.5mmol)加入到300mL DCM中，冷却至-78℃，低温下加入60％吡啶氢氟酸溶液(368mL,2473.6mmol)，搅拌45min。将O-(6-溴-4-甲基吡啶-3-基)S-甲基二硫代碳酸酯(006C)(8.0g,28.7mmol)的100mL DCM溶液缓慢滴入，滴完后缓慢升温至-5℃，搅拌1.5h。将反应液倒入500mL冷的饱和NaHCO 3溶液中，用NaOH调节pH＝10～12，用DCM(200mL×3)萃取，合并有机相，有机相用饱和食盐水(200mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(PE:EA＝10:1)得标题化合物淡黄色液体6-溴-4-甲基-3-(三氟甲氧基)吡啶(006D)(6.0g，产率81.9％)。
LC-MS,M/Z(ESI):256.3(M+1).
第四步：1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-醇(006E)的合成
1-(4-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-ol(006E)
Figure PCTCN2020110622-appb-000032
室温下将6-溴-4-甲基-3-(三氟甲氧基)吡啶(006D)(6.0g,23.4mmol)加入到65mL DMSO中，加入氮杂环丁基-3-醇盐酸盐(3.6g,32.7mmol)、碘化亚铜(0.50g,2.63mmol)、L-脯氨酸(3.0g,26.1mmol)、磷酸钾(10.0g,47.1mmol)，加热至110℃，搅拌过夜。冷却至室温，加入水(150mL)稀释，用乙酸乙酯(50mL×3)萃取，合并有机相，有机相用饱和食盐水(50mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(PE:EA＝2:1)得标题化合物淡黄色固体1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-醇(006E)(4.6g,产率79.1％)。
LC-MS,M/Z(ESI):249.4(M+1).
第五步：1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁-3-基甲磺酸酯(006F)的合成
1-(4-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl methanesulfonate(006F)
Figure PCTCN2020110622-appb-000033
室温下将1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-醇(006E)(600mg,2.42mmol)，加入到8mL二氯甲烷中，加入三乙胺(733mg,7.26mmol)，加入甲基磺酰氯(413mg,3.63mmol)，搅拌4h。加入二氯甲烷(20mL)稀释，用水(10mL×3)洗，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(PE:EA＝2:1)得标题化合物淡黄色固体1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁-3-基甲磺酸酯(006F)(750mg，产率95.0％)。
LC-MS,M/Z(ESI):327.2(M+1).
第六步：((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧)苯基)-3-甲基吡咯烷-1-基)甲酮(006G)的合成
((S)-2,2-dimethyl-1,3-dioxolan-4-yl)((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-((1-(4-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl)methanone(006G)
Figure PCTCN2020110622-appb-000034
将化合物((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)((3S,4S)(3-羟基-4-甲氧基苯基)-(3-(R)-1-羟乙基)-3-甲基吡咯烷-1-基)甲酮(1.0g,2.64mmol)加入DMF(20mL)中，加入磷酸钾(3.40g,16.0mmol)，加入1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-甲基磺酸酯(006F)(0.86g,2.64mmol)，加热至110℃，搅拌过夜。冷却至室温，加入水(60mL)稀释，用乙酸乙酯(60mL×3)萃取，合并有机相，有机相用饱和食盐水(60mL×2)洗涤，分液，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱纯化(PE:EA＝2:1)得标题化合物淡黄色固体((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(4-甲 基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧)苯基)-3-甲基吡咯烷-1-基)甲酮(006G)(1.05g,产率65.3％)。
LC-MS,M/Z(ESI):610.3(M+1).
第七步：(S)-2,3-二羟基-1-((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧)苯基)-3-甲基吡咯烷-1-基)丙烷-1-酮(006)的合成
(S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-((1-(4-methyl-5-(trifluoromethoxy)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl)propan-1-one(006)的合成
Figure PCTCN2020110622-appb-000035
将((S)-2,2-二甲基-1,3-二氧杂环戊烷-4-基)((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧)苯基)-3-甲基吡咯烷-1-基)甲酮(006G)(100mg,0.16mmol)溶于四氢呋喃(2mL)，加入2N盐酸(1mL)，室温搅拌过夜。加入饱和碳酸氢钠水溶液，调节pH＝8～9，用乙酸乙酯(5mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(纯EA)，得标题化合物白色固体(S)-2,3-二羟基-1-((3S,4S)-3-((R)-1-羟乙基)-4-(4-甲氧基-3-((1-(4-甲基-5-(三氟甲氧基)吡啶-2-基)氮杂环丁基-3-基)氧)苯基)-3-甲基吡咯烷-1-基)丙烷-1-酮(006)(73mg,产率78.1％)。
1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),6.96(dd,1H),6.89(d,1H),6.69(s,1H),6.46(s,1H),5.13(d,1H),4.92-4.84(m,2H),4.77-4.72(m,1H),4.41(t,2H),4.27-4.25(m,1H),3.94-3.91(m,3H),3.76(s,3H),3.74-3.48(m,7H),2.22(s,3H),1.02(d,3H),0.64(s,3H).
LC-MS,M/Z(ESI):570.3(M+1)
生物学活性及相关性质实施例
实施例7：PDE4B和PDE4D酶活试验
阳性对照化合物以及本发明提供的化合物001～006对PDE4B和PDE4D的抑制活性可以利用PDE-Glo Phosphodiesterase Assay Kit(promega，V1361)进行检测。简单来说，首 先将待检测化合物在DMSO溶剂中配制成10mM的浓储液，随后以试剂盒提供的Reaction buffer稀释成10×的工作液。在冰上操作，用Reaction buffer将PDE4B酶(Enzo Life Sciences，BML-SE522-0020)稀释至浓度为1ng/μL，PDE4D酶(Enzo Life Sciences，BML-SE523-0020)稀释至浓度为4ng/μL。在384孔板(Corning，CLS3707)的孔中加入1.5ul PDE4B或PDE4D工作液和1μL化合物工作液，室温震荡孵育5分钟，随后加入2.5μL/孔cAMP(2μM in Reaction buffer)，继续室温震荡孵育20分钟，加入2.5μL/孔1×Termination Buffer，随后加入2.5μL/孔1×Detection Buffer，继续室温震荡20分钟。最后加入10μL/孔1×Kinase-Glo，室温震荡孵育10分钟，以PheraStar仪器检测生物发光。实验结果输入GraphPad Prism软件，经拟合计算得到各化合物的IC 50。
表1显示了通过酶活实验测定的阳性对照组化合物、本发明提供的化合物001～006对PDE4B和PDE4D的抑制活性。
表1测试化合物对PDE4B和PDE4D的抑制活性结果
Figure PCTCN2020110622-appb-000036
实验结果表明，与阳性对照组化合物相比，本发明化合物001/003～006明显表现出更好的PDE4B选择性抑制作用，化合物002相比阳性对照组，具有更好的PDE4B和PDE4D的抑制活性。因此，本发明化合物可作为PDE4抑制剂。并且由于化合物001/003～006能够选择性抑制PDE4B的活性，因此，将其用于与PED4相关的疾病的治疗中时，能有效改善呕吐等副作用的发生。
实施例8：LPS诱导人PBMC分泌TNFα模型试验
PBMC提取过程：获取新鲜人外周浓缩血，吸取1单位人外周浓缩血(浓缩自200cc外周血)，定量加入0.9％生理盐水至总体积为120ml，混匀。取50ml离心管，分别加入15ml Lymphoprep TM，手持离心管，约斜45度角，吸取30ml稀释后的浓缩血，小心而缓慢地贴 壁加入，使稀释血液重叠于分层液上，避免将稀释血液混入分离液或冲破分离液液面。Lymphoprep TM与稀释血液的比例为1:2。将离心管配平放置入水平离心机(eppendorf，5810R)，20℃，800g离心20min，升速设为1，降速设为0。小心取出离心管。直接将巴氏吸管深入白膜层，吸取PBMC。加3倍体积0.9％生理盐水或PBS(不含钙镁)，轻轻吹打混匀。混匀后20℃，250g离心10min，去除细胞悬液中留存的血小板，去上清液，将细胞沉淀以20ml PBS悬起，台盼蓝染色计数。
PBMC筛选过程：将步骤1取得的PBMC离心，去除PBS，然后用完全培养基(RPMI1640+10％FBS+1％P/S)重悬计数。按照5×10 4/孔，100μL/孔接入细胞。将待筛选的化合物配制成终浓度的4×。按照50μL/孔加入到细胞中。提前预孵育30min。同时设定对照孔，不加化合物。LPS的刺激终浓度为10ng/ml，配制成4×，按照50μl/孔加入到细胞中。同时设定对照孔，不加LPS孔。继续孵育细胞，在24h时收集10％上清进行检测。收集的上清按照Invitrogen公司的Human TNFα试剂盒检测(REF：88-7346-88)。
按照上述方法测定阳性对照化合物、本发明提供的化合物001～006对LPS诱导人PBMC分泌TNFα的抑制活性。
表2测试化合物对LPS诱导人PBMC分泌TNFα的抑制活性结果
测试化合物 IC 50(nM)
阳性对照组 3.32
001 0.96
002 1.45
003 1.67
004 5.32
005 0.63
006 0.50
实验结果表明，与阳性对照组相比，本发明化合物001～003以及005、006获得更好的人PBMC分泌TNFα抑制活性，能更好地抑制人PBMC中炎症因子TNFα的分泌，具有更为突出的抗炎效果。化合物004具有与阳性对照组相当的人PBMC分泌TNFα抑制活性，也可以抑制人PBMC中炎症因子TNFα的分泌，具有抗炎效果。
实施例9：LPS刺激的小鼠体内释放TNFα的测定
取18只Balb/c小鼠，周龄：6-8周，随机分配为空白组、模型组和给药组，口服灌胃 给予溶媒(空白组、模型组)或50mg/kg的化合物(给药组，其中阳性对照组给药剂量为100mg/kg)。灌胃给药30分钟后，腹腔注射PBS(空白组)或1mg/kg的LPS(模型组和给药组)。腹腔注射后90分钟或120分钟后分别取小鼠心脏采血，2-8℃静置4h后5000rpm离心10分钟，收集血清，血清-80℃保存待测。
用小鼠TNFα检测试剂盒(Mouse TNFa ELISA试剂盒：Biolegend，Cat：430904)检测血清中TNFα水平。根据血清TNFα水平计算化合物对TNFα的释放抑制活性。
化合物抑制活性％＝{1-(给药组TNFα浓度-空白组TNFα浓度)/(模型组TNFα浓度-空白组TNFα浓度)}×100
按照上述实验方法测定阳性对照化合物、本发明提供的化合物001～003以及005、006对LPS刺激的小鼠体内释放TNFα的效果。
表3 LPS刺激的小鼠体内释放TNFα的测定
Figure PCTCN2020110622-appb-000037
实验结果表明，与阳性对照组中的化合物相比，化合物001～003以及005、006能够更好的抑制小鼠体内LPS刺激的TNFα的释放，抑制活性显著优于阳性对照组，具有更为突出的抗炎效果。
实施例10：小鼠药代动力学试验
小鼠药代动力学试验，采用雄性CD-1小鼠9只，20-25g，禁食过夜，口服灌胃给药10mg/kg。每个采血时间点3只小鼠，共9只小鼠交替在给药前和在给药后15、30分钟以及1、2、4、8、24小时分别采血。血液样品8000转/分钟4℃离心6分钟，收集血浆，于-20℃保存。分别取各时间点血浆，加入3-5倍量含内标的乙腈溶液，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。 主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。
表4小鼠的药代动力学试验结果
Figure PCTCN2020110622-appb-000038
实验结果表明，与阳性对照组中的化合物相比，本发明化合物002表现出更为优良的血浆暴露，Cmax和AUC0-t均优于阳性对照组，约为阳性对照的3倍，本发明化合物有优良的药代动力学性质。
实施例11：犬药代动力学试验
犬药代动力学试验，使用雄性比格犬3只，8-10kg，禁食过夜，口服灌胃给药5mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品8000转/分钟4℃离心6分钟，收集血浆，于-20℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。表5犬的药代动力学试验结果
Figure PCTCN2020110622-appb-000039
实验结果表明，与阳性对照组中的化合物相比，本发明化合物001和002表现出更为优良的血浆暴露，Cmax和AUC0-t均优于阳性对照组，Cmax约为阳性对照的2倍，暴露量AUC0-t约为阳性对照的3倍；本发明化合物有优良的药代动力学性质。
实施例12：小鼠CIA关节炎模型试验
1.实验方法
(1)Ⅱ型胶原/完全弗氏佐剂的配制
乙酸的配制：稀释2N的乙酸至100mM，用0.22微米滤膜过滤后，4℃保存。
牛Ⅱ型胶原溶液配制：将牛Ⅱ型胶原(CII)溶解于100mM的乙酸溶液中，并置于4℃过夜保存。胶原蛋白的终浓度为8mg/mL。
乳剂的制备：将过夜保存的CII溶液与等体积的完全弗氏佐剂混合，使用高速匀浆机，在冰上以30,000转每分钟匀浆大约60分钟，直至溶液形成稳定的乳剂。
(2)关节炎的诱导：
DBA/1小鼠经异氟烷麻醉后，在尾部皮下(距尾根部2-3厘米)注射50微升的制备好的胶原乳剂(包含200微克CII)进行免疫。第一次免疫当天记为第0天，随后的天数依序标注。第21天，尾部同法注射相同体积胶原乳剂。正常组的小鼠无需免疫。
(3)给药和剂量设计
第21天，将关节炎诱导的小鼠按照体重进行随机分组，使各组间平均体重一致，随机分为4个治疗组进行给药，每组10只小鼠。
G1为正常小鼠，不做任何处理；G2组施用空白溶媒；G3和G4组分别施用化合物(阳性对照化合物和化合物002)，剂量为30mg/kg，每天给药2次，共持续21天。灌胃给药体积为10mL/kg。
(4)关节炎发病指标测定
增强免疫后，每天观察小鼠发病情况。当小鼠开始发病之后(出现关节炎的临床症状)，根据病变的不同程度(红肿，关节变形)按照0-4分的标准进行临床评分，每个肢体的最高评分为4分，每只动物最高评分为16分。至少每周评分三次。
计算各组别21天到42天的临床评分曲线下面积(AUC)，并计算给药组的临床评分AUC抑制率百分比：
抑制率％＝1-(给药组AUC/空白溶媒组AUC)*100％
(5)统计学处理
实验数据应用平均数±标准误表示(Mean±SEM)，临床评分用单因素方差分析(One-way ANOVA)，p<0.05认为有显著性差异。
2.实验结果
附图1和图2显示了各组别临床评分和临床评分AUC抑制率结果，表6展示了实验终 点临床评分和临床评分AUC抑制率结果。
表6：
组别 编号 临床评分(终点) 临床评分AUC抑制率
G1 正常小鼠 0  
G2 空白溶媒 8.5  
G3 阳性对照组 4.4 42.3％
G4 002 2.3 80.3％
在实验终点(第42天)时，G3、G4组临床评分显著低于空白溶媒组。第21天到42天的临床评分AUC抑制率结果显示，与阳性对照组相比，本发明化合物002表现出更为优良的抑制关节炎的药效。
尽管上面已经示出和描述了本公开的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本公开的限制，本领域的普通技术人员在本公开的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (18)

  1. 一种化合物，所述化合物为通式(A-1)所示化合物或者通式(A-1)所示化合物的立体异构体、水合物、溶剂化物、药学可接受的盐或前药：
    Figure PCTCN2020110622-appb-100001
    其中，
    R 1选自H、无取代或任选被至少一个R a取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 6-C 20芳基、5-20元杂芳基；
    所述至少一个R a的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、无取代或任选被至少一个R b取代的下列基团：-NH 2、C 1-C 10烷基、C 1-C 10烷氧基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 10环烷基、C 3-C 10环烷基氧基、3-10元杂环基、3-10元杂环基氧基、C 6-C 20芳基、C 6-C 20芳基氧基、5-20元杂芳基、5-20元杂芳基氧基；
    所述至少一个R b的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、或下列基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 20芳基、5-20元杂芳基；
    R 2选自H、无取代或任选被至少一个R c取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 6-C 20芳基、5-20元杂芳基；
    所述至少一个R c的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2，
    前提是，当R 2为H时，R 1不为甲基、乙基、异丙基。
  2. 一种通式(A)所示化合物，其立体异构体、水合物、溶剂化物、药学可接受的盐或前药：
    Figure PCTCN2020110622-appb-100002
    其中R 1选自H、无取代或任选被一个或多个R a取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 6-C 20芳基、5-20元杂芳基；
    每一个R a相同或不同，彼此独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、无取代或任选被一个或多个R b取代的下列基团：-NH 2、C 1-C 10烷基、C 1-C 10烷氧基、C 2-C 10烯基、C 2-C 10烯氧基、C 2-C 10炔基、C 2-C 10炔氧基、C 3-C 10环烷基、C 3-C 10环烷基氧基、3-10元杂环基、3-10元杂环基氧基、C 6-C 20芳基、C 6-C 20芳基氧基、5-20元杂芳基、5-20元杂芳基氧基；
    每一个R b相同或不同，各自独立选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、或下列基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基、C 2-C 10烯基、C 2-C 10炔基、C 6-C 20芳基、5-20元杂芳基；
    其中R 1不为甲基、乙基、异丙基。
  3. 根据权利要求1或2所述的化合物，其特征在于，在通式(A-1)或(A)中，R 1选自无取代或任选被至少一个R a取代的C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基；
    所述至少一个R a的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2、或下列基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基。
  4. 根据权利要求1所述的化合物，其特征在于，在通式(A-1)中，R 2选自H、无取代或任选被至少一个R c取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基、3-10元杂环基；
    所述至少一个R c的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、CN、＝O、NO 2、NH 2。
  5. 根据权利要求1所述的化合物，其特征在于，在通式(A-1)中，R 2选自H、无取代或任选被至少一个R c取代的以下基团：C 1-C 10烷基、C 3-C 10环烷基；
    所述至少一个R c的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、＝O。
  6. 根据权利要求1所述的化合物，其特征在于，在通式(A-1)中，R 2选自H、无取代或任选被至少一个R c取代的以下基团：C 1-C 5烷基、C 3-C 5环烷基；
    所述至少一个R c的每一个相同或不同并且分别独立地选自F、Cl、Br、I、OH、＝O。
  7. 根据权利要求1所述的化合物，其特征在于，在通式(A-1)中，R 2选自H、无取代或任选被至少一个R c取代的以下基团：C 1-C 5烷基、C 3-C 5环烷基；
    所述至少一个R c的每一个相同或不同并且分别独立地选自F、Cl、Br、I。
  8. 根据权利要求1或2所述的化合物，其中所述化合物选自如下结构之一：
    Figure PCTCN2020110622-appb-100003
  9. 一种药物组合物，其特征在于，所述组合物包含权利要求1-8中任一项的化合物。
  10. 权利要求1-8中任一项的化合物，其立体异构体、水合物、溶剂化物、药学可接受的盐或前药，在制备治疗与PDE4相关疾病的药物中的用途。
  11. 根据权利要求10所述的用途，其特征在于，其中所述的与PDE4相关疾病选自炎性疾病、变应性疾病、自身免疫性疾病、移植排斥反应、关节炎性疾病、皮肤炎性疾病、炎症性肠病以及与平滑肌收缩性相关的疾病。
  12. 根据权利要求10或权利要求11所述的用途，其特征在于，其中所述的与PDE4相关疾病选自哮喘、慢性支气管炎、慢性阻塞性肺炎、变应性鼻炎、成人呼吸窘迫综合征、特发性皮炎、银屑病、荨麻疹、类风湿性关节炎、骨关节炎、痛风性关节炎或脊椎炎、溃疡性结肠炎、克罗恩病、膀胱过度活动症。
  13. 权利要求1-8中任一项的化合物，其立体异构体、水合物、溶剂化物、药学可接受的盐或前药，在治疗与PDE4相关疾病中的用途。
  14. 根据权利要求13所述的用途，其特征在于，其中所述的与PDE4相关疾病选自炎性疾病、变应性疾病、自身免疫性疾病、移植排斥反应、关节炎性疾病、皮肤炎性疾病、炎症性肠病以及与平滑肌收缩性相关的疾病。
  15. 根据权利要求13或14所述的用途，其特征在于，其中所述的与PDE4相关疾病选 自哮喘、慢性支气管炎、慢性阻塞性肺炎、变应性鼻炎、成人呼吸窘迫综合征、特发性皮炎、银屑病、荨麻疹、类风湿性关节炎、骨关节炎、痛风性关节炎或脊椎炎、溃疡性结肠炎、克罗恩病、膀胱过度活动症。
  16. 一种治疗与PDE4相关疾病的方法，其特征在于，所述方法包括向患有与PDE4相关疾病的患者施用权利要求9所述的药物组合物。
  17. 根据权利要求16所述的方法，其特征在于，其中所述的与PDE4相关疾病选自炎性疾病、变应性疾病、自身免疫性疾病、移植排斥反应、关节炎性疾病、皮肤炎性疾病、炎症性肠病以及与平滑肌收缩性相关的疾病。
  18. 根据权利要求16或17所述的方法，其特征在于，其中所述的与PDE4相关疾病选自哮喘、慢性支气管炎、慢性阻塞性肺炎、变应性鼻炎、成人呼吸窘迫综合征、特发性皮炎、银屑病、荨麻疹、类风湿性关节炎、骨关节炎、痛风性关节炎或脊椎炎、溃疡性结肠炎、克罗恩病、膀胱过度活动症。
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