WO2019154395A1 - 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 - Google Patents

四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 Download PDF

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WO2019154395A1
WO2019154395A1 PCT/CN2019/074704 CN2019074704W WO2019154395A1 WO 2019154395 A1 WO2019154395 A1 WO 2019154395A1 CN 2019074704 W CN2019074704 W CN 2019074704W WO 2019154395 A1 WO2019154395 A1 WO 2019154395A1
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compound
group
synthesis
maj
substituted
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PCT/CN2019/074704
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English (en)
French (fr)
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许叶春
柳红
唐炜
张向磊
顾詹妮
李恒
韩旭
朱峰华
冯春兰
董光玉
陈甜甜
陈五妍
蒋华良
陈凯先
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中国科学院上海药物研究所
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Priority to EP19750381.6A priority Critical patent/EP3750886A4/en
Priority to CA3090598A priority patent/CA3090598C/en
Priority to US16/967,721 priority patent/US20210040066A1/en
Priority to KR1020207025606A priority patent/KR102556482B1/ko
Priority to CN201980012210.3A priority patent/CN111712491B/zh
Priority to AU2019217408A priority patent/AU2019217408B2/en
Priority to RU2020129199A priority patent/RU2792034C2/ru
Priority to JP2020542635A priority patent/JP7125495B2/ja
Publication of WO2019154395A1 publication Critical patent/WO2019154395A1/zh
Priority to AU2022202463A priority patent/AU2022202463A1/en

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Definitions

  • the present invention relates to novel tetrahydroisoquinoline compounds, a process for the preparation thereof, a pharmaceutical composition comprising the same, and uses thereof, and belongs to the technical field of medicine.
  • the invention relates to a novel tetrahydroisoquinoline compound represented by the general formula (I), a pharmaceutically acceptable salt, an isomer, a solvate thereof, a metabolite, a metabolic precursor, a pharmaceutical combination containing the same, and a preventive compound of the same And/or therapeutic or adjuvant treatment of psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, asthma, allergic rhinitis, ankylosing spondylitis, systemic lupus erythematosus associated with phosphodiesterase activity, Rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease,
  • Cyclic nucleotide phosphodiesterases selectively catalyze the hydrolysis of 3-phosphate linkages in intracellular second messenger cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) to form product 5 -AMP or 5-GMP, thereby inactivating cAMP or cGMP signals.
  • cAMP cyclic adenosine monophosphate
  • cGMP cyclic guanosine monophosphate
  • the normal function of PDEs directly affects the intracellular cAMP and/or cGMP concentration, which in turn affects the signaling pathway downstream of such second messengers (Omori K, et al. Circ. Res. 2007, 100: 309-327) ; Maurice DH, et al. Nat. Rev. Drug Discov. 2014, 13: 290-314).
  • proteins directly interacting with cAMP downstream including PDEs, classical cAMP concentration-dependent protein kinases, cAMP direct activation exchange proteins, cyclic nucleotide-gated ion channels, and cAMP direct binding to DNA-binding protein CRP/CAP. And a part of a protein containing a GAF domain, and the like.
  • proteins directly interacting with cGMP include cGMP concentration-dependent protein kinases, cyclic nucleotide-gated ion channels, and some proteins containing GAF domains in addition to PDEs.
  • PDEs are important family of drug targets, and PDEs inhibitors have been widely used in the study and treatment of a variety of disease pathologies (Maurice DH, et al. Nat. Rev. Drug Discov. 2014, 13: 290-314; Menniti FS , et al. Nat. Rev. Drug Discov. 2006, 5(8), 660-670).
  • PDEs are a supergene superfamily. So far, 21 PDE genes have been found in mammals, divided into 11 subfamilies, containing more than 100 different substrate specificities, enzymatic kinetics, heterogeneous regulatory characteristics, and distribution in tissues and sub-cells. Different PDE isozymes (or subtypes) involved in signaling pathways and sensitivity to inhibitors (Lugnier C, Pharmacol. Ther. 2006, 109: 366-398; Francis SH, et al. Handb. Exp. Pharmacol. 2011, 204: 47-84).
  • PDE 4, 7 and 8 mainly hydrolyze cAMP; PDE 5, 6 and 9 selectively act on cGMP; and PDE 1, 2, 3, 10 and 11 can both hydrolyze cAMP and hydrolyze cGMP, although different isozymes for both substrates
  • the affinity and hydrolysis activity are different. Different from the different selectivity to the substrate, the structural characteristics of the members of the PDEs family are very similar, usually consisting of the N-terminal regulatory domain and the adjacent C-terminal catalytic domain, and the catalytic domain (about 270 amino acids) is responsible for the substrate. Hydrolysis reaction.
  • PDEs inhibitors function primarily to inhibit their activity by acting on the catalytic domain of PDEs.
  • PDE4-specific hydrolysis of intracellular second messenger molecule cAMP inhibition of PDE4 activity will lead to accumulation of cAMP, high concentration of cAMP will activate protein kinase A, activated protein kinase A can phosphorylate downstream transcription factors, thereby regulating a large number of cytokines Transcription and expression (Houslay MD, et al. Biochem. J., 2003, 370: 1-18).
  • the PDE4 family includes four genes (PDE4A/B/C/D) that selectively spliced to form more than 25 isozymes during expression.
  • PDE4 is widely distributed in vivo and is mainly expressed in immune-related cells such as neutrophils, eosinophils, and monocytes (Maurice DH, et al. Mol. Pharmacol., 2003, 64: 533-546).
  • PDE4 involves a wide variety of diseases, including chronic obstructive pulmonary disease, asthma, psoriasis, allergic rhinitis, idiopathic pulmonary fibrosis, and rheumatoid arthritis, which are associated with the role of PDE4 in the inflammatory process.
  • Diseases involving the nervous system include Alzheimer's disease, Parkinson's disease, depression, and schizophrenia (Menniti FS, et al. Nat. Rev.
  • Psoriasis is an immune-mediated chronic recurrent skin inflammation characterized by keratinocyte proliferation and massive leukocyte infiltration. This disease is refractory and seriously affects patients' quality of life and physical and mental health.
  • the disease is one of the most common autoimmune diseases in the world, accounting for 0.1% to 3% of the world's population.
  • psoriasis is closely related to other inflammatory diseases such as psoriatic arthritis, inflammatory bowel disease and coronary artery disease.
  • TNF- ⁇ is highly expressed in psoriasis, and the blocking treatment against TNF- ⁇ is clinically effective.
  • Increasing the concentration of cAMP by inhibiting PDE4 hydrolysis activity down-regulates the expression of pro-inflammatory factors such as TNF- ⁇ . Therefore, PDE4 inhibitor Apremilast was approved by the FDA in 2014 for plaque psoriasis and psoriatic arthritis treatment.
  • Oral drug Man HW, et al. J. Med. Chem., 2009, 52: 1522-1524).
  • Crisaborole a topical treatment for eczema (ie, atopic dermatitis) from Anacor Pharmaceuticals. Similar to psoriasis, atopic dermatitis is a common recurrent chronic inflammatory skin disease, and Crisaborole is a non-steroidal PDE4 inhibitor. This drug is the first new molecule approved by the FDA for the treatment of allergic dermatitis in the past 15 years. entity.
  • PDE4 involves a variety of important diseases and some PDE4 inhibitors have been used in clinical treatment, the design and discovery of novel inhibitors targeting PDE4 is a hot spot in the development of new drugs.
  • PDE4 phosphodiesterase type 4
  • the chiral carbon atom C* is independently S-type, R-type, or a combination thereof;
  • n 1 or 2;
  • X is -CH 2 - or -NH-
  • Y is selected from the group consisting of a C1 to C6 straight or branched alkylene group, a C2 to C6 straight or branched alkenylene group, -CH 2 O-, -CH 2 NH 2 -, -CH 2 S-, -CONH-, -NHCO-, -COO-, -OOC-,
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, halogen, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted C2-C6 straight chain or branch.
  • the substituent is selected from hydrazine or halogen; or R 1 , R 2 together with the carbon atom to which they are attached constitute a 5-7 membered carbocyclic or heterocyclic ring (including a saturated ring, an unsaturated ring or an aromatic ring);
  • R 3 is selected from the group consisting of unsubstituted or substituted with 1 to 3 substituents: -C(O)-5 to 7-membered heteroaryl, -C(O)-4 to 7-membered heterocyclic group, - C1 ⁇ C4 acyl group (preferably a formyl group -CHO), - C1 ⁇ C4 alkyl, R 7 SO 2 -, NH 2 (CH 2) m SO 2 -, R 7 SO 2 (CH 2) m -, R 7 O(CH 2 ) m CO-, R 7 OCO(CH 2 ) m -, difluoromethyl, trifluoromethyl, C1-C4 sulfinyl, phenylsulfonyl, 5-7-membered heteroarylsulfonyl, a phenyl group, a benzyl group, a 5- to 7-membered heteroaryl group, and a 4 to 7-membered heterocyclic group;
  • R 5 , R 6 , R 7 are each independently selected from hydrogen, substituted or unsubstituted C1-C4 straight or branched alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6- a C10 aryl group; the substituent is selected from hydrazine or a halogen;
  • n is selected from 0, 1, 2, 3 or 4;
  • R 4 is selected from the group consisting of C3 to C7 cycloalkyl, 5 to 12 membered heterocyclic group, C7 to C12 aryl group, and 5 to 12 membered heteroaryl group which are unsubstituted or substituted with 1 to 3 substituents.
  • each of the heterocyclic or heteroaryl groups contains 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituents are each independently selected From hydrazine, halogen, C1 to C6 straight or branched alkyl, C2 to C6 straight or branched alkenyl, C2 to C6 straight or branched alkynyl, C1 to C6 straight or branched alkoxy, C1-C6 linear or branched alkylcarbonyloxy, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, COOR 5 , CONR 5 R 6 , C1-C6 carboxyl group, mercapto group, C1 to C4 acyl group, C1-C4 amide group, sulfonyl group, aminosulfony
  • n 1;
  • R 1 and R 2 are each independently selected from the group consisting of a substituted or unsubstituted C1-C6 straight or branched alkoxy group, a substituted or unsubstituted C3-C7 cycloalkoxy group, a substituted or unsubstituted C3 ⁇ C7 cycloalkyl methoxy, C1-C6 acyloxy, carboxy substituted C2 to C8 linear alkoxy, N,N-dimethylamino substituted C2 to C8 linear alkoxy, carboxy substituted C2 a C8 linear alkoxy group, an N,N-dimethylamino substituted C2 to C8 linear alkoxy group, COOR 5 or CONR 5 R 6 ; the substituent is selected from hydrazine or halogen (including fluorine, chlorine, Bromine and iodine).
  • R 5 and R 6 are each independently selected from hydrogen, C1-C4 straight or branched alkyl.
  • X is -CH 2 -;
  • R 4 is selected from the group consisting of unsubstituted or substituted by 1 to 3 substituents: 5 to 12 membered heterocyclic group, C6 to C12 aryl group, 5 to 12 membered heteroaryl group (preferably benzo 5 to 7)
  • the heterocyclic and heteroaryl ring moieties in the group are selected from the group consisting of hydrazine, benzodioxole, isoxazole, pyridine, pyrazole, dihydroimidazopyridine , imidazopyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, pyrrole, benzofuran, carbazole, benzimidazole, quinoline, 1,3-dioxoisoindoline formation Group.
  • R 3 is selected from the group consisting of unsubstituted or substituted by 1 to 3 substituents: C1 to C4 acyl (preferably formyl), C1 to C4 alkyl, R 7 SO 2 -, NH 2 (CH 2 m SO 2 -, R 7 SO 2 (CH 2 ) m -, R 7 O(CH 2 ) m CO-, difluoromethyl, trifluoromethyl, C1 to C3 sulfinyl, benzenesulfonyl, 5 a -7 membered heteroarylsulfonyl group, a phenyl group, a benzyl group, a 5 to 7 membered heteroaryl group, a 4 to 7 membered heterocyclic group; wherein each of said heterocyclic group or heteroaryl group has 1 to 3 selected from the group consisting of a hetero atom of oxygen, sulfur and nitrogen; the substituents are each independently selected from the group consisting of hydrazine, halogen
  • R 7 is selected from the group consisting of hydrogen, C1-C4 straight or branched alkyl
  • n is selected from 0, 1, or 2.
  • each of R1 and R2 is independently a C1 to C6 linear or branched alkoxy group, a trifluoromethoxy group, a difluoromethoxy group, a COOR 5 group, and a CONR 5 R 6 group .
  • the R 4 is a fluorenyl group which is unsubstituted or substituted with 1 to 3 substituents; preferably, the fluorenyl group is substituted with a substituent selected from the group consisting of halogen , C1-C4 alkyl, C1-C4 alkoxy, cyano, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, COOR 5 , CONR 5 R 6 .
  • the chiral carbon atom C* is an S type.
  • the condensing agent is EDCI (1-ethyl-(3-dimethyl) Aminopropyl)carbodiimide hydrochloride);
  • the reduction reaction uses a borohydride as a reducing agent or a Noyori catalyst as an asymmetric reduction catalyst;
  • each group is as defined in the first aspect of the invention.
  • a pharmaceutical composition comprising: a therapeutically effective amount of one or more compounds of the formula (I) according to the first aspect of the invention, or A pharmaceutically acceptable salt.
  • the disease is an immune and inflammatory disease associated with PDE4 activity or expression.
  • the disease associated with PDE4 activity or expression is selected from the group consisting of psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, asthma, allergic rhinitis, and rigidity. Spondylitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, ADHD, depression, and spirit Schizophrenia.
  • Figure 1 shows the therapeutic effects of the test compounds ZN17 and ZN42 on a model of acute inflammation of the back pocket of mice.
  • the present inventors After long-term and intensive research, the present inventors have prepared a class of compounds of formula I which are capable of inhibiting phosphodiesterase (PDE4). And the compound has higher inhibitory activity than the phosphodiesterase 4 (PDE4) inhibitory compound of the prior art. Based on the above findings, the inventors completed the present invention.
  • An object of the present invention is to provide a tetrahydroisoquinoline compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer or a racemate thereof. .
  • Another object of the present invention is to provide a process for producing a compound of the above formula (I).
  • a further object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the above formula (I) or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide a use of the compound of the above formula (I) for the preparation of a medicament for the treatment of an autoimmune disease such as psoriasis, psoriatic arthritis, atopic dermatitis and the like.
  • the compounds of the invention are useful for inhibiting phosphodiesterase 4 (PDE4).
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 naphthenic a group, a C 1 -C 10 alkoxy group, a halogen, a hydroxyl group, a carboxyl group (-COOH), a C 1 -C 10 aldehyde group, a C 2 -C 10 acyl group, a C 2 -C 10 ester group, an amino group, a phenyl group;
  • the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 10 alkyl, cyano, hydroxy, nitro, C 3 ⁇ C 10 cycloalkyl, C 1 -C 10 alkoxy, amino.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • C1-C6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Tert-butyl, or a similar group.
  • 3-8 membered heterocyclic group refers to a group formed by a 3 to 8 membered saturated ring having from 1 to 3 hetero atoms selected from the group consisting of N, S, O; for example, pyrrolidinyl group, Piperidinyl, piperazinyl, morpholinyl, or the like.
  • 6-10 membered aryl refers to a group formed by the loss of one hydrogen atom of a 6 to 10 membered aryl group; for example, a phenyl group, a naphthyl group, or the like.
  • 5-10 membered heteroaryl refers to a group of 5 to 8 membered aryl groups having from 1 to 3 heteroatoms selected from the group consisting of N, S, and O, each of which is heteroaryl.
  • the cyclic system of the group may be monocyclic or polycyclic; for example, pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, fluorenyl, imidazopyridyl, quinolyl Or a similar group.
  • C1-C6 alkoxy refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy, tert-butoxy, or the like.
  • halogen refers to F, Cl, Br and I.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetric centers R, S configuration, (Z), (E) isomers of the double bond and conformational isomers of (Z), (E).
  • isomeric forms such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetric centers R, S configuration, (Z), (E) isomers of the double bond and conformational isomers of (Z), (E).
  • a single stereochemical isomer of the compound of the invention or its enantiomer Mixtures of isomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the invention.
  • tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
  • proton tautomers ie, proton shifts
  • the valence tautomers include interconversion through some bonding electron recombination.
  • C1 to C6 means that the group may have 1 to 6 carbon atoms, for example, 1, 2, 3, 4 or 5.
  • the compounds of the present application may include isotopically-formed compounds known in the art, such as isotopes of hydrogen ( ⁇ , ⁇ , etc.), carbon isotopes (C14).
  • isotopes of hydrogen ⁇ , ⁇ , etc.
  • C14 carbon isotopes
  • the abundance of the above isotope is not greater than its abundance in the natural environment, but it can also be prepared by using a reaction raw material containing the isotope to obtain an isotope-substituted compound having abundance higher than the natural abundance, such as a deuterated compound. Wait.
  • the abundance of deuterium atoms in the deuterated compound is >99%.
  • the present invention provides a tetrahydroisoquinoline compound represented by the formula (I), an enantiomer thereof, a diastereomer, a racemate, a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • each group is as described above.
  • n, X, Y, R 1 , R 2 , R 3 , R 4 are each independently the corresponding group corresponding to each specific compound in the examples.
  • tetrahydroisoquinoline compounds of the present invention are preferably selected from the compounds shown in Table A below:
  • the invention also provides a process for the synthesis of a compound of formula I, in particular, wherein the compound of formula I is prepared by the following scheme:
  • Step a dissolving I c in a solvent, and performing a condensation reaction with II with the aid of a condensing agent to obtain a compound I d ;
  • the solvent is dichloromethane;
  • Step b dissolving I d in a solvent, adding an excess of phosphorus oxychloride, and stirring under reflux to obtain a compound I e ;
  • the solvent is anhydrous acetonitrile;
  • Step c dissolving I e in a solvent, adding excess sodium borohydride, stirring until the reaction is complete, and spinning the solvent to obtain compound I f , the solvent is methanol; or adding Noyori catalyst, stirring until the reaction is complete, the solvent is A mixed solvent of water and dichloromethane.
  • Step d dissolving I f in a solvent, and reacting with a corresponding starting material to obtain a compound I g ;
  • the solvent is ethyl formate or DMF or tetrahydrofuran;
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a tetrahydroisoquinoline compound represented by the formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, and a hydrate thereof and a solvent thereof
  • a pharmaceutically acceptable carrier which is useful for treating autoimmune-related diseases such as psoriasis.
  • the pharmaceutical composition can be prepared in various forms depending on the route of administration.
  • a pharmaceutical composition of one or more of a tetrahydroisoquinoline compound represented by (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, and a hydrate thereof and a solvate thereof can be used as phosphodiesterase 4 (PDE4) Inhibitor for the treatment of autoimmune-related diseases such as psoriasis.
  • PDE4 phosphodiesterase 4
  • the preparation of the pharmaceutically acceptable salt of the compound of the present invention can be carried out by directly reacting a free base of the compound with an inorganic or organic acid.
  • the inorganic or organic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonate. Acid and p-toluenesulfonic acid and the like.
  • the compound of the present invention has excellent inhibitory activity against phosphodiesterase 4 (PDE4), the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and
  • the pharmaceutical composition of the present invention as a main active ingredient can be used for the treatment and alleviation of diseases associated with phosphodiesterase 4 (PDE4), for example, treatment of diseases associated with abnormal expression of phosphodiesterase 4 (PDE4).
  • the compounds of the invention are useful in the treatment of diseases such as psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease and the like.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) a slow solvent such as paraffin; (f) absorption Accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the compounds according to the invention as described above can be used clinically in mammals, including humans and animals, by route of administration to the mouth, nose, skin, lungs, or gastrointestinal tract, and more preferably orally.
  • the daily dose is preferably 0.01 to 200 mg/kg body weight, taken at once, or 0.01 to 100 mg/kg body weight in divided doses.
  • the optimal dosage for the individual should be based on the particular treatment. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the tetrahydroisoquinoline compound of the present invention has a good inhibitory effect on tetratype phosphodiesterase (PDE4) and can be used for the prevention, treatment or adjuvant treatment of psoriasis and psoriasis associated with phosphodiesterase activity.
  • PDE4 tetratype phosphodiesterase
  • the analytical data of the samples were determined by the following instruments: NMR was determined by GEMINI-300, Bruker AMX-400 and INVOA-600 NMR, TMS (tetramethylsilane) was used as internal standard, and the chemical shift was in ppm. The constant unit is Hz; the mass spectra were determined by Finnigan Model MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.
  • the compound 1-4 was dissolved in methanol, and sodium borohydride was added portionwise in an ice bath, stirred at room temperature for 4 hours, and the reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, saturated sodium hydrogen carbonate and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated.
  • Example (S)-A1 was replaced with a (S,S)-Noyori catalyst, and the synthesis method was carried out with reference to the synthesis of the compound (S)-A1 to give the compound (R)-A1.
  • Or (R)-A1 can be isolated from A1 by chiral column.
  • Lithium tetrahydrogen aluminum was added to argon-protected tetrahydrofuran in batches under ice-cooling. A 4-4 solution of tetrahydrofuran was added dropwise with stirring. After refluxing for 2 h, the reaction was quenched slowly with ice, and filtered. The cake was evaporated to dryness to a slightly yellow transparent oil. The step was taken directly without purification.
  • Example A2 The 4-2 in Example A2 was replaced with ethyl bromide, and the synthesis method was carried out with reference to the synthesis of Compound A2 to give Compound A4.
  • Example A2 The 4-2 in Example A2 was replaced with benzyl bromide, and the synthesis method was carried out with reference to the synthesis of the compound (S)-A2 to give the compound (S)-A5.
  • the compound (S)-A5 is catalytically hydrogenated by palladium on carbon, debenzylated, and reacted with (2-bromomethyl)dimethylamine in potassium carbonate and acetonitrile to obtain (S)-A6.
  • the compound (R)-A5 is catalytically hydrogenated by palladium on carbon, debenzylated, and reacted with (2-bromomethyl)dimethylamine in potassium carbonate and acetonitrile to obtain (S)-A6.
  • the compound (S)-A5 is catalytically hydrogenated by palladium on carbon, debenzylated, and reacted with 3-bromopropionic acid in potassium carbonate and acetonitrile to obtain (S)-A7.
  • the compound (R)-A5 is catalytically hydrogenated by palladium on carbon, debenzylated, and reacted with 3-bromopropionic acid in potassium carbonate and acetonitrile to obtain (S)-A7.
  • Example B1 Substituting 11-1 of Example B1 with Compound 13-1, the synthesis method was carried out with reference to the synthesis of Compound (S)-B1 to give Compound (S)-B3.
  • ESI-MS m/z 449.2 [M+H] + .
  • Example B1 Substituting 11-1 of Example B1 with Compound 14-1, the synthesis method was carried out with reference to the synthesis of Compound (S)-B1 to give Compound (S)-B4.
  • ESI-MS m/z 409.2 [M+H] + .
  • Example B1 Substituting 11-1 of Example B1 with Compound 14-1, the synthesis method is carried out with reference to the synthesis of Compound (R)-B1 to give Compound (R)-B4.
  • ESI-MS m/z 409.2 [M+H] + .
  • Example A2 Substituting 4-2 of Example A2 with ethyl bromide and 11-1 of Example B1 with compound 14-1, the synthesis method refers to the synthesis of compound (S)-B11 to give (S)-B12. ESI-MS m/z 423.0 [M+H] + .
  • Example A2 Substituting 4-2 of Example A2 with ethyl bromide and 11-1 of Example B1 with compound 14-1, the synthesis method refers to the synthesis of compound (R)-B11 to give (R)-B12. ESI-MS m/z 423.0 [M+H] + .
  • Example B2 The ethyl bromide was replaced by 4-2,2-iodoacetamide in Example A2 in place of 12-1 in Example B2, and Example B2 was obtained to give Compound B16.
  • Example B2 The ethyl bromide was replaced by 4-2,2-iodoacetamide in Example A2 in place of 12-1 in Example B2, and Example B2 was obtained to give Compound B16.
  • Example B2 The ethyl bromide was replaced by 4-2,2-iodoacetamide in Example A2 in place of 12-1 in Example B2, and Example B2 was obtained to give Compound B16.
  • Example A1 Substituting 1-1 of Example A1 with Compound 4-5, and replacing 1-2 of Example A1 with Compound 23-4, the synthesis method refers to the synthesis of Compound A1 to give Compound C1.
  • Example A1 Substituting 1-2 of Example A1 with Compound 32-1, the synthesis method was carried out with reference to the synthesis of Example B9 to give Compound C13.
  • Example A1 Substituting 1-2 of Example A1 with Compound 32-1, the synthesis method was carried out with reference to the synthesis of Example (S)-B9 to give Compound (S)-C13.
  • ESI-MS m/z 443.2[M+H]+.
  • Example A1 Substituting 1-2 of Example A1 with Compound 32-1, the synthesis method was carried out with reference to the synthesis of Example (R)-B9 to give Compound (R)-C13.
  • ESI-MS m/z 443.2[M+H]+.
  • Example A1 Substituting 1-2 of Example A1 with Compound 32-1, the synthesis method was carried out with reference to the synthesis of Example A4 and Example B9 to give Compound C15.
  • Example A1 Substituting 1-2 of Example A1 with Compound 32-1, the synthesis method was carried out with reference to the synthesis of Examples (S)-A4 and Examples (S)-B9 to give Compound C15.
  • ESI-MS m/z 457.2 [M+H] + .
  • Example A1 Substituting 1-2 of Example A1 with Compound 32-1, the synthesis method was carried out with reference to the synthesis of Example A4 and Example B4 to give Compound C16.
  • Example A1 Substitution of 1-2 in Example A1 with Compound 32-1, the synthesis method Referring to the synthesis of Examples (S)-A4 and Examples (S)-B4, Compounds (S)-C16 were obtained.
  • the 24-1 was dissolved in anhydrous tetrahydrofuran, and the n-butyllithium solution was slowly added dropwise at -78 ° C. After 30 min of reaction, the solution of zinc chloride in tetrahydrofuran was added dropwise, and the temperature was raised to room temperature. -1, stirred for 24 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate three times. The organic layer was washed with water, washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Oil (605 mg, 70%).
  • C30-1 was dissolved in anhydrous dichloromethane, and chloroacetyl chloride and triethylamine were added dropwise under ice-cooling. The mixture was reacted to room temperature for 1 hour, quenched with water, and dried by DCM.
  • C30-3 was dissolved in acetonitrile, cesium carbonate was added, stirred at room temperature for 2 h, added with C30-2 under nitrogen atmosphere, stirred for 18 h, quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with saturated brine, C30-4. Substitution of 1-3 in Example A1 with C30-4, with reference to the synthesis of A4, gave Compound C30.
  • the intermediate C36-1 was replaced with (S)-C36-1, and (S)-C36 was synthesized with reference to C36.
  • the intermediate C36-1 was replaced with (R)-C36-1, and (R)-C36 was obtained by reference to the synthesis of C36.
  • Example A1 Substituting 1-2 of Example A1 with Compound 32-1, and B14-1 of Example B14 with acetyl chloride, the synthesis method was carried out with reference to the synthesis of Compound (S)-B14 to give Compound (S)-C38.
  • Example A1 Substituting 1-2 in Example A1 with Compound 32-1, and replacing 12-1 in Example B2 with Compound 15-1, the synthesis was carried out with reference to the synthesis of Compound B2 to give Compound C43.
  • Example B13 The methanesulfonyl chloride in Example B13 was replaced with benzenesulfonyl chloride, and the synthesis method was carried out with reference to the synthesis of the compounds (S)-C8 and B13 to give the compound (S)-C47.
  • Example (S)-C65 was replaced with 5-difluoromethylhydrazine, and the synthesis method was carried out with reference to the synthesis of the compound (S)-C65 to give the compound (S)-C74.
  • Example (S)-C65 was replaced with 5-trifluoromethoxy oxime, and the synthesis method was carried out with reference to the synthesis of the compound (S)-C65 to give the compound (S)-C76.
  • Example (S)-C65 was replaced with 5-difluoromethoxy oxime, and the synthesis method was carried out with reference to the synthesis of the compound (S)-C65 to give the compound (S)-C77.
  • Example (S)-C65 Substitution of 65-1 in Example (S)-C65 with 5-fluoroindole, the synthesis method was carried out with reference to the synthesis of the compound (S)-C65 to give the compound (S)-C78.
  • ESI-MS m/z 397.2.
  • Example (S)-C65 was replaced with 6-chloro-5-methoxyindole, and the synthesis method was carried out with reference to the synthesis of the compound (S)-C65 to give the compound (S)-C80.
  • Example (S)-C65 Substitution of 65-1 in Example (S)-C65 with 5-fluoro-6-chloropurine, the synthesis method was carried out with reference to the synthesis of the compound (S)-C65 to give the compound (S)-C81.
  • the enzyme inhibition activity of the PDE4D catalytic domain was determined by the Scintillation Proximity Assay (SPA) method.
  • the human PDE4D catalytic domain protein was obtained by expression and purification in E. coli.
  • the positive compound Apremilast was purchased from Tao Biochemical, microplate scintillation counter (MicroBeta2, Perkin Elmer), constant temperature water bath (DK420, Shanghai Medical Instrument Factory).
  • the micro-vibration instrument (XW-80A, Shanghai Jingke Industrial Co., Ltd.) is a radioactive laboratory utility instrument, a multi-channel pipette (Multipette Plus, Eppendorf) and a matching gun head purchased from Ai Bend Biotechnology Co., Ltd., 3.5.
  • 10x SPA buffer was prepared in the laboratory (500 mM Tris pH 7.5, 83 mM MgCl2, 17 mM EGTA).
  • Table B1 shows the inhibition rate and IC 50 value of the compound on PDE4D activity.
  • the IC 50 value of the inhibitory activity against PDE4 was determined by measuring the inhibition rate of PDE4 at a concentration of 1 ⁇ M. Among them, 14 compounds have an IC 50 value of one hundred nanomolar, and three compounds (C10, (S)-C10 and (S)-C8) have IC 50 values lower than one hundred nanomoles, which is equivalent to the IC 50 value of the positive control compound Apremilast. .
  • PDE4 peripheral blood mononuclear cell
  • the cell type is mononuclear cells in the blood, mainly including lymphocytes (T/ B), monocytes, macrophages, dendritic cells and other small cell types, in which lymphocytes account for a large part, so that the blood immune environment in vitro can be directly simulated.
  • LPS Lipopolysaccharide
  • the positive compound Apremilast was purchased from Taosu Biochemical Technology Co., Ltd. Whole blood of healthy people was provided by Shanghai Blood Center; Fetal Bovine Serum (FBS) was purchased from Hyclone (South Logan, UT, USA); RPMI-1640 medium and human TNF- ⁇ ELISA test kit were purchased from Invitrogen (San Diego, CA, USA); bacterial lipopolysaccharide LPS was purchased from Sigma (L9764, St. Louis, MO, USA).
  • FBS Fetal Bovine Serum
  • Hyclone South Logan, UT, USA
  • RPMI-1640 medium and human TNF- ⁇ ELISA test kit were purchased from Invitrogen (San Diego, CA, USA)
  • bacterial lipopolysaccharide LPS was purchased from Sigma (L9764, St. Louis, MO, USA).
  • PBMC cells isolated from human blood were implanted into 96-well plates at 2*10 5 /ml; gradient compounds were added with at least three replicates per gradient; after incubation for 1 hour at 37 ° C, 5% CO 2 PBMCs were stimulated to express TNF- ⁇ by LPS (final concentration of 10 ug/ml); 96-well plates were collected by incubating at 37 ° C, 5% CO 2 for 18-20 h. A non-irritant background control and stimulation control wells were also provided, with a total volume of 200 ⁇ l. The culture supernatant was collected by centrifugation, and the expression level of TNF- ⁇ in the culture supernatant was measured by ELISA.
  • Table 2 shows the results of inhibition of inflammatory factor TNF- ⁇ secretion by PBMC in the compound.
  • Tumor necrosis factor- ⁇ is an important inflammatory mediator in the development of diseases such as inflammation and autoimmune diseases. It is mainly produced by activated monocytes/macrophages, which can mediate the occurrence of various inflammatory reactions and accelerate the progression of disease.
  • Mouse mononuclear/macrophage leukemia cell line RAW 264.7 is one of the commonly used inflammatory cell models. After bacterial lipopolysaccharide (LPS) induction, it can release the release of various inflammatory mediators such as tumor necrosis factor- ⁇ .
  • LPS bacterial lipopolysaccharide
  • the phosphodiesterase PDE4 is expressed in macrophages, and the inhibitory activity of the compound against phosphodiesterase PDE4 can be reflected by detecting the secretion of tumor necrosis factor- ⁇ .
  • Detection of RAW 264.7 cytotoxicity of the compound The cytotoxicity of the test compound on RAW 264.7 cells was detected by the CCK-8 method, and the mouse RAW 264.7 cells were purchased from the American Type Culture Collection (Manassas, VA, USA) and cultured in 10 % fetal bovine serum (Hyclone, South Logan, UT, USA) in DMEM medium (Hyclone, South Logan, UT, USA), cells were collected and counted immediately before use, (1 ⁇ 10 5 /well) inoculated into 96 wells In the plate (Corning, NY, USA), after incubation for 24 h, different concentrations of the compound were added, and the corresponding vehicle control and culture background control were set up, and the total volume was 200 ⁇ l.
  • the culture supernatant was collected by centrifugation, and the secretion level of tumor necrosis factor- ⁇ in the culture supernatant was measured by enzyme-linked immunosorbent assay, and the tumor necrosis factor- ⁇ detection kit was purchased from BD Pharmingen (San Diego, CA, USA).
  • Table B3 is the result of inhibition of compound TNF 264.7 cell inflammatory factor tumor necrosis factor- ⁇ secretion
  • Table B4 shows the results of inhibition of RAW 264.7 cytotoxicity (CC50) and secretion of tumor necrosis factor- ⁇ by some compounds (IC50)
  • a CC 50 is the concentration of the drug required for causing half of the cytotoxicity; b IC 50 is the drug concentration at which 50% of tumor necrosis factor- ⁇ is effectively inhibited; c SI is CC 50 /IC 50 .
  • the acute inflammation model of the back pocket of the mouse is a classic model for evaluating the anti-inflammatory activity of the candidate compound in vivo, and the feasibility is high and the repeatability is good.
  • the mice were injected subcutaneously with 3 ml of air on the back, and on the third day, 1.5 ml of air was injected subcutaneously on the back, and on the 6th day, 1 ml of 2% carrageenan (Sigma-Aldrich, St. Louis, MO, USA) solution was injected subcutaneously.
  • Sensitization 4 hours after sensitization, phosphate buffer was used to perfuse the secretions in the air sac.
  • the lavage fluid was used for white blood cell count and inflammatory factor detection.
  • the positive drug Apremilast, the test drug (S)-C5, (S)-C8 with 0.5% sodium carboxymethylcellulose (Sigma-Aldrich, St. Louis, MO, USA) + 0.25% Tween-80 (purchased Dispersed from Sinopharm Group, the drug was administered orally (5mg/kg) 24h and 1h before sensitization, and the tumor necrosis factor- ⁇ and interleukin-6 test kits were purchased from BD Pharmingen (San Diego, CA, USA). ).
  • test compounds (S)-C5, (S)-C8 can significantly reduce the inflammatory response of the acute inflammatory model of the balloon in the back of the mouse, and reduce the number of leukocyte infiltration in the lavage fluid. Tumor necrosis factor- ⁇ and interleukin-6 secretion levels.
  • Compounds 14, 16, 17, 18, 22 and 29 of the present invention were administered by intragastric administration and intravenous injection, respectively, in a volume of 10 mL/kg, and the drug was administered in DMSO/Tween 80/normal saline (5:5:90, v/). v/v) formulated. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration.
  • Administration by intragastric administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • Intravenous administration 5 min after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h;
  • venous blood was taken from the posterior venous plexus of the rat eye, placed in a heparinized tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen in a refrigerator at -20 °C.
  • the concentration of the compound in rat plasma was determined by LC/MS/MS.
  • the pharmacokinetic parameters after administration were calculated using a non-compartmental model of DAS 3.0 software.
  • Table B5 shows the results of pharmacokinetic experiments of compounds (S)-C7 and (S)-C8 in rats
  • Compound (S)-C7 After administration of 20 mg/kg compound (S)-C7 in rats, the peak plasma concentration Tmax was 1 h, the peak concentration Cmax was 2383.6 ng/ml, and the area under the curve was AUC0-t. It was 9232.3 ng ⁇ h/ml; the terminal elimination half-life t1/2 was 1 h. After intravenous administration of 10 mg/kg of compound (S)-C7, AUC0-t was 6761.8 ng ⁇ h/ml; after dose-normalized, the absolute bioavailability of rats after intragastric administration of 20 mg/kg of compound (S)-C7 It is 68.3%.
  • Compound (S)-C8 After administration of 20 mg/kg compound (S)-C8 in rats, the peak plasma concentration Tmax was 1.33 h, the peak concentration Cmax was 491 ng/ml, and the area under the curve was AUC0-t. It was 508 ng ⁇ h/ml; the terminal elimination half-life t1/2 was 1.03 h. After intravenous administration of 10 mg/kg of compound (S)-C7, AUC0-t was 2640 ng ⁇ h/ml; after dose standardization, the absolute bioavailability of rats after intragastric administration of 20 mg/kg compound (S)-C8 was 9.30%.
  • the compound (S)-C8 of the present invention was administered by intragastric administration and intravenous injection respectively, and the administration volume was 5 mL/kg and 1 mL/kg, respectively, and the intragastric administration was formulated with 0.5% CMC-Na + 0.25% Tween 80, and intravenous administration.
  • Administration by intragastric administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • Intravenous administration 5 min after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h;
  • the concentration of compound (S)-C8 in beagle dogs plasma was determined by LC/MS/MS.
  • the pharmacokinetic parameters after administration were calculated using a non-compartmental model of Phoenix 1.3 software (Pharsight, USA).
  • Table B6 shows the results of pharmacokinetic experiments of compound (S)-C8 in beagle dogs
  • the plasma concentration peak time T max was 0.5 h
  • the peak concentration C max was 4685 ng/ml
  • the area under the curve was AUC 0-t was 16601 ng ⁇ h/ml
  • terminal elimination half-life t 1/2 was 2.92 h.
  • AUC 0-t was 9610 ng ⁇ h/ml

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Abstract

本发明公开了一种新型四氢异喹啉类化合物及其中间体的制备方法、药物组合物和用途。本发明的四氢异喹啉类化合物对磷酸二酯酶(PDE4)具有良好的抑制效果，可以用于预防、治疗或辅助治疗与磷酸二酯酶活性或表达相关的多种疾病，尤其是与PDE4相关的免疫和炎症性疾病如银屑病和关节炎等。(I)

Description

四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 技术领域
本发明涉及新型四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途，属于医药技术领域。涉及通式(I)所示的新型四氢异喹啉类化合物，其药物上可接受盐、异构体、溶剂化物、代谢产物、代谢前体，含有他们的药物组合以及这类化合物在预防和、或治疗或辅助治疗与磷酸二酯酶活性相关的银屑病、银屑病关节炎、过敏性皮炎、慢性阻塞性肺病、哮喘、过敏性鼻炎、强直性脊柱炎、系统性红斑狼疮、风湿性关节炎、炎症性肠病、肺纤维化、多发性硬化症、阿尔兹海默症、亨廷顿舞蹈症、帕金森氏症、多动症、抑郁症和精神分裂症等疾病，尤其是与PDE4相关的免疫和炎症性疾病如银屑病和关节炎等。
背景技术
环核苷酸磷酸二酯酶(Cyclic nucleotide phosphodiesterases,PDEs)选择性催化水解细胞内第二信使环磷酸腺苷(cAMP)或环磷酸鸟苷(cGMP)中的3-磷酸酯键，生成产物5-AMP或5-GMP，从而灭活cAMP或cGMP信号。PDEs活性功能发挥正常与否直接影响细胞内cAMP和/或cGMP浓度，进而影响此类第二信使参与的信号通路下游信号传递(Omori K,et al.Circ.Res.2007,100:309-327；Maurice DH,et al.Nat.Rev.Drug Discov.2014,13:290-314)。目前已知cAMP下游存在多种与其直接相互作用的蛋白质，包括PDEs、经典的cAMP浓度依赖蛋白激酶、cAMP直接激活交换蛋白、环核苷酸门控离子通道、cAMP直接结合DNA结合蛋白CRP/CAP和部分包含GAF结构域的蛋白质等。相应地，与cGMP直接相互作用蛋白质除了PDEs以外还有cGMP浓度依赖蛋白激酶、环核苷酸门控离子通道和部分包含GAF结构域的蛋白质等。这些信号通路与细胞周期控制、细胞分化、炎症、心脏功能、平滑肌舒张与收缩、视觉信号传导、学习与记忆等生理及相关病理过程密切相关。抑制PDEs水解活性，改变细胞内cAMP或cGMP浓度，从而直接调控cAMP或cGMP相关的信号通路，改变相关功能症状。因此，PDEs是重要的药物作用靶标家族，PDEs抑制剂已经广泛应用于多种疾病病理机制研究及治疗(Maurice DH,et al.Nat.Rev.Drug Discov.2014,13:290-314；Menniti FS,et al.Nat.Rev.Drug Discov.2006,5(8),660-670)。
PDEs是一个多基因的超家族。迄今为止已在哺乳动物中发现21个PDE基因，分为11个亚家族，共包含100余种具有不同底物专一性、酶动力学特征、异构调控特点以及在组织和亚细胞中分布、参与信号通路和对抑制剂敏感性等不同的PDE同功酶(或称为亚型)(Lugnier C，Pharmacol.Ther.2006,109：366-398；Francis SH,et al.Handb.Exp.Pharmacol.2011,204:47-84)。例如PDE4、7和8主要水解cAMP；PDE5、6和9则选择性作用于cGMP；而PDE1、2、3、10和11既可以水解cAMP又可以水解cGMP，虽然不同同工酶对两底物的亲合力和水解活性有所差别。与对底物具有不同选择性不同，PDEs家族成员的结构特征非常相似，通常由靠近N端调控结构域和邻近C端催化结构域组成，催化结构域(约270个氨基酸)负责对底物进行水解反应。目前已知的PDEs抑制剂主要通过作用于PDEs的催化结构域而实现抑制其活性的功能。
PDE4特异性水解细胞内第二信使分子cAMP，抑制PDE4的活性将导致cAMP的积累，高浓度的cAMP将激活蛋白激酶A，活化的蛋白激酶A可以将下游转录因子磷酸化，从而调控大量细胞因子的转录和表达(Houslay MD,et al.Biochem.J.,2003,370:1-18)。 PDE4家族包括四个基因(PDE4A/B/C/D)，在表达过程中选择性剪接形成超过25种同工酶。PDE4在体内分布广泛，主要表达于免疫相关细胞如中性粒细胞、嗜酸性粒细胞和单核细胞等(Maurice DH,et al.Mol.Pharmacol.,2003,64:533-546)。PDE4涉及的疾病种类繁多，其中与PDE4在炎症进程中的作用相关的有慢性阻塞性肺疾病、哮喘、银屑病、过敏性鼻炎、特发性肺纤维化和风湿性关节炎等疾病，而涉及神经系统的疾病包括阿尔兹海默症、帕金森氏症、抑郁症和精神分裂症等(Menniti FS,et al.Nat.Rev.Drug Discov.,2006,5:660-670；Burgin AB,et al.Nat.Biotechnol.,2010,28:63-70；Garcia-Osta A,et al.ACS Chem.Neurosci.,2012,3:832-844.)。
银屑病是一种免疫介导的、以角质形成细胞增殖和大量白细胞浸润为特征的慢性复发性皮肤炎症，该疾病顽固难治且严重影响患者的生活质量及身心健康，是当今世界皮肤科领域拟解决的重要疾病之一。该疾病是全球最为常见的自身免疫疾病之一，发病率占世界人口的0.1％-3％。此外银屑病还与其它炎症性疾病如银屑病性关节炎、炎症性肠病和冠状动脉疾病等密切相关。目前虽已有一系列药物(包括外用、口服和生物药物等)用于银屑病的对症治疗，但仍在巨大缺口，迫切需要发现新靶点和研发新药物。TNF-α在银屑病中高度表达，针对TNF-α的阻断治疗在临床上效果显著。通过抑制PDE4水解活性而增加cAMP的浓度能下调TNF-α等促炎因子的表达，因此，PDE4的抑制剂Apremilast于2014年被FDA批准为斑块型银屑病和银屑病关节炎治疗的口服药物(Man H-W,et al.J.Med.Chem.,2009,52:1522-1524)。此外，2016年12月，FDA批准Anacor制药公司的湿疹(即过敏性皮炎)局部治疗药Crisaborole上市。与银屑病类似，过敏性皮炎是一种常见的复发性慢性炎性皮肤疾病，而Crisaborole是非甾体PDE4抑制剂，该药物是FDA在过去15年中批准治疗过敏性皮炎的首个新分子实体。
因此，由于PDE4涉及多种重要疾病且已有部分PDE4抑制剂用于临床治疗，设计和发现靶向PDE4的新型抑制剂是新药研发领域的一大热点。
发明内容
本发明的目的是提供一类新型的四型磷酸二酯酶(PDE4)抑制剂即一类新型四氢异喹啉类化合物、其中间体、制备方法、药物组合物和应用。
本发明的第一方面，提供了一种通式(I)所示的四氢异喹啉类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体：
Figure PCTCN2019074704-appb-000001
其中，
手性碳原子C*独立地为S型、R型，或其组合；
n＝1或2；
X为-CH 2-或-NH-；
Y选自连接基团：C1～C6直链或支链亚烷基、C2～C6直链或支链亚烯基、-CH 2O-、-CH 2NH 2-、-CH 2S-、-CONH-、-NHCO-、-COO-、-OOC-、
Figure PCTCN2019074704-appb-000002
R 1、R 2各自独立地选自下组：氢、氘、羟基、卤素、取代或未取代的C1～C6直链 或支链烷氧基、取代或未取代的C2～C6直链或支链烯氧基、取代或未取代的C2～C6直链或支链炔氧基、取代或未取代的C3～C7环烷氧基、取代或未取代的C3～C7环烷基甲氧基、苄氧基、C1-C6酰氧基、羧基取代的C2～C8直链烷氧基、N,N-二甲基氨基取代的C2～C8直链烷氧基，COOR 5或CONR 5R 6；所述取代基选自氘或者卤素；或者R 1、R 2连同与其连接的碳原子共同构成5-7元碳环或杂环(包括饱和环、不饱和环或芳香性环)；
R 3选自未被取代或者被1-3个取代基取代的以下基团：-C(O)-5～7元杂芳基、-C(O)-4～7元杂环基、-C1～C4酰基(优选为甲酰基-CHO)、-C1～C4烷基、R 7SO 2-、NH 2(CH 2) m SO 2-、R 7SO 2(CH 2) m-、R 7O(CH 2) mCO-、R 7OCO(CH 2) m-、二氟甲基，三氟甲基，C1～C4亚磺酰基，苯磺酰基，5-7元杂芳基磺酰基，苯基，苄基，5～7元杂芳基，4～7元杂环基；其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；所述的取代基各自独立地选自氘、卤素、C1～C6直链或支链烷氧基、C1～C6直链或支链烷基羰氧基、C1～C6直链或支链烷氧羰基、氰基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、羧基、羟肟基、磷酸基、巯基、C1～C4酰胺基、C0～C4磺酰基、氨基C0～C4磺酰基、C1-C4烷基取代的磺酰基苯基，苄基，5～7元杂芳基，4～7元杂环基，其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；
R 5、R 6、R 7各自独立地选自氢、取代或未取代的C1～C4直链或支链烷基、取代或未取代的C3～C8环烷基、取代或未取代的C6-C10芳基；所述取代基选自氘或者卤素；
m选自0、1、2、3或者4；
R 4选自未被取代或者被1-3个取代基取代的以下基团：C3～C7环烷基、5～12元杂环基、C7～C12芳基、5～12元杂芳基(优选为苯并5～7元杂芳基)；其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；所述的取代基各自独立地选自氘、卤素、C1～C6直链或支链烷基、C2～C6直链或支链烯基、C2～C6直链或支链炔基、C1～C6直链或支链烷氧基、C1～C6直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、二氟甲基、二氟甲氧基、COOR 5、CONR 5R 6、C1-C6羧基、巯基、C1～C4酰基、C1～C4酰胺基、磺酰基、氨基磺酰基、C1～C4烷基取代的磺酰基，C1～C4烷基取代的磺酰胺基，N,N-二甲基取代的C1-C6烷氧基，羧基取代的C1-C6烷氧基，或者两个相邻的取代基连同与其连接的碳原子共同构成5-7元碳环或杂环(包括饱和环、不饱和环或芳香性环)；
在另一优选例中，通式(I)中：
n＝1；
R 1、R 2各自独立地选自下组：取代或未取代的C1～C6直链或支链烷氧基、取代或未取代的C3～C7环烷氧基、取代或未取代的C3～C7环烷基甲氧基、C1-C6酰氧基、羧基取代的C2～C8直链烷氧基、N,N-二甲基氨基取代的C2～C8直链烷氧基、羧基取代的C2～C8直链烷氧基、N,N-二甲基氨基取代的C2～C8直链烷氧基，COOR 5或CONR 5R 6；所述取代基选自氘或者卤素(包括氟、氯、溴和碘)。
在另一优选例中，R 5、R 6各自独立地选自氢、C1～C4直链或支链烷基。
在另一优选例中，通式(I)中：
X为-CH 2-；
Y选自下组：-CH 2-、-CH 2-CH 2-、-CH＝CH-、
Figure PCTCN2019074704-appb-000003
R 4选自未被取代或者被1-3个取代基取代的以下基团：5～12元杂环基、C6～C12芳基、5～12元杂芳基(优选为苯并5～7元杂芳基)；优选地，所述基团中的杂环和杂芳 环部分选自吲哚、苯并二氧杂环戊烯、异噁唑、吡啶、吡唑、二氢咪唑并吡啶、咪唑并吡啶、苯并噻吩、二氢苯并二氧六环、喹喔林、吡咯、苯并呋喃、吲唑、苯并咪唑、喹啉、1,3-二氧代异吲哚啉形成的基团。
在另一优选例中，通式(I)中：
R 3选自未被取代或者被1-3个取代基取代的以下基团：C1～C4酰基(优选为甲酰基)，C1～C4烷基，、R 7SO 2-、NH 2(CH 2) m SO 2-、R 7SO 2(CH 2) m-、R 7O(CH 2) mCO-、二氟甲基、三氟甲基、C1～C3亚磺酰基、苯磺酰基、5-7元杂芳基磺酰基、苯基、苄基、5～7元杂芳基、4～7元杂环基；其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；所述的取代基各自独立地选自氘、卤素、C1～C6直链或支链烷氧基、C1～C6直链或支链烷基羰氧基、C1～C6直链或支链烷氧羰基、氰基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、羧基、羟肟基、磷酸基、巯基、C1～C4酰胺基、C1～C4磺酰基、氨基C1～C4磺酰基、C1-C4烷基取代的磺酰基苯基，苄基，5～7元杂芳基，4～7元杂环基，其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；
R 7选自氢、C1～C4直链或支链烷基；
m选自0、1或者2。
在另一优选例中，所述的R1、R2各自独立地为C1～C6直链或支链烷氧基、三氟甲氧基、二氟甲氧基、COOR 5、CONR 5R 6。
在另一优选例中，所述的R 4为未被取代或者被1-3个取代基取代的吲哚基；优选地，所述的吲哚基被选自下组的取代基取代：卤素、C1～C4烷基、C1～C4烷氧基、氰基、三氟甲基、三氟甲氧基、二氟甲基、二氟甲氧基、COOR 5、CONR 5R 6。
在另一优选例中，通式(I)中：
手性碳原子C*为S型。
本发明的第二方面，提供了一种如本发明第一方面所述通式(I)所示的化合物的制备方法，包括步骤：
(1)在惰性溶剂中，在缩合剂存在下，用式II化合物和式Ic化合物反应，得到式Id化合物；优选地，所述的缩合剂为EDCI(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐)；
Figure PCTCN2019074704-appb-000004
(2)在惰性溶剂中，用式Id化合物进行Bischler–Napieralski关环反应，得到式Ie化合物；优选地，所述的关环反应用三氯氧磷作为路易斯酸；
Figure PCTCN2019074704-appb-000005
(3)在惰性溶剂中，用式Ie化合物进行还原反应，得到式If化合物；优选地，所述的还原反应用硼氢化物作为还原剂或用Noyori催化剂作为不对称还原催化剂；
Figure PCTCN2019074704-appb-000006
(4)在惰性溶剂中，用式If化合物进行成缩合反应或N-烷基化反应或Buchwald–Hartwig反应，得到式(I)化合物；
Figure PCTCN2019074704-appb-000007
上述各式中，各基团的定义如本发明第一方面所述。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括：治疗有效量的一种或多种本发明第一方面所述通式(I)所示化合物，或其药学上可接受的盐。
本发明的第四方面，提供了一种如本发明第一方面所述的通式(I)的用途，用于制备预防、治疗或辅助治疗与PDE4活性或表达量相关的疾病的药物组合物；优选地，所述的疾病为与PDE4活性或表达量相关的免疫和炎症性疾病。
在另一优选例中，所述的与PDE4活性或表达量相关的疾病选自下组：银屑病、银屑病关节炎、过敏性皮炎、慢性阻塞性肺病、哮喘、过敏性鼻炎、强直性脊柱炎、系统性红斑狼疮、风湿性关节炎、炎症性肠病、肺纤维化、多发性硬化症、阿尔兹海默症、亨廷顿舞蹈症、帕金森氏症、多动症、抑郁症、和精神分裂症。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了受试化合物ZN17、ZN42对小鼠背部气囊急性炎症模型的治疗作用。
具体实施方式
本发明人经过长期而深入的研究，制备得到了一类能够抑制磷酸二酯酶(PDE4)的式I化合物。且与现有技术中的磷酸二酯酶4(PDE4)抑制化合物相比，所述的化合物具有更高的抑制活性。基于上述发现，发明人完成了本发明。
本发明的一个目的在于提供一种通式(I)所示的四氢异喹啉类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体。
本发明的另一个目的在于提供一种上述通式(I)所示化合物的制备方法。
本发明的再一个目的在于提供一种包含治疗有效量的一种或多种上述通式(I)所示化合物或其药学上可接受的盐的药物组合物。
本发明的又一个目的在于提供上述通式(I)所示化合物在制备用于治疗自身免疫性疾病，例如银屑病、银屑病关节炎、特应性皮炎等的药物中的用途。
本发明的化合物可用于抑制磷酸二酯酶4(PDE4)。
术语
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：C 1～C 10烷基、C 3～C 10环烷基、C 1～C 10烷氧基、卤素、羟基、羧基(-COOH)、C 1～C 10醛基、C 2～C 10酰基、C 2～C 10酯基、氨基、苯基；所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基，所述取代基选自：卤素、C 1-C 10烷基、氰基、羟基、硝基、C 3～C 10环烷基、C 1～C 10烷氧基、氨基。
除特别说明之处，本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
术语“C1～C6烷基”指具有1～6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“3-8元杂环基”指具有选自下组的1-3个杂原子的3～8元饱和环失去一个氢原子形成的基团：N、S、O；例如吡咯烷基、哌啶基、哌嗪基、吗啉基、或类似基团。
术语“6-10元芳基”指6～10元芳基失去一个氢原子形成的基团；例如苯基、萘基，或类似基团。
术语“5-10元杂芳基”指具有选自下组的1-3个杂原子的5～8元芳基失去一个氢原子形成的基团：N、S、O，其中每个杂芳基的环状体系可以是单环或多环的；例如吡咯基、吡啶基、噻吩基、呋喃基、咪唑基、嘧啶基、苯并噻吩基、吲哚基、咪唑并吡啶基、喹啉基或类似基团。
术语“C1～C6烷氧基”指具有1-6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“C2-C6酯基”指具有2-6个碳原子的R-O-C(＝O)-基团，如-COOCH 3、-COOC 2H 5、-COOC 3H 7、-COOC 4H 9，或类似基团。
术语“C2-C6烯基”指具有2-6个碳原子的烯烃失去一个或两个氢原子所形成的基团，所述的烯烃可以是单烯烃、二烯烃或三烯烃，例如-CH＝CH 2、-C 2H 4＝CH 2、-CH＝C 2H 4，或类似基团。
术语“卤素”指F、Cl、Br和I。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑，化合价互变异构体包括通过一些成键电子重组而进行互变。
在本文中，形如“C1～C6”，表示该基团可以具有1个至6个碳原子，例如1个、2个、3个、4个或5个。
如无特别说明，本申请的化合物可以包括本领域已知的同位素形成的化合物，例如氢的同位素(氘、氚等)、碳的同位素(C14)。通常，上述同位素的丰度不大于其在天然环境中的丰度，但也可以通过采用含有该同位素的反应原料进行制备，从而得到丰度高于自然丰度的同位素取代化合物，例如氘代化合物等。在优选的实施方式中，氘代化合物中氘原子的丰度＞99％。
式(I)所示的四氢异喹啉类化合物
本发明提供一种通式(Ⅰ)表示的四氢异喹啉类化合物，其对映异构体、非对映异构体、外消旋体及其混合物或其药学上可接受的盐，
Figure PCTCN2019074704-appb-000008
其中，各基团的定义如上所述。
在另一优选例中，n、X、Y、R 1、R 2、R 3、R 4各自独立地为实施例中各个具体化合物所对应的相应基团。
特别地，本发明所述的四氢异喹啉类化合物优选自下表A中所示的化合物：
表A
Figure PCTCN2019074704-appb-000009
Figure PCTCN2019074704-appb-000010
Figure PCTCN2019074704-appb-000011
Figure PCTCN2019074704-appb-000012
Figure PCTCN2019074704-appb-000013
Figure PCTCN2019074704-appb-000014
Figure PCTCN2019074704-appb-000015
Figure PCTCN2019074704-appb-000016
Figure PCTCN2019074704-appb-000017
Figure PCTCN2019074704-appb-000018
Figure PCTCN2019074704-appb-000019
Figure PCTCN2019074704-appb-000020
Figure PCTCN2019074704-appb-000021
Figure PCTCN2019074704-appb-000022
Figure PCTCN2019074704-appb-000023
Figure PCTCN2019074704-appb-000024
Figure PCTCN2019074704-appb-000025
Figure PCTCN2019074704-appb-000026
Figure PCTCN2019074704-appb-000027
Figure PCTCN2019074704-appb-000028
Figure PCTCN2019074704-appb-000029
Figure PCTCN2019074704-appb-000030
Figure PCTCN2019074704-appb-000031
式(I)化合物的制备
本发明还提供了一种具有通式I的化合物的合成方法，具体地，所述的式I化合物通过下列所示流程进行制备：
Figure PCTCN2019074704-appb-000032
步骤a:将I c溶解在溶剂中，在缩合剂辅助下与II进行缩合反应得到化合物I d；所述溶剂为二氯甲烷；
步骤b:将I d溶解在溶剂中，加入过量三氯氧磷，回流搅拌，得化合物I e；所述溶剂为无水乙腈；
步骤c:将I e溶解在溶剂中，加入过量硼氢化钠，搅拌至反应完全，旋干溶剂得化合物I f，所述溶剂为甲醇；或加入Noyori催化剂，搅拌至反应完全，所述溶剂为水和二氯甲烷混合溶剂。
步骤d:将I f溶于溶剂中，与相应原料反应得到化合物I g；所述溶剂为甲酸乙酯或DMF或四氢呋喃；
X、Y、R 1、R 2、R 3、R 4与前述要求中的定义相同。
含有式(I)化合物的药物组合物
本发明还涉及一种药物组合物，所述药物组合物包含治疗有效量的选自式(Ⅰ)表示的四氢异喹啉类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种以及任选地，药学上可接受的载体，其可用于治疗银屑病等自身免疫性相关的疾病。所述药物组合物可以根据不同给药途径而制备成各种形式。
本发明所述的式(Ⅰ)表示的醛基类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种，或者上述包含治疗有效量的选自式(Ⅰ)表示的四氢异喹啉类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种的药物组合物可以作为磷酸二酯酶4(PDE4)抑制剂，用于治疗银屑病等自身免疫性相关疾病。
本发明化合物的药用盐的制备，可以采用化合物的游离碱与无机或有机酸直接成盐反应 进行。无机或有机酸可选自盐酸、硫酸、磷酸、硝酸、氢氟酸、氢溴酸、甲酸、乙酸、苦味酸、柠檬酸、马来酸、甲烷磺酸、三氟甲烷磺酸、乙烷磺酸和对甲苯磺酸等。
由于本发明化合物具有优异的对磷酸二酯酶4(PDE4)的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗以及缓解与磷酸二酯酶4(PDE4)相关的疾病，例如治疗与磷酸二酯酶4(PDE4)表达异常相关的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：银屑病、银屑病关节炎、特应性皮炎、慢性阻塞性肺病等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
Figure PCTCN2019074704-appb-000033
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味 剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
如上所述的根据本发明的化合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径，更优选为口服。日剂量优选为0.01～200mg/kg体重，一次性服用，或0.01～100mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明的主要优点包括：
本发明的四氢异喹啉类化合物对四型磷酸二酯酶(PDE4)具有良好的抑制效果，可以用于预防、治疗或辅助治疗与磷酸二酯酶活性相关的银屑病、银屑病关节炎、过敏性皮炎、慢性阻塞性肺病、哮喘、过敏性鼻炎、强直性脊柱炎、系统性红斑狼疮、风湿性关节炎、炎症性肠病、肺纤维化、多发性硬化症、阿尔兹海默症、亨廷顿舞蹈症、帕金森氏症、多动症、抑郁症和精神分裂症等疾病，尤其是与PDE4相关的免疫和炎症性疾病如银屑病和关节炎等。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明，但不以任何方式限制本发明。实施例中的所有参数以及其余的说明，除另有说明外，都是以质量为说明依据的。
样品的分析数据由以下仪器测定：核磁共振由GEMINI-300型、Bruker AMX-400型和INVOA-600型核磁共振仪测定，TMS(四甲基硅烷)为内标，化学位移单位为ppm，耦合常数单位为Hz；质谱由Finnigan MAT-711型，MAT-95和LCQ-DECA型质谱仪以及IonSpec 4.7 Tesla质谱仪测定。
柱层析用硅胶200-300目(青岛海洋化工厂生产)；TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析预制板；石油醚沸程为60-90℃；采用紫外灯，碘缸显色。除另有说明外，以下实施例中所用常规试剂、药品均购自国药集团。实验中所用试剂及溶剂均按反应具体情况处理。
实施例A1:化合物A1的合成
Figure PCTCN2019074704-appb-000034
合成路线：
Figure PCTCN2019074704-appb-000035
化合物1-3的合成：
1-2溶于二氯甲烷中，加入EDCI，HOBT，TEA搅拌30min，缓慢加入1-1的二氯甲烷溶液，搅拌过夜，加二氯甲烷稀释，依次用饱和碳酸氢钠、1N稀盐酸、饱和氯化钠洗涤，无水硫酸钠干燥，蒸干，石油醚/乙酸乙酯＝1:1柱层析纯化得黄白色固体1.2g，收率为92％。 1H NMR(400MHz,CDCl 3)δ7.75(s,1H),7.57(dd,J＝7.5,1.4Hz,1H),7.33(dd,J＝7.5,1.4Hz,1H),7.23–7.15(m,2H),6.98(td,J＝7.4,1.5Hz,1H),6.79(d,J＝7.5Hz,1H),6.74(d,J＝1.4Hz,1H),6.60(dd,J＝7.5,1.4Hz,1H),5.62(s,1H),3.83(s,3H),3.75(s,3H),3.37(t,J＝7.7Hz,2H),2.68(t,J＝8.1Hz,2H),2.60(t,J＝7.7Hz,2H),2.28(t,J＝8.1Hz,2H).ESI-MS m/z 353.2[M+H] +.
化合物1-4的合成：
将化合物1-3 1g溶于100mL无水乙腈中，加入三氯氧磷，在氩气保护下，回流搅拌。TLC监测反应完全后减压蒸干，加入冰的饱和碳酸氢钠调至弱碱性，二氯甲烷萃取，无水硫酸钠干燥，蒸干得橙色油状物，未经纯化直接投下一步反应。
化合物1-5的合成：
将化合物1-4溶于甲醇中，冰浴下分批加入硼氢化钠，室温搅拌4小时，饱和氯化铵溶液淬灭反应，加入二氯甲烷萃取，饱和碳酸氢钠，饱和氯化钠洗涤，无水硫酸钠干燥有机层，浓缩，二氯甲烷/甲醇＝20:1柱层析纯化得黄色固体，两步收率70％。 1H NMR(400MHz,CDCl3)δ8.19(brs,1H),7.53(d,J＝7.8Hz,1H),7.32(d,J＝8.1Hz,1H),7.20–7.03(m,3H),6.51(s,1H),6.23(s,1H),4.41(t,J＝5.8Hz,1H),3.81(s,3H),3.58(s,3H),3.54–3.43(m,1H),3.31–3.18(m,1H),3.08–2.78(m,4H),2.39(dd,J＝13.7,7.1Hz,2H).ESI-MS m/z 337.2[M+H] +.
化合物A1的合成：
将1-5 100mg溶于甲酸乙酯中、滴入催化量的三乙胺，搅拌回流过夜。TLC监测反应完全后蒸干溶剂，石油醚/乙酸乙酯＝1:1柱层析纯化得白色固体A1，收率为90％。 1H NMR(400MHz,CDCl 3)δ8.29(s,1H(min)),8.21(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.63(d,J＝8.0Hz,1H(maj)),7.58(d,J＝7.9Hz,1H(min)),7.39(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.06(m,2H(maj,min)1H(min)),7.03(s,1H(maj)),6.57(s,1H(maj)),6.55(s,1H(min)),6.41(s,1H(min)),6.39(s,1H (maj)),5.47(dd,J＝7.6,6.3Hz,1H(min)),4.55(dd,J＝13.4,5.2Hz,1H(maj)),4.44(dd,J＝9.5,4.1Hz,1H(maj)),3.84(s,3H(maj)),3.83(s,3H(min)),3.78–3.70(m,1H(min)3H(maj)),3.68(s,3H(min)),3.62(ddd,J＝13.4,12.0,4.4Hz,1H(min)),3.13(ddd,J＝13.4,12.0,4.4Hz,1H(maj)),3.02–2.63(m,4H),2.36–2.17(m,2H).ESI-MS m/z 365.2[M+H] +.
实施例(S)-A1:化合物(S)-A1的合成
Figure PCTCN2019074704-appb-000036
将1-4溶于少量二氯甲烷，加入去离子水，加入(R,R)-Noyori催化剂、六氟锑酸银、三氟甲烷磺酸镧、TBAB、甲酸钠，氩气保护下40度搅拌过夜，二氯甲烷萃取，水洗，有机层硅藻土助滤，浓缩，二氯甲烷/甲醇＝40:1柱层析得2-5，参考化合物A1的合成方法，得到化合物(S)-A1。或由A1经手性色谱柱分离得到(S)-A1。 1H NMR(400MHz,CDCl 3)δ8.29(s,1H(min)),8.21(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.63(d,J＝8.0Hz,1H(maj)),7.58(d,J＝7.9Hz,1H(min)),7.39(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.06(m,2H(maj,min)1H(min)),7.03(s,1H(maj)),6.57(s,1H(maj)),6.55(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.47(dd,J＝7.6,6.3Hz,1H(min)),4.55(dd,J＝13.4,5.2Hz,1H(maj)),4.44(dd,J＝9.5,4.1Hz,1H(maj)),3.84(s,3H(maj)),3.83(s,3H(min)),3.78–3.70(m,1H(min)3H(maj)),3.68(s,3H(min)),3.62(ddd,J＝13.4,12.0,4.4Hz,1H(min)),3.13(ddd,J＝13.4,12.0,4.4Hz,1H(maj)),3.02–2.63(m,4H),2.36–2.17(m,2H).ESI-MS m/z 365.2[M+H] +.
实施例(R)-A1:化合物(R)-A1的合成
Figure PCTCN2019074704-appb-000037
用(S,S)-Noyori催化剂替换实施例(S)-A1中的(R,R)-Noyori催化剂，合成方法参考化合物(S)-A1的合成，得到化合物(R)-A1。或由A1经手性色谱柱分离得到(R)-A1。 1H NMR(400MHz,CDCl 3)δ8.29(s,1H(min)),8.21(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.63(d,J＝8.0Hz,1H(maj)),7.58(d,J＝7.9Hz,1H(min)),7.39(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.06(m,2H(maj,min)1H(min)),7.03(s, 1H(maj)),6.57(s,1H(maj)),6.55(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.47(dd,J＝7.6,6.3Hz,1H(min)),4.55(dd,J＝13.4,5.2Hz,1H(maj)),4.44(dd,J＝9.5,4.1Hz,1H(maj)),3.84(s,3H(maj)),3.83(s,3H(min)),3.78–3.70(m,1H(min)3H(maj)),3.68(s,3H(min)),3.62(ddd,J＝13.4,12.0,4.4Hz,1H(min)),3.13(ddd,J＝13.4,12.0,4.4Hz,1H(maj)),3.02–2.63(m,4H),2.36–2.17(m,2H). 1H NMR ESI-MS m/z 365.2[M+H] +.
实施例A2:化合物A2的合成
Figure PCTCN2019074704-appb-000038
化合物4-3的合成：
4-1溶于丙酮，加入碳酸钾、滴加4-2，回流搅拌过夜。反应液过滤，蒸干，二氯甲烷稀释，加水搅拌10min，静置分层，有机层蒸干得黄色固体4-3，未经纯化直接投下步。
化合物4-4的合成：
4-3溶于硝基甲烷，加醋酸铵回流2h，蒸干溶剂，加入冰水中搅拌2h，静置，过滤得黄色固体，产率90％。 1H NMR(400MHz,CDCl 3)δ7.96(s,2H),7.42(dd,J＝7.5,1.4Hz,1H),7.23(d,J＝1.4Hz,1H),6.93(d,J＝7.5Hz,1H),4.58(dd,J＝7.8Hz,1H),3.85(s,3H),2.12–2.00(m,2H),1.84–1.66(m,2H),1.67–1.54(m,1H).ESI-MS m/z 264.1[M+H] +
化合物4-5的合成：
冰浴下分批将四氢铝锂加入氩气保护的四氢呋喃中，搅拌下滴加4-4的四氢呋喃溶液，加毕回流2h，冰浴下缓慢加水淬灭反应，过滤，乙酸乙酯洗涤滤饼，蒸干得微黄透明油状物。未经纯化直接投下步。
用化合物4-5替换实施例A1中的1-1，合成方法参考化合物A1的合成，得到化合物A2。 1H NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.14(brs,1H(maj)),8.07(brs,1H(min)),7.63(d,J＝7.9Hz,1H(maj)),7.58(d,J＝7.9Hz,1H(min)),7.39(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.15(s,1H(maj)),7.13–7.06(m,2H(min)),7.02(s,1H(min)),6.56(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.45(dd,J＝8.6,5.0Hz,1H(min)),4.57(m,1H),4.52(m,1H(maj)),4.41(dd,J＝9.5,4.4Hz,1H(maj)),3.80(s,3H(maj)),3.79(s,3H(min)),3.72(dd,J＝13.4,5.3Hz,1H(min)),3.62(ddd,J＝13.6,12.0,4.5Hz,1H(min)),3.12(ddd,J＝13.0,12.0,4.7Hz,1H(maj)),3.01–2.61(m,4H),2.32–2.17(m,2H),1.92–1.66(m,6H),1.64–1.48(m,2H).ESI-MS m/z 419.2[M+H] +.
实施例(S)-A2:化合物(S)-A2的合成
Figure PCTCN2019074704-appb-000039
用化合物4-5替换实施例A1中的1-1，合成方法参考化合物(S)-A1，得化合物(S)-A2。 1H NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.14(brs,1H(maj)),8.07(brs,1H(min)),7.63(d,J＝7.9Hz,1H(maj)),7.58(d,J＝7.9Hz,1H(min)),7.39(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.15(s,1H(maj)),7.13–7.06(m,2H(min)),7.02(s,1H(min)),6.56(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.45(dd,J＝8.6,5.0Hz,1H(min)),4.57(m,1H),4.52(m,1H(maj)),4.41(dd,J＝9.5,4.4Hz,1H(maj)),3.80(s,3H(maj)),3.79(s,3H(min)),3.72(dd,J＝13.4,5.3Hz,1H(min)),3.62(ddd,J＝13.6,12.0,4.5Hz,1H(min)),3.12(ddd,J＝13.0,12.0,4.7Hz,1H(maj)),3.01–2.61(m,4H),2.32–2.17(m,2H),1.92–1.66(m,6H),1.64–1.48(m,2H).ESI-MS m/z 419.2[M+H] +.
实施例(R)-A2:化合物(R)-A2的合成
Figure PCTCN2019074704-appb-000040
用化合物4-5替换实施例A1中的1-1，合成方法参考化合物(R)-A1，得化合物(R)-A2。 1H NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.14(brs,1H(maj)),8.07(brs,1H(min)),7.63(d,J＝7.9Hz,1H(maj)),7.58(d,J＝7.9Hz,1H(min)),7.39(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.15(s,1H(maj)),7.13–7.06(m,2H(min)),7.02(s,1H(min)),6.56(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.39(s,1H(maj)),5.45(dd,J＝8.6,5.0Hz,1H(min)),4.57(m,1H),4.52(m,1H(maj)),4.41(dd,J＝9.5,4.4Hz,1H(maj)),3.80(s,3H(maj)),3.79(s,3H(min)),3.72(dd,J＝13.4,5.3Hz,1H(min)),3.62(ddd,J＝13.6,12.0,4.5Hz,1H(min)),3.12(ddd,J＝13.0,12.0,4.7Hz,1H(maj)),3.01–2.61(m,4H),2.32–2.17(m,2H),1.92–1.66(m,6H),1.64–1.48(m,2H).ESI-MS m/z 419.2[M+H] +.
实施例A3:化合物A3的合成
Figure PCTCN2019074704-appb-000041
用化合物6-1替换实施例A2中的4-2，合成方法参考化合物A2的合成，得到化合物A3。H 1NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.21(brs,1H(maj)),8.20(s,1H(maj)),8.12(brs,1H(min)),7.62(d,J＝7.9Hz,1H(maj)),7.56(d,J＝7.9Hz,1H(min)),7.38(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.13(s,1H(maj)),7.12–7.05(m,2H(min)),7.02(s,1H(min)),6.57(s,1H(maj)),6.55(s,1H(min)),6.42(s,1H(min)),6.40(s,1H(maj)),5.44(dd,J＝8.6,5.0Hz,1H(min)),4.54(dd,J＝13.2,5.0Hz,1H(maj)),4.40 (dd,J＝9.3,4.3Hz,1H(maj)),3.83(s,3H),3.77–3.56(m,2H(min),2H(maj,min)),3.12(ddd,J＝12.4,4.7,4.7Hz,1H(maj)),3.00–2.62(m,4H),2.32–2.15(m,2H),1.36–1.17(m,1H),0.68–0.51(m,2H),0.29(m,2H).ESI-MS m/z 405.2[M+H] +.
实施例(S)-A3:化合物(S)-A3的合成
Figure PCTCN2019074704-appb-000042
用化合物6-1替换实施例A2中的4-2，合成方法参考化合物(S)-A2的合成，得到化合物(S)-A3。H 1NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.21(brs,1H(maj)),8.20(s,1H(maj)),8.12(brs,1H(min)),7.62(d,J＝7.9Hz,1H(maj)),7.56(d,J＝7.9Hz,1H(min)),7.38(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.13(s,1H(maj)),7.12–7.05(m,2H(min)),7.02(s,1H(min)),6.57(s,1H(maj)),6.55(s,1H(min)),6.42(s,1H(min)),6.40(s,1H(maj)),5.44(dd,J＝8.6,5.0Hz,1H(min)),4.54(dd,J＝13.2,5.0Hz,1H(maj)),4.40(dd,J＝9.3,4.3Hz,1H(maj)),3.83(s,3H),3.77–3.56(m,2H(min),2H(maj,min)),3.12(ddd,J＝12.4,4.7,4.7Hz,1H(maj)),3.00–2.62(m,4H),2.32–2.15(m,2H),1.36–1.17(m,1H),0.68–0.51(m,2H),0.29(m,2H).ESI-MS m/z 405.2[M+H] +.
实施例(R)-A3:化合物(R)-A3的合成
Figure PCTCN2019074704-appb-000043
用化合物6-1替换实施例A2中的4-2，合成方法参考化合物(R)-A2的合成，得到化合物(R)-A3。H 1NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.21(brs,1H(maj)),8.20(s,1H(maj)),8.12(brs,1H(min)),7.62(d,J＝7.9Hz,1H(maj)),7.56(d,J＝7.9Hz,1H(min)),7.38(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.16(m,2H(maj)),7.13(s,1H(maj)),7.12–7.05(m,2H(min)),7.02(s,1H(min)),6.57(s,1H(maj)),6.55(s,1H(min)),6.42(s,1H(min)),6.40(s,1H(maj)),5.44(dd,J＝8.6,5.0Hz,1H(min)),4.54(dd,J＝13.2,5.0Hz,1H(maj)),4.40(dd,J＝9.3,4.3Hz,1H(maj)),3.83(s,3H),3.77–3.56(m,2H(min),2H(maj,min)),3.12(ddd,J＝12.4,4.7,4.7Hz,1H(maj)),3.00–2.62(m,4H),2.32–2.15(m,2H),1.36–1.17(m,1H),0.68–0.51(m,2H),0.29(m,2H).ESI-MS m/z 405.2[M+H] +.
实施例A4:化合物A4的合成
Figure PCTCN2019074704-appb-000044
用溴乙烷替换实施例A2中的4-2，合成方法参考化合物A2的合成，得到化合物A4。 1H NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.62(d,J＝7.8Hz,1H(maj)),7.57(d,J＝7.9Hz,1H(min)),7.39(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.00(m,3H),6.57(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.40(s,1H(maj)),5.45(dd,J＝8.2,5.1Hz,1H(min)), 4.54(dd,J＝13.0,4.4Hz,1H(maj)),4.42(dd,J＝9.2,4.7Hz,1H(maj)),4.01–3.83(m,2H),3.83(s,3H(maj)),3.82(s,3H(min)),3.73(dd,J＝13.3,5.3Hz,1H(min)),3.62(ddd,J＝13.4,11.8,4.6Hz,1H(min)),3.12(ddd,J＝13.0,11.7,4.7Hz,1H(maj)),2.99–2.63(m,4H),2.31–2.17(m,2H),1.40(t,J＝7.0Hz,3H(maj)),1.36(t,J＝7.0Hz,3H(min)).ESI-MS m/z 379.2[M+H] +.
实施例(S)-A4:化合物(S)-A4的合成
Figure PCTCN2019074704-appb-000045
用溴乙烷替换实施例A2中的4-2，合成方法参考化合物(S)-A2的合成，得到化合物(S)-A4。 1H NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.62(d,J＝7.8Hz,1H(maj)),7.57(d,J＝7.9Hz,1H(min)),7.39(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.00(m,3H),6.57(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.40(s,1H(maj)),5.45(dd,J＝8.2,5.1Hz,1H(min)),4.54(dd,J＝13.0,4.4Hz,1H(maj)),4.42(dd,J＝9.2,4.7Hz,1H(maj)),4.01–3.83(m,2H),3.83(s,3H(maj)),3.82(s,3H(min)),3.73(dd,J＝13.3,5.3Hz,1H(min)),3.62(ddd,J＝13.4,11.8,4.6Hz,1H(min)),3.12(ddd,J＝13.0,11.7,4.7Hz,1H(maj)),2.99–2.63(m,4H),2.31–2.17(m,2H),1.40(t,J＝7.0Hz,3H(maj)),1.36(t,J＝7.0Hz,3H(min)).ESI-MS m/z 379.2[M+H] +.
实施例(R)-A4:化合物(R)-A4的合成
Figure PCTCN2019074704-appb-000046
用溴乙烷替换实施例A2中的4-2，合成方法参考化合物(R)-A2的合成，得到化合物(R)-A4。 1H NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.20(s,1H(maj)),8.13(brs,1H(maj)),8.06(brs,1H(min)),7.62(d,J＝7.8Hz,1H(maj)),7.57(d,J＝7.9Hz,1H(min)),7.39(d,J＝8.1Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.24–7.00(m,3H),6.57(s,1H(maj)),6.54(s,1H(min)),6.41(s,1H(min)),6.40(s,1H(maj)),5.45(dd,J＝8.2,5.1Hz,1H(min)),4.54(dd,J＝13.0,4.4Hz,1H(maj)),4.42(dd,J＝9.2,4.7Hz,1H(maj)),4.01–3.83(m,2H),3.83(s,3H(maj)),3.82(s,3H(min)),3.73(dd,J＝13.3,5.3Hz,1H(min)),3.62(ddd,J＝13.4,11.8,4.6Hz,1H(min)),3.12(ddd,J＝13.0,11.7,4.7Hz,1H(maj)),2.99–2.63(m,4H),2.31–2.17(m,2H),1.40(t,J＝7.0Hz,3H(maj)),1.36(t,J＝7.0Hz,3H(min)).ESI-MS m/z 379.2[M+H] +.
实施例A5:化合物A5的合成
Figure PCTCN2019074704-appb-000047
用溴苄替换实施例A2中的4-2，合成方法参考化合物A2的合成，得到化合物A5。 1H NMR(400MHz,CDCl 3)δ8.27(s,1H(min)),8.15(s,1H(maj)),8.11(brs,1H(maj)),8.05(brs,1H(min)),7.59(d,J＝8.0Hz,1H(maj)),7.56(d,J＝7.9Hz,1H(min)),7.44–7.27(m,6H),7.24–7.11(m,2H),7.09(s,1H(min)),6.95(s,1H(maj)),6.59(s,1H(maj)),6.57(s,1H(min)),6.45(s,1H(min)),6.41(s,1H(maj)),5.38(dd,J＝9.2,4.3Hz,1H(min)),5.06–4.88(m,2H),4.52(dd,J＝13.1,4.9Hz,1H(maj)),4.34(dd,J＝8.4,5.6Hz,1H(maj)),3.85(s,3H(maj)),3.84(s,3H(min)),3.71(dd,J＝13.4,5.2Hz,1H(min)),3.64–3.55(m,1H(min)),3.15–3.03(m,1H(maj)),2.80(m,4H),2.13(m,2H).ESI-MS m/z 441.2[M+H] +.
实施例(S)-A5:化合物(S)-A5的合成
Figure PCTCN2019074704-appb-000048
用溴苄替换实施例A2中的4-2，合成方法参考化合物(S)-A2的合成，得到化合物(S)-A5。 1H NMR(400MHz,CDCl 3)δ8.27(s,1H(min)),8.15(s,1H(maj)),8.11(brs,1H(maj)),8.05(brs,1H(min)),7.59(d,J＝8.0Hz,1H(maj)),7.56(d,J＝7.9Hz,1H(min)),7.44–7.27(m,6H),7.24–7.11(m,2H),7.09(s,1H(min)),6.95(s,1H(maj)),6.59(s,1H(maj)),6.57(s,1H(min)),6.45(s,1H(min)),6.41(s,1H(maj)),5.38(dd,J＝9.2,4.3Hz,1H(min)),5.06–4.88(m,2H),4.52(dd,J＝13.1,4.9Hz,1H(maj)),4.34(dd,J＝8.4,5.6Hz,1H(maj)),3.85(s,3H(maj)),3.84(s,3H(min)),3.71(dd,J＝13.4,5.2Hz,1H(min)),3.64–3.55(m,1H(min)),3.15–3.03(m,1H(maj)),2.80(m,4H),2.13(m,2H).ESI-MS m/z 441.2[M+H] +.
实施例(R)-A5:化合物(R)-A5的合成
Figure PCTCN2019074704-appb-000049
用溴苄替换实施例A2中的4-2，合成方法参考化合物(R)-A2的合成，得到化合物(R)-A5。 1H NMR(400MHz,CDCl 3)δ8.27(s,1H(min)),8.15(s,1H(maj)),8.11(brs,1H(maj)),8.05(brs,1H(min)),7.59(d,J＝8.0Hz,1H(maj)),7.56(d,J＝7.9Hz,1H(min)),7.44–7.27(m,6H),7.24–7.11(m,2H),7.09(s,1H(min)),6.95(s,1H(maj)),6.59(s,1H(maj)),6.57(s,1H(min)),6.45(s,1H(min)),6.41(s,1H(maj)),5.38(dd,J＝9.2,4.3Hz,1H(min)),5.06–4.88(m,2H),4.52(dd,J＝13.1,4.9Hz,1H(maj)),4.34(dd,J＝8.4,5.6Hz,1H(maj)),3.85(s,3H(maj)),3.84(s,3H(min)),3.71(dd,J＝13.4,5.2Hz,1H(min)),3.64–3.55(m,1H(min)),3.15–3.03(m,1H(maj)),2.80(m,4H),2.13(m,2H).ESI-MS m/z 441.2[M+H] +.
实施例A6:化合物A6的合成
Figure PCTCN2019074704-appb-000050
化合物A5经钯碳催化加氢，脱去苄基，与(2-溴甲基)二甲胺在碳酸钾、乙腈体系中反应得A6
实施例(S)-A6:化合物A6的合成
Figure PCTCN2019074704-appb-000051
化合物(S)-A5经钯碳催化加氢，脱去苄基，与(2-溴甲基)二甲胺在碳酸钾、乙腈体系中反应得(S)-A6
实施例(R)-A6:化合物A6的合成
Figure PCTCN2019074704-appb-000052
化合物(R)-A5经钯碳催化加氢，脱去苄基，与(2-溴甲基)二甲胺在碳酸钾、乙腈体系中反应得(S)-A6
实施例A7:化合物A7的合成
Figure PCTCN2019074704-appb-000053
化合物A5经钯碳催化加氢，脱去苄基，与3-溴丙酸在碳酸钾、乙腈体系中反应得A7
实施例(S)-A7:化合物A7的合成
Figure PCTCN2019074704-appb-000054
化合物(S)-A5经钯碳催化加氢，脱去苄基，与3-溴丙酸在碳酸钾、乙腈体系中反应得(S)-A7
实施例(R)-A7:化合物A7的合成
Figure PCTCN2019074704-appb-000055
化合物(R)-A5经钯碳催化加氢，脱去苄基，与3-溴丙酸在碳酸钾、乙腈体系中反应得(S)-A7
实施例B1:化合物B1的合成
Figure PCTCN2019074704-appb-000056
11-1溶于二氯甲烷中，加入EDCI，HOBT，TEA搅拌30min，缓慢加入1-5的二氯甲烷溶液，搅拌过夜，加二氯甲烷稀释，依次用饱和碳酸氢钠、1N稀盐酸、饱和氯化钠洗涤，无水硫酸钠干燥，蒸干，石油醚/乙酸乙酯＝1:1柱层析纯化得化合物B1白色固体50mg，收率为％。 1H NMR(400MHz,CDCl 3)δ8.72(d,J＝5.7Hz,2H(maj)),8.56(d,J＝4.5Hz,2H(min)),8.14(brs,1H(maj)),8.06(brs,1H(min)),7.61(d,J＝7.8Hz,1H(maj)),7.49(d,J＝7.9Hz,1H(min)),7.40–7.32(m,1H),7.31–7.08(m,4H(min,maj)1H(maj)),6.65(s,1H(min)),6.60(s,1H(min)),6.56(s,1H(maj)),6.48(s,1H(maj)),6.23(s,1H(min)),5.83(dd,J＝9.5,4.4Hz,1H(maj)),4.82(dd,J＝13.2,5.1Hz,1H(min)),4.64(dd,J＝8.3,5.5Hz,1H(min)),3.87(s,3H(min)),3.84(s,3H(maj)),3.75–3.62(m,3H(min,maj)1H(maj)),3.57(ddd,J＝13.7,11.6,4.2Hz,1H(maj)),3.39(ddd,J＝13.2,11.4,5.0Hz,1H(min)),3.16–2.74(m,3H),2.71–2.57(m,1H),2.47–2.36(m,1H(maj)),2.35–2.23(m,1H),2.20–2.10(m,1H(min)).ESI-MS m/z 442.2[M+H] +.
实施例(S)-B1:化合物(S)-B1的合成
Figure PCTCN2019074704-appb-000057
2-5替换实施例B1中的1-5，得化合物(S)-B1白色固体50mg，收率为60％。 1H NMR(400MHz,CDCl 3)δ8.72(d,J＝5.7Hz,2H(maj)),8.56(d,J＝4.5Hz,2H(min)),8.14(brs,1H(maj)),8.06(brs,1H(min)),7.61(d,J＝7.8Hz,1H(maj)),7.49(d,J＝7.9Hz,1H(min)),7.40–7.32(m,1H),7.31–7.08(m,4H(min,maj)1H(maj)),6.65(s,1H(min)),6.60(s,1H(min)),6.56(s,1H(maj)),6.48(s,1H(maj)),6.23(s,1H(min)),5.83(dd,J＝9.5,4.4Hz,1H(maj)),4.82(dd,J＝13.2,5.1Hz,1H(min)),4.64(dd,J＝8.3,5.5Hz,1H(min)),3.87(s,3H(min)),3.84(s,3H(maj)),3.75–3.62(m,3H(min,maj)1H(maj)),3.57(ddd,J＝13.7,11.6,4.2Hz,1H(maj)),3.39(ddd,J＝13.2,11.4,5.0Hz,1H(min)),3.16–2.74(m,3H),2.71–2.57(m,1H),2.47–2.36(m,1H(maj)),2.35–2.23(m,1H),2.20–2.10(m,1H(min)).ESI-MS m/z 442.2[M+H] +.
实施例(R)-B1:化合物(R)-B1的合成
Figure PCTCN2019074704-appb-000058
3-5替换实施例B1中的1-5，得化合物(R)-B1白色固体50mg，收率为60％。 1H NMR(400MHz,CDCl 3)δ8.72(d,J＝5.7Hz,2H(maj)),8.56(d,J＝4.5Hz,2H(min)),8.14(brs,1H(maj)),8.06(brs,1H(min)),7.61(d,J＝7.8Hz,1H(maj)),7.49(d,J＝7.9Hz,1H(min)),7.40–7.32(m,1H),7.31–7.08(m,4H(min,maj)1H(maj)),6.65(s,1H(min)),6.60(s,1H(min)),6.56(s,1H(maj)),6.48(s,1H(maj)),6.23(s,1H(min)),5.83(dd,J＝9.5,4.4Hz,1H(maj)),4.82(dd,J＝13.2,5.1Hz,1H(min)),4.64(dd,J＝8.3,5.5Hz,1H(min)),3.87(s,3H(min)),3.84(s,3H(maj)),3.75–3.62(m,3H(min,maj)1H(maj)),3.57(ddd,J＝13.7,11.6,4.2Hz,1H(maj)),3.39(ddd,J＝13.2,11.4,5.0Hz,1H(min)),3.16–2.74(m,3H),2.71–2.57(m,1H),2.47–2.36(m,1H(maj)),2.35–2.23(m,1H),2.20–2.10(m,1H(min)).ESI-MS m/z 442.2[M+H] +.
实施例B2:化合物B2的合成
Figure PCTCN2019074704-appb-000059
化合物1-5溶于乙腈，加入碳酸钾，12-1回流过夜，蒸干，石油醚/乙酸乙酯＝1:1柱层析纯化得化合物B2白色固体50mg，收率为％。 1H NMR(400MHz,CDCl 3)δ8.06(brs,1H),7.61(d,J＝7.9Hz,1H),7.36(d,J＝8.1Hz,1H),7.21–7.15(m,1H),7.13–7.05(m,2H),6.56(s,1H),6.37(s,1H),3.84(s,4H),3.75(s,3H),3.67(s,3H),3.65–3.54(m,2H),3.36(s,3H),3.11–3.00(m,1H),2.96(t,J＝7.5Hz,2H),2.92–2.77(m,3H),2.57(d,J＝16.0Hz,1H),2.31(m,1H),2.15–2.01(m,1H).ESI-MS m/z 395.2[M+H] +.
实施例(S)-B2:化合物(S)-B2的合成
Figure PCTCN2019074704-appb-000060
化合物2-5替换实施例B2中的1-5，得(S)-B2。 1H NMR(400MHz,CDCl 3)δ8.06(brs,1H),7.61(d,J＝7.9Hz,1H),7.36(d,J＝8.1Hz,1H),7.21–7.15(m,1H),7.13–7.05(m,2H),6.56(s,1H),6.37(s,1H),3.84(s,4H),3.75(s,3H),3.67(s,3H),3.65–3.54(m,2H),3.36(s,3H),3.11–3.00(m,1H),2.96(t,J＝7.5Hz,2H),2.92–2.77(m,3H),2.57(d,J＝16.0Hz,1H),2.31(m,1H),2.15–2.01(m,1H).ESI-MS m/z 395.2[M+H] +.
实施例(R)-B2:化合物(R)-B2的合成
Figure PCTCN2019074704-appb-000061
化合物3-5替换实施例B2中的1-5，得(R)-B2。 1H NMR(400MHz,CDCl 3)δ8.06(brs,1H),7.61(d,J＝7.9Hz,1H),7.36(d,J＝8.1Hz,1H),7.21–7.15(m,1H),7.13–7.05(m,2H),6.56(s,1H),6.37(s,1H),3.84(s,4H),3.75(s,3H),3.67(s,3H),3.65–3.54(m,2H),3.36(s,3H),3.11–3.00(m,1H),2.96(t,J＝7.5Hz,2H),2.92–2.77(m,3H),2.57(d,J＝16.0Hz,1H),2.31(m,1H),2.15–2.01(m,1H).ESI-MS m/z 395.2[M+H] +.
实施例B3:化合物B3的合成
Figure PCTCN2019074704-appb-000062
用化合物13-1替换实施例B1中的11-1，合成方法参考化合物B1的合成，得到化合物B3。 1H NMR(500MHz,CDCl 3)δ9.54(t,J＝2.4Hz,1H),7.64–7.58(m,1H),7.38–7.31(m,1H),7.17(ddd,J＝8.1,7.4,1.0Hz,1H),7.14–7.07(m,2H),6.73(d,J＝1.1Hz,1H),6.62(t,J＝1.0Hz,1H),4.91(td,J＝6.1,0.9Hz,1H),3.90–3.81(m,7H),3.78(ddd,J＝11.5,7.3,5.0Hz,2H),3.60(ddd,J＝12.1,6.5,4.1Hz,1H),3.40(ddd,J＝11.7,7.4,5.1Hz,2H),3.08(dddd,J＝14.7,6.4,4.1,0.9Hz,1H),2.94(dt,J＝14.7,7.3Hz,1H),2.88–2.74(m,2H),2.52(dtd,J＝12.6,7.3,6.0Hz,1H),2.44(p,J＝6.5Hz,1H),2.25(dtd,J＝12.6,7.3,6.1Hz,1H),1.93–1.82(m,2H),1.68(dddd,J＝13.2,7.3,6.5,5.0Hz,2H).ESI-MS m/z 449.2[M+H] +.
实施例(S)-B3:化合物(S)-B3的合成
Figure PCTCN2019074704-appb-000063
用化合物13-1替换实施例B1中的11-1，合成方法参考化合物(S)-B1的合成，得到化合物(S)-B3。ESI-MS m/z 449.2[M+H] +.
实施例(R)-B3:化合物(R)-B3的合成
Figure PCTCN2019074704-appb-000064
用化合物13-1替换实施例B1中的11-1，合成方法参考化合物(R)-B1的合成，得到化合物(R)-B3。ESI-MS m/z 449.2[M+H] +.
实施例B4:化合物B4的合成
Figure PCTCN2019074704-appb-000065
用化合物14-1替换实施例B1中的11-1，合成方法参考化合物B1的合成，得到化合物B4。 1H NMR(400MHz,CDCl 3)δ8.19(brs,1H(min)),8.15(brs,1H(maj)),7.61–7.54(m,1H),7.39–7.33(m,1H),7.24–7.00(m,3H),6.60(s,1H(min)),6.57(s,1H(maj)),6.53(s,1H(min)),6.40(s,1H(maj)),5.66(dd,J＝9.2,4.8Hz,1H(maj)),4.77(dd,J＝7.1,7.1Hz,1H(min)),4.66(ddd,J＝7.5,6.3,2.0Hz,1H(min)),4.27–4.05(m,2H),3.90–3.82(m,3H(min,maj)1H(maj)),3.81(s,3H(min)),3.65(s,3H(maj)),3.55(ddd,J＝13.7,11.0,4.6Hz,1H(maj)),3.48(s,3H(maj)),3.32(s,3H(min)),3.21(ddd,J＝13.3,11.5,4.9Hz,1H(min)),2.97–2.64(m,4H),2.35–2.10(m,2H).ESI-MS m/z 409.2[M+H] +.
实施例(S)-B4:化合物(S)-B4的合成
Figure PCTCN2019074704-appb-000066
用化合物14-1替换实施例B1中的11-1，合成方法参考化合物(S)-B1的合成，得到化合物(S)-B4。ESI-MS m/z 409.2[M+H] +.
实施例(R)-B4:化合物(R)-B4的合成
Figure PCTCN2019074704-appb-000067
用化合物14-1替换实施例B1中的11-1，合成方法参考化合物(R)-B1的合成，得到化合物(R)-B4。ESI-MS m/z 409.2[M+H] +.
实施例B5:化合物B5的合成
Figure PCTCN2019074704-appb-000068
用化合物15-1替换实施例B2中的12-1，合成方法参考化合物B2的合成，得到化合物B5。 1H NMR(400MHz,CDCl 3)δ7.97(brs,1H),7.60(d,J＝7.9Hz,1H),7.35(d,J＝8.1Hz,1H),7.17(ddd,J＝8.2,7.2,1.1Hz,1H),7.09(ddd,J＝7.9,7.1,1.0Hz,1H),7.04(d,J＝2.0Hz,1H),6.56(s,1H),6.37(s,1H),3.84(s,3H),3.78–3.70(m,4H),3.68(s,3H),3.48(dd,J＝39.3,16.6Hz,2H),3.34(ddd,J＝13.5,9.8,5.2Hz,1H),3.04(dt,J＝9.7,5.2Hz,1H),3.00–2.87(m,2H),2.82(ddd,J＝15.6,9.7,5.6Hz,1H),2.60(dt,J＝16.5,4.5Hz,1H),2.27–2.15(m,1H),2.14–2.03(m,1H).ESI-MS m/z 409.2[M+H] +.
实施例(S)-B5:化合物(S)-B5的合成
Figure PCTCN2019074704-appb-000069
用化合物15-1替换实施例B2中的12-1，合成方法参考化合物(S)-B2的合成，得到化合物(S)-B5。
实施例(R)-B5:化合物(R)-B5的合成
Figure PCTCN2019074704-appb-000070
用化合物15-1替换实施例B2中的12-1，合成方法参考化合物(R)-B2的合成，得到化合物(R)-B5。
实施例B6:化合物B6的合成
Figure PCTCN2019074704-appb-000071
用化合物16-1替换实施例B2中的12-1，合成方法参考化合物B2的合成，得到化合物B6。 1H NMR(400MHz,CDCl 3)δ7.94(brs,1H),7.61(d,J＝7.8Hz,1H),7.36(d,J＝8.1Hz,1H),7.21–7.14(m,1H),7.13–7.06(m,1H),7.02(s,1H),6.56(s,1H),6.37(s,1H),3.84(s,3H),3.72(s,3H),3.67(dd,J＝8.4,4.1Hz,1H),3.43–3.31(m,1H),3.24(dq,J＝15.4,9.5Hz,1H),3.11–2.81(m,5H),2.52(d,J＝14.7Hz,1H),2.16(dt,J＝13.9,7.0Hz,1H),2.10–1.98(m,1H).ESI-MS m/z 419.2[M+H] +.
实施例(S)-B6:化合物(S)-B6的合成
Figure PCTCN2019074704-appb-000072
用化合物16-1替换实施例B2中的12-1，合成方法参考化合物(S)-B2的合成，得到化合物(S)-B6。ESI-MS m/z 419.2[M+H] +.
实施例(R)-B6:化合物(R)-B6的合成
Figure PCTCN2019074704-appb-000073
用化合物16-1替换实施例B2中的12-1，合成方法参考化合物(R)-B2的合成，得到化合物(R)-B6。ESI-MS m/z 419.2[M+H] +.
实施例B7:化合物B7的合成
Figure PCTCN2019074704-appb-000074
用化合物17-1替换实施例B2中的12-1，合成方法参考化合物B2的合成，得到化合物B7。 1H NMR(400MHz,CDCl 3)δ7.98(brs,1H),7.59(d,J＝7.8Hz,1H),7.36(d,J＝8.1Hz,1H),7.18(t,J＝7.1Hz,1H),7.11(dd,J＝11.0,3.9Hz,1H),6.99(s,1H),6.56(s,1H),6.46(s,1H),3.98(dd,J＝11.4,2.9Hz,1H),3.84(s,3H),3.76(s,3H),3.63–3.47(m,1H),3.38(td,J＝10.9,3.3Hz,2H),3.31–3.16(m,1H),3.05–2.67(m,4H),2.60–2.30(m,3H),2.24–1.96(m,2H),1.88–1.67(m,3H),1.28(m,1H).ESI-MS m/z 435.3[M+H] +.
实施例(S)-B7:化合物(S)-B7的合成
Figure PCTCN2019074704-appb-000075
用化合物17-1替换实施例B2中的12-1，合成方法参考化合物(S)-B2的合成，得到化合物(S)-B7。ESI-MS m/z 435.3[M+H] +.
实施例(R)-B7:化合物(R)-B7的合成
Figure PCTCN2019074704-appb-000076
用化合物17-1替换实施例B2中的12-1，合成方法参考化合物(R)-B2的合成，得到化合物(R)-B7。ESI-MS m/z 435.3[M+H] +.
实施例B8:化合物B8的合成
Figure PCTCN2019074704-appb-000077
用化合物18-1替换实施例B2中的12-1，合成方法参考化合物B2的合成，得到化合物B8。 1H NMR(400MHz,CDCl 3)δ7.59(d,J＝7.9Hz,1H),7.36(d,J＝8.2Hz,1H),7.26(t,J＝7.6Hz,1H),7.14(m,2H),6.56(s,1H),6.36(s,1H),4.77–4.58(m,2H),3.84(s,3H),3.73(s,3H),3.53(t,J＝6.4Hz,2H),3.31–3.21(m,1H),3.18–3.06(m,2H),3.04–2.81(m,7H),2.38–2.15(m,1H),2.17–2.04(m,1H).ESI-MS m/z 443.2[M+H] +.
实施例(S)-B8:化合物(S)-B8的合成
Figure PCTCN2019074704-appb-000078
用化合物18-1替换实施例B2中的12-1，合成方法参考化合物(S)-B2的合成，得到化合物(S)-B8。ESI-MS m/z 443.2[M+H] +.
实施例(R)-B8:化合物(R)-B8的合成
Figure PCTCN2019074704-appb-000079
用化合物18-1替换实施例B2中的12-1，合成方法参考化合物(R)-B2的合成，得到化合物(R)-B8。ESI-MS m/z 443.2[M+H] +.
实施例B9:化合物B9的合成
Figure PCTCN2019074704-appb-000080
用化合物19-1替换实施例B1中的11-1，合成方法参考化合物B1的合成，得到化合物B9。 1H NMR(500MHz,CDCl 3)δ9.55(t,J＝2.4Hz,1H),7.61(dt,J＝7.3,0.9Hz,1H),7.38–7.31(m,1H),7.17(ddd,J＝8.1,7.4,1.0Hz,1H),7.14–7.06(m,2H),6.90(d,J＝0.9Hz,1H),6.62(t,J＝1.0Hz,1H),5.00(td,J＝6.0,1.0Hz,1H),4.38(d,J＝17.2Hz,1H),4.04(d,J＝17.0Hz,1H),3.91(ddd,J＝12.1,6.3,4.3Hz,1H),3.83(s,6H),3.75(ddd,J＝11.9,6.2,4.2Hz,1H),2.98(s,3H),3.03–2.87(m,3H),2.81(dt,J＝14.9,7.3Hz,1H),2.39(dtd,J＝12.6,7.3,6.1Hz,1H),2.26(dtd,J＝12.6,7.3,6.1Hz,1H).ESI-MS m/z 457.2[M+H] +
实施例(S)-B9:化合物(S)-B9的合成
Figure PCTCN2019074704-appb-000081
用化合物19-1替换实施例B1中的11-1，合成方法参考化合物(S)-B1的合成，得到化合物(S)-B9。ESI-MS m/z 457.2[M+H] +.
实施例(R)-B9:化合物(R)-B9的合成
Figure PCTCN2019074704-appb-000082
用化合物19-1替换实施例B1中的11-1，合成方法参考化合物(R)-B1的合成，得到化合物(R)-B9。ESI-MS m/z 457.2[M+H] +.
实施例B10:化合物B10的合成
Figure PCTCN2019074704-appb-000083
1-5溶于THF中，加入20-1室温搅拌20h，DCM稀释，饱和碳酸氢钠、饱和氯化洗涤，无水硫酸钠干燥蒸干，石油醚/乙酸乙酯＝1:1柱层析纯化得黄色油状物20mg，收率为58％。 1H NMR(500MHz,CDCl 3)δ9.63(t,J＝2.4Hz,1H),7.59(ddd,J＝7.3,1.1,0.6Hz,1H),7.38–7.32(m,1H),7.17(td,J＝7.7,1.1Hz,1H),7.15–7.07(m,2H),6.83(d,J＝1.1Hz,1H),6.61(t,J＝1.0Hz,1H),4.96(td,J＝5.4,1.0Hz,1H),3.95(ddd,J＝11.9,6.4,4.0Hz,1H),3.86–3.78(m,7H),3.12–2.98(m,2H),2.89–2.78(m,2H),2.42–2.25(m,2H).ESI-MS m/z433.2[M+H] +.
实施例(S)-B10:化合物(S)-B10的合成
Figure PCTCN2019074704-appb-000084
用2-5替换实施例B10中的1-5，得化合物(S)-B10。ESI-MS m/z 433.2.
实施例(R)-B10:化合物(R)-B10的合成
Figure PCTCN2019074704-appb-000085
用3-5替换实施例B10中的1-5，得化合物(R)-B10。ESI-MS m/z 433.2[M+H] +.
实施例B11:化合物B11的合成
Figure PCTCN2019074704-appb-000086
用化合物14-1替换实施例B1中的11-1，合成方法参考化合物B1的合成，得到白色固体25mg，产率88％。 1H NMR(400MHz,CDCl 3)δ8.19(brs,1H(min)),8.15(brs,1H(maj)),7.61–7.54(m,1H),7.39–7.33(m,1H),7.24–7.00(m,3H),6.60(s,1H(min)),6.57(s,1H(maj)),6.53(s,1H(min)),6.40(s,1H(maj)),5.66(dd,J＝9.2,4.8Hz,1H(maj)),4.77(dd,J＝7.1,7.1Hz,1H(min)),4.66(ddd,J＝7.5,6.3,2.0Hz,1H(min)),4.27–4.05(m,2H),3.90–3.82(m,3H(min,maj)1H(maj)),3.81(s,3H(min)),3.65(s,3H(maj)),3.55(ddd,J＝13.7,11.0,4.6Hz,1H(maj)),3.48(s,3H(maj)),3.32(s,3H(min)),3.21(ddd,J＝13.3,11.5,4.9Hz,1H(min)),2.97–2.64(m,4H),2.35–2.10(m,2H).ESI-MS m/z 409.2 [M+H] +.
实施例(S)-B11:化合物(S)-B11的合成
Figure PCTCN2019074704-appb-000087
用化合物14-1替换实施例B1中的11-1，合成方法参考化合物(S)-B1的合成，得(S)-B11。ESI-MS m/z 409.2[M+H] +.
实施例(R)-B11:化合物(R)-B11的合成
Figure PCTCN2019074704-appb-000088
用化合物14-1替换实施例B1中的11-1，合成方法参考化合物(R)-B1的合成，得(R)-B11。ESI-MS m/z 409.2[M+H] +.
实施例B12:化合物B12的合成
Figure PCTCN2019074704-appb-000089
用溴乙烷替换实施例A2中的4-2，用化合物14-1替换实施例B1中的11-1，合成方法参考化合物B11的合成，得B12，产率85％。 1H NMR(400MHz,CDCl 3)δ8.17(brs,1H(min)),8.13(brs,1H(maj)),7.62–7.52(m,1H),7.41–7.32(m,1H),7.23–6.98(m,3H),6.60(s,1H(min)),6.57(s,1H(maj)),6.54(s,1H(min)),6.40(s,1H(maj)),5.64(dd,J＝9.1,4.7Hz,1H(maj)),4.76(dd,J＝7.6,6.7Hz,1H(min)),4.64(ddd,J＝8.2,5.7,1.9Hz,1H(min)),4.20(q,J＝13.6Hz,2H(maj)),4.06(s,2H(min)),3.89–3.78(m,3H(min,maj)1H(min)1H(maj)),3.55(ddd,J＝13.5,10.8,4.4Hz,1H(maj)),3.48(s,3H(maj)),3.31(s,3H(min)),3.21(ddd,J＝12.6,11.0,4.2Hz,1H(min)),3.03–2.61(m,4H),2.38–2.20(m,2H(maj)),2.18–2.08(m,2H(min)),1.44(t,J＝7.0Hz,3H(min)),1.35(t,J＝7.0Hz,3H(maj)).ESI-MS m/z 423.0[M+H] +.
实施例(S)-B12:化合物(S)-B12的合成
Figure PCTCN2019074704-appb-000090
用溴乙烷替换实施例A2中的4-2，用化合物14-1替换实施例B1中的11-1，合成方法参考化合物(S)-B11的合成，得(S)-B12。ESI-MS m/z 423.0[M+H] +.
实施例(R)-B12:化合物(R)-B12的合成
Figure PCTCN2019074704-appb-000091
用溴乙烷替换实施例A2中的4-2，用化合物14-1替换实施例B1中的11-1，合成方法参考化合物(R)-B11的合成，得(R)-B12。ESI-MS m/z 423.0[M+H] +.
实施例B13:化合物B13的合成
Figure PCTCN2019074704-appb-000092
中间体1-5溶于二氯甲烷，加入吡啶、46-1，室温搅拌1h，0.1N NaOH溶液淬灭反应，二氯甲烷萃取，1N稀盐酸洗涤，有机层干燥蒸干过柱得化合物B13。 1H NMR(400MHz,CDCl 3)δ7.69(s,1H),7.55(dd,J＝14.9,3.1Hz,1H),7.32(dd,J＝15.0,3.1Hz,1H),7.23–7.12(m,2H),7.02–6.91(m,2H),6.87(s,1H),4.49(t,J＝13.0Hz,1H),3.74(s,6H),3.42(dt,J＝24.7,10.8Hz,1H),3.14(dt,J＝24.7,10.8Hz,1H),2.94(s,3H),2.86–2.66(m,4H),2.12(td,J＝15.7,13.1Hz,2H).ESI-MS m/z 415.2[M+H] +.
实施例(S)-B13:化合物(S)-B13的合成
Figure PCTCN2019074704-appb-000093
2-5替换实施例B13中的1-5，得化合物(S)-B13。ESI-MS m/z 415.2[M+H] +.
实施例(R)-B13:化合物(R)-B13的合成
Figure PCTCN2019074704-appb-000094
3-5替换实施例B13中的1-5，得化合物(R)-B13。ESI-MS m/z 415.2[M+H] +.
实施例B14:化合物B14的合成
Figure PCTCN2019074704-appb-000095
中间体1-5溶于二氯甲烷，加入B14-1、三乙胺，室温搅拌2h，饱和氯化铵溶液淬灭反应，二氯甲烷萃取，饱和食盐水洗涤，有机层干燥蒸干过柱得化合物B14。 1H NMR(500MHz,CDCl 3)δ9.41(t,J＝2.4Hz,1H),7.61(ddt,J＝7.3,1.1,0.6Hz,1H),7.39–7.32(m,1H),7.21–7.13(m,1H),7.14–7.07(m,2H),6.64(t,J＝1.0Hz,1H),6.50(d,J＝1.1Hz,1H),5.09(td,J＝5.4,1.0Hz,1H),4.03(ddd,J＝11.9,6.2,4.2Hz,1H),3.83(d,J＝2.4Hz,6H),3.64– 3.53(m,5H),3.17–3.08(m,4H),3.04–2.87(m,3H),2.79–2.69(m,1H),2.50(dtd,J＝12.6,7.3,5.3Hz,1H),2.28(dtd,J＝12.6,7.3,5.4Hz,1H).ESI-MS m/z 450.2[M+H] +.
实施例(S)-B14:化合物(S)-B14的合成
Figure PCTCN2019074704-appb-000096
2-5替换实施例B14中的1-5，得化合物(S)-B14。ESI-MS m/z 450.2[M+H] +.
实施例(R)-B14:化合物(R)-B14的合成
Figure PCTCN2019074704-appb-000097
3-5替换实施例B14中的1-5，得化合物(R)-B14。ESI-MS m/z 450.2[M+H] +.
实施例B15:化合物B15的合成
Figure PCTCN2019074704-appb-000098
氯甲酸甲酯替换实施例B14中的B14-1，得化合物B15。 1H NMR(500MHz,CDCl 3)δ7.62–7.56(m,1H),7.38–7.32(m,1H),7.20–7.11(m,2H),7.06(td,J＝7.5,1.6Hz,1H),6.84(d,J＝0.9Hz,1H),6.73(t,J＝0.9Hz,1H),5.04(td,J＝5.3,1.0Hz,1H),3.85–3.73(m,8H),3.68(s,2H),3.19(qt,J＝14.8,7.3Hz,2H),2.92(ddd,J＝6.2,5.0,1.1Hz,2H),2.47(dtd,J＝12.7,7.3,5.3Hz,1H),2.39(dtd,J＝12.7,7.3,5.4Hz,1H).ESI-MS m/z 395.2[M+H] +.
实施例(S)-B15:化合物(S)-B15的合成
Figure PCTCN2019074704-appb-000099
2-5替换实施例B14中的1-5，氯甲酸甲酯替换实施例B15中的B14-1，参考实施例B15，得化合物(S)-B15。ESI-MS m/z 395.2[M+H] +.
实施例(R)-B15:化合物(R)-B15的合成
Figure PCTCN2019074704-appb-000100
3-5替换实施例B14中的1-5，氯甲酸甲酯替换实施例B15中的B14-1，参考实施例B15，得化合物(R)-B15。ESI-MS m/z 395.2[M+H] +.
实施例B16:化合物B16的合成
Figure PCTCN2019074704-appb-000101
溴乙烷替换实施例A2中的4-2，2-碘乙酰胺替换实施例B2中的12-1，参考实施例B2，得化合物B16。
实施例(S)-B16:化合物(S)-B16的合成
Figure PCTCN2019074704-appb-000102
溴乙烷替换实施例A2中的4-2，2-碘乙酰胺替换实施例B2中的12-1，参考实施例B2，得化合物B16。
实施例(R)-B16:化合物(R)-B16的合成
Figure PCTCN2019074704-appb-000103
溴乙烷替换实施例A2中的4-2，2-碘乙酰胺替换实施例B2中的12-1，参考实施例B2，得化合物B16。
实施例C1:化合物C1的合成
Figure PCTCN2019074704-appb-000104
化合物23-3的合成：
23-2溶于二氯甲烷，加入四氯化锆，缓慢滴加23-1的二氯甲烷溶液，室温搅拌1h。加二氯甲烷稀释，水洗，有机层蒸干直接投下步。
化合物23-4的合成：
23-3溶于四氢呋喃/水＝1:1溶剂中，加氢氧化锂，室温搅拌16h。加乙酸乙酯萃取，收集水层，1N稀盐酸调pH至酸性，乙酸乙酯萃取三遍，收集有机层，无水硫酸钠干燥，蒸干得棕色固体420mg，两步产率68％。 1H NMR(500MHz,Methanol-d 4)δ10.04(brs,1H)7.66(d,J＝1.9Hz,1H),7.24(d,J＝8.6Hz,1H),7.16(dd,J＝8.6,1.9Hz,1H),7.08(s,1H),3.01(t,J＝7.4Hz,2H),2.65(t,J＝7.5Hz,2H).ESI-MS m/z 268.0[M+H] +
用化合物4-5替换实施例A1中的1-1，用化合物23-4替换实施例A1中的1-2，合成方法参考化合物A1的合成，得到化合物C1。 1H NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.19(s,2H(maj)),8.13(brs,1H(min)),7.77(s,1H(min)),7.70(s,1H(maj)),7.32–7.27(m,1H),7.26–7.23(m,1H),7.21(s,1H(min)),7.04(s,1H(maj)),6.56(s,1H(maj)),6.54(s,1H(min)),6.37(s,1H(maj)),6.33(s,1H(min)),5.40(dd,J＝9.0,4.2Hz,1H(min)), 4.67–4.61(m,1H(min)),4.58–4.54(m,1H(min)),4.54–4.48(m,1H(maj)),4.37(dd,J＝9.2,4.4Hz,1H(maj)),3.80(s,3H(maj)),3.79(s,3H(min)),3.73(dd,J＝13.3,5.6Hz,1H(maj)),3.61(ddd,J＝12.6,12.6,4.2Hz,1H(min)),3.10(ddd,J＝12.6,12.6,4.8Hz,1H(maj)),2.96–2.63(m,4H),2.31–2.13(m,2H),1.98–1.70(m,6H),1.68–1.47(m,2H).ESI-MS m/z 497.1[M+H] +.
实施例(S)-C1:化合物(S)-C1的合成
Figure PCTCN2019074704-appb-000105
参考实施例(S)-A2和实施例C1，得化合物(S)-C1，ESI-MS m/z 497.1[M+H] +.
实施例(R)-C1:化合物(R)-C1的合成
Figure PCTCN2019074704-appb-000106
参考实施例(R)-A2和实施例C1，得化合物(R)-C1，ESI-MS m/z 497.1[M+H] +.
实施例C2:化合物C2的合成
Figure PCTCN2019074704-appb-000107
用化合物24-1替换实施例C1中的23-1，合成方法参考化合物C1的合成，得到化合物C2。 1H NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.21(s,1H(maj)),8.02(brs,1H(maj)),7.95(brs,1H(min)),7.41(s,1H(maj)),7.35(s,1H(min)),7.31–7.22(m,1H),7.11(s,1H(min)),7.07–6.99(m,1H),6.99(s,1H(maj)),6.56(s,1H(maj)),6.54(s,1H(min)),6.40(s,1H(min)),6.38(s,1H(maj)),5.45(dd,J＝8.1,5.6Hz,1H(min)),4.62–4.48(m,1H(maj,min),1H(maj)),4.42(dd,J＝9.9,3.9Hz,1H(maj)),3.80(s,3H),3.73(dd,J＝13.2,5.8Hz,1H(min)),3.62(ddd,J＝13.3,11.9,4.4Hz,1H(min)),3.12(ddd,J＝12.5,12.5,4.7Hz,1H(maj)),2.98–2.63(m,4H),2.46(s,3H(maj)),2.44(s,3H(min)),2.30–2.16(m,2H),1.91–1.68(m,6H),1.61–1.48(m,2H).ESI-MS m/z 433.2[M+H] +.
实施例(S)-C2:化合物(S)-C2的合成
Figure PCTCN2019074704-appb-000108
用化合物24-1替换实施例C1中的23-1，参考化合物(S)-C1的合成，得化合物(S)-C2。ESI-MS m/z 433.2[M+H] +.
实施例(R)-C2:化合物(R)-C2的合成
Figure PCTCN2019074704-appb-000109
用化合物24-1替换实施例C1中的23-1，参考化合物(R)-C1的合成，得化合物(R)-C2。ESI-MS m/z 433.2[M+H] +.
实施例C3:化合物C3的合成
Figure PCTCN2019074704-appb-000110
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物C1的合成，得到化合物C3。 1H NMR(400MHz,CDCl 3)δ8.27(s,1H(min)),8.19(s,1H(maj)),8.02(brs,1H(maj)),7.94(brs,1H(min)),7.51(d,J＝8.0Hz,1H(maj)),7.45(d,J＝8.0Hz,1H(min)),7.18(s,1H(maj)),7.15(s,1H(min)),7.06(s,1H(min)),6.99–6.90(m,1H(maj,min)1H(maj))6.56(s,1H(maj)),6.53(s,1H(min)),6.40(s,1H(min)),6.38(s,1H(maj)),5.44(dd,J＝8.4,5.3Hz,1H(min)),4.61–4.47(m,1H(maj,min)1H(maj)),4.40(dd,J＝9.4,4.1Hz,1H(maj)),3.80(s,3H(maj)),3.79(s,3H(min)),3.72(dd,J＝13.2,6.4Hz,1H(min)),3.62(dd,J＝18.3,7.1Hz,1H(min)),3.11(ddd,J＝12.4,4.6,4.6Hz,1H(maj)),2.97–2.58(m,4H),2.46(s,3H(maj)),2.45(s,3H(min)),2.32–2.13(m,2H),1.92–1.64(m,6H),1.65–1.45(m,2H).ESI-MS m/z 433.2[M+H] +.
实施例(S)-C3:化合物(S)-C3的合成
Figure PCTCN2019074704-appb-000111
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物(S)-C1的合成，得到化合物(S)-C3。ESI-MS m/z 433.2[M+H] +.
实施例(R)-C3:化合物(R)-C3的合成
Figure PCTCN2019074704-appb-000112
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物(R)-C1的合成，得到化合物(R)-C3。ESI-MS m/z 433.2[M+H] +.
实施例C4:化合物C4的合成
Figure PCTCN2019074704-appb-000113
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物A3的合成，得到化合物C4。 1H NMR(400MHz,CDCl 3)δ8.27(s,1H(min)),8.18(s,1H(maj)),7.97(brs,1H(maj)),7.90(brs,1H(min)),7.50(d,J＝8.1Hz,1H(maj)),7.44(d,J＝8.0Hz,1H(min)),7.18(s,1H(maj)),7.15(s,1H(min)),7.05(s,1H(min)),6.95(m,1H(min,maj)1H(maj)),6.57(s,1H(maj)),6.55(s,1H(min)),6.43(s,1H(min)),6.40(s,1H(maj)),5.44(dd,J＝8.5,5.3Hz,1H(min)),4.53(dd,J＝13.1,5.7Hz,1H(min)),4.39(dd,J＝9.6,4.2Hz,1H(maj)),3.83(s,3H),3.77–3.55(m,2H(min),2H(maj,min)),3.11(ddd,J＝12.5,12.5,4.8Hz,1H(maj)),2.98–2.60(m,4H),2.47(s,3H(maj)),2.45(s,3H(min)),2.29–2.13(m,2H),0.67–0.54(m,2H),0.35–0.24(m,2H).ESI-MS m/z 419.2[M+H] +.
实施例(S)-C4:化合物(S)-C4的合成
Figure PCTCN2019074704-appb-000114
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物(S)-A3的合成，得到化合物(S)-C4。ESI-MS m/z 419.2[M+H] +.
实施例(R)-C4:化合物(R)-C4的合成
Figure PCTCN2019074704-appb-000115
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物(R)-A3的合成，得到化合物(R)-C4。ESI-MS m/z 419.2[M+H] +.
实施例C5:化合物C5的合成
Figure PCTCN2019074704-appb-000116
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物A1的合成，得到化合物C5。 1H NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.19(s,1H(maj)),7.97(brs,1H(maj)),7.89(brs,1H(min)),7.51(d,J＝8.0Hz,1H(maj)),7.45(d,J＝8.1Hz,1H(min)),7.18(s,1H(maj)),7.15(s,1H(min)),7.04(s,1H(min)),7.00–6.89(m,1H(min,maj)1H(maj)),6.57(s,1H(maj)),6.55(s,1H(min)),6.43(s,1H(min)),6.40(s,1H(maj)),5.46(dd,J＝7.3,6.3Hz,1H(min)),4.54(dd,J＝13.2,6.1Hz,1H(min)),4.43(dd,J＝9.8,3.8Hz,1H(maj)),3.83(s,3H),3.75(s,3H(maj)),3.78–3.68(m,3H(min,maj)1H(min)),3.62(ddd,J＝12.2,12.2,4.2Hz,1H(min)),3.12(ddd,J＝12.2,12.2,4.5Hz,1H(maj)),2.98– 2.63(m,4H),2.46(s,3H(maj)),2.45(s,3H(min)),2.31–2.17(m,2H).ESI-MS m/z 379.2[M+H] +.
实施例(S)-C5:化合物(S)-C5的合成
Figure PCTCN2019074704-appb-000117
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物(S)-A1的合成，得到化合物(S)-C5。ESI-MS m/z 379.2[M+H] +.
实施例(R)-C5:化合物(R)-C5的合成
Figure PCTCN2019074704-appb-000118
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物(R)-A1的合成，得到化合物(R)-C5。ESI-MS m/z 379.2[M+H] +.
实施例C6:化合物C6的合成
Figure PCTCN2019074704-appb-000119
用化合物29-1替换实施例C1中的23-1，合成方法参考化合物A1的合成，得到化合物C6。 1H NMR(400MHz,CDCl 3)δ8.29(s,1H(min)),8.20(s,1H(maj)),8.19(brs,1H(maj)),8.11(brs,1H(min)),7.51(dd,J＝8.7,5.3Hz,1H(maj)),7.46(dd,J＝8.7,5.3Hz,1H(min)),7.14–6.98(m,2H),6.94–6.81(m,2H),6.58(s,1H(maj)),6.55(s,1H(min)),6.41(s,1H(min)),6.40(s,1H(maj)),5.45(dd,J＝8.5,5.3Hz,1H(min)),4.54(ddd,J＝13.1,6.4,1.4Hz,1H(maj)),4.43(dd,J＝7.0,7.0Hz,1H(maj)),3.84(s,3H(maj)),3.84(s,3H(min)),3.77(s,3H(maj)),3.76–3.68(m,4H(min)),3.62(ddd,J＝13.4,11.9,4.5Hz,1H(min)),3.12(ddd,J＝13.1,11.8,4.7Hz,1H(maj)),2.98–2.63(m,4H),2.30–2.15(m,2H).ESI-MS m/z 383.2[M+H] +.
实施例(S)-C6:化合物(S)-C6的合成
Figure PCTCN2019074704-appb-000120
用化合物29-1替换实施例C1中的23-1，合成方法参考化合物(S)-A1的合成，得化合物(S)-C6。ESI-MS m/z 383.2[M+H] +.
实施例(R)-C6:化合物(R)-C6的合成
Figure PCTCN2019074704-appb-000121
用化合物29-1替换实施例C1中的23-1，合成方法参考化合物(R)-A1的合成，得化合物(R)-C6。ESI-MS m/z 383.2[M+H] +.
实施例C7:化合物C7的合成
Figure PCTCN2019074704-appb-000122
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物A4的合成，得到化合物C7。 1H NMR(400MHz,Chloroform)δ8.02(s,1H),7.60(s,1H),7.53(s,1H),7.25–7.16(m,3H),6.97(s,1H),6.88(s,1H),4.70(s,1H),4.13(s,2H),3.92(s,1H),3.75(s,3H),3.33(s,1H),2.91(d,J＝15.0Hz,2H),2.76(s,1H),2.44(s,3H),2.26(s,2H),1.42(s,3H).ESI-MS m/z 393.2[M+H] +.
实施例(S)-C7:化合物(S)-C7的合成
Figure PCTCN2019074704-appb-000123
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物(S)-A4的合成，得到化合物(S)-C7。ESI-MS m/z 393.2[M+H] +.
实施例(R)-C7:化合物(R)-C7的合成
Figure PCTCN2019074704-appb-000124
用化合物25-1替换实施例C1中的23-1，合成方法参考化合物(R)-A4的合成，得到化合物(R)-C7。ESI-MS m/z 393.2[M+H] +.
实施例C8:化合物C8的合成
Figure PCTCN2019074704-appb-000125
用化合物31-1替换实施例C1中的23-1，合成方法参考化合物A4的合成，得到化合物C8。 1H NMR(400MHz,CDCl 3)δ8.28(s,1H(min)),8.21(s,1H(maj)),8.03(brs,1H (maj)),7.96(brs,1H(min)),7.28(d,J＝8.8Hz,1H(maj)),7.25(d,J＝8.8Hz,1H(min)),7.11(s,1H(min)),7.03(d,J＝2.3Hz,1H(maj)),7.00(d,J＝2.0Hz,1H(min)1H(maj)),6.88(dd,J＝8.8,2.4Hz,1H(maj)),6.84(dd,J＝8.8,2.4Hz,1H(min)),6.57(s,1H(maj)),6.55(s,1H(min)),6.42(s,1H(maj)),6.42(s,1H(min)),5.45(dd,J＝8.3,5.5Hz,1H(min)),4.53(ddd,J＝13.0,6.3,1.7Hz,1H(maj)),4.43(dd,J＝7.9,5.2Hz,1H(maj)),3.98–3.84(m,5H),3.83(s,3H(maj)),3.82(s,3H(min)),3.73(dd,J＝12.9,6.1Hz,1H(min)),3.66–3.57(m,1H(min)),3.12(ddd,J＝13.1,11.8,4.8Hz,1H(maj)),2.96–2.64(m,4H),2.28–2.16(m,2H),1.43–1.34(m,3H).ESI-MS m/z 409.2[M+H] +.
实施例(S)-C8:化合物(S)-C8的合成
Figure PCTCN2019074704-appb-000126
用化合物31-1替换实施例C1中的23-1，合成方法参考化合物(S)-A4的合成，得到化合物(S)-C8。ESI-MS m/z 409.2[M+H] +.
实施例(R)-C8:化合物(R)-C8的合成
Figure PCTCN2019074704-appb-000127
用化合物31-1替换实施例C1中的23-1，合成方法参考化合物(R)-A4的合成，得到化合物(R)-C8。ESI-MS m/z 409.2[M+H] +.
实施例C9:化合物C9的合成
Figure PCTCN2019074704-appb-000128
用化合物32-1替换
Figure PCTCN2019074704-appb-000129
实施例A1中的1-2，合成方法参考化合物A1的合成，得到化合物C9。 1H NMR(400MHz,CDCl3)δ8.32(brs,1H(maj)),8.18(s,1H(min)),8.16(brs,1H(min)),7.65(d,J＝7.7Hz,1H(maj)),7.60(m,1H(min)1H(maj)),7.41(d,J＝7.9Hz,1H(maj)),7.36(d,J＝8.1Hz,1H(min)),7.28–7.07(m,2H),6.95(s,1H(maj)),6.93(s,1H(min)),6.70(s,1H(maj)),6.67(s,1H(maj)),6.57(s,1H(min)),6.34(s,1H(min)),5.69(dd,J＝6.5Hz,1H(min)),4.74(dd,J＝9.8,3.8Hz,1H(maj)),4.53(dd,J＝13.0,4.4Hz,1H(maj)),3.91(s,3H(maj)),3.88(s,3H(maj)),3.87(s,3H(min)),3.64–3.54(m,4H(min)),3.48–3.13(m,3H),3.00–2.81(m,1H),2.77(dd,J＝16.0,2.5Hz,1H(maj)),2.69(dd,J＝16.2,2.3Hz,1H(min)).ESI-MS m/z 351.2[M+H] +.
实施例(S)-C9:化合物(S)-C9的合成
Figure PCTCN2019074704-appb-000130
实施例(R)-C9:化合物(R)-C9的合成
Figure PCTCN2019074704-appb-000131
用化合物32-1替换实施例A1中的1-2，合成方法参考化合物(R)-A1的合成，得到化合物(R)-C9。ESI-MS m/z 351.2[M+H] +.
实施例C10:化合物C10的合成
Figure PCTCN2019074704-appb-000132
用化合物32-1替换实施例A1中的1-2，合成方法参考化合物A4的合成，得到化合物C10。 1H NMR(400MHz,CDCl 3)δ8.27(brs,1H(maj)),8.15(s,1H(min)),8.11(brs,1H(min)),7.62(d,J＝7.5Hz,1H(maj)),7.59–7.53(m,1H(min),1H(maj)),7.38(d,J＝8.0Hz,1H(maj)),7.33(d,J＝8.1Hz,1H(min)),7.25–7.04(m,2H),6.93(s,1H(maj)),6.93(s,1H(min)),6.71(s,1H(maj)),6.64(s,1H(maj)),6.55(s,1H(min)),6.37(s,1H(min)),5.66(t,J＝6.5Hz,1H(min)),4.69(dd,J＝9.8,3.8Hz,1H(maj)),4.49(ddd,J＝13.1,6.2,2.1Hz,1H(maj)),4.07(qd,J＝7.0,1.9Hz,2H(maj)),3.87(s,3H(maj)),3.83(s,3H(min)),3.81–3.65(m,2H(min)),3.54(ddd,J＝13.0,6.0,1.7Hz,1H(min)),3.43–3.07(m,3H),2.97–2.58(m,2H),1.47(t,J＝7.0Hz,3H(maj)),1.32(t,J＝7.0Hz,3H(min)).ESI-MS m/z 365.2[M+H] +.
实施例(S)-C10:化合物(S)-C10的合成
Figure PCTCN2019074704-appb-000133
用化合物32-1替换实施例A1中的1-2，合成方法参考化合物(S)-A1的合成，得到化合物(S)-C10。ESI-MS m/z 365.2[M+H] +.
实施例(R)-C10:化合物(R)-C10的合成
Figure PCTCN2019074704-appb-000134
用化合物32-1替换实施例A1中的1-2，合成方法参考化合物(R)-A1的合成，得到化合物(R)-C10。ESI-MS m/z 365.2[M+H] +.
实施例C11:化合物C11的合成
Figure PCTCN2019074704-appb-000135
用化合物32-1替换实施例A1中的1-2,参考化合物B1的合成，得到化合物C11。 1H NMR(400MHz,CDCl 3)δ8.32(brs,1H(min)),8.08(brs,1H(maj)),7.67(m,1H),7.40(d,J＝7.4Hz,1H(min)),7.33(d,J＝8.1Hz,1H(maj)),7.24–7.05(m,2H),6.93(s,1H(min)),6.88(s,1H(maj)),6.64(s,1H(min)),6.58(s,1H(maj)),6.54(s,1H(min)),6.20(s,1H(maj)),5.79(dd,J＝7.1,6.0Hz,1H(maj)),4.92(dd,J＝8.6,5.7Hz,1H(min)),4.80(dd,J＝12.6,5.7Hz,1H(min)),4.14(s,1H(maj)),3.87(s,3H(min)),3.84(s,3H(maj)),3.78(s,3H(min)),3.69(m,1H),3.49(s,3H(maj)),3.48–3.41(m,1H(min)),3.39(s,3H(maj)),3.37–3.15(m,3H),2.98(s,3H(min)),2.96–2.79(m,1H),2.77–2.63(m,1H).ESI-MS m/z 395.2[M+H] +.
实施例(S)-C11:化合物(S)-C11的合成
Figure PCTCN2019074704-appb-000136
用化合物32-1替换实施例A1中的1-2,参考化合物(S)-B1的合成，得到化合物(S)-C11。ESI-MS m/z 395.2[M+H] +.
实施例(R)-C11:化合物(R)-C11的合成
Figure PCTCN2019074704-appb-000137
用化合物32-1替换实施例A1中的1-2,参考化合物(R)-B1的合成，得到化合物(R)-C11。ESI-MS m/z 395.2[M+H] +.
实施例C12:化合物C12的合成
Figure PCTCN2019074704-appb-000138
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物B8的合成，得到化合物C12。 1H NMR(400MHz,CDCl 3)δ7.83(brs,1H),7.57(dd,J＝14.9,3.0Hz,1H),7.33(dd,J＝15.0,3.1Hz,1H),7.24–7.13(m,2H),7.05–6.93(m,2H),6.88(s,1H),3.96(t,J＝14.0Hz,1H),3.84(dd,J＝16.4,15.4Hz,1H),3.77–3.68(m,6H),3.55–3.23(m,4H),3.15–2.96(m,2H),2.84–2.66(m,5H),2.58(m,1H).ESI-MS m/z 429.2[M+H] +.
实施例(S)-C12:化合物(S)-C12的合成
Figure PCTCN2019074704-appb-000139
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物(S)-B8的合成，得到 化合物(S)-C12。ESI-MS m/z 429.2[M+H] +.
实施例(R)-C12:化合物(R)-C12的合成
Figure PCTCN2019074704-appb-000140
用化合物32-1替换实施例A1中的1-2,合成方法参考化合物(R)-B8的合成，得到化合物(R)-C12。ESI-MS m/z 429.2[M+H] +.
实施例C13:化合物C13的合成
Figure PCTCN2019074704-appb-000141
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例B9的合成，得到化合物C13。 1H NMR(400MHz,CDCl 3)δ8.37(brs,1H(min)),8.12(brs,1H(maj)),7.62(d,J＝7.8Hz,1H(maj)),7.57(d,J＝7.6Hz,1H(min)),7.39(d,J＝7.8Hz,1H(min)),7.33(d,J＝8.1Hz,1H(maj)),7.26–7.07(m,2H),7.02(s,1H(min)),6.87(s,1H(maj)),6.68(s,1H(min)),6.64(s,1H(min)),6.58(s,1H(maj)),6.19(s,1H(maj)),5.81(dd,J＝6.8,6.8Hz,1H(maj)),5.01(dd,J＝9.7,4.4Hz,1H(min)),4.74(dd,J＝13.3,3.2Hz,1H(min)),4.09(q,J＝14.4Hz,2H(maj)),3.87(s,3H(maj)),3.86(s,3H(min)),3.84(s,3H(maj)),3.74–3.64(m,1H(maj)),3.50(s,2H),2.99(s,3H),2.78(s,2H).ESI-MS m/z 443.2[M+H] +.
实施例(S)-C13:化合物(S)-C13的合成
Figure PCTCN2019074704-appb-000142
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(S)-B9的合成，得到化合物(S)-C13。ESI-MS m/z 443.2[M+H]+.
实施例(R)-C13:化合物(R)-C13的合成
Figure PCTCN2019074704-appb-000143
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(R)-B9的合成，得到化合物(R)-C13。ESI-MS m/z 443.2[M+H]+.
实施例C14:化合物C14的合成
Figure PCTCN2019074704-appb-000144
用化合物32-1替换实施例A1中的1-2，参考实施例A4及实施例B8的合成，得到化合物C14。 1H NMR(400MHz,CDCl3)δ8.13(brs,1H),7.58(d,J＝7.8Hz,1H),7.36(d,J＝8.1Hz,1H),7.20(t,J＝7.3Hz,1H),7.13(t,J＝7.3Hz,1H),6.98(s,1H),6.59(s,1H),6.36(s,1H),4.02–3.93(m,1H),3.92–3.74(m,5H),3.51–3.38(m,1H),3.20(m,2H),3.12–2.83(m,6H),2.55(d,J＝15.6Hz,1H),2.41(s,3H),1.36(t,J＝7.0Hz,3H).ESI-MS m/z 443.2[M+H] +.
实施例(S)-C14:化合物(S)-C14的合成
Figure PCTCN2019074704-appb-000145
用化合物32-1替换实施例A1中的1-2，参考实施例(S)-A4及实施例(S)-B8的合成，得到化合物(S)-C14。ESI-MS m/z 443.2[M+H] +.
实施例(R)-C14:化合物(R)-C14的合成
Figure PCTCN2019074704-appb-000146
用化合物32-1替换实施例A1中的1-2，参考实施例(R)-A4及实施例(R)-B8的合成，得到化合物(R)-C14。ESI-MS m/z 443.2[M+H] +.
实施例C15:化合物C15的合成
Figure PCTCN2019074704-appb-000147
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例A4及实施例B9的合成，得到化合物C15。 1H NMR(400MHz,CDCl 3)δ7.71(brs,1H),7.57(dd,J＝7.5,1.4Hz,1H),7.33(dd,J＝7.5,1.4Hz,1H),7.23–7.15(m,2H),7.02–6.94(m,2H),6.88(s,1H),5.66(t,J＝7.1Hz,1H),4.35(s,2H),4.17–4.05(m,3H),3.75(s,3H),3.58(dd,J＝12.4,7.1Hz,1H),3.49(dt,J＝12.4,5.5Hz,1H),3.32(dd,J＝12.5,7.0Hz,1H),2.98–2.84(m,5H),1.42(t,J＝5.9Hz,3H).ESI-MS m/z 457.2[M+H] +.
实施例(S)-C15:化合物(S)-C15的合成
Figure PCTCN2019074704-appb-000148
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(S)-A4及实施例(S)-B9的合成，得到化合物C15。ESI-MS m/z 457.2[M+H] +.
实施例(R)-C15:化合物(R)-C15的合成
Figure PCTCN2019074704-appb-000149
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(R)-A4及实施例(R)-B9的合成，得到化合物(R)-C15。ESI-MS m/z 457.2[M+H] +.
实施例C16:化合物C16的合成
Figure PCTCN2019074704-appb-000150
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例A4及实施例B4的合成，得到化合物C16。 1H NMR(400MHz,CDCl 3)δ8.42(brs,1H(min)),8.14(brs,1H(maj)),7.66(d,J＝7.1Hz,1H(min)),7.63(d,J＝7.9Hz,1H(maj)),7.39(d,J＝7.2Hz,1H(min)),7.33(d,J＝8.1Hz,1H(maj)),7.25–7.05(m,2H),6.93(s,1H(min)),6.87(s,1H(maj)),6.63(s,1H(min)),6.60(s,1H(min)),6.57(s,1H(maj)),6.26(s,1H(maj)),5.78(dd,J＝6.6,6.6Hz,1H(maj)),4.88(dd,J＝9.0,4.8Hz,1H(min)),4.80(dd,J＝12.7,5.2Hz,1H(min)),4.13(s,2H(maj)),3.99(dt,J＝16.4,9.4Hz,2H(maj)),3.86(s,3H(min)),3.83(s,3H(maj)),3.78–3.57(m,1H(min)1H(maj)),3.48–3.13(m,3H(maj)3H(min,maj)2H(min)),2.95(s,3H(min)),2.76(m,2H),1.44(t,J＝7.0Hz,3H(min)),1.28(t,J＝7.0Hz,3H(maj)).ESI-MS m/z 409.2[M+H] +.
实施例(S)-C16:化合物(S)-C16的合成
Figure PCTCN2019074704-appb-000151
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(S)-A4及实施例(S)-B4的合成，得到化合物(S)-C16。
实施例(R)-C16:化合物(R)-C16的合成
Figure PCTCN2019074704-appb-000152
用化合物32-1替换实施例A1中的1-2,合成方法参考实施例(R)-A4及实施例(R)-B4的合成，得到化合物(R)-C16。
实施例C17:化合物C17的合成
Figure PCTCN2019074704-appb-000153
Figure PCTCN2019074704-appb-000154
化合物43-1的合成：
氩气保护下将24-1溶于无水四氢呋喃中，-78℃下搅拌缓慢滴加正丁基锂溶液，反应30min后，逐滴加入氯化锌的四氢呋喃溶液，升至室温下，加入15-1，搅拌24h。反应液倒入饱和氯化铵溶液，乙酸乙酯萃取三遍，有机层水洗、饱和氯化钠洗，无水硫酸钠干燥，蒸干石油醚/乙酸乙酯＝10:1柱层析得黄色油状物(605mg,70％)。
化合物43-2的合成：
43-1溶于四氢呋喃/水＝1:1溶剂中，加入氢氧化锂，室温搅拌16h。加乙酸乙酯萃取，收集水层，1N稀盐酸调pH至酸性，乙酸乙酯萃取三遍，收集有机层，无水硫酸钠干燥，蒸干得棕黄色固体g，产率95％。
用化合物43-2替换实施例A1中的1-2，参考实施例C10的合成方法，得到白色固体C17。 1H NMR(400MHz,CDCl 3)δ8.19(brs,1H(maj)),8.15(s,1H(min)),8.03(brs,1H(min)),7.57(s,1H(maj)),7.36(s,1H(maj)),7.29(s,1H(min)),7.27(d,J＝7.5Hz,1H(maj)),7.21(d,J＝8.3Hz,1H(min)),7.05(d,J＝8.4Hz,1H(maj)),6.99(d,J＝8.4Hz,1H(min)),6.88(s,1H(maj)),6.84(s,1H(min)),6.72(s,1H(maj)),6.64(s,1H(maj)),6.55(s,1H(min)),6.39(s,1H(min)),5.64(dd,J＝6.3,6.3Hz,1H(min)),4.69(dd,J＝9.8,4.0Hz,1H(maj)),4.47(ddd,J＝13.3,6.3,2.2Hz,1H(maj)),4.07(qd,J＝6.9,1.7Hz,2H(maj)),3.87(s,3H(maj)),3.84(s,3H(min)),3.83–3.68(m,2H(min)),3.54(ddd,J＝13.3,6.3,2.3Hz,1H(min)),3.42–3.05(m,3H),2.96–2.78(m,1H),2.78–2.59(m,1H),2.49(s,3H(maj)),2.41(s,3H(min)),1.48(t,J＝7.0Hz,3H(maj)),1.33(t,J＝7.0Hz,3H(min)).ESI-MS m/z 379.2[M+H] +.
实施例(S)-C17:化合物(S)-C17的合成
Figure PCTCN2019074704-appb-000155
用化合物43-2替换实施例A1中的1-2，参考实施例(S)-C10的合成方法，得到白色固体(S)-C17。
实施例(R)-C17:化合物(R)-C17的合成
Figure PCTCN2019074704-appb-000156
用化合物43-2替换实施例A1中的1-2，参考实施例(R)-C10的合成方法，得到白色固体(R)-C17。
实施例C18:化合物C18的合成
Figure PCTCN2019074704-appb-000157
用化合物44-1替换实施例C17中的24-1，合成方法参考化合物C17的合成，得到白色固体C18。 1H NMR(400MHz,CDCl 3)δ8.17(s,1H(maj)1H(min)),8.00(brs,1H(min)),7.62(s,1H(maj)),7.27(d,J＝8.9Hz,1H),7.21(d,J＝8.8Hz,1H(maj)),7.00(d,J＝2.4Hz,1H(min)),6.98(d,J＝2.4Hz,1H(maj)),6.91(s,1H(maj)),6.88(dd,J＝8.8,2.4Hz,1H(maj)),6.86(s,1H(min)),6.82(dd,J＝8.7,2.4Hz,1H(min)),6.69(s,1H(maj)),6.63(s,1H(maj)),6.54(s,1H(min)),6.39(s,1H(min)),5.63(t,J＝6.1Hz,1H(min)),4.68(dd,J＝9.6,4.4Hz,1H(maj)),4.46(ddd,J＝12.7,6.2,2.1Hz,1H(maj)),4.05(qd,J＝6.9,2.3Hz,2H(maj)),3.87(s,3H(maj)),3.87(s,3H(min)),3.85–3.71(m,3H(min,maj)2H(min)),3.54(ddd,J＝8.2,6.1,2.5Hz,1H(min)),3.37–3.08(m,3H),2.95–2.77(m,1H),2.77–2.56(m,1H),1.46(t,J＝7.0Hz,3H(maj)),1.33(t,J＝7.0Hz,3H(min)).ESI-MSm/z 395.2[M+H] +.
实施例(S)-C18:化合物(S)-C18的合成
Figure PCTCN2019074704-appb-000158
用化合物44-1替换实施例C17中的24-1，合成方法参考化合物(S)-C17的合成，得到白色固体(S)-C18。
实施例(R)-C18:化合物(R)-C18的合成
Figure PCTCN2019074704-appb-000159
用化合物44-1替换实施例C17中的24-1，合成方法参考化合物(R)-C17的合成，得到白色固体(R)-C18。
实施例C19:化合物C19的合成
Figure PCTCN2019074704-appb-000160
用化合物5-乙酰氨基-吲哚-3丙酸替换实施例C1中的23-1，合成方法参考化合物A4的合成，得到化合物C19。
实施例(S)-C19:化合物(S)-C19的合成
Figure PCTCN2019074704-appb-000161
用化合物5-乙酰氨基-吲哚-3丙酸替换实施例C1中的23-1，合成方法参考化合物(S)-A4的合成，得到化合物(S)-C19。
实施例(R)-C19:化合物(R)-C19的合成
Figure PCTCN2019074704-appb-000162
用化合物5-乙酰氨基-吲哚-3丙酸替换实施例C1中的23-1，合成方法参考化合物(R)-A4的合成，得到化合物(R)-C19。
实施例C20:化合物C20的合成
Figure PCTCN2019074704-appb-000163
用中间体C20-1替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物C20。ESI-MS m/z 407.0[M+H] +.
实施例(S)-C20:化合物(S)-C20的合成
Figure PCTCN2019074704-appb-000164
用中间体C20-1替换实施例A1中的1-2，参考化合物(S)-A4的合成路线，得化合物(S)-C20。 1H NMR(500MHz,Chloroform-d)δ9.74(t,J＝2.4Hz,1H),8.20(s,1H),7.48(dd,J＝2.5,0.5Hz,1H),7.34(dt,J＝2.7,0.6Hz,1H),7.08(ddd,J＝8.4,2.2,0.6Hz,1H),6.93(dd,J＝15.4,0.9Hz,1H),6.84–6.77(m,2H),6.65(dd,J＝15.6,6.4Hz,1H),6.49(d,J＝1.0Hz,1H),5.22(dt,J＝6.4,0.9Hz,1H),4.20–4.03(m,2H),3.85(d,J＝13.4Hz,5H),3.73(ddd,J＝11.7,6.4,4.3Hz,1H),3.65(ddd,J＝11.5,6.4,4.3Hz,1H),2.97(dddd,J＝14.6,6.4,4.2,1.0Hz,1H),2.89(dddd,J＝14.6,6.4,4.2,1.0Hz,1H),1.43(t,J＝6.9Hz,3H).ESI-MS m/z 407.2[M+H] +.
实施例(R)-C20:化合物(R)-C20的合成
Figure PCTCN2019074704-appb-000165
用中间体C20-1替换实施例A1中的1-2，参考化合物(R)-A4的合成路线，得化合物(R)-C20。ESI-MS m/z 407.0[M+H] +.
实施例C21:化合物C21的合成
Figure PCTCN2019074704-appb-000166
用中间体C21-1替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物C21。ESI-MS m/z 463.0[M+H] +.
实施例(S)-C21:化合物(S)-C21的合成
Figure PCTCN2019074704-appb-000167
用中间体C21-1替换实施例A1中的1-2，参考化合物(S)-A4的合成路线，得化合物(S)-C21。 1H NMR(500MHz,Chloroform-d)δ9.04(t,J＝2.4Hz,1H),8.28(s,1H),7.28–7.22(m,1H),7.11–7.06(m,2H),6.83(d,J＝1.0Hz,1H),6.72(dd,J＝8.4,2.7Hz,1H),6.63(t,J＝1.0Hz,1H),4.66(dd,J＝6.0,1.1Hz,1H),4.20–4.02(m,2H),3.84(d,J＝10.1Hz,6H),3.68(ddd,J＝11.7,6.3,4.4Hz,1H),3.50(ddd,J＝11.7,6.3,4.4Hz,1H),3.42(p,J＝5.9Hz,1H),2.99–2.84(m,2H),2.31(h,J＝6.0Hz,1H),2.07–1.96(m,2H),1.82–1.70(m,4H),1.70–1.60(m,2H),1.42(t,J＝6.9Hz,3H).ESI-MS m/z 463.3[M+H] +.
实施例(R)-C21:化合物(R)-C21的合成
Figure PCTCN2019074704-appb-000168
用中间体C21-1替换实施例A1中的1-2，参考化合物(R)-A4的合成路线，得化合物(R)-C21。ESI-MS m/z 463.3[M+H] +.
实施例C22:化合物C22的合成
Figure PCTCN2019074704-appb-000169
用中间体C21-1替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物C22。 1H NMR(500MHz,CDCl 3)δ8.29(s,1H),7.74(ddd,J＝7.9,1.3,0.6Hz,1H),7.53–7.47(m,1H),7.37(td,J＝7.7,1.3Hz,1H),7.21–7.14(m,1H),6.67(d,J＝0.9Hz,1H),6.60(t,J＝1.0Hz,1H),4.98–4.91(m,1H),4.20–4.03(m,2H),3.84(s,2H),3.73(ddd,J＝11.5,6.2,4.2Hz,1H),3.56(ddd,J＝11.7,6.4,4.3Hz,1H),3.04–2.83(m,3H),2.48–2.29(m,3H),1.42(t,J＝6.9Hz,3H).ESI-MS m/z 380.2[M+H] +.
实施例(S)-C22:化合物(S)-C22的合成
Figure PCTCN2019074704-appb-000170
用中间体C22-1替换实施例A1中的1-2，参考化合物(S)-A4的合成路线，得化合物(S)-C22。ESI-MS m/z 380.2[M+H] +.
实施例(R)-C22:化合物(R)-C22的合成
Figure PCTCN2019074704-appb-000171
用中间体C22-1替换实施例A1中的1-2，参考化合物(R)-A4的合成路线，得化合物(R)-C22。ESI-MS m/z 380.2[M+H] +.
实施例C23:化合物C23的合成
Figure PCTCN2019074704-appb-000172
用中间体C23-1替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物C23。 1H NMR(500MHz,CDCl 3)δ8.28(s,1H),7.55–7.49(m,1H),7.44–7.37(m,1H),7.32–7.25(m,1H),7.18(ddd,J＝7.9,7.3,1.1Hz,1H),6.67(d,J＝0.9Hz,1H),6.60(t,J＝1.0Hz,1H),6.47–6.42(m,1H),4.85(td,J＝5.4,1.0Hz,1H),4.20–4.03(m,2H),3.84(s,2H),3.70(ddd,J＝11.5,6.2,4.3Hz,1H),3.54(ddd,J＝11.7,6.3,4.4Hz,1H),2.97–2.83(m,3H),2.62(dt,J＝13.7,7.3Hz,1H),2.30–2.12(m,2H),1.42(t,J＝6.9Hz,3H).ESI-MS m/z 380.2[M+H] +.
实施例(S)-C23:化合物(S)-C23的合成
Figure PCTCN2019074704-appb-000173
用中间体C23-1替换实施例A1中的1-2，参考化合物(S)-A4的合成路线，得化合物(S)-C23。ESI-MS m/z 380.0[M+H] +.
实施例(R)-C23:化合物(R)-C23的合成
Figure PCTCN2019074704-appb-000174
用中间体C23-1替换实施例A1中的1-2，参考化合物(R)-A4的合成路线，得化合物(R)-C23。ESI-MS m/z 380.0[M+H] +.
实施例C24:化合物C24的合成
Figure PCTCN2019074704-appb-000175
用中间体C24-1替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物C24。 1H NMR(500MHz,CDCl 3)δ8.29(s,1H),7.77–7.67(m,2H),7.39–7.32(m,1H),7.16–7.06(m,2H),6.67(d,J＝0.9Hz,1H),6.61(t,J＝1.0Hz,1H),4.88(td,J＝5.4,1.0Hz,1H),4.20–4.03(m,2H),3.84(s,2H),3.72(ddd,J＝11.7,6.2,4.5Hz,1H),3.55(ddd,J＝11.7,6.2,4.5Hz,1H),3.00–2.91(m,1H),2.94–2.84(m,2H),2.76(dt,J＝13.7,7.3Hz,1H),2.24(ddtd,J＝35.3,12.5,7.3,5.4Hz,2H),1.42(t,J＝7.0Hz,3H).ESI-MS m/z 396.2[M+H] +.
实施例(S)-C24:化合物(S)-C24的合成
Figure PCTCN2019074704-appb-000176
用中间体C24-1替换实施例A1中的1-2，参考化合物(S)-A4的合成路线，得化合物(S)-C24。ESI-MS m/z 396.2[M+H] +.
实施例(R)-C24:化合物(R)-C24的合成
Figure PCTCN2019074704-appb-000177
用中间体C24-1替换实施例A1中的1-2，参考化合物(R)-A4的合成路线，得化合物(R)-C24。ESI-MS m/z 396.2[M+H] +.
实施例C25:化合物C25的合成
Figure PCTCN2019074704-appb-000178
合成路线，得化合物C25。 1H NMR(500MHz,CDCl 3)δ8.30(s,1H),7.38–7.25(m,2H),7.18–7.08(m,2H),6.70(d,J＝1.9Hz,1H),6.65–6.59(m,2H),5.06(td,J＝5.3,1.0Hz,1H),4.20–4.03(m,2H),3.84(s,2H),3.71(ddd,J＝11.5,6.2,4.3Hz,1H),3.55(ddd,J＝11.7,6.2,4.4Hz,1H),2.97–2.83(m,2H),2.77(dt,J＝13.5,7.3Hz,1H),2.60(dt,J＝13.7,7.4Hz,1H),2.26(dtd,J＝12.6,7.3,5.3Hz,1H),2.16(dtd,J＝12.5,7.2,5.3Hz,1H),1.42(t,J＝6.9Hz,3H).ESI-MS m/z 379.2[M+H] +.
实施例(S)-C25:化合物(S)-C25的合成
Figure PCTCN2019074704-appb-000179
用中间体C25-1替换实施例A1中的1-2，参考化合物(S)-A4的合成路线，得化合物(S)-C25。ESI-MS m/z 379.2[M+H] +.
实施例(R)-C25:化合物(R)-C25的合成
Figure PCTCN2019074704-appb-000180
用中间体C25-1替换实施例A1中的1-2，参考化合物(R)-A4的合成路线，得化合物(R)-C25。ESI-MS m/z 379.2[M+H] +.
实施例C26:化合物C26的合成
Figure PCTCN2019074704-appb-000181
用中间体C26-1替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物C26。 1H NMR(500MHz,Chloroform-d)δ8.83–8.76(m,2H),8.30(s,1H),8.03–7.97(m,1H),7.34(dd,J＝7.9,3.5Hz,1H),6.87–6.82(m,1H),6.65–6.60(m,2H),4.92(td,J＝5.3,1.0Hz,1H),4.20–4.03(m,2H),3.84(s,2H),3.73(ddd,J＝11.5,6.2,4.3Hz,1H),3.56(ddd,J＝11.7,6.3,4.4Hz,1H),2.97–2.88(m,1H),2.92–2.84(m,1H),2.88–2.79(m,1H),2.47–2.30(m,2H),2.26(dtd,J＝12.6,7.2,5.3Hz,1H),1.42(t,J＝6.9Hz,3H).ESI-MS m/z 380.2[M+H] +
实施例(S)-C26:化合物(S)-C26的合成
Figure PCTCN2019074704-appb-000182
用中间体C26-1替换实施例A1中的1-2，参考化合物(S)-A4的合成路线，得化合物(S)-C26。ESI-MS m/z 380.0[M+H] +.
实施例(R)-C26:化合物(R)-C26的合成
Figure PCTCN2019074704-appb-000183
用中间体C26-1替换实施例A1中的1-2，参考化合物(R)-A4的合成路线，得化合物(R)-C26。ESI-MS m/z 380.0[M+H] +.
实施例C27:化合物C27的合成
Figure PCTCN2019074704-appb-000184
的合成路线，得化合物C27。 1H NMR(500MHz,CDCl 3)δ8.24(s,1H),6.86(d,J＝1.1Hz,1H),6.61(t,J＝1.0Hz,1H),4.86(td,J＝5.4,1.0Hz,1H),4.19–4.02(m,2H),3.84(s,2H),3.69(ddd,J＝11.7,6.3,4.4Hz,1H),3.51(ddd,J＝11.7,6.4,4.4Hz,1H),2.97–2.82(m,2H),2.01(dtd,J＝12.8,7.4,5.3Hz,1H),1.77(dtd,J＝12.8,7.5,5.4Hz,1H),1.66–1.38(m,11H),1.35–1.12(m,7H).ESI-MS m/z 346.2[M+H] +.
实施例(S)-C27:化合物(S)-C27的合成
Figure PCTCN2019074704-appb-000185
用中间体C27-1替换实施例A1中的1-2，参考化合物(S)-A4的合成路线，得化合物(S)-C27。ESI-MS m/z 346.2[M+H] +.
实施例(R)-C27:化合物(R)-C27的合成
Figure PCTCN2019074704-appb-000186
用中间体C27-1替换实施例A1中的1-2，参考化合物(R)-A4的合成路线，得化合物(R)-C27。ESI-MS m/z 346.2[M+H] +.
实施例C28:化合物C28的合成
Figure PCTCN2019074704-appb-000187
用中间体C28-1替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物C28。 1H NMR(500MHz,Chloroform-d)δ8.24(s,1H),6.95(d,J＝0.9Hz,1H),6.62(t,J＝1.0Hz,1H),4.72(td,J＝5.4,1.0Hz,1H),4.19–4.02(m,2H),3.84(s,3H),3.87–3.79(m,1H),3.76(t,J＝6.0Hz,4H),3.49(ddd,J＝11.7,6.2,4.5Hz,1H),2.95–2.83(m,2H),2.72(dt,J＝11.9,7.2Hz,1H),2.58–2.42(m,5H),2.06(dtd,J＝12.6,7.3,5.3Hz,1H),1.92(dtd,J＝12.6,7.3,5.5Hz,1H),1.42(t,J＝7.0Hz,3H).ESI-MS m/z 349.2[M+H] +.
实施例(S)-C28:化合物(S)-C28的合成
Figure PCTCN2019074704-appb-000188
用中间体C28-1替换实施例A1中的1-2，参考化合物(S)-A4的合成路线，得化合物(S)-C28。ESI-MS m/z 349.2[M+H] +.
实施例(R)-C28:化合物(R)-C28的合成
Figure PCTCN2019074704-appb-000189
用中间体C28-1替换实施例A1中的1-2，参考化合物(R)-A4的合成路线，得化合物(R)-C28。ESI-MS m/z 349.2[M+H] +.
实施例C29:化合物C29的合成
Figure PCTCN2019074704-appb-000190
用
Figure PCTCN2019074704-appb-000191
中间体C29-1替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物C29。 1H NMR(500MHz,CDCl 3)δ8.48–8.38(m,2H),8.27(s,1H),7.46(dt,J＝7.9,2.1Hz,1H),7.19(dd,J＝7.8,3.5Hz,1H),6.63(t,J＝1.0Hz,1H),6.55(d,J＝1.1Hz,1H),4.77(td,J＝5.3,1.0Hz,1H),4.19–4.02(m,2H),3.84(s,2H),3.76(ddd,J＝11.7,6.3,4.4Hz,1H),3.54(ddd,J＝11.7,6.4,4.3Hz,1H),2.96–2.80(m,3H),2.66(dt,J＝13.9,7.3Hz,1H),2.27(dtd,J＝12.6,7.3,5.3Hz,1H),2.15(dtd,J＝12.6,7.2,5.3Hz,1H),1.42(t,J＝7.0Hz,3H).ESI-MS m/z 341.2[M+H] +.
实施例(S)-C29:化合物(S)-C29的合成
Figure PCTCN2019074704-appb-000192
用中间体C29-1替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物(S)-C29。ESI-MS m/z 341.2[M+H] +.
实施例(R)-C29:化合物(R)-C29的合成
Figure PCTCN2019074704-appb-000193
用中间体C29-1替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物(R)-C29。ESI-MS m/z 341.2[M+H] +.
实施例C30:化合物C30的合成
Figure PCTCN2019074704-appb-000194
C30-1溶于无水二氯甲烷，冰浴下滴加氯乙酰氯、三乙胺，移至室温反应1h，加水淬灭，DCM萃取干燥蒸干柱层析得C30-2。C30-3溶于乙腈，加碳酸铯，室温搅拌2h，氮气保护下加C30-2，搅拌18h，饱和氯化铵淬灭，乙酸乙酯萃取，饱和食盐水洗涤，干燥蒸干柱层析得C30-4。以C30-4替换实施例A1中的1-3，参考A4的合成，得化合物C30。 1H NMR(500MHz,Chloroform-d)δ9.86(dd,J＝2.6,2.1Hz,1H),8.28(s,1H),7.46–7.39(m,2H),7.16(dd,J＝2.5,0.6Hz,1H),6.81(dd,J＝8.4,2.7Hz,1H),6.74(d,J＝1.0Hz,1H),6.62(t,J＝1.0Hz,1H),5.23(td,J＝5.4,1.0Hz,1H),4.70(dd,J＝10.5,5.4Hz,1H),4.61(dd,J＝10.6,5.5Hz,1H),4.18–4.02(m,2H),3.84(d,J＝11.7Hz,5H),3.67(ddd,J＝11.7,6.4,4.2Hz,1H),3.57(ddd,J＝11.7,6.5,4.2Hz,1H),2.97(dddd,J＝14.6,6.4,4.2,1.1Hz,1H),2.87(dddd,J＝14.5,6.2,4.1,1.0Hz,1H),1.42(t,J＝7.0Hz,3H).ESI-MS m/z 411.2[M+H] +.
实施例(S)-C30:化合物(S)-C30的合成
Figure PCTCN2019074704-appb-000195
以C30-4替换实施例A1中的1-3，参考(S)-A4的合成，得化合物(S)-C30。ESI-MS m/z 411.2[M+H] +.
实施例(R)-C30:化合物(R)-C30的合成
Figure PCTCN2019074704-appb-000196
以C30-4替换实施例A1中的1-3，参考(R)-A4的合成，得化合物(R)-C30。ESI-MS m/z 411.2[M+H] +.
实施例C31:化合物C31的合成
Figure PCTCN2019074704-appb-000197
以
Figure PCTCN2019074704-appb-000198
C31-1替换实施例C30中的C30-3，参考C30的合成，得化合物C31。 1H NMR(500MHz,Chloroform-d)δ9.99(dd,J＝2.6,2.0Hz,1H),8.21(s,1H),7.57(dd,J＝2.5,0.5Hz,1H),7.47(ddd,J＝8.4,2.2,0.5Hz,1H),7.35–7.30(m, 1H),6.81(dd,J＝8.4,2.7Hz,1H),6.67(d,J＝1.1Hz,1H),6.61(t,J＝1.0Hz,1H),5.22(td,J＝4.1,1.0Hz,1H),4.20–4.03(m,2H),3.85(d,J＝17.0Hz,5H),3.75(dd,J＝13.5,4.1Hz,1H),3.66(ddd,J＝11.7,6.1,4.6Hz,1H),3.56(dd,J＝13.5,4.1Hz,1H),3.42(ddd,J＝11.7,6.2,4.4Hz,1H),2.94–2.81(m,2H),1.43(t,J＝6.9Hz,3H).ESI-MS m/z 427.2[M+H] +.
实施例(S)-C31:化合物(S)-C31的合成
Figure PCTCN2019074704-appb-000199
以C31-1替换实施例C30中的C30-3，参考(S)-C30的合成，得化合物(S)-C31。ESI-MS m/z 427.2[M+H] +.
实施例(R)-C31:化合物(R)-C31的合成
Figure PCTCN2019074704-appb-000200
以C31-1替换实施例C30中的C30-3，参考(R)-C30的合成，得化合物(R)-C31。ESI-MS m/z 427.2[M+H] +.
实施例C32:化合物C32的合成
Figure PCTCN2019074704-appb-000201
以C32-1替换实施例C30中的C30-3，参考C30的合成，得化合物C32。 1H NMR(500MHz,Chloroform-d)δ9.43(t,J＝2.4Hz,1H),8.26(s,1H),7.45–7.39(m,1H),7.22(ddd,J＝14.8,2.6,0.6Hz,2H),6.80(dd,J＝8.4,2.7Hz,1H),6.64(t,J＝1.1Hz,1H),6.53(d,J＝1.0Hz,1H),4.64(td,J＝4.7,1.0Hz,1H),4.10(q,J＝6.9Hz,2H),3.84(d,J＝17.0Hz,5H),3.66(ddd,J＝11.7,6.4,4.3Hz,1H),3.60–3.47(m,3H),3.48–3.40(m,2H),2.95(dddd,J＝14.6,6.4,4.2,1.0Hz,1H),2.87(dddd,J＝14.6,6.4,4.2,1.0Hz,1H),2.82(d,J＝4.8Hz,2H),2.75(t,J＝5.3Hz,4H),1.42(t,J＝7.0Hz,3H).ESI-MS m/z 479.3[M+H] +.
实施例(S)-C32:化合物(S)-C32的合成
Figure PCTCN2019074704-appb-000202
以C32-1替换实施例C30中的C30-3，参考(S)-C30的合成，得化合物(S)-C32。ESI-MS m/z 479.3[M+H] +.
实施例(R)-C32:化合物(R)-C32的合成
Figure PCTCN2019074704-appb-000203
以C32-1替换实施例C30中的C30-3，参考(R)-C30的合成，得化合物(R)-C32。ESI-MS m/z 479.3[M+H] +.
实施例C33:化合物C33的合成
Figure PCTCN2019074704-appb-000204
用中间体5-羟基-吲哚-3丙酸替换实施例A1中的1-2，参考化合物A4的合成路线，得化合物C33。
实施例(S)-C33:化合物(S)-C33的合成
Figure PCTCN2019074704-appb-000205
用中间体5-羟基-吲哚-3丙酸替换实施例A1中的1-2，参考化合物(S)-A4的合成路线，得化合物(S)-C33。
实施例(R)-C33:化合物(R)-C33的合成
Figure PCTCN2019074704-appb-000206
用中间体5-羟基-吲哚-3丙酸替换实施例A1中的1-2，参考化合物(R)-A4的合成路线，得化合物(R)-C33。
实施例C34:化合物C34的合成
Figure PCTCN2019074704-appb-000207
C33-1替换实施例A1中的1-5，参考化合物B9的合成，得化合物C34。 1H NMR(500MHz,Chloroform-d)δ6.94(t,J＝1.0Hz,1H),6.74(t,J＝1.0Hz,1H),4.54(d,J＝0.9Hz,2H),4.18(s,1H),4.11(q,J＝7.0Hz,2H),3.84(s,2H),3.82–3.68(m,2H),2.95(s,2H),2.89(td,J＝5.3,1.0Hz,2H),1.42(t,J＝6.9Hz,3H).ESI-MS m/z 328.1[M+H] +.
实施例C35:化合物C35的合成
Figure PCTCN2019074704-appb-000208
以3-氨基吲哚替换实施例C30中的C30-3，参考C30的合成，得化合物C35。
实施例(S)-C35:化合物(S)-C35的合成
Figure PCTCN2019074704-appb-000209
以3-氨基吲哚替换实施例C30中的C30-3，参考(S)-C30的合成，得化合物(S)-C35。
实施例(R)-C35:化合物(R)-C35的合成
Figure PCTCN2019074704-appb-000210
以3-氨基吲哚替换实施例C30中的C30-3，参考(R)-C30的合成，得化合物(R)-C35。
实施例C36:化合物C36的合成
Figure PCTCN2019074704-appb-000211
中间体C36-1，3-吲哚丙酸与EDCI、HOBT、TEA在二氯甲烷中室温反应过夜得C36-2。C36-2经HCl-二氧六环溶液反应两小时得C36-3。C36-3于甲酸乙酯中回流过夜，经石油醚、乙酸乙酯体系过柱纯化得C36。
实施例(S)-C36:化合物(S)-C36的合成
Figure PCTCN2019074704-appb-000212
以(S)-C36-1替换中间体C36-1，参考C36的合成得(S)-C36。
实施例(R)-C36:化合物(R)-C36的合成
Figure PCTCN2019074704-appb-000213
以(R)-C36-1替换中间体C36-1，参考C36的合成得(R)-C36。
实施例C37:化合物C37的合成
Figure PCTCN2019074704-appb-000214
用化合物C37-1替换实施例A1中的2-1，合成方法参考化合物A1，得化合物C37。 1H NMR(400MHz,DMSO):δ10.86,10.74(2×s,1H),8.18,8.15(2×s,1H),7.42–7.22(m,2H),7.08–6.90(m,2H),6.81–6.73(m,1H),6.65–6.52(m,2H),5.55–5.46,5.06–4.96(2×m,1H),3.71–3.63,3.41–3.25(2×m,1H),3.65(s,3H),3.58,3.54(2×s,3H),3.21–3.10,3.06–2.94(2×m,1H),2.80–2.57(m,4H),2.08–1.68(m,4H).ESI-MS m/z 379.2[M+H] +HR-MS:(ESI,m/z)calcd for C 23H 26N 2O 3 +[M+H] +379.2016,found:379.2027.
实施例(S)-C37:化合物(S)-C37的合成
Figure PCTCN2019074704-appb-000215
用化合物C37-1替换实施例A1中的2-1，合成方法参考化合物(S)-A1，得化合物(S)-C37。 1H NMR(400MHz,DMSO):δ10.87,10.74(2×s,1H),8.18,8.15(2×s,1H),7.43–7.23(m,2H),7.08–6.90(m,2H),6.82–6.72(m,1H),6.64–6.52(m,2H),5.55–5.46,5.06–4.95(2×m,1H),3.73–3.63,3.41–3.24(2×m,1H),3.65(s,3H),3.58,3.54(2×s,3H),3.22–3.10,3.09–2.94(2×m,1H),2.81–2.57(m,4H),2.08–1.71(m,4H).ESI-MS m/z 379.2[M+H] +HR-MS:(ESI,m/z)calcd for C 23H 26N 2O 3 +[M+H] +379.2016,found:379.2027.
实施例(R)-C37:化合物(R)-C37的合成
Figure PCTCN2019074704-appb-000216
用化合物C37-1替换实施例A1中的2-1，合成方法参考化合物(R)-A1，得化合物(R)-C37。 1H NMR(400MHz,DMSO):δ10.86,10.74(2×s,1H),8.18,8.15(2×s,1H),7.44–7.24(m,2H),7.08–6.90(m,2H),6.82–6.73(m,1H),6.65–6.52(m,2H),5.55–5.46,5.06–4.96(2×m, 1H),3.71–3.63,3.41–3.25(2×m,1H),3.65(s,3H),3.58,3.54(2×s,3H),3.21–3.10,3.06–2.94(2×m,1H),2.80–2.57(m,4H),2.08–1.68(m,4H).ESI-MS m/z 379.2[M+H] +C 23H 26N 2O 3 +[M+H] +:379.1943,found:379.2008.
实施例C38:化合物C38的合成
Figure PCTCN2019074704-appb-000217
用化合物32-1替换实施例A1中的1-2,用乙酰氯替换实施例B14中的B14-1，合成方法参考化合物B14的合成，得到化合物C38。 1H NMR(500MHz,CDCl 3)δ8.89,8.59(2×s,1H),7.63,7.58(2×d,J＝31.9,7.8Hz,1H),7.34(2×d,J＝37.5,7.9Hz,1H),7.22–7.03(m,2H),6.87,6.83(2×s,1H),6.64,6.58(2×s,1H),,6.20(s,1H),5.85–5.23(m,1H),4.92,4.81(2×dd,J＝5.52,6.32,5.92,6.32Hz,1H),3.86,3.83(2×s,3H),3.80(s,1H),3.68–3.48(m,1H),3.46(s,2H),3.36–3.26(m,1H),3.25–3.16(m,2H),2.96–2.77(m,1H),2.75–2.64(m,1H),2.15,1.54(2×s,3H).ESI-MS m/z 365.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 22H 23N 2O 3 +[M+H] +365.1787,found 365.1863.
实施例(S)-C38:化合物(S)-C38的合成
Figure PCTCN2019074704-appb-000218
用化合物32-1替换实施例A1中的1-2,用乙酰氯替换实施例B14中的B14-1，合成方法参考化合物(S)-B14的合成，得到化合物(S)-C38。 1H NMR(500MHz,CDCl 3)δ8.88,8.57(2×s,1H),7.64,7.58(2×d,J＝31.9,7.8Hz,1H),7.34(2×d,J＝37.5,7.9Hz,1H),7.22–7.03(m,2H),6.87,6.83(2×s,1H),6.64,6.57(2×s,1H),6.20(s,1H),5.85–5.23(m,1H),4.92,4.81(2×dd,J＝5.52,6.32,5.92,6.32Hz,1H),3.86,3.83(2×s,3H),3.80(s,1H),3.68–3.48(m,1H),3.46(s,2H),3.36–3.26(m,1H),3.25–3.16(m,2H),2.96–2.77(m,1H),2.74–2.64(m,1H),2.14,1.52(2×s,3H).ESI-MS m/z 365.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 22H 23N 2O 3 +[M+H] +365.1787,found 365.1867.
实施例C39:化合物C39的合成
Figure PCTCN2019074704-appb-000219
用化合物32-1替换实施例A1中的1-2，合成方法参考化合物B1的合成，得到化合物C39。 1H NMR(400MHz,CDCl 3)δ8.63,8.50(2×s,1H),8.35,8.18(2×s,1H),7.70,7.63(2×s,1H),7.39(dd,J＝8.1,3.9Hz,1H),7.22(td,J＝7.2,3.5Hz,1H),7.09–6.96(m,1H),6.89(d,J＝1.9Hz,1H),6.71,6.60(2×s,1H),6.42(dd,J＝16.8,11.8Hz,1H),6.00(t,J＝6.8Hz,1H),4.93,4.82(2×dd,J＝5.83,6.97,5.83,5.51Hz,1H),4.14(q,J＝7.1Hz,1H),3.90(d,J＝13.8Hz,3H),3.77(s,1H),3.64(d,J＝9.5Hz,1H),3.56–3.35(m,2H),3.27–3.06(m,2H),2.92–2.73(m,1H),2.07(s,1H).ESI-MS m/z428.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 20H 25N 3O 3 +[M+H] +428.1896,found 428.1971.
实施例C40:化合物C40的合成
Figure PCTCN2019074704-appb-000220
用化合物32-1替换实施例A1中的1-2，合成方法参考化合物B14的合成，得到化合物C40。 1H NMR(500MHz,CDCl 3)δ8.26(s,1H),7.67(d,J＝7.6Hz,1H),7.36(d,J＝7.9Hz,1H),7.17(dt,J＝21.1,7.1Hz,2H),6.95(s,1H),6.61(s,1H),6.41(s,1H),5.20–5.11(m,1H),3.85(s,3H),3.67(s,3H),3.52–3.38(m,3H),3.30(dd,J＝14.5,8.6Hz,1H),3.19(ddd,J＝20.5,10.7,5.0Hz,3H),3.06–2.97(m,2H),2.96–2.88(m,1H),2.71(ddd,J＝27.6,13.4,3.5Hz,3H).ESI-MS m/z 436.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 25H 29N 3O 4 +[M+H] +436.2158,found 436.2241.
实施例(S)-C40:化合物(S)-C40的合成
Figure PCTCN2019074704-appb-000221
用化合物32-1替换实施例A1中的1-2，合成方法参考化合物(S)-B14的合成，得到化合物(S)-C40。 1H NMR(500MHz,CDCl 3)δ8.26(s,1H),7.67(d,J＝7.6Hz,1H),7.36(d,J＝7.9Hz,1H),7.17(dt,J＝21.1,7.1Hz,2H),6.95(s,1H),6.61(s,1H),6.41(s,1H),5.20–5.11(m,1H),3.85(s,3H),3.67(s,3H),3.52–3.38(m,3H),3.30(dd,J＝14.5,8.6Hz,1H),3.19(ddd,J＝20.5,10.7,5.0Hz,3H),3.06–2.97(m,2H),2.96–2.88(m,1H),2.71(ddd,J＝27.6,13.4,3.5Hz,3H).ESI-MS m/z 436.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 25H 29N 3O 4 +[M+H] +436.2158,found 436.2236.
实施例C41:化合物C41的合成
Figure PCTCN2019074704-appb-000222
用化合物32-1替换实施例A1中的1-2，用化合物13-1替换实施例B1中的11-1，合成方法参考化合物B1的合成，得到化合物C41。 1H NMR(500MHz,CDCl 3)δ8.35,8.13(2×s,1H),7.81–7.58(m,1H),7.43–7.29(m,1H),7.33(d,J＝8.1Hz,6H),7.25(d,J＝3.1Hz,1H),7.15,7.07(dt,J＝15.1,15.1Hz,1H),6.94,6.87(2×s,1H),6.77,6.65(2×s,1H),6.57–5.83(m,1H),5.07,4.83(2×dd,J＝10.5,3.0,12.9,5.1,Hz,1H),4.04–3.96(m,1H),3.94(s,2H),3.88(s,2H),3.84(s,1H),3.81–3.67(m,1H),3.50–3.43(m,2H),3.41–3.12(m,3H),3.02–2.65(m,3H).ESI-MS m/z 436.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 25H 30N 3O 4 +[M+H] +435.2206,found 435.2290.
实施例(S)-C41:化合物(S)-C41的合成
Figure PCTCN2019074704-appb-000223
用化合物32-1替换实施例A1中的1-2，用化合物13-1替换实施例B1中的11-1，合成方法参考化合物(S)-B1的合成，得到化合物(S)-C41。 1H NMR(500MHz,CDCl 3)δ9.12,8.63(2×d,J＝32.9,30.9Hz,1H),7.76,7.57(2×d,J＝5.12,8.47Hz,1H),7.39,7.30(2×d,,J＝7.13,9.13Hz,1H),7.25–7.20(m,1H),7.13,7.04(2×t,J＝13.8,14.4Hz,1H),6.92,6.86(2×s,1H),6.80,6.66(2×s,1H),6.58,6.22,5.85(2×s,t,J＝6.5Hz,1H),5.09,4.85(2×d,J＝10.0,7.7Hz,1H),4.02–3.78(m,6H),3.72–3.52(m,1H),3.46–3.27(m,3H),2.96–2.70(m,3H),2.09–1.87(m,2H),1.76–1.40(m,3H),1.36–1.12(m,2H).ESI-MS m/z 435.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 25H 30N 3O 4 +[M+H] +435.2206,found 435.2279.
实施例C42:化合物C42的合成
Figure PCTCN2019074704-appb-000224
用化合物32-1替换实施例A1中的1-2，用化合物C42-1替换实施例B1中的11-1，合成方法参考化合物B1的合成，得到化合物C42。 1H NMR(400MHz,CDCl 3)δ8.09,7.90(2×d,J＝12.4,2.5Hz,1H),7.90(2×d,J＝7.7,3.1Hz,1H),7.57–7.52(m,1H),7.34–7.25 (m 1H),7.23–7.15(m,1H),7.12–7.08(m,1H),7.05–6.95(m,1H),6.84–6.78(m,1H),6.62(d,J＝16.6Hz,1H),6.34,6.08(2×s,1H),5.93,4.77(2×dd,J＝8.3,5.4,13.4,3.7Hz,1H),3.85(d,J＝7.1Hz,3H),3.83–3.76(m,1H),3.56(s,1H),3.54–3.44(m,1H),3.44–3.37(m,2H),3.28(dd,J＝14.2,6.7Hz,1H),3.10–3.00(m,1H),2.89–2.73(m,1H),1.66(s,2H).ESI-MS m/z 434.9[M+H] +.HR-MS:(ESI,m/z)calcd for C 24H 24N 3O 3S +[M+H] +434.1460,found 434.1546.
实施例(S)-C42:化合物(S)-C42的合成
Figure PCTCN2019074704-appb-000225
用化合物32-1替换实施例A1中的1-2，用化合物C42-1替换实施例B1中的11-1，合成方法参考化合物B1的合成，得到化合物(S)-C42。 1H NMR(500MHz,CDCl 3)δ8.07(d,J＝20.6Hz,1H),7.73,7.67(3×d,J＝3.2,7.9,6.1Hz,1H),7.54(t,J＝6.1Hz,2H),7.38–7.21(m,1H),7.17–7.07(m,1H),7.03–6.90(m,1H),6.81(dd,J＝11.8,4.5Hz,1H),6.65,6.60(2×s,1H),6.34,6.09(2×s,1H),5.30–4.73(m,1H),3.95–3.77(m,3H),3.56(s,2H),3.52–3.41(m,1H),3.42–3.37(m,2H),3.34–3.25(m,1H),3.12–2.99(m,1H),2.89–2.73(m,1H),2.62(s,1H).ESI-MS m/z 434.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 24H 24N 3O 3S +[M+H] +434.1460,found 434.1542.
实施例C43:化合物C43的合成
Figure PCTCN2019074704-appb-000226
用化合物32-1替换实施例A1中的1-2，用化合物15-1替换实施例B2中的12-1，合成方法参考化合物B2的合成，得到化合物C43。 1H NMR(400MHz,CDCl 3)δ8.06(s,1H),7.59(d,J＝7.7Hz,1H),7.35(d,J＝8.0Hz,1H),7.14(ddd,J＝14.9,14.0,7.0Hz,2H),6.94(d,J＝2.0Hz,1H),6.56(s,1H),5.96(s,1H),4.14–4.05(m,1H),3.83(s,3H),3.67(s,3H),3.54(q,J＝16.7Hz,2H),3.38(s,3H),3.05(dd,J＝14.4,7.9Hz,2H),2.87(ddd,J＝16.4,10.4,6.0Hz,1H),2.61(dd,J＝12.3,3.8Hz,1H),1.40(t,J＝7.3Hz,1H).ESI-MS m/z 395.2[M+H] +.HR-MS:(ESI,m/z)calcd for C 23H 27N 2O 3 +[M+H] +395.1893,found 395.1971.
实施例C44:化合物C44的合成
Figure PCTCN2019074704-appb-000227
用化合物C44-1替换实施例A1中的1-2，合成方法参考化合物A1的合成，得到化合物C44。 1H NMR(400MHz,CDCl 3)δ9.05,8.80(2×s,1H),8.13,7.52(2×s,1H),7.48,7.43(2×d,J＝8.7,8.3Hz,1H),7.33,7.29(2×d,J＝1.3,1.4Hz,1H),7.10,7.01(2×dd,J＝8.4,1.7,8.5,1.7Hz,1H),6.89,6.84(2×d,J＝1.6,1.7Hz,1H),6.67,6.64(2×s,1H),6.30,6.61(s,t,J＝6.5Hz 1H),4.67,4.48(2×dd,J＝9.9,3.8,12.1,5.5Hz,1H),3.87(d,J＝2.2Hz,3H),3.84(s,1H),3.57,3.46(2×s,3H),3.39–3.00(m,2H),2.96–2.60(m,2H),1.35(t,J＝7.3Hz,1H).ESI-MS m/z 385.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 21H 22ClN 2O 3 +[M+H] +385.1241,found 385.2241.
实施例(S)-C44:化合物(S)-C44的合成
Figure PCTCN2019074704-appb-000228
用化合物C44-1替换实施例A1中的1-2，合成方法参考化合物(S)-A1的合成，得到化合物(S)-C44。 1H NMR(500MHz,CDCl 3)δ8.48,8.27(2×s,1H),8.15,7.57(2×s,1H),7.47(dd,J＝18.5,8.4Hz,1H),7.34(dd,J＝19.3,1.6Hz,1H),7.09(2×dd,J＝1.8,1.8,1.9,1.7Hz,1H),6.92,6.87(2×s,1H),6.65(d,J＝9.2Hz,1H),6.56,6.32(2×s,1H),4.68–4.46(m,1H),3.94–3.83(m,4H),3.59(s,1H),3.58–f3.34(m,1H),3.26(dd,J＝11.3,5.2Hz,1H),3.23–3.10(m,1H),2.96–2.77(m,1H),2.79–2.61(m,1H),2.06(d,J＝16.5Hz,1H),1.80(s,1H).ESI-MS m/z 385.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 21H 22ClN 2O 3 +[M+H] +385.1241,found385.1323.
实施例C45:化合物C45的合成
Figure PCTCN2019074704-appb-000229
用化合物C45-1替换实施例A1中的1-2，合成方法参考化合物A1的合成，得到化合物C45。 1H NMR(400MHz,CDCl 3)δ8.16(s,1H),7.64–7.53(m,2H),7.33(d,J＝8.2 Hz,1H),7.18(dt,J＝14.8,7.0Hz,1H),7.08,6.80(m,1H),6.65(2×s,1H),6.55,6.26,5.64(2×s,t,J＝6.4Hz,1H),4.72–4.47(m,1H),3.88(s,1H),3.85(d,J＝2.1Hz,3H),3.75(s,1H),3.71(s,1H),3.60–3.53(m,1H),3.52(s,1H),3.38–3.07(m,3H),2.96–2.79(m,1H),2.79–2.63(m,1H),1.72(s,2H).ESI-MS m/z 365.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 22H 25N 2O 3 +[M+H] +365.1787,found 365.1868.
实施例C46:化合物C46的合成
Figure PCTCN2019074704-appb-000230
用化合物32-1替换实施例A1中的1-2，用化合物溴苄替换实施例A2中的4-2，合成方法参考化合物A2的合成,得到化合物C46。 1H NMR(400MHz,CDCl 3)δ8.36,8.17(2×s,1H),7.55(dd,J＝17.0,8.6Hz,2H),7.47(d,J＝7.3Hz,1H),7.38(dd,J＝12.8,3.9Hz,1H),7.31(d,J＝7.4Hz,1H),7.26(t,J＝7.2Hz,2H),7.17(m,1H),6.87,6.73(2×s,1H),6.69(d,J＝4.5Hz,1H),6.58,6.32(2×s,1H),5.58(t,3H),5.15(s,1H),4.79(dd,J＝39.4,12.5Hz,1H),4.56(m,1H),4.15(q,J＝7.1Hz,1H),3.92,3.87(2×s,3H),3.61–3.29(m,1H),3.27–3.02(m,2H),2.98–2.79(m,1H),2.79–2.61(m,1H),2.07(s,1H).ESI-MS m/z 427.1[M+H] +.HR-MS:(ESI,m/z)calcd for C 27H 27N 2O 3 +[M+H] +427.1943,found 427.2025.
实施例(S)-C47:化合物(S)-C47的合成
Figure PCTCN2019074704-appb-000231
用苯磺酰氯替换实施例B13中的甲磺酰氯，合成方法参考化合物(S)-C8和B13的合成,得到化合物(S)-C47。 1H NMR(500MHz,Chloroform-d)δ7.96(s,1H),7.72(d,J＝7.8Hz,2H),7.41(t,J＝7.4Hz,1H),7.30(t,J＝7.7Hz,2H),7.27–7.23(m,1H),7.12(d,J＝2.2Hz,1H),7.01(d,J＝2.4Hz,1H),6.85(dd,J＝8.8,2.4Hz,1H),6.29(d,J＝2.3Hz,2H),5.01(dd,J＝9.4,4.2Hz,1H),3.95(dt,J＝14.3,4.5Hz,1H),3.85(s,3H),3.85–3.80(m,2H),3.73(s,3H),3.56–3.46(m,1H),2.98–2.86(m,2H),2.40(dt,J＝6.2,3.8Hz,2H),2.23(dtd,J＝14.6,8.6,5.9Hz,1H),2.13(qd,J＝9.0,8.4,3.8Hz,1H),1.36(t,J＝7.0Hz,3H).
实施例(S)-C48:化合物(S)-C48的合成
Figure PCTCN2019074704-appb-000232
用环丙基磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C48。 1H NMR(500MHz,Chloroform-d)δ7.84(s,1H),7.25(s,1H),7.12(d,J＝2.0Hz,1H),7.03(d,J＝2.4Hz,1H),6.85(dd,J＝8.8,2.4Hz,1H),6.56(s,1H),6.30(s,1H),4.78(dd,J＝9.9,3.8Hz,1H),4.02(dd,J＝14.8,6.8Hz,1H),3.85(s,3H),3.85(q,J＝7.0Hz,2H),3.82(s,3H),3.54(ddd,J＝14.8,12.0,5.1Hz,1H),3.11–3.00(m,1H),3.00–2.90(m,2H),2.68(dd,J＝16.7,5.0Hz,1H),2.24(ddt,J＝14.2,8.3,4.3Hz,1H),2.15–2.03(m,2H),1.36(t,J＝7.0Hz,3H),1.22–1.16(m,1H),1.07(ddt,J＝10.2,6.8,4.9Hz,1H),0.82(qd,J＝7.9,4.8Hz,1H),0.72(dt,J＝9.6,6.0Hz,1H).
实施例(S)-C49:化合物(S)-C49的合成
Figure PCTCN2019074704-appb-000233
用环己基磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C49。 1H NMR(500MHz,Chloroform-d)δ7.67(s,1H),7.22(d,J＝7.5Hz,1H),7.13(s,1H),7.04(s,1H),6.96(s,1H),6.70(d,J＝7.5Hz,1H),6.26(s,1H),4.61(dq,J＝12.3,7.9Hz,1H),4.19(s,1H),4.06(dq,J＝12.5,8.1Hz,1H),3.89(d,J＝15.0Hz,6H),3.62–3.50(m,2H),3.42(dt,J＝16.9,7.1Hz,1H),3.26(dt,J＝12.5,7.0Hz,1H),2.88–2.72(m,2H),2.50–2.39(m,3H),2.02–1.85(m,6H),1.78–1.66(m,1H),1.61–1.31(m,6H).
实施例(S)-C50:化合物(S)-C50的合成
Figure PCTCN2019074704-appb-000234
用3-氟苯磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C50。 1H NMR(500MHz,Chloroform-d)δ7.98–7.94(m,1H),7.47(td,J＝7.9,1.7Hz,2H),7.30–7.23(m,2H),7.13–7.08(m,2H),7.01(d,J＝2.4Hz,1H),6.86(dd,J＝8.8,2.4Hz,1H),6.33(s,1H),6.29(s,1H),4.97(dd,J＝9.3,4.3Hz,1H),3.98–3.93(m,1H),3.86(s,3H),3.83(t,J＝7.0Hz,2H),3.75(s,3H),3.58–3.51(m,1H),2.98–2.86(m,2H),2.49–2.43(m,2H),2.24(dtd,J＝14.6,8.2,6.0Hz,1H),2.17–2.08(m,1H), 1.36(t,J＝7.0Hz,3H).
实施例(S)-C51:化合物(S)-C51的合成
Figure PCTCN2019074704-appb-000235
用3,4-二氟苯磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C51。 1H NMR(500MHz,Chloroform-d)δ7.95(s,1H),7.56(ddd,J＝9.5,7.2,2.2Hz,1H),7.44(ddd,J＝8.7,3.8,1.8Hz,1H),7.26(d,J＝2.5Hz,1H),7.12(d,J＝2.1Hz,1H),7.06(td,J＝9.3,7.5Hz,1H),7.01(d,J＝2.4Hz,1H),6.86(dd,J＝8.8,2.4Hz,1H),6.34(s,1H),6.29(s,1H),4.95(dd,J＝9.3,4.3Hz,1H),3.97–3.90(m,1H),3.86(s,3H),3.83(q,J＝7.0Hz,2H),3.76(s,3H),3.55(ddd,J＝14.5,11.0,5.7Hz,1H),2.98–2.87(m,2H),2.51–2.39(m,2H),2.24(dtd,J＝14.5,8.4,6.0Hz,1H),2.18–2.10(m,1H),1.37(t,J＝7.0Hz,3H).
实施例(S)-C52:化合物(S)-C52的合成
Figure PCTCN2019074704-appb-000236
用2,4-二氟苯磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C52。 1H NMR(500MHz,Chloroform-d)δ7.97(s,1H),7.95–7.88(m,1H),7.24(d,J＝8.7Hz,1H),7.07(d,J＝2.2Hz,1H),6.98(d,J＝2.4Hz,1H),6.91–6.87(m,1H),6.85(dd,J＝8.8,2.5Hz,1H),6.69(ddd,J＝10.6,8.5,2.4Hz,1H),6.39(s,1H),6.32(s,1H),5.04(dd,J＝9.3,4.4Hz,1H),4.05–3.97(m,1H),3.85(d,J＝2.7Hz,4H),3.83(q,J＝7.0Hz,2H),3.77(s,3H),3.57(ddd,J＝14.3,9.5,7.0Hz,1H),2.95–2.81(m,2H),2.55–2.48(m,2H),2.24(dtd,J＝14.6,8.9,5.7Hz,1H),2.17–2.08(m,1H),1.36(t,J＝7.0Hz,3H).
实施例(S)-C53:化合物(S)-C53的合成
Figure PCTCN2019074704-appb-000237
用乙基磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C53。 1H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.24(d,J＝8.7 Hz,1H),7.10(d,J＝2.3Hz,1H),7.02(d,J＝2.4Hz,1H),6.84(dd,J＝8.8,2.4Hz,1H),6.57(s,1H),6.32(s,1H),4.77(dd,J＝9.4,4.2Hz,1H),4.03–3.95(m,1H),3.84(s,3H),3.83(q,J＝7.0Hz,2H),3.82(s,3H),3.54(ddd,J＝14.6,11.8,5.0Hz,1H),3.01–2.78(m,5H),2.68(ddd,J＝16.8,5.0,1.9Hz,1H),2.25(dtd,J＝14.6,8.7,5.8Hz,1H),2.11(dtd,J＝14.3,8.1,4.2Hz,1H),1.36(t,J＝7.0Hz,3H),1.26(t,J＝7.4Hz,3H).
实施例(S)-C54:化合物(S)-C54的合成
Figure PCTCN2019074704-appb-000238
用三氟乙酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C54。 1H NMR(500MHz,Chloroform-d)δ8.32(d,J＝9.0Hz,1H),7.31(d,J＝2.4Hz,1H),7.03–6.93(m,2H),6.61(s,1H),6.52(s,1H),5.59(dd,J＝9.6,4.5Hz,1H),4.09–3.97(m,2H),3.93–3.80(m,8H),3.67(tdd,J＝11.3,9.2,5.0Hz,1H),2.99(ddd,J＝16.7,11.3,5.6Hz,1H),2.89–2.67(m,3H),2.38–2.16(m,2H),1.41(t,J＝7.0Hz,3H).
实施例(S)-C55:化合物(S)-C55的合成
Figure PCTCN2019074704-appb-000239
用吡啶-3-磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C55。 1H NMR(500MHz,Chloroform-d)δ8.99(d,J＝2.2Hz,1H),8.64–8.57(m,1H),8.03(s,1H),7.92(dt,J＝8.1,2.0Hz,1H),7.26(s,1H),7.20(dd,J＝8.1,4.9Hz,1H),7.14(d,J＝2.0Hz,1H),7.01(d,J＝2.3Hz,1H),6.87(dd,J＝8.8,2.4Hz,1H),6.30(s,1H),6.26(s,1H),4.97(dd,J＝9.4,4.2Hz,1H),4.01(ddd,J＝14.7,7.0,2.4Hz,1H),3.86(s,3H),3.82(q,J＝7.0Hz,2H),3.74(s,3H),3.57(ddd,J＝14.6,11.0,5.8Hz,1H),2.94(q,J＝7.1,6.3Hz,2H),2.53–2.40(m,2H),2.25(dddd,J＝14.8,13.2,9.6,5.7Hz,1H),2.15(dtd,J＝14.3,7.9,4.4Hz,1H),1.36(t,J＝6.9Hz,3H).
实施例(S)-C56:化合物(S)-C56的合成
Figure PCTCN2019074704-appb-000240
用3-氟-4-溴磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47 的合成,得到化合物(S)-C56。 1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.51–7.43(m,2H),7.31(dd,J＝8.3,2.0Hz,1H),7.11(d,J＝2.3Hz,1H),7.01(d,J＝2.4Hz,1H),6.86(dd,J＝8.8,2.4Hz,1H),6.33(s,1H),6.29(s,1H),4.96(dd,J＝9.3,4.4Hz,1H),3.93(ddd,J＝14.7,6.4,2.9Hz,1H),3.86(s,3H),3.83(q,J＝6.9Hz,2H),3.76(s,3H),3.55(ddd,J＝14.5,10.6,6.0Hz,1H),2.92(td,J＝7.9,4.7Hz,2H),2.46(dq,J＝11.4,6.3,4.8Hz,2H),2.24(dtd,J＝14.5,8.3,6.0Hz,1H),2.14(dtd,J＝14.4,7.8,4.3Hz,1H),1.37(t,J＝7.0Hz,3H).
实施例(S)-C57:化合物(S)-C57的合成
Figure PCTCN2019074704-appb-000241
用2-氟磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C57。 1H NMR(500MHz,Chloroform-d)δ7.99–7.94(m,1H),7.94–7.90(m,1H),7.45–7.39(m,1H),7.17(td,J＝7.7,1.1Hz,1H),7.07(d,J＝2.3Hz,1H),7.00–6.93(m,2H),6.84(dd,J＝8.8,2.4Hz,1H),6.36(s,1H),6.31(s,1H),5.07(dd,J＝9.4,4.3Hz,1H),4.04(ddd,J＝14.5,6.2,2.7Hz,1H),3.85(s,3H),3.83(q,J＝7.0Hz,2H),3.75(s,3H),3.56(ddd,J＝14.3,10.9,5.6Hz,1H),2.93–2.81(m,2H),2.57–2.46(m,2H),2.24(dtd,J＝14.6,9.1,5.5Hz,1H),2.12(dddd,J＝13.9,8.9,7.1,4.4Hz,1H),1.36(t,J＝7.0Hz,3H).
实施例(S)-C58:化合物(S)-C58的合成
Figure PCTCN2019074704-appb-000242
用4-氟磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C58。 1H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.73–7.67(m,2H),7.12(d,J＝2.3Hz,1H),7.01(d,J＝2.4Hz,1H),6.96(t,J＝8.6Hz,2H),6.86(dd,J＝8.7,2.4Hz,1H),6.30(s,1H),6.28(s,1H),4.98(dd,J＝9.5,4.1Hz,1H),3.94(ddd,J＝14.4,7.0,2.2Hz,1H),3.85(s,3H),3.83(q,J＝6.9Hz,2H),3.74(s,3H),3.52(ddd,J＝14.5,11.3,5.5Hz,1H),2.99–2.88(m,2H),2.46–2.32(m,2H),2.23(dtd,J＝14.5,8.7,5.7Hz,1H),2.16–2.09(m,1H),1.37(t,J＝7.0Hz,3H).
实施例(S)-C59:化合物(S)-C59的合成
Figure PCTCN2019074704-appb-000243
用二氟乙酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C59。 1H NMR(500MHz,Chloroform-d)δ7.61(s,1H),7.22(d,J＝7.5Hz,1H),7.14(d,J＝1.0Hz,1H),7.04(s,1H),6.79(d,J＝1.6Hz,1H),6.70(dd,J＝7.5,1.5Hz,1H),6.23–6.16(m,1H),4.95(s,1H),4.57(dq,J＝12.3,7.9Hz,1H),4.40–4.26(m,1H),3.89(m,8H),3.56(dt,J＝12.5,7.1Hz,1H),3.38(dtd,J＝14.1,7.0,1.0Hz,1H),2.95–2.76(m,2H),2.54(ddd,J＝12.5,9.9,6.5Hz,1H),2.16–2.06(m,2H),1.46(t,J＝8.0Hz,3H).
实施例(S)-C60:化合物(S)-C60的合成
Figure PCTCN2019074704-appb-000244
用4-甲氧基磺酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C60。 1H NMR(500MHz,Chloroform-d)δ7.92(s,1H),7.63(d,J＝8.8Hz,2H),7.12(d,J＝1.8Hz,1H),7.01(d,J＝2.4Hz,1H),6.85(dd,J＝8.7,2.4Hz,1H),6.79–6.74(m,2H),6.31(d,J＝11.7Hz,2H),4.98(dd,J＝9.3,4.3Hz,1H),3.94–3.88(m,1H),3.85(s,3H),3.83(q,J＝7.0Hz,2H),3.77(s,3H),3.75(s,3H),3.50(dt,J＝14.4,8.8Hz,1H),2.92(q,J＝7.7,7.0Hz,2H),2.45–2.39(m,2H),2.21(ddd,J＝14.7,10.1,5.9Hz,1H),2.16–2.08(m,1H),1.36(t,J＝7.0Hz,3H).
实施例(S)-C61:化合物(S)-C61的合成
Figure PCTCN2019074704-appb-000245
用61-1替换实施例(S)-A1中的1-2，合成方法参考化合物(S)-A1的合成,得到化合物(S)-C61。 1H NMR(500MHz,Chloroform-d)δ8.28(2×s,1H),7.86–7.83(2×m,1H),7.71(2×dd,J＝6.7,2.0Hz,1H),7.45–7.37(2×m,2H),7.22(2×s,1H),6.60(2×s,1H),6.47(2×s,1H),4.51(2×dd,J＝9.4,4.7Hz,1H),3.84(2×s,3H),3.74(2×s,3H),3.60(2×m,1H),3.04(2×dd,J＝15.4,7.9Hz,1H),2.94–2.90(2×m,3H),2.71(2×ddd,J＝16.2,4.8,2.1Hz,1H),2.26(2×m,2H).
实施例(S)-C62:化合物(S)-C62的合成
Figure PCTCN2019074704-appb-000246
用甲氧基乙酰氯替换实施例(S)-C47中的苯磺酰氯，合成方法参考化合物(S)-C47的合成,得到化合物(S)-C62。 1H NMR(500MHz,Chloroform-d)δ7.82(2×s,1H),7.39(2×d,J＝2.3Hz,1H),7.22(2×d,J＝7.5Hz,1H),7.16(2×d,J＝0.9Hz,1H),7.10(2×d,J＝1.7Hz,1H),6.70(2×dd,J＝7.5,1.5Hz,1H),5.02(2×dd,J＝7.6,6.6Hz,1H),4.93(2×d,J＝12.5Hz,1H),4.66(2×d,J＝12.3Hz,1H),4.35(2×dq,J＝12.3,7.9Hz,1H),4.04–3.85(2×m,8H),3.64(2×dt,J＝12.5,7.1Hz,1H),3.36–3.26(2×m,1H),3.25(2×s,3H),3.01(2×dt,J＝12.5,7.9Hz,1H),2.89–2.71(2×m,2H),2.15–2.07(2×m,2H),1.46(2×t,J＝8.0Hz,3H).
实施例(S)-C63:化合物(S)-C63的合成
Figure PCTCN2019074704-appb-000247
用63-1替换实施例(S)-A1中的1-1，合成方法参考化合物(S)-A1和(S)-C8的合成,得到化合物(S)-C63。ESI-MS m/z 449.2。
实施例(S)-C64:化合物(S)-C64的合成
Figure PCTCN2019074704-appb-000248
用64-1替换实施例(S)-C63中的63-1，合成方法参考化合物(S)-C63的合成,得到化合物(S)-C64。ESI-MS m/z 431.2。
实施例(S)-C65:化合物(S)-C65的合成
Figure PCTCN2019074704-appb-000249
用65-1替换实施例(S)-C8中的31-1，合成方法参考化合物(S)-C8的合成,得到化合 物(S)-C65。ESI-MS m/z 404.2。
实施例(S)-C66:化合物(S)-C66的合成
Figure PCTCN2019074704-appb-000250
用66-1替换实施例(S)-C63中的63-1，合成方法参考化合物(S)-C63的合成,得到化合物(S)-C66。ESI-MS m/z 423.1。
实施例(S)-C67:化合物(S)-C67的合成
Figure PCTCN2019074704-appb-000251
用67-1替换实施例(S)-C63中的63-1，合成方法参考化合物(S)-C63的合成,得到化合物(S)-C67。ESI-MS m/z 423.1。
实施例(S)-C68:化合物(S)-C68的合成
Figure PCTCN2019074704-appb-000252
化合物(S)-C66溶于甲醇中，加入1M NaOH室温搅拌2小时，1M盐酸溶液中和至中性，乙酸乙酯萃取，柱层析分离得到化合物(S)-C68。ESI-MS m/z 409.2。
实施例(S)-C69:化合物(S)-C69的合成
Figure PCTCN2019074704-appb-000253
化合物(S)-C68溶于二氯甲烷中，加入2当量甲胺四氢呋喃溶液，1.5当量HATU和2当量三乙胺室温搅拌过夜，加入二氯甲烷，水洗，有机相干燥后柱层析分离得到化合物(S)-C69。ESI-MS m/z 422.2。
实施例(S)-C70:化合物(S)-C70的合成
Figure PCTCN2019074704-appb-000254
化合物(S)-C68溶于二氧六环中，加入2当量碳酸氢铵，2当量BOC酸酐，5当量吡啶，室温搅拌过夜，加入二氯甲烷，水洗，有机相干燥后柱层析分离得到化合物(S)-C70。ESI-MS m/z 408.2。
实施例(S)-C71:化合物(S)-C71的合成
Figure PCTCN2019074704-appb-000255
用71-1替换实施例(S)-C63中的63-1，合成方法参考化合物(S)-C63的合成,得到化合物(S)-C71。ESI-MS m/z 415.2。
实施例(S)-C72:化合物(S)-C72的合成
Figure PCTCN2019074704-appb-000256
用二氟碘甲烷替换实施例(S)-B2中的12-1，合成方法参考化合物(S)-B2的合成,得到化合物(S)-C72。ESI-MS m/z 431.2。
实施例(S)-C73:化合物(S)-C73的合成
Figure PCTCN2019074704-appb-000257
用73-1替换实施例(S)-C65中的65-1，合成方法参考化合物(S)-C65的合成,得到化合物(S)-C73。ESI-MS m/z 447.2。
实施例(S)-C74:化合物(S)-C74的合成
Figure PCTCN2019074704-appb-000258
用5-二氟甲基吲哚替换实施例(S)-C65中的65-1，合成方法参考化合物(S)-C65的合成,得到化合物(S)-C74。ESI-MS m/z 429.2。
实施例(S)-C75:化合物(S)-C75的合成
Figure PCTCN2019074704-appb-000259
用吲哚-5-甲酸甲酯替换实施例(S)-C65中的65-1，合成方法参考化合物(S)-C65的合成,得到化合物(S)-C75。ESI-MS m/z 437.2。
实施例(S)-C76:化合物(S)-C76的合成
Figure PCTCN2019074704-appb-000260
用5-三氟甲氧基吲哚替换实施例(S)-C65中的65-1，合成方法参考化合物(S)-C65的合成,得到化合物(S)-C76。ESI-MS m/z 463.2。
实施例(S)-C77:化合物(S)-C77的合成
Figure PCTCN2019074704-appb-000261
用5-二氟甲氧基吲哚替换实施例(S)-C65中的65-1，合成方法参考化合物(S)-C65的合成,得到化合物(S)-C77。ESI-MS m/z 445.2。
实施例(S)-C78:化合物(S)-C78的合成
Figure PCTCN2019074704-appb-000262
用5-氟吲哚替换实施例(S)-C65中的65-1，合成方法参考化合物(S)-C65的合成,得到化合物(S)-C78。ESI-MS m/z 397.2。
实施例(S)-C79:化合物(S)-C79的合成
Figure PCTCN2019074704-appb-000263
用79-1替换实施例(S)-C63中的63-1，合成方法参考化合物(S)-C63的合成,得到化合物(S)-C79。ESI-MS m/z 409.20。
实施例(S)-C80:化合物(S)-C80的合成
Figure PCTCN2019074704-appb-000264
用6-氯-5-甲氧基吲哚替换实施例(S)-C65中的65-1，合成方法参考化合物(S)-C65的合成,得到化合物(S)-C80。ESI-MS m/z 443.2。
实施例(S)-C81:化合物(S)-C81的合成
Figure PCTCN2019074704-appb-000265
用5-氟-6-氯吲哚替换实施例(S)-C65中的65-1，合成方法参考化合物(S)-C65的合成,得到化合物(S)-C81。ESI-MS m/z 431.1。
实施例(S)-C82:化合物(S)-C82的合成
Figure PCTCN2019074704-appb-000266
用5-氟吲哚替换实施例(S)-C62中的5-甲氧基吲哚，合成方法参考化合物(S)-C62的合成,得到化合物(S)-C82。ESI-MS m/z 441.2。
实施例(S)-C83:化合物(S)-C83的合成
Figure PCTCN2019074704-appb-000267
用1-氯-2-(甲基磺酰基)乙烷替换实施例(S)-C72中的二氟碘甲烷，合成方法参考化合物(S)-C72的合成,得到化合物(S)-C83。ESI-MS m/z 487.2。
生物学活性实验例部分
实验例B1.化合物对PDE4的分子酶活抑制测定
采用临近闪烁实验(Scintillation Proximity Assay,SPA)方法测定化合物对PDE4D催化结构域的酶活抑制效果。人源PDE4D催化结构域蛋白质通过在大肠杆菌中表达和纯化获得，阳性化合物Apremilast购于陶素生化，微孔板闪烁计数仪(MicroBeta2，Perkin Elmer)，恒温水浴锅(DK420，上海医疗器械厂)，微样震荡仪(XW-80A，上海精科实业有限公司)为放射性实验室公用仪器，分步移液器(Multipette Plus，Eppendorf)及配套枪头购于艾本德生物技术公司，3.5.[ 3H]-cAMP，闪烁微珠(RPNQ0150，Perkin Elmer),96孔闪烁微孔板(Isoplate-96,Perkin Elmer)购于Perkin Elmer公司。10x SPA buffer于实验室配制(500mM Tris pH7.5,83mM MgCl2,17mM EGTA)。
在实验中，在总体积为100μl的反应体积中，加入60μl水，10μl反应液并使各组分终浓度分别为50mM Tris-HCl、pH7.5、8.3mM MgCl2、1.7mM EGTA，10μl化合物 和10μl酶(0.1ng/ul)，最后统一加入10μl[ 3H]-cAMP(0.005μCi/μl)，30℃水浴锅孵育30min，加入50μl SPA beads终止反应，适当振摇，静置20min，微孔板闪烁计数器读数。
表B1为化合物对PDE4D酶活抑制率及IC 50值
表B1
Figure PCTCN2019074704-appb-000268
Figure PCTCN2019074704-appb-000269
aMan HW,et al.J.Med.Chem.2009,52:1522-1524 b拆分得到
结论：通过对化合物在1μM浓度时对PDE4的抑制率测定后，进而对抑制效率高的化合物测定测定其对PDE4抑制活性的IC 50值。其中14个化合物的IC 50值达百纳摩尔，3个化合物(C10、(S)-C10和(S)-C8)IC 50值低于百纳摩尔，与阳性对照化合物Apremilast的IC 50值相当。
实验例2.化合物对PBMC中TNF-α分泌的抑制活性测定
PDE4诸多功能中被研究的最多的是抗炎症效应。免疫系统中单核细胞和巨噬细胞是TNF-α的重要生产者，PDE4在这些细胞中是主要酶，现有靶向PDE4抑制剂的抗炎症效应密切关联着免疫系统中TNF-α表达量。我们根据人体血液中细胞密度的差异，通过淋巴细胞分离液梯度离心法直接分离纯化得到PBMC(peripheral blood mononuclear cell,PBMC)，其细胞类型为血液里单个核的细胞，主要包括淋巴细胞(T/B)、单核细胞、巨噬细胞、树突状细胞和其他少量细胞类型，其中淋巴细胞占很大一部分，从而能够很直接地模拟体外的血液免疫环境。脂多糖(Lipopolysaccharide,LPS)是革兰氏阴性菌胞壁的成份，可通过MAPK等多种信号通路显著激发致炎因子TNF-α的表达，从而评价PDE4部分抑制剂的细胞活性，模拟体外炎症效应。PDE4部分抑制剂对人PBMC细胞TNF-α表达的抑制效应主要参照George W.Muller等人的工作。
实验过程中，阳性化合物Apremilast购自陶素生化科技有限公司。健康人的全血由上海市血液中心提供；胎牛血清(Fetal Bovine Serum,FBS)购自Hyclone(South Logan,UT,USA)；RPMI-1640培养基及人源TNF-αELISA检测试剂盒购自Invitrogen(San Diego,CA,USA)；细菌脂多糖LPS购自Sigma(L9764,St.Louis,MO,USA)。
将从人血中分离获得的PBMC细胞以2*10 5/ml植入96孔板内；加入梯度化合物，每个梯度至少设三个重复；于37℃，5％CO 2孵育1个小时后加LPS(终浓度为10ug/ml)刺激PBMC表达TNF-α；37℃，5％CO2孵育18-20h收集96孔板。另设无刺激剂本底对照及刺激对照孔，总体积为200μl。离心收取培养上清，ELISA法检测培养上清中TNF-α的表达水平。
表2为化合物对PBMC中炎症因子TNF-α分泌的抑制实验结果 表2
Figure PCTCN2019074704-appb-000270
Figure PCTCN2019074704-appb-000271
a Man HW,et al.J.Med.Chem.2009,52:1522-1524 b拆分得到
结论：分子水平抑制酶活效率较优的化合物对PBMC中TNF-α分泌抑制的效果也较好，其IC 50值在个位数微摩尔左右，而活性最优的化合物(S)-C8的IC 50值达26纳摩尔，优于阳性对照化合物Apremilast。
实验例B3.化合物对RAW 264.7细胞分泌肿瘤坏死因子-α的抑制活性测定
肿瘤坏死因子-α作为炎症、自身免疫病等疾病发展过程中重要的炎症介质，主要由活化的单核/巨噬细胞产生，可介导多种炎症反应的发生，加速恶化疾病进程。小鼠单核/巨噬细胞白血病细胞株RAW 264.7细胞是常用的炎症细胞模型之一，在细菌脂多糖(LPS)诱导激活后，可释放肿瘤坏死因子-α等多种炎症介质的释放；同时磷酸二酯酶PDE4在巨噬细胞中有表达，通过检测肿瘤坏死因子-α的分泌可反映化合物对磷酸二酯酶PDE4的抑制活性。
(1)化合物对RAW 264.7细胞毒性检测：受试化合物对RAW 264.7细胞的细胞毒性通过CCK-8法检测，小鼠RAW 264.7细胞购自American Type Culture Collection(Manassas,VA,USA)培养于含10％胎牛血清(Hyclone,South Logan,UT,USA)的DMEM培养液(Hyclone,South Logan,UT,USA)中，临用前收集细胞并计数，(1×10 5/孔)接种于96孔板(Corning,NY,USA)中，细胞孵育24h后，加入不同浓度的化合物，另设相应的溶媒对照及培养液本底对照，总体积为200μl。于37℃，5％CO 2培养箱中培养4h。培养结束前30min加入20μl CCK-8溶液(Dojindo,Kumamoto,Japan)，至培养结束，于酶标仪(Molecular Devices,Sunnyvale,CA,USA)450nm(参比650nm)处测定吸光度OD值。化合物对RAW 264.7细胞的毒性作用以待测样品OD值除以细胞对照孔OD值计算，标记为细胞存活率(％)。
(2)化合物对RAW 264.7细胞肿瘤坏死因子-α分泌的抑制活性：RAW 264.7细胞(1×10 5/孔)接种于96孔板，孵育24h后，加入不同浓度的化合物孵育30min，在1μg/ml LPS(L5886,Sigma,St.Louis,MO,USA)刺激作用下，于37℃，5％CO 2培养箱中培养4h。另设无刺激剂本底对照及刺激对照孔，总体积为200μl。离心收取培养上清，采用酶联免疫吸附法检测培养上清中肿瘤坏死因子-α的分泌水平，肿瘤坏死因子-α检测试剂盒购自BD Pharmingen(San Diego,CA,USA)。
表B3为化合物对RAW 264.7细胞炎症因子肿瘤坏死因子-α分泌的抑制实验结果
表B3
Figure PCTCN2019074704-appb-000272
Figure PCTCN2019074704-appb-000273
表B4为部分化合物对RAW 264.7细胞毒性(CC50)及分泌肿瘤坏死因子-α的抑制(IC50)实验结果
表B4
Figure PCTCN2019074704-appb-000274
a CC 50为致半数细胞毒性所需药物浓度； b IC 50为有效抑制50％肿瘤坏死因子-α时药物浓度； c SI为CC 50/IC 50。
结论：通过检测受试化合物对RAW 264.7细胞肿瘤坏死因子-α分泌的抑制活性，发现了部分抑制活性较好的化合物，结合化合物对PDE4D催化结构域的抑制活性以及PBMCs生物活性结果，选取了化合物(S)-A1、(S)-C5、(S)-C6、(S)-C8、(S)-C7检测了化合物RAW 264.7细胞细胞毒性及肿瘤坏死因子-α抑制活性，实验结果见表B3和表B4。与阳性化合物Apremilast相比，化合物(S)-C5、(S)-C8具有相当或更强的肿瘤坏死因子-α抑制活性。
实验例B4.化合物(S)-C5、(S)-C8对小鼠背部气囊急性炎症模型的治疗效果
小鼠背部气囊急性炎症模型作为候选化合物体内抗炎活性评价的经典模型，可行性高，且重复性好。实验第1天，小鼠背部皮下注射3ml空气，第3天背部皮下注射1.5ml空气，第6天背部皮下注射1ml 2％角叉菜胶(Sigma-Aldrich,St.Louis,MO,USA)溶液致敏，致敏后4h使用磷酸盐缓冲液灌洗空气囊中分泌物，灌洗液用于白细胞计数以及炎症因子检测。其中阳性药物Apremilast、受试药物(S)-C5、(S)-C8以0.5％羧甲基纤维素钠(Sigma-Aldrich,St.Louis,MO,USA)+0.25％吐温-80(购自国药集团)进行分散，药物分别在致敏前24h、1h灌胃口服给药(5mg/kg)，肿瘤坏死因子-α、白介素-6检测试剂盒购自BD Pharmingen(San Diego,CA,USA)。
结论：如图1所示，受试化合物(S)-C5、(S)-C8灌胃口服给药可明显降低小鼠背部气囊急性炎症模型的炎症反应，降低灌洗液中白细胞浸润数目、肿瘤坏死因子-α以及白介素-6分泌水平。
实验例5：大鼠药代动力学试验
1.实验步骤：
健康大鼠6只，雄性，体重150-200g，随机分成2组，每组3只。分别灌胃和静脉注射给予本发明的化合物14、16、17、18、22和29，给药体积为10mL/kg，药物以DMSO/吐温80/生理盐水(5:5:90，v/v/v)配制。试验前禁食12h，自由饮水。给药后2h统一进食。
2.采血时间点及样品处理：
灌胃给药：给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；
静脉给药：给药后5min，0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；
在以上设定时间点经大鼠眼球后静脉丛取静脉血0.3ml，置肝素化试管中，11000rpm离心5min，分离血浆，于–20℃冰箱中冷冻。
3.样品测试和数据分析
采用LC/MS/MS法测定大鼠血浆中化合物的浓度。采用DAS 3.0软件的非房室模型计算给药后的药代动力学参数。
4.实验结果：
表B5为化合物(S)-C7和(S)-C8在大鼠体内药代动力学实验结果
表B5
Figure PCTCN2019074704-appb-000275
化合物(S)-C7：大鼠灌胃给予20mg/kg化合物(S)-C7后，血浆浓度达峰时间Tmax为1h，达峰浓度Cmax为2383.6ng/ml；药时曲线下面积AUC0-t为9232.3ng·h/ml；末端消除半衰期t1/2为1h。静脉注射给予10mg/kg化合物(S)-C7后，AUC0-t为6761.8ng·h/ml；经剂量标准化后，大鼠灌胃给予20mg/kg化合物(S)-C7后的绝对生物利用度为68.3％。
化合物(S)-C8：大鼠灌胃给予20mg/kg化合物(S)-C8后，血浆浓度达峰时间Tmax为1.33h，达峰浓度Cmax为491ng/ml；药时曲线下面积AUC0-t为508ng·h/ml；末端消除半衰期t1/2为1.03h。静脉注射给予10mg/kg化合物(S)-C7后，AUC0-t为2640ng·h/ml；经剂量标准化后，大鼠灌胃给予20mg/kg化合物(S)-C8后的绝对生物利用度为9.30％。
实验结论：从以上实验结果可以看出，在大鼠药代动力学实验中，化合物(S)-C7表现出较好的生物利用度，达到68.3％。
实验例6：比格犬药代动力学试验
1.实验步骤：
健康比格犬6只，雄性，体重9-11kg，随机分成2组，每组3只。分别灌胃和静脉注射给予本发明的化合物(S)-C8，给药体积分别为5mL/kg和1mL/kg，灌胃给药以0.5％CMC-Na+0.25％Tween 80配制，静脉给药以5％DMSO/40％PEG400/55％生理盐水配制。
2.采血时间点及样品处理：
灌胃给药：给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；
静脉给药：给药后5min，0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；
在以上设定时间点经四肢静脉取静脉血1ml，置EDTA-2K抗凝管中，3500rpm离心10min，分离血浆，于–20℃冰箱中冷冻。
3.样品测试和数据分析
采用LC/MS/MS法测定比格犬血浆中化合物(S)-C8的浓度。
采用Phoenix 1.3软件(美国Pharsight公司)的非房室模型计算给药后的药代动力学参数。
4.实验结果：
表B6为化合物(S)-C8在比格犬体内的药物动力学实验结果
表B6
Figure PCTCN2019074704-appb-000276
比格犬灌胃给予10mg/kg化合物(S)-C8后，血浆浓度达峰时间T max为0.5h，达峰浓度C max为4685ng/ml；药时曲线下面积AUC 0-t为16601ng·h/ml；末端消除半衰期t 1/2为2.92h。静脉注射给予3mg/kg化合物(S)-C8后，AUC 0-t为9610ng·h/ml；经剂量标准化后，比格犬灌胃给予10mg/kg化合物(S)-C8后的绝对生物利用度为52.3％。
实验结论：从以上实验结果可以看出，在比格犬药代动力学实验中，化合物(S)-C8表现出良好的绝对生物利用度.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种通式(I)所示的四氢异喹啉类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体：
    Figure PCTCN2019074704-appb-100001
    其中，
    手性碳原子C*独立地为S型、R型，或其组合；
    n＝1或2；
    X为-CH 2-或-NH-；
    Y选自连接基团：C1～C6直链或支链亚烷基、C2～C6直链或支链亚烯基、-CH 2O-、-CH 2NH-、-CH 2S-、-CONH-、-NHCO-、-COO-、-OOC-、
    Figure PCTCN2019074704-appb-100002
    R 1、R 2各自独立地选自下组：氢、氘、羟基、卤素、取代或未取代的C1～C6直链或支链烷氧基、取代或未取代的C2～C6直链或支链烯氧基、取代或未取代的C2～C6直链或支链炔氧基、取代或未取代的C3～C7环烷氧基、取代或未取代的C3～C7环烷基甲氧基、苄氧基、C1-C6酰氧基、羧基取代的C2～C8直链烷氧基、N,N-二甲基氨基取代的C2～C8直链烷氧基，-COOR 5或-CONR 5R 6；所述取代基选自氘或者卤素；或者R 1、R 2连同与其连接的碳原子共同构成5-7元碳环或杂环(包括饱和环、不饱和环或芳香性环)；
    R 3选自未被取代或者被1-3个取代基取代的以下基团：-C(O)-5～7元杂芳基、-C(O)-4～7元杂环基、-C1～C4酰基(优选为甲酰基-CHO)、-C1～C4烷基、R 7SO 2-、NH 2(CH 2) mSO 2-、R 7SO 2(CH 2) m-、R 7O(CH 2) mCO-、R 7OCO(CH 2) m-、二氟甲基、三氟甲基、C1～C4亚磺酰基、苯磺酰基、5-7元杂芳基磺酰基、苯基，苄基，5～7元杂芳基，4～7元杂环基；其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；所述的取代基各自独立地选自氘、卤素、C1～C6直链或支链烷氧基、C1～C6直链或支链烷基羰氧基、C1～C6直链或支链烷氧羰基、氰基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、羧基、羟肟基、磷酸基、巯基、C1～C4酰胺基、C0～C4磺酰基、氨基C0～C4磺酰基、C1-C4烷基取代的磺酰基苯基，苄基，5～7元杂芳基，4～7元杂环基，其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；
    R 5、R 6、R 7各自独立地选自氢、取代或未取代的C1～C4直链或支链烷基、取代或未取代的C3～C8环烷基、取代或未取代的C6-C10芳基；所述取代基选自氘或者卤素；
    m选自0、1、2、3或者4；
    R 4选自未被取代或者被1-3个取代基取代的以下基团：C3～C7环烷基、5～12元杂环基、C7～C12芳基、5～12元杂芳基(优选为苯并5～7元杂芳基)；其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；所述的取代基各自独立地选自氘、卤素、C1～C6直链或支链烷基、C2～C6直链或支链烯基、C2～C6直链或支链炔基、C1～C6直链或支链烷氧基、C1～C6直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、二氟甲基、二氟甲氧基、COOR 5、CONR 5R 6、C1-C6羧基、巯基、C1～C4酰基、C1～C4酰胺基、磺酰基、氨基磺酰基、C1～C4烷基取代 的磺酰基，C1～C4烷基取代的磺酰胺基，N,N-二甲基取代的C1-C6烷氧基，羧基取代的C1-C6烷氧基，或者两个相邻的取代基连同与其连接的原子共同构成5-7元碳环或杂环(包括饱和环、不饱和环或芳香性环)；
  2. 如权利要求1所述的四氢异喹啉类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其特征在于，通式(I)中：
    n＝1；
    R 1、R 2各自独立地选自下组：取代或未取代的C1～C6直链或支链烷氧基、取代或未取代的C3～C7环烷氧基、取代或未取代的C3～C7环烷基甲氧基、C1-C6酰氧基、羧基取代的C2～C8直链烷氧基、N,N-二甲基氨基取代的C2～C8直链烷氧基，COOR 5或CONR 5R 6；所述取代基选自氘或者卤素(包括氟、氯、溴和碘)。
  3. 如权利要求2所述的四氢异喹啉类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其特征在于，通式(I)中：
    X为-CH 2-；
    Y选自下组：-CH 2-、-CH 2-CH 2-、-CH＝CH-、
    Figure PCTCN2019074704-appb-100003
    R 4选自未被取代或者被1-3个取代基取代的以下基团：5～12元杂环基、C6～C12芳基、5～12元杂芳基(优选为苯并5～7元杂芳基)；优选地，所述基团中的杂环和杂芳环部分选自吲哚、苯并二氧杂环戊烯、异噁唑、吡啶、吡唑、二氢咪唑并吡啶、咪唑并吡啶、苯并噻吩、二氢苯并二氧六环、喹喔林、吡咯、苯并呋喃、吲唑、苯并咪唑、喹啉、1,3-二氧代异吲哚啉形成的基团。
  4. 根据权利要求3所述的四氢异喹啉类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其特征在于，通式(I)中：
    R 3选自未被取代或者被1-3个取代基取代的以下基团：C1～C4酰基(优选为甲酰基)，C1～C4烷基，R 7SO 2-、NH 2(CH 2) mSO 2-、R 7SO 2(CH 2) m-、R 7O(CH 2) mCO-、二氟甲基、三氟甲基、C1～C3亚磺酰基、苯磺酰基、5-7元杂芳基磺酰基，苯基，苄基，5～7元杂芳基，4～7元杂环基；其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子；所述的取代基各自独立地选自氘、卤素、C1～C6直链或支链烷氧基、C1～C6直链或支链烷基羰氧基、C1～C6直链或支链烷氧羰基、氰基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、羧基、羟肟基、磷酸基、巯基、C1～C4酰胺基、C1～C4磺酰基、氨基C1～C4磺酰基、C1-C4烷基取代的磺酰基苯基，苄基，5～7元杂芳基，4～7元杂环基，其中，各个所述杂环基或杂芳基含有1～3个选自氧、硫和氮的杂原子
    R 7选自氢、C1～C4直链或支链烷基；
    m选自0、1或者2。
  5. 如权利要求1所述的四氢异喹啉类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其特征在于，通式(I)中：
    手性碳原子C*为S型。
  6. 如权利要求1所述的四氢异喹啉类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体，其中，所述四氢异喹啉类化合物选自以下化合物：
    Figure PCTCN2019074704-appb-100004
    Figure PCTCN2019074704-appb-100005
    Figure PCTCN2019074704-appb-100006
    Figure PCTCN2019074704-appb-100007
    Figure PCTCN2019074704-appb-100008
    Figure PCTCN2019074704-appb-100009
    Figure PCTCN2019074704-appb-100010
    Figure PCTCN2019074704-appb-100011
    Figure PCTCN2019074704-appb-100012
    Figure PCTCN2019074704-appb-100013
    Figure PCTCN2019074704-appb-100014
    Figure PCTCN2019074704-appb-100015
    Figure PCTCN2019074704-appb-100016
    Figure PCTCN2019074704-appb-100017
    Figure PCTCN2019074704-appb-100018
    Figure PCTCN2019074704-appb-100019
    Figure PCTCN2019074704-appb-100020
    Figure PCTCN2019074704-appb-100021
    Figure PCTCN2019074704-appb-100022
    Figure PCTCN2019074704-appb-100023
    Figure PCTCN2019074704-appb-100024
    Figure PCTCN2019074704-appb-100025
    Figure PCTCN2019074704-appb-100026
  7. 一种如权利要求1所述通式(I)所示的化合物的制备方法，包括步骤：
    (1)在惰性溶剂中，在缩合剂存在下，用式II化合物和式Ic化合物反应，得到式Id化合物；优选地，所述的缩合剂为EDCI(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐)；
    Figure PCTCN2019074704-appb-100027
    (2)在惰性溶剂中，用式Id化合物进行Bischler–Napieralski关环反应，得到式Ie化合物；优选地，所述的关环反应用三氯氧磷作为路易斯酸；
    Figure PCTCN2019074704-appb-100028
    (3)在惰性溶剂中，用式Ie化合物进行还原反应，得到式If化合物；优选地，所述的 还原反应用硼氢化物作为还原剂或用Noyori催化剂作为不对称还原催化剂；
    Figure PCTCN2019074704-appb-100029
    (4)在惰性溶剂中，用式If化合物进行成缩合反应或N-烷基化反应或Buchwald–Hartwig反应，得到式(I)化合物；
    Figure PCTCN2019074704-appb-100030
    上述各式中，各基团的定义如权利要求1-6任一所述。
  8. 一种药物组合物，其特征在于，所述的药物组合物包括：治疗有效量的一种或多种权利要求1所述通式(I)所示化合物，或其药学上可接受的盐。
  9. 如权利要求1所述的通式(I)的用途，其特征在于，用于制备预防、治疗或辅助治疗与PDE4活性或表达量相关的疾病的药物组合物；优选地，所述的疾病为与PDE4活性或表达量相关的免疫和炎症性疾病。
  10. 如权利要求9所述的用途，其特征在于，所述的与PDE4活性或表达量相关的疾病选自下组：银屑病、银屑病关节炎、过敏性皮炎、慢性阻塞性肺病、哮喘、过敏性鼻炎、强直性脊柱炎、系统性红斑狼疮、风湿性关节炎、炎症性肠病、肺纤维化、多发性硬化症、阿尔兹海默症、亨廷顿舞蹈症、帕金森氏症、多动症、抑郁症、和精神分裂症。
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EP4149471A4 (en) * 2020-06-30 2024-07-10 Prosetta Biosciences Inc ISOQUINOLINE DERIVATIVES, THEIR SYNTHESIS PROCESSES AND THEIR USES
WO2023222137A1 (zh) * 2022-05-20 2023-11-23 中国科学院上海药物研究所 新型四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途

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