WO2020143626A1 - Pde9抑制剂及其用途 - Google Patents

Pde9抑制剂及其用途 Download PDF

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WO2020143626A1
WO2020143626A1 PCT/CN2020/070707 CN2020070707W WO2020143626A1 WO 2020143626 A1 WO2020143626 A1 WO 2020143626A1 CN 2020070707 W CN2020070707 W CN 2020070707W WO 2020143626 A1 WO2020143626 A1 WO 2020143626A1
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alkyl
group
alkoxy
membered
amino
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PCT/CN2020/070707
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French (fr)
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万中晖
吴笛
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南京药捷安康生物科技有限公司
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Priority to US17/420,997 priority Critical patent/US20220081409A1/en
Publication of WO2020143626A1 publication Critical patent/WO2020143626A1/zh

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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • the invention belongs to the technical field of medicine, and relates to a phosphodiesterase 9 inhibitor represented by formula (I), or a pharmaceutically acceptable salt, isomer and application thereof.
  • PDEs Phosphodiesterases
  • cGMP cyclic guanosine phosphate
  • cAMP cyclic adenosine phosphate
  • PDE9A is an important member of the PDE family, which is widely expressed in the testis, brain, small intestine, skeletal muscle, heart, lung, thymus, and pancreas.
  • cAMP and cGMP are important second messengers and play a central role in cell signaling; they mainly activate protein kinases: those activated by cAMP are called protein kinase A (PKA) and those activated by cGMP It is called protein kinase G (PKG).
  • PKA protein kinase A
  • PKG protein kinase G
  • the activated PKA and PKG can phosphorylate many cell effector proteins, such as ion channels, G-protein coupled receptors, structural proteins, and transduction factors. Therefore, cAMP and cGMP may control most physiological processes in many organs in this way. At the same time, cAMP and cGMP can also directly act on the effector protein, thus playing the same role as above.
  • Phosphodiesterases hydrolyze cyclic monophosphates cAMP and cGMP and convert them into inactivated monophosphates AMP and GMP.
  • Human PDE9 was first cloned and sequenced in 1998, and it is the most selective PDE reported to date for cGMP.
  • the binding constant (Km) of PDE9 and cGMP is 170nM, while the binding constant value of cAMP is up to 230,000nM, and the selectivity is more than 1000 times.
  • PDE9 inhibitors may increase the baseline cGMP concentration.
  • PDE9 inhibitor drugs There are currently no PDE9 inhibitor drugs on the market, only some inhibitors that are in clinical development, such as Pfizer's PF-04447943 (WO2008139293A1, Example 111) and BI's BI-409306 (WO2009121919A1, Exp.51) PDE9 inhibitors, currently two compounds are in clinical stage I and II.
  • An object of the present invention is to provide a class of compounds used as PDE9 protease inhibitors, or pharmaceutically acceptable salts and isomers thereof.
  • the compounds of the present invention have good PDE9 protease inhibitory activity, selectivity, and drug-forming properties (such as High liver microsome stability), which can treat or prevent related diseases mediated by PDE9, and can play an important role in the treatment of cognitive impairment diseases caused by central nervous system disorders.
  • Each R 2 is independently selected from hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl , C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclic group, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl Group) 2 aminocarbonyl, aryl, 5-6 membered heteroaryl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C 1-6 alkyl, C 1- 6 alkoxy, C 1-6 alkylamino, (C 1-6 al
  • substituents of the above-mentioned 4-6 membered heterocyclic group optionally substituted by substituents and heteroaryl groups optionally substituted by substituents are selected from the group consisting of hydroxy, amino, carboxy, cyano, nitro, halogen, and C 1-6 alkyl Group and C 1-6 alkoxy;
  • L is a bond, -NH-(CH 2 )t-, t is 0, 1, 2 or 3;
  • Ring A is a 3-8 membered monoheterocyclic group, 6-12 membered bridged heterocyclic group, 6-12 membered spiro heterocyclic group, 6-12 membered heterocyclic group, aryl group, 5-10 membered heteroaryl group, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, wherein the hetero atom of the heterocyclic group is selected from one of O, S, N or any combination thereof, S atom may be optionally oxidized to S (O) or S(O) 2 , the C atom may be optionally oxidized to C(O), and the hetero atom of the 5-10 membered heteroaryl group is selected from one of O, S, N or any combination thereof ;
  • Each R 1 is independently selected from hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl , C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, aryl and 5-10 membered heteroaryl, wherein the C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy , C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 al
  • n and n are independently 0, 1, 2 or 3;
  • R 2 is not hydrogen
  • R 2 is not hydrogen.
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • Each R 2 is independently selected from hydrogen, amino, carboxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl ) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered nitrogen-containing Heterocyclic group, C 1-6 alkylcarbonyl group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl) 2 aminocarbonyl group and aminocarbonyl group, wherein the C 1-6 alkyl group, C 1-6 alkoxy group Group, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkyl Sulfur, C 3-6 cycloalky
  • Ring A is a 3-8 membered monoheterocyclic group, 6-12 membered bridge heterocyclic group, 6-12 membered spiro heterocyclic group, 6-12 membered heterocyclic group, phenyl group, 5-10 membered heteroaryl group,
  • the hetero atom of the heterocyclic group is selected from one of O, S, and N or any combination thereof, the S atom may be optionally oxidized to S(O) or S(O) 2 , and the C atom may be optionally oxidized Is C(O);
  • Each R 1 is independently selected from hydrogen, hydroxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, and 5-6 membered heteroaryl, wherein the C 1-6 alkyl , C 1-6 alkoxy and 5-6 membered heteroaryl are unsubstituted or substituted by hydroxy;
  • n and n are independently 0, 1, 2;
  • R 2 is not hydrogen
  • R 2 is not hydrogen.
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • Each R 2 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylaminocarbonyl, wherein the C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 alkylaminocarbonyl is unsubstituted or optionally substituted with one or more groups independently selected from hydroxyl, C 1-6 alkoxy, C 3-6 cycloalkyl;
  • Ring A is a 3-8 membered monoheterocyclic group, 6-12 membered spiroheterocyclic group, wherein the heteroatom of the membered heterocyclic group is selected from one of O, S, N or any combination thereof, S atom may Optionally oxidized to S(O) or S(O) 2 , C atom can be optionally oxidized to C(O);
  • Each R 1 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 alkoxy;
  • n and n are independently 0, 1, 2 or 3;
  • R 2 is not hydrogen
  • R 2 is not hydrogen.
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • Ring A is a 4-7 membered monoheterocyclic group, the heteroatom of the 4-7 membered monoheterocyclic group is selected from one or a combination of two of O, S, N, and contains at least one N, ring A
  • N atoms By connecting N atoms with L, S atoms can be optionally oxidized to S(O) or S(O) 2 , and C atoms can be optionally oxidized to C(O);
  • ring A is a 4-7 membered nitrogen-containing saturated monoheterocyclic group, further preferably:
  • Each R 2 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, morpholinyl, C 2-6 alkenyl, C 1-4 alkylcarbonyl, C 1-4 alkylamino Carbonyl, (C 1-4 alkyl) 2 aminocarbonyl and aminocarbonyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, morpholinyl, C 2-6 alkenyl, C 1-4 Alkylcarbonyl, C 1-4 alkylaminocarbonyl, (C 1-4 alkyl) 2 aminocarbonyl and aminocarbonyl are unsubstituted or optionally one or more independently selected from hydroxyl, C 1-4 alkyl, C 1- 4 alkoxy, C 3-6 cycloalkyl, amino, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, unsubstituted or optionally substituted with C 1-4 alkyl -6-membered heterocyclic group substitution;
  • Each R 1 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, pyrazolyl, thiazolyl, and triazolyl.
  • the C 1-4 alkyl, C 1-4 alkoxy, pyrazolyl, thiazolyl and triazolyl are unsubstituted or substituted by hydroxy;
  • n and n are independently 0, 1, or 2.
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • Each R 2 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl and aminocarbonyl , Wherein the C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl and aminocarbonyl groups are unsubstituted or optionally substituted One or more independently selected from the group consisting of hydroxy, C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, and a 4-6 membered heterocyclic group which is unsubstituted or optionally substituted with C 1-4 alkyl Group substitution;
  • Each R 1 is independently selected from hydrogen, C 1-4 alkyl and C 1-4 alkoxy;
  • n and n are independently 0, 1, or 2.
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • Each R 2 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylaminocarbonyl, wherein the C 1-4 alkyl, C 1-4 alkoxy Group, C 1-4 alkylaminocarbonyl group is unsubstituted or optionally substituted with one or more groups independently selected from hydroxyl, C 1-4 alkoxy, cyclopropyl;
  • Each R 1 is independently selected from hydrogen, C 1-4 alkyl and C 1-4 alkoxy;
  • n and n are independently 0, 1, or 2.
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • Each R 2 is independently selected from amino, carboxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 Amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered nitrogen-containing heterocycle Group, C 1-6 alkylcarbonyl group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl) 2 aminocarbonyl group and aminocarbonyl group, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio , C 3-6 cycloalkyl, 4-6 member
  • Each R 1 is independently selected from pyrazolyl, thiazolyl, and triazolyl.
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • L is the key
  • Each R 2 is independently selected from hydrogen, amino, cyano, halogen, carboxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylcarbonyl, C 2-6 alkynyl, C 1-4 alkylaminocarbonyl, (C 1-4 alkyl) 2 aminocarbonyl, C 1-4 alkylthio, C 1-4 alkylsulfonyl, C 1-4 alkylamino, (C 1-4 Alkyl) 2 amino, azetidinyl, morpholinyl, piperazinyl, C 2-6 alkenyl and cyclopropyl, the C 1-4 alkyl, C 1-4 alkoxy group , C 1-4 alkylcarbonyl, C 2-6 alkynyl, C 1-4 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-4 alkylthio, C 1-4 alkyl Sulfonyl, C 1-4 alkylamino, (C
  • Ring A is a 7-12 membered spiro heterocyclic group, and the hetero atom of the spiro heterocyclic group is selected from one or a combination of two of O, S, and N, and contains at least one N.
  • Ring A is L phase is connected, S atom can be optionally oxidized to S(O) or S(O) 2 , C atom can be optionally oxidized to C(O);
  • the 7-12 membered spiro heterocyclic group is 7- 12-membered nitrogen-containing saturated spiro heterocyclic group; more preferably, 7-12 membered nitrogen-containing saturated spiro heterocyclic group is selected from the following groups:
  • R 2 is not hydrogen.
  • Ring A is selected from
  • R 2 is not hydrogen.
  • ring A is selected from
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • Each R 2 is independently selected from hydrogen, cyano, amino, halogen, carboxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 1-4 alkylcarbonyl, C 2-6 alkynyl, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 1-4 alkylaminocarbonyl, C 1-4 alkylthio, C 1-4 alkylsulfonyl , Cyclopropyl, azetidinyl, morpholinyl, piperazinyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 1-4 alkyl Carbonyl, C 2-6 alkynyl, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 1-4 alkylaminocarbonyl, C 1-4 alkylthio, C 1-4 alkyl Sulfonyl, cyclopropyl, azet
  • Ring A is selected from
  • n and n are independently 0, 1, or 2.
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • R 2 is selected from C 1-4 alkylaminocarbonyl, (C 1-4 alkyl) 2 aminocarbonyl;
  • Ring A is selected from
  • n 0;
  • n 0, 1, or 2.
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • R 2 is selected from hydrogen, amino, cyano, halogen, carboxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, aminocarbonyl, cyclopropyl, azetidine, morpholinyl and piperazinyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1 -4 alkylamino, (C 1-4 alkyl) 2 amino, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl, (C 1- 6 alkyl) 2 aminocarbonyl, C 1-4 al
  • Each R 1 is independently selected from hydrogen, hydroxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, pyrazolyl, thiazolyl, and triazolyl, wherein C 1 -6 alkyl, C 1-6 alkoxy, pyrazolyl, thiazolyl and triazolyl are unsubstituted or substituted by hydroxyl;
  • n 0, 1 or 2;
  • Ring A is selected from the following groups:
  • ring A is selected from
  • ring A is selected from
  • R 2 is not hydrogen.
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • L is -NH-(CH 2 )t- or bond, and t is 0, 1 or 2;
  • Ring A is aryl, preferably phenyl, naphthyl
  • R 2 is selected from hydrogen, amino, carboxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-6 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered nitrogen-containing heterocyclic group, C 1-6 alkylcarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl and aminocarbonyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-6 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3 -6 cycloalkyl, 4-6 membered nitrogen-containing heterocycl
  • Each R 1 is independently selected from hydrogen, hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl and C 1-6 alkoxy, the C 1-6 alkyl, C 1-6 alkoxy is unsubstituted or optionally substituted with a group selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl and C 1-6 alkoxy;
  • n 0, 1 or 2;
  • Some embodiments of the present invention relate to compounds represented by formula (I) or pharmaceutically acceptable salts and isomers thereof,
  • R 2 is selected from hydrogen, amino, carboxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-6 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered nitrogen-containing heterocyclic group, C 1-6 alkylcarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl and aminocarbonyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-6 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3 -6 cycloalkyl, 4-6 membered nitrogen-containing heterocycl
  • Ring A is a 6-12 membered heterocyclic group, and the hetero atom of the 6-12 membered heterocyclic group is selected from one of O, S, and N or any combination thereof;
  • Each R 1 is independently selected from hydrogen, hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, phenyl, and 5-6 membered heteroaryl,
  • the C 1-6 alkyl group, C 1-6 alkoxy group, phenyl group, and 5-6 membered heteroaryl group substituted by a substituent are unsubstituted or optionally selected from hydroxyl group, amino group, carboxyl group, cyano group, nitro group Group substitution, halogen, C 1-6 alkyl and C 1-6 alkoxy groups;
  • n 0, 1, 2;
  • ring A is a 9-10 membered heterocyclic group.
  • ring A is a 9-10 membered nitrogen-containing heterocyclic group.
  • ring A is selected from
  • the isomers of the compound represented by the general formula (I) refer to stereoisomers and tautomers.
  • the compound represented by the general formula (I) has a tautomer represented by the general formula (I’)
  • the tautomer is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • R 1 , R 2 , L, ring A and m are as described above;
  • R 2 is not hydrogen
  • R 2 is not hydrogen.
  • R 2 is bromo, methyl, ethyl, propyl, isopropyl, isopropyl substituted with hydroxy, methylaminocarbonyl, or methyl substituted with hydroxy and cyclopropyl (or Ethyl, or propyl, or butyl), or ethoxy substituted by methoxy.
  • Ring A is selected from m is 0; n(R 2 ) is bromo, methyl, ethyl, propyl, isopropyl, isopropyl substituted by hydroxy, methylaminocarbonyl, or methyl substituted by hydroxy and cyclopropyl ( Or ethyl, or propyl, or butyl), or ethoxy substituted by methoxy.
  • the present invention also provides a pharmaceutical composition containing the compound represented by the aforementioned formula (I) or formula (II) or a pharmaceutically acceptable salt, isomer thereof, and one or more second therapeutically active agents.
  • the composition may be a "therapeutically effective amount" of the compound represented by the aforementioned formula (I) or formula (II) or a pharmaceutically acceptable salt or isomer thereof, It is used in combination with one or more second therapeutically active agents, such as sequential administration, simultaneous administration, or the compound provided by the present invention or a pharmaceutically acceptable salt, isomer and second The therapeutic active agent is administered as a compound preparation.
  • the second therapeutically active agent is an acetylcholinesterase inhibitor, amyloid- ⁇ (or a fragment thereof), an antibody to amyloid- ⁇ (or a fragment thereof), an amyloid-lowering or inhibitory agent, ⁇ -adrenal Receptor antagonists, ⁇ -adrenergic receptor blockers, anticholinergics, anticonvulsants, tranquilizers, calcium channel blockers, catechol-O transmethylase inhibitors, central nervous system Stimulators, corticosteroids, dopamine receptor agonists, dopamine receptor antagonists, dopamine reuptake inhibitors, gamma-aminobutyric acid receptor agonists, immunomodulators, immunosuppressants, interferons, levodopa, N-methyl-D aspartate receptor antagonists, monoamine oxidase inhibitors, muscarinic receptor agonists, nicotinic receptor agonists, neuroprotective drugs, norepinephrine (norepine
  • PDE9 inhibitors and “other phosphodiesterase (PDE) inhibitors” refer to drugs under investigation or marketed that have proven to be active against PDE9 or PDE.
  • the present invention also provides a pharmaceutical preparation containing the compound represented by the aforementioned formula (I) or formula (II) or a pharmaceutically acceptable salt or isomer thereof.
  • the pharmaceutical formulation may contain one or more pharmaceutically acceptable carriers.
  • the pharmaceutical carrier of the present invention may be one or more solid or liquid fillers or gel substances suitable for human use.
  • the pharmaceutical carrier preferably has sufficient purity and sufficiently low toxicity, and is compatible with the compound provided by the present invention or its pharmaceutically acceptable salts and isomers without significantly reducing its efficacy.
  • the pharmaceutical carrier may be a filler, binder, disintegrant, lubricant, aqueous solvent or non-aqueous solvent.
  • the pharmaceutical preparation of the present invention can be made into any pharmaceutically acceptable dosage form, and can be administered to patients in need of such treatment by any suitable means of administration, such as oral, parenteral, rectal, or pulmonary administration. Or subject.
  • oral administration it can be made into tablets, capsules, pills, granules, etc.
  • parenteral administration it can be made into injections, sterile powders for injection, etc.
  • the present invention also provides the compound represented by the aforementioned formula (I) or formula (II) or a pharmaceutically acceptable salt, isomer, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in preparation for treatment or prevention by PDE9-mediated
  • the related diseases mediated by PDE9 are cognitive impairments caused by disorders of the central nervous system; more specifically, the cognitive impairments include: perception, attention, Impaired memory and learning; including but not limited to Alzheimer's disease, schizophrenia, age-related memory loss, vascular dementia, craniocerebral trauma, stroke, dementia after stroke, dementia after trauma, general attention impairment, children Attention impairment with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies, dementia with frontal lobe, dementia with cortical basal ganglia, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, thalamus degeneration, dementia Jia's dementia, HIV dementia, schizophrenia, Korsakov psychosis or depression and bipolar disorder.
  • the present invention also provides the use of the compound represented by the aforementioned formula (I) or formula (II) or a pharmaceutically acceptable salt, isomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the treatment or prevention of disease .
  • the present invention also provides that the compound represented by the aforementioned formula (I) or formula (II) or a pharmaceutically acceptable salt, isomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition is mediated by PDE9 in the treatment or prevention Use in related diseases; specifically, the PDE9-mediated related diseases are cognitive impairments caused by disorders of the central nervous system; more specifically, the cognitive impairments include: perception, attention, memory, and learning Impairment; including but not limited to Alzheimer's disease, schizophrenia, age-related memory loss, vascular dementia, craniocerebral trauma, stroke, dementia after stroke, dementia after trauma, general attention impairment, children's attention impairment With learning and memory problems, Alzheimer's disease, dementia with Lewy bodies, dementia with frontal lobe degeneration, dementia with cortical basal ganglia, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, thalamus degeneration, Kujia dementia , HIV dementia, schizophrenia, Korsakov psychosis or depression or bipolar
  • the present invention also provides a method for treating or preventing diseases, which method comprises administering to a patient in need thereof a therapeutically effective amount of the compound represented by the aforementioned formula (I) or formula (II) or a pharmaceutically acceptable salt thereof , Isomers, the aforementioned pharmaceutical preparations or the aforementioned pharmaceutical compositions; the diseases are related diseases mediated by PDE9; specifically, the related diseases mediated by PDE9 are cognitive impairment caused by disorders of the central nervous system; More specifically, the cognitive impairment includes: impaired perception, attention, memory and learning; including but not limited to Alzheimer's disease, schizophrenia, age-related memory loss, vascular dementia, craniocerebral trauma, stroke, Dementia after stroke, dementia after trauma, general attention impairment, attention impairment in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies, dementia with frontal lobe degeneration, dementia with cortical basal ganglia, muscular atrophy Lateral sclerosis, Huntington's disease, multiple sclerosis, thalamus degeneration, Ku
  • halogen in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine, chlorine.
  • halo in the present invention means that any hydrogen atom in the substituent may be substituted by one or more halogen atoms which are the same or different.
  • Halogen is as defined above.
  • C 1-6 alkyl group refers to a linear or branched alkyl group derived from a hydrocarbon portion containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohex Group, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, and 1-methylmethyl, ethyl,
  • C 2-8 alkenyl group refers to a linear or branched or cyclic alkenyl group derived from an olefin portion of 2 to 8 carbon atoms containing a carbon-carbon double bond by removing one hydrogen atom, such as a vinyl group , 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 1,4-hexadienyl.
  • a vinyl group 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 1,4-hex
  • C 2-8 alkynyl group in the present invention refers to a linear or branched alkynyl group derived from an alkyne group containing 2 to 8 carbon atoms with a carbon-carbon triple bond removed by one hydrogen atom, such as ethynyl and propylene Alkynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl and the like.
  • C 1-6 alkoxy group refers to the group defined as the "C 1-6 alkyl group” connected to the parent molecule through an oxygen atom, that is, “C 1-6 alkyl-O- "Groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, etc.
  • the "C 1-4 alkoxy group” refers to the above example containing 1-4 carbon atoms, that is, a "C 1-4 alkyl-O-" group.
  • C 1-6 alkylamino "(C 1-6 alkyl) 2 amino", “C 1-6 alkylcarbonylamino”, “C 1-6 alkylsulfonylamino” described in the invention
  • the "condensed ring” in the present invention refers to a multi-ring system structure formed by two or more ring structures connected by a union, a spiro, and a bridge.
  • the fused ring refers to a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms with each other (that is, sharing a bond).
  • the bridged ring refers to a fused ring structure formed by two or more ring-mounted structures sharing two non-adjacent ring atoms with each other.
  • the spiro ring refers to a condensed ring structure formed by two or more ring structures sharing one ring atom with each other.
  • the "3-12 membered cycloalkenyl group" described in the present invention includes all monocyclic and condensed rings (including condensed in the form of dimer, spiro and bridge) that may be formed unless otherwise specified, for example 3-8 membered monocyclic olefins, 7-11 membered spirocycloolefins, 7-11 membered paracycloolefins, 6-11 membered bridged cycloolefins, etc
  • the cycloalkyl group described in the present invention includes all possible monocyclic and fused rings (including fused in the form of mer, spiro, and bridge); for example, "3-12 membered cycloalkyl" may be monocyclic, Bicyclic or polycyclic cycloalkyl systems (also called fused ring systems). Unless otherwise specified, a single ring system is a cyclic hydrocarbon group containing 3-8 carbon atoms. Examples of 3-8 membered cycloalkyls include, but are not limited to: cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, and the like.
  • the fused ring cycloalkyl includes paracycloalkyl, bridged cycloalkyl, and spirocycloalkyl.
  • Cyclocycloalkyl can be 6-11 membered cyclic cycloalkyl, 7-10 membered cyclic cycloalkyl, and representative examples thereof include but are not limited to bicyclo[3.1.1]heptane, bicyclo[2.2.1 ] Heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane.
  • the spirocyclic group may be a 7-12 membered spirocyclic group or a 7-11 membered spirocyclic group. Examples include but are not limited to:
  • the bridge ring group may be a 6-11 member bridge ring group or a 7-10 member bridge ring group. Examples include but are not limited to:
  • heterocyclic group in the present invention refers to a non-aromatic cyclic group in which at least one ring carbon atom of 3-12 members is replaced by a hetero atom selected from O, S, and N, preferably 1 to 3 hetero groups Atoms, including carbon atoms, nitrogen atoms and sulfur atoms can be oxo.
  • 3-12 membered heterocyclic group means a monocyclic heterocyclic group, a bicyclic heterocyclic group system or a polycyclic heterocyclic group system (also referred to as a fused ring system), including saturated and partially saturated heterocyclic groups, but Does not include aromatic rings. Unless otherwise specified, it includes all possible formation of single rings, fused rings (including fused in the form of merges, spiro, bridges), saturated, partially saturated.
  • the single heterocyclic group may be 3-8 membered heterocyclic group, 3-8 membered saturated heterocyclic group, 3-6 membered heterocyclic group, 4-7 membered heterocyclic group, 5-7 membered heterocyclic group, 5-6 Member heterocyclic group, 5-6 member oxygen-containing heterocyclic group, 3-8 member nitrogen-containing heterocyclic group, 5-6 member nitrogen-containing heterocyclic group, 5-6 member saturated heterocyclic group and the like.
  • "3-8" member saturated heterocyclic group examples of which include, but are not limited to, aziridine, oxepanyl, thietane, azetidine, oxetanyl, sulfur Heterocyclobutane, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazole Alkyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxane Alkyl, 1,4-oxathiocyclohexyl; "3-8" partially saturated heterocyclic, examples of which include but are not limited to 4,5-dihydroisoxazoly
  • the fused heterocyclic ring includes a heterocyclic group, a spiro heterocyclic group, and a bridged heterocyclic group, and may be saturated, partially saturated, or unsaturated, but not aromatic.
  • a fused heterocyclic group is fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group, or a 5-6 membered monocyclic heteroaryl group 5-6 membered monocyclic heterocyclyl ring.
  • the heterocyclic group may be a 6-12 membered cyclic group, a 7-10 membered cyclic group, a 6-10 membered cyclic group, a 6-12 membered saturated cyclic group, and representative examples include but are not limited to: 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptane, 3,8-diazabicyclo[4.2.0]octyl, 3, 7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3, 4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydro Benz
  • the spiro heterocyclic group may be a 6-12 membered spiro heterocyclic group, a 7-11 membered spiro heterocyclic group, a 6-12 membered saturated spiro heterocyclic group, examples of which include but are not limited to:
  • the bridged heterocyclic group may be a 6-12 membered bridged heterocyclic group, a 7-11 membered bridged heterocyclic group, a 6-12 membered saturated bridged ring group, and examples thereof include but are not limited to:
  • aryl group in the present invention refers to a cyclic aromatic group containing 6-14 carbon atoms, including phenyl, naphthalene, phenanthrene and the like.
  • heteroaryl group in the present invention includes all monocyclic, condensed, fully aromatic and partially aromatic cases that may be formed.
  • “5-10 membered heteroaryl” refers to an aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1 to 3 heteroatoms, including carbon atoms 1.
  • Sulfur atom is replaced by oxo, for example, carbon atom is replaced by C(O)
  • sulfur atom is replaced by S(O)
  • Heteroaryl groups include monoheteroaryl groups and fused heteroaryl groups.
  • monoheteroaryl groups may be 5-7 membered heteroaryl groups and 5-6 membered heteroaryl groups, examples of which include but are not limited to Furanyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazole Group, thiadiazolyl, thienyl, triazolyl and triazinyl.
  • the fused heteroaryl group refers to a group formed by condensing a monocyclic heteroaryl ring to a phenyl group, a cycloalkenyl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group.
  • the fused heteroaryl group may be 8-12 membered heteroaryl, 9-10 membered heteroaryl, examples include but are not limited to benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzothiadiyl Oxazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indole , Isoindolyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydro Quinolinyl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl
  • the "pharmaceutically acceptable salt” in the present invention refers to a pharmaceutically acceptable addition salt of acid and base or a solvate thereof.
  • Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid , Hydroiodic acid, alkanoic acid (such as acetic acid, HOOC- (CH 2 ) n-COOH (where n is 0 ⁇ 4)) and so on.
  • Alkali salts sodium salt, potassium salt, calcium salt, ammonium salt, etc.
  • the “isomer” in the present invention refers to stereoisomers and tautomers.
  • Stereoisomers mean that when a compound has an asymmetric carbon atom, it will produce an enantiomer; when a compound has a carbon-carbon double bond or a cyclic structure, it will produce a cis-trans isomer; all compounds of formula (I)
  • the enantiomers, diastereomers, racemates, cis-trans isomers, geometric isomers, epimers and mixtures thereof are all included in the scope of the present invention.
  • Tautomer refers to a functional group isomer due to the rapid movement of an atom in a molecule at two positions.
  • a tautomer is a special functional group isomer. Such as tautomerization of carbonyl compounds containing ⁇ -H, as Such as other proton migration tautomerism, specifically phenol-ketone tautomerism, nitroso-oxime tautomerism, imine-enamine tautomerism.
  • T, T1, and T2 are each independently any group that conforms to the bonding rule of the compound.
  • the compound of the present invention contains a lactam structure and exists Tautomerism, when referring to a compound of the invention, means that the tautomer of the compound is also mentioned.
  • the “therapeutically effective amount” in the present invention refers to the amount of the aforementioned compound or its pharmaceutically acceptable salt, isomer, composition or pharmaceutical preparation that can at least alleviate the symptoms of the patient's condition when administered to the patient.
  • the actual amount containing a "therapeutically effective amount” will vary depending on a variety of conditions, including but not limited to the specific condition being treated, the severity of the condition, the patient's physical and health status, and the route of administration. Skilled medical practitioners can easily determine the appropriate amount using methods known in the medical field.
  • the compound of the present invention can be prepared by various methods including standard chemical methods. Unless otherwise noted, any previously defined variables will continue to have the previously defined meaning. Exemplary general synthetic methods are described in the following schemes, and can be easily modified to prepare other compounds of the present invention. The specific compounds of the invention are prepared in the Examples section.
  • the compound of formula (I) can be prepared by a compound of formula (I-d) and a compound of formula (I-e) through a metal-catalyzed coupling or aromatic nucleophilic substitution reaction, as follows:
  • the compound of formula (I-d) can be prepared by the action of the compound of formula (I-c) with a halogenated reagent, substituted or unsubstituted sulfonyl chloride or sulfonic anhydride, as follows:
  • the compound of formula (I-c) can be prepared by ring closure of the compound of formula (I-b) under the action of a suitable base, as follows:
  • the compound of formula (I-b) can be prepared by reacting the compound of formula (I-a) with cyanoacetic acid under the action of a suitable peptide coupling agent, as follows:
  • R 1 , R 2 , A, L, m and n are as defined above, Ra 1 is selected from hydrogen or C 1-6 alkyl, X is selected from halogen, substituted or unsubstituted benzenesulfonate, C 1-6 alkylsulfonate, trifluoromethanesulfonate, etc.
  • the compound of formula (I) can be passed through a metal-catalyzed coupling reaction of the compound of formula (Ij) with a suitable reagent containing an R 2 group, or the compound of formula (Ij) can be passed with a suitable reagent After the metal-catalyzed coupling reaction, it is prepared by one or more steps of conventional chemical reaction conversion (such as oxidation, reduction, addition, substitution, hydrogenation, chlorination, amination, etc.), as follows:
  • the compound of (I-j) can be prepared by reacting the compound of formula (I-i) with the compound of formula (I-e) by aromatic nucleophilic substitution, etc., as follows:
  • the compound of formula (I-i) can be prepared by the action of the compound of formula (I-h) with a halogenated reagent, substituted or unsubstituted sulfonyl chloride or sulfonic anhydride, as follows:
  • the compound of formula (I-h) can be prepared by ring closure of the compound of formula (I-g) under the action of a suitable base, as follows:
  • the compound of formula (I-g) can be prepared by reacting the compound of formula (I-f) with cyanoacetic acid under the action of a suitable peptide coupling agent, as follows:
  • R 1 , R 2 , A, L, m, n, Ra 1 and X are as defined above, and X 2 is selected from bromine or iodine.
  • Halogenated reagents refer to reagents used for halogenation reactions, including but not limited to N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, dibromide
  • phosphorus tribromide phosphine trichloride, sulfoxide chloride, phosphorus oxychloride, phosphorus pentachloride or phosphorus oxybromide.
  • Suitable bases include organic bases and inorganic bases.
  • organic bases include but are not limited to sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, LiHMDS, N,N-diisopropylethylamine, triethylamine, lithium diisopropylamide, etc.
  • inorganic bases include but are not limited to sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, magnesium hydroxide, calcium hydroxide, and the like.
  • Substituted or unsubstituted sulfonyl chloride refers to Ra 2 -SO 2 Cl.
  • the substituted or unsubstituted sulfonic anhydride refers to (Ra 2 -SO 2 ) 2 -O.
  • Ra 2 is selected from C 1-6 alkyl, C 1-6 haloalkyl, substituted or unsubstituted aryl, and the like.
  • Peptide coupling agent refers to a reagent capable of activating carboxylic acid and amine to form an amide, including but not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-( 7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate, N,N '-Carbonyldiimidazole, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, propylphosphonic anhydride, carbodiimide, etc.
  • DCM dichloromethane
  • DMF means N,N-dimethylformamide
  • DIPEA means N,N-diisopropylethylamine
  • PE means petroleum ether
  • EA Refers to ethyl acetate
  • EDCI refers to carbodiimide
  • HATU refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexa Fluorophosphate
  • THF means tetrahydrofuran.
  • Step 2 Synthesis of ethyl 5-bromo-2-(2-cyanoacetamido)benzoate
  • Step 6 Synthesis of 6-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile:
  • Step 4 Synthesis of 3-cyano-2-oxo-4-(6-azaspiro[2.5]octan-6-yl)-1,2-dihydroquinoline-6-carboxylic acid
  • Step 1 Synthesis of 4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-6-vinyl-1,2-dihydroquinoline-3-carbonitrile
  • Example 6 product 6-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile (20g, 0.053mol, 1.0eq) was dissolved in a mixed solvent of 1,4-dioxane (300mL) and water (80mL), and potassium trifluoro(vinyl) borate (10.68g, 0.08mmol, 1.5eq) was added ), cesium carbonate (51.8g, 0.159mol, 3.0eq) after nitrogen replacement, then add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.886mg, 5.3mmol, 0.1 eq), reaction at 100°C for 3 hours under nitrogen protection, LC-MS detection complete reaction, liquid separation, the aqueous phase was extracted with dichloromethane (200mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated
  • Step 1 Synthesis of 4-(4-methoxy-4-methylpiperidin-1-yl)-6-methyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile
  • Example 6 product 6-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile (500mg, 1.33mmol, 1.0eq) dissolved in a mixed solvent of 1,4-dioxane (5mL) and water (1mL), and added cesium carbonate (1.3g, 3.98mol, 3.0eq) and [1,1 '-Bis(diphenylphosphino)ferrocene]palladium dichloride (97mg, 0.133mmol, 0.1eq), after nitrogen substitution, trimethylcyclotriboroxane (50% THF solution, 1.33g, 5.31mmol, 4.0eq), under nitrogen protection at 100 °C for 12 hours, LC-MS detection of the reaction was complete, liquid separation, the aqueous phase was extracted with ethyl acetate (200mL ⁇ 3), the organic phase was combined, dried over anhydrous sodium sulfate,
  • Step 1 4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-6-(prop-1-en-2-yl)-1,2-dihydroquine Porphyrin-3-carbonitrile synthesis
  • Example 6 product 6-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile (500mg, 1.33mmol, 1.0eq) was dissolved in a mixed solvent of 1,4-dioxane (5mL) and H 2 O (1mL), and potassium trifluoro(prop-1-en-2-yl) borate was added (295mg, 2.0mmol, 1.5eq), cesium carbonate (1.3g, 4.0mmol, 3.0eq) was replaced with nitrogen and then added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (97mg , 0.13mmol, 0.1eq), under nitrogen conditions at 100 °C for 12 hours, LC-MS detection reaction was complete.
  • Step 2 Synthesis of 6-isopropyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile
  • Step 1 6-(1,2-dihydroxyethyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoline Synthesis of -3-carbonitrile
  • Example 3 Step 1 product 4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-6-vinyl-1,2-dihydroquinoline-3-methyl Nitrile (14g, 0.043mol, 1.0eq) was dissolved in a mixed solvent of tert-butanol (280mL) and water (280mL), and methanesulfonamide (4.11g, 0.043mol, 1.0eq) AD-mix (168g) was added at room temperature After 12 hours of reaction, LC-MS detects that the reaction is complete, and is used directly in the next step without treatment.
  • Tetrahydrofuran 200 mL was added to the reaction bottle in the previous step, and sodium periodate (36.9 g, 0.17 mol, 4.0 eq) was added, and the reaction was performed for 24 hours.
  • the reaction was detected by LC-MS.
  • Dichloromethane 200 mL was added, stirred for 30 min, filtered, and separated.
  • the aqueous phase was extracted with dichloromethane (200 mL ⁇ 2).
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 4 Synthesis of 6-acetyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile
  • Step 5 6-(2-Hydroxypropan-2-yl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoline Synthesis of -3-carbonitrile
  • Step 1 6-(cyclopropyl(hydroxy)methyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoline Synthesis of -3-carbonitrile
  • Example 6 product 6-formyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoline-3-methyl Nitrile (500mg, 1.54mmol, 1.0eq) was dissolved in tetrahydrofuran (10mL), cyclopropylmagnesium bromide (2.3mL, 2.3mmol, 1.5eq) was added dropwise at -30°C, the reaction was performed for 3 hours, and the reaction was detected by LC-MS. . Water (10 mL) was added, extracted with dichloromethane (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 7 4-(4-methoxy-4-methylpiperidin-1-yl)-6-(2-methoxyethoxy)-2-oxo-1,2-dihydroquinoline Synthesis of -3-carbonitrile
  • Test article The compound of the present invention was prepared from the corresponding example of the present invention.
  • PDE9A2 enzyme (BPS, Cat. No. 60090)
  • Compound preparation The compound was prepared into a 10 mM compound storage solution for long-term storage with DMSO, diluted 100-fold with DMSO to obtain a 100 ⁇ M compound working mother solution, and then DMSO was used to dilute the compound working mother solution 3-fold to obtain a total of 8-10 concentration gradient compound dilution mother solutions ( 100 ⁇ ).
  • Additive incubation Use the Echo liquid pipetting system Echo to transfer the compound dilution mother solution to a 384-well plate; add 200 nL compound dilution mother solution and 10 ⁇ L PDE9A2 enzyme solution to each compound well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 15 min. Subsequently, 10 ⁇ L of the substrate mixture was added, and after centrifugation at 1000 rpm for 1 min, it was incubated at room temperature with shaking for 30 min. Finally, stop solution was added to stop the reaction system, and incubated at room temperature for 60 min with shaking. In the maximum reading well (Max), the solvent is used to replace the compound; in the minimum reading well (Min), the solvent and compound are replaced by the solvent.
  • Max maximum reading well
  • Min the solvent is used to replace the compound
  • Min the solvent and compound are replaced by the solvent.
  • Detection Use a microplate reader to detect the fluorescence reading (F) at 480nm/535nm.
  • Test object PDE9A2 IC 50 (nM) Compound 96 5 Compound 107 8 Compound 109 15 Compound 130 2 Compound 145 12 Compound 158 12 Compound 179 18 Compound 180 8
  • the compound of the invention has very good PDE9 enzymatic inhibitory activity and has potential clinical application value.
  • Test object The compound of the present invention and the compound I-8 of the international patent application WO2017019723A1 (prepared according to the synthesis examples in WO2017019723A1), the structural formula is as follows:
  • composition of the incubation system is the composition of the incubation system:
  • liver microsomes (20 mg protein/mL) from the -80°C refrigerator, place on a 37°C water bath constant temperature oscillator and pre-incubate for 3 min.
  • Control group (without ⁇ -NADPH): 30 ⁇ L of water and 30 ⁇ L of compound working solution (10 ⁇ M) were added to 240 ⁇ L of the mixed solution of the incubation system described in step (2), vortexed for 30s, mixed well, the total reaction A volume of 300 ⁇ L, 2 parallel samples. Place in a 37°C water bath constant temperature oscillator for incubation and start timing. The sampling time points are 0min and 60min.
  • Sample group 70 ⁇ L ⁇ -NADPH solution (10mM) and 70 ⁇ L compound working solution (10 ⁇ M) were added to the 560 ⁇ L mixed solution described in step (2), the total reaction volume was 700 ⁇ L, vortexed for 30s, mixed, parallel sample 2 Copies. Place in a 37°C water bath thermostat for incubation and start timing. The sampling time points are 0min, 5min, 10min, 20min, 30min, 60min after timing.
  • k is the slope of the log of the remaining amount of the compound plotted against time
  • V d is the apparent volume of distribution
  • C 0 is the drug concentration at 0 h.
  • the compounds of the present invention have a lower clearance rate in rat liver microsomes than the prior art compounds.

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Abstract

本发明属于医药技术领域，具体涉及式(I)所示的PDE9抑制剂化合物或其药学上可接受的盐、异构体，本发明还涉及这些化合物的药物制剂、药物组合物及其应用。R1、R2、环A、L、m和n如说明书中所定义。本发明化合物可用于制备治疗或者预防由PDE9介导的相关疾病的药物。

Description

PDE9抑制剂及其用途 技术领域
本发明属于医药技术领域，涉及式(I)所示的磷酸二酯酶9抑制剂，或其药学上可接受的盐、异构体及其应用。
背景技术
磷酸二酯酶(phosphodiesterase,PDEs)是一类蛋白酶，能选择性的降解体内重要的第二信使cGMP(环磷酸鸟苷)和cAMP(环磷酸腺苷)，从而参与体内重要的生理过程。依据基因的序列同源性和对cGMP或cAMP的选择性，PDEs可分为(PDE1～PDE11)11个成员。其中，PDE9A是PDE家族中的重要一员，其广泛表达于睾丸、大脑、小肠、骨肌、心脏、肺、胸腺和胰脏。随着近几年的研究深入，已有多篇文献报道和临床数据证明，PDE9A抑制剂用于治疗由于中枢神经系统紊乱导致的认知损害方面的疾病，比如老年痴呆症和精神分裂症、大脑的神经变性过程疾病。
cAMP和cGMP这两种核苷酸是重要的第二信使，在细胞信号传导过程中起着核心作用；它们主要活化蛋白激酶：由cAMP激活的称作蛋白激酶A(PKA)，由cGMP激活的称作蛋白激酶G(PKG)。被激活的PKA和PKG可以磷酸化许多细胞效应蛋白，比如离子通道、G-蛋白耦联受体、结构蛋白、传导因子。因此，cAMP和cGMP通过这种方式可能控制许多器官中的大多数生理过程。同时，cAMP和cGMP也可以直接作用于效应蛋白，从而起到上述相同的作用。众所周知，cGMP可以直接作用于离子受体，从而影响细胞中的离子浓度。磷酸二酯酶(PDEs)水解环状单磷酸酯cAMP和cGMP，将其转化为失活的单磷酸酯AMP和GMP。
人类的PDE9最早在1998年被克隆和测序，是迄今为止报道的对cGMP选择性最高的PDE。PDE9与cGMP的结合常数(Km)为170nM，而对cAMP的结合常数值高达230000nM，选择性超过1000倍。和PDE2A及PDE5A比较，由于PDE9没有cGMP的结合区域，因此PDE9的催化活性并不会被cGMP增强，所以PDE9抑制剂可能提高基线cGMP浓度。
传统的PDE抑制剂不能抑制人类PDE9，因此，药物IBMX、dipyridamole、SKF94120、rolipram和vinpocetine对PDE9没有抑制活性或者很低。
目前市场上没有PDE9抑制剂药物，只有一些正在处于临床研发阶段的抑制剂，例如Pfizer公司的PF-04447943(WO2008139293A1，实施例111)和BI公司的BI-409306(WO2009121919A1，Exp.51)两类PDE9抑制剂，目前两个化合物正处于I期和II期临床阶段。
另外，Merck也在专利WO2017019723A1、WO2017019726A1和WO2017019724A1中报道了一些具有PDE9抑制作用的化合物。如专利WO2017019723A1中的化合物I-8，其结构如下：
Figure PCTCN2020070707-appb-000001
发明内容
本发明的一个目的是提供一类用作PDE9蛋白酶抑制剂的化合物，或其药学上可接受的盐、异构体，本发明化合物具有良好的PDE9蛋白酶抑制活性、选择性和成药性(如较高的肝微粒体稳定性)，能够治疗或者预防由PDE9介导的相关疾病，可在中枢神经系统紊乱导致的认知损害方面的疾病的治疗方面发挥重要的作用。
本发明的技术方案如下：
通式(I)所示的化合物或其药学上可接受的盐、异构体：
Figure PCTCN2020070707-appb-000002
每个R 2分别独立地选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元杂环基、C 1-6烷羰基、氨基羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基、芳基、5-6元杂芳基、4-6元杂环基羰基和5-6元杂芳基-氧基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元杂环基、C 1-6烷羰基、氨基羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基、芳基、5-6元杂芳基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、C 1-6烷羰氧基、C 3-6环烷基、C 2-8炔基、卤代C 1-6烷基、C 2-8烯基、卤代C 1-6烷氧基、未被取代或任选被取代基取代的4-6元杂环基、未被取代或任选被取代基取代的杂芳基的基团取代；
上述任选被取代基取代的4-6元杂环基、任选被取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基和C 1-6烷氧基；
L为键、-NH-(CH 2)t-，t为0、1、2或3；
环A为3-8元单杂环基、6-12元桥杂环基、6-12元螺杂环基、6-12元并杂环基、芳基、5-10元杂芳基、3-12元环烷基、3-12元环烯基，其中所述杂环基的杂原子选自O、S、N中的一种或其任意组合，S原子可任选被氧化为S(O)或S(O) 2，C原子可 任选被氧化为C(O)，所述5-10元杂芳基的杂原子选自O、S、N中的一种或其任意组合；
每个R 1分别独立地选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基和C 1-6烷基磺酰氨基的基团取代；
m和n分别独立地为0、1、2或3；
当环A为3-8元单杂环基时，R 2不为氢；
当环A为苯基时，L不为键；
当环A为
Figure PCTCN2020070707-appb-000003
时，R 2不为氢。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
每个R 2分别独立地选自氢、氨基、羧基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基未被取代和任选被一至多个独立选自羟基、氨基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷羰氧基、C 3-6环烷基、未被取代和任选被C 1-6烷基取代的4-6元杂环基的基团取代；
L为键；
环A为3-8元单杂环基、6-12元桥杂环基、6-12元螺杂环基、6-12元并杂环基、苯基、5-10元杂芳基，所述杂环基的杂原子选自O、S、N中的一种或其任意组合，S原子可任选被氧化为S(O)或S(O) 2，C原子可任选被氧化为C(O)；
每个R 1分别独立地选自氢、羟基、氰基、卤素、C 1-6烷基、C 1-6烷氧基和5-6元杂芳基，其中所述C 1-6烷基、C 1-6烷氧基和5-6元杂芳基未被取代或被羟基取代；
m和n分别独立地为0、1、2；
当环A为3-8元单杂环基时，R 2不为氢；
当环A为苯基时，L不为键；
当环A为
Figure PCTCN2020070707-appb-000004
时，R 2不为氢。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
每个R 2分别独立地选自氢、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨羰基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨羰基未被取代或任选被一至多个独立选自羟基、C 1-6烷氧基、C 3-6环烷基的基团取代；
L为键；
环A为3-8元单杂环基、6-12元螺杂环基，其中所述元杂环基的杂原子选自O、S、N中的一种或其任意组合，S原子可任选被氧化为S(O)或S(O) 2，C原子可任选被氧化为C(O)；
每个R 1分别独立地选自氢、C 1-6烷基、C 1-6烷氧基；
m和n分别独立地为0、1、2或3；
当环A为3-8元单杂环基时，R 2不为氢；
当环A为
Figure PCTCN2020070707-appb-000005
时，R 2不为氢。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
L为键；
环A为4-7元单杂环基，所述4-7元单杂环基的杂原子选自O、S、N中的一种或两种的组合，且至少含有一个N，环A通过N原子与L相连接，S原子可任选被氧化为S(O)或S(O) 2，C原子可任选被氧化为C(O)；
优选地，环A为4-7元含氮饱和单杂环基，进一步优选为：
Figure PCTCN2020070707-appb-000006
更进一步优选为
Figure PCTCN2020070707-appb-000007
Figure PCTCN2020070707-appb-000008
每个R 2分别独立地选自卤素、C 1-4烷基、C 1-4烷氧基、吗啉基、C 2-6烯基、C 1-4烷羰基、C 1-4烷氨羰基、(C 1-4烷基) 2氨羰基和氨基羰基，其中所述C 1-4烷基、C 1-4烷氧基、吗啉基、C 2-6烯基、C 1-4烷羰基、C 1-4烷氨羰基、(C 1-4烷基) 2氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、氨基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、未被取代或任选被C 1-4烷基取代的4-6元杂环基的基团取代；
每个R 1分别独立地选自氢、卤素、C 1-4烷基、C 1-4烷氧基、吡唑基、噻唑基和三唑基，基中所述C 1-4烷基、C 1-4烷氧基、吡唑基、噻唑基和三唑基未被取代或被羟基取代；
m和n分别独立地为0、1或2。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
每个R 2分别独立地选自卤素、C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 1-4烷羰基、C 1-4烷氨羰基和氨基羰基，其中所述C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 1-4烷羰基、C 1-4烷氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、C 1-4烷基、C 1-4烷氧基、环丙基和未被取代或任选被C 1-4烷基取代的4-6元杂环基的基团取代；
L为键；
环A为
Figure PCTCN2020070707-appb-000009
每个R 1分别独立地选自氢、C 1-4烷基和C 1-4烷氧基；
m和n分别独立地为0、1或2。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
每个R 2分别独立地选自卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨羰基，其中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷氨羰基未被取代或任选被一至多个独立选自羟基、C 1-4烷氧基、环丙基的基团取代；
L为键；
环A为
Figure PCTCN2020070707-appb-000010
每个R 1分别独立地选自氢、C 1-4烷基和C 1-4烷氧基；
m和n分别独立地为0、1或2。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
每个R 2分别独立地选自氨基、羧基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷羰氧基、C 3-6环烷基和未被取代或被C 1-6烷基取代的4-6元杂环基的基团取代；
L为键；
环A为
Figure PCTCN2020070707-appb-000011
每个R 1分别独立地选自吡唑基、噻唑基和三唑基。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
其中，L为键；
每个R 2分别独立地选自氢、氨基、氰基、卤素、羧基、C 1-4烷基、C 1-4烷氧基、C 1-4烷羰基、C 2-6炔基、C 1-4烷氨羰基、(C 1-4烷基) 2氨羰基、C 1-4烷基硫基、C 1-4烷基磺酰基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、氮杂环丁烷基、吗啉基、哌嗪基、C 2-6烯基和环丙基，基中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷羰基、C 2-6炔基、C 1-4烷氨羰基、(C 1-6烷基) 2氨羰基、C 1-4烷基硫基、C 1-4烷基磺酰基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、氮杂环丁烷基、吗啉基、哌嗪基、C 2-6烯基和环丙基未被取代或任选被一至多个独立选自羟基、氨基、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、环丙基和C 1-4烷羰氧基的基团取代；
环A为7-12元螺杂环基，所述螺杂环基的杂原子选自O、S、N中的一种或两种的组合，且至少含有一个N，环A通过N原子与L相连接，S原子可任选被氧化为S(O)或S(O) 2，C原子可任选被氧化为C(O)；优选地，7-12元螺杂环基为7-12元含氮饱和螺杂环基；更优选地，7-12元含氮饱和螺杂环基选自如下基团：
Figure PCTCN2020070707-appb-000012
当环A为
Figure PCTCN2020070707-appb-000013
时，R 2不为氢。
在一些实施方式中，环A选自
Figure PCTCN2020070707-appb-000014
Figure PCTCN2020070707-appb-000015
当环A为
Figure PCTCN2020070707-appb-000016
时，R 2不为氢。
进一步优选地，环A选自
Figure PCTCN2020070707-appb-000017
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
每个R 2分别独立地选自氢、氰基、氨基、卤素、羧基、C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 1-4烷羰基、C 2-6炔基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷氨羰基、C 1-4烷基硫基、C 1-4烷基磺酰基、环丙基、氮杂环丁烷基、吗啉基、哌嗪基，其中所述C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 1-4烷羰基、C 2-6炔基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷氨羰基、C 1-4烷基硫基、C 1-4烷基磺酰基、环丙基、氮杂环丁烷基、吗啉基、哌嗪基未被取代或任选被一至多个独立选自羟基、氨基、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、环丙基、C 1-4烷羰氧基的基团取代；
L为键；
环A选自
Figure PCTCN2020070707-appb-000018
m和n分别独立地为0、1或2。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
R 2选自C 1-4烷氨羰基、(C 1-4烷基) 2氨羰基；
L为键；
环A选自
Figure PCTCN2020070707-appb-000019
m为0；
n为0、1或2。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
R 2选自氢、氨基、氰基、卤素、羧基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 2-6烯基、C 2-6炔基、C 1-4烷羰基、C 1-4烷氨羰基、(C 1-6烷基) 2氨羰基、C 1-4烷基磺酰基、C 1-4烷基硫基、氨基羰基、环丙基、氮杂环丁烷基、吗啉基和哌嗪基，其中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 2-6烯基、C 2-6炔基、C 1-4烷羰基、C 1-4烷氨羰基、(C 1-6烷基) 2氨羰基、C 1-4烷基磺酰基、C 1-4烷基硫基、氨基羰基、环丙基、氮杂环丁烷基、吗啉基和哌嗪基未被取代或任选被一至多个独立选自羟基、氨基、氰基、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、环丙基、C 1-4烷羰氧基、未被取代或任选被C 1-6烷基取代的4-6元杂环 基的基团取代；
L为键；
每个R 1分别独立地选自氢、羟基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、吡唑基、噻唑基和三唑基，基中所述C 1-6烷基、C 1-6烷氧基、吡唑基、噻唑基和三唑基未被取代或被羟基取代；
m为0、1或2；
环A选自如下基团：
Figure PCTCN2020070707-appb-000020
优选地，环A选自
Figure PCTCN2020070707-appb-000021
Figure PCTCN2020070707-appb-000022
更优选地，环A选自
Figure PCTCN2020070707-appb-000023
当环A为
Figure PCTCN2020070707-appb-000024
时，R 2不为氢。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
L为-NH-(CH 2)t-或键，t为0、1或2；
环A为芳基，优选苯基、萘基；
R 2选自氢、氨基、羧基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-6炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、 4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-6炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷羰氧基、C 3-6环烷基和未被取代或被C 1-6烷基取代的4-6元杂环基的基团取代；
每个R 1分别独立地选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基和C 1-6烷氧基，所述C 1-6烷基、C 1-6烷氧基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基和C 1-6烷氧基的基团取代；
m为0、1或2；
当环A为苯基时，L不为键。
本发明的一些实施方式涉及式(I)所示的化合物或其药学上可接受的盐、异构体，
L为键；
R 2选自氢、氨基、羧基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-6炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-6炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷羰氧基、C 3-6环烷基和未被取代或被C 1-6烷基取代的4-6元杂环基的基团取代；
L为键；
环A为6-12元并杂环基，所述6-12元并杂环基的杂原子选自O、S、N中的一种或其任意组合；
每个R 1独立地选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、苯基和5-6元杂芳基，取代基取代的所述C 1-6烷基、C 1-6烷氧基、苯基和5-6元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基和C 1-6烷氧基的基团取代；
m为0、1、2；
优选地，环A为9-10元并杂环基。
更优选地，环A为9-10元含氮并杂环基。
最优选地，环A选自
Figure PCTCN2020070707-appb-000025
本发明的一个实施方式，通式(I)所示的化合物的异构体是指立体异构体和互变异构体。
本发明的一个实施方式，通式(I)所示的化合物具有通式(I’)所示的互变异构体
Figure PCTCN2020070707-appb-000026
的互变异构体为
Figure PCTCN2020070707-appb-000027
上述本发明的任一实施方式中，涉及式(I)所示的化合物或其药学上可接受的盐、异构体，具有通式(II)所示结构，
Figure PCTCN2020070707-appb-000028
其中，R 1、R 2、L、环A和m如上所述；
条件是：
当环A为3-8元单杂环基时，R 2不为氢；
当环A为苯基时，L不为键；
当环A为
Figure PCTCN2020070707-appb-000029
时，R 2不为氢。
对于上述本发明的式(I)或(II)所示的化合物或其药学上可接受的盐、异构体，在一些实施方式中，环A选自
Figure PCTCN2020070707-appb-000030
在一些实施方式中，环A选自
Figure PCTCN2020070707-appb-000031
在一些实施方式中，n(R 2)位于式(I)中喹啉环的6位上，如同在式(II)中的R 2的位置，且n＝1；在一些实施方式中，R 2为卤素，C 1-4烷氨羰基，任选被一至多个独立选自羟基或C 3-6环烷基取代的C 1-4烷基，或任选被C 1-4烷氧基取代的C 1-4烷氧基。在一些实施方式中，R 2为溴、甲基、乙基、丙基、异丙基、被羟基取代的异丙基、甲基氨基羰基、或被羟基和环丙基取代的甲基(或乙基、或丙基，或丁基)、或被甲氧基取代的乙氧基。在一些实施方式中，m(R 1)位于环A被L取代位点的对位；在一些实施方式中，R 1为C 1-4烷基或C 1-4烷氧基；在一些实施方式中，m＝2；在一些实施方式中， m＝0。
对于上述本发明的式(I)或(II)所示的化合物或其药学上可接受的盐、异构体，在一些实施方式中，环A选自
Figure PCTCN2020070707-appb-000032
m(R 1)位于环A被L取代位点的对位，R 1为C 1-4烷基和C 1-4烷氧基，m＝2；n(R 2)为卤素，C 1-4烷氨羰基，任选被一至多个独立选自羟基或C 3-6环烷基取代的C 1-4烷基，或任选被C 1-4烷氧基取代的C 1-4烷氧基，且其中n＝1。在一些实施方式中，环A选自
Figure PCTCN2020070707-appb-000033
m为0；n(R 2)为卤素，C 1-4烷氨羰基，任选被一至多个独立选自羟基或C 3-6环烷基取代的C 1-4烷基，或任选被C 1-4烷氧基取代的C 1-4烷氧基，且其中n＝1。
对于上述本发明的式(I)或(II)所示的化合物或其药学上可接受的盐、异构体，在一些实施方式中，环A选自
Figure PCTCN2020070707-appb-000034
m(R 1)位于环A被L取代位点的对位，R 1为C 1-4烷基和C 1-4烷氧基，m＝2；n(R 2)为溴、甲基、乙基、丙基、异丙基、被羟基取代的异丙基、甲基氨基羰基、或被羟基和环丙基取代的甲基(或乙基、或丙基，或丁基)、或被甲氧基取代的乙氧基。在一些实施方式中，环A选自
Figure PCTCN2020070707-appb-000035
m为0；n(R 2)为溴、甲基、乙基、丙基、异丙基、被羟基取代的异丙基、甲基氨基羰基、或被羟基和环丙基取代的甲基(或乙基、或丙基，或丁基)、或被甲氧基取代的乙氧基。
在本发明的一种实施方式中，如前述式(I)或(II)所示的化合物、其药学上可接受的盐、异构体见表1：
表1
Figure PCTCN2020070707-appb-000036
Figure PCTCN2020070707-appb-000037
Figure PCTCN2020070707-appb-000038
Figure PCTCN2020070707-appb-000039
Figure PCTCN2020070707-appb-000040
Figure PCTCN2020070707-appb-000041
Figure PCTCN2020070707-appb-000042
Figure PCTCN2020070707-appb-000043
Figure PCTCN2020070707-appb-000044
Figure PCTCN2020070707-appb-000045
Figure PCTCN2020070707-appb-000046
Figure PCTCN2020070707-appb-000047
Figure PCTCN2020070707-appb-000048
Figure PCTCN2020070707-appb-000049
Figure PCTCN2020070707-appb-000050
Figure PCTCN2020070707-appb-000051
Figure PCTCN2020070707-appb-000052
Figure PCTCN2020070707-appb-000053
Figure PCTCN2020070707-appb-000054
Figure PCTCN2020070707-appb-000055
Figure PCTCN2020070707-appb-000056
Figure PCTCN2020070707-appb-000057
本发明还提供了含有前述式(I)或式(II)所示的化合物或其药学上可接受的盐、异构体，及一种或多种第二治疗活性剂的药物组合物。
在本发明的一种具体实施方式中，该组合物可以是将“治疗有效量”的前述式(I)或式(II)所示的化合物或其药学上可接受的盐、异构体，与一种或多种第二治疗活性剂采用联合给药的方式使用，例如先后给药，同时给药，或将本发明提供的化合物或其药学上可接受的盐、异构体与第二治疗活性剂做成复方制剂给药。
所述第二治疗活性剂为乙酰胆碱酯酶抑制剂、淀粉样蛋白-β(或其片段)、淀粉样蛋白-β(或其片段)的抗体、淀粉样蛋白的降低或抑制试剂、α-肾上腺素受体拮抗剂、β-肾上腺素受体阻断剂、抗胆碱能药、抗惊厥药、安定药、钙通道阻断剂、儿茶酚-O转甲基酶抑制剂、中枢神经系统刺激剂、皮质类固醇、多巴胺受体激动剂、多巴胺受体拮抗剂、多巴胺再摄入抑制剂、γ-氨基丁酸受体激动剂、免疫调节剂、免疫抑制剂、干扰素、左旋多巴、N-甲基-D天冬氨酸受体拮抗剂、单胺氧化酶抑制剂、毒蕈碱受体激动剂、烟碱受体激动剂、神经保护药物、降肾上腺素(去甲肾上腺素)再摄入抑制剂、其他PDE9抑制剂、其他磷酸二酯酶(PDE)抑制剂、β-分泌酶抑制剂、γ-分泌酶抑制剂、血清素(5-羟色胺)1A(5-HT 1A)受体拮抗剂、血清素(5-羟色胺)6(5-HT 6)受体拮抗剂、血清素(5-HT)再摄入抑制剂和营养因子。
所述“其他PDE9抑制剂”和“其他磷酸二酯酶(PDE)抑制剂”是指经证实对PDE9或PDE有活性的在研或者上市药物。
本发明还提供了含有前述式(I)或式(II)所示的化合物或其药学上可接受的盐、异构体的药物制剂。
在发明的一些实施方式中，药物制剂可以包含一种或多种药用载体。
本发明所述的药用载体可以是一种或多种适合于人使用的固体或液体填料或凝胶物质。所述药用载体优选具有足够的纯度和足够低的毒性，并且与本发明提供的化合物或其药学上可接受的盐、异构体具有相容性且不明显减低其药效。例如，药用载体可以填充剂、粘合剂、崩解剂、润滑剂、水性溶剂或非水性溶剂等。
本发明所述的药物制剂，可以制成药学上可接受的任意剂型，以任何合适的给药方式，例如通过口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，可以制成片剂、胶囊剂、丸剂、颗粒剂等。用于肠胃外给药时，可以制成注射液、注射用无菌粉末等。
本发明还提供了前述式(I)或式(II)所示的化合物或其药学上可接受的盐、异构体、前述的药物制剂或前述的药物组合物在制备治疗或者预防由PDE9介导的相关 疾病的药物中的用途；具体地，所述PDE9介导的相关疾病为由中枢神经系统紊乱导致的认知损害；更为具体地，所述认知损害包括：知觉、注意力、记忆力及学习损害；包括但不限于老年痴呆症、精神分裂症、年龄相关性记忆丧失、血管性痴呆、颅脑外伤、中风、中风后发生的痴呆、外伤后痴呆、一般性注意力损害、儿童注意力损害伴学习及记忆问题、阿尔茨海默病、路易体痴呆、额叶变性痴呆、皮质基底节变性痴呆、肌萎缩性脊髓侧索硬化症、亨廷顿病、多发性硬化、丘脑变性、库贾氏痴呆、HIV痴呆、精神分裂症、科尔萨科夫精神病或与抑郁症或双相情感障碍。
本发明还提供了前述式(I)或式(II)所示的化合物或其药学上可接受的盐、异构体、前述的药物制剂或前述的药物组合物在治疗或者预防疾病中的用途。
本发明还提供了前述式(I)或式(II)所示的化合物或其药学上可接受的盐、异构体、前述的药物制剂或前述的药物组合物在治疗或者预防由PDE9介导的相关疾病中的用途；具体地，所述PDE9介导的相关疾病为由中枢神经系统紊乱导致的认知损害；更为具体地，所述认知损害包括：知觉、注意力、记忆力及学习损害；包括但不限于老年痴呆症、精神分裂症、年龄相关性记忆丧失、血管性痴呆、颅脑外伤、中风、中风后发生的痴呆、外伤后痴呆、一般性注意力损害、儿童注意力损害伴学习及记忆问题、阿尔茨海默病、路易体痴呆、额叶变性痴呆、皮质基底节变性痴呆、肌萎缩性脊髓侧索硬化症、亨廷顿病、多发性硬化、丘脑变性、库贾氏痴呆、HIV痴呆、精神分裂症、科尔萨科夫精神病或与抑郁症或双相情感障碍。
本发明还提供了一种治疗或预防疾病的方法，该方法包括向有需要的患者给药治疗有效量的前述式(I)或式(II)所示的化合物或其药学上可接受的盐、异构体、前述的药物制剂或前述的药物组合物；所述疾病为PDE9介导的相关疾病；具体地，所述PDE9介导的相关疾病为由中枢神经系统紊乱导致的认知损害；更为具体地，所述认知损害包括：知觉、注意力、记忆力及学习损害；包括但不限于老年痴呆症、精神分裂症、年龄相关性记忆丧失、血管性痴呆、颅脑外伤、中风、中风后发生的痴呆、外伤后痴呆、一般性注意力损害、儿童注意力损害伴学习及记忆问题、阿尔茨海默病、路易体痴呆、额叶变性痴呆、皮质基底节变性痴呆、肌萎缩性脊髓侧索硬化症、亨廷顿病、多发性硬化、丘脑变性、库贾氏痴呆、HIV痴呆、精神分裂症、科尔萨科夫精神病或与抑郁症或双相情感障碍。
发明详述
本发明所述的“卤素”是指氟、氯、溴、碘等，优选氟，氯。
本发明所述的“卤代”是指取代基中的任一氢原子可被一个或多个相同或不同的卤素原子取代。“卤素”如前文所定义。
本发明所述的“C 1-6烷基”指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，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、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基和1-甲基-2-甲基丙基等。所述“C 1-4烷基”指含有1-4个碳原子的上述实例。
本发明所述的“C 2-8烯基”指含有碳碳双键的2～8个碳原子的烯烃部分去除一个氢 原子衍生的直链或支链或环状的烯烃基，如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1,3-丁二烯基、1-戊烯基、2-戊烯基、3-戊烯基、1,3-戊二烯基、1,4-戊二烯基、1-己烯基、1,4-己二烯基。
本发明所述的“C 2-8炔基”指含有碳碳叁键的2～8个碳原子的炔烃部分去除一个氢原子衍生的直链或支链的炔烃基，如乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基等。
本发明所述的“C 1-6烷氧基”是指前文所定义的“C 1-6烷基”通过氧原子与母体分子连接的基团，即“C 1-6烷基-O-”基团，如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、新戊氧基和正己氧基等。所述的“C 1-4烷氧基”指含有1-4个碳原子的上述实例，即“C 1-4烷基-O-”基团。
发明所述的“C 1-6烷基氨基”、“(C 1-6烷基) 2氨基”、“C 1-6烷基羰基氨基”、“C 1-6烷基磺酰氨基”、“C 1-6烷基氨基羰基”、“(C 1-6烷基) 2氨基-羰基”、“C 1-6烷氧基-羰基”、“C 1-6烷基磺酰基”、“C 1-6烷基硫基”、“C 1-6烷基羰基”、分别指C 1-6烷基-NH-、(C 1-6烷基)(C 1-6烷基)N-、C 1-6烷基-C(O)-NH-、C 1-6烷基-S(O) 2-NH 2-、C 1-6烷基-NH-C(O)-、(C 1-6烷基)(C 1-6烷基)N-C(O)-、C 1-6烷基-O-C(O)-、C 1-6烷基-S(O) 2-、C 1-6烷基-S-、C 1-6烷基-C(O)-；所述“C 1-6烷基”如前文所定义，优选为“C 1-4烷基”。
本发明所述的“稠环”是指由两个或两个以上环状结构以并、螺、桥的连接方式所形成的多环系结构。所述的并环是指由两个或两个以上环状结构彼此公用两个相邻的环原子(即共用一个键)所形成的稠环结构。所述的桥环是指有两个或两个以上环装结构彼此共用两个非相邻的环原子所形成的稠环结构。所述的螺环是指由两个或两个以上环状结构彼此共用一个环原子所形成的稠环结构。
本发明所述的“3-12元环烯基”，在不特别指明的情况下，包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)的情形，例如3-8元单环烯、7-11元螺环烯、7-11元并环烯、6-11元桥环烯等。
本发明所述的环烷基包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)的情形；例如“3-12元环烷基”，可以是单环、双环、或者多环环烷基系统(也称为稠环系统)。在不特别指明的情况下，单环系统是含3-8个碳原子的环烃基基团。3-8元环烷基实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基等。稠环环烷基包括并环环烷基、桥环烷基、螺环烷基。并环环烷基可以为6-11元并环环烷基、7-10元并环环烷基，其的代表性例子包括但不限于双环[3.1.1]庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷和双环[4.2.1]壬烷。所述的螺环基可以为7-12元螺环基、7-11元螺环基，其实例包括但不限于：
Figure PCTCN2020070707-appb-000058
所述的桥环基可以为6-11元桥环基、7-10元桥环基，其实例包括但不限于：
Figure PCTCN2020070707-appb-000059
Figure PCTCN2020070707-appb-000060
本发明所述的“杂环基”是指3-12元的至少一个环碳原子被选自O、S、N的杂原子替代的非芳香性的环状基团，优选1-3个杂原子，同时包括碳原子、氮原子和硫原 子可以被氧代。
“3-12元杂环基”，是指单环杂环基、双环杂环基系统或多环杂环基系统(也称为稠环系统)，包括饱和、部分饱和的杂环基，但不包括芳环。在不特别指明的情况下，包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)、饱和、部分饱和的情形。
单杂环基可以为3-8元杂环基、3-8元饱和杂环基、3-6元杂环基、4-7元杂环基、5-7元杂环基、5-6元杂环基、5-6元含氧杂环基、3-8元含氮杂环基、5-6元含氮杂环基、5-6元饱和杂环基等。“3-8”元饱和杂环基，其实例包括但不限于氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、吡咯烷基、四氢噻吩基、咪唑烷基、吡唑烷基、1,2-噁唑烷基、1,3-噁唑烷基、1,2-噻唑烷基、1,3-噻唑烷基、四氢-2H-吡喃基、四氢-2H-噻喃基、哌啶基、哌嗪基、吗啉基、1,4-二氧杂环己烷基、1,4-氧硫杂环己烷基；“3-8”元部分饱和杂环基，其实例包括但不限于4,5-二氢异噁唑基、4,5-二氢噁唑基、2,5-二氢噁唑基、2,3-二氢噁唑基、3,4-二氢-2H-吡咯基、2,3-二氢-1H-吡咯基、2,5-二氢-1H-咪唑基、4,5-二氢-1H-咪唑基、4,5-二氢-1H-吡唑基、4,5-二氢-3H-吡唑基、4,5-二氢噻唑基、2,5-二氢噻唑基、2H-吡喃基、4H-吡喃基、2H-噻喃基、4H-噻喃基、2,3,4,5-四氢吡啶基、1,2-异噁嗪基、1,4-异噁嗪基或6H-1,3-噁嗪基等。稠杂环包括并杂环基、螺杂环基、桥杂环基，可以是饱和的、部分饱和的或不饱和的，但不是芳香性的。稠杂环基是稠合到苯环、5-6元的单环环烷基、5-6元单环环烯基、5-6元单环杂环基或5-6元单环杂芳基的5-6元单环杂环基环。所述的并杂环基可以为6-12元并环基、7-10元并环基、6-10元并环基、6-12元饱和并环基，代表性实例包括但不限于：3-氮杂双环[3.1.0]己烷基、3,6-二氮杂双环[3.2.0]庚烷基、3,8-二氮杂双环[4.2.0]辛烷基、3,7-二氮杂双环[4.2.0]辛烷基、八氢吡咯并[3,4-c]吡咯基、八氢吡咯并[3,4-b]吡咯基、八氢吡咯并[3,4-b][1,4]噁嗪基、八氢-1H-吡咯并[3,4-c]吡啶基、2,3-二氢苯并呋喃-2-基、2,3-二氢苯并呋喃-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚3-基、2,3-二氢苯并噻吩-2基、八氢-1H-吲哚基、八氢苯并呋喃基。所述的螺杂环基可以为6-12元螺杂环基、7-11元螺杂环基、6-12元饱和螺环基，其实例包括但不限于：
Figure PCTCN2020070707-appb-000061
Figure PCTCN2020070707-appb-000062
所述的桥杂环基可以为6-12元桥杂环基、7-11元桥杂环基、6-12元饱和桥环基，其实例包括但不限于：
Figure PCTCN2020070707-appb-000063
Figure PCTCN2020070707-appb-000064
本发明所述“芳基”，是指含有6-14个碳原子的环状芳香性基团，包括，苯基、萘、菲等。
本发明所述的杂芳基，包括可能形成的所有单环、稠环、全部芳香、部分芳香的情形。例如“5-10元杂芳基”是指至少一个环碳原子被选自O、S、N的杂原子替代的芳香性的环状基团，优选1-3个杂原子，同时包括碳原子、硫原子被氧代的情况，例如碳原子被C(O)替代，硫原子被S(O)、S(O) 2替代。杂芳基包括单杂芳基和稠杂芳基，在不特别指明的情况下，单杂芳基可以为5-7元杂芳基、5-6元杂芳基，其实例包括但不仅限于呋喃基、咪唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻吩基、三唑基和三嗪基。在某些实施例中，稠杂芳基是指单环杂芳环稠合到苯基、环烯基、杂芳基、环烷基、杂环基所形成的基团，稠杂芳基可以为8-12元并杂芳基、9-10元并杂芳基，例子包括但不限于苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁二唑基、苯并噻二唑基、苯并噻唑基、噌啉基、5,6-二氢喹啉-2-基、5,6-二氢异喹啉-1-基、呋喃并吡啶基、吲唑基、吲哚基、异吲哚基、异喹啉基、萘啶基、嘌呤基、喹啉基、5,6,7,8-四氢喹啉-2-基、5,6,7,8-四氢喹啉基、5,6,7,8-四氢喹啉-4-基、5,6,7,8-四氢异喹啉-1-基、噻吩并吡啶基、4,5,6,7-四氢并[c][1,2,5]噁二唑基和6,7-二氢并[c][1,2,5]噁二唑-4(5H)酮基。
本发明所述的“药学上可接受的盐”是指可药用的酸和碱的加成盐或其溶剂化物。这样的可药用盐包括诸如以下的酸的盐：盐酸、磷酸、氢溴酸、硫酸、亚硫酸、甲酸、甲苯磺酸、甲磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、马来酸、氢碘酸、链烷酸(诸如乙酸、HOOC-(CH 2)n-COOH(其中n是0～4))等。碱的盐：钠盐、钾盐、钙盐、铵盐等。本领域技术人员知晓多种无毒的可药用加成盐。
本发明所述“异构体”是指立体异构体和互变异构体。
立体异构体是指当化合物存在不对称碳原子时，会产生对映异构体；当化合物存在碳碳双键或环状结构时，会产生顺反异构体；所有式(I)化合物的对映异构体、非对映异构体、消旋异构体、顺反异构体、几何异构体、差向异构体及其混合物，均包括在本发明范围中。
“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体，互变异构体是一种特殊的官能团异构体。如含有α-H的羰基化合物的互变异构，具体如
Figure PCTCN2020070707-appb-000065
如其他质子迁移互变异构，具体如酚-酮互变异构、亚硝基-肟互变异构、亚胺-烯胺互变异构。
T、T1、T2分别独立地为任意符合化合物成键规律的基团。
本发明化合物含有内酰胺结构，存在
Figure PCTCN2020070707-appb-000066
互变异构，当提到本发明化合物时，意味着该化合物的互变异构体也同时提及。
本发明所述的“治疗有效量”是指当给药到患者时至少能够减轻患者病症的症状的前述化合物或其药学上可接受的盐、异构体、组合物或药物制剂的量。包含“治疗有效量”的实际量会根据多种情况而变化，多种情况包括但不限于所治疗的特定病症、病症的严重程度、患者的体格和健康状况以及给药途径。熟练的医疗从业者可容易地使用医疗领域中已知的方法确定合适的量。
化合物制备
通过标准化学方法在内的多种方法，可以制备本发明的化合物。除非另外指出，否则任何前面定义的变量将继续具有前面定义的含义。示例性的一般合成方法阐述在下述方案中，并且可以很容易的改进以制备本发明的其它化合物。在实施例部分中制备本发明的具体化合物。
在一些实施方式中，式(I)的化合物可以通过式(I-d)的化合物与式(I-e)的化合物通过金属催化的偶联或芳香亲核取代等反应来制备，如下：
Figure PCTCN2020070707-appb-000067
在一些实施方式中，式(I-d)的化合物可以通过式(I-c)的化合物与卤代试剂、取代或未取代的磺酰氯或磺酸酐的作用来制备，如下：
Figure PCTCN2020070707-appb-000068
在一些实施方式中，式(I-c)的化合物可以通过式(I-b)的化合物在合适的碱的作用下，关环来制备，如下：
Figure PCTCN2020070707-appb-000069
在一些实施方式中，式(I-b)的化合物可以通过式(I-a)的化合物与氰基乙酸在合适的肽偶联剂作用下反应来制备，如下：
Figure PCTCN2020070707-appb-000070
上述实施方式中，R 1、R 2、A、L、m和n如上文中所定义，Ra 1选自氢或C 1-6烷基，X选自卤素、取代或未取代苯磺酸酯、C 1-6烷基磺酸酯、三氟甲磺酸酯等。
在一些实施方式中，式(I)的化合物可以通过式(I-j)的化合物与合适的含有R 2基团的试剂通过金属催化的偶联反应，或者式(I-j)的化合物与合适的试剂通过金属催化的偶联反应后，再经过一步或多步常规的化学反应转化(如氧化、还原、加成、取代、氢化、氯代、氨化等)制备得到，如下：
Figure PCTCN2020070707-appb-000071
在一些实施方式中，(I-j)的化合物可以通过式(I-i)的化合物与式(I-e)的化合物通过芳香亲核取代等反应来制备，如下：
Figure PCTCN2020070707-appb-000072
在一些实施方式中，式(I-i)的化合物可以通过式(I-h)的化合物与卤代试剂、取代或未取代的磺酰氯或磺酸酐的作用来制备，如下：
Figure PCTCN2020070707-appb-000073
在一些实施方式中，式(I-h)的化合物可以通过式(I-g)的化合物在合适的碱的作用下，关环来制备，如下：
Figure PCTCN2020070707-appb-000074
在一些实施方式中，式(I-g)的化合物可以通过式(I-f)的化合物与氰基乙酸在合适的肽偶联剂作用下反应来制备，如下：
Figure PCTCN2020070707-appb-000075
上述实施方式中，R 1、R 2、A、L、m、n、Ra 1和X如上文中所定义，X 2选自溴或碘。
卤代试剂，是指用于卤化反应的试剂，包括但不限制于N-溴代琥珀酰亚胺、 N-氯代丁二酰亚胺、N-碘代丁二酰亚胺、二溴海因、三溴化磷、三氯化膦、氯化亚砜、三氯氧磷、五氯化磷或三溴氧磷。
合适的碱，是指包括有机碱和无机碱。其中，有机碱包括但不限制于叔丁醇钠、叔丁醇钾、乙醇钠、甲醇钠、LiHMDS、N,N-二异丙基乙胺、三乙胺、二异丙基胺基锂等。无机碱包括但不限制于氢化钠，碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化钾、氢氧化钠、氢氧化镁、氢氧化钙等。
取代或未取代的磺酰氯是指Ra 2-SO 2Cl。
取代或未取代的磺酸酐是指(Ra 2-SO 2) 2-O。
其中，Ra 2选自C 1-6烷基、C 1-6卤代烷基、取代或未取代的芳基等。
肽偶联剂，是指能够活化羧酸与胺形成酰胺的试剂，包括但不限制于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，O-苯并三氮唑-四甲基脲六氟磷酸酯，N,N'-羰基二咪唑，苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐，丙基磷酸酐，碳化二亚胺等。
具体实施方式
本文中使用的缩写：
“DCM”是指二氯甲烷；“DMF”是指N，N-二甲基甲酰胺；“DIPEA”是指N，N-二异丙基乙胺；“PE”是指石油醚；“EA”是指乙酸乙酯；“EDCI”是指碳化二亚胺；“HATU”是指2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；“THF”是指四氢呋喃。
实施例1:6-溴-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成(化合物180)
Figure PCTCN2020070707-appb-000076
步骤1：2-氨基-5-溴苯甲酸乙酯的合成
Figure PCTCN2020070707-appb-000077
将中间体2-氨基-5-溴苯甲酸(50g,0.231mol,1.0eq)和浓硫酸(20mL)溶解在无水乙醇(500mL)中，80℃反应96h，LC-MS监测反应完全，减压浓缩，加入乙酸乙酯(200mL)，在0℃下加入饱和碳酸钾水溶液调节pH值至10，分液，水相用乙酸乙酯(200mL×2)萃取，有机相合并，无水硫酸钠干燥，过滤，减压浓缩，粗品用PE:EA(100:1,200mL)打浆，抽滤，滤饼烘干得到产品(37g,收率:65％)。
步骤2：5-溴-2-(2-氰基乙酰胺基)苯甲酸乙酯的合成
Figure PCTCN2020070707-appb-000078
将中间体2-氨基-5-溴苯甲酸乙酯(37g,0.151mol,1.0eq)和氰基乙酸(15.5g,0.182mol,1.2eq)溶解在DCM(400mL)中，冷却至0℃，分批加入EDCI(43.4g,0.227mol,1.5eq)，反应50min，TLC监测反应完全，加入水(300mL)，搅拌30min，抽滤，滤饼收集，用水(300mL)淋洗，滤液分液，水相用乙酸乙酯(200mL×2)萃取，有机相合并，无水硫酸钠干燥，过滤，减压浓缩，粗品用PE:EA(20:1,50mL)打浆，抽滤，两批滤饼烘干得到产品(45.2g,收率:96％)。
步骤3：6-溴-4-羟基-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000079
将中间体5-溴-2-(2-氰基乙酰胺基)苯甲酸乙酯(45.2g,0.145mol,1.0eq)溶于乙醇(600mL)，在冰浴下加入乙醇钠(29.58mg，0.435mol,1.5eq)，反应30min，TLC检测反应完全。减压浓缩，加入水(500mL)，用浓盐酸调pH值至2，有白色固体析出，过滤，滤饼烘干得到产品(38.4g,收率:100％)。
步骤4：6-溴-2,4-二氯喹啉-3-甲腈的合成：
Figure PCTCN2020070707-appb-000080
将中间体6-溴-4-羟基-2-氧代-1,2-二氢喹啉-3-甲腈(38.4g,0.145mol,1.0eq)溶于乙腈(200mL)，加入三氯氧磷(77.8g,0.507mol,3.5eq)，90℃反应3h，LC-MS检测反应完全，减压浓缩得到粗品，按理论量用于下步反应
步骤5：6-溴-4-氯-2-氧代-1,2-二氢喹啉-3-甲腈的合成：
Figure PCTCN2020070707-appb-000081
将中间体6-溴-2,4-二氯喹啉-3-甲腈(43.7g,0.145mol,1.0eq)溶于三氟乙酸(300mL)和水(80mL)的混合溶剂中，升温90℃反应2.5h，TLC检测反应完全，将反应液滴入冰水(1L)中，搅拌20min，抽滤，滤饼烘干得产品(37.5g，收率:91％)。
步骤6：6-溴-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成：
Figure PCTCN2020070707-appb-000082
将中间体6-溴-4-氯-2-氧代-1,2-二氢喹啉-3-甲腈(30g,0.106mol,1.0eq)、4-甲氧基-4-甲基哌啶盐酸盐(19.28g,0.116mol,1.1eq)和DIPEA(41.12g,0.318mol,3.0eq)溶于DMF(150mL)，80℃反应1h，LC-MS检测反应完全，将反应液滴入冰水(750mL)中，搅拌30min，抽滤，滤饼烘干得产品(30g,收率:75％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):11.91(s,1H),7.79-7.80(s,1H),7.73-7.76(m,1H),7.23-7.25(s,1H),3.55-3.58(d,2H),3.50-3.52(m,2H),3.18(s,3H),1.88-1.91(d,2H),1.72-1.79(m,2H),1.22(s,3H).
分子式:C 17H 18BrN 3O 2分子量:376.25 LC-MS(Pos，m/z)＝376.06[M+H] +.
实施例2：3-氰基-N-甲基-2-氧代-4-(6-氮杂螺[2.5]辛烷-6-基)-1,2-二氢喹啉-6-甲酰胺的合成(化合物96)
Figure PCTCN2020070707-appb-000083
步骤1:6-溴-2-氧代-4-(6-氮杂螺[2.5]辛烷-6-基)-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000084
将实施例1步骤5产物6-溴-4-氯-2-氧代-1,2-二氢喹啉-3-甲腈(7.0g,24.69mmol,1.0eq)溶于N,N-二甲基甲酰胺(35mL)，加入DIPEA(12.7g,98.76mmol,4.0eq)和6-氮杂螺[2.5]辛烷盐酸盐(5.1g,34.56mmol,1.4eq)，加毕，升温至80℃反应1h，LC-MS检测无原料，将反应液降至室温，倒入冰水(175mL)中，析出固体，抽滤，滤饼用石油醚淋洗，烘干得到产品(7.2g,收率:81.8％)。
步骤2:2-氧代-4-(6-氮杂螺[2.5]辛烷-6-基)-6-乙烯基-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000085
将中间体6-溴-2-氧代-4-(6-氮杂螺[2.5]辛烷-6-基)-1,2-二氢喹啉-3-甲腈(7.2g,20mmol,1.0eq)、乙烯基氟硼酸钾(4.0g,30mmol,1.5eq)和碳酸铯(19.5g,60mmol,3.0eq)溶于1,4-二氧六环(200mL)和水(40mL)的混合溶剂中，氮气置换三次，加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.5g,2mmol,0.1eq)，氮气置换三次，升温至100℃反应18h。LC-MS检测无原料，降温至60℃，过滤，滤饼用乙酸乙酯淋洗，分液，水相用乙酸乙酯(50mL×2)萃取，有机相合并，用无水硫酸镁干燥，过滤，滤液减压浓缩，粗品用甲基叔丁基醚打浆，过滤，滤饼烘干得到产品(5.8g,收率:95％)。
步骤3:6-甲酰基-2-氧代-4-(6-氮杂螺[2.5]辛烷-6-基)-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000086
将中间体2-氧代-4-(6-氮杂螺[2.5]辛烷-6-基)-6-乙烯基-1,2-二氢喹啉-3-甲腈(2.8g,9.17mmol,1.0eq)溶于叔丁醇(60mL)和水(60mL)的混合溶剂中，加甲磺酰胺(872.1mg,9.17mmol,1.0eq)和AD-mix-β(33.6g)，氮气保护下室温搅拌反应68h。TLC显示无原料，加高碘酸钠(3.9g,18.34mmol,2.0eq)、四氢呋喃(10mL)和水(10mL)，加毕，室温搅拌7h，LC-MS检测有原料剩余，补加高碘酸钠(3.9g,18.34mmol,2.0eq)、四氢呋喃(10mL)和水(10mL)，加毕，室温搅拌16h，LC-MS检测无原料，过滤，滤饼用二氯甲烷(100mL)打浆，分液，有机相用无水硫酸镁干燥，过滤，滤饼用二氯甲烷淋洗，滤液减压浓缩，粗品经硅胶柱层析(MeOH:DCM＝1:100)纯化得到产品(754mg,收率:26.9％)。
步骤4:3-氰基-2-氧代-4-(6-氮杂螺[2.5]辛烷-6-基)-1,2-二氢喹啉-6-羧酸的合成
Figure PCTCN2020070707-appb-000087
将中间体6-甲酰基-2-氧代-4-(6-氮杂螺[2.5]辛烷-6-基)-1,2-二氢喹啉-3-甲腈(754mg,2.45mmol,1.0eq)溶于甲酸(5mL)中，降温至-5～0℃，滴加(30％)双氧水(1.4g,12.26mmol,5.0eq)，加毕，保温-5～0℃反应16h，加水(50mL)，用二氯甲烷(50mL×3) 萃取，有机相合并，用无水硫酸镁干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析(MeOH:DCM＝1:40)纯化，所得产品溶于水(20mL)中，用2mol/L盐酸调pH＝6，用乙酸乙酯(10mL×3)萃取，水相冻干得到产品(183mg,收率:23％)。
步骤5:3-氰基-N-甲基-2-氧代-4-(6-氮杂螺[2.5]辛烷-6-基)-1,2-二氢喹啉-6-甲酰胺的合成
Figure PCTCN2020070707-appb-000088
将中间体3-氰基-2-氧代-4-(6-氮杂螺[2.5]辛烷-6-基)-1,2-二氢喹啉-6-羧酸(170mg,0.53mmol,1.0eq)溶于N,N-二甲基乙酰胺(2mL)，加DIPEA(339mg,2.63mmol,5.0eq)，氮气保护下，冰水降温至0℃，加HATU(400mg,1.05mmol,2.0eq)，室温反应1h，加甲胺盐酸盐(70.8mg,1.05mmol,2.0eq)，室温反应1h，LC-MS检测无原料，加水(50mL)，用乙酸乙酯(50mL×3)萃取，有机相合并，水洗(50mL×2)，无水硫酸镁干燥，过滤，滤液减压浓缩，粗品经制备薄层色谱纯化得到产品(27mg,收率:15.2％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):11.98(s,1H),8.54-8.53(m,1H),8.30-8.29(s,1H),8.02-7.99(d,1H),7.31-7.29(d,1H),3.65-3.62(m,4H),2.81-2.80(s,3H),1.64-1.63(m,4H),0.45(m,4H).
分子式:C 19H 20N 4O 2分子量:336.40 LC-MS(Pos,m/z)＝337.4[M+H] +.
实施例3:6-乙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成(化合物107)
Figure PCTCN2020070707-appb-000089
步骤1：4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000090
将实施例1步骤6产物6-溴-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈(20g,0.053mol,1.0eq)溶于1,4-二氧六环(300mL)和水(80mL)的混合溶剂中，加入三氟(乙烯基)硼酸钾(10.68g,0.08mmol,1.5eq)、碳酸铯(51.8g,0.159mol,3.0eq)氮气置换后，再加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(3.886mg,5.3mmol,0.1eq)，氮气保护下100℃反应3小时，LC-MS检测反应完全，分液，水相用二氯甲烷(200mL×3)萃取，有机相合并，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝60:1)纯化得到产品(14.3g,收率:83％)。
步骤2：6-乙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000091
将中间体4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢喹啉-3-甲腈(300mg,0.92mmol,1.0eq)溶于甲醇(5mL)，加入Pd/C(30mg)，氢气置换三次，氢气条件下反应2小时，LC-MS检测反应完全，抽滤，滤液减压浓缩得到产品(126mg,收率:42％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):11.71(s,1H),7.50(s,1H),7.45-7.47(m,1H),7.21-7.23(d,1H),
3.5-3.61(m,4H),3.18(s,3H),2.64-2.70(m,2H),1.88-1.92(d,2H),1.74-1.81(m,2H),1.22(s,6H).
分子式:C 19H 23N 3O 2分子量:325.41 LC-MS(Pos,m/z)＝326.18[M+H] +.
实施例4:4-(4-甲氧基-4-甲基哌啶-1-基)-6-甲基-2-氧代-1,2-二氢喹啉-3-甲腈的合成(化合物158)
Figure PCTCN2020070707-appb-000092
步骤1:4-(4-甲氧基-4-甲基哌啶-1-基)-6-甲基-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000093
将实施例1步骤6产物6-溴-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈(500mg,1.33mmol,1.0eq)溶于1,4-二氧六环(5mL)和水(1mL)的混合溶剂中，加入碳酸铯(1.3g,3.98mol,3.0eq)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(97mg,0.133mmol,0.1eq)，氮气置换后，加入三甲基环三硼氧烷(50％THF溶液,1.33g,5.31mmol,4.0eq)、氮气保护下100℃反应12小时，LC-MS检测反应完全，分液，水相用乙酸乙酯(200mL×3)萃取，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经制备HPLC纯化(0.1％氨水:甲醇＝1:4)得到产品(66mg,收率:15％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):7.40-7.50(d,2H),7.19-7.21(d,1H),3.53-3.57(m,4H),3.18(s,3H),2.36(s,3H),1.78-1.91(m,4H),1.22(s,3H).
分子式:C 18H 21N 3O 2分子量:311.39 LC-MS(Pos,m/z)＝312.16[M+H] +.
实施例5:6-异丙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成(化合物179)
Figure PCTCN2020070707-appb-000094
步骤1：4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-(丙-1-烯-2-基)-1,2-二氢喹啉-3-甲腈合成
Figure PCTCN2020070707-appb-000095
将实施例1步骤6产物6-溴-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈(500mg,1.33mmol,1.0eq)溶于1,4-二氧六环(5mL)和H 2O(1mL)的混合溶剂中，加入三氟(丙-1-烯-2-基)硼酸钾(295mg,2.0mmol,1.5eq)、碳酸铯(1.3g,4.0mmol,3.0eq)氮气置换再加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(97mg,0.13mmol,0.1eq)，氮气条件下100℃反应12小时，LC-MS检测反应完全。加入水(10mL)，二氯甲烷(10mL×3)萃取，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩，粗品 经柱层析(DCM:MeOH＝60:1)纯化得到产品(400mg,收率:89％)。
步骤2：6-异丙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000096
将中间体4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-(丙-1-烯-2-基)-1,2-二氢喹啉-3-甲腈(400mg,1.18mmol,1.0eq)溶于甲醇(5mL)，加入Pd/C(40mg)，氢气条件下反应12小时，LC-MS检测反应完全，抽滤，减压浓缩，粗品用甲基叔丁醚打浆得到产品(300mg,收率:75％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):11.68(s,1H),7.50-7.51(d,2H),7.24-7.24(d,1H),3.51-3.61(m,4H),3.18(s,3H),2.95-2.97(m,1H),1.89-1.93(d,2H),1.75-1.80(m,2H),1.22-1.23(m,9H).
分子式:C 20H 25N 3O 2分子量:339.44 LC-MS(Pos，m/z)＝340.19[M+H] +.
实施例6：6-(2-羟基丙烷-2-基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈合成(化合物109)
Figure PCTCN2020070707-appb-000097
步骤1：6-(1,2-二羟基乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000098
将实施例3步骤1产物4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢喹啉-3-甲腈(14g,0.043mol,1.0eq)溶于叔丁醇(280mL)和水(280mL)的混合溶剂中，加入甲磺酰胺(4.11g,0.043mol,1.0eq)AD-mix(168g)，常温反应12个小时，LC-MS检测反应完全,不做处理直接用于下步反应。
步骤2：6-甲酰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000099
在上步反应瓶中加入四氢呋喃(200mL)，加入高碘酸钠(36.9g,0.17mol,4.0eq)，反应24个小时，LC-MS检测反应完全。加入二氯甲烷(200mL)，搅拌30min，过滤，分液，水相用二氯甲烷(200mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝100:1)纯化得到产物(5.9g,两步收率:42％)。
步骤3：6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000100
将中间体6-甲酰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈(4g,12.3mmol,1.0eq)溶于四氢呋喃(40mL)，降温至-30℃，加入甲基氯化镁(12.4mL,36.9mmol,3.0eq)，反应5小时，LC-MS检测反应完全，加入水(40mL)，用乙酸乙酯(50mL×3)萃取，有机相合并，无水硫酸钠干燥，抽滤，滤液减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝50:1)纯化得到产品(2.28g,收率:54％)。
步骤4：6-乙酰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000101
将中间体6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈(2.2g,6.44mmol,1.0eq)溶于二氯甲烷(40mL)，降温至0℃,加入戴斯-马丁氧化剂(5.47g,12.88mmol,2.0eq)，反应3小时，LC-MS检测反应完全。抽滤，滤液减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝80:1)纯化得到产品(1.9g,收率:87％)。
步骤5：6-(2-羟基丙烷-2-基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000102
将中间体6-乙酰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈(1.9g,5.6mmol,1.0eq)溶于四氢呋喃(40mL)，降温在-30℃，滴加甲基溴化镁(5.6mL,16.8mmol,3.0eq)，反应3小时，LC-MS检测反应完全。加入水(30mL)，用乙酸乙酯(10mL×3)萃取，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝60:1)纯化得产品(1.52g,收率:76％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):11.69(s,1H),7.85-7.86(d,1H),7.65-7.68(m,1H),7.22-7.24(d,1H),5.16(s,1H),3.53-3.62(m,4H),3.19(s,3H),1.90-1.94(d,2H),1.73-1.80(m,2H),1.45(s,6H),1.23(s,3H).
分子式:C 20H 25N 3O 3分子量:355.44 LC-MS(Pos,m/z)＝356.19[M+H] +.
实施例7:6-(环丙基(羟基)甲基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈合成(化合物130)
Figure PCTCN2020070707-appb-000103
步骤1：6-(环丙基(羟基)甲基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000104
将实施例6步骤2产物6-甲酰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢喹啉-3-甲腈(500mg,1.54mmol,1.0eq)溶于四氢呋喃(10mL)，-30℃下滴加环丙基溴化镁(2.3mL,2.3mmol,1.5eq)，反应3小时，LC-MS检测反应完全。加入水(10mL)，用二氯甲烷(10mL×3)萃取，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品先经硅胶柱层析(DCM:MeOH＝50:1)纯化，再用甲基叔丁基醚(10mL)打浆得产品(300mg,收率:53％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):11.71(s,1H),7.74(s,1H),7.60-7.63(d,1H),7.24-7.26( m,1H),5.27-5.28(d,1H),4.04-4.06(m,1H),3.55-3.57(m,4H),3.19(s,3H),1.89-1.92(d,2H),1.75-1.79(d,2H),1.23(s,3H),1.01-1.05(s,1H),0.45-0.48(d,4H).
分子式:C 21H 25N 3O 3分子量:367.45 LC-MS(Pos,m/z)＝368.19[M+H] +.
实施例8:4-(4-甲氧基-4-甲基哌啶-1-基)-6-(2-甲氧基乙氧基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成(化合物145)
Figure PCTCN2020070707-appb-000105
步骤1:2-甲氧基乙基5-(2-甲氧基乙氧基)-2-硝基苯甲酸酯的合成
Figure PCTCN2020070707-appb-000106
将原料5-羟基-2-硝基苯甲酸(5.0g,27.31mmol,1.0eq)溶于DMF(50mL)，加入无水碳酸钾(15g,109.21mmol,4.0eq)和1-溴-2-甲氧基乙烷(11.4g,82.02mmol,3eq)，60℃反应23小时，LC-MS检测反应完全。降至室温，加入水(200mL)，用乙酸乙酯(200mL×2)萃取，有机相合并，用水(100mL×2)洗涤，分液，无水硫酸钠干燥，过滤，减压浓缩得到产品(4.0g,收率:49％)。
步骤2:2-甲氧基乙基2-氨基-5-(2-甲氧基乙氧基)苯甲酸酯的合成
Figure PCTCN2020070707-appb-000107
将中间体2-甲氧基乙基5-(2-甲氧基乙氧基)-2-硝基苯甲酸酯(4.0g,13.36mmol,1.0eq)溶于无水甲醇(100mL)，加入(10％)钯碳(1g)，氢气置换三次，室温反应20h，LC-MS检测反应完全，过滤，滤饼用甲醇淋洗，滤液减压浓缩得到产品(5g粗品)，按理论量投入下一步。
步骤3:2-甲氧基乙基2-(2-氰基乙酰氨基)-5-(2-甲氧基乙氧基)苯甲酸酯的合成
Figure PCTCN2020070707-appb-000108
将中间体2-甲氧基乙基2-氨基-5-(2-甲氧基乙氧基)苯甲酸酯(5g粗品,13.36mmol)溶于二氯甲烷(60mL)，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(3.8g,20mmol,1.5eq)和氰基乙酸(1.36g,16mmol,1.2eq)，加毕，室温搅拌1h。TLC显示 无原料，加二氯甲烷(100mL)，用水(50mL×2)洗涤，分液，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩得到产品(4.78g粗品)，按理论量投入下一步。
步骤4:4-羟基-6-(2-甲氧基乙氧基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000109
将中间体2-甲氧基乙基2-(2-氰基乙酰氨基)-5-(2-甲氧基乙氧基)苯甲酸酯(4.5g,13.36mmol,1.0eq)溶于无水乙醇(150mL)，加热至50℃溶解，加入乙醇钠(2.7g,40.08mmol,3.0eq)，50℃搅拌1h。TLC显示无原料，减压浓缩，加水(50mL)，用浓盐酸调节pH＝2，析出固体，过滤，滤饼依次用水和丙酮淋洗，烘干得到产品(3.2g,三步收率:92.2％)。
步骤5:2,4-二氯-6-(2-甲氧基乙氧基)-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000110
将中间体4-羟基-6-(2-甲氧基乙氧基)-2-氧代-1,2-二氢喹啉-3-甲腈(3.2g,12.30mmol,1.0eq)溶于无水乙腈(150mL)，加五氯化磷(5.1g,24.60mmol,2.0eq)和三氯氧磷(6.6g,43.05mmol,3.5eq)，加毕，升温至80℃反应3h。LC-MS检测少量原料剩余，降至室温，倒入冰水(200mL)中，搅拌10min，析出黄色固体，过滤，滤饼用水淋洗得到产品(5.4g粗品)，按理论量投入下一步。
步骤6:4-氯-6-(2-甲氧基乙氧基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000111
将中间体2,4-二氯-6-(2-甲氧基乙氧基)-1,2-二氢喹啉-3-甲腈(3.6g,12.30mmol,1.0eq)溶于三氟乙酸(36mL)和水(9mL)的混合溶剂中，加热至90℃反应4h，然后室温搅拌14h。将反应液倒入水(100mL)中，析出黄色固体，过滤，滤饼依次用水和丙酮淋洗，滤饼烘干得到产物(2.39g,收率:69.8％)。
步骤7:4-(4-甲氧基-4-甲基哌啶-1-基)-6-(2-甲氧基乙氧基)-2-氧代-1,2-二氢喹啉-3-甲腈的合成
Figure PCTCN2020070707-appb-000112
将中间体4-氯-6-(2-甲氧基乙氧基)-2-氧代-1,2-二氢喹啉-3-甲腈(500mg,1.79mmol,1.0eq)溶于N,N-二甲基乙酰胺(5mL)，加DIPEA(926.8mg,7.18mmol,4.0eq)和4-甲氧基-4-甲基哌啶盐酸盐(415.1mg,2.51mmol,1.4eq)，加毕，升温至80℃反应1h，LC-MS检测无原料剩余，将反应液降至室温，倒入冰水(50mL)中，用乙酸乙酯(50mL×3)萃取，有机相合并，用水(50mL×2)洗涤，无水硫酸镁干燥，过滤，滤液减压浓缩得到淡黄色固体，加入乙酸乙酯(2mL)和甲基叔丁基醚(8mL)的混合溶剂中，50℃打浆0.5h，趁热抽滤，滤饼烘干得到产品(369.3mg,收率:55.5％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):11.70(s,1H),7.31-7.28(d,1H),7.25-7.23(d,1H),7.11-7.10(s,1H),4.17-4.14(m,2H),3.70-3.68(m,2H),3.60-3.50(m,4H),3.32(s,3H),3.18(s,3H),1.92-1.86(m,2H),1.81-1.75(m,2H),1.22(s,3H).
分子式:C 20H 25N 3O 4分子量:371.44 LC-MS(Pos,m/z)＝372.17[M+H] +.
根据下述实验例，可以更好地理解本发明。然而，本领域的技术人员容易理解，实验例所描述的内容仅用于说明本发明，而不应当也不会限制权利要求书中所详细描述的本发明。
实验例1：PDE9酶学评价方法
测试物：本发明化合物，由本发明相应的实施例所制备。
一、实验材料及仪器
PDE9A2酶(BPS,Cat.No.60090)
384孔板(Perkin Elmer,Cat.No.6007279)
二、试验步骤
准备化合物：用DMSO将化合物配制成10mM化合物储存液长期储存，以DMSO100倍稀释得到100μM化合物工作母液，再以DMSO将化合物工作母液3倍稀释，共得到8-10个浓度梯度的化合物稀释母液(100×)。
加药孵育：使用极微量液体移液系统Echo移取化合物稀释母液至384孔板中；每个化合物孔加入200nL化合物稀释母液以及10μL PDE9A2酶液，1000rpm离心1min后，室温孵育15min。随后加入10μL底物混合液，1000rpm离心1min后，室温振荡孵育30min。最后，加入终止液终止反应体系，室温振荡孵育60min。最大读值孔(Max)中，以溶剂代替化合物；最小读值孔(Min)中，以溶剂代替化合物以及酶液。
检测：使用酶标仪检测480nm/535nm处荧光读值(F)。
计算：抑制率按照如下公式计算，使用GraphPad Prism5.0拟合IC 50：
Figure PCTCN2020070707-appb-000113
三、试验结果如下表2所示：
表2
测试物 PDE9A2 IC 50(nM)
化合物96 5
化合物107 8
化合物109 15
化合物130 2
化合物145 12
化合物158 12
化合物179 18
化合物180 8
本发明化合物具有非常好的PDE9酶学抑制活性，具有潜在的临床应用价值。
实验例2本发明化合物的肝微粒体稳定性评价
测试物：本发明化合物和国际专利申请WO2017019723A1的化合物I-8(参照WO2017019723A1中合成实施例制备)，其结构式如下：
Figure PCTCN2020070707-appb-000114
温孵体系的构成：
Figure PCTCN2020070707-appb-000115
化合物配制：
精确称取适量化合物，用DMSO溶解配成5.0mM储备液。将5.0mM的储备液，用DMSO稀释成1.0mM，最后用水稀释成10μM的化合物工作溶液，待用(反应体 系中DMSO含量为0.1％，v/v)。
试验步骤：
(1).从-80℃冰箱中取出肝微粒体(20mg蛋白/mL)，置于37℃水浴恒温振荡器上预温孵3min，融化待用。
(2).按照上面“实验温孵体系的构成”比例，制备温孵体系混合溶液(不含化合物和β-NADPH)，置于37℃水浴恒温振荡器上预孵育2min。
3).对照组(不含β-NADPH)：分别取30μL水和30μL化合物工作溶液(10μM)加入到240μL步骤(2)所述温孵体系混合液中，涡旋30s，混匀，反应总体积300μL，平行样2份。放入到37℃水浴恒温振荡器中进行孵育，并开始计时，取样时间点为0min和60min。
4).样品组：分别取70μLβ-NADPH溶液(10mM)和70μL化合物工作溶液(10μM)加入560μL步骤(2)所述混合溶液中，反应总体积700μL，涡旋30s，混匀，平行样2份。放入到37℃水浴恒温振荡器中进行孵育，并开始计时，取样时间点为计时后0min,5min,10min,20min,30min,60min。
(5).涡旋3min后，4000rpm离心10min。
(6).取上清液50μL加入150μL水，涡旋混匀，LC/MS/MS进样分析。
数据分析：
用下列一级动力学公式计算半衰期(t 1/2)和清除率(Cl)：
Ct＝C 0*e –kt
t 1/2＝ln2/k＝0.693/k
Cl int＝V d*k
Vd＝1/肝微粒体中蛋白含量
注：k为化合物剩余量的对数与时间作图的斜率，V d为表观分布容积，C 0为0h药物浓度。
结果：
本发明化合物的大鼠肝微粒体稳定性实验
  CL int(mL/min/mg) t 1/2(min)
化合物I-8 0.0292 47.5
化合物96 0.0072 193
化合物109 0.0030 462
化合物130 0.0082 169
化合物145 0.0108 128
化合物180 0.0242 57.3
从上述结果可以看出本发明化合物较现有技术化合物在大鼠肝微粒体有较低的清除率。

Claims (16)

  1. 通式(I)所示的化合物或其药学上可接受的盐、异构体：
    Figure PCTCN2020070707-appb-100001
    每个R 2分别独立地选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元杂环基、C 1-6烷羰基、氨基羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基、芳基、5-6元杂芳基、4-6元杂环基羰基和5-6元杂芳基-氧基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元杂环基、C 1-6烷羰基、氨基羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基、芳基、5-6元杂芳基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、C 1-6烷羰氧基、C 3-6环烷基、C 2-8炔基、卤代C 1-6烷基、C 2-8烯基、卤代C 1-6烷氧基、未被取代或任选被取代基取代的4-6元杂环基和未被取代或任选被取代基取代的杂芳基的基团取代；
    上述任选被取代基取代的4-6元杂环基、任选被取代基取代的杂芳基的取代基选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基和C 1-6烷氧基；
    L为键、-NH-(CH 2)t-，t为0、1、2或3；
    环A为3-8元单杂环基、6-12元桥杂环基、6-12元螺杂环基、6-12元并杂环基、芳基、5-10元杂芳基、3-12元环烷基、3-12元环烯基，其中所述杂环基的杂原子选自O、S、N中的一种或其任意组合，S原子可任选被氧化为S(O)或S(O) 2，C原子可任选被氧化为C(O)，所述5-10元杂芳基的杂原子选自O、S、N中的一种或其任意组合；
    每个R 1分别独立地选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、3-12元环烷基、3-12元环烯基、3-12元杂环基、芳基和5-10元杂芳基未被取代或任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基和C 1-6烷基磺酰氨基的基团取代；
    m和n分别独立地为0、1、2或3；
    当环A为3-8元单杂环基时，R 2不为氢；
    当环A为苯基时，L不为键；
    当环A为
    Figure PCTCN2020070707-appb-100002
    时，R 2不为氢。
  2. 如权利要求1所述的化合物或其药学上可接受的盐、异构体，
    每个R 2分别独立地选自氢、氨基、羧基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷羰氧基、C 3-6环烷基和未被取代或被C 1-6烷基取代的4-6元杂环基的基团取代；
    L为键、-NH-(CH 2)t-，t为0、1、2或3；
    环A为3-8元单杂环基、6-12元桥杂环基、6-12元螺杂环基、6-12元并杂环基、苯基、5-10元杂芳基，所述杂环基的杂原子选自O、S、N中的一种或其任意组合，S原子可任选被氧化为S(O)或S(O) 2，C原子可任选被氧化为C(O)；
    每个R 1分别独立地选自氢、羟基、氰基、卤素、C 1-6烷基、C 1-6烷氧基和5-6元杂芳基，其中所述C 1-6烷基、C 1-6烷氧基和5-6元杂芳基未被取代或被羟基取代；
    m和n分别独立地为0、1或2；
    当环A为3-8元单杂环基时，R 2不为氢；
    当环A为苯基时，L不为键；
    当环A为
    Figure PCTCN2020070707-appb-100003
    时，R 2不为氢。
  3. 如权利要求2所述的化合物或其药学上可接受的盐、异构体，
    其中，
    每个R 2分别独立地选自卤素、C 1-4烷基、C 1-4烷氧基、吗啉基、C 2-6烯基、C 1-4烷羰基、C 1-4烷氨羰基、(C 1-4烷基) 2氨羰基和氨基羰基，其中所述C 1-4烷基、C 1-4烷氧基、吗啉基、C 2-6烯基、C 1-4烷羰基、C 1-4烷氨羰基、(C 1-4烷基) 2氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、氨基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、未被取代或被C 1-4烷基取代的4-6元杂环基的基团取代；
    L为键；
    环A为4-7元单杂环基，所述4-7元单杂环基的杂原子选自O、S、N中的一种或两种的组合，且至少含有一个N，环A通过N原子与L相连接，S原子可任选被氧化为S(O)或S(O) 2，C原子可任选被氧化为C(O)；
    优选地，环A选自
    Figure PCTCN2020070707-appb-100004
    每个R 1分别独立地选自氢、卤素、C 1-4烷基、C 1-4烷氧基、吡唑基、噻唑基和三唑基，其中所述C 1-4烷基、C 1-4烷氧基、吡唑基、噻唑基和三唑基未被取代或被羟基取代；
    m和n分别独立为0、1或2。
  4. 如权利要求3所述的化合物或其药学上可接受的盐、异构体，
    其中，
    每个R 2分别独立地选自卤素、C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 1-4烷氨羰基和氨基羰基，其中所述C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 1-4烷氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、C 1-4烷基、C 1-4烷氧基、环丙基、C 1-4烷基氨基、(C 1-4烷基) 2氨基和未被取代或被C 1-4烷基取代的4-6元杂环基的基团取代；
    L为键；
    环A为
    Figure PCTCN2020070707-appb-100005
    每个R 1分别独立地选自氢、C 1-4烷基和C 1-4烷氧基；
    m和n分别独立地为0、1或2。
  5. 如权利要求2所述的化合物或其药学上可接受的盐、异构体，
    其中，
    每个R 2分别独立地选自氨基、羧基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 3-6环烷基、4-6元含氮杂环基、C 1-6烷羰基、C 1-6烷氨羰基、(C 1-6烷基) 2氨羰基和氨基羰基未被取代或任选被一至多个独立选自羟基、氨基、氰基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷羰氧基、C 3-6环烷基和未被取代或被C 1-6烷基取代的4-6元杂环基的基团取代；
    L为键；
    环A为
    Figure PCTCN2020070707-appb-100006
    每个R 1分别独立地选自吡唑基、噻唑基和三唑基。
  6. 如权利要求1或2所述的化合物或其药学上可接受的盐、异构体，
    其中，
    每个R 2分别独立地选自氢、氨基、氰基、卤素、羧基、C 1-4烷基、C 1-4烷氧基、C 1-4烷羰基、C 2-6炔基、C 1-4烷氨羰基、(C 1-4烷基) 2氨羰基、C 1-4烷基硫基、C 1-4烷基磺酰基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、氮杂环丁烷基、吗啉基、哌嗪基、C 2-6烯基和环丙基，基中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷羰基、C 2-6炔基、C 1-4烷氨羰基、 (C 1-6烷基) 2氨羰基、C 1-4烷基硫基、C 1-4烷基磺酰基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、氮杂环丁烷基、吗啉基、哌嗪基、C 2-6烯基和环丙基未被取代或任选被一至多个独立选自羟基、氨基、卤素、C 1-4烷基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、环丙基和C 1-4烷羰氧基的基团取代；
    L为键；
    环A为7-12元螺杂环基，所述螺杂环基的杂原子选自O、S、N中的一种或两种的组合，且至少含有一个N，环A通过N原子与L相连接，S原子可任选被氧化为S(O)或S(O) 2，C原子可任选被氧化为C(O)；
    优选地，环A选自
    Figure PCTCN2020070707-appb-100007
    每个R 1分别独立地选自氢、氰基、卤素、羟基、及未被取代或被羟基取代的C 1-4烷基；
    m和n分别独立地为0、1或2；
    当环A为
    Figure PCTCN2020070707-appb-100008
    时，R 2不为氢。
  7. 如权利要求6所述的化合物或其药学上可接受的盐、异构体，
    其中，
    每个R 2分别独立地选自氢、氰基、氨基、卤素、羧基、C 1-4烷基、C 1-4烷氧基、C 1-4烷羰基、C 2-6炔基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷氨羰基、C 1-4烷基硫基、C 1-4烷基磺酰基、环丙基、氮杂环丁烷基、吗啉基、哌嗪基，其中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷羰基、C 2-6炔基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷氨羰基、C 1-4烷基硫基、C 1-4烷基磺酰基、环丙基、氮杂环丁烷基、吗啉基、哌嗪基未被取代或任选被一至多个独立选自羟基、氨基、卤素、C 1-4烷基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、环丙基、C 1-4烷羰氧基的基团取代；
    L为键；
    环A选自
    Figure PCTCN2020070707-appb-100009
    m和n分别独立地为0、1或2。
  8. 如权利要求1或2所述的化合物或其药学上可接受的盐、异构体，
    其中，L为键；
    环A选自如下基团：
    Figure PCTCN2020070707-appb-100010
    当环A为
    Figure PCTCN2020070707-appb-100011
    时，R 2不为氢。
  9. 如权利要求1所述的化合物或其药学上可接受的盐、异构体，其中通式(I)具有通式(II)所示结构，
    Figure PCTCN2020070707-appb-100012
    其中，R 1、R 2、L、环A和m如权利要求1所述。
  10. 如权利要求9所述的化合物或其药学上可接受的盐、异构体，其中R 2为卤素，C 1-4烷氨羰基，任选被一至多个独立选自羟基或C 3-6环烷基取代的C 1-4烷基，或任选被C 1-4烷氧基取代的C 1-4烷氧基。
  11. 如权利要求10所述的化合物或其药学上可接受的盐、异构体，其中，R 2为溴，甲基，乙基，丙基，异丙基，被羟基取代的异丙基，甲基氨基羰基，或被羟基和环丙基取代的甲基、乙基、丙基或丁基，被甲氧基取代的乙氧基。
  12. 如权利要求10所述的化合物或其药学上可接受的盐、异构体，其中，m(R 1)位于环A被L取代位点的对位，R 1为C 1-4烷基或C 1-4烷氧基，且m＝2。
  13. 如权利要求1-2任一项所述的化合物或其药学上可接受的盐、异构体，选自如下结构的化合物：
    Figure PCTCN2020070707-appb-100013
    Figure PCTCN2020070707-appb-100014
    Figure PCTCN2020070707-appb-100015
    Figure PCTCN2020070707-appb-100016
    Figure PCTCN2020070707-appb-100017
    Figure PCTCN2020070707-appb-100018
    Figure PCTCN2020070707-appb-100019
    Figure PCTCN2020070707-appb-100020
    Figure PCTCN2020070707-appb-100021
  14. 含有权利要求1-13任一项所述的化合物或其药学上可接受的盐、异构体，及一种或多种第二治疗活性剂的药物组合物，所述的第二治疗活性剂为乙酰胆碱酯酶抑制剂、淀粉样蛋白-β(或其片段)、淀粉样蛋白-β(或其片段)的抗体、淀粉样蛋白的降低或抑制试剂、α-肾上腺素受体拮抗剂、β-肾上腺素受体阻断剂、抗胆碱能药、抗惊厥药、安定药、钙通道阻断剂、儿茶酚-O转甲基酶抑制剂、中枢神经系统刺激剂、皮质类固醇、多巴胺受体激动剂、多巴胺受体拮抗剂、多巴胺再摄入抑制剂、γ-氨基丁酸受体激动剂、免疫调节剂、免疫抑制剂、干扰素、左旋多巴、N-甲基-D天冬氨酸受体拮抗剂、单胺氧化酶抑制剂、毒蕈碱受体激动剂、烟碱受体激动剂、神经保护药物、降肾上腺素(去甲肾上腺素)再摄入抑制剂、其他PDE9抑制剂、其 他磷酸二酯酶抑制剂、β-分泌酶抑制剂、γ-分泌酶抑制剂、血清素(5-羟色胺)1A(5-HT 1A)受体拮抗剂、血清素(5-羟色胺)6(5-HT 6)受体拮抗剂、血清素(5-HT)再摄入抑制剂和营养因子。
  15. 含有权利要求1-13任一项所述的化合物或其药学上可接受的盐、异构体的药物制剂，所述药物制剂包含一种或多种药用载体。
  16. 权利要求1-13任一项所述的化合物或其药学上可接受的盐、异构体或权利要求14所述的药物组合物或权利要求15所述的药物制剂在制备治疗或者预防由PDE9介导的相关疾病的药物中的用途。
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