WO2020011254A1 - 作为pde3/pde4双重抑制剂的三并环类化合物 - Google Patents

作为pde3/pde4双重抑制剂的三并环类化合物 Download PDF

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Publication number
WO2020011254A1
WO2020011254A1 PCT/CN2019/095826 CN2019095826W WO2020011254A1 WO 2020011254 A1 WO2020011254 A1 WO 2020011254A1 CN 2019095826 W CN2019095826 W CN 2019095826W WO 2020011254 A1 WO2020011254 A1 WO 2020011254A1
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Prior art keywords
alkyl
optionally
amino
halogen
compound
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PCT/CN2019/095826
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English (en)
French (fr)
Inventor
罗云富
潘建峰
张国利
苏胜
王勇
陈曙辉
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
Medshine Discovery Inc
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
Medshine Discovery Inc
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Priority to CN201980045308.9A priority Critical patent/CN112368281B/zh
Priority to SI201930911T priority patent/SI3822272T1/sl
Priority to KR1020257023758A priority patent/KR20250111408A/ko
Priority to EP19834834.4A priority patent/EP3822272B1/en
Priority to CA3106052A priority patent/CA3106052A1/en
Priority to HRP20250282TT priority patent/HRP20250282T1/hr
Priority to MX2021000456A priority patent/MX2021000456A/es
Priority to ES19834834T priority patent/ES3003857T3/es
Priority to JP2021501020A priority patent/JP7491896B2/ja
Priority to PL19834834.4T priority patent/PL3822272T4/pl
Priority to AU2019302610A priority patent/AU2019302610B2/en
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd, Medshine Discovery Inc filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to US17/259,089 priority patent/US11993596B2/en
Priority to CN202210301047.6A priority patent/CN114644630A/zh
Priority to KR1020217004102A priority patent/KR102836158B1/ko
Priority to FIEP19834834.4T priority patent/FI3822272T3/fi
Priority to LTEPPCT/CN2019/095826T priority patent/LT3822272T/lt
Priority to IL280075A priority patent/IL280075B2/en
Priority to DK19834834.4T priority patent/DK3822272T5/da
Publication of WO2020011254A1 publication Critical patent/WO2020011254A1/zh
Priority to ZA2021/00221A priority patent/ZA202100221B/en
Anticipated expiration legal-status Critical
Priority to AU2024201135A priority patent/AU2024201135B2/en
Priority to US18/641,912 priority patent/US20240294526A1/en
Priority to JP2024080444A priority patent/JP2024105613A/ja
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present application relates to a tricyclic compound as a dual inhibitor of PDE3 / PDE4, a preparation method thereof, a pharmaceutical composition containing the compound, and application thereof in treating diseases related to PDE3 / PDE4, and particularly relates to chronic obstructive pulmonary disease COPD).
  • Phosphodiesterase belongs to the superfamily enzyme system, which includes 11 families, and each family participates in different signaling and regulates different physiological processes.
  • PDE3 is the main phosphodiesterase in human airway smooth muscle (ASM). Inhibition of PDE3 will increase the concentration of cAMP in cells and relax bronchial smooth muscle.
  • ASM airway smooth muscle
  • PDE4 plays a major regulatory role in the expression of pro-inflammatory and anti-inflammatory mediators
  • PDE4 inhibitors can inhibit inflammatory cells from releasing harmful mediators.
  • an inhibitor that has an inhibitory effect on PDE3 and PDE4 will have both the bronchodilation of a ⁇ -adrenergic receptor agonist and the anti-inflammatory effect of inhaled glucocorticoids.
  • the functional complementation of dual-targeting has a theoretical basis of greater efficacy than single-targeting.
  • a single drug can achieve a therapeutic effect that can only be achieved through combined use at present. It overcomes the shortcomings of the physical and chemical properties of the combined drug components that cannot be fully matched, and simplifies It is convenient to quantify the dosage.
  • the application provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • the ring atom of the ring Cy contains at least one nitrogen atom
  • L is selected from -N (R 6 )-, -N (R 6 ) C (O)-, -C (O) N (R 6 )-, -O-, -S-, -OC (O)-, -C (O) O-, -CH 2 N (R 6 ) C (O)-, -CH 2 C (O) N (R 6 )-, -S (O) 2 NH-, -NHS (O) 2 -or single key;
  • n 1, 2, 3, or 4;
  • E 1 is selected from-(CH 2 ) m- , where m is 1, 2 or 3;
  • E 2 is selected from -O-, -NH-, -S- or a single bond
  • R 3 , R 4 and R 5 are each independently selected from hydrogen, halogen or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted by one or more groups selected from halogen, amino or hydroxy Group replacement
  • Each R 6 is independently selected from hydrogen, hydroxy, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more groups selected from halogen, amino, or hydroxyl.
  • Ring Cy is selected from a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with one or more of the following: amino, hydroxyl, fluorine, chlorine, bromine, iodine, cyanide group, C 1-3 alkyl, -C (O) NH 2, -C (O) O (C 1-3 alkyl), C 1-3 alkoxy or by one or more halogen substituted C 1 -3 alkyl; in some embodiments, ring Cy is selected from imidazolyl, pyrazolyl, oxazolyl, triazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, or isoxazolyl, wherein The imidazolyl, pyrazolyl, oxazolyl, triazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, or isoxazolyl is optionally substituted with one or
  • Ring Cy is selected from a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with one or more of the following: amino, hydroxyl, fluorine, chlorine, cyano, methyl -C (O) NH 2 , -C (O) OCH 3 , methoxy or trifluoromethyl; in some embodiments, ring Cy is selected from imidazolyl, pyrazolyl, oxazolyl, triazolyl , Oxadiazolyl, tetrazolyl, thiadiazolyl or isoxazolyl, the imidazolyl, pyrazolyl, oxazolyl, triazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl Or isoxazolyl is optionally substituted with one or more of the following: amino, hydroxyl, fluorine, chlorine, cyano, methyl, -C (O) NH 2 ,
  • Ring Cy is selected from the structural unit among them,
  • Each R 1 is independently selected from hydrogen, amino, hydroxyl, halogen, cyano, C 1-12 alkyl, -C (O) NH 2 , -C (O) NH (C 1-6 alkyl), -C (O) N (C 1-6 alkyl) 2 , -COOH, -C (O) O (C 1-6 alkyl) or C 1-12 alkoxy, wherein the C 1-12 alkoxy Or C 1-12 alkoxy is optionally substituted with one or more groups selected from halogen, amino or hydroxyl;
  • Each R 2 is independently selected from hydrogen, hydroxy, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more groups selected from halogen, amino, or hydroxyl.
  • Ring Cy is selected from the structural unit among them,
  • T 1 , T 2 , T 3 and T 4 are each independently selected from C (R 1 ), C (R 1 ) 2 , O, N (R 2 ), N or S;
  • Each R 1 is independently selected from hydrogen, amino, hydroxyl, halogen, cyano, C 1-12 alkyl, -C (O) NH 2 , -C (O) NH (C 1-6 alkyl), -C (O) N (C 1-6 alkyl) 2 , -COOH, -C (O) O (C 1-6 alkyl) or C 1-12 alkoxy, wherein the C 1-12 alkoxy Or C 1-12 alkoxy is optionally substituted with one or more groups selected from halogen, amino or hydroxyl;
  • Each R 2 is independently selected from hydrogen, hydroxy, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more groups selected from halogen, amino, or hydroxyl.
  • Ring Cy is selected from the structural unit among them,
  • Each R 1 is independently selected from hydrogen, amino, hydroxyl, halogen, cyano, C 1-12 alkyl, -C (O) NH 2 , -C (O) NH (C 1-6 alkyl), -C (O) N (C 1-6 alkyl) 2 , -COOH, -C (O) O (C 1-6 alkyl) or C 1-12 alkoxy, wherein the C 1-12 alkoxy Or C 1-12 alkoxy is optionally substituted with one or more groups selected from halogen, amino or hydroxyl;
  • Each R 2 is independently selected from hydrogen, hydroxy, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more groups selected from halogen, amino, or hydroxyl.
  • T 1 is selected from C (R 1 ), C (R 1 ) 2 or N
  • T 1 is selected from C (R 1) or N
  • T 1 is selected from C (R 1) or N
  • T 2 are each independently selected from C (R 1), O, N (R 2), N or S.
  • T 1 is selected from C (R 1 ) or N
  • T 2 , T 3 and T 4 are each independently selected from C (R 1 ), O, N (R 2 ) or N.
  • the structural unit Wherein at least one of T 1 , T 2 , T 3 and T 4 is selected from N (R 2 ) or N.
  • T 1 is selected from C (R 1 ) 2
  • each R 1 is independently selected from hydrogen, amino, hydroxyl, halogen, cyano, C 1-6 alkyl, -C (O) NH 2 , -C (O) NH (C 1 -3 alkyl), -C (O) N (C 1-3 alkyl) 2 , -COOH, -C (O) O (C 1-3 alkyl), or C 1-6 alkoxy, where The C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more groups selected from halogen, amino, or hydroxy; in some embodiments, each R 1 is independently selected from Hydrogen, amino, hydroxyl, halogen, cyano, C 1-6 alkyl, -C (O) NH 2 , -C (O) O (C 1-3 alkyl), or C 1-3 alkoxy, where The C 1-6 alkyl or C 1-3 alkoxy is optionally substituted with one or more groups selected from halogen, amino, or hydroxyl; in
  • each R 1 is independently selected from hydrogen, amino, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1- 6 alkyl or C 1-6 An alkoxy group is optionally substituted with one or more groups selected from halogen, amino, or hydroxyl; in some embodiments, each R 1 is independently selected from hydrogen, amino, hydroxyl, C 1-3 alkane Or C 1-3 alkoxy; in some embodiments, each R 1 is independently selected from hydrogen, amino, hydroxy, methyl, or methoxy.
  • each R 2 is independently selected from hydrogen, hydroxy, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more halogen, amino, or hydroxyl; In some embodiments, each R 2 is independently selected from hydrogen, hydroxy, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 halogen, amino, or hydroxyl; In some embodiments, each R 2 is independently selected from hydrogen, hydroxy, or methyl; in some embodiments, each R 2 is independently selected from hydrogen or methyl.
  • the structural unit From Further selected from Further selected from And further selected from Still further selected from
  • the structural unit From Further selected from Further selected from Further selected from
  • L is selected from -N (R 6 )-, -N (R 6 ) C (O)-, -C (O) N (R 6 )-, -CH 2 N (R 6 ) C (O)-, -CH 2 C (O) N (R 6 )-, -S (O) 2 NH-, -NHS (O) 2- , or a single bond; in some embodiments, L is selected from -N (R 6 )-, -N (R 6 ) C (O)-, -C (O) N (R 6 )-, -CH 2 N (R 6 ) C (O)-, -S (O) 2 NH- or single bond; in some embodiments, L is selected from -N (R 6 )-, -N (R 6 ) C (O)-, -C (O) N (R 6 )-, or -S ( O) 2 NH-; in some embodiments, L is selected from -N (N (R 6
  • n is selected from 1, 2, or 3; in some embodiments, n is selected from 1 or 2; in some embodiments, n is selected from 2.
  • the structural unit From Further selected from Further selected from And further selected from Still further selected from And one more step from
  • the structural unit From Further selected from Further selected from Further selected from
  • R 3 , R 4 and R 5 are each independently selected from halogen or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogen, amino Or hydroxy substitution; in some embodiments, R 3 , R 4, and R 5 are each independently selected from halogen or methyl, wherein the methyl is optionally substituted with 1, 2 or 3 halogen, amino, or hydroxyl; In some embodiments, R 3 , R 4 and R 5 are each independently selected from methyl.
  • each R 6 is independently selected from hydrogen, hydroxy, or methyl, wherein the methyl is optionally substituted with 1, 2 or 3 halogen, amino, or hydroxyl; in some embodiments, Each R 6 is independently selected from hydrogen, hydroxy, or methyl; in some embodiments, each R 6 is independently selected from hydrogen or hydroxy.
  • E 1 is selected from-(CH 2 ) 2 -or-(CH 2 ) 3- .
  • E 2 is selected from the group consisting of -O- or a bond.
  • the structural unit -E 1 -E 2 - is selected from-(CH 2 ) 2 -,-(CH 2 ) 3-, or-(CH 2 ) 2 -O-.
  • the compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • a structural unit in a compound of formula (II) Is as defined above.
  • the structural unit -E 1 -E 2 -in a compound of formula (II) is as defined above.
  • the compound of formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of formula (II-1), formula (II-2), or formula (II-3) ) Compound, its isomer, or a pharmaceutically acceptable salt thereof
  • R 6 is selected from hydrogen or hydroxyl
  • T 1 , T 2 , T 3 , T 4 , E 1 and E 2 and structural units
  • the definition is as defined in formula (II) of this application.
  • a structural unit in a compound of formula (II-1), formula (II-2), or formula (II-3) As defined above.
  • the structural unit -E 1 -E 2 -in a compound of formula (II-1), formula (II-2) or formula (II-3) is as defined above.
  • the present application also provides a compound of the formula, an isomer thereof, or a pharmaceutically acceptable salt thereof, the compound of which is selected from
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I), formula (II), (II-1), formula (II-2), formula (II-3) or the above Specific compounds, their isomers or their pharmaceutically acceptable salts.
  • the pharmaceutical compositions of the present application further include a pharmaceutically acceptable excipient, carrier, or diluent.
  • the present application also provides a method for treating PDE3 and / or PDE4-related disorders in mammals, comprising administering a therapeutically effective amount of formula (I), formula (II) to a mammal, preferably a human, in need of the treatment.
  • a mammal preferably a human
  • formula (II-1) a compound of formula (II-2), formula (II-3), or a specific compound thereof, an isomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present application also provides the compound of the above formula (I), (II), (II-1), (II-2), (II-3) or the above specific compound, and isomers thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the manufacture of a medicament for the prevention or treatment of a condition associated with PDE3 and / or PDE4.
  • the present application also provides a compound of formula (I), formula (II), (II-1), formula (II-2), formula (II-3) or the above specific compound, an isomer thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the prevention or treatment of a condition associated with PDE3 and / or PDE4.
  • the present application also provides formula (I), formula (II), (II-1), formula (II-2), and formula (II-) for preventing or treating disorders related to PDE3 and / or PDE4. 3) A compound or a specific compound described above, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the PDE3 and / or PDE4-related disorder is selected from asthma or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the compound of the present application has significant dual PDE3 and PDE4 inhibitory effects, and has a significant inhibitory effect on TNF- ⁇ in human peripheral blood mononuclear cells (hPBMC).
  • hPBMC peripheral blood mononuclear cells
  • LPS lipopolysaccharide, lipopolysaccharide
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 have low inhibitory effects and no risk of drug-drug interactions; reduce the total number of BALF white blood cells, have significant anti-inflammatory effects, and have a low effective dose; reduce airway resistance Penh.
  • Each group is a compound formed by interconnecting each other, the valence of each atom is normal, and the compound formed can exist stably.
  • the linking groups listed in this application are directional, for example,
  • the middle linking group L is -N (R 6 ) C (O)-.
  • -N (R 6 ) C (O)- is connected to both ends in the same direction as the reading order from left to right.
  • L is -C (O) N (R 6 )-, the two ends are connected in the order of reading from left to right
  • Combinations of the linking groups, substituents, and / or variants thereof are permitted only if such combinations result in stable compounds.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without More toxic, irritating, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like can be mentioned. .
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing an acid group or a base by a conventional chemical method.
  • such salts are prepared by reacting these compounds in the form of a free acid or base with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms.
  • This application contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and racemic and other mixtures thereof, such as enantiomers or diastereomerically enriched mixtures, all of which belong to Within the scope of this application.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included within the scope of this application.
  • tautomers or “tautomeric forms” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton transfer tautomers include interconversions via migration of protons, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is an imidazole moiety, where the protons can migrate between two ring nitrogens.
  • Valence tautomers include interconversions through recombination of some bonding electrons.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the compounds containing asymmetric carbon atoms of the present application can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • Optically active (R)-and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then by a conventional method known in the art Diastereomeric resolution is performed and the pure enantiomer is recovered.
  • Diastereomeric resolution is performed and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography that employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines) Formate).
  • the application also includes isotopically-labeled compounds of the present application that are the same as those described herein, but in which one or more atoms are replaced with atoms having an atomic weight or mass number different from that normally found in nature.
  • isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl.
  • the compounds of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have lower toxicity and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. Transformations of all isotopic compositions of the compounds of this application, whether radioactive or not, are included within the scope of this application.
  • deuterium substitution may be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • Oxygen substitution does not occur on aromatic groups.
  • any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • R when any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and R in each case has independent options.
  • combinations of substituents and / or variants are only permitted if such combinations result in stable compounds.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • amino refers to the -NH 2 group.
  • substituents When a substituent is vacant, it means that the substituent does not exist.
  • X in A-X indicates that the structure is actually A.
  • substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be passed through any of the pyridine rings The carbon atom is attached to a substituted group.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group may be linear or branched.
  • C 1 - 6 alkyl refers to (e.g., methyl, ethyl, n-propyl, isopropyl, alkyl containing 1 to 6 carbon atoms, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl portion (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definitions as described above.
  • alkoxy refers to -O-alkyl
  • C n-n + m or C n -C n + m includes any specific case of n to n + m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , and also include any range from n to n + m, for example, C 1-12 includes C 1- 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.
  • n yuan to n + m means that the number of atoms on the ring is n to n + m.
  • 3-12-membered rings include 3-, 4-, 5-, 6-, 7-, 8-, and 9-membered rings.
  • 10-membered ring, 11-membered ring, and 12-membered ring including any range from n to n + m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring Ring, 5-7 member ring, 6-7 member ring, 6-8 member ring, and 6-10 member ring, etc.
  • heterocyclyl refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spiro ring.
  • the heterocyclic ring is generally a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen.
  • heterocyclyl examples include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl , Pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, dihydropyridazine, dihydropyrimidine, dihydropyridine, dihydroimidazole, dihydroisoxazole, Dihydrotriazole, dihydropyridazine, etc.
  • a monocyclic heterocyclic group having 5 ring atoms is preferred.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4- to 8-membered ring, especially a 5- to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, etc. .
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treats or prevents a specific disease, condition or disorder, (ii) reduces, improves or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) prevents or delays
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the state of the disease and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on Determined by its own knowledge and this disclosure.
  • composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant stimulating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with a suitable pharmaceutically acceptable excipient, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as a tablet, pill, capsule, powder , Granules, creams, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • a suitable pharmaceutically acceptable excipient for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as a tablet, pill, capsule, powder , Granules, creams, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering a compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coated pill method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, dragees, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets. Or the core of a sugar coating.
  • suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.
  • compositions are also suitable for parenteral administration, such as sterile unit solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the daily dose is from 0.01 to 200 mg / kg body weight.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those familiar to those skilled in the art. Equivalent alternatives. Preferred implementations include, but are not limited to, the examples of this application.
  • compounds of general formula (I) of the present application can be prepared by those skilled in the art of organic synthesis by standard methods in the art through the following routes: Preparation of intermediates:
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate
  • DMF stands for N , N-dimethylformamide
  • DMSO stands for dimethyl sulfoxide
  • Boc stands for tert-butoxycarbonyl is an amine protecting group
  • DIPEA stands for diisopropylethylamine
  • Me stands for methyl
  • SEM stands for Me 3 SiCH 2 CH 2 OCH 2-
  • LHMDS stands for lithium hexamethyldisilazide
  • prep-TLC stands for preparative thin layer chromatography
  • T 3 P stands for 1-n-propyl phosphoric anhydride
  • Tris-HCl stands for tris (hydroxymethyl) amino Methane-hydrochloric acid
  • AMP for adenylate
  • GMP for guanylate
  • TNF-acid for
  • FIG. 1 Total number of white blood cells in BALF (alveolar lavage fluid);
  • Figure 2 Mechochine Mch-induced lower lung function test (airway resistance index Penh).
  • Step 1 Synthesis of the compound BB-1-2
  • Step 2 Synthesis of the compound BB-1-3
  • phosphorus oxychloride (379.50 g, 230.00 mL) was heated to 85 ° C, and compound BB-1-2 (26.00 g) was added in portions. The reaction mixture was stirred at 85 ° C for 2 hours. After the reaction was completed, most of the phosphorus oxychloride was distilled off under reduced pressure. Dichloromethane (200 mL) was added to the residue, and washed with water (100 mL). After the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by beating with ethyl acetate (20 mL) to obtain compound BB-1-3.
  • Step 3 Synthesis of the compound BB-1-4
  • Step 4 The synthesis of compound BB-1-5
  • Step 1 Synthesis of the compound BB-2-2
  • the compound BB-2-1 (8 g) and urea (9.18 g) were dissolved in water (80 mL) at room temperature, concentrated hydrochloric acid (12 mol / L, 9.56 mL) was added dropwise, and the temperature was raised to 110 ° C and stirred for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with water (50 mL x 2) and dried under vacuum to obtain compound BB-2-2.
  • Step 2 Synthesis of the compound BB-2-3
  • Step 3 Synthesis of the compound BB-2-4
  • Step 1 Synthesis of the compound BB-3-2
  • Step 2 Synthesis of the compound BB-3-3
  • Step 3 Synthesis of the compound BB-3-4
  • Step 1 Synthesis of the compound BB-4-1
  • the compound BB-1 (4.5 g) was dissolved in 2-butanone (120 mL) at room temperature, and 3-bromopropionitrile (8.92 g), potassium carbonate (13.8 g), and potassium iodide (11.05 g) were sequentially added.
  • the reaction mixture was stirred at 85 ° C for 60 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. Water (100 mL) and ethyl acetate (150 mL) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure.
  • WX002-1 silica gel column chromatography
  • the compound WX002-1 (160.00 mg) was dissolved in toluene (4 mL) at room temperature, and trimethylsilazide (120.60 mg) and dibutyltin oxide (300.00 mg) were sequentially added.
  • the reaction mixture was stirred at 110 ° C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to 25 ° C, concentrated, and water (5 mL) was added, followed by extraction with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography to obtain compound WX002.
  • Example 10 Referring to the synthesis method of Example 10, the examples in the following table were synthesized.
  • Example 12 Referring to the synthesis method of Example 12, the examples in the following table were synthesized.
  • the compound BB-1 (5.00g) was dissolved in 2-butanone (100mL) at room temperature, and 2- (3-bromopropyl) isoindolin-1,3-dione (13.22g) and carbonic acid were added sequentially. Potassium (10.23 g) and sodium iodide (7.39 g). The reaction mixture was stirred at 80 ° C for 30 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated to remove most of the organic solvent, and water (50 mL) was added, followed by extraction with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure.
  • the compound WX054-1 (174.4 mg) was dissolved in THF (4 mL) at room temperature, cooled to 0 ° C, and LHMDS (1 mol / L, 1.02 mL) was added dropwise, and the mixture was stirred at 0.5 ° C for 0.5 hours, and then compound BB-7 was added dropwise (200 mg) in THF (2 mL). After the dropwise addition was completed, the temperature was naturally raised to 30 ° C, and stirring was continued for 2 hours. The reaction solution was quenched by adding water (10 mL), and extracted with ethyl acetate (10 mL).
  • Example 57 Referring to the synthesis method of Example 57, the examples in the following table were synthesized.
  • Example 62 Referring to the synthesis method of Example 62, the examples in the following table were synthesized.
  • the compounds WX064-2 (3.66 g) and BB-1 (1.5 g) were dissolved in DMF (20 mL), and anhydrous potassium phosphate (4.71 g) and sodium iodide (3.33 g) were added, and then the temperature was raised to 100. Stir at 48 ° C for 48 hours. After cooling to room temperature, the reaction solution was quenched with saturated brine (100 mL), and extracted with ethyl acetate (40 mL). The organic phases were combined, washed with water (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the compound WX064-3 (700 mg) was dissolved in a hydrogen chloride-ethyl acetate solution (4M, 7.67 mL) at room temperature, and the mixture was heated to 40 ° C and stirred for 3 hours.
  • the reaction solution was quenched with a saturated sodium bicarbonate solution (50 mL), and extracted with dichloromethane (10 mL).
  • the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound WX064-4, which was directly used in the next reaction.
  • the compound WX064-4 (410 mg) was dissolved in methanol (10 mL) under a nitrogen atmosphere, and wet palladium carbon (200 mg, 10% purity) was added, and stirred at room temperature under a hydrogen balloon (15 psi) atmosphere for 8 hours.
  • the reaction solution was filtered (diatomite-assisted filtration) to remove the catalyst, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was stirred in a mixed solvent of petroleum ether (15 mL) and ethyl acetate (0.5 mL) for 30 minutes, and filtered to obtain compound WX064-5.
  • Example 65 Referring to the synthesis method of Example 65, the examples in the following table were synthesized.
  • the purpose of the experiment is to determine the expression of AMP / GMP according to fluorescence polarization, that is, to trace the binding of AMP / GMP antibodies to indicate the enzyme activity.
  • Experimental buffer solution 10 mM Tris-HCl (pH 7.5), 5 mM MgCl 2 , 0.01% Brij 35, 1 mM dithiothreitol (DTT), and 1% DMSO.
  • Enzyme Recombinant human-derived PDE3A (gene accession number NM_000921; amino acid 669-terminus) was expressed using an N-terminal GST tag baculovirus in Sf9 insect cells, and its molecular weight was 84 kDa.
  • the purpose of the experiment is to determine the expression of AMP / GMP according to fluorescence polarization, that is, to trace the binding of AMP / GMP antibodies to indicate the enzyme activity.
  • Experimental buffer solution 10 mM Tris-HCl (pH 7.5), 5 mM MgCl 2 , 0.01% Brij 35, 1 mM DTT, and 1% DMSO.
  • the fluorescence polarization signal was calculated as the% enzyme activity relative to the DMSO control according to the AMP / GMP standard curve and Excel software, and converted into nM. For curve fitting, GraphPad Prism (drawing medical icons) was used.
  • the clear solution of compound WX036 was injected into two 10-12 kg Beagle dogs via the cephalic vein or saphenous vein, and the clear solution of the test compound was administered to two 10-12 kg Beagle dogs by gavage (overnight fasting) .
  • Animals were transferred from peripheral venous blood about 500 ⁇ L to 0.0333, 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration to K 2 EDTA * 2H 2 O anticoagulant containing 0.85-1.15 mg
  • plasma was collected by centrifugation at 3000C for 10 min at 4 ° C.
  • a total of 5 specific probe substrates of 5 isozymes of CYP namely phenacetin (CYP1A2), diclofenac (CYP2C9), (S) -Mephenytoin (S) -Mephenytoin, CYP2C19), dextromethorphan (CYP2D6) and midazolam (CYP3A4) were incubated with human liver microsomes and test compounds, respectively, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction.
  • CYP1A2 phenacetin
  • CYP2C9 diclofenac
  • S -Mephenytoin
  • CYP2C19 dextromethorphan
  • CYP3A4 midazolam
  • Animals are adaptively reared for one week after arriving at the facility and randomly divided into 3 groups according to weight;
  • the whole body exposure nebulization device atomizes the test compound at the maximum nebulization rate (about 12 mL) for 30 minutes.
  • Dosing frequency Nebulized administration or solvent for 30 minutes before smoking in the morning every day, and administration before LPS nebulization inhalation on the 4th day.
  • BALF alveolar lavage fluid

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Abstract

公开了一类作为PDE3/PDE4双重抑制剂的三并环类化合物，及其在制备PDE3/PDE4相关疾病方面的药物的应用，尤其是在如慢性阻塞性肺病(COPD)等方面的药用功能。具体公开了式(Ⅰ)所示化合物及其药学上可接受的盐。

Description

作为PDE3/PDE4双重抑制剂的三并环类化合物
本申请主张如下优先权：
本申请要求于2018年07月13日向中华人民共和国国家知识产权局提交的第201810772374.3号中国发明专利申请的权益和优先权，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请涉及作为PDE3/PDE4双重抑制剂的三并环类化合物、其制备方法、含有该化合物的药物组合物，及其在治疗与PDE3/PDE4相关疾病中的应用，具体涉及慢性阻塞性肺病(COPD)。
背景技术
磷酸二酯酶(PDE)属超家族酶系，包含11个家族，每个家族参与不同的信号传导，调节不同的生理过程。其中，PDE3是人气道平滑肌(ASM)中主要的磷酸二酯酶，抑制PDE3会提高细胞内cAMP的浓度，使支气管平滑肌松弛。而PDE4在促炎介质和抗炎介质的表达中起主要调节作用，PDE4抑制剂能够抑制炎症细胞释放有害介质。因此，原则上一个对PDE3和PDE4都有抑制作用的抑制剂将会兼具β-肾上腺素受体激动剂的支气管扩张效果(bronchodilation)和吸入糖皮质激素的抗炎功效(anti-inflammatory action)。双重靶向功能性的互补具有比单独靶向更大功效的理论基础，通过单药达到目前只能通过联合用药才能达到的治疗效果，克服联合用药药物成分理化性质无法完全匹配的缺陷，简化给药方式，方便定量给药剂量。
Victoria Boswell et al,J.Pharmaco.Experi.Therap.2006,318,840-848和WO200005830报道了化合物RPL554和RPL565，具有长效支气管扩张和抗炎作用的药效，以及溶解度差、血浆清除率高等理化性质，适宜吸入给药，但是数据同时也显示其PDE4的抑制活性无法令人满意，抗炎效果不够理想，因此需要开发同时具备良好的PDE3/4的抑制活性的化合物。
Figure PCTCN2019095826-appb-000001
发明内容
一方面，本申请提供了式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019095826-appb-000002
其中，
环Cy选自5元杂环基或5元杂芳基，其中所述5元杂环基或5元杂芳基任选地被一个或多个以下基团取代：氨基、羟基、＝O、卤素、氰基、C 1-12烷基、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基) 2、-COOH、-C(O)O(C 1-6烷基)或C 1-12烷氧基，其中所述C 1-12烷基或C 1-12烷氧基任选被一个或多个选自卤素、氨基或羟基的基团取代；
所述环Cy的环原子中至少含有一个氮原子；
L选自-N(R 6)-、-N(R 6)C(O)-、-C(O)N(R 6)-、-O-、-S-、-OC(O)-、-C(O)O-、-CH 2N(R 6)C(O)-、-CH 2C(O)N(R 6)-、-S(O) 2NH-、-NHS(O) 2-或单键；
n为1、2、3或4；
E 1选自-(CH 2) m-，其中m为1、2或3；
E 2选自-O-、-NH-、-S-或单键；
R 3、R 4和R 5分别独立地选自氢、卤素或C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个选自卤素、氨基或羟基的基团取代；
每一个R 6分别独立地选自氢、羟基或C 1-3烷基，其中所述C 1-3烷基任选地被一个或多个选自卤素、氨基或羟基的基团取代。
在一些实施方案中，环Cy选自5元杂环基或5元杂芳基，其中所述5元杂环基或5元杂芳基任选地被一个或多个以下基团取代：氨基、羟基、＝O、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-COOH、-C(O)O(C 1-3烷基)、C 1-6烷氧基或被一个或多个卤素取代的C 1-6烷基；在一些实施方案中，环Cy选自5元杂环基或5元杂芳基，其中所述5元杂芳基任选地被一个或多个以下基团取代：氨基、羟基、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-COOH、-C(O)O(C 1-3烷基)、C 1-6烷氧基或被一个或多个卤素取代的C 1-6烷基，其中所述5元杂环基任选地被一个或多个选自＝O的基团取代；在一些实施方案中，环Cy选自噁唑烷-2-酮基、咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基，其中所述咪唑基、吡唑基、噁唑基、三唑基、 噁二唑基、四唑基、噻二唑基或异噁唑基任选地被一个或多个以下基团取代：氨基、羟基、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-COOH、-C(O)O(C 1-3烷基)、C 1-6烷氧基或被一个或多个卤素取代的C 1-6烷基。
在一些实施方案中，环Cy选自5元杂芳基，其中所述5元杂芳基任选地被一个或多个以下基团取代：氨基、羟基、氟、氯、溴、碘、氰基、C 1-3烷基、-C(O)NH 2、-C(O)O(C 1-3烷基)、C 1-3烷氧基或被一个或多个卤素取代的C 1-3烷基；在一些实施方案中，环Cy选自咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基，其中所述咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基任选地被一个或多个以下基团取代：氨基、羟基、氟、氯、溴、碘、氰基、C 1-3烷基、-C(O)NH 2、-C(O)O(C 1-3烷基)、C 1-3烷氧基或被一个或多个卤素取代的C 1-3烷基。
在一些实施方案中，环Cy选自5元杂芳基，其中所述5元杂芳基任选地被一个或多个以下基团取代：氨基、羟基、氟、氯、氰基、甲基、-C(O)NH 2、-C(O)OCH 3、甲氧基或三氟甲基；在一些实施方案中，环Cy选自咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基，所述咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基任选地被一个或多个以下基团取代：氨基、羟基、氟、氯、氰基、甲基、-C(O)NH 2、-C(O)OCH 3、甲氧基或三氟甲基。
在一些实施方案中，环Cy选自结构单元
Figure PCTCN2019095826-appb-000003
其中，
Figure PCTCN2019095826-appb-000004
表示单键或双键；
T 1、T 2、T 3和T 4分别独立地选自C＝O、C(R 1)、C(R 1) 2、O、N(R 2)、N或S；
每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-12烷基、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基) 2、-COOH、-C(O)O(C 1-6烷基)或C 1-12烷氧基，其中所述C 1-12烷基或C 1-12烷氧基任选地被一个或多个选自卤素、氨基或羟基的基团取代；
每一个R 2分别独立地选自氢、羟基或C 1-3烷基，其中所述C 1-3烷基任选被一个或多个选自卤素、氨基或羟基的基团取代。
在一些实施方案中，环Cy选自结构单元
Figure PCTCN2019095826-appb-000005
其中，
Figure PCTCN2019095826-appb-000006
表示单键或双键；
T 1、T 2、T 3和T 4分别独立地选自C(R 1)、C(R 1) 2、O、N(R 2)、N或S；
每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-12烷基、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基) 2、-COOH、-C(O)O(C 1-6烷基)或C 1-12烷氧基，其中所述C 1-12烷基或C 1-12烷氧基任 选地被一个或多个选自卤素、氨基或羟基的基团取代；
每一个R 2分别独立地选自氢、羟基或C 1-3烷基，其中所述C 1-3烷基任选被一个或多个选自卤素、氨基或羟基的基团取代。在一些实施方案中，环Cy选自结构单元
Figure PCTCN2019095826-appb-000007
其中，
T 1、T 2、T 3和T 4分别独立地选自C＝O、C(R 1) 2、O、N(R 2)或S；
每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-12烷基、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基) 2、-COOH、-C(O)O(C 1-6烷基)或C 1-12烷氧基，其中所述C 1-12烷基或C 1-12烷氧基任选地被一个或多个选自卤素、氨基或羟基的基团取代；
每一个R 2分别独立地选自氢、羟基或C 1-3烷基，其中所述C 1-3烷基任选被一个或多个选自卤素、氨基或羟基的基团取代。在一些实施方案中，T 1选自C(R 1)、C(R 1) 2或N，T 2、T 3和T 4分别独立地选自C＝O、C(R 1)、C(R 1) 2、O、N(R 2)、N或S。
在一些实施方案中，T 1选自C(R 1)或N，T 2、T 3和T 4分别独立地选自C＝O、C(R 1)、O、N(R 2)、N或S。
在一些实施方案中，T 1选自C(R 1)或N，T 2、T 3和T 4分别独立地选自C(R 1)、O、N(R 2)、N或S。
在一些实施方案中，在结构单元
Figure PCTCN2019095826-appb-000008
中，T 1选自C(R 1)或N，T 2、T 3和T 4分别独立地选自C(R 1)、O、N(R 2)或N。
在一些实施方案中，在结构单元
Figure PCTCN2019095826-appb-000009
中，T 1、T 2、T 3和T 4中至少有一个选自N(R 2)或N。
在一些实施方案中，在结构单元
Figure PCTCN2019095826-appb-000010
中，T 1选自C(R 1) 2，T 2、T 3和T 4分别独立地选自C＝O、C(R 1) 2或O。
在一些实施方案中，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-COOH、-C(O)O(C 1-3烷基)或C 1-6烷氧基，其中所述C 1-6烷基或C 1-6烷氧基任选地被一个或多个选自卤素、氨基或羟基的基团取代；在一些实施方案中，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)O(C 1-3烷基)或C 1-3烷氧基，其中所述C 1-6烷基或C 1-3烷氧基任选地被一个或多个选自卤素、氨基或羟基的基团取代；在一些实施方案中，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)O(C 1-3烷基)或C 1-3烷氧基，其中所述C 1-6烷基任选地被一个或多个选自卤素、氨基或羟基的基团取代；在一些实施方案中，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-3烷基、-C(O)NH 2、-C(O)OCH 3或C 1- 3烷氧基，其中所述C 1-3烷基或C 1-3烷氧基任选被一个或多个选自卤素、氨基或羟基取代；在一些实施方案中，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-3烷基、-C(O)NH 2、-C(O)OCH 3或C 1-3烷氧基，其中所述C 1-3烷基任选被一个或多个选自卤素、氨基或羟基取代；在一些实施方案中，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-3烷基、-C(O)NH 2、-C(O)OCH 3或C 1-3烷氧基，其中所述C 1-3烷基任选被1、2或3个卤素、氨基或羟基取代；在一些实施方案中，每一个R 1分别独立地选自氢、氨基、羟基、氟、氯、氰基、甲基、-C(O)NH 2、-C(O)OCH 3、甲氧基或三氟甲基。
在一些实施方案中，每一个R 1分别独立地选自氢、氨基、羟基、C 1-6烷基或C 1-6烷氧基，其中所述C 1- 6烷基或C 1-6烷氧基任选地被被一个或多个选自卤素、氨基或羟基的基团取代；在一些实施方案中，每一个R 1分别独立地选自氢、氨基、羟基、C 1-3烷基或C 1-3烷氧基；在一些实施方案中，每一个R 1分别独立地选自氢、氨基、羟基、甲基或甲氧基。
在一些实施方案中，每一个R 2分别独立地选自氢、羟基或C 1-3烷基，其中所述C 1-3烷基任选被一个或多个卤素、氨基或羟基取代；在一些实施方案中，每一个R 2分别独立地选自氢、羟基或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个卤素、氨基或羟基取代；在一些实施方案中，每一个R 2分别独立地选自氢、羟基或甲基；在一些实施方案中，每一个R 2分别独立地选自氢或甲基。
在一些实施方案中，结构单元
Figure PCTCN2019095826-appb-000011
选自
Figure PCTCN2019095826-appb-000012
进一步选自
Figure PCTCN2019095826-appb-000013
更进一步选自
Figure PCTCN2019095826-appb-000014
Figure PCTCN2019095826-appb-000015
Figure PCTCN2019095826-appb-000016
又更进一步选自
Figure PCTCN2019095826-appb-000017
Figure PCTCN2019095826-appb-000018
Figure PCTCN2019095826-appb-000019
Figure PCTCN2019095826-appb-000020
再更进一步选自
Figure PCTCN2019095826-appb-000021
Figure PCTCN2019095826-appb-000022
在一些实施方案中，结构单元
Figure PCTCN2019095826-appb-000023
选自
Figure PCTCN2019095826-appb-000024
进一步选自
Figure PCTCN2019095826-appb-000025
更进一步选自
Figure PCTCN2019095826-appb-000026
在一些实施方案中，L选自-N(R 6)-、-N(R 6)C(O)-、-C(O)N(R 6)-、-CH 2N(R 6)C(O)-、-CH 2C(O)N(R 6)-、-S(O) 2NH-、-NHS(O) 2-或单键；在一些实施方案中，L选自-N(R 6)-、-N(R 6)C(O)-、-C(O)N(R 6)-、-CH 2N(R 6)C(O)-、-S(O) 2NH-或单键；在一些实施方案中，L选自-N(R 6)-、-N(R 6)C(O)-、-C(O)N(R 6)-或-S(O) 2NH-；在一些实施方案中，L选自-N(R 6)-、-N(R 6)C(O)-或-C(O)N(R 6)-；在一些实施方案中，L选自-NH-、-NHC(O)-、-C(O)NH-、-C(O)N(OH)-、-S(O) 2NH-或单键；在一些实施方案中，L选自-NH-、-NHC(O)-、-C(O)NH-或-C(O)N(OH)-。
在一些实施方案中，n选自1、2或3；在一些实施方案中，n选自1或2；在一些实施方案中，n选自2。
在一些实施方案中，结构单元
Figure PCTCN2019095826-appb-000027
选自
Figure PCTCN2019095826-appb-000028
进一步选自
Figure PCTCN2019095826-appb-000029
Figure PCTCN2019095826-appb-000030
更进一步选自
Figure PCTCN2019095826-appb-000031
又更进一步选自
Figure PCTCN2019095826-appb-000032
Figure PCTCN2019095826-appb-000033
再更进一步选自
Figure PCTCN2019095826-appb-000034
Figure PCTCN2019095826-appb-000035
又再更进一步选自
Figure PCTCN2019095826-appb-000036
Figure PCTCN2019095826-appb-000037
在一些实施方案中，结构单元
Figure PCTCN2019095826-appb-000038
选自
Figure PCTCN2019095826-appb-000039
进一步选自
Figure PCTCN2019095826-appb-000040
更进一步选自
Figure PCTCN2019095826-appb-000041
在一些实施方案中，结构单元
Figure PCTCN2019095826-appb-000042
选自
Figure PCTCN2019095826-appb-000043
Figure PCTCN2019095826-appb-000044
Figure PCTCN2019095826-appb-000045
在一些实施方案中，R 3、R 4和R 5分别独立地选自卤素或C 1-3烷基，其中所述C 1-3烷基任选地被1、2或3个卤素、氨基或羟基取代；在一些实施方案中，R 3、R 4和R 5分别独立地选自卤素或甲基，其中所述甲基任选地被1、2或3个卤素、氨基或羟基取代；在一些实施方案中，R 3、R 4和R 5分别独立地选自甲基。
在一些实施方案中，每一个R 6分别独立地选自氢、羟基或甲基，其中所述甲基任选地被1、2或3个卤素、氨基或羟基取代；在一些实施方案中，每一个R 6分别独立地选自氢、羟基或甲基；在一些实施方案中，每一个R 6分别独立地选自氢或羟基。
在一些实施方案中，E 1选自-(CH 2) 2-或-(CH 2) 3-。
在一些实施方案中，E 2选自选自-O-或键。
在一些实施方案中，结构单元-E 1-E 2-选自-(CH 2) 2-、-(CH 2) 3-或-(CH 2) 2-O-。
本申请的一些优选实施方案中，上述式(I)化合物、其异构体或其药学上可接受的盐，选自式(II)化合物、其异构体或其药学上可接受的盐
Figure PCTCN2019095826-appb-000046
其中，
T 1、T 2、T 3、T 4、E 1、E 2和L的定义，以及结构单元
Figure PCTCN2019095826-appb-000047
的定义如上文所定义。
在一些实施方案中，式(II)化合物中的结构单元
Figure PCTCN2019095826-appb-000048
的定义如上文所定义。
在一些实施方案中，式(II)化合物中的结构单元-E 1-E 2-的定义如上文所定义。
在本申请一些优选实施方案中，上述式(II)化合物、其异构体或其药学上可接受的盐，选自式(II-1)、式(II-2)或式(II-3)化合物、其异构体或其药学上可接受的盐
Figure PCTCN2019095826-appb-000049
其中，
R 6选自氢或羟基；
T 1、T 2、T 3、T 4、E 1和E 2的定义，以及结构单元
Figure PCTCN2019095826-appb-000050
的定义如本申请式(II)中的定义。
在一些实施方案中，式(II-1)、式(II-2)或式(II-3)化合物中的结构单元
Figure PCTCN2019095826-appb-000051
Figure PCTCN2019095826-appb-000052
的定义，如上文所定义。
在一些实施方案中，式(II-1)、式(II-2)或式(II-3)化合物中的结构单元-E 1-E 2-的定义如上文所定义。
另一方面，本申请还提供了下式化合物、其异构体或其药学上可接受的盐，其化合物选自
Figure PCTCN2019095826-appb-000053
Figure PCTCN2019095826-appb-000054
Figure PCTCN2019095826-appb-000055
Figure PCTCN2019095826-appb-000056
Figure PCTCN2019095826-appb-000057
其异构体或其药学上可接受的盐。
另一方面，本申请还提供了一种药物组合物，包括上述的式(I)、式(II)、(II-1)、式(II-2)、式(II-3)化合物或上述具体化合物，其异构体或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料、载体或稀释剂。
另一方面，本申请还提供了治疗哺乳动物的与PDE3和/或PDE4相关病症的方法，包括对需要该治疗的哺乳动物，优选人，给予治疗有效量的式(I)、式(II)、(II-1)、式(II-2)、式(II-3)化合物或上述具体化合物，其异构体或其药学上可接受的盐，或其药物组合物。
另一方面，本申请还提供了上述的式(I)、式(II)、(II-1)、式(II-2)、式(II-3)化合物或上述具体化合物，其异构体或其药学上可接受的盐，或其药物组合物在制备用于预防或治疗与PDE3和/或PDE4相关病症的药物中的应用。
另一方面，本申请还提供了式(I)、式(II)、(II-1)、式(II-2)、式(II-3)化合物或上述具体化合物，其异构体或其药学上可接受的盐，或其药物组合物在预防或治疗与PDE3和/或PDE4相关病症中的用途。
另一方面，本申请还提供了用于预防或治疗与PDE3和/或PDE4相关病症的式(I)、式(II)、(II-1)、式(II-2)、式(II-3)化合物或上述具体化合物、其异构体或其药学上可接受的盐，或其药物组合物。
本申请的一些实施方案中，所述与PDE3和/或PDE4相关病症选自哮喘或慢性阻塞性肺病(COPD)。
技术效果
本申请化合物具有显著的双重PDE3和PDE4抑制作用，并且对人外周血单核细胞(hPBMC)中TNF-α有显著的抑制作用，在LPS(lipopolysaccharide，脂多糖)诱导的大鼠急性肺损伤模型中也显示出优异的抗炎作用；具有高的体内血浆清除率，低的口服血浆系统暴露量以及低的口服生物利用度，局部途径给药安全性好；对人肝微粒体细胞色素P450的5种同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)抑制作用低，无药物-药物相互作用风险；降低BALF白细胞总数，具有显著抗炎效果，且起效剂量低；降低气道阻力指数Penh。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
每个基团相互连接形成的化合物，各个原子的价态是正常的，并且形成的化合物是可以稳定存在的。
本申请中所列举的连接基团是有方向的，例如，
Figure PCTCN2019095826-appb-000058
中连接基团L为-N(R 6)C(O)-，此时-N(R 6)C(O)-按与从左往右的读取顺序相同的方向连接两端构成
Figure PCTCN2019095826-appb-000059
当L为-C(O)N(R 6)-，按照与从左往右的读取顺序连接两端构成
Figure PCTCN2019095826-appb-000060
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
本申请的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计 量的适当的碱或酸反应来制备。
本申请的化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本申请的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本申请的范围之内。
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本申请某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
本申请的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。
术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2019095826-appb-000061
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羟基”指-OH基团。
术语“氰基”指-CN基团。
术语“氨基”指-NH 2基团。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。
术语“烷氧基”指-O-烷基。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、桥环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至7元环。杂环基的非限制性实例包括但不限于环氧乙烷基、四氢呋喃基、二氢呋喃基、吡咯烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基、二氢哒嗪、二氢嘧啶、二氢吡啶、二氢咪唑、二氢异噁唑、二氢三唑、二氢哒嗪等。优选为具有5个环原子的单环杂环基。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个4至8元环，尤其是5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基、异噁唑基、噁二唑基、噻二唑基、噻唑基等。
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及 性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本文所述的通式Ⅰ化合物的所有施用方法中，每天给药的剂量为0.01到200mg/kg体重。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:Joh n Wiley&Sons,Inc.本申请引用的所有参考文献整体上并入本申请。
在一些实施方案中，本申请通式(I)的化合物可以由有机合成领域技术人员通过以下路线用本领域的标准方法来制备： 中间体的制备：
Figure PCTCN2019095826-appb-000062
式(I)化合物的制备：
<路线1>
Figure PCTCN2019095826-appb-000063
<路线2>
Figure PCTCN2019095826-appb-000064
<路线3>
Figure PCTCN2019095826-appb-000065
<路线4>
Figure PCTCN2019095826-appb-000066
本申请所使用的溶剂可经市售获得。本申请采用下述缩略词：HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；Boc代表 叔丁氧羰基是一种胺保护基团；DIPEA代表二异丙基乙基胺；Me代表甲基；SEM代表Me 3SiCH 2CH 2OCH 2-；LHMDS代表六甲基二硅基氨基锂；prep-TLC代表制备薄层色谱；T 3P代表1-正丙基磷酸酐；Tris-HCl代表三(羟甲基)氨基甲烷-盐酸；AMP代表腺苷酸；GMP代表鸟苷酸；TNF-酸代表肿瘤坏死因子α；EDTA代表乙二胺四乙酸；THP代表四氢吡喃基；OTs代表对甲苯磺酰基；NMP代表N-甲基吡咯烷酮；THF代表四氢呋喃；MeCN代表乙腈；PyBop代表六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷；Et代表乙基。
附图说明
图1：BALF(肺泡灌洗液)白细胞总数；
图2：乙酰甲胆碱Mch诱导下肺功能检测(气道阻力指数Penh)。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着对本申请任何不利限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
实施例1：化合物BB-1的合成
Figure PCTCN2019095826-appb-000067
步骤1：化合物BB-1-2的合成
氮气氛围下，化合物BB-1-1(21.10g)和氰基乙酸乙酯(11.00g,10.38mL)的混合物在100℃下搅拌16小时。反应完毕后，将混合物冷却至70℃，慢慢滴加乙醇(30mL)，有大量固体析出。过滤，滤饼减压干燥得到产物BB-1-2。
1H NMR(400MHz,DMSO-d6)δ＝8.26(t,J＝5.2Hz,1H),6.86(d,J＝8.0Hz,1H),6.79(br s,1H),6.71(d,8.0Hz,1H),4.00(q,J＝6.8Hz,2H),3.72(s,3H),3.59(s,2H),3.31-3.23(m,2H),2.64(t,J＝7.2Hz,2H),1.32(t,J＝6.8Hz,3H).MS–ESI m/z:263.1[M+H] +.
步骤2：化合物BB-1-3的合成
氮气氛围下，将三氯氧磷(379.50g,230.00mL)升温至85℃，分批加入化合物BB-1-2(26.00g)。反应混合物在85℃下搅拌反应2小时。反应完毕后，减压蒸馏除去大部分三氯氧磷。向剩余物中加入二氯甲烷(200mL),用水(100mL x 2)洗涤。有机相用无水硫酸钠干燥后，过滤去除干燥剂，减压浓缩。所得粗品经乙酸乙酯(20mL)打浆纯化得到化合物BB-1-3。
1H NMR(400MHz,CD 3OD)δ＝7.16(s,1H),6.83(s,1H),4.62(s,1H),4.12(q,J＝6.8Hz,2H),3.86(s,3H),3.35(d,J＝6.4Hz,2H),2.84(t,J＝6.4Hz,2H),1.44(t,J＝6.8Hz,3H).MS–ESI m/z:245.1[M+H] +.
步骤3：化合物BB-1-4的合成
在0℃下，向98％浓硫酸(12.88g,128.69mmol,7.00mL)中分批加入化合物BB-1-3(1.00g)。反应混合物在27℃下搅拌3小时。反应完毕后，将混合物加入到冷水(15mL)中，然后滴加氢氧化钠水溶液(4mol/L,32mL)调节pH值至中性，再用乙酸乙酯(100mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤去除干燥剂，减压浓缩，得到化合物BB-1-4。
MS–ESI m/z:263.1[M+H] +.
步骤4：化合物BB-1-5的合成
在0℃下，将钠(2.42g)分批加入到乙醇(80mL)中。混合物在28℃搅拌0.5小时后，向溶液中分批加入化合物BB-1-4(6.90g)，在80℃下搅拌0.5小时。随后一次性加入碳酸二乙酯(9.32g,9.51mL)，该混合物继续在80℃下搅拌5小时。反应完毕后，混合物冷却至室温，慢慢加入冰水(30mL)，然后用稀盐酸(2mol/L,53mL)调节pH值至中性，有大量固体析出，过滤，所得滤饼经乙醇(10mL)打浆纯化得到化合物BB-1-5。
1H NMR(400MHz,DMSO-d 6)δ＝11.22(br s,1H),7.35(s,1H),6.95(s,1H),6.22(s,1H),4.09(q,J＝6.8Hz,2H),3.90(br s,2H),3.83(s,3H),2.89(br s,2H),1.35(t,J＝6.8Hz,3H).MS–ESI m/z:289.1[M+H] +.
步骤5：化合物BB-1-6的合成
室温下将化合物BB-1-5(5.00g)溶于三氯氧磷(30mL)中。氮气氛围下，反应混合物于100℃搅拌16小时。反应完毕后，减压蒸馏除去大部分溶剂。加入水(100mL)，用二氯甲烷(150mL x 2)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，得到化合物BB-1-6。MS–ESI m/z:306.9[M+H] +.
步骤6：化合物BB-1的合成
室温下将化合物BB-1-6(925.67mg)溶于异丙醇(8mL)中，加入2,4,6-三甲基苯胺(2.10g)。氮气氛围下，反应混合物于90℃搅拌15小时。反应完毕后，混合物降至室温，减压浓缩，所得残留物经乙 醇(6mL)打浆纯化得到化合物BB-1。
1H NMR(400MHz,DMSO-d 6)δ＝8.85(br s,1H),7.27(s,1H),6.97(s,1H),6.90(s,2H),6.45(s,1H),4.10(q,J＝6.8Hz,2H),3.90(t,J＝6.0Hz,2H),3.86(s,3H),2.87(t,J＝6.0Hz,2H),2.45(s,3H),2.11(s,6H),1.37(t,J＝6.8Hz,3H).MS–ESI m/z:406.2[M+H] +.
实施例2：化合物BB-2的合成
Figure PCTCN2019095826-appb-000068
步骤1：化合物BB-2-2的合成
室温下将化合物BB-2-1(8g)和尿素(9.18g)溶于水(80mL)中，滴加浓盐酸(12mol/L,9.56mL)，升温至110℃搅拌24小时。反应完毕后，反应液冷却至室温，过滤，滤饼用水(50mL x 2)洗涤，真空干燥，得到化合物BB-2-2。
1H NMR(400MHz,DMSO-d 6)δ＝6.84(br d,J＝8.0Hz,1H),6.78(br s,1H),6.69(br d,J＝8.0Hz,1H),6.02(br t,J＝5.2Hz,1H),5.43(br s,2H),4.04-3.94(m,2H),3.71(s,3H),2.95(q,J＝6.4Hz,2H),2.50-2.40(m,2H),1.66-1.59(m,2H),1.35-1.25(m,3H).MS–ESI m/z:253.2[M+H] +.
步骤2：化合物BB-2-3的合成
氮气氛围下，将钠(6.38g)分批加到无水乙醇(150mL)中，搅拌至钠完全溶解，得到新制乙醇钠溶液。向其中加入化合物BB-2-2(7g)和丙二酸二乙酯(11.11g)，加热回流16小时。反应液冷却至室温，减压浓缩除去乙醇，残留物加水溶解，冰浴下滴加2mol/L盐酸调节pH＝5，硅藻土过滤，滤液用乙酸乙酯(150mL x 2)萃取，合并有机相，用饱和食盐水(150mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝5/1～1/1；二氯甲烷/甲醇＝50/1～20/1)纯化得到化合物BB-2-3。
1H NMR(400MHz,CD 3OD)δ＝6.90-6.82(m,2H),6.78-6.72(m,1H),4.07(q,J＝6.8Hz,2H),3.89-3.84(m,2H),3.81(s,3H),3.37(s,2H),2.62(t,J＝7.2Hz,2H),1.94(q,J＝7.2Hz,2H),1.39(t,J＝6.8Hz,3H).MS–ESI m/z:321.2[M+H] +.
步骤3：化合物BB-2-4的合成
氮气氛围下，向三氯氧磷(26.40g)中加入化合物BB-2-3(2.4g)，升温至80℃搅拌12小时。反应液冷却至室温，减压浓缩除去三氯氧磷，得到BB-2-4，直接用于下步反应。MS–ESI m/z:321.1[M+H] +.
步骤4：化合物BB-2的合成
在20℃下，向化合物BB-2-4(2.4g)的THF(24mL)溶液中滴加2,4,6-三甲基苯胺(2.02g)的THF溶液(10mL)。滴完后在20℃搅拌3小时，再加热至50℃搅拌2小时。反应完毕后，反应液减压浓缩除去大部分溶剂，残留物用乙酸乙酯(50mL)溶解后，依次用水(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，浓缩物经快速硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝100/1～20/1)纯化得到化合物BB-2。
1H NMR(400MHz,CD 3OD)δ＝7.26(s,1H),7.11(br s,2H),6.97(s,1H),6.31(s,1H),4.20-4.14(m,2H),4.03-4.01(m,2H),3.95(s,3H),2.84-2.82(m,2H),2.37(s,3H),2.29(s,6H),1.90-1.78(m,2H),1.49-1.42(m,3H).MS–ESI m/z:420.3[M+H] +.
实施例3：化合物BB-3的合成
Figure PCTCN2019095826-appb-000069
步骤1：化合物BB-3-2的合成
室温下将化合物BB-3-1(2g)溶于1,2-二氯乙烷(20mL)中，滴加三甲基硅异氰酸酯(3.82g)，再升温至90℃搅拌18小时。反应完毕后，反应液冷却至室温，减压浓缩，所得残留物经甲基叔丁基醚(10mL)打浆得到化合物BB-3-2。
MS–ESI m/z:255.1[M+H] +.
步骤2：化合物BB-3-3的合成
氮气氛围下，将钠(1.13g)分批加到无水乙醇(85mL)中，搅拌至钠完全溶解，得到新制乙醇钠溶液。向其中加入化合物BB-3-2(2.5g)和丙二酸二乙酯(3.94g)，加热回流12小时。反应液冷却至室温，浓缩除去乙醇，残留物加水溶解，冰浴下滴加2mol/L盐酸调节pH＝5，硅藻土过滤，滤液用乙酸乙酯(50mL x 2)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，得到化合物BB-3-3。
1H NMR(400MHz,CD 3OD)δ＝6.83(dd,J＝8.8Hz,2.4Hz,1H),6.58(d,J＝3.2Hz,1H),6.44(dd,J＝8.8Hz,3.2Hz,1H),4.19-4.15(m,2H),4.11-4.09(m,2H),4.04-4.00(m,2H),3.76(s,3H),3.35(s,2H),1.39(t,J＝6.8Hz,3H).MS–ESI m/z:323.1[M+H] +.
步骤3：化合物BB-3-4的合成
氮气氛围下，向三氯氧磷(12.37g)中加入化合物BB-3-3(1.3g)，升温至80℃搅拌12小时。反应液冷却至室温，减压浓缩除去三氯氧磷，得到BB-3-4，直接用于下步反应。MS–ESI m/z:323.1[M+H] +.
步骤4：化合物BB-3的合成
在20℃下，向化合物BB-3-4(1.2g)的THF(20mL)溶液中滴加2,4,6-三甲基苯胺(1.01g)。滴完后在25℃搅拌12小时，再加热至40℃搅拌3小时。反应完毕后，反应液减压浓缩除去大部分溶剂，残留物用乙酸乙酯(50mL)溶解后，依次用水(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤去除干燥剂，减压浓缩，浓缩物经快速硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝200/1～30/1)纯化得到化合物BB-3。
1H NMR(400MHz,DMSO-d 6)δ＝8.89(s,1H),7.11(s,1H),6.92(br s,2H),6.81(s,1H),6.05(s,1H),4.28(t,J＝5.6Hz,2H),4.11-4.04(m,4H),3.84(s,3H),2.26(s,3H),2.13(br s,6H),1.38-1.32(m,3H).MS–ESI m/z:422.2[M+H] +.
实施例4：化合物BB-4的合成
Figure PCTCN2019095826-appb-000070
Figure PCTCN2019095826-appb-000071
步骤1：化合物BB-4-1的合成
室温下将化合物BB-1(1.00g)溶于2-丁酮(35mL)中，依次加入2-(2-溴乙基)异吲哚啉-1,3-二酮(3.76g)、碳酸钾(3.07g)和碘化钠(2.22g)。氮气氛围下，反应混合物于85℃搅拌72小时。反应完毕后，混合物浓缩除去大部分有机溶剂，加水(30mL)，乙酸乙酯(25mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝15/1～3/1)纯化得到化合物BB-4-1。
MS–ESI m/z:579.3[M+H] +.
步骤2：化合物BB-4的合成
室温下将化合物BB-4-1(500.00mg)溶于三氯甲烷(3mL)和乙醇(3mL)中，加入水合肼(152.67mg,85％纯度)。氮气氛围下，混合物于28℃搅拌16小时。反应完毕后，混合物浓缩除去大部分有机溶剂，加水(15mL)，二氯甲烷(15mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩得到化合物BB-4。
1H NMR(400MHz,DMSO-d 6)δ＝6.95(s,1H),6.85(br s,2H),6.66(s,1H),5.31(s,1H),4.14(t,J＝6.8Hz,2H),4.05(q,J＝6.8Hz,2H),3.91(t,J＝6.4Hz,2H),3.62(s,3H),2.90-2.86(m,4H),2.22(s,3H),1.95(br s,6H),1.33(t,J＝6.8Hz,3H).MS–ESI m/z:449.2[M+H] +.
参照实施例4的合成方法，合成下表中各实施例。
Figure PCTCN2019095826-appb-000072
实施例7：化合物BB-7的合成
Figure PCTCN2019095826-appb-000073
步骤1：化合物BB-7的合成
室温下将化合物BB-1(1.0g)溶于2-丁酮(50mL)中，依次加入3-溴丙酸甲酯(2.47g)、碘化钠(2.22g)和磷酸钾(4.71g)，反应液加热到95℃搅拌40小时。冷却到室温，加入水(50mL)和乙酸乙酯(50mL)，分液。有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝10/1～2/1)纯化得到化合物BB-7。
1H NMR(400MHz,CDCl 3)δ＝6.85(br s,2H),6.72(s,1H),6.63(s,1H),5.44(s,1H),4.58-4.51(m,2H),4.13-4.06(m,2H),4.03-4.00(m,2H),3.74(s,3H),3.67(s,3H),2.90-2.83(m,4H),2.25(s,3H),2.02(s,6H),1.46(t,J＝6.8Hz,3H).MS–ESI m/z:492.1[M+H] +.
实施例8：化合物WX001的合成
Figure PCTCN2019095826-appb-000074
步骤1：化合物WX001的合成
室温下将化合物BB-1(100.00mg)溶于DMF(2mL)中，依次加入4-甲基苯磺酸-2-(2-恶唑烷酮-3-基)乙酯(422.19mg)、碳酸钾(306.76mg)和碘化钠(221.79mg)。氮气氛围下，反应混合物于80℃搅 拌72小时。反应完毕后，过滤，滤液浓缩，加水(6mL)稀释，乙酸乙酯(6mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，所得残留物经高效液相色谱纯化得到化合物WX001。
1H NMR(400MHz,CDCl 3)δ＝6.93(s,2H),6.62(s,1H),6.56(s,1H),5.31(s,1H),4.27(br s,2H),4.15-4.01(m,6H),3.91(br s,2H),3.65(s,3H),3.52(br s,2H),2.84(br s,2H),2.26(s,3H),2.15(br s,6H),1.41(t,J＝6.8Hz,3H).MS–ESI m/z:519.0[M+H] +.
实施例9：化合物WX002的合成
Figure PCTCN2019095826-appb-000075
步骤1：化合物WX002-1的合成
室温下将化合物BB-1(4.5g)溶于2-丁酮(120mL)中，依次加入3-溴丙腈(8.92g)、碳酸钾(13.8g)和碘化钾(11.05g)。氮气氛围下，反应混合物于85℃搅拌60小时。反应完毕后，过滤，滤液浓缩，加水(100mL)，乙酸乙酯(150mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，所得残留物经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝3/1至1/1)纯化得到化合物WX002-1。
1H NMR(400MHz,CDCl 3)δ＝6.79(br s,2H),6.66(s,1H),6.59(s,1H),5.39(s,1H),4.51(t,J＝6.8Hz,2H),4.24(q,J＝6.8Hz,2H),3.98(t,J＝6.0Hz,2H),3.70(s,3H),2.90(t,J＝6.8Hz,2H),2.84(t,J＝6.0Hz,2H),2.20(s,3H),1.98(br s,6H),1.41(t,J＝6.8Hz,3H).MS–ESI m/z:459.5[M+H] +.
步骤2：化合物WX002的合成
室温下将化合物WX002-1(160.00mg)溶于甲苯(4mL)中，依次加入三甲基硅基叠氮(120.60mg)和二丁基氧化锡(300.00mg)。氮气氛围下，反应混合物于110℃搅拌12小时。反应完毕后，混合物冷却至25℃，浓缩，加水(5mL)，乙酸乙酯(5mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤去除干燥剂，减压浓缩，所得残留物经高效液相色谱纯化得到化合物WX002。
1H NMR(400MHz,CD 3OD)δ＝7.18(br s,2H),7.00(s,1H),6.83(br s,1H),5.70(br s,1H),4.76(t,J＝6.8Hz,2H),4.19-4.12(m,4H),3.72(s,3H),3.60(t,J＝6.8Hz,2H),3.06(t,J＝6.8Hz,2H),2.40(s,3H),2.30(br  s,6H),1.45(t,J＝6.8Hz,3H).MS–ESI m/z:502.1[M+H] +.
实施例10：化合物WX003的合成
Figure PCTCN2019095826-appb-000076
步骤1：化合物WX001-2的合成
室温下将化合物BB-4(500.00mg)和WX003-1(413.91mg)溶于叔丁醇(20mL)中，向上述溶液中加入三(二亚苄基丙酮)二钯(81.66mg)，2-二叔丁基膦基-3,4,5,6-四甲基-2,4,6-三异丙基-1,1-联苯(85.74mg)和无水磷酸钾(378.58mg)。氮气保护下，反应混合物于110℃搅拌12小时。反应完毕后，恢复至室温，加入水(30mL)和乙酸乙酯(50mL)淬灭反应，分液得到有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤去除干燥剂，减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝50/1～10/1)纯化得到化合物WX003-2。
MS–ESI m/z:600.3[M+H] +.
步骤2：化合物WX003的合成
室温下将化合物WX003-2(0.22g)和盐酸乙酸乙酯溶液(3mL，4mol/L)溶于乙酸乙酯(20mL)中。氮气氛围下，反应混合物于25℃搅拌1小时。混合物减压浓缩，所得残留物经高效液相色谱纯化得到化合物WX003。
1H NMR(400MHz,CD 3OD-d 4)δ＝8.26(br s,1H),7.19(s,2H),7.00(s,1H),6.82(s,1H),5.70(s,1H),4.62(t,J＝6.0Hz,2H),4.21-4.16(m,4H),3.86(t,J＝6.0Hz,2H),3.72(s,3H),3.07(t,J＝6.4Hz,2H),2.40(s,3H),2.31(s,6H),1.45(t,J＝6.8Hz,3H).MS–ESI m/z:516.2[M+H] +.
参照实施例10的合成方法，合成下表中实施例。
Figure PCTCN2019095826-appb-000077
Figure PCTCN2019095826-appb-000078
实施例12：化合物WX005的合成
Figure PCTCN2019095826-appb-000079
步骤1：化合物WX005-2的合成
室温下将化合物BB-1(3.22g)溶于DMF(30mL)中，依次加入WX005-1(9.00g)、碳酸钾(9.88g)和碘化钠(7.14g)。氮气氛围下，反应混合物于83℃搅拌72小时。反应完毕后，混合物浓缩除去大部分有机溶剂，加水(70mL)，乙酸乙酯(70mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝4/1～3/2)纯化得到化合物WX005-2。MS–ESI m/z:494.3[M+H] +.
步骤2：化合物WX005-3的合成
室温下将化合物WX005-2(0.42g)和浓盐酸(1mL,12mol/L)溶于1,4-二氧六环(3mL)中。氮气氛围下，反应混合物于25℃搅拌12小时。向混合物中加入饱和碳酸钠水溶液(3mL)调节pH值至7-8，再加水(3mL)，乙酸乙酯(5mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩得到化合物WX005-3，直接用于下一步反应。
MS–ESI m/z:448.0[M+H] +.
步骤3：化合物WX005的合成
室温下将化合物WX005-3(100.00mg)和2-氨基-1,3,4-噻二唑(45.19mg)溶于乙醇(2mL)中。氮气氛围下，混合物于78℃搅拌12小时后，冷却至室温，加入NaBH 4(67.62mg)和甲醇(0.5mL)，再升温至78℃继续搅拌12小时。反应液加水(1mL)淬灭，减压浓缩，所得残留物经高效液相色谱纯化得到化合物WX005。
1H NMR(400MHz,CDCl 3)δ＝8.26(s,1H),6.92(br s,1H),6.82(s,2H),6.64(s,1H),6.59(s,1H),5.41(s,1H),4.61-4.54(m,2H),4.08-3.94(m,4H),3.81-3.73(m,2H),3.68(s,3H),2.82(t,J＝6.0Hz,2H),2.22(s,3H),2.00(s,6H),1.41(t,J＝6.8Hz,3H).MS–ESI m/z:533.0[M+H] +.
参照实施例12的合成方法，合成下表中实施例。
Figure PCTCN2019095826-appb-000080
实施例17：化合物WX010的合成
Figure PCTCN2019095826-appb-000081
步骤1：化合物WX010-1的合成
室温下将化合物BB-1(5.00g)溶于2-丁酮(100mL)中，依次加入2-(3-溴丙基)异吲哚啉-1,3-二酮(13.22g)、碳酸钾(10.23g)和碘化钠(7.39g)。氮气氛围下，反应混合物于80℃搅拌30小时。反应完毕后，混合物浓缩除去大部分有机溶剂，加水(50mL)，二氯甲烷(50mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝5/1～1/1)纯化得到化合物WX010-1。MS–ESI m/z:593.2[M+H] +.
步骤2：化合物WX010-2的合成
室温下将化合物WX010-1(1.30g)溶于三氯甲烷(10mL)和乙醇(10mL)中，加入水合肼(5.15g,85％纯度)。氮气氛围下，混合物于70℃搅拌10小时。反应完毕后，混合物浓缩除去大部分有机溶剂，加水(30mL)，乙酸乙酯(15mL x 2)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩得到化合物WX010-2。MS–ESI m/z:463.2[M+H] +.
步骤3：化合物WX010-4的合成
室温下将化合物WX010-2(900.00mg)和WX003-1(903.06mg)溶于叔丁醇(5mL)中，向上述溶液中加入三(二亚苄基丙酮)二钯(356.32mg)，2-二叔丁基膦基-3,4,5,6-四甲基-2,4,6-三异丙基-1,1-联苯(187.07mg)和无水磷酸钾(825.98mg)。氮气保护下，反应混合物于100℃搅拌12小时。反应完毕后，恢复至室温，过滤，滤液减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝20/1～1/1)纯化得到化合物WX010-4。MS–ESI m/z:614.1[M+H] +.
步骤4：化合物WX010的合成
室温下将化合物WX010-4(1.00g)和盐酸-乙酸乙酯溶液(5mL,，4mol/L)溶于乙酸乙酯(5mL)中。氮气氛围下，反应混合物于25℃搅拌10分钟。混合物减压浓缩，所得残留物经高效液相色谱纯化得到化合物WX010。
1H NMR(400MHz,CD 3OD)δ＝8.27(s,1H),7.18(s,2H),6.99(s,1H),6.81(s,1H),5.68(s,1H),4.49(t,J＝6.8Hz,2H),4.25-4.13(m,4H),3.71(s,3H),3.63(t,J＝6.8Hz,2H),3.08(t,J＝6.4Hz,2H),2.40(s,3H),2.32-2.16(m,8H),1.45(t,J＝6.8Hz,3H).MS–ESI m/z:530.1[M+H] +.
实施例18：化合物WX015的合成
Figure PCTCN2019095826-appb-000082
Figure PCTCN2019095826-appb-000083
步骤1：化合物WX015的合成
室温下将化合物BB-4(50.0mg)和4H-1,2,4-三氮唑-3-羧酸(12.6mg)溶于DMF(2mL)中，加入HATU(50.86mg)和DIPEA(28.81mg)。反应液在25℃搅拌24小时。反应完毕后，混合物减压浓缩，所得残留物经高效液相色谱纯化得到化合物WX015。
1H NMR(400MHz,CD 3OD)δ＝8.39(br s,1H),6.91(s,2H),6.85(s,1H),6.76(s,1H),5.50(s,1H),4.54-4.51(m,2H),4.11(q,J＝6.8Hz,2H),3.98(t,J＝6.0Hz,2H),3.90(t,J＝5.6Hz,2H),3.69(s,3H),2.91(t,J＝6.0Hz,2H),2.29(s,3H),2.03(s,6H),1.42(t,J＝6.8Hz,3H).MS–ESI m/z:544.5[M+H] +.
参照实施例18的合成方法，合成下表中各实施例。
Figure PCTCN2019095826-appb-000084
Figure PCTCN2019095826-appb-000085
Figure PCTCN2019095826-appb-000086
Figure PCTCN2019095826-appb-000087
Figure PCTCN2019095826-appb-000088
实施例57：化合物WX054的合成
Figure PCTCN2019095826-appb-000089
步骤1：化合物WX054-2的合成
室温下将化合物WX054-1(174.4mg)溶于THF(4mL)中，冷却至0℃，滴加LHMDS(1mol/L,1.02mL)，保持0℃搅拌0.5小时，再滴加化合物BB-7(200mg)的THF(2mL)溶液，滴加完毕后自然升温至30℃，继续搅拌2小时。反应液加水(10mL)淬灭，乙酸乙酯(10mL x 3)萃取。合并有机相，依次用水(10mL)和饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物经高效液相色谱纯化得到化合物WX054-2。
MS–ESI m/z:674.6[M+H] +.
步骤2：化合物WX054的合成
氮气氛围下将化合物WX054-2(20mg)溶于二氯甲烷(5mL)中，加入三氟乙酸(1.54g)，25℃搅拌3小时。反应完毕后，混合物减压浓缩除去大部分溶剂，所得残留物经高效液相色谱纯化得到化合物WX054。
1H NMR(400MHz,CD 3OD)δ＝8.75(br s,1H),7.14(s,2H),6.96(s,1H),6.77(s,1H),5.65(s,1H),4.70-4.62(m,2H),4.20-4.10(m,4H),3.68(s,3H),3.20-3.10(m,2H),3.04(t,J＝6.4Hz,2H),2.36(s,3H),2.26(s,6H),1.41(t,J＝6.8Hz,3H).MS–ESI m/z:544.3[M+H] +.
参照实施例57的合成方法，合成下表中实施例。
Figure PCTCN2019095826-appb-000090
实施例61：化合物WX058的合成
Figure PCTCN2019095826-appb-000091
步骤1：化合物WX058-1的合成
室温下将化合物BB-1(5.00g)溶于2-丁酮(20mL)中，依次加入2-溴乙酸乙酯(4.12g)、碘化钠 (0.37g)和碳酸钾(3.41g)，反应液加热到80℃搅拌12小时。冷却到室温，加入二氯甲烷(50mL)稀释，过滤。滤液减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝100/1～10/1)纯化得到化合物WX058-1。
1H NMR(400MHz,CDCl 3)δ＝6.77(s,2H),6.69(s,1H),6.58(s,1H),5.42(s,1H),4.93(br s,2H),4.16(q,J＝7.2Hz,2H),4.05-3.96(m,4H),3.69(s,3H),2.82(t,J＝6.0Hz,2H),2.19(s,3H),1.93(s,6H),1.40(t,J＝7.2Hz,3H),1.21(t,J＝7.2Hz,3H).
步骤2：化合物WX058-2的合成
室温下将化合物WX058-1(0.30g)溶于乙醇(10mL)、水(4mL)和四氢呋喃(6mL)中，加入一水合氢氧化锂(0.10g)，反应液在25℃搅拌8小时。减压浓缩，加入10mL水，水相用4mol/L的HCl调节pH值至3～4，析出固体，过滤，干燥得到化合物WX058-2。MS–ESI m/z:464.2[M+H] +.
步骤3：化合物WX058-3的合成
室温下将化合物58-1A(2.50g)溶于乙酸乙酯(20mL)中，依次加入(Boc) 2O(9.19g)、冰醋酸(8mL)和Pd/C(0.25g,10％纯度)，反应液在30℃下25psi氢气氛围搅拌12小时。过滤，滤液减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝10/1～2/1)纯化得到化合物58-2A。
1H NMR(400MHz,CDCl 3)δ＝8.20(s,1H),5.42-5.39(m,1H),5.24(br s,1H),4.44(d,J＝5.2Hz,2H),4.08-4.06(m,1H),3.74-3.70(m,1H),2.10-2.04(m,4H),1.70-1.63(m,2H),1.46(s,9H).
室温下将化合物58-2A(0.60g)和盐酸-乙酸乙酯溶液(1mL，4mol/L)溶于乙酸乙酯(2mL)中。氮气氛围下，反应混合物于30℃搅拌30分钟。析出固体，过滤，滤饼用2mL乙酸乙酯洗涤，干燥得到化合物WX058-3。 1H NMR(400MHz,CD 3OD)δ＝9.06(s,1H),4.39(s,2H).
步骤4：化合物WX058的合成
室温下将化合物WX058-2(0.15g)和WX058-3(0.43g)溶于DMF(2mL)中，依次加入三乙胺(0.1mL)和HATU(0.18g)，反应液在30℃搅拌10小时，倒入水中(20mL)，乙酸乙酯(20mL x 2)萃取。合并有机相，无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，所得残留物经高效液相色谱纯化得到化合物WX058。
1H NMR(400MHz,CD 3OD)δ＝8.64(s,1H),7.14(s,2H),6.99(s,1H),6.83(s,1H),5.70(s,1H),5.18(s,2H),4.69(s,2H),4.28-4.11(m,4H),3.71(s,3H),3.07(t,J＝6.4Hz,2H),2.38(s,3H),2.22(br s,6H),1.53-1.39(m,3H).MS–ESI m/z:544.1[M+H] +.
实施例62：化合物WX059的合成
Figure PCTCN2019095826-appb-000092
步骤1：化合物WX059的合成
室温下将化合物BB-4(30mg)和1H-1,2,3-三氮唑-5-磺酰氯(22.42mg)溶于DMF(1mL)中，加入三乙胺(13.54mg)，20℃下搅拌。反应完毕后，将混合物倾倒入30mL饱和食盐水中，用乙酸乙酯(15mL x 3)萃取，合并有机相，分别用50mL水和50mL饱和食盐水洗涤1次，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，所得残留物经高效液相色谱纯化得到化合物WX059。
1H NMR(400MHz,CD 3OD)δ＝8.29(br s,1H),7.14(br s,2H),6.98(s,1H),6.79(s,1H),5.66(s,1H),4.51(br s,2H),4.24-4.10(m,4H),3.70(s,3H),3.64(br s,2H),3.06(br s,2H),2.37(s,3H),2.29(s,6H),1.43(t,J＝6.8Hz,3H).MS–ESI m/z:580.0[M+H] +.
参照实施例62的合成方法，合成下表中实施例。
Figure PCTCN2019095826-appb-000093
实施例64：化合物WX064的合成
Figure PCTCN2019095826-appb-000094
Figure PCTCN2019095826-appb-000095
步骤1：化合物WX064-2的合成
室温下将化合物WX064-1(20g)溶于DMF(300mL)中，加入钠氢(4.30g,60％纯度)，搅拌0.5小时后快速加入1,2-二溴乙烷(100.97g,)，然后升温至60℃搅拌11.5小时。冷却至室温，反应液用饱和食盐水(600mL)淬灭，乙酸乙酯(200mL x 3)萃取。合并有机相，依次用水(600mL)和饱和食盐水(600mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物经快速硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝20/1～50/1)纯化得到化合物WX064-2。
MS–ESI m/z:231.8[M-100+2+H] +.
步骤2：化合物WX064-3的合成
氮气氛围下将化合物WX064-2(3.66g)和BB-1(1.5g)溶于DMF(20mL)中，加入无水磷酸钾(4.71g)和碘化钠(3.33g)，然后升温至100℃搅拌48小时。冷却至室温，反应液用饱和食盐水(100mL)淬灭，乙酸乙酯(40mL x 3)萃取。合并有机相，用水(200mL x 2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物在乙酸乙酯(25mL)中搅拌5分钟，过滤除去不溶物，滤液浓缩后经制备级薄层层析(洗脱剂：二氯甲烷/甲醇＝10/1)纯化得到化合物WX064-3。
MS–ESI m/z:655.6[M+H] +.
步骤3：化合物WX064-4的合成
室温下将化合物WX064-3(700mg)溶于氯化氢-乙酸乙酯溶液(4M,7.67mL)中，升温至40℃搅拌3小时。反应液用饱和碳酸氢钠溶液(50mL)淬灭，二氯甲烷(10mL x 4)萃取。合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物WX064-4，直接用于下一步反应。
MS–ESI m/z:555.1[M+H] +.
步骤4：化合物WX064-5的合成
氮气氛围下将化合物WX064-4(410mg)溶于甲醇(10mL)中，加入湿钯碳(200mg,10％purity)，室温下在氢气球(15psi)氛围下搅拌8小时。反应液过滤(硅藻土助滤)除去催化剂，滤液减压浓缩得粗产品。粗产品在石油醚(15mL)和乙酸乙酯(0.5mL)的混合溶剂中搅拌30分钟，过滤得到化合物WX064- 5。
MS–ESI m/z:465.3[M+H] +.
步骤5：化合物WX064的合成
室温下将化合物WX064-5(100mg)、1,2,3-三氮唑-5-羧酸(48.68mg)和三乙胺(65.35mg)溶于二氯甲烷(2mL)中，加入T 3P(273.97mg)，然后升温至40℃搅拌6小时。反应液用二氯甲烷(13mL)稀释后，用水(20mL x 3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物经高效液相色谱纯化得到化合物WX064。
1H NMR(400MHz,CDCl 3)δ＝8.25(s,1H),7.00(s,2H),6.71(s,1H),6.67(s,1H),5.46(s,1H),4.24(t,J＝5.6Hz,2H),4.14(q,J＝6.8Hz,2H),4.04-3.97(m,2H),3.80(br s,2H),3.74(s,3H),2.94(t,J＝6.0Hz,2H),2.34(s,3H),2.17(br s,6H),1.49(t,J＝6.8Hz,3H).MS–ESI m/z:560.3[M+H] +.
实施例65：化合物WX065的合成
Figure PCTCN2019095826-appb-000096
步骤1：化合物WX065-5的合成
室温下向化合物65-1A(2.00g)和对甲苯磺酸(1.10g)的四氢呋喃(50mL)中滴加DHP(2.15g)，滴加完毕后，混合物在20℃搅拌12小时。反应液减压浓缩，浓缩物溶于乙酸乙酯(100mL)，用饱和碳酸氢钠(80mL)和饱和食盐水(80mL)分别洗涤1次，无水硫酸钠干燥，过滤，减压浓缩，得到化合物65-2A。MS–ESI m/z:241.2[M+H] +.
0℃下向化合物65-2A(0.80g)和碳酸钾(2.30g)的DMF(10mL)混合物中滴加碘甲烷(0.95g)，滴加完毕后，混合物在25℃搅拌12小时。反应液倒入水(20mL)中，乙酸乙酯(10mL x 2)萃取。合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到化合物65-3A。MS–ESI m/z:255.2[M+H] +.
0℃下向化合物65-3A(0.80g)的四氢呋喃(4mL)溶液中滴加氢氧化钠(0.38g)水(8mL)溶液，滴加完毕后，混合物在25℃搅拌12小时。反应液冰浴冷却下用2mol/L盐酸调节pH值至4，乙酸乙酯(20mL x 2)萃取。合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到化合物WX065-5。MS–ESI m/z:227.0[M+H] +.
步骤2：化合物WX065-6的合成
室温下将化合物WX064-5(60.0mg)、WX065-5(58.44mg)和三乙胺(65.35mg)溶于DMF(1mL)中，加入PyBOP(201.64mg)，然后在20℃搅拌12小时。混合物经高效液相色谱纯化得到化合物WX065-6。MS–ESI m/z:673.4[M+H] +.
步骤5：化合物WX065的合成
将化合物WX065-6(40mg)溶于氯化氢-乙酸乙酯溶液(4M,1mL)中，20℃搅拌1小时。反应液减压浓缩，浓缩物经高效液相色谱纯化得到化合物WX065。
1H NMR(400MHz,CD 3OD)δ＝7.95(s,1H),7.12(s,2H),6.98(s,1H),6.80(s,1H),5.68(s,1H),4.69-4.66(m,2H),4.45(br s,2H),4.21(t,J＝6.4Hz,2H),4.16(q,J＝7.2Hz,2H),3.99(br s,3H),3.70(s,3H),3.07(t,J＝6.4Hz,2H),2.36(s,3H),2.24(s,6H),1.43(t,J＝7.2Hz,3H).MS–ESI m/z:589.1[M+H] +.
参照实施例65的合成方法，合成下表中实施例。
Figure PCTCN2019095826-appb-000097
各实施例的NMR和MS数据
Figure PCTCN2019095826-appb-000098
Figure PCTCN2019095826-appb-000099
Figure PCTCN2019095826-appb-000100
Figure PCTCN2019095826-appb-000101
Figure PCTCN2019095826-appb-000102
Figure PCTCN2019095826-appb-000103
Figure PCTCN2019095826-appb-000104
实验例1：体外检测化合物对PDE 3A酶的抑制活性
实验目的：根据荧光偏振测定AMP/GMP表达，即示踪AMP/GMP抗体结合来表示酶的活性。
试剂：
实验缓冲溶液：10mM Tris–HCl(pH 7.5)，5mM MgCl 2，0.01％Brij 35，1mM二硫苏糖醇(DTT)，和1％DMSO。
酶：重组人源PDE3A(基因登录号NM_000921；氨基酸669端)用N端GST标签在Sf9昆虫细胞中的杆状病毒来表达，其分子量＝84kDa。
酶作用物：1μM cAMP
检测：
Figure PCTCN2019095826-appb-000105
AMP2/GMP2抗体和AMP2/GMP2 AlexaFluor633示踪。
操作步骤：
1.将重组人源PDE3A酶和酶作用物(1μM cAMP)分别溶解到新鲜制备的实验缓冲液中；
2.将上述PDE3A酶缓冲溶液转移到反应孔中；
3.通过声学技术(回声550；毫微升范围)将100％DMSO溶解的化合物加到PDE3A酶缓冲溶液反应孔中，并在室温下孵育10分钟；
4.将酶作用物缓冲溶液加到上述反应孔中以启动反应；
5.在室温下孵育1小时；
6.添加检测混合物(
Figure PCTCN2019095826-appb-000106
AMP2/GMP2抗体和AMP2/GMP2 AlexaFluor633示踪)以终止反应，并在缓慢混合下孵育90分钟。荧光偏振测定范围是Ex/Em＝620/688。
数据分析：荧光偏振信号根据AMP/GMP标准曲线和通过Excel软件计算相对DMSO对照的酶活性百分比，换算成nM。曲线拟合使用GraphPad Prism(绘制医学图标)。实验结果见表1。
实验例2：体外检测化合物对PDE 4B酶的抑制活性
实验目的：根据荧光偏振测定AMP/GMP表达，即示踪AMP/GMP抗体结合来表示酶的活性。
试剂：
实验缓冲溶液：10mM Tris–HCl(pH 7.5)，5mM MgCl 2，0.01％Brij 35，1mM DTT，和1％DMSO。
酶：重组人源PDE4B(基因登录号NM_002600；氨基酸305端)用N端GST标签在Sf9昆虫细胞中的杆状病毒来表达，其分子量＝78kDa。
酶作用物：1μM cAMP
检测：
Figure PCTCN2019095826-appb-000107
AMP2/GMP2抗体和AMP2/GMP2 AlexaFluor633示踪。
操作步骤：
1.将重组人源PDE4B酶和酶作用物(1μM cAMP)分别溶解到新鲜制备的实验缓冲液中；
2.将上述PDE4B酶缓冲溶液转移到反应孔中；
3.通过声学技术(回声550；毫微升范围)将100％DMSO溶解的化合物加到PDE4B酶缓冲溶液反应孔中，并在室温下孵育10分钟
4.将酶作用物缓冲溶液加到上述反应孔中以启动反应
5.在室温下孵育1小时
6.添加检测混合物(
Figure PCTCN2019095826-appb-000108
AMP2/GMP2抗体和AMP2/GMP2 AlexaFluor633示踪)以终止反应，并在缓慢混合下孵育90分钟。荧光偏振测定范围是Ex/Em＝620/688。
数据分析：荧光偏振信号根据AMP/GMP标准曲线和通过Excel软件计算相对DMSO对照的％酶活性，换算成nM。曲线拟合使用GraphPad Prism(绘制医学图标)。
实验结果见表1：
表1 化合物体外筛选测试结果
Figure PCTCN2019095826-appb-000109
Figure PCTCN2019095826-appb-000110
实验例3：体外检测化合物对人外周血单核细胞TNF-α的抑制活性
实验目的：根据人外周血单核细胞(hPBMC)中TNF-α的水平来表达测试化合物细胞水平的抗炎活性。操作步骤：
1.采集正常人全血，EDTA抗凝管抗凝；
2.Ficoll密度梯度离心分离PBMC，计数，调整细胞浓度为2x10 6/ml；
3.U底96孔板，每孔加入细胞2x10 5，LPS 1ng/ml,化合物分别在100μM，10μM，1μM，100nM，10nM，1nM，100pM，10pM浓度下的DMSO溶液，每孔200μL体系；
4.培养24小时，收取上清；
5.ELISA检测上清中TNF-α的水平，Graphpad Prism软件拟合抑制曲线并计算IC 50。
实验结果见表2：
表2 化合物体外测试结果
Figure PCTCN2019095826-appb-000111
实验例4比格犬药代动力学试验
本研究受试动物选用雄性比格犬，应用LC-MS/MS法定量测定比格犬经静脉注射或口服给予化合物WX036不同时间点的血浆中的药物浓度，以评价化合物WX036在比格犬体内的药代动力学特征。
将化合物WX036的澄清溶液经头静脉或隐静脉注射到两只10-12公斤的比格犬体内，将试验化合物的澄清溶液灌胃给予两只10-12公斤的比格犬(过夜禁食)。动物均于给药后0.0333,0.0833,0.25,0.5,1,2,4,6, 8和24小时从外周静脉采血约500μL转移至含有0.85-1.15mg的K 2EDTA*2H 2O抗凝剂商品化离心管中，4℃，3000g离心10min取血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
表3 化合物WX036在比格犬中的药代动力学参数
Figure PCTCN2019095826-appb-000112
实验例5 人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的抑制作用
将CYP的5种同工酶的一共5个特异性探针底物非那西丁(Phenacetin，CYP1A2)、双氯芬酸(Diclofenac，CYP2C9)、(S)-美芬妥英((S)-Mephenytoin，CYP2C19)、右美沙芬(Dextromethorphan，CYP2D6)和咪达唑仑(Midazolam，CYP3A4)分别与人肝微粒体以及测试化合物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后对样品处理并采用液相色谱串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的5种代谢产物对乙酰氨基酚(Acetaminophen)、4’-羟基双氯芬酸(4’-Hydroxydiclofenac)、4’-羟基美芬妥英(4’-Hydroxymephenytoin)、右啡烷(Dextrorphan)、1’-羟基咪达唑仑(1’-Hydroxymidazolam)的浓度，以计算相应的半抑制浓度(IC 50)。
表4 化合物WX026、WX036对于五种CYP酶的抑制作用参数
Figure PCTCN2019095826-appb-000113
实验例6 烟熏诱导的大鼠急性肺损伤模型中的药效研究
实验动物
雄性Sprague-Dawley大鼠(上海斯莱克实验动物有限公司提供)，SPF级，体重约200g。
实验流程
1.动物到达设施后适应性饲养一周，按体重随机分为3组；
2.实验第1～3天，雾化各组对应的化合物30分钟，然后模型组及各化合物处理组的动物烟熏暴露 1小时，间隔4小时后，再次烟熏暴露1小时。香烟烟雾每天暴露2次，连续3天暴露。对照组动物暴露于室内空气；
3.实验第4天，雾化各组对应的化合物30分钟，在模型组及各化合物处理组的动物雾化吸入暴露150μg/mL的LPS 15分钟，3小时后(距开始雾化的时间)烟熏暴露1小时，再检测动物肺功能(Penh)，CO 2安乐死动物后收集肺泡灌洗液用于细胞计数。
4.给药处理
给药方式：全身暴露雾化装置以最大雾化率(约12mL)雾化待测化合物，30分钟。
给药频率：每天早上烟熏之前雾化给药或溶剂30分钟，第4天在LPS雾化吸入前给药。
5药效终点测量
(1)BALF(肺泡灌洗液)白细胞总数；
(2)乙酰甲胆碱Mch诱导下肺功能检测(气道阻力指数Penh)；
表5 实验分组
组别 动物数量 雾化溶液化合物浓度 给药时间
模型组 10 - 每天第一次烟熏前30min
WX036低剂量组 10 0.05mg/ml 每天第一次烟熏前30min
WX036高剂量组 10 0.15mg/ml 每天第一次烟熏前30min
实验结果见图1及图2。

Claims (15)

  1. 式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019095826-appb-100001
    其中，
    环Cy选自5元杂环基或5元杂芳基，其中所述5元杂环基或5元杂芳基任选地被一个或多个以下基团取代：氨基、羟基、＝O、卤素、氰基、C 1-12烷基、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基) 2、-COOH、-C(O)O(C 1-6烷基)或C 1-12烷氧基，其中所述C 1-12烷基或C 1-12烷氧基任选被一个或多个选自卤素、氨基或羟基的基团取代；
    所述环Cy的环原子中至少含有一个氮原子；
    L选自-N(R 6)-、-N(R 6)C(O)-、-C(O)N(R 6)-、-O-、-S-、-OC(O)-、-C(O)O-、-CH 2N(R 6)C(O)-、-CH 2C(O)N(R 6)-、-S(O) 2NH-、-NHS(O) 2-或单键；
    n为1、2、3或4；
    E 1选自-(CH 2) m-，其中m为1、2或3；
    E 2选自-O-、-NH-、-S-或单键；
    R 3、R 4和R 5分别独立地选自氢、卤素或C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个选自卤素、氨基或羟基的基团取代；
    每一个R 6分别独立地选自氢、羟基或C 1-3烷基，其中所述C 1-3烷基任选地被一个或多个选自卤素、氨基或羟基的基团取代。
  2. 如权利要求1所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中环Cy选自5元杂环基或5元杂芳基，其中所述5元杂环基或5元杂芳基任选地被一个或多个以下基团取代：氨基、羟基、＝O、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-COOH、-C(O)O(C 1-3烷基)、C 1-6烷氧基或被一个或多个卤素取代的C 1-6烷基；
    任选地，其中环Cy选自5元杂环基或5元杂芳基，其中所述5元杂芳基任选地被一个或多个以下基团取代：氨基、羟基、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、 -COOH、-C(O)O(C 1-3烷基)、C 1-6烷氧基或被一个或多个卤素取代的C 1-6烷基，其中所述5元杂环基任选地被一个或多个选自＝O的基团取代；
    任选地，其中环Cy选自噁唑烷-2-酮基、咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基，其中所述咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基任选地被一个或多个以下基团取代：氨基、羟基、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-COOH、-C(O)O(C 1-3烷基)、C 1-6烷氧基或被一个或多个卤素取代的C 1-6烷基；
    任选地，其中环Cy选自5元杂芳基，其中所述5元杂芳基任选地被一个或多个以下基团取代：氨基、羟基、氟、氯、溴、碘、氰基、C 1-3烷基、-C(O)NH 2、-C(O)O(C 1-3烷基)、C 1-3烷氧基或被一个或多个卤素取代的C 1-3烷基；
    任选地，其中环Cy选自咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基，其中所述咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基任选地被一个或多个以下基团取代：氨基、羟基、氟、氯、溴、碘、氰基、C 1-3烷基、-C(O)NH 2、-C(O)O(C 1-3烷基)、C 1-3烷氧基或被一个或多个卤素取代的C 1-3烷基；
    任选地，其中环Cy选自5元杂芳基，所述5元杂芳基任选地被一个或多个以下基团取代：氨基、羟基、氟、氯、氰基、甲基、-C(O)NH 2、-C(O)OCH 3、甲氧基或三氟甲基；
    任选地，其中环Cy选自咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基，所述咪唑基、吡唑基、噁唑基、三唑基、噁二唑基、四唑基、噻二唑基或异噁唑基任选地被一个或多个以下基团取代：氨基、羟基、氟、氯、氰基、甲基、-C(O)NH 2、-C(O)OCH 3、甲氧基或三氟甲基。
  3. 如权利要求1所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中环Cy选自结构单元
    Figure PCTCN2019095826-appb-100002
    其中，
    Figure PCTCN2019095826-appb-100003
    表示单键或双键；
    T 1、T 2、T 3和T 4分别独立地选自C＝O、C(R 1)、C(R 1) 2、O、N(R 2)、N或S；
    每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-12烷基、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基) 2、-COOH、-C(O)O(C 1-6烷基)或C 1-12烷氧基，其中所述C 1-12烷基或C 1-12烷氧基任选地被一个或多个选自卤素、氨基或羟基的基团取代；
    每一个R 2分别独立地选自氢、羟基或C 1-3烷基，其中所述C 1-3烷基任选被一个或多个选自卤素、氨基或羟基的基团取代；
    任选地，T 1选自C(R 1)、C(R 1) 2或N，T 2、T 3和T 4分别独立地选自C＝O、C(R 1)、C(R 1) 2、O、N(R 2)、N或S；
    任选地，T 1选自C(R 1)或N，T 2、T 3和T 4分别独立地选自C＝O、C(R 1)、O、N(R 2)、N或S；
    任选地，T 1选自C(R 1)或N，T 2、T 3和T 4分别独立地选自C(R 1)、O、N(R 2)、N或S；
    任选地，在结构单元
    Figure PCTCN2019095826-appb-100004
    中，T 1选自C(R 1)或N，T 2、T 3和T 4分别独立地选自C(R 1)、O、N(R 2)或N；
    任选地，在结构单元
    Figure PCTCN2019095826-appb-100005
    中，T 1选自C(R 1) 2，T 2、T 3和T 4分别独立地选自C＝O、C(R 1) 2或O；
    任选地，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)NH(C 1- 3烷基)、-C(O)N(C 1-3烷基) 2、-COOH、-C(O)O(C 1-3烷基)或C 1-6烷氧基，其中所述C 1-6烷基或C 1- 6烷氧基任选地被一个或多个选自卤素、氨基或羟基的基团取代；
    任选地，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)O(C 1-3烷基)或C 1-3烷氧基，其中所述C 1-6烷基或C 1-3烷氧基任选地被一个或多个选自卤素、氨基或羟基的基团取代；
    任选地，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-6烷基、-C(O)NH 2、-C(O)O(C 1- 3烷基)或C 1-3烷氧基，其中所述C 1-6烷基任选地被一个或多个选自卤素、氨基或羟基的基团取代；
    任选地，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-3烷基、-C(O)NH 2、-C(O)OCH 3或C 1-3烷氧基，其中所述C 1-3烷基或C 1-3烷氧基任选被一个或多个选自卤素、氨基或羟基取代；
    任选地，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-3烷基、-C(O)NH 2、-C(O)OCH 3或C 1-3烷氧基，其中所述C 1-3烷基任选被一个或多个选自卤素、氨基或羟基取代；
    任选地，每一个R 1分别独立地选自氢、氨基、羟基、卤素、氰基、C 1-3烷基、-C(O)NH 2、-C(O)OCH 3或C 1-3烷氧基，其中所述C 1-3烷基任选被1、2或3个卤素、氨基或羟基取代；
    任选地，每一个R 1分别独立地选自氢、氨基、羟基、氟、氯、氰基、甲基、-C(O)NH 2、-C(O)OCH 3、甲氧基或三氟甲基；
    任选地，每一个R 1分别独立地选自氢、氨基、羟基、C 1-6烷基或C 1-6烷氧基，其中所述C 1-6烷基或C 1-6烷氧基任选地被被一个或多个选自卤素、氨基或羟基的基团取代；
    任选地，每一个R 1分别独立地选自氢、氨基、羟基、C 1-3烷基或C 1-3烷氧基；
    任选地，每一个R 1分别独立地选自氢、氨基、羟基、甲基或甲氧基；
    任选地，每一个R 2分别独立地选自氢、羟基或C 1-3烷基，其中所述C 1-3烷基任选被一个或多个卤素、氨基或羟基取代；
    任选地，每一个R 2分别独立地选自氢、羟基或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个卤素、氨基或羟基取代；
    任选地，每一个R 2分别独立地选自氢、羟基或甲基；
    任选地，每一个R 2分别独立地选自氢或甲基。
  4. 如权利要求3所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中结构单元
    Figure PCTCN2019095826-appb-100006
    选自
    Figure PCTCN2019095826-appb-100007
    任选地，结构单元
    Figure PCTCN2019095826-appb-100008
    选自
    Figure PCTCN2019095826-appb-100009
    任选地，结构单元
    Figure PCTCN2019095826-appb-100010
    选自
    Figure PCTCN2019095826-appb-100011
    Figure PCTCN2019095826-appb-100012
    任选地，结构单元
    Figure PCTCN2019095826-appb-100013
    选自
    Figure PCTCN2019095826-appb-100014
    Figure PCTCN2019095826-appb-100015
    Figure PCTCN2019095826-appb-100016
    任选地，结构单元
    Figure PCTCN2019095826-appb-100017
    选自
    Figure PCTCN2019095826-appb-100018
    Figure PCTCN2019095826-appb-100019
  5. 如权利要求1-4中任一项所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中L选自-N(R 6)-、-N(R 6)C(O)-、-C(O)N(R 6)-、-CH 2N(R 6)C(O)-、-CH 2C(O)N(R 6)-、-S(O) 2NH-、-NHS(O) 2-或单键；
    任选地，L选自-N(R 6)-、-N(R 6)C(O)-、-C(O)N(R 6)-、-CH 2N(R 6)C(O)-、-S(O) 2NH-或单键；
    任选地，L选自-N(R 6)-、-N(R 6)C(O)-、-C(O)N(R 6)-或-S(O) 2NH-；
    任选地，L选自-N(R 6)-、-N(R 6)C(O)-或-C(O)N(R 6)-；
    任选地，L选自-NH-、-NHC(O)-、-C(O)NH-或-C(O)N(OH)-、-S(O) 2NH-或单键；
    任选地，L选自-NH-、-NHC(O)-、-C(O)NH-或-C(O)N(OH)-。
  6. 如权利要求1-4中任一项所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中n选自1、2或3；
    任选地，n选自1或2；
    任选地，n选自2。
  7. 如权利要求1-4中任一项所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中R 3、R 4和R 5分别独立地选自卤素或C 1-3烷基，其中所述C 1-3烷基任选地被1、2或3个卤素、氨基或羟基取代；
    任选地，R 3、R 4和R 5分别独立地选自卤素或甲基，其中所述甲基任选地被1、2或3个卤素、氨基或羟基取代；
    任选地，R 3、R 4和R 5分别独立地选自甲基。
  8. 如权利要求1-4中任一项所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中每一个R 6分别独立地选自氢、羟基或甲基，其中所述甲基任选地被1、2或3个卤素、氨基或羟基取代；
    任选地，每一个R 6分别独立地选自氢、羟基或甲基；
    任选地，每一个R 6分别独立地选自氢或羟基。
  9. 如权利要求1-4任一项所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中E 1选自-(CH 2) 2-或-(CH 2) 3-。
  10. 如权利要求1-4任一项所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，其中E 2选自-O-或键。
  11. 如权利要求1所述的式(Ⅰ)化合物、其异构体或其药学上可接受的盐，所述式(Ⅰ)化合物选自式(II)化合物
    Figure PCTCN2019095826-appb-100020
    其中E 1、E 2和L的定义如权利要求1、5、9-10中任一项所述；
    T 1、T 2、T 3、T 4以及结构单元
    Figure PCTCN2019095826-appb-100021
    的定义如权利要求3-4中任一项所述。
  12. 以下化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019095826-appb-100022
    Figure PCTCN2019095826-appb-100023
    Figure PCTCN2019095826-appb-100024
    Figure PCTCN2019095826-appb-100025
  13. 一种药物组合物，包括如权利要求1-12中任一项所述的化合物或其药学上可接受的盐，还包括药学上可接受的辅料、载体或稀释剂。
  14. 如权利要求1-12中任一项所述的化合物、其药学上可接受的盐或如权利要求13所述的药物组合物在制备用于治疗与PDE3和/或PDE4相关病症的药物中的应用，任选地，其中所述与PDE3和/或PDE4相关病症选自慢性阻塞性肺病或哮喘。
  15. 一种治疗哺乳动物的与PDE3和/或PDE4相关病症的方法，包括对需要该治疗的哺乳动物，给予治疗有效量的权利要求1-12中任一项所述的化合物、其药学上可接受的盐或如权利要求13所述的其药物组合物，任选地，其中所述与PDE3和/或PDE4相关病症选自慢性阻塞性肺病或哮喘。
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021143843A1 (zh) * 2020-01-15 2021-07-22 正大天晴药业集团股份有限公司 一种pde3/pde4双重抑制剂的结晶及其应用
WO2021143841A1 (zh) * 2020-01-15 2021-07-22 正大天晴药业集团股份有限公司 三并环类pde3/pde4双重抑制剂化合物的药物组合物
WO2022228544A1 (zh) 2021-04-29 2022-11-03 苏州盛迪亚生物医药有限公司 异喹啉酮类化合物及其用途
WO2023109802A1 (zh) * 2021-12-14 2023-06-22 海思科医药集团股份有限公司 三环稠杂环类pde3/4双重抑制及其用途
WO2023138676A1 (zh) 2022-01-21 2023-07-27 四川海思科制药有限公司 三环稠杂环类pde3/4双重抑制及其用途
CN117946099A (zh) * 2022-10-28 2024-04-30 江苏恒瑞医药股份有限公司 一种异喹啉酮类化合物的可药用盐、晶型及其制备方法
WO2025124462A1 (zh) * 2023-12-13 2025-06-19 石家庄以岭药业股份有限公司 三环稠杂环类pde3/4双重抑制剂及其制备方法与应用
WO2025124459A1 (zh) * 2023-12-13 2025-06-19 石家庄以岭药业股份有限公司 三环稠杂环类pde3/4双重抑制剂及其制备方法与应用
US12384777B2 (en) 2019-04-24 2025-08-12 Tay Therapeutics Limited Compounds comprising N-methyl-2-pyridone, and pharmaceutically acceptable salts
WO2026002106A1 (zh) * 2024-06-28 2026-01-02 辽宁海思科制药有限公司 一种三环稠杂环类pde3/4双重抑制剂关键中间体的制备方法
EP4610257A4 (en) * 2022-10-28 2026-01-14 Jiangsu Hengrui Pharmaceuticals Co Ltd CRYSTALLINE FORM OF AN ISOQUINOLINONE COMPOUND AND ITS PREPARATION PROCESS
WO2026052051A1 (zh) * 2024-09-06 2026-03-12 正大天晴药业集团股份有限公司 杂环化合物在治疗肺疾病中的应用

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT3822272T (pt) * 2018-07-13 2025-01-22 Chia Tai Tianqing Pharmaceutical Group Co Ltd Composto tricíclico fundido como inibidor duplo de pde3/pde4
CN119241534B (zh) * 2024-09-18 2025-12-05 武汉九州钰民医药科技有限公司 一种恩塞芬汀的制备方法
CN120699016A (zh) * 2025-06-20 2025-09-26 济南大学 一种恩塞芬汀的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1597717A (en) 1976-12-10 1981-09-09 Hoechst Ag Pyrimido (6,1-a) isoquinolin-4-one derivatives
US4482556A (en) * 1977-05-05 1984-11-13 Hoechst Aktiengesellschaft Pyrimido (6,1-a)isoquinolin-4-one derivatives
EP0124893A2 (de) * 1983-05-05 1984-11-14 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Neue Pyrimidonderivate
WO2000005830A1 (en) 1998-07-22 2000-02-03 Mitsubishi Denki Kabushiki Kaisha Mobile communication system and mobile communication method
WO2000058308A1 (en) 1999-03-31 2000-10-05 Vernalis Limited DERIVATIVES OF PYRIMIDO[6,1-a]ISOQUINOLIN-4-ONE

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH12013500261A1 (en) 2010-08-09 2013-03-04 Verona Pharma Plc Crystalline form of pyrimidio[6,1-a]isoquinolin-4-one compound
PT3822272T (pt) * 2018-07-13 2025-01-22 Chia Tai Tianqing Pharmaceutical Group Co Ltd Composto tricíclico fundido como inibidor duplo de pde3/pde4

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1597717A (en) 1976-12-10 1981-09-09 Hoechst Ag Pyrimido (6,1-a) isoquinolin-4-one derivatives
US4482556A (en) * 1977-05-05 1984-11-13 Hoechst Aktiengesellschaft Pyrimido (6,1-a)isoquinolin-4-one derivatives
EP0124893A2 (de) * 1983-05-05 1984-11-14 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Neue Pyrimidonderivate
WO2000005830A1 (en) 1998-07-22 2000-02-03 Mitsubishi Denki Kabushiki Kaisha Mobile communication system and mobile communication method
WO2000058308A1 (en) 1999-03-31 2000-10-05 Vernalis Limited DERIVATIVES OF PYRIMIDO[6,1-a]ISOQUINOLIN-4-ONE
CN1348453A (zh) * 1999-03-31 2002-05-08 韦尔纳利斯有限公司 嘧啶并[6,1－a] 异喹啉－4－酮衍生物

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Greene's Protective Groups in Organic Synthesis", JOHN WILEY & SONS, INC
BONANDI ELISA; CHRISTODOULOU MICHAEL S.; FUMAGALLI GAIA; PERDICCHIA DARIO; RASTELLI GIULIO; PASSARELLA DANIELE: "The 1,2,3-triazole ring as a bioisostere in medicinal chemistry", DRUG DISCOVERY TODAY, vol. 22, no. 10, 1 January 1900 (1900-01-01), AMSTERDAM, NL , pages 1572 - 1581, XP085215112, ISSN: 1359-6446, DOI: 10.1016/j.drudis.2017.05.014
DUNDEE J W; HALLIDAY N J; HARPER K W; BROGDEN R N: "Midazolam. A review of its pharmacological properties and therapeutic", DRUGS, vol. 28, no. 6, 1 January 1984 (1984-01-01), NZ , pages 519 - 543, XP009152231, ISSN: 0012-6667
JONAS BOSTRÖM, ANDERS HOGNER, ANTONIO LLINÀS, ERIC WELLNER, ALLEYN T. PLOWRIGHT: "Oxadiazoles in Medicinal Chemistry", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 5, 8 March 2012 (2012-03-08), pages 1817 - 1830, XP055050959, ISSN: 00222623, DOI: 10.1021/jm2013248
KATHARINE H BANNER; NEIL J PRESS: "Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease", BRITISH JOURNAL OF PHARMACOLOGY, vol. 157, no. 6, 5 June 2009 (2009-06-05), UK , pages 892 - 906, XP071055990, ISSN: 0007-1188, DOI: 10.1111/j.1476-5381.2009.00170.x
NICHOLAS A. MEANWELL: "Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 8, 28 April 2011 (2011-04-28), pages 2529 - 2591, XP055032041, ISSN: 00222623, DOI: 10.1021/jm1013693
SUBRAMANIAN VENKATARAMAN, KNIGHT JASON S., PARELKAR SANGRAM, ANGUISH LYNNE, COONROD SCOTT A., KAPLAN MARIANA J., THOMPSON PAUL R.: "Design, Synthesis, and Biological Evaluation of Tetrazole Analogs of Cl-Amidine as Protein Arginine Deiminase Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 3, 12 February 2015 (2015-02-12), US , pages 1337 - 1344, XP055922617, ISSN: 0022-2623, DOI: 10.1021/jm501636x
VICTORIA BOSWELL ET AL., J. PHARMACO. EXPERI. THERAP., vol. 318, 2006, pages 840 - 848

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12384777B2 (en) 2019-04-24 2025-08-12 Tay Therapeutics Limited Compounds comprising N-methyl-2-pyridone, and pharmaceutically acceptable salts
CN114929700B (zh) * 2020-01-15 2024-11-22 正大天晴药业集团股份有限公司 三并环类pde3/pde4双重抑制剂化合物的药物组合物
WO2021143841A1 (zh) * 2020-01-15 2021-07-22 正大天晴药业集团股份有限公司 三并环类pde3/pde4双重抑制剂化合物的药物组合物
CN114929700A (zh) * 2020-01-15 2022-08-19 正大天晴药业集团股份有限公司 三并环类pde3/pde4双重抑制剂化合物的药物组合物
EP4643947A3 (en) * 2020-01-15 2025-11-19 Chia Tai Tianqing Pharmaceutical Group Co., Ltd Crystal of pde3/pde4 dual inhibitor and use thereof
US20230060174A1 (en) * 2020-01-15 2023-03-02 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Pharmaceutical composition of tricyclic pde3/pde4 dual inhibitor compound
JP2023512475A (ja) * 2020-01-15 2023-03-27 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド 三環式ｐｄｅ３／ｐｄｅ４二重阻害剤化合物の医薬組成物
US20230115817A1 (en) * 2020-01-15 2023-04-13 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Crystal of pde3/pde4 dual inhibitor and use thereof
JP7712276B2 (ja) 2020-01-15 2025-07-23 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド 三環式ｐｄｅ３／ｐｄｅ４二重阻害剤化合物の医薬組成物
EP4092025A4 (en) * 2020-01-15 2023-08-30 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. PHARMACEUTICAL COMPOSITION OF A TRICYCLIC PDE3/PDE4 DOUBLE INHIBITOR COMPOUND
WO2021143843A1 (zh) * 2020-01-15 2021-07-22 正大天晴药业集团股份有限公司 一种pde3/pde4双重抑制剂的结晶及其应用
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WO2023109802A1 (zh) * 2021-12-14 2023-06-22 海思科医药集团股份有限公司 三环稠杂环类pde3/4双重抑制及其用途
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CN117946099A (zh) * 2022-10-28 2024-04-30 江苏恒瑞医药股份有限公司 一种异喹啉酮类化合物的可药用盐、晶型及其制备方法
EP4610257A4 (en) * 2022-10-28 2026-01-14 Jiangsu Hengrui Pharmaceuticals Co Ltd CRYSTALLINE FORM OF AN ISOQUINOLINONE COMPOUND AND ITS PREPARATION PROCESS
WO2025124462A1 (zh) * 2023-12-13 2025-06-19 石家庄以岭药业股份有限公司 三环稠杂环类pde3/4双重抑制剂及其制备方法与应用
WO2025124459A1 (zh) * 2023-12-13 2025-06-19 石家庄以岭药业股份有限公司 三环稠杂环类pde3/4双重抑制剂及其制备方法与应用
WO2026002106A1 (zh) * 2024-06-28 2026-01-02 辽宁海思科制药有限公司 一种三环稠杂环类pde3/4双重抑制剂关键中间体的制备方法
WO2026052051A1 (zh) * 2024-09-06 2026-03-12 正大天晴药业集团股份有限公司 杂环化合物在治疗肺疾病中的应用

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CN112368281A (zh) 2021-02-12
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