WO2020182076A1 - 磷酸二酯酶抑制剂的用途 - Google Patents

磷酸二酯酶抑制剂的用途 Download PDF

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WO2020182076A1
WO2020182076A1 PCT/CN2020/078215 CN2020078215W WO2020182076A1 WO 2020182076 A1 WO2020182076 A1 WO 2020182076A1 CN 2020078215 W CN2020078215 W CN 2020078215W WO 2020182076 A1 WO2020182076 A1 WO 2020182076A1
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alkyl
heart failure
alkoxy
membered
amino
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PCT/CN2020/078215
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English (en)
French (fr)
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盛泽娟
吴永谦
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南京药捷安康生物科技有限公司
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Priority to AU2020235187A priority Critical patent/AU2020235187B8/en
Priority to SG11202109781Q priority patent/SG11202109781QA/en
Priority to JP2021553378A priority patent/JP7404616B2/ja
Priority to EP20768911.8A priority patent/EP3939588A4/en
Priority to CA3132895A priority patent/CA3132895A1/en
Priority to KR1020217032529A priority patent/KR20210136104A/ko
Priority to US17/436,879 priority patent/US20220160696A1/en
Publication of WO2020182076A1 publication Critical patent/WO2020182076A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to a phosphodiesterase 9 (PDE9) inhibitor compound represented by the general formula (I) and its pharmaceutically acceptable salts, isomers, and deuterated compounds for preparing and treating mammalian heart Use in medicine for aging diseases.
  • PDE9 phosphodiesterase 9
  • Heart failure (Heat Failure, referred to as heart failure) is a clinical syndrome, which is characterized by abnormal heart structure and/or function, which causes a decrease in cardiac output and/or an increase in intracardiac pressure at rest or under load.
  • Pathophysiological conditions such as dyspnea, ankle edema, and fatigue, can also be accompanied by physical signs, such as increased jugular venous pressure, pulmonary rales, and peripheral edema.
  • LVEF left ventricular ejection fraction
  • HFpEF preserved ejection fraction
  • HFmrEF median ejection fraction
  • HFrEF reduced ejection fraction
  • time course or severity of heart failure it is divided into acute heart failure, chronic heart failure, decompensated heart failure, pre-heart failure stage, pre-clinical heart failure stage, clinical heart failure stage, and refractory end-stage heart failure. Stage of failure; New York Heart Association (NYHA) heart function classification I, II, III, IV heart failure, etc.
  • NYHA New York Heart Association
  • heart failure hypertension, valve and myocardial structural defects, pericardial and endocardial cardiomyopathy, high output state, volume overload, lung disease
  • cardiomyopathy ischemic heart disease, toxicity Injury, immune-mediated and inflammatory damage, myocardial infiltrating disease, endocrine metabolic disease, genetic or stress-induced cardiomyopathy, etc.
  • arrhythmia tachycardia, bradycardia
  • infection anemia, pregnancy, Childbirth, heart rhythm disorders, pulmonary embolism, diabetes, and heart-suppressing drugs can aggravate heart failure.
  • the incidence of heart failure is about 1-2% of the adult population, and it rises to more than 10% in people older than 70 years old.
  • the lifetime risk of heart failure at the age of 55 is 33% for men and 28% for women.
  • myocardial remodeling (such as myocardial hypertrophy, heart enlargement, heart wall thinning, etc.) caused by the activation of the neuroendocrine system is a key factor in the occurrence and development of heart failure.
  • Myocardial remodeling can partially compensate for cardiac function at first, but as myocardial remodeling intensifies, cardiac function gradually changes from compensation to decompensation, leading to more obvious symptoms and signs. Therefore, how to prevent or reverse cardiac remodeling has become one of the main treatment goals of chronic heart failure.
  • Heart Failure Group of Cardiovascular Branch of Chinese Medical Association Editorial Committee of Chinese Journal of Cardiovascular Disease, Heart Failure Professional Committee of Chinese Medical Doctor Association. Chinese Heart Failure Diagnosis and Treatment Guide 2018[J].Chinese Journal of Cardiovascular Disease, 2018,46 (10):760-789.DOI:10.3760/cma.j.issn.0253-3758.2018.10.004
  • HFpEF type heart failure accounts for about 50% of the total heart failure.
  • PDEs Phosphodiesterass
  • cGMP cyclic guanosine monophosphate, cyclic guanosine monophosphate
  • cAMP cyclic adenosine phosphate
  • Physiological processes such as transmission, cell growth and differentiation. According to the sequence homology of genes and the selectivity to cGMP or cAMP, PDEs can be divided into 11 members (PDE1 ⁇ PDE11).
  • PDE9 is an important member of the PDE family, and it is widely expressed in the testis, brain, small intestine, skeletal muscle, heart, lung, thymus and pancreas.
  • PDE9 inhibitors are used to treat cognitive impairment diseases caused by central nervous system disorders, such as Alzheimer’s and schizophrenia, and brain The neurodegenerative process disease.
  • Literature research has found that in cardiomyocytes, the increase of cGMP can activate protein kinase G (PKG), and this protein can play a role in myocardial protection, so this pathway is an important signaling pathway in the treatment of heart failure.
  • PKG protein kinase G
  • PDE9 can selectively hydrolyze cGMP, thereby reducing the myocardial protective effect of PKG.
  • PDE9 expression is significantly increased during heart failure, especially HFpEF, so the myocardial protection ability is greatly weakened. Therefore, inhibiting PDE9 in patients with heart failure can protect the heart.
  • the inventors have further studied the biological functions of PDE9, aiming to explore its role in the treatment of heart failure.
  • the present invention studies the use of PDE9 inhibitors in the field of heart failure, and studies have found that the PDE9 inhibitor compounds of the present invention and their pharmaceutically acceptable salts, isomers and deuterated compounds have significant effects on the treatment of heart failure. Therefore, the purpose of the present invention is to provide a new use of PDE9 inhibitors in the treatment of heart failure.
  • PDE9 phosphodiesterase 9
  • X 1 , X 2 , X 3 , and X 4 are independently selected from CR 3 or N, and N heteroatoms can be optionally oxidized to
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl Amino, (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) 2 aminocarbonyl, 4-6 membered heterocyclic carbonyl and 5-6 membered heteroaryl-oxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, (C 1-6 alkyl) 2 amino
  • substituents of the above-mentioned 4-6 membered heterocyclic group optionally substituted by substituents and heteroaryl optionally substituted by substituents are selected from the group consisting of hydroxyl, amino, carboxy, cyano, nitro, halogen, and C 1-6 alkane Group and C 1-6 alkoxy;
  • L is a bond, -NH-(CH 2 )t-, t is 0, 1, 2 or 3;
  • Ring A is 3-12 membered heterocyclyl, aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, wherein the heterocyclic group of 3-12 membered
  • the atom is selected from one or any combination of O, S, N, S atom can be optionally oxidized to S(O) or S(O) 2 , C atom can be optionally oxidized to C(O), N Heteroatoms can optionally be oxidized to The heteroatom of the 5-10 membered heteroaryl group is selected from one of O, S, and N or any combination thereof;
  • Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, 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 alkyl Sulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein 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 alkane Oxy, C 2-8 alkenyl, C 2-8 alkynyl,
  • n 0, 1, 2 or 3;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and halogenated C 1-6 alkyl.
  • X 1 , X 2 , and X 4 are each independently CH, and X 3 is CR 3 .
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time.
  • the phosphodiesterase 9 (PDE9) inhibitor compound represented by the general formula (I) and its pharmaceutically acceptable salts, isomers and deuterated compounds are used in the preparation of the treatment of mammalian heart failure disease Use in medicines,
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • R 3 is independently selected from hydrogen, deuterium, amino, cyano, halogen, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, (C 1 -4 alkyl) 2 amino, C C2-6 alkenyl group, C C2-6 alkynyl group, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, aminocarbonyl, cyclopropyl, azetidinyl, 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 al
  • Ring A is a 3-12 membered heterocyclic group, and the heteroatom of the 3-12 membered heterocyclic group is selected from one or any combination of O, S, N, and the S atom can be optionally oxidized to S(O ) Or S(O) 2 ;
  • Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-4 alkyl, C 1-4 alkoxy and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 alkoxy and 5-6 membered heteroaryl are unsubstituted or substituted by hydroxy;
  • n 0, 1 or 2;
  • R 2 is selected from hydrogen or C 1-6 alkyl.
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • A is a 3-12 membered heterocyclic group, preferably a 4-7 membered heterocyclic group.
  • A is a 3-12 membered heterocyclic group, preferably a 7-12 membered spiroheterocyclic group.
  • the phosphodiesterase 9 (PDE9) inhibitor compound represented by the general formula (I) and its pharmaceutically acceptable salts, isomers and deuterated compounds are used in the preparation of the treatment of mammalian heart failure disease Use in medicines,
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 1-4 alkylcarbonyl, cyclopropyl, C 1-4 alkylaminocarbonyl and aminocarbonyl, wherein the C 1-4 alkyl group, C 1-4 alkoxy group, C 2-6 alkenyl group, C 1-4 alkylcarbonyl group, C 1-4 alkylaminocarbonyl group And the aminocarbonyl group is unsubstituted or optionally substituted by one or more independently selected from hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, C 1-4 alkylamino, (C 1 -4 alkyl) 2 amino and 4-6 membered heterocyclic group substituted by unsubstituted or substituted by C 1-4 alkyl;
  • Each R 1 is independently selected from hydrogen, deuterium, C 1-4 alkyl and C 1-4 alkoxy;
  • n 0, 1, or 2.
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • the phosphodiesterase 9 (PDE9) inhibitor compound represented by the general formula (I) and its pharmaceutically acceptable salts, isomers and deuterated compounds are used in the preparation of the treatment of mammalian heart failure disease Use in medicines
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, 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 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, cycloprop
  • Ring A is selected from
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • PDE9 inhibitor compound represented by general formula (I) and pharmaceutically acceptable salts, isomers and deuterated compounds thereof are used for the treatment of heart failure diseases in mammals,
  • X 1 , X 2 , X 3 , and X 4 are independently selected from CR 3 or N, and N heteroatoms can be optionally oxidized to
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl Amino, (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) 2 aminocarbonyl, 4-6 membered heterocyclic carbonyl and 5-6 membered heteroaryl-oxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, (C 1-6 alkyl) 2 amino
  • substituents of the above-mentioned 4-6 membered heterocyclic group optionally substituted by substituents and heteroaryl optionally substituted by substituents are selected from the group consisting of hydroxyl, amino, carboxy, cyano, nitro, halogen, and C 1-6 alkane Group and C 1-6 alkoxy;
  • L is a bond, -NH-(CH 2 )t-, t is 0, 1, 2 or 3;
  • Ring A is 3-12 membered heterocyclyl, aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, wherein the heterocyclic group of 3-12 membered
  • the atom is selected from one or any combination of O, S, N, S atom can be optionally oxidized to S(O) or S(O) 2 , C atom can be optionally oxidized to C(O), N Heteroatoms can optionally be oxidized to The heteroatom of the 5-10 membered heteroaryl group is selected from one of O, S, and N or any combination thereof;
  • Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, 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 alkyl Sulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein 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 alkane Oxy, C 2-8 alkenyl, C 2-8 alkynyl,
  • n 0, 1, 2 or 3;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and halogenated C 1-6 alkyl.
  • X 1 , X 2 , and X 4 are each independently CH, and X 3 is CR 3 .
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time.
  • the phosphodiesterase 9 (PDE9) inhibitor compound represented by the general formula (I) and pharmaceutically acceptable salts, isomers and deuterated compounds thereof are used for the treatment of mammalian heart Aging disease,
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • R 3 is independently selected from hydrogen, deuterium, amino, cyano, halogen, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, (C 1 -4 alkyl) 2 amino, C C2-6 alkenyl group, C C2-6 alkynyl group, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, aminocarbonyl, cyclopropyl, azetidinyl, 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 al
  • Ring A is a 3-12 membered heterocyclic group, and the heteroatom of the 3-12 membered heterocyclic group is selected from one or any combination of O, S, N, and the S atom can be optionally oxidized to S(O ) Or S(O) 2 ;
  • Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-4 alkyl, C 1-4 alkoxy and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 alkoxy and 5-6 membered heteroaryl are unsubstituted or substituted by hydroxy;
  • n 0, 1 or 2;
  • R 2 is selected from hydrogen or C 1-6 alkyl.
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • A is a 3-12 membered heterocyclic group, preferably a 4-7 membered heterocyclic group.
  • A is a 3-12 membered heterocyclic group, preferably a 7-12 membered spiroheterocyclic group.
  • the phosphodiesterase 9 (PDE9) inhibitor compound represented by the general formula (I) and pharmaceutically acceptable salts, isomers and deuterated compounds thereof are used for the treatment of mammalian heart Aging disease,
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 1-4 alkylcarbonyl, cyclopropyl, C 1-4 alkylaminocarbonyl and aminocarbonyl, wherein the C 1-4 alkyl group, C 1-4 alkoxy group, C 2-6 alkenyl group, C 1-4 alkylcarbonyl group, C 1-4 alkylaminocarbonyl group And the aminocarbonyl group is unsubstituted or optionally substituted by one or more independently selected from hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, C 1-4 alkylamino, (C 1 -4 alkyl) 2 amino and 4-6 membered heterocyclic group substituted by unsubstituted or substituted by C 1-4 alkyl;
  • Each R 1 is independently selected from hydrogen, deuterium, C 1-4 alkyl and C 1-4 alkoxy;
  • n 0, 1, or 2.
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • the phosphodiesterase 9 (PDE9) inhibitor compound represented by the general formula (I) and pharmaceutically acceptable salts, isomers and deuterated compounds thereof are used for the treatment of mammalian heart Aging disease,
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, cyano, amino, halogen, carboxyl, 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 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, cyclo
  • Ring A is selected from
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • a method for treating a mammalian heart failure disease which comprises administering to a patient or subject a phosphodiesterase 9 (PDE9) inhibitor compound represented by general formula (I) and a pharmaceutically acceptable salt, isomer and Deuterated compounds,
  • PDE9 phosphodiesterase 9
  • X 1 , X 2 , X 3 , and X 4 are independently selected from CR 3 or N, and N heteroatoms can be optionally oxidized to
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl Amino, (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) 2 aminocarbonyl, 4-6 membered heterocyclic carbonyl and 5-6 membered heteroaryl-oxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, (C 1-6 alkyl) 2 amino
  • substituents of the above-mentioned 4-6 membered heterocyclic group optionally substituted by substituents and heteroaryl optionally substituted by substituents are selected from the group consisting of hydroxyl, amino, carboxy, cyano, nitro, halogen, and C 1-6 alkane Group and C 1-6 alkoxy;
  • L is a bond, -NH-(CH 2 )t-, t is 0, 1, 2 or 3;
  • Ring A is 3-12 membered heterocyclyl, aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, wherein the heterocyclic group of 3-12 membered
  • the atom is selected from one or any combination of O, S, N, S atom can be optionally oxidized to S(O) or S(O) 2 , C atom can be optionally oxidized to C(O), N Heteroatoms can optionally be oxidized to The heteroatom of the 5-10 membered heteroaryl group is selected from one of O, S, and N or any combination thereof;
  • Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, 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 alkyl Sulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein 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 alkane Oxy, C 2-8 alkenyl, C 2-8 alkynyl,
  • n 0, 1, 2 or 3;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and halogenated C 1-6 alkyl.
  • X 1 , X 2 , and X 4 are each independently CH, and X 3 is CR 3 .
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time.
  • a method for treating a heart failure disease in a mammal includes administering a phosphodiesterase 9 (PDE9) inhibitor compound represented by general formula (I) and a pharmaceutically acceptable compound thereof to a patient or subject Salts, isomers and deuterated compounds of
  • PDE9 phosphodiesterase 9
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • R 3 is independently selected from hydrogen, deuterium, amino, cyano, halogen, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, (C 1 -4 alkyl) 2 amino, C C2-6 alkenyl group, C C2-6 alkynyl group, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, aminocarbonyl, cyclopropyl, azetidinyl, 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 al
  • Ring A is a 3-12 membered heterocyclic group, and the heteroatom of the 3-12 membered heterocyclic group is selected from one or any combination of O, S, N, and the S atom can be optionally oxidized to S(O ) Or S(O) 2 ;
  • Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-4 alkyl, C 1-4 alkoxy and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 alkoxy and 5-6 membered heteroaryl are unsubstituted or substituted by hydroxy;
  • n 0, 1 or 2;
  • R 2 is selected from hydrogen or C 1-6 alkyl.
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • A is a 3-12 membered heterocyclic group, preferably a 4-7 membered heterocyclic group.
  • A is a 3-12 membered heterocyclic group, preferably a 7-12 membered spiroheterocyclic group.
  • a method for treating a heart failure disease in a mammal includes administering a phosphodiesterase 9 (PDE9) inhibitor compound represented by general formula (I) and a pharmaceutically acceptable compound thereof to a patient or subject Salts, isomers and deuterated compounds of
  • PDE9 phosphodiesterase 9
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 1-4 alkylcarbonyl, cyclopropyl, C 1-4 alkylaminocarbonyl and aminocarbonyl, wherein the C 1-4 alkyl group, C 1-4 alkoxy group, C 2-6 alkenyl group, C 1-4 alkylcarbonyl group, C 1-4 alkylaminocarbonyl group And the aminocarbonyl group is unsubstituted or optionally substituted by one or more independently selected from hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, C 1-4 alkylamino, (C 1 -4 alkyl) 2 amino and 4-6 membered heterocyclic group substituted by unsubstituted or substituted by C 1-4 alkyl;
  • Each R 1 is independently selected from hydrogen, deuterium, C 1-4 alkyl and C 1-4 alkoxy;
  • n 0, 1, or 2.
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • a method for treating a heart failure disease in a mammal includes administering a phosphodiesterase 9 (PDE9) inhibitor compound represented by general formula (I) and a pharmaceutically acceptable compound thereof to a patient or subject Salts, isomers and deuterated compounds of
  • PDE9 phosphodiesterase 9
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, cyano, amino, halogen, carboxyl, 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 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, cyclo
  • Ring A is selected from
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • a pharmaceutical composition comprising (a) a phosphodiesterase 9 (PDE9) inhibitor compound represented by general formula (I) and its pharmaceutically acceptable salts, isomers and deuterated compounds, for treatment Mammalian heart failure disease.
  • PDE9 phosphodiesterase 9
  • a kit comprising (a) a phosphodiesterase 9 (PDE9) inhibitor compound represented by general formula (I) and its pharmaceutically acceptable salts, isomers and deuterated compounds, and (b) using the The compound and its pharmaceutically acceptable salt or its isomer or its deuterated compound are used to treat heart failure in mammals.
  • PDE9 phosphodiesterase 9
  • X 1 , X 2 , X 3 , and X 4 are independently selected from CR 3 or N, and N heteroatoms can be optionally oxidized to
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl Amino, (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) 2 aminocarbonyl, 4-6 membered heterocyclic carbonyl and 5-6 membered heteroaryl-oxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, (C 1-6 alkyl) 2 amino
  • substituents of the above-mentioned 4-6 membered heterocyclic group optionally substituted by substituents and heteroaryl optionally substituted by substituents are selected from the group consisting of hydroxyl, amino, carboxy, cyano, nitro, halogen, and C 1-6 alkane Group and C 1-6 alkoxy;
  • L is a bond, -NH-(CH 2 )t-, t is 0, 1, 2 or 3;
  • Ring A is 3-12 membered heterocyclyl, aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, wherein the heterocyclic group of 3-12 membered
  • the atom is selected from one or any combination of O, S, N, S atom can be optionally oxidized to S(O) or S(O) 2 , C atom can be optionally oxidized to C(O), N Heteroatoms can optionally be oxidized to The heteroatom of the 5-10 membered heteroaryl group is selected from one of O, S, and N or any combination thereof;
  • Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, 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 alkyl Sulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, aryl and 5-10 membered heteroaryl, wherein 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 alkane Oxy, C 2-8 alkenyl, C 2-8 alkynyl,
  • n 0, 1, 2 or 3;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and halogenated C 1-6 alkyl.
  • X 1 , X 2 , and X 4 are each independently CH, and X 3 is CR 3 .
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a phosphodiesterase 9 (PDE9) inhibitor compound represented by the general formula (I) and a pharmaceutically acceptable salt, iso Conformers and deuterated compounds are used to treat heart failure in mammals.
  • PDE9 phosphodiesterase 9
  • a kit comprises (a) a phosphodiesterase 9 (PDE9) inhibitor compound represented by general formula (I) and pharmaceutically acceptable salts, isomers and deuterated compounds thereof And (b) instructions for using the compound and its pharmaceutically acceptable salts or isomers or deuterated compounds thereof for the treatment of heart failure in mammals.
  • PDE9 phosphodiesterase 9
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • R 3 is independently selected from hydrogen, deuterium, amino, cyano, halogen, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, (C 1 -4 alkyl) 2 amino, C C2-6 alkenyl group, C C2-6 alkynyl group, C 1-4 alkylcarbonyl, C 1-4 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, aminocarbonyl, cyclopropyl, azetidinyl, 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 al
  • Ring A is a 3-12 membered heterocyclic group, and the heteroatom of the 3-12 membered heterocyclic group is selected from one or any combination of O, S, N, and the S atom can be optionally oxidized to S(O ) Or S(O) 2 ;
  • Each R 1 is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-4 alkyl, C 1-4 alkoxy and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 alkoxy and 5-6 membered heteroaryl are unsubstituted or substituted by hydroxy;
  • n 0, 1 or 2;
  • R 2 is selected from hydrogen or C 1-6 alkyl.
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • A is a 3-12 membered heterocyclic group, preferably a 4-7 membered heterocyclic group.
  • A is a 3-12 membered heterocyclic group, preferably a 7-12 membered spiroheterocyclic group.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a phosphodiesterase 9 (PDE9) inhibitor compound represented by the general formula (I) and a pharmaceutically acceptable salt, iso Conformers and deuterated compounds are used to treat heart failure in mammals.
  • PDE9 phosphodiesterase 9
  • a kit comprises (a) a phosphodiesterase 9 (PDE9) inhibitor compound represented by general formula (I) and pharmaceutically acceptable salts, isomers and deuterated compounds thereof And (b) instructions for using the compound and its pharmaceutically acceptable salts or isomers or deuterated compounds thereof for the treatment of heart failure in mammals.
  • PDE9 phosphodiesterase 9
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 1-4 alkylcarbonyl, cyclopropyl, C 1-4 alkylaminocarbonyl and aminocarbonyl, wherein the C 1-4 alkyl group, C 1-4 alkoxy group, C 2-6 alkenyl group, C 1-4 alkylcarbonyl group, C 1-4 alkylaminocarbonyl group And the aminocarbonyl group is unsubstituted or optionally substituted by one or more independently selected from hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, C 1-4 alkylamino, (C 1 -4 alkyl) 2 amino and 4-6 membered heterocyclic group substituted by unsubstituted or substituted by C 1-4 alkyl;
  • Each R 1 is independently selected from hydrogen, deuterium, C 1-4 alkyl and C 1-4 alkoxy;
  • n 0, 1, or 2.
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a phosphodiesterase 9 (PDE9) inhibitor compound represented by the general formula (I) and a pharmaceutically acceptable salt, iso Conformers and deuterated compounds are used to treat heart failure in mammals.
  • PDE9 phosphodiesterase 9
  • a kit comprises (a) a phosphodiesterase 9 (PDE9) inhibitor compound represented by general formula (I) and pharmaceutically acceptable salts, isomers and deuterated compounds thereof And (b) instructions for using the compound and its pharmaceutically acceptable salts or isomers or deuterated compounds thereof for the treatment of heart failure in mammals.
  • PDE9 phosphodiesterase 9
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR 3 or N, and X 1 , X 2 , X 3 , and X 4 are not CR 3 at the same time;
  • Each occurrence of R 3 is independently selected from hydrogen, deuterium, cyano, amino, halogen, carboxyl, 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 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, cyclo
  • Ring A is selected from
  • X 1 and X 4 are each independently CH, X 2 is N, and X 3 is CR 3 .
  • X 1 and X 2 are each independently CH, X 3 is CR 3 , and X 4 is N.
  • the isomers refer to stereoisomers and tautomers.
  • 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
  • the hydrogen atom in the structure can be arbitrarily deuterated by one or more deuterium atoms.
  • the mammals are humans and animals.
  • the compound of general formula (I) and pharmaceutically acceptable salts, isomers, and deuterated compounds of the present invention are selected from the structures shown in Table 1.
  • the compound of general formula (I) and pharmaceutically acceptable salts, isomers and deuterated compounds of the present invention are selected from the following structures:
  • the compound of general formula (I) and pharmaceutically acceptable salts, isomers and deuterated compounds of the present invention are selected from the following structures:
  • the mammalian heart failure refers to that the mammal is experiencing or has suffered from heart failure, or that the mammal is a susceptible mammal of heart failure.
  • the types and diseases of the heart failure are due to any one or more of the mentioned in the present invention.
  • the heart failure disease is a variety of heart failures under different classifications, including but not limited to left heart failure, right heart failure, total heart failure; acute heart failure, chronic heart failure , Decompensated heart failure; systolic and diastolic heart failure; pre-heart failure stage, pre-clinical heart failure stage, clinical heart failure stage, refractory end-stage heart failure stage; New York Heart Association (NYHA) heart function classification Heart failure of grade I, II, III, IV, etc.; heart failure with reduced left ventricular ejection fraction, heart failure with median left ventricular ejection fraction, and heart failure with preserved left ventricular ejection fraction.
  • NYHA New York Heart Association
  • the heart failure disease is selected from but not limited to heart failure caused by ischemic heart disease, heart failure caused by toxic damage, heart failure caused by immune-mediated and inflammatory damage, Heart failure caused by invasive disease, heart failure caused by metabolic disorders, heart failure caused by genetic abnormality, heart failure caused by abnormal load, and heart failure caused by arrhythmia.
  • the heart failure disease is heart failure caused by ischemic heart disease.
  • the heart failure disease is selected from systolic heart failure and diastolic heart failure.
  • the systolic heart failure includes, but is not limited to, having at least one of the following characteristics: decreased myocardial systolic function; decreased left ventricular ejection fraction; increased ventricular or systolic and/or end-diastolic volume; detection of myocardial fibrosis; Thickening and then thinning (such as hypertrophic cardiomyopathy dilatation) and other characteristics.
  • the diastolic heart failure includes, but is not limited to, having at least one of the following characteristics: decreased myocardial diastolic function; decreased left ventricular ejection fraction; retained left ventricular ejection fraction; median left ventricular ejection fraction; increased heart mass or cardiac hypertrophy ; Disordered or disordered arrangement of cardiomyocytes.
  • the compound of general formula (I) and its pharmaceutically acceptable salts, isomers and deuterated compounds inhibit the activity of PDE9, increase the level of cyclic guanylate phosphate, and play a therapeutic role The effect of heart failure.
  • the compound of general formula (I) and its pharmaceutically acceptable salts, isomers and deuterated compounds can reverse heart failure patients by improving the heart function of patients or subjects with heart failure Or the subject’s myocardial remodeling has the effect of treating heart failure.
  • the medicine for treating heart failure disease further includes a second or more therapeutic agents.
  • the medicament for treating heart failure disease can be made into any pharmaceutically acceptable pharmaceutical preparation with a pharmaceutical carrier.
  • the pharmaceutical carrier of the present invention can be one or more solid or liquid excipients suitable for human use.
  • the pharmaceutical carrier preferably has sufficient purity and sufficiently low toxicity, and is compatible with the active ingredient of the present invention without significantly reducing the efficacy of the active ingredient.
  • the pharmaceutical carrier can be a filler, a binder, a disintegrant, a lubricant, an aqueous solvent or a non-aqueous solvent, and the like.
  • the pharmaceutical preparations of the present invention can be made into any pharmaceutically acceptable dosage form, in any suitable way of administration, such as oral, parenteral, transdermal, rectal, nasal, pulmonary, implantation, topical, etc. Administration and other methods are administered to patients or subjects in need of such treatment.
  • oral administration it can be made into tablets, capsules, pills, granules, emulsions, suspensions, etc.
  • parenteral administration it can be made into injection, sterile powder for injection, gel, suppository, etc.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.
  • the unit dosage form can be packaged as a package containing discrete quantities of preparation, such as packaged tablets, capsules, or powders in vials or ampoules.
  • the dosage of the drug depends on various factors, including the age, weight and condition of the patient, and the route of administration. The precise dose administered is determined based on the judgment of the treating physician.
  • the usual dosage for administering the active compound may be, for example, about 1 mg to about 1000 mg, about 5 mg to about 1000 mg per day.
  • the desired dosage also depends on the specific compound used, the severity of the disease, the route of administration, the weight and health of the patient, and the judgment of the treating physician. Perhaps the dose may exceed the given dose range in some cases, but there are data to support the choice of dose.
  • the drug is administered to the patient or subject in need of treatment by oral, parenteral, transdermal, rectal, nasal, transpulmonary, implantation, or local administration.
  • Figure 1 Compound 102 up-regulates the cGMP content in HEK293T cells double transfected with human PDE9A2 and natriuretic peptide protein receptor 1 (NPR1)
  • Figure 5 The effect of compounds on left ventricular systolic volume in rats with heart failure
  • halogen in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.
  • halo in the present invention means that any hydrogen atom in the substituent can be replaced by one or more identical or different halogen atoms.
  • Halogen is as defined above.
  • C 1-6 alkyl group in the present invention refers to a straight or branched alkyl group derived from a hydrocarbon moiety 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, isohexyl Base, 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-methyl
  • C 2-8 alkenyl group in the present invention refers to a linear or branched chain or cyclic alkene group derived from an alkene group of 2-8 carbon atoms containing a carbon-carbon double bond by removing one hydrogen atom, such as vinyl , 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.
  • C 2-8 alkynyl group refers to a linear or branched alkynyl group derived from an alkyne group of 2-8 carbon atoms containing a carbon-carbon triple bond by removing one hydrogen atom, such as ethynyl and propane. Alkynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl and the like.
  • C 1-6 alkoxy refers to the present invention as hereinbefore defined "C 1-6 alkyl” group linked to the parent molecule through an oxygen atom, i.e., "C 1-6 alkyl -O- "Groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentyloxy and n-hexoxy, etc.
  • the "C 1-4 alkoxy group” refers to the above-mentioned example containing 1-4 carbon atoms, that is, the "C 1-4 alkyl-O-" group.
  • C 1-6 alkylamino "(C 1-6 alkyl) 2 amino", “C 1-6 alkylcarbonylamino”, “C 1-6 alkylsulfonylamino””C 1-6 alkylaminocarbonyl", “(C 1-6 alkyl) 2 amino-carbonyl”, “C 1-6 alkoxy-carbonyl”, “C 1-6 alkylsulfonyl”, “"C 1-6 alkylthio" and “C 1-6 alkylcarbonyl” respectively refer to C 1-6 alkyl-NH-, (C 1-6 alkyl)(C 1-6 alkyl)N- , C 1-6 alkyl-C(O)-NH-, C 1-6 alkyl-S(O) 2 -NH 2 -, C 1-6 alkyl-NH-C(O)-, (C 1-6 alkyl) (C 1-6 alkyl) NC(O)-, C 1-6 alkyl-OC(O)-, C 1-6 alkyl
  • the "fused ring" in the present invention refers to a multi-ring system structure formed by two or more ring structures connected in a union, spiro, or bridge connection.
  • the combined ring refers to a condensed ring structure formed by two or more ring structures sharing two adjacent ring atoms (that is, sharing a bond).
  • the bridged ring refers to a condensed ring structure formed by two or more ring-mounted structures sharing two non-adjacent ring atoms.
  • 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" mentioned in the present invention includes all possible monocyclic and condensed rings (including condensed in the form of union, spiro and bridge), such as 3-8 membered monocyclic olefin, 7-11 membered spirocyclic olefin, 7-11 membered pentacyclic olefin, 6-11 membered bridged cyclic olefin, etc.
  • the cycloalkyl group described in the present invention includes all possible monocyclic and condensed rings (including condensed in the form of union, spiro and bridge); for example, "3-12 membered cycloalkyl" can be monocyclic, Bicyclic or polycyclic cycloalkyl system (also called fused ring system). Unless otherwise specified, a monocyclic ring system is a cyclic hydrocarbon group containing 3-8 carbon atoms. Examples of 3-8 membered cycloalkyl groups include, but are not limited to, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl and the like.
  • the fused-ring cycloalkyl group includes a bicyclic cycloalkyl group, a bridged cycloalkyl group, and a spirocycloalkyl group.
  • the bicyclic cycloalkyl group can be a 6-11 membered bicyclic cycloalkyl group, a 7-10 membered bicyclic cycloalkyl group, 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 spiro ring group can be a 7-12 membered spiro ring group or a 7-11 membered spiro ring group, examples of which include but are not limited to:
  • the bridging ring group may be 6-11 membered bridging ring group, 7-10 membered bridging ring group, examples of which 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 heteroatom selected from O, S, and N, preferably 1-3 heteroatoms. Atoms, including carbon atoms, nitrogen atoms and sulfur atoms can be oxo.
  • 3-12 membered heterocyclic group refers to a monocyclic heterocyclic group, a bicyclic heterocyclic group system or a polycyclic heterocyclic group system (also called a fused ring system), including saturated and partially saturated heterocyclic groups, but Does not include aromatic rings. Unless otherwise specified, it includes all possible monocyclic, condensed rings (including condensed in the form of union, spiro and bridge), saturated and partially saturated conditions.
  • the single heterocyclic group can 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-membered heterocyclic group, 5-6 membered oxygen-containing heterocyclic group, 3-8 membered nitrogen-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered saturated heterocyclic group, etc.
  • "3-8" membered saturated heterocyclic group examples of which include, but are not limited to, aziridinyl, oxetanyl, thiiridine, azetidinyl, oxetanyl, sulfur Etanyl, 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-dioxanyl Alkyl, 1,4-oxathiolanyl; "3-8" membered partially saturated heterocyclic group, examples of which include but are not limited to 4,5-dihydroisox
  • the fused heterocyclic ring includes a heterocyclic group, a spiro heterocyclic group, and a bridged heterocyclic group, which may be saturated, partially saturated or unsaturated, but not aromatic.
  • the fused heterocyclic group is fused to a benzene ring, 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic cycloalkenyl, 5-6 membered monocyclic heterocyclic group or 5-6 membered monocyclic heteroaromatic 5-6 membered monocyclic heterocyclyl ring.
  • the heterocyclic group may be 6-12 membered cyclic group, 7-10 membered cyclic group, 6-10 membered cyclic group, 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]heptyl, 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 Benzofuran-3-yl, in
  • the spiro heterocyclic group can be 6-12 membered spiro heterocyclic group, 7-11 membered spiro heterocyclic group, 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 described in the present invention includes all the possible formation of monocyclic rings, condensed rings, all aromatics, and partial aromatics.
  • "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 1-3 heteroatoms, including carbon atoms.
  • Sulfur atom is replaced by oxo, for example, carbon atom is replaced by C(O), sulfur atom is replaced by S(O), S(O) 2 , nitrogen atom Can be Substitute.
  • Heteroaryl groups include monoheteroaryl groups and condensed heteroaryl groups.
  • monoheteroaryl groups can be 5-7 membered heteroaryl groups, 5-6 membered heteroaryl groups, examples of which include but are not limited to Furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazole Group, thiadiazolyl, thienyl, triazolyl and triazinyl.
  • a fused heteroaryl group refers to a group formed by fusing a single ring heteroaromatic ring to a phenyl group, a cycloalkenyl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group.
  • the fused heteroaryl group can be It is 8-12 membered heteroaryl, 9-10 membered heteroaryl, examples include but are not limited to benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzothiadiyl Azolyl, benzothiazolyl, cinolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridyl, indazolyl, indole Group, isoindolyl, isoquinolyl, naphthyridinyl, purinyl, quinolyl, 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, thi
  • the "pharmaceutically acceptable salt” in the present invention refers to pharmaceutically acceptable acid and base addition salts or solvates thereof.
  • Such pharmaceutically acceptable salts include the 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 to 4)), etc.
  • Alkaline salts sodium salt, potassium salt, calcium salt, ammonium salt, etc. Those skilled in the art know a variety of non-toxic pharmaceutically acceptable addition salts.
  • the “isomer” in the present invention refers to stereoisomers and tautomers.
  • Stereoisomer refers to when a compound has an asymmetric atom, it will produce an enantiomer; when a compound has a double bond or a cyclic structure, it will produce a cis-trans isomer; all the enantiomers of the compound of formula (I) Isomers, diastereomers, racemic isomers, cis-trans isomers, geometric isomers, epimers and mixtures thereof are all included in the scope of the present invention.
  • Tautomer refers to the functional group isomer caused by the rapid movement of an atom in the molecule at two positions. Tautomer is a special functional group isomer. Such as the tautomerism of carbonyl compounds containing ⁇ -H, such as Such as other proton migration tautomerism, such as phenol-ketone tautomerism, nitroso-oxime tautomerism, imine-enamine tautomerism.
  • T, T1, and T2 are each independently any group that conforms to the bonding law of the compound.
  • the compound of the present invention contains a lactam structure and exists Tautomerism, when referring to a compound of the present invention, means that the tautomer of the compound is also mentioned.
  • the synthesis embodiment of the present invention synthesizes any type of tautomer, which means that another tautomer configuration is obtained at the same time, which can be converted to each other quickly and is in dynamic equilibrium.
  • the "C atom” in the present invention can be replaced by C(O); the "S atom” can be replaced by S(O) and S(O) 2 .
  • deuterated in the present invention refers to the replacement of one or more hydrogens in a compound or group with deuterium.
  • the "mammal” in the present invention refers to a kind of warm-blooded vertebrates in the subphylum Mammalia that use the lungs to breathe air, which secrete milk from the mammary glands to suckle their larvae, and can be divided into humans and animals.
  • animal mammals include, but are not limited to, tiger, leopard, wolf, deer, giraffe, mink, monkey, orangutan, tapir, fox, sloth, bear, koala, polar bear, elephant, musk, rhino, Manatee, lion, red panda, panda, warthog, antelope, koala, lynx, pangolin, anteater, otter, dolphin, walrus, seal, whale, platypus, hedgehog, kangaroo, hippopotamus, ferret, badger, raccoon, Horse, cow, sheep, mule, donkey, dog, rat, cat, rabbit.
  • the PDE9 inhibitor compound of the present invention can effectively inhibit the degradation of cGMP by inhibiting the activity of the PDE9 enzyme, increase the level of cGMP, and then activate protein kinase G (PKG), thereby having the effect of treating heart failure.
  • PKG protein kinase G
  • the compound of the present invention can effectively act on the PDE9 enzyme, increase the cGMP content of cardiomyocytes, effectively improve heart function in animal models, reverse myocardial remodeling, and have the effect of treating heart failure.
  • animal heart failure In animal models, animal heart failure often manifests as reduced activity, lack of energy, reduced diet, accelerated breathing, loose fur, cyanosis, ascites, lower extremity edema, liver stasis and hematoma, etc.
  • the evaluation indicators are through electrocardiogram, echocardiogram, heart Catheter examination, myocardial biopsy and pathological analysis, etc., to measure left ventricular end volume (EDV/ESV), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), left ventricular stroke work (SW), output per beat Volume (SV), rate of change from left ventricular pressure ( ⁇ dp/dtmax), cardiac output (CO), left ventricular ejection fraction (LVEF), left ventricular mass/volume ratio, etc.
  • EDV/ESV left ventricular end volume
  • LVSP left ventricular systolic pressure
  • LVEDP left ventricular end diastolic pressure
  • SW left ventricular stroke work
  • SV output per beat Volume
  • Heart failure model caused by myocardial infarction belongs to the heart failure model with weakened myocardial contractility.
  • this animal model has a high similarity with the clinical heart failure caused by myocardial infarction, and this type of patient has a certain representative in the heart failure population Sex.
  • DMF dimethylformamide
  • DIPEA N,N-diisopropylethylamine
  • EA ethyl acetate
  • PE petroleum ether
  • THF tetrahydrofuran
  • DCM dichloromethane
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluoro Phosphate
  • AD-mix- ⁇ refers to containing 0.0016 moles of (DHQD) 2PHAL (hydroquinidine 1,4-(2,3-naphthalene) diether), 0.4988 moles of potassium carbonate powder, A mixture of 0.4988 moles of potassium ferricyanide and 0.0007 moles of potassium osmate dihydrate
  • EDCI means 1-(3-dimethylaminopropyl)-3-ethyl
  • Triethylamine (35.182g, 0.3478mol, 2eq) and ethyl cyanoacetate (19.665g, 0.1738mol) were added to the above reaction solution, reacted at 150°C for 3h, LC-MS monitored the reaction to be complete, and the reaction solution was cooled to room temperature. Concentrate by pressure, add water (200mL), adjust the pH to 1 with hydrochloric acid (1mol/L), stir for 15 minutes, filter with suction, wash the filter cake twice with EA, and dry at 40°C to obtain a light brick red solid product (25.655) g, yield: 66%).
  • Step 1 Synthesis of methyl 6-ethyl-3-(cyanoacetamido)-1-pyridine-4-carboxylate
  • Step 3 6-Ethyl-4chloro-2-oxo-1,2-dihydro-1,7-naphthalene-3-carbonitrile and 2,4-dichloro-6-ethyl-1 Synthesis of ,7-Naphthalene-3-carbonitrile
  • reaction solution was cooled, concentrated, added acetonitrile dispersion (1L), poured into ice water, adjusted the pH value to about 5-6 with saturated sodium hydroxide solution, a large amount of yellow solid precipitated, suction filtered, dried to obtain a crude product, which is used for crude product
  • acetonitrile dispersion (1L)
  • poured into ice water adjusted the pH value to about 5-6 with saturated sodium hydroxide solution, a large amount of yellow solid precipitated, suction filtered, dried to obtain a crude product, which is used for crude product
  • n-heptane/ethyl acetate (3L/0.6L) was beaten and filtered with suction to obtain 6-ethyl-4chloro-2-oxo-1,2-dihydro-1,7-naphthalene-3-methyl Nitrile (510g, yield: 78%).
  • Triethylamine (35.182g, 0.3478mol, 2eq) and ethyl cyanoacetate (19.665g, 0.1738mol) were added to the above reaction solution, reacted at 150°C for 3h, LC-MS monitored the reaction to be complete, and the reaction solution was cooled to room temperature. Concentrate by pressure, add water (200mL), adjust the pH to 1 with hydrochloric acid (1mol/L), stir for 15 minutes, filter with suction, wash the filter cake twice with EA, and dry at 40°C to obtain a light brick red solid product (25.655) g, yield: 66%).
  • Step 4 6-Chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthalene-3 -Synthesis of formonitrile
  • Step 5 4-(4-Methoxy-4-methylpiperidin-1-yl)-2-oxo-6-(prop-1-en-2-yl)-1,2-dihydro- Synthesis of 1,7-naphthalene-3-carbonitrile
  • Step 1 6-(1,2-Dihydroxyethyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1 Synthesis of ,7-Naphthalene-3-carbonitrile
  • Step 3 6-(1-hydroxyethyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7- Synthesis of naphthalene-3-carbonitrile
  • Step 2 6-(2-Hydroxypropan-2-yl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1 Synthesis of ,7-Naphthalene-3-carbonitrile
  • Step 1 (2-(3-cyano-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-di Synthesis of tert-butyl azolin-6-carboxamido)ethyl)carbamate
  • Step 2 N-(2-Aminoethyl)-3-cyano-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro Synthesis of -1,7-naphthalazine-6-carboxamide hydrochloride
  • Step 1 Synthesis of methyl 2-(2-methoxyethoxy)-5-nitroisonicotinate
  • Step 2 Synthesis of methyl 5-amino-2-(2-methoxyethoxy)isonicotinate
  • Step 3 Synthesis of methyl 5-(2-cyanoacetamido)-2-(2-methoxyethoxy)isonicotinate
  • Step 4 Synthesis of 4-hydroxy-6-(2-methoxyethoxy)-2-oxo-1,2-dihydro-1,7-naphthalene-3-carbonitrile
  • Step 5 Synthesis of 4-chloro-6-(2-methoxyethoxy)-2-oxo-1,2-dihydro-1,7-naphthalene-3-carbonitrile
  • Step 6 4-(4-Methoxy-4-methylpiperidin-1-yl)-6-(2-methoxyethoxy)-2-oxo-1,2-dihydro-1 Synthesis of ,7-Naphthalene-3-carbonitrile
  • Step 1 Synthesis of ethyl 2-chloro-5-nitroisonicotinate
  • Step 2 Synthesis of ethyl 2-cyclopropyl-5-nitroisonicotinate
  • Step 3 Synthesis of ethyl 5-amino-2-cyclopropylisonicotinate
  • Step 4 Synthesis of ethyl 5-(2-cyanoacetamido)-2-cyclopropylisonicotinate
  • TLC monitors that there is no raw material add dichloromethane (40mL), wash with water (50mL ⁇ 2), wash the organic phase with saturated sodium carbonate aqueous solution (50mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (5.6g , Yield: 100%), put into the next step according to the theoretical amount.
  • Step 7 Synthesis of 2-chloro-6-cyclopropyl-4-(4-methoxy-4-methylpiperidin-1-yl)-1,7-naphthalene-3-carbonitrile
  • reaction solution was cooled to room temperature, poured into ice water (20mL), extracted with ethyl acetate (50mL ⁇ 3), the organic phases were combined, and water (50mL ⁇ 2) Washed, dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, the crude product was slurried with methyl tert-butyl ether (5 mL) for 1 h, filtered with suction, and the filter cake was dried to obtain the product (182 mg, yield: 66%).
  • Step 1 6-Chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-naphthalene-3 -Synthesis of formonitrile
  • Step 2 4-(4-Methoxy-4-methylpiperidin-1-yl)-2-oxo-6-vinyl-1,2-dihydro-1,7-naphthalene- Synthesis of 3-carbonitrile
  • reaction solution was cooled to 10-15°C, filtered with suction, the filtrate was concentrated to dryness, and recrystallized with PE and EA to obtain the product 6-(1-bromoethyl)-2,4-dichloro-1,7-diazepine Naphthalene-3-carbonitrile 35g.
  • Step 2 6-(1-Bromoethyl)-2-chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-1,7-naphthalene-3-methyl Synthesis of Nitriles
  • reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, 400 mL of water was added and stirred for 1 hour, filtered with suction, and the filter cake was recrystallized with ethanol to obtain the product 6-(1-bromoethyl)-2 -Chloro-4-(4-methoxy-4-methylpiperidin-1-yl)-1,7-naphthalene-3-carbonitrile 20g.
  • the crude product was first beaten with EA and recrystallized with ethanol to obtain the product 2-hydroxy-6-(1-hydroxyethyl)-4-(4-methoxy-4-methylpiperidin-1-yl)- 1,7-Naphthalene-3-carbonitrile 6g.
  • Step 4 Synthesis of 6-acetyl-2-hydroxy-4-(4-methoxy-4-methylpiperidin-1-yl)-1,7-naphthalene-3-carbonitrile
  • Step 1 Synthesis of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(methoxy-d 3 )-4-methylpiperidine-1-carboxylate
  • reaction solution was concentrated to dryness under reduced pressure, 100mL EA was added, the liquid was separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the product 4-(methoxy-d 3 )- Tert-Butyl 4-methylpiperidine-1-carboxylate (4.3 g).
  • Step 4 6-Ethyl-2-hydroxy-4-(4-(methoxy-d 3 )-4-methylpiperidin-1-yl)-1,7-naphthalene-3-methyl Synthesis of Nitriles
  • Test substance the compound of the present invention, prepared from the corresponding example of the present invention.
  • PDE9A2 enzyme (BPS, Cat.No.60090)
  • Dosing and incubation Use a very small amount of liquid pipetting system Echo to transfer the compound dilution mother solution to a 384-well plate; add 200 nL of the 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. Then add 10 ⁇ L of the substrate mixture, centrifuge at 1000 rpm for 1 min, and incubate with shaking at room temperature for 30 min. Finally, stop the reaction system by adding stop solution, and incubate with shaking at room temperature for 60 minutes. In the maximum reading hole (Max), replace the compound with solvent; in the minimum reading hole (Min), replace the compound and enzyme solution with solvent.
  • Max maximum reading hole
  • Min replace the compound and enzyme solution with solvent.
  • Detection Use a microplate reader to detect the fluorescence reading (F) at 480nm/535nm.
  • Test object PDE9A2 IC 50 (nM) Compound 63 4 Compound 64 38 Compound 68 3 Compound 69 11 Compound 70 twenty four Compound 74 14 Compound 75 69 Compound 76 61 Compound 77 52 Compound 78 85 Compound 80 25 Compound 81 31 Compound 84 38 Compound 87 9 Compound 90 20 Compound 91 50 Compound 92 25 Compound 102 15 Compound 114 48 Compound 115 19
  • Test substance Compound 102 of the present invention.
  • For its structure please refer to the structure of Compound No. 102 in Table 1 herein.
  • NPR1 Natriuretic peptide receptor 1 Natriuretic peptide receptor 1
  • HEK293T cells were plated in a 6-well plate with 2 ⁇ 10 6 cells/well and cultured for 6 hours to make the cells adhere to the wall.
  • Transfection wells Add 0.333 ⁇ g of NPR1 and 0.333 ⁇ g of PDE9 plasmid to each 100 ⁇ L of FBS-free DMEM starvation medium, pipette, and then add 20 ⁇ L of PolyFect transfection reagent, pipette and mix, and after standing for 10 minutes, add 600 ⁇ L of DMEM total culture Pipette and mix well, pipette 700 ⁇ L and slowly drop into the wells, and incubate for 18h. The method of each transfection hole is the same as above.
  • Non-transfected wells add an equal volume of DMEM complete medium (700 ⁇ LDMEM complete medium) to the non-transfected wells.
  • B/B 0 which is the ratio of the binding of the sample or standard to the maximum binding, and convert it according to the following formula, and then convert the logit obtained (B/B0) and lg (compound concentration) were linearly regressed to obtain a standard curve.
  • the B/B 0 value of the sample is converted to the logit (B/B0) value, and the cGMP content in the sample is calculated according to the standard curve.
  • N untransfected HEK293T cells
  • T HEK293T cells co-transfected with hNPR and hPDE9A.
  • ANF can significantly induce the expression of intracellular cGMP, and the compound of the present invention can significantly increase ANF-mediated cGMP by inhibiting PDE9 at the cellular level. Level, has good application potential in the treatment of heart failure.
  • Test substance Compound 102 of the present invention.
  • For its structure please refer to the structure of Compound No. 102 in Table 1 herein.
  • 1% gelatin is used to coat culture dishes when culturing primary cardiomyocytes of neonatal rats. Weigh 1g gelatin, dissolve it in 100mL deionized water, dilute it to 0.2% concentration before use;
  • the primary SD neonatal rat cardiomyocytes were extracted and plated in a 6-well plate. After RNCM adheres to the wall, stretches and beats, starvation for 24 hours. Before administration, replace with fresh whole medium, 1mL/well, add 10 ⁇ L of 100 ⁇ working solution of different concentrations of compound to each well to obtain a series of compound solutions with final concentration of 30 ⁇ M, 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M and 0.37 ⁇ M gradient concentration. After administration and incubation for 30 minutes, ANF was added to make the final concentration 1 ⁇ M, and after a total of 30 minutes of incubation, cells in each well were collected.
  • RNCM primary SD neonatal rat cardiomyocytes
  • the B/B 0 value of the sample is converted to the logit (B/B 0 ) value, and the cGMP content in the sample is calculated according to the standard curve.
  • ANF can significantly induce the expression of cGMP in primary cardiomyocytes of newborn rats, and the compound of the present invention can increase the level of cGMP by inhibiting PDE9 in primary cardiomyocytes of rats. This indicates that the compound of the present invention has the ability to increase myocardial cGMP and has a good clinical application potential in the treatment of heart failure.
  • d means twice a day administration
  • LVEF means left ventricular ejection fraction
  • EDV means left ventricular end-diastolic volume
  • ESV means left ventricular end-systolic volume
  • DMSO dimethyl sulfoxide
  • MC refers to methyl cellulose
  • mpk refers to mg/kg
  • SD refers to Sprague- Durer.
  • S.E.M means standard error.
  • PEG400 refers to polyethylene glycol 400
  • captisol is sodium sulfobutyl beta cyclodextrin.
  • FS is the left ventricular short axis shortening rate
  • HR is the heart rate.
  • SD rat Sprague Dawley rat
  • the animals were anesthetized by intraperitoneal injection of sodium pentobarbital, and atropine was injected intraperitoneally to expectorant.
  • the ventilator assisted breathing the chest was opened between the third and fourth ribs, and the left anterior descending coronary artery was ligated with a 5-0 suture needle.
  • the chest cavity is closed, the skin is sutured, and the insulation blanket is put in to recover.
  • the sham operation group also performed the same operation, but did not perform silk ligation.
  • model rats After surgery, intramuscular injection of meloxicam for pain relief and intraperitoneal injection of gentamicin sulfate injection to prevent infection, and intraperitoneal injection of lidocaine to prevent ventricular fibrillation.
  • the model rats After the animals recovered for one week, the model rats were divided into a model group and a therapeutic drug group (compound 102 group), and the vehicle and compound 102 were administered by gavage, respectively, twice a day for four consecutive weeks.
  • the rats were anesthetized with isoflurane, and the Vevo small animal ultrasound imaging system was used to examine the left ventricular function of the model rats.
  • the model was successful if the LVEF% decreased by 30%. Except for the sham operation group, they were randomly divided into 2 groups according to LVEF% and body weight. The number of animals in each group and the way of administration are as follows:
  • rats were sacrificed and the infarcted heart tissue was fixed with 4% formaldehyde, dehydrated, embedded in paraffin, and sectioned.
  • the collagen deposition was observed under the Sirius scarlet staining microscope, and the Leica aperio digital slice scanning system was used for scanning analysis.
  • the main evaluation indicators are LVEF% (left ventricular ejection fraction), FS (left ventricular short axis shortening rate), ESV (left ventricular end systolic volume), EDV (left ventricular end diastolic volume), and heart rate (HR).
  • LVEF% left ventricular ejection fraction
  • FS left ventricular short axis shortening rate
  • ESV left ventricular end systolic volume
  • EDV left ventricular end diastolic volume
  • HR heart rate
  • the data is represented by Mean ⁇ S.E.M, and Graphpad Prism 5.0 is used for statistical mapping. Statistical analysis was performed with T-test. P ⁇ 0.05 indicates that the difference is statistically significant.
  • the rats are 30mpk, bid, and the rats are in good condition after 28 days of continuous administration. Compared with the sham operation group, there is no weight abnormality, indicating that the compound is safer.
  • Compound 102 can improve the reduction of LVEF and FS in rats with heart failure, and there is a statistically significant difference compared with the model group (P ⁇ 0.001). At the same time, compound 102 has a significant improvement effect on the increase of cardiac EDV and ESV caused by heart failure (P ⁇ 0.05, P ⁇ 0.01). Therefore, the compound can significantly improve the contractile function and myocardial remodeling in rats with heart failure.
  • the percentage of collagen deposition in the sham operation group was 0.121 ⁇ 0.017%, while the percentage of collagen deposition in the marginal zone of left ventricular myocardial infarction in the model group was 28.9 ⁇ 1.35%, which was significantly higher than that in the sham operation group.
  • the difference is extremely significant (P ⁇ 0.001). It can be seen that after myocardial infarction in the model group, collagen deposition in the infarct area and the marginal zone leads to cardiac fibrosis. Compared with the model group, compound 102 can significantly reduce the collagen deposition in the marginal zone of infarction (P ⁇ 0.001), and effectively improve myocardial fibrosis caused by the heart failure model.
  • compound 102 can improve the cardiac function of rats with heart failure, reverse the myocardial remodeling caused by heart failure in rats, and reduce the fibrosis of the infarct marginal area. It has excellent clinical application potential in the treatment of heart failure.

Abstract

通式(I)的化合物及其药学上可接受的盐、异构体和氘代化合物在制备治疗心衰疾病的药物中的用途。实验证明，该化合物可以改善心衰大鼠的心脏功能，逆转大鼠心衰后导致的心肌重构，降低梗死边缘区域纤维化。

Description

磷酸二酯酶抑制剂的用途 技术领域
本发明属于医药技术领域，具体涉及通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体、氘代化合物在制备治疗哺乳动物心衰疾病的药物中的用途。
背景技术
心力衰竭(Heat Failure，简称心衰)是一种临床综合征，其特征是由于心脏结构和/或功能异常，引起静息或负荷时心输出量减少和/或心内压力增高，从而导致的病理生理状态，例如呼吸困难、踝部水肿和疲乏，也可伴有体征，例如颈静脉压升高、肺部啰音和外周水肿等。根据左心室射血分数(LVEF)的测量、利钠肽水平及心脏功能异常等指标，分为射血分数保留的心衰(HFpEF，LVEF>50％)、射血分数中间值的心衰(HFmrEF，LVEF在40％-49％)和射血分数降低的心衰(HFrEF，LVEF<40％)。根据心衰时间过程或严重程度等，又分为急性心衰、慢性心衰、失代偿性心衰、前心衰阶段、前临床心衰阶段、临床心衰阶段、难治性终末期心衰阶段；纽约心脏协会(NYHA)心功能分级I级、II级、III级、IV级的心衰等。心衰的发病与异常负荷(高血压、瓣膜和心肌结构缺陷、心包和心内膜心肌病变、高输出量状态、容量负荷过重、肺部疾病)、心肌病变(缺血性心脏病、毒性损伤、免疫介导的和炎症损害、心肌浸润性病变、内分泌代谢性疾病、遗传或应激导致心肌病变等)、心律失常(心动过速、心动过缓)有关，而感染、贫血、妊娠、分娩、心律紊乱、肺栓塞、糖尿病、服用抑制心脏的药物会加重心衰。在发达国家，心衰的发病率约为成年人群的1-2％，在年龄大于70周岁的人群中，升高到10％以上。在年龄55岁时的心衰终生风险，男性为33％，女性为28％。
经研究，神经内分泌***的激活所导致的心肌重构(如心肌肥厚、心脏扩大、心脏壁变薄等)是引起心衰发生和发展的关键因素。心肌重构最初可以对心功能产生部分代偿，但随着心肌重构的加剧，心功能逐渐由代偿向失代偿转变，导致出现更明显的症状和体征。因此如何预防或逆转心脏重构成为慢性心衰的主要治疗目标之一。(中华医学会心血管病学分会心力衰竭学组,中国医师协会心力衰竭专业委员会中华心血管病杂志编辑委员会.中国心力衰竭诊断和治疗指南2018[J].中华心血管病杂志,2018,46(10):760-789.DOI:10.3760/cma.j.issn.0253-3758.2018.10.004)
目前对于心衰的治疗，大部分是通过药物缓解疾病病症，而无法明显改善心脏功能，同时现有治疗药物多具有一定的副作用。同时许多现有治疗未能改善HFpEF患者的预后，也未降低病死率。而HFpEF型心衰占总心衰人数的50％左右。
磷酸二酯酶(phosphodiesterass,PDEs)是一类蛋白酶，能选择性的降解体内重要的第二信使cGMP(cyclic guanosine monophosphate，环磷酸鸟苷)和cAMP(环磷酸腺苷)，从而参与代谢、神经传递、细胞生长和分化等生理过程。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，PDE9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，PDE9抑制剂用于治疗由于中枢神经***紊乱导致的认知损害方面的疾病，比如老年痴呆症和精神***症、大脑的神经变性过程疾病。
经文献调研发现，在心肌细胞中，cGMP的升高可激活蛋白激酶G(PKG)，而该蛋白可起到心肌保护的作用，因此该通路是心衰治疗时的一个重要信号通路。而PDE9可选择性水解cGMP，从而降低了PKG的心肌保护作用。同时，心衰时PDE9表达量显著升高，尤其是HFpEF，因此心肌保护能力大大减弱。因此，抑制心衰患者中的PDE9可以起到心脏保护。本发明人对PDE9的生物功能进一步的研究，旨在探索其在治疗心衰领域中的作用。
发明内容
本发明研究了PDE9抑制剂在心衰领域的用途，研究发现，本发明的PDE9抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物对于心衰的治疗有显著的作用。因此，本发明的目的是，提供PDE9抑制剂在治疗心衰方面的新用途。
本发明采用的技术方案如下：
通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物在制备治疗哺乳动物心衰疾病的药物中的用途，
Figure PCTCN2020078215-appb-000001
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，N杂原子可以任选被氧化为
Figure PCTCN2020078215-appb-000002
R 3在每次出现时独立地选自氢、氘、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、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、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3-12元杂环基、芳基、5-10元杂芳基、3-12元环烷基、3-12元环烯基，其中所述3-12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)，N杂原子可以任选被氧化为
Figure PCTCN2020078215-appb-000003
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、氘、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为0、1、2或3；
R 2选自氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、卤代C 1-6烷基。
在一个实施方案中，X 1、X 2、X 4分别独立地为CH，X 3为CR 3。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在一个实施方案中，X 1、X 2、X 3、X 4不同时为CR 3。
在另一实施方式中，通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物在制备治疗哺乳动物心衰疾病的药物中的用途，
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
其中，
R 3在每次出现时独立地选自氢、氘、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、未被取代或被C 1-4烷基取代的4-6元杂环基的基团取代；
环A为3-12元杂环基，所述3-12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；
每个R 1分别独立地选自氢、氘、羟基、氰基、卤素、C 1-4烷基、C 1-4烷氧基和5-6元杂芳基，其中所述C 1-4烷基、C 1-4烷氧基和5-6元杂芳基未被取代或被羟基取代；
m为0、1或2；
R 2选自氢或C 1-6烷基。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在一个实施方案中，A为3-12元杂环基，优选为4-7元杂环基。
在一个实施方案中，A为3-12元杂环基，优选为7-12元螺杂环基。
在另一实施方式中，通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物在制备治疗哺乳动物心衰疾病的药物中的用途，
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
R 3在每次出现时独立地选自氢、氘、卤素、C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 1-4烷羰基、环丙基、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、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 PCTCN2020078215-appb-000004
每个R 1分别独立地选自氢、氘、C 1-4烷基和C 1-4烷氧基；
m为0、1或2。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在另一实施方式中，通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物在制备治疗哺乳动物心衰疾病的药物中的用途
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
R 3在每次出现时独立地选自氢、氘、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 PCTCN2020078215-appb-000005
m为0。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，其用于治疗哺乳动物心衰疾病，
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，N杂原子可以任选被氧化为
Figure PCTCN2020078215-appb-000006
R 3在每次出现时独立地选自氢、氘、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、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、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3-12元杂环基、芳基、5-10元杂芳基、3-12元环烷基、3-12元环烯基，其中所述3-12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)，N杂原子可以任选被氧化为
Figure PCTCN2020078215-appb-000007
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、氘、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为0、1、2或3；
R 2选自氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、卤代C 1-6烷基。
在一个实施方案中，X 1、X 2、X 4分别独立地为CH，X 3为CR 3。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在一个实施方案中，X 1、X 2、X 3、X 4不同时为CR 3。
在另一实施方式中，通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，其用于治疗哺乳动物心衰疾病，
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
其中，
R 3在每次出现时独立地选自氢、氘、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、未被取代或被C 1-4烷基取代的4-6元杂环基的基团取代；
环A为3-12元杂环基，所述3-12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；
每个R 1分别独立地选自氢、氘、羟基、氰基、卤素、C 1-4烷基、C 1-4烷氧基和5-6元杂芳基，其中所述C 1-4烷基、C 1-4烷氧基和5-6元杂芳基未被取代或被羟基取代；
m为0、1或2；
R 2选自氢或C 1-6烷基。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在一个实施方案中，A为3-12元杂环基，优选为4-7元杂环基。
在一个实施方案中，A为3-12元杂环基，优选为7-12元螺杂环基。
在另一实施方式中，通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，其用于治疗哺乳动物心衰疾病，
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
R 3在每次出现时独立地选自氢、氘、卤素、C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 1-4烷羰基、环丙基、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、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 PCTCN2020078215-appb-000008
每个R 1分别独立地选自氢、氘、C 1-4烷基和C 1-4烷氧基；
m为0、1或2。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在另一实施方式中，通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，其用于治疗哺乳动物心衰疾病，
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
R 3在每次出现时独立地选自氢、氘、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 PCTCN2020078215-appb-000009
m为0。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
治疗哺乳动物心衰疾病的方法，其包括对患者或受试者施用通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，N杂原子可以任选被氧化为
Figure PCTCN2020078215-appb-000010
R 3在每次出现时独立地选自氢、氘、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、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、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3-12元杂环基、芳基、5-10元杂芳基、3-12元环烷基、3-12元环烯基，其中所述3-12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)，N杂原子可以任选被氧化为
Figure PCTCN2020078215-appb-000011
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、氘、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为0、1、2或3；
R 2选自氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、卤代C 1-6烷基。
在一个实施方案中，X 1、X 2、X 4分别独立地为CH，X 3为CR 3。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在一个实施方案中，X 1、X 2、X 3、X 4不同时为CR 3。
在另一实施方式中，治疗哺乳动物心衰疾病的方法，其包括对患者或受试者施用通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
其中，
R 3在每次出现时独立地选自氢、氘、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、未被取代或被C 1-4烷基取代的4-6元杂环基的基团取代；
环A为3-12元杂环基，所述3-12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；
每个R 1分别独立地选自氢、氘、羟基、氰基、卤素、C 1-4烷基、C 1-4烷氧基和5-6元杂芳基，其中所述C 1-4烷基、C 1-4烷氧基和5-6元杂芳基未被取代或被羟基取代；
m为0、1或2；
R 2选自氢或C 1-6烷基。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在一个实施方案中，A为3-12元杂环基，优选为4-7元杂环基。
在一个实施方案中，A为3-12元杂环基，优选为7-12元螺杂环基。
在另一实施方式中，治疗哺乳动物心衰疾病的方法，其包括对患者或受试者施用通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
R 3在每次出现时独立地选自氢、氘、卤素、C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 1-4烷羰基、环丙基、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、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 PCTCN2020078215-appb-000012
每个R 1分别独立地选自氢、氘、C 1-4烷基和C 1-4烷氧基；
m为0、1或2。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在另一实施方式中，治疗哺乳动物心衰疾病的方法，其包括对患者或受试者施用通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
R 3在每次出现时独立地选自氢、氘、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 PCTCN2020078215-appb-000013
m为0。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
一种药物组合物，其包含(a)通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，用于治疗哺乳动物心衰疾病。
一个药盒，包含(a)通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物和(b)使用所述化合物及其药学上可接受的盐或其异构体或其氘代化合物用于治疗哺乳动物心衰疾病药物的说明书。
在涉及药物组合物和药盒的实施方案中，通式(I)中：
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，N杂原子可以任选被氧化为
Figure PCTCN2020078215-appb-000014
R 3在每次出现时独立地选自氢、氘、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、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、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3-12元杂环基、芳基、5-10元杂芳基、3-12元环烷基、3-12元环烯基，其中所述3-12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)，N杂原子可以任选被氧化为
Figure PCTCN2020078215-appb-000015
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、氘、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为0、1、2或3；
R 2选自氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、卤代C 1-6烷基。
在一个实施方案中，X 1、X 2、X 4分别独立地为CH，X 3为CR 3。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在一个实施方案中，X 1、X 2、X 3、X 4不同时为CR 3。
在另一实施方式中，本发明涉及一种药物组合物，其包含(a)通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，用于治疗哺乳动物心衰疾病。
在另一实施方式中，一个药盒，包含(a)通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物和(b)使用所述化合物及其药学上可接受的盐或其异构体或其氘代化合物用于治疗哺乳动物心衰疾病药物的说明书。
在涉及药物组合物和药盒的实施方案中，通式(I)中：
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
其中，
R 3在每次出现时独立地选自氢、氘、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、未被取代或被C 1-4烷基取代的4-6元杂环基的基团取代；
环A为3-12元杂环基，所述3-12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；
每个R 1分别独立地选自氢、氘、羟基、氰基、卤素、C 1-4烷基、C 1-4烷氧基和5-6元杂芳基，其中所述C 1-4烷基、C 1-4烷氧基和5-6元杂芳基未被取代或被羟基取代；
m为0、1或2；
R 2选自氢或C 1-6烷基。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在一个实施方案中，A为3-12元杂环基，优选为4-7元杂环基。
在一个实施方案中，A为3-12元杂环基，优选为7-12元螺杂环基。
在另一实施方式中，本发明涉及一种药物组合物，其包含(a)通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，用于治疗哺乳动物心衰疾病。
在另一实施方式中，一个药盒，包含(a)通式(I)所示的磷酸二酯酶9(PDE9)抑制 剂化合物及其药学上可接受的盐、异构体和氘代化合物和(b)使用所述化合物及其药学上可接受的盐或其异构体或其氘代化合物用于治疗哺乳动物心衰疾病药物的说明书。
在涉及药物组合物和药盒的实施方案中，通式(I)中：
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
R 3在每次出现时独立地选自氢、氘、卤素、C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 1-4烷羰基、环丙基、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、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 PCTCN2020078215-appb-000016
每个R 1分别独立地选自氢、氘、C 1-4烷基和C 1-4烷氧基；
m为0、1或2。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在另一实施方式中，本发明涉及一种药物组合物，其包含(a)通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物，用于治疗哺乳动物心衰疾病。
在另一实施方式中，一个药盒，包含(a)通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物和(b)使用所述化合物及其药学上可接受的盐或其异构体或其氘代化合物用于治疗哺乳动物心衰疾病药物的说明书。
在涉及药物组合物和药盒的实施方案中，通式(I)中：
其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，且X 1、X 2、X 3、X 4不同时为CR 3；
R 3在每次出现时独立地选自氢、氘、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 PCTCN2020078215-appb-000017
m为0。
在一个实施方案中，X 1、X 4分别独立地为CH，X 2为N，X 3为CR 3。
在一个实施方案中，X 1、X 2分别独立地为CH，X 3为CR 3，X 4为N。
在另一种实施方式中，所述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)所示的结构R 2为氢时，具有通式(I’)所示的互变异构体
Figure PCTCN2020078215-appb-000018
的互变异构体为
Figure PCTCN2020078215-appb-000019
在本发明的一种实施方式中，通式(I)所示的化合物的氘代化合物，其结构上的氢原子可任意被一至多个氘原子所氘代。
在另一实施方式中，所述的哺乳动物是人类和动物类。
在本发明的一种实施方式中，本发明所述通式(I)的化合物及其药学上可接受的盐、异构体和氘代化合物选自表1所示结构。
表1
Figure PCTCN2020078215-appb-000020
Figure PCTCN2020078215-appb-000021
Figure PCTCN2020078215-appb-000022
Figure PCTCN2020078215-appb-000023
Figure PCTCN2020078215-appb-000024
Figure PCTCN2020078215-appb-000025
Figure PCTCN2020078215-appb-000026
Figure PCTCN2020078215-appb-000027
Figure PCTCN2020078215-appb-000028
Figure PCTCN2020078215-appb-000029
在本发明的一种实施方式中，本发明所述通式(I)的化合物及其药学上可接受的盐、异构体和氘代化合物选自以下结构:
Figure PCTCN2020078215-appb-000030
在本发明的一种实施方式中，本发明所述通式(I)的化合物及其药学上可接受的盐、异 构体和氘代化合物选自以下结构:
Figure PCTCN2020078215-appb-000031
所述哺乳动物心衰，是指该哺乳动物正在经历或曾经患有心力衰歇，或该哺乳动物为心衰的易感型哺乳动物。而所述心力衰歇的类型及病因为本发明中说提及的任何一种或几种。
在本发明的另一种实施方式中，所述心衰疾病为不同分类依据下的各种心衰，包括但不限于左心衰竭、右心衰竭、全心衰竭；急性心衰、慢性心衰、失代偿性心衰；收缩性和舒张性心力衰竭；前心衰阶段、前临床心衰阶段、临床心衰阶段、难治性终末期心衰阶段；纽约心脏协会(NYHA)心功能分级I级、II级、III级、IV级的心衰等；左心室射血分数降低型心衰、左心室射血分数中间值心衰、左心室射血分数保留型心衰。
在本发明的另一种实施方式中，所述心衰疾病选自但不限于缺血性心脏病导致的心衰、毒性损害导致的心衰、免疫介导的和炎症损害导致的心衰、浸润性病变导致的心衰、代谢紊乱导致的心衰、遗传异常导致的心衰、异常负荷导致的心衰、心律失常导致的心衰。在本发明的另一种实施方式中，所述心衰疾病为缺血性心脏病导致的心衰。
在本发明的另一种实施方式中，所述心衰疾病选自收缩性心力衰竭和舒张性心力衰歇。
所述的收缩性心力衰竭包括但不限于具备至少一个以下特征：心肌收缩功能减退；左心室射血分数降低；心室或心脏收缩及/或舒张末期容积增加；检测显示有心肌纤维化；心室壁先变厚再变薄(如肥厚型心肌病扩张期)等特征。
所述的舒张性心力衰竭包括但不限于具备至少一个以下特征：心肌舒张功能减退；左心室射血分数降低；左心室射血分数保留；左心室射血分数中间值；心脏质量增加或心脏肥厚；心肌细胞紊乱或无序排列等特征。
在本发明的另一种实施方式中，通式(I)化合物及其药学上可接受的盐、异构体和氘代化合物通过抑制PDE9活性，提高环磷酸鸟苷酸的水平，起到治疗心衰的作用效果。
在本发明的另一种实施方式中，通式(I)化合物及其药学上可接受的盐、异构体和氘代化合物通过改善心衰患者或受试者的心脏功能，逆转心衰患者或受试者的心肌重构，起到治疗心衰的作用效果。
在本发明的另一种实施方式中，所述的治疗心衰疾病的药物还包括第二种或多种治疗剂。
在本发明的另一种实施方式中，所述治疗心衰疾病的药物可以与药用载体制成药学上可接受的任意药物制剂。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辅料。所述药用载体优选具有足够的纯度和足够低的毒性，并且与本发明活性成分具有相容性且不明显减低活性成分的药效。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、透皮、直肠、经鼻、经肺、植入、局部等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、乳剂、混悬剂等。用于肠胃外给药时，可以制成注射液、注射用无菌粉末、凝胶剂、栓剂等。
在本发明的另一种实施方式中，药物制剂优选为单位剂量形式。在该形式中，制剂被细分成含有适当量的活性组分的单位剂量。可以将单位剂量形式包装成含有离散量的制剂的包装，诸如包装的片剂、胶囊剂或在小瓶或安瓿中的粉剂。
药物的施用剂量取决于各种因素，包括患者的年龄、体重和状态以及给药途径。施用的精确剂量基于治疗医生的判断确定。用于施用活性化合物的通常剂量可以是例如每天约1mg至大约1000mg，大约5mg至大约1000mg/天。期望的剂量还取决于采用的具体化合物、疾病的严重程度、施用途径、患者的体重和健康状况以及治疗医生的判断。或许某些情况下剂量或超过给出的剂量范围，但有数据支持剂量的选择即可。
在本发明的另一种实施方式中，所述的药物通过口服、肠胃外、透皮、直肠、经鼻、经肺、植入、局部给药方式施用于需要治疗的患者或受试者。
附图说明
图1化合物102对人PDE9A2和利钠肽蛋白受体1(NPR1)双转染的HEK293T细胞内cGMP含量的上调作用
图2化合物102对心钠素刺激的新生大鼠原代心肌细胞中cGMP的影响
图3化合物对心衰大鼠左心室射血分数的影响
图4化合物对心衰大鼠短轴缩短率的影响
图5化合物对心衰大鼠左心室收缩容积的影响
图6化合物对心衰大鼠左心室舒张容积的影响
图7化合物对心衰大鼠HR的影响
图8各组大鼠心脏梗死边缘区纤维化染色
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***(也称为稠环***)。在不特别指明的情况下，单环***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 PCTCN2020078215-appb-000032
Figure PCTCN2020078215-appb-000033
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 PCTCN2020078215-appb-000034
Figure PCTCN2020078215-appb-000035
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***或多环杂环基***(也称为稠环***)，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 PCTCN2020078215-appb-000036
Figure PCTCN2020078215-appb-000037
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 PCTCN2020078215-appb-000038
Figure PCTCN2020078215-appb-000039
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，氮原子
Figure PCTCN2020078215-appb-000040
可被
Figure PCTCN2020078215-appb-000041
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、***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原子时，会产生对映异构体；当化合物存在双键或环状结构时，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 PCTCN2020078215-appb-000042
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 PCTCN2020078215-appb-000043
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。本发明合成实施例合成得到任意一种互变异构体的类型，意味着同时得到另一种互变异构构型，其能迅速地相互转换，且处于动态平衡中。
本发明所述的“C原子”可被C(O)替代；“S原子”可被S(O)、S(O) 2替代。
本发明所述的“氘代”指化合物或基团中的一个或多个氢被氘所取代。
本发明所述的“哺乳动物”是指脊椎动物亚门下哺乳纲的一类用肺呼吸空气的温血脊椎动物，其通过乳腺分泌乳汁来给幼体哺乳，其可分为人类和动物类。动物类的哺乳动物的实例包括但不限制于虎、豹、狼、鹿、长颈鹿、貂、猴、猩猩、貘、狐、树懒、熊、无尾熊、北极熊、象、麝牛、犀牛、海牛、狮子、小熊猫、熊猫、疣猪、羚羊、考拉、猞猁、穿山甲、食蚁兽、水獭、海豚、海象、海豹、鲸鱼、鸭嘴兽、刺猬、袋鼠、河马、鼬、獾、狸、马、牛、羊、骡、驴、狗、鼠、猫、兔。
本发明的优异效果
本发明的PDE9抑制剂化合物，通过抑制PDE9酶的活性，有效抑制cGMP的降解，升高cGMP水平，进而激活蛋白激酶G(PKG)，从而起到治疗心衰的作用效果。研究表明，本发明化合物能有效作用于PDE9酶，升高心肌细胞cGMP含量，有效改善动物模型上心脏功能，逆转心肌重构，起到治疗心衰的作用效果。
临床上对于非急性疑似心衰患者，主要根据患者临床病史、表现症状、体格检查、心电图检测、利钠肽水平及超声心动图来排除或确诊心衰，尤其是超声心动图可提供心室容量、心舒张功能、室壁厚度、瓣膜功能和肺动脉高压的即时信息，因此被广泛用于疑似心衰患者的检测。临床上对于急性心衰患者的初步诊断也会应用超声心动图来进一步证实病症。
在动物模型上，动物心衰时常表现为活动减少，精神不振，饮食减少，呼吸加快，皮毛疏松，紫绀，腹水，下肢水肿，肝瘀血肿大等，评价指标为通过心电图、超声心动图、心导管检查，心肌活检病理分析等手段，测定左心室末期容积(EDV/ESV)、左心室收缩压(LVSP)、左心室舒张末压(LVEDP)、左心室搏出功(SW)、每博输出量(SV)、自左心室压力变化速率(±dp/dtmax)、心排出量(CO)、左心室射血分数(LVEF)、左心室质量/容量比值等。常用的模型为压力超负荷型HF模型、容量超负荷型HF模型、心肌收缩力减弱型HF模型、体外HF模型、基因工程HF模型。其中心肌梗死所导致的心衰模型属于心肌收缩力减弱心衰模型，同时该动物模型与临床心肌梗死所致心衰患者的相似度较高，且该类患者在心衰群体中具有一定的代表性。
以下结合实施例对本发明进行阐述；然而，这些实施例并不意味着以任何的方式限制本发明的范围。
具体实施方式
本文中使用的缩写，“DMF”是指二甲基甲酰胺；“DIPEA”是指N,N-二异丙基乙胺；“EA”是指乙酸乙酯；“PE”是指石油醚；“THF”是指四氢呋喃；“DCM”是指二氯甲烷；“HATU”是指2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；“AD-mix-β”是指含有0.0016摩尔的(DHQD)2PHAL(氢化奎尼定1,4-(2,3-二氮杂萘)二醚)、0.4988摩尔的碳酸钾粉末、0.4988摩尔的铁***和0.0007摩尔的二水合锇酸钾混合物；“EDCI”是指1-(3-二甲氨基丙基)-3- 乙基碳二亚胺盐酸盐；“NBS”是指N-溴代琥珀酰亚胺；“AIBN”是指偶氮二异丁腈；“TEA”是指三乙胺。
制备例1：中间体4,6-二氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
步骤1：6-氯-2H-吡啶并[3,4-d][1,3]恶嗪-2,4(1H)-二酮的合成
Figure PCTCN2020078215-appb-000044
将5-氨基-2-氯异烟酸(30g,0.1738mol,1.0eq)，溶于N,N-二甲基甲酰胺(300mL)中，0℃下分批加入N,N’-羰基二咪唑(48g,0.2955mol,1.7eq)，缓慢升至室温过夜。LC-MS显示反应完全，冷却至室温，不经处理直接进行下一步。
步骤2：6-氯-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000045
向上述反应液中加入三乙胺(35.182g,0.3478mol,2eq)和氰乙酸乙酯(19.665g,0.1738mol)，150℃反应3h，LC-MS监测反应完全，反应液冷却至室温，减压浓缩，加入水(200mL)，用盐酸(1mol/L)调节pH值至1，搅拌15分钟，抽滤，滤饼用EA洗涤两次，40℃烘干得浅砖红色固体状产物(25.655g,产率:66％)。
步骤3：4,6-二氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000046
将6-氯-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(5.0g,0.0226mol,1eq)和三氯氧磷(15mL)加入反应瓶，将反应瓶放入已经加热至100℃的油浴中，反应约6min，固体开始慢慢溶解，颜色由淡黄色开始加慢慢加深。TLC检测反应完全，冷却至室温，向瓶中加入适量DCM，倒入冰水(100mL)中，搅拌10min，抽滤，滤饼用甲基叔丁基醚洗，抽干，40℃真空干燥得淡黄色固体状产品。分五批投料，共投料6-氯-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈25.655g(0.1157mol)得到产品19.486g(产率:70.1％)。
制备例2:中间体6-乙基-4氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈和2,4-二氯-6-乙基-1,7-二氮杂萘-3-甲腈的合成
步骤1：6-乙基-3-(氰基乙酰胺基)-1-吡啶-4-甲酸甲酯的合成
Figure PCTCN2020078215-appb-000047
将中间体6-乙基-3-氨基-1-吡啶-4-甲酸甲酯(131g,727.13mmol,1.0eq)溶于二氯甲烷(1.31L)，在冰浴条件下加入氰基乙酸(74.22g,872.56mmol,1.2eq)，分批加入EDCI(209.07g,1090.70mmol,1.5eq),25℃反应2小时，LC-MS检测反应完全。向反应液中加入H 2O(1.5L)，分液，有机相用H 2O(2×800mL)洗，无水硫酸钠干燥，抽滤，滤液浓缩，粗品经甲基叔丁基醚(500mL)打浆得到产品(165g,收率:91.78％)。
步骤2：6-乙基-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000048
将中间体6-乙基-3-(氰基乙酰胺基)-1-吡啶-4-甲酸甲酯(165g,667.34mmol,1.0eq)溶于乙醇(1.65L)中，冰浴条件下分批加入乙醇钠(136.24g,2002.62mmol,3.0eq)，加完25℃反应2小时，LC-MS检测反应完全。浓缩，加H 2O(1.5L)，在冰浴条件下用浓盐酸调pH值至4以下，析出大量淡黄色固体，抽滤，滤饼干燥得到产品(138g,收率:96.09％)。
步骤3：6-乙基-4氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈和2,4-二氯-6-乙基-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000049
将中间体6-乙基-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(605g,2.81mol,1.0eq)溶于乙腈(3L)，冰浴下加入三氯氧膦(1723g,11.24mol,4.0eq)，100℃反应2小时。将反应液降温，浓缩，加入乙腈分散(1L)，倒入冰水中，用饱和氢氧化钠溶液调pH值至5-6左右，有大量黄色固体析出，抽滤，烘干得粗品，粗品用正庚烷/乙酸乙酯(3L/0.6L)打浆，抽滤得到6-乙基-4氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(510g,收率:78％)。
滤液浓缩，粗品经硅胶柱层析纯化(PE:EA＝10:1)得到2,4-二氯-6-乙基-1,7-二氮杂萘-3-甲腈(50g,收率:7％)。
实施例1：6-异丙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物91)
步骤1：6-氯-2H-吡啶并[3,4-d][1,3]恶嗪-2,4(1H)-二酮的合成
Figure PCTCN2020078215-appb-000050
将5-氨基-2-氯异烟酸(30g,0.1738mol,1.0eq)，溶于N,N-二甲基甲酰胺(300mL)中，0℃下分批加入N,N’-羰基二咪唑(48g,0.2955mol,1.7eq)，缓慢升至室温过夜。LC-MS显示反应完全，冷却至室温，不经处理直接进行下一步。
步骤2：6-氯-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000051
向上述反应液中加入三乙胺(35.182g,0.3478mol,2eq)和氰乙酸乙酯(19.665g,0.1738mol)，150℃反应3h，LC-MS监测反应完全，反应液冷却至室温，减压浓缩，加入水(200mL)，用盐酸(1mol/L)调节pH值至1，搅拌15分钟，抽滤，滤饼用EA洗涤两次，40℃烘干得浅砖红色固体状产物(25.655g,产率:66％)。
步骤3：4,6-二氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000052
将6-氯-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(5.0g,0.0226mol,1eq)和三氯氧磷(15mL)加入反应瓶，将反应瓶放入已经加热至100℃的油浴中，反应约6min，固体开始慢慢溶解，颜色由淡黄色开始加慢慢加深。TLC检测反应完全，冷却至室温，向瓶中加入适量DCM，倒入冰水(100mL)中，搅拌10min，抽滤，滤饼用甲基叔丁基醚洗，抽干，40℃真空干燥得淡黄色固体状产品。分五批投料，共投料6-氯-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈25.655g(0.1157mol)得到产品19.486g(产率:70.1％)。
步骤4：6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000053
将中间体4,6-二氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.0g,8.33mmol,1.0eq)溶于DMF(10mL)，加入DIPEA(6.45g,50mmol,6.0eq)和4-甲氧基-4-甲基哌啶三氟乙酸盐(2.2g,9.16mmol,1.1eq)，80℃反应2小时。LC-MS检测反应完全，加入水(10mL)，二氯甲烷(10mL×3)萃取，有机相用水洗(10mL×3)，无水硫酸钠干燥，过滤，减压浓缩得到黄色固体状产物(2.7g粗品)。
步骤5：4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-(丙-1-烯-2-基)-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000054
将中间体6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(500mg,1.5mmol,1.0eq)溶于1,4-二氧六环(5mL)和H 2O(1mL)中，加入三氟(丙-1-烯-2-基)硼酸钾(668mg,4.5mmol,3.0eq)和碳酸铯(1.466g,4.5mmol,3.0eq)，氮气保护下加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(110mg,0.15mmol,0.1eq)，100℃反应12小时，LC-MS检测反应完全。加入水(20mL)，乙酸乙酯(20mL×3)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经硅胶柱层析纯化(DCM:MeOH＝50:1)得到产品(390mg,收率:76.9％)。
步骤6：6-异丙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000055
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-1,7-二氮杂萘-3-甲腈(390mg,1.15mmol,1.0eq)溶于甲醇(10mL)，加入Pd/C(100mg)，氢气条件下反应12小时，LC-MS检测反应完全。抽滤，滤液减压浓缩，粗品用甲基叔丁醚打浆，抽滤，粗品再经制备薄层层析分离(DCM:MeOH＝15:1)得到产品(100mg,收率:25.6％)。 1HNMR(400MHz,DMSO-d 6)δ(ppm):11.82(s,1H),8.61(s,1H),7.38(s,1H),3.60-3.61(m,4H),3.19(s,3H),3.06-3.13(m,1H),1.90-1.93(m,2H),1.75-1.82(d,2H),1.26(s,9H).
分子式:C 19H 24N 4O 2分子量:340.43 LC-MS(Pos，m/z)＝341.19[M+H] +.
实施例2：4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物70)
Figure PCTCN2020078215-appb-000056
将中间体6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(20.1g,60.40mmol,1.0eq)溶于1,4-二氧六环(600mL)和H 2O(150mL)，加入三氟(乙烯基)硼酸钾(12.14g,90.6mmol,1.5eq)、碳酸铯(58g,181.2mmol,3.0eq)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(4.4g,6.04mmol,1.0eq)，氮气保护下100℃反应8小时，LC-MS检测反应完全。加入水(20mL)，二氯甲烷(30mL×3)萃取，有机相用水(10mL×3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝50:1)纯化得到产品(14.63g,收率:74％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):12.03(s,1H),8.64(s,1H),7.56(s,1H),6.89-6.96(m,1H),6.15-6.19(m,1H),5.39-5.42(m,1H),3.61-3.64(m,4H),3.19(s,3H),1.77-1.93(m,4H),1.21(s,3H).
分子式:C 18H 20N 4O 2 分子量:324.38 LC-MS(Pos,m/z)＝325.16[M+H] +.
实施例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-1,7-二氮杂萘-3-甲腈的合成(化合物63)
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-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000057
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-1,7-二氮杂萘-3-甲腈(500mg,1.542mmol,1.0eq)溶于叔丁醇(10mL)和水(10mL)，加入甲磺酰胺(147mg,1.542mmol,1.0eq)和AD-mix-β(6.0g)，常温反应12小时，LC-MS检测反应完全。加入水(10mL)，二氯甲烷(30mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩得到产品(552mg,收率:100％)。
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-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000058
将中间体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-1,7-二氮杂萘-3-甲腈(552mg,1.542mmol,1.0eq)溶于四氢呋喃(10mL)和水(2mL)，加入高碘酸钠(650mg,3.084mmol,2.0eq)，反应4个小时，LC-MS检测反应完全。加入水(10mL)，乙酸乙酯(20mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析纯化(DCM:MeOH＝60:1)得到黄色固体状产品(160g,两步收率:32％)。
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-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000059
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-1,7-二氮杂萘-3-甲腈(160mg,0.49mmol,1.0eq)溶于四氢呋喃(5mL)，在0℃下滴加甲基氯化镁(1mL)，反应1小时，LC-MS检测反应完全。加入水(10mL)，乙酸乙酯(20mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析纯化(DCM:MeOH＝40:1)得到产品(108mg,收率：64％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):11.93(s,1H),8.58(s,1H),7.72(s,1H),5.48-5.49(d,1H),4.75-4.81(m,1H),3.56-3.65(m,4H),3.20(s,3H),1.91-1.95(m,2H),1.73-1.79(m,2H),1.38-1.40(d,3H),1.23(s,3H).
分子式:C 18H 22N 4O 3 分子量:342.40 LC-MS(Pos,m/z)＝343.17[M+H] +.
取0.3925g化合物63用甲醇溶解为浓度为2mg/ml的溶液，采用Shimadzu LC-20AD制备液相进行对映异构体分离，分离条件如下：分别收集6分钟及12分钟相应组分得到的化合物。6分钟相应组分得到的化合物是化合物A，12分钟相应组分得到化合物B。旋转蒸发出去溶剂，分别得到化合物A 0.1814g和化合物B 0.1984g。化合物A和B为对映异构体，二者的结构如下，当化合物A为其中一个结构时，化合物B为另外一个：
Figure PCTCN2020078215-appb-000060
实施例4：6-(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-1,7-二氮杂萘-3-甲腈的合成(化合物64)
步骤1：6-乙酰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000061
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-1,7-二氮杂萘-3-甲腈(187mg,0.55mmol,1.0eq)溶解在干燥的二氯甲烷(5mL)中，降温至0～5℃，加入戴斯-马丁氧化剂(463.5mg,1.10mmol,2.0eq)，加完自然升至室温反应2h，TLC监测反应完全，减压浓缩，粗品经硅胶柱层析(MeOH:DCM＝1:100～1:50)纯化得到产品(185.8mg,收率:100％)。
步骤2：6-(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-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000062
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-1,7-二氮杂萘-3-甲腈(185.8mg,0.55mmol,1.0eq)溶于N,N-二甲基乙酰胺(3mL)中，降温至-10～0℃，氮气保护下滴加3mol/L甲基氯化镁四氢呋喃溶液(0.6mL,3.0eq)，加完自然升至室温搅拌过夜，TCL检测有大量原料剩余，补加3mol/L甲基氯化镁四氢呋喃溶液(0.6mL,3.0eq)，反应3h，再补加3mol/L甲基氯化镁四氢呋喃溶液(0.6mL,3.0eq)，反应2h。降温至0～10℃，用乙酸调pH＝5～6，浓缩，粗品经硅胶柱层析(MeOH:DCM＝1:100～1:70)纯化得到产品(63.9mg,收率:32.8％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):11.91(s,1H),8.59(s,1H),7.89(s,1H),5.35(s,1H),3.62-3.60(m,4H),3.20(s,3H),1.95-1.92(m,2H),1.80-1.73(m,2H),1.45(s,6H),1.23(s,3H).
分子式:C 19H 24N 4O 3 分子量:356.43 LC-MS(Pos,m/z)＝357.25[M+H] +.
实施例5：6-(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-1,7-二氮杂萘-3-甲腈的合成(化合物68)
Figure PCTCN2020078215-appb-000063
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-1,7-二氮杂萘-3-甲腈(500mg,1.53mmol,1.0eq)溶解在无水四氢呋喃(20mL)中，氮气保护下，降温至-10℃，滴加1mol/L环丙基溴化镁的四氢呋喃溶液(4.6mL,4.60mmol,3eq)，加完0℃反应3h，LC-MS检测有20％原料剩余，再补加1mol/L环丙基溴化镁的四氢呋喃溶液(3mL,3mmol,2eq)，反应2～3h。LC-MS检测还有10％原料，滴加乙酸至pH＝5～6左右，减压浓缩，粗品经硅胶柱层析(MeOH:DCM＝1:100～1:40)纯化得到产品(225.7mg,收率:40.0％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):11.93(s,1H),8.59(s,1H),7.68(s,1H),5.42-5.40(d,1H),4.24-4.22(m,1H),3.63-3.60(m,4H),3.19(s,3H),1.95-1.91(m,2H),1.79-1.72(m,2H),1.23(s, 3H),1.23(s,1H),0.42(m,4H).
分子式:C 20H 24N 4O 3 分子量:368.44 LC-MS(Pos,m/z)＝369.40[M+H] +.
实施例6：3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-N-甲基-2-氧代-1,2-二氢-1,7-萘啶-6-甲酰胺的合成(化合物69)
步骤1：3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-羧酸的合成
Figure PCTCN2020078215-appb-000064
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-1,7-二氮杂萘-3-甲腈(681mg,2.09mmol,1.0eq)溶解在甲酸(5mL)中，降温-5～0℃，加入30％双氧水(1.32mL,10.44mmol,5eq)，加完0℃反应12h，再补加30％双氧水(1.32mL,10.44mmol,5eq)，室温反应2-3h。TLC监测反应完全，将反应液倒入甲基叔丁基醚(50mL)溶液中，析出淡黄色固体，过滤，滤饼干燥得到产品(300mg,收率:42.0％)。
步骤2：3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-N-甲基-2-氧代-1,2-二氢-1,7-萘啶-6-甲酰胺的合成
Figure PCTCN2020078215-appb-000065
将中间体3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-羧酸(300mg,0.88mmol,1.0eq)溶于无水N,N-二甲基乙酰胺(3mL)中，加入DIPEA(565.8mg,4.38mmol,5.0eq)，加毕，降温至0℃，加入HATU(499.7mg,1.31mmol,1.5eq)，室温搅拌0.5～1h，再加入甲胺盐酸盐(118.2mg,1.75mmol,2.0eq)，室温反应1h，析出固体，TLC监测反应完全，加水(50mL)，搅拌5min，过滤，滤饼用水淋洗，加入到乙酸乙酯(10mL)中加热回流1h，趁热过滤，滤饼干燥得到产品(199mg,收率:63.8％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):12.21(s,1H),8.74-8.73(s,1H),8.64(s,1H),8.27(s,1H),3.64-3.62(m,4H),3.20(s,3H),2.84-2.83(d,3H),1.96(m,1H),1.93(m,1H),1.79-1.77(m,2H),1.24(s,3H).
分子式:C 18H 21N 5O 3 分子量:355.40 LC-MS(Pos,m/z)＝356.26[M+H] +.
实施例7:N-(2-氨基乙基)-3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-甲酰胺(化合物74)盐酸盐的合成
步骤1：(2-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-甲酰氨基)乙基)氨基甲酸叔丁酯的合成
Figure PCTCN2020078215-appb-000066
将中间体3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-羧酸(200mg,0.58mmol,1.0eq)、HATU(333mg,0.88mmol,1.5eq)和DIPEA(376mg,1.76mmol,3.0eq)溶于DMAC(2mL)，常温搅拌30min，再加入(2-氨基乙基)氨基甲酸叔丁酯(281mg,1.76mmol,2.0eq)，常温反应1h，LC-MS检测反应完全。加入水(10mL)，二氯甲烷(10mL×3)萃取，有机相用水(10mL×3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝30:1)纯化得到产品(220mg,收率:78.3％)。
步骤2：N-(2-氨基乙基)-3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-甲酰胺盐酸盐的合成
Figure PCTCN2020078215-appb-000067
将中间体(2-(3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-甲酰氨基)乙基)氨基甲酸叔丁酯(220mg,0.45mmol,1.0eq)溶于甲醇(3mL)，加入氯化氢乙醇溶液(25％，2mL)，常温反应2h，TLC检测反应完全。有固体析出，过滤，滤饼干燥得到产品(150mg,收率:79％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):12.28(s,1H),9.01-9.03(m,1H),8.68(s,1H),8.29(s,1H),7.91(s,3H),3.55-3.64(m,6H),3.21(s,3H),3.00-3.02(m,2H),1.94-1.97(d,2H),1.73-1.80(d,2H),1.24(s,3H).
分子式:C 19H 24N 6O 3 分子量:384.44 LC-MS(Pos,m/z)＝385.19[M+H] +.
实施例8:3-氰基-N-(2-(二甲基氨基)乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-甲酰胺的合成(化合物75)
Figure PCTCN2020078215-appb-000068
将中间体3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-羧酸(200mg,0.58mmol,1.0eq)、HATU(333mg,0.88mmol,1.5eq)和DIPEA(226mg,1.76mmol,3.0eq)溶于DMAC(2mL)，常温搅拌30min，再加入N,N-二甲基乙二胺(103mg,1.16mmol,2.0eq)，常温反应1h，LC-MS检测反应完全。加入水(10mL)，二氯甲烷(10mL×3)萃取，有机相用水(10mL×3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝20:1)纯化得到产品(86mg,收率:36％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):12.20(s,1H),8.79(s,1H),8.66(s,1H),8.28(s,1H),3.62-3.64(d,4H),3.50-3.51(d,2H),3.21(s,3H),2.76(s,2H),2.44(s,6H),1.94-1.97(d,2H),1.74-1.81(m,2H),1.25(s,3H).
分子式:C 21H 28N 6O 3 分子量:412.49 LC-MS(Pos,m/z)＝413.22[M+H] +.
实施例9:3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-N-(2-(吡咯烷-1-基)乙基)-1,2-二氢-1,7-二氮杂萘-6-甲酰胺的合成(化合物76)
Figure PCTCN2020078215-appb-000069
将中间体3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-羧酸(200mg,0.58mmol,1.0eq)、HATU(333mg,0.88mmol,1.5eq)和DIPEA(226mg,1.76mmol,3.0eq)溶于DMAC(2mL)，常温搅拌30min，再加入2-(吡咯烷-1-基)乙-1-胺(134mg,1.16mmol,2.0eq)，常温反应1h，LC-MS检测反应完全。加入水(10mL)，二氯甲烷(10mL×3)萃取，有机相用水(10mL×3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝20:1)纯化得到产品(106mg,收率:41％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):12.26(s,1H),9.08-9.11(m,1H),8.67(s,1H),8.30(s,1H),3.63-3.64(d,8H),3.06-3.20(m,6H),1.73-1.98(m,9H),1.25(s,3H).
分子式:C 23H 30N 6O 3 分子量:438.53 LC-MS(Pos,m/z)＝439.24[M+H] +.
实施例10：3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-N-((1-甲基哌啶-4-基)甲基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-甲酰胺(化合物77)三氟乙酸盐的合成
Figure PCTCN2020078215-appb-000070
将中间体3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-羧酸(200mg,0.58mmol,1.0eq)溶于无水N,N-二甲基乙酰胺(2mL)中，加入DIPEA(226.3mg,1.75mmol,3.0eq)和HATU(333.1mg,0.88mmol,1.5eq)，室温搅拌0.5～1h，加入(1-甲基哌啶-4-基)甲胺(150mg,1.17mmol,2.0eq)，室温反应1h，LC-MS监测仍有原料剩余，补加(1-甲基哌啶-4-基)甲胺(150mg,1.17mmol,2.0eq)，继续反应2h，经制备HPLC纯化(0.1％三氟乙酸水溶液：乙腈＝70:30)得到产品(68.8mg,收率:20.7％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):12.22(s,1H),9.00-8.99(s,1H),8.95-8.94(s,1H),8.65(s,1H),8.28(s,1H),3.63-3.62(m,4H),3.43-3.40(m,2H),3.23(s,3H),2.95-2.83(m,2H),2.75-2.74(m,2H),1.97-1.94(m,2H),1.85-1.80(m,2H),1.78-1.75(m,3H),1.24(s,3H).
分子式:C 24H 32N 6O 3 分子量:452.56 LC-MS(Pos,m/z)＝453.45[M+H] +.
实施例11：3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-N-(1-甲基氮杂环丁烷-3-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-甲酰胺(化合物78)三氟乙酸盐的合成
Figure PCTCN2020078215-appb-000071
将中间体3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-羧酸(200mg,0.58mmol,1.0eq)溶于无水N,N-二甲基乙酰胺(2mL)中，加入DIPEA(226.3mg,1.75mmol,3.0eq)和HATU(333.1mg,0.88mmol,1.5eq)，室温搅拌0.5～1h，加入1-甲基氮杂环丁烷-3-胺(100.6mg,1.17mmol,2.0eq)，室温反应12h，粗品经制备HPLC纯化(0.1％三氟乙酸水溶液:乙腈＝70:30)得到产品(113.13mg,收率:37.1％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):12.27(s,1H),9.59-9.53(s,2H),8.68(s,1H),8.27(s,1H),4.90-4.86(m,1H),4.45(m,2H),4.16(m,2H),3.63-3.62(m,4H),3.20(s,3H),2.91(s,3H),1.96-1.93(m,2H),1.79-1.72(m,2H),1.24(s,3H).
分子式:C 21H 26N 6O 3 分子量:410.48 LC-MS(Pos,m/z)＝411.40[M+H] +.
实施例12：3-氰基-N-(2,3-二羟基丙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-萘啶-6-甲酰胺的合成(化合物80)
Figure PCTCN2020078215-appb-000072
将中间体3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-羧酸(200mg,0.58mmol,1.0eq)溶于无水N,N-二甲基乙酰胺(2mL)中，加入DIPEA(226.3mg,1.75mmol,3.0eq)和HATU(333.1mg,0.88mmol,1.5eq)，室温搅拌0.5～1h，加入3-氨基丙烷-1,2-二醇(106.4mg,1.17mmol,2.0eq)，室温反应12h，粗品经制备HPLC纯化(0.1％三氟乙酸水溶液:乙腈＝70:30)，冻干得到产品(93.79mg)，将样品溶于水，用碳酸氢钠水溶液调pH至8，用正丁醇萃取(20mL×5)，有机相浓缩得产品(47.2mg,产率:19.4％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):8.42-8.39(s,1H),8.36(s,1H),8.08(s,1H),4.96(s,1H),4.66(s,1H),3.49(m,1H),3.47-3.45(m,6H),3.25-3.23(m,2H),3.19(s,3H),1.91-1.88(m,2H),1.75-1.70(m,2H),1.23(s,3H).
分子式:C 20H 25N 5O 5 分子量:415.45 LC-MS(Neg,m/z)＝414.34[M-H] -.
实施例13:3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-N,N-二甲基-2-氧代-1,2-二氢-1,7-萘啶-6-甲酰胺的合成(化合物90)
Figure PCTCN2020078215-appb-000073
将中间体3-氰基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-6-羧酸(200mg,0.58mmol,1.0eq)、HATU(333mg,0.88mmol,1.5eq)和DIPEA(376mg,1.76mmol,3.0eq)溶于DMAC(2mL)，常温搅拌30min，加入二甲胺盐酸盐(95mg,1.16mmol,2.0eq)，常温反应1h，LC-MS检测反应完全。加入水(10mL)，二氯甲烷(10mL×3)萃取，有机相用水(10mL×3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析(DCM:MeOH＝50:1)纯化得到产品(120mg,收率:55％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):12.16(s,1H),8.61(s,1H),7.83(s,1H),3.61-3.63(m,4H),3.19(s,3H),3.03-3.05(d,6H),1.90-1.93(d,2H),1.71-1.78(m,2H),1.22(s,3H).
分子式:C 19H 23N 5O 3 分子量:369.18 LC-MS(Pos,m/z)＝370.43[M+H] +.
实施例14：4-(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-1,7-二氮杂萘-3-甲腈的合成(化合物81)
步骤1：2-(2-甲氧基乙氧基)-5-硝基异烟酸甲酯的合成
Figure PCTCN2020078215-appb-000074
将原料乙二醇单甲醚(3.5g,46.17mmol,1.0eq)溶于四氢呋喃(50mL)中，降温至0℃，加入氢化钠(3.7g,92.34mmol,2.0eq)，反应1小时后，加入2-氯-5-硝基异烟酸甲酯(10.0g,46.17mmol,1.0eq)。TLC(PE:EA＝5:1)检测反应完全，反应液倒入冰水(100mL)中淬灭，水相用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经硅胶柱层析纯化(PE:EA＝5:1)得淡黄色油状产物(1.8g,收率:15％)。
步骤2：5-氨基-2-(2-甲氧基乙氧基)异烟酸甲酯的合成
Figure PCTCN2020078215-appb-000075
将中间体2-(2-甲氧基乙氧基)-5-硝基异烟酸甲酯(1.8g,7.02mmol,1.0eq)溶于甲醇(10mL)中，加入10％钯碳(500mg)，通入氢气室温反应过夜。TLC(PE:EA＝3:1)检测反应完全，反应液过滤浓缩，粗品经硅胶柱层析纯化(PE:EA＝5:1)得淡黄色固体状产物(1.2g,收率:75％)。
步骤3：5-(2-氰基乙酰氨基)-2-(2-甲氧基乙氧基)异烟酸甲酯的合成
Figure PCTCN2020078215-appb-000076
将中间体5-氨基-2-(2-甲氧基乙氧基)异烟酸甲酯(1.2g,5.3mmol,1.0eq)和氰基乙酸(901mg,10.6mmol,2.0eq)溶于二氯甲烷(20mL)中，加入EDCI(3.04g,15.9mmol,3.0eq)，室温反应2小时。LC-MS检测反应完全，反应液倒入冰水(30mL)中淬灭，水相用二氯甲烷(30mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经甲基叔丁基醚打浆后得淡黄色固体状产物(1.2g,收率:77％)。
步骤4：4-羟基-6-(2-甲氧基乙氧基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000077
将中间体5-(2-氰基乙酰氨基)-2-(2-甲氧基乙氧基)异烟酸甲酯(1.2g,4.09mmol,1.0eq)溶于四氢呋喃(20mL)中，加入氢化钠(327mg,8.18mmol,2.0eq)，升温至80℃反应4小时。LC-MS检测反应完全，反应液降温至0℃左右，用2mol/L盐酸水溶液调节pH值至2，析出固体，过滤，滤饼50℃常压干燥后得黄色固体状产物(800mg,收率:75％)。
步骤5：4-氯-6-(2-甲氧基乙氧基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000078
将中间体4-羟基-6-(2-甲氧基乙氧基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(800mg,3.06mmol,1.0eq)溶于三氯氧磷(8mL)中，升温至100℃反应一个小时。LC-MS检测反应完全，反应液倒入冰水(20mL)中淬灭，水相用二氯甲烷(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经甲基叔丁基醚打浆后得淡黄色固体状产物(180mg,收率:21％)。
步骤6：4-(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-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000079
将中间体4-氯-6-(2-甲氧基乙氧基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(180mg,0.64mmol,1.0eq)溶于N,N-二甲基甲酰胺(2mL)中，加入N,N-二异丙基乙胺(332mg,2.58mmol,4.0eq)和4-甲氧基-4-甲基哌啶(110mg,0.97mmol,1.0eq)，升至80℃反应两个小时。LC-MS检测反应完全，反应液倒入冰水(20mL)中淬灭，水相用二氯甲烷(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经硅胶柱层析(DCM:MeOH＝15:1)纯化得淡黄色油状产物(60mg,收率:25％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):11.78(s,1H),8.28(s,1H),6.94(s,1H),4.37(m,2H),3.67(m,2H),3.56-3.58(m,4H),3.30(s,3H),3.18(s,3H),1.88-1.91(m,2H),1.75-1.80(m,2H),1.21(s,3H).
分子式:C 19H 24N 4O 4 分子量:372.43 LC-MS(Pos,m/z)＝373.3[M+H] +
实施例15：4-(4-甲氧基-4-甲基哌啶-1-基)-6-甲基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物87)
Figure PCTCN2020078215-appb-000080
将中间体6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(1.3g,3.91mmol,1.0eq)、碳酸铯(3.8g,11.73mmol,3.0eq)和三甲基环三硼氧烷(50％THF溶液,3.9g,15.62mmol,4.0eq)溶于1,4-二氧六环(20mL)，加毕，氮气置换三次，在加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(286mg,0.39mmol,0.1eq)，加毕，氮气置换三次，加热回流12h，TLC检测还有原料，再补加三甲基环三硼氧烷(50％THF溶液,3.9g,15.62mmol,4.0eq)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(286mg,0.39mmol,0.1eq)，继续回流4h，TLC检测无原料，降至室温，加水(50mL)和二氯甲烷(100mL)，搅拌5min，析出固体，过滤，滤饼用二氯甲烷淋洗，分液，水相用二氯甲烷(100mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，母液减压浓缩，粗品先经硅胶柱层析(MeOH:DCM＝1:100～1:50)纯化得产品(309.9mg,收率: 25.4％)。
1HNMR(400MHz,DMSO-d 6)δ(ppm):11.88(s,1H),8.55(s,1H),7.42(s,1H),3.61-3.59(m,4H),3.19(s,3H),2.53(s,3H),1.92-1.89(m,2H),1.82-1.75(m,2H),1.22(s,3H).
分子式:C 17H 20N 4O 2 分子量:312.37 LC-MS(Pos，m/z)＝313.25[M+H] +.
实施例16：6-环丙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物92)
步骤1:2-氯-5-硝基异烟酸乙酯的合成
Figure PCTCN2020078215-appb-000081
将2-氯-5-硝基异烟酸(20.0g,98.74mmol,1.0eq)溶于原甲酸三乙酯(43.9g,296.20mmol,3.0eq)，120℃反应3h，TLC检测无原料，减压浓缩，得到黄色油状液体，加石油醚(150mL)，搅拌12h，过滤，滤饼室温烘干得到产品(11.0g,收率:51.6％)。
步骤2:2-环丙基-5-硝基异烟酸乙酯的合成
Figure PCTCN2020078215-appb-000082
将2-氯-5-硝基异烟酸乙酯(11.0g,47.70mmol,1.0eq)、环丙基硼酸(10.2g,119.25mmol,2.5eq)和磷酸钾(35.4g,166.95mmol,3.5eq)溶于水(27.5mL)和甲苯(275mL)的混合溶剂中，氮气保护下加三苯基膦(2.5g,9.54mmol,0.2eq)和醋酸钯(1.1g,4.77mmol,0.1eq)，氮气置换三次，回流反应24h，TLC检测反应完全，减压浓缩，粗品经硅胶柱层析(EA:PE＝1:30)纯化得到产品(6.18g,收率:55％)。
步骤3:5-氨基-2-环丙基异烟酸乙酯的合成
Figure PCTCN2020078215-appb-000083
将中间体2-环丙基-5-硝基异烟酸乙酯(6.18g,26.16mmol,1.0eq)溶于无水乙醇(60mL)，加入铁粉(5.86g,104.64mmol,4.0eq)，升温至回流，滴加乙酸(9.4g,156.96mmol,6.0eq)，回流反应3h，TLC检测反应完全，向反应液中加入乙酸乙酯(100mL)，趁热过滤，滤饼用乙酸乙酯淋洗，滤液减压浓缩，加水(50mL)和乙酸乙酯(100mL)，冰水浴降温，加碳酸氢钠固体调pH值至8左右，分液，水相用乙酸乙酯(50mL×3)萃取，有机相合并，用无水硫酸镁干燥，过滤，滤液减压浓缩得到产品(4.77g,收率:90％)。
步骤4:5-(2-氰基乙酰胺基)-2-环丙基异烟酸乙酯的合成
Figure PCTCN2020078215-appb-000084
将中间体5-氨基-2-环丙基异烟酸乙酯(4.77g,23.13mmol,1.0eq)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(8.7g,46.25mmol,2.0eq)和氰基乙酸(3g, 34.69mmol,1.5eq)，室温搅拌16h。TLC监测无原料，加二氯甲烷(40mL)，用水(50mL×2)洗涤，有机相用饱和碳酸钠水溶液(50mL)洗涤，无水硫酸镁干燥，过滤，滤液减压浓缩得到产品(5.6g,收率:100％)，按理论量投入下一步。
步骤4:6-环丙基-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000085
将中间体5-(2-氰基乙酰胺基)-2-环丙基异烟酸乙酯(5.6g,20.51mmol,1.0eq)溶于无水乙醇(100mL)，搅拌10min，加乙醇钠(4.7g,69.39mmol,3.0eq)，室温搅拌1h。TLC检测有原料剩余，补加乙醇钠(4.7g,69.39mmol,3.0eq)，室温搅拌2h。TLC检测无原料，减压浓缩，加水(200mL)，用甲基叔丁基醚(100mL×2)萃取，水相冰水降温，用浓盐酸调pH值至1～2，析出固体，过滤，滤饼用水淋洗，滤饼烘干得到产品(3.95g,收率:84.84％)。
步骤5:2,4-二氯-6-环丙基-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000086
将中间体6-环丙基-4-羟基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(1g,4.4mmol,1.0eq)溶于无水乙腈(15mL)，加三氯氧磷(1.35g,8.8mmol,2.0eq)，升温至80℃反应1h。TLC检测剩余大部分原料，补加三氯氧磷(1.35g,8.8mmol,2.0eq)，加热至90℃，LC-MS检测反应完全，降至室温，减压浓缩，加乙腈(10mL)，冰水降温，用氢氧化钠溶液调pH值至8～9，析出黄色固体，过滤，滤饼用水淋洗得到产品(1.5g粗品)，按理论量投入下一步。
步骤6:4-氯-6-环丙基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000087
将中间体2,4-二氯-6-环丙基-1,7-二氮杂萘-3-甲腈(1.16g粗品,4.40mmol,1.0eq)溶于三氟乙酸(10mL)和水(2.5mL)的混合溶剂中，加热至60℃反应18h，降温0℃，加水(20mL)，用氢氧化钠固体调pH值至8～9，析出黄色固体，过滤，滤饼用水淋洗，烘干，加乙酸乙酯(10mL)，加热至60℃搅拌1h，趁热过滤，滤饼烘干得到产品(660mg,两步收率:61％)。
步骤7:2-氯-6-环丙基-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000088
将中间体4-氯-6-环丙基-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(200mg,0.81mmol,1.0eq) 溶于N,N-二甲基乙酰胺(2mL)，加DIPEA(420.5mg,3.26mmol,4.0eq)和4-甲氧基-4-甲基哌啶盐酸盐(188.8mg,1.14mmol,1.4eq)，升温至80℃反应1h，TLC检测无原料，将反应液降至室温，倒入冰水(20mL)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，粗品用甲基叔丁基醚(5mL)打浆1h，抽滤，滤饼烘干得到产品(182mg,收率:66％)。
1H NMR(400MHz,DMSO-d 6)δ(ppm):11.85(s,1H),8.51(d,1H),7.45(s,1H),3.61-3.60(d,4H),3.19(s,3H),2.27-2.21(m,1H),1.93-1.90(m,2H),1.84-1.80(m,2H),1.22(s,3H),0.95(m,2H),0.85(m,2H).
分子式:C 19H 22N 4O 2 分子量:338.17 LC-MS(Pos,m/z)＝339.13[M+H] +.
实施例17：6-乙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成(化合物102)
步骤1：6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000089
将中间体4,6-二氯-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.0g,8.33mmol,1.0eq)溶于DMF(10mL)，加入DIPEA(6.45g,50mmol,6.0eq)和4-甲氧基-4-甲基哌啶三氟乙酸盐(2.2g,9.16mmol,1.1eq)，80℃反应2小时。LC-MS检测反应完全，加入水(10mL)，二氯甲烷(10mL×3)萃取，有机相用水洗(10mL×3)，无水硫酸钠干燥，过滤，减压浓缩得到黄色固体状产物(2.7g粗品)。 1H NMR(400MHz,DMSO-d 6)δ(ppm):12.11(s,1H),8.45(s,1H),7.61(s,1H),3.61-3.59(m,4H),3.18(s,3H),1.91-1.88(m,2H),1.81-1.76(m,2H),1.21(s,3H).
分子式:C 16H 17N 4O 2Cl 分子量:332.79 LC-MS(Pos,m/z)＝333.7[M+H] +
步骤2：4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-6-乙烯基-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000090
将中间体6-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈(2.7g粗品,8.11mmol,1.0eq)溶于1,4-二氧六环(20mL)和H 2O(5mL)，加入乙烯基三氟硼酸钾(1.63g,12.17mmol,1.5eq)、碳酸铯(3.965g,12.17mmol,1.5eq)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(297mg,0.41mmol,0.05eq)，氮气保护下100℃反应8小时。LC-MS检测反应完全，加入水(20mL)，二氯甲烷(30mL×3)萃取，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＝70:1)纯化得到黄色固体状产品(1.15g,收率:43％)。
步骤3：6-乙基-4-(4-甲氧基-4-甲基哌啶-1-基)-2-氧代-1,2-二氢-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-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-1,7-二氮杂萘-3-甲腈(150mg,0.46mmol,1.0eq)溶于甲醇(5mL)，加入Pd/C(100mg)，氢气置换三次，氢气氛围下反应1小时，LC-MS检测反应完全。抽滤，滤液减压浓缩得到产品(120mg,收率:80％)。 1HNMR(400MHz,DMSO-d 6)δ(ppm):11.89(s,1H),8.59(s,1H),7.41(s,1H),3.60-3.62(m,4H),3.19(s,3H),2.79-2.84(m,2H),1.89-1.93(m,2H),1.75-1.82(m,2H),1.22-1.27(m,6H).
分子式:C 18H 22N 4O 2 分子量:326.40 LC-MS(Pos,m/z)＝327.26[M+H] +.
实施例18：6-乙酰基-2-羟基-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成(化合物114的互变异构体)
步骤1：6-(1-溴乙基)-2,4-二氯-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000092
在1L单口瓶中加入四氯化碳(600.00mL)，2,4-二氯-6-乙基-1,7-二氮杂萘-3-甲腈(30.00g,119.00mmol,1eq)，NBS(42.36g,238.00mmol,2eq)和AIBN(15.00g)。90℃反应2小时。LC-MS显示反应完全。将反应液降温至10-15℃，抽滤，滤液浓缩至干，用PE和EA重结晶得到产品6-(1-溴乙基)-2,4-二氯-1,7-二氮杂萘-3-甲腈35g。
步骤2：6-(1-溴乙基)-2-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000093
在1L单口瓶中，加入乙醇(400.00mL)，6-(1-溴乙基)-2,4-二氯-1,7-二氮杂萘-3-甲腈(20.00g,60.40mmol,1eq)，4-甲氧基-4-甲基哌啶盐酸盐(11.00g,66.44mmol,1.1eq)和三乙胺(13.45g,132.88mmol,2.2eq)。90℃反应2小时。LC-MS显示反应完全，将反应液降温至室温，减压浓缩至干，加入400mL水搅拌1小时，抽滤，滤饼用乙醇重结晶，得到产品6-(1-溴乙基)-2-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈20g。
步骤3：2-羟基-6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000094
在250mL单口瓶中加入乙酸(60.00mL)，水(30.00mL)，6-(1-溴乙基)-2-氯-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈(15.00g)，100℃反应6小时，LC-MS显示反应完全。降温至室温，反应液减压浓缩至干。加入100mL水，调pH＝7-8，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，抽滤，滤液减压浓缩至干得到粗品。粗品先用EA热打浆，再用乙醇重结晶，得到产品2-羟基-6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈6g。
步骤4：6-乙酰基-2-羟基-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000095
在250mL单口瓶中，加入DCM(90.00mL)，2-羟基-6-(1-羟乙基)-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈(4.50g,13.15mmol,1eq)，戴斯-马丁氧化剂(6.14g,1.1eq,14.47mmol)，室温搅拌2小时。LC-MS显示反应完全，加入60mL水，30mL饱和硫代硫酸钠溶液，搅拌1小时，分液，有机相用无水硫酸钠干燥，抽滤，滤液减压浓缩至干，得粗品，经柱层析纯化，得到产品6-乙酰基-2-羟基-4-(4-甲氧基-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈0.7g。
1HNMR(400MHz,DMSO)δ(ppm):12.33(s,1H),8.70(s,1H),8.19(s,1H),3.62-3.64(d,4H),3.20(s,3H),2.63(s,3H),1.92-1.96(m,2H),1.76-1.78(m,2H),1.24(s,3H).
分子式:C 18H 20N 4O 3,分子量:340.38,LC-MS(Pos,m/z)＝341.21[M+H +].
实施例19：6-乙基-2-羟基-4-(4-(甲氧基-d 3)-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成(化合物115的互变异构体)
步骤1：4-羟基-4-甲基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2020078215-appb-000096
将原料4-氧代哌啶-1-羧酸叔丁酯(5.0g,25mmol,1.0eq)溶于四氢呋喃(25mL)，氮气保护0℃下加入甲基氯化镁试剂(9mL,27mmol,1.1eq)。反应2小时后TLC检测反应完全，加入稀盐酸调节pH＝4，再加入水(30mL)，乙酸乙酯(30mL×3)萃取，有机相干燥，过滤，减压浓缩，粗品经硅胶柱层析(PE:EA＝5:1)纯化得产品(5.2g,收率:96％)。
步骤2：4-(甲氧基-d 3)-4-甲基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2020078215-appb-000097
在100mL单口瓶中，氮气置换，加入4-羟基-4-甲基哌啶-1-羧酸叔丁酯(2.70g,12.55mmol,1eq)，THF(27.00mL)，分批加入氢化钠(60％,0.76g,1.5eq)，室温反应0.5小时。滴加CD 3I(4.00g,27.62mmol,2.2eq)，加完后30℃反应过夜。TLC显示反应完全。将反应液减压浓缩至干，加入100mL EA，分液，有机相水洗后，无水硫酸钠干燥，抽滤，滤液减压浓缩至干，得到产品4-(甲氧基-d 3)-4-甲基哌啶-1-羧酸叔丁酯(4.3g)。
步骤3：4-(甲氧基-d 3)-4-甲基哌啶盐酸盐的合成
Figure PCTCN2020078215-appb-000098
在500mL单口瓶中氮气置换，加入4-(甲氧基-d 3)-4-甲基哌啶-1-羧酸叔丁酯(4.30g)，加入氯化氢乙醇(8.60mL)和乙醇(8.60mL)。30℃反应2小时。TLC显示反应完全，将反应液减压浓缩至干，加入30mL EA搅拌0.5小时，抽滤，得到产品4-(甲氧基-d 3)-4-甲基哌啶盐酸盐1.20g。
步骤4：6-乙基-2-羟基-4-(4-(甲氧基-d 3)-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈的合成
Figure PCTCN2020078215-appb-000099
在100mL单口瓶中加入4-氯-6-乙基-2-羟基-1,7-二氮杂萘-3-甲腈(1.50g,6.47mmol,1eq)，4-(甲氧基-d 3)-4-甲基哌啶盐酸盐(1.20g,7.12mmol 1.1eq)，乙醇(15.00mL)，TEA(1.44g,14.23mmol,2.2eq)，90℃反应1小时，LC-MS显示反应完全。降温，反应液减压浓缩至干。加入50mL水，搅拌0.5小时，抽滤，得到粗品。粗品经乙醇重结晶，得到产品6-乙基-2-羟基-4-(4-(甲氧基-d 3)-4-甲基哌啶-1-基)-1,7-二氮杂萘-3-甲腈(2.03)。
1HNMR(400MHz,DMSO)δ(ppm):11.91(s,1H),8.58(s,1H),7.40(s,1H),3.60-3.61(d,4H),2.78-2.84(q,2H),1.89-1.92(m,2H),1.77-1.82(m,2H),1.26(s,6H).
分子式:C 18H 19D 3N 4O 2,分子量:329.42,LC-MS(Pos,m/z)＝330.21[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。
实验例一：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DMSO 100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***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 PCTCN2020078215-appb-000100
三、试验结果如下表2所示：
表2
测试物 PDE9A2 IC 50(nM)
化合物63 4
化合物64 38
化合物68 3
化合物69 11
化合物70 24
化合物74 14
化合物75 69
化合物76 61
化合物77 52
化合物78 85
化合物80 25
化合物81 31
化合物84 38
化合物87 9
化合物90 20
化合物91 50
化合物92 25
化合物102 15
化合物114 48
化合物115 19
化合物A 61
化合物B 3
由表2可知，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。
实验例二 本发明化合物对瞬转HEK293T细胞cGMP含量影响的测试
测试物：本发明中的化合物102，其结构参见本文表1中序号102化合物的结构。
缩略词：
FBS    胎牛血清
ANF    心房利钠因子，心钠素
B 0     最大结合
cGMP   3,5-环磷酸鸟苷
ELISA  酶联免疫吸附试验
NPR1   Natriuretic peptide receptor 1，利钠肽蛋白受体1
NSB    非特异性结合
PDE9   Phosphodiesterase 9，磷酸二酯酶9
WB     Western Blotting，免疫印迹法
TA     总活力
GAPDH  甘油醛-3-磷酸脱氢酶
材料及仪器
实验仪器及耗材
Figure PCTCN2020078215-appb-000101
质粒
Figure PCTCN2020078215-appb-000102
细胞株
细胞名：人胚肾细胞HEK293T
试验方法：
1.细胞铺板和转染
1.1细胞铺板
HEK293T细胞铺于6孔板中，2×10 6细胞/孔，培养6h，使细胞贴壁。
1.2转染
更换各孔培养基为1.5mL DMEM全培养基；
转染孔：向每100μL不含FBS的DMEM饥饿培养基，加入0.333μg的NPR1和0.333μg的PDE9质粒吹打，再加入20μL PolyFect转染试剂吹打混匀，静置10min后，加入600μL DMEM全培养基吹打、混匀，吸取700μL缓慢滴加入孔中，培养18h。各转染孔的方法同上。
不转染孔：不转染的孔加入等体积的DMEM全培养基(700μLDMEM全培养基)。
2.给药刺激
取化合物在DMSO中的50mM母液，用全培养基稀释为3mM、1mM、333μM、111μM、37μM、和12μM的梯度浓度的一系列化合物溶液(100×工作液)。将转染过的培养板中的培养基换为1mL DMEM全培养基后，每孔加入10μL不同浓度的上述100×工作液溶液得到终浓度为30μM、10μM、3.33μM、1.11μM、0.37μM和0.12μM的梯度浓度的一系列化合物溶液，置于培养箱中孵育30min后，每孔加入3μL 326μM的ANF，使其终浓度为1μM，再与药物共孵育30min。
3.cGMP含量检测(参照cGMP ELISA试剂盒说明书操作)
1.1细胞收集
各孔吸取培养基，用PBS洗一次细胞，加入250μL的0.5M高氯酸，用细胞刮刀收集细胞，转移至1.5mL离心管中。涡旋混匀后在4℃、6000g离心20min。取上清200μL用4M的KOH调节pH至中性。
另取一个非转染孔和一个转染孔细胞，加入含蛋白酶抑制剂和磷酸酶抑制剂的RIPA裂解液，收集细胞，用于转染验证的WB试验。
1.2cGMP含量测定
配制30-0.23pmol/mL浓度范围(2倍梯度稀释)的cGMP标准品后，按下表加样，4℃孵育18h。
Figure PCTCN2020078215-appb-000103
充分洗板5次后，各孔加入200μL的Ellman’s Reagent，封板、避光震荡、显色60min后，检测在412nm处的吸光度值。
1.3cGMP含量测定
首先，扣除非特异性结合(各孔读值减去NSB孔读值)，然后计算B/B 0，即样品或标准品的结合与最大结合的比值，按照如下公式进行转换，然后将得到的logit(B/B0)与lg(化合物浓度)进行线性回归，得到标准曲线。
logit(B/B0)＝ln[B/B0/(1-B/B0)]
将样品的B/B 0值转换为logit(B/B0)值，根据标准曲线计算出样品中cGMP的含量。
2.利用蛋白免疫印迹法(WB)对转染的验证
使用蛋白免疫印迹法方法检测质粒Flag标签蛋白的表达，表达则表示转染成功。试验结果如图1所示。
在图1中，左上角图示为通过蛋白免疫印迹法对转染进行验证。符号N表示未转染的HEK293T细胞；以及T表示hNPR和hPDE9A共转染的HEK293T细胞。
如图1所示，在共转染人源NPR1和PDE9的HEK293T构建细胞内，ANF可显著诱导胞内cGMP的表达，本发明化合物在细胞水平上通过抑制PDE9，可显著提高ANF介导的cGMP水平，在治疗心衰方面具有较好的应用潜力。
实验例三 本发明化合物对RNCM中cGMP含量影响的测试
测试物：本发明中的化合物102，其结构参见本文表1中序号102化合物的结构。
缩略词表
ANF    心房利钠因子，心钠素
cGMP   3,5-环磷酸鸟苷
ELISA  酶联免疫吸附试验
RNCM   新生大鼠原代心肌细胞
试剂耗材：
1.实验仪器及试剂
Figure PCTCN2020078215-appb-000104
Figure PCTCN2020078215-appb-000105
2.SD新生大鼠原代心肌细胞的制备试剂准备
2.1.1 1％明胶溶液
1％明胶用于培养乳鼠原代心肌细胞时包被培养皿。称取1g明胶，溶解于100mL去离子水中，使用时稀释至0.2％浓度后使用；
2.1.2有丝***抑制剂
取10mM诺考达唑DMSO母液，用DMSO稀释为1mM，得到20000×溶液，使用时用培养基稀释至终浓度为1×；
2.1.3 L-谷氨酰胺
取L-谷氨酰胺2.92g，溶解于100mL去离子水中，得到200mM溶液；
2.1.4乳鼠原代心肌细胞培养液
取低糖DMEM培养基150mL，M199培养基50mL，Gibco胎牛血清10mL，马血清20mL，L-谷氨酰胺2mL，双抗2.34mL，配置完成后过滤；
2.1.5 10×ADS缓冲液
称取NaCl 6.8g，Na 2HPO 4·2H 2O 120mg，KCl 400mg，MgSO 4·7H 2O 197mg，Glucose 1g，Hepes 4.8g，加入90mL去离子水溶解，调节pH至7.4，然后定容至100mL备用，使用时稀释为1×。
2.2乳鼠原代心肌细胞的培养及提取
2.2.1取SD大鼠的新生乳鼠(2-5天)心脏，置于预冷的1×ADS缓冲液中；
2.2.2先剪去心房，再剥离心脏外的血管组织，最后轻轻将心室切开后剪几下；
2.2.3取1.5ml EP管加入900μL 1×ADS缓冲液，然后将3-5个乳鼠心室加入EP管中，再加入10μL100×II型胶原酶；
2.2.4恒温震荡仪37℃、1100rpm消化15min，取消化液后加入1mL心肌细胞培养液；
2.2.5中和后1500g离心5min，弃上清加入2mL心肌细胞培养液；
2.2.6再次重复震荡消化、离心两次，得到6mL的原代心肌细胞悬液(共消化三次)；
2.2.7将6mL原代心肌细胞悬液转移至50mL离心管中，再加入细胞培养液混匀，平均每10个乳鼠心脏有10mL细胞培养液；
2.2.8将10mL原代心肌细胞悬液加入到培养皿中，放细胞培养箱中正常培养；
2.2.9 45min后小心取细胞培养液加入到新培养皿中，正常培养；
2.2.10 45min后小心取细胞培养液，1500g离心5min得到原代心肌细胞；
2.2.11用0.2％明胶包被培养板，置培养箱中最少放置30min；
2.2.12重悬后用台盼蓝染色法计数，6孔板中每孔加入1×10 6个细胞,并按1：20000加入有丝***抑制剂诺考达唑；
2.2.13铺板于用0.2％明胶包被30min后的培养板，培养3h后再换成正常心肌细胞培养液；
2.2.14第二天观察细胞可发现原代心肌细胞呈现有节律的跳动，备用于后续检测。
试验方法：
1.含化合物的培养板的准备
取化合物在DMSO中的50mM母液，先用DMSO稀释为30mM、10mM、3.3mM、1.1mM和0.37mM的一系列梯度浓度化合物溶液，再用培养基稀释为3mM、1mM、333μM、111μM和37μM的一系列梯度浓度化合物溶液(100×工作液)。
2.实验步骤
按上述方法，提取SD新生大鼠原代心肌细胞(RNCM)，铺于6孔板中。待RNCM 贴壁伸展并搏动后，饥饿24h。给药前更换为新鲜全培养基，1mL/孔，每孔加入不同浓度化合物100×工作液10μL得到终浓度为30μM、10μM、3.33μM、1.11μM和0.37μM的梯度浓度的一系列化合物溶液。给药孵育30min后，加入ANF，使终浓度为1μM，继续共孵育30min后，收集各孔细胞。
3.cGMP含量检测(参照cGMP ELISA试剂盒说明书操作)
3.1细胞收集
各孔吸取培养基，用PBS洗一次细胞，加入250μL的0.5M高氯酸，用细胞刮刀收集细胞，转移至1.5mL离心管中。涡旋混匀后在4℃6000g离心20min。取上清200μL用4M的KOH调节pH至中性。
另取一个非转染孔和一个转染孔细胞，加入含蛋白酶抑制剂和磷酸酶抑制剂的RIPA裂解液，收集细胞，用于转染验证的WB试验。
3.2 cGMP含量测定
配制30-0.23pmol/mL浓度范围(2倍梯度稀释)的cGMP标品后，按下表加样，4℃孵育18h。
Figure PCTCN2020078215-appb-000106
充分洗板5次后，各孔加入200μL的Ellman’s Reagent，封板避光震荡显色60min后，检测412nm处吸光度值。
3.3 cGMP含量测定
首先扣除非特异性结合(各孔读值减去NSB孔读值)，然后计算B/B0，即样品或标准品的结合与最大结合的比值，按照如下公式进行转换，然后将得到的logit(B/B0)与lg(化合物浓度)进行线性回归，得到标准曲线。
logit(B/B0)＝ln[B/B0/(1-B/B0)]
将样品的B/B 0值转换为logit(B/B 0)值，根据标准曲线计算出样品中cGMP的含量。
测试结果如图2所示：
如图2所示，ANF可显著诱导新生大鼠原代心肌细胞内cGMP的表达，本发明化合物在大鼠原代心肌细胞内通过抑制PDE9，提高cGMP水平。这说明本发明化合物具有升高心肌cGMP的能力，在治疗心衰方面具有较好的临床应用潜力。
实验例四：冠状动脉结扎诱导的大鼠心衰模型
本文中，使用的缩写，“bid”是指每天给药两次；“LVEF”是指左心室射血分数；“EDV”是指左心室舒张末期容积；“ESV”是指左心室收缩末期容积；“DMSO”是指二甲基亚砜；“MC”是指甲基纤维素；“p.o”是指口服给药；“mpk”是指毫克/千克；“SD”是指斯普拉格-杜勒鼠。“S.E.M”是指标准误差。“PEG400”是指聚乙二醇400；“captisol”是磺丁基倍他环糊精钠。“FS”是左室短轴缩短率；“HR”是心率。
仪器
小动物呼吸机
Powerlab 8/35信号采集处理***；
Millar导管
Vevo小动物超声成像***
分析天平；
测试药物
化合物102，给药剂量30mg/kg，给药溶媒5％DMSO+10％PEG400+85％(20％Captisol+0.5％MC in water)
实验动物
Sprague Dawley大鼠(SD大鼠),，雄性，造模时体重220g左右。
实验方法
手术前腹腔注射戊巴比妥钠注射液麻醉动物，腹腔注射阿托品祛痰。大鼠麻醉后仰位固定，呼吸机辅助呼吸，在第三和第四肋骨间开胸，使用5-0带线缝合针结扎冠状动脉左前降支。结扎完成后关闭胸腔，缝合皮肤，放入保温毯恢复。假手术组(Sham组)也进行相同手术操作，只是不进行丝线结扎操作。术后肌肉注射美洛昔康止痛以及腹腔注射硫酸庆大霉素注射液抗感染，腹腔注射利多卡因，预防室颤。动物术后恢复一周后，将模型大鼠分为模型组和治疗药物组(化合物102组)，分别灌胃给药溶媒和化合物102，每天两次，连续四周。实验期间，观察动物生活状态，对异常状况进行记录以评估化合物安全性；给药28天，末次药后第二天，腹腔注射戊巴比妥钠麻醉动物，进行超声心动图检测和血流动力学检测，评价化合物对心脏收缩功能及心室容量的影响。结束后进行终点处理，取心脏进行取材收集，以便后续进行cGMP及蛋白表达的相关研究。
动物术后恢复一周后，使用异氟烷麻醉大鼠，Vevo小动物超声成像***检查模型大鼠左心室功能，以LVEF％降低30％即为模型成功。除假手术组外，根据LVEF％和体重随机分为2组，每组动物数及给药方式如下表：
Figure PCTCN2020078215-appb-000107
实验终点大鼠处死后取梗死心脏组织用4％甲醛固定，经脱水、石蜡包埋、切片，使用天狼猩红染色显微镜下观察胶原沉积状况，使用徕卡aperio数字切片扫描***进行扫描分析。
检测指标
主要评价指标为LVEF％(左室射血分数)、FS(左室短轴缩短率)、ESV(左心室收缩末期容积)、EDV(左心室舒张末期容积)、心率(HR)。实验终点统计心肌梗死边缘区(Pro-infarction zone)天狼猩红比例来评价胶原沉积状况。
数据统计
数据使用Mean±S.E.M表示，Graphpad Prism 5.0进行统计作图。用T-检验进行统计学分析。P<0.05表示差异有统计学意义。
研究结果
大鼠30mpk，bid，连续给药28天后大鼠状态良好，与假手术组相比未见体重异常，提示化合物安全性较佳。
从图3－4可以看出，模型组大鼠的LVEF和FS分别为36.0±1.86％和18.3±1.03％，显著低于假手术组的72.2±1.40％和43.0±1.29％，统计学差异显著(P<0.001)。从图5－6可以看出，与假手术组大鼠相比，模型组大鼠心脏EDV和ESV均明显升高，有显著的统计学差异(P<0.001)。因此模型组左心室收缩功能显著降低，心肌重构变化显著，提示模型造模成功。化合物102对心衰大鼠LVEF及FS的降低有改善作用，且与模型组比较具有显著性统计学差异(P<0.001)。同时，化合物102对心衰造成的心脏EDV和ESV增大有显著改善作用(P<0.05,P<0.01)。因此化合物可显著改善心衰大鼠的收缩功能及心肌重构。
从图7可以看出，与假手术组大鼠相比，模型组及化合物给药组未观察到心率的变化。
表3 化合物对心衰大鼠心肌纤维化的影响(Mean±S.E.M)
Figure PCTCN2020078215-appb-000108
***P<0.001vs假手术,###P<0.001vs模型组，t-检验
与图8和表3可知，假手术组胶原沉积百分比为0.121±0.017％，而模型组大鼠左心室心肌梗死边缘区的胶原沉积百分比为28.9±1.35％，显著高于假手术组，统计学差异极显著(P<0.001)。由此可知，模型组心肌梗死后引起梗死区域及边缘区的胶原沉积从而发生心肌纤维化(Cardiac fibrosis)。与模型组比较，化合物102可以显著降低梗死边缘区胶原沉积(P<0.001)，有效改善心衰模型导致的心肌纤维化。
结论：综上所述，化合物102可以改善心衰大鼠的心脏功能，逆转大鼠心衰后导致的心肌重构，降低梗死边缘区域纤维化，具有优秀的治疗心衰的临床应用潜力。

Claims (12)

  1. 通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物在制备治疗哺乳动物心衰疾病的药物中的用途，
    Figure PCTCN2020078215-appb-100001
    其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，N杂原子可以任选被氧化为
    Figure PCTCN2020078215-appb-100002
    R 3在每次出现时独立地选自氢、氘、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、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、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3-12元杂环基、芳基、5-10元杂芳基、3-12元环烷基、3-12元环烯基，其中所述3-12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)，N杂原子可以任选被氧化为
    Figure PCTCN2020078215-appb-100003
    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、氘、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为0、1、2或3；
    R 2选自氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、卤代C 1-6烷基。
  2. 根据权利要求1所述的用途，其中通式(I)的化合物及其药学上可接受的盐、异构体和氘代化合物选自以下结构：
    Figure PCTCN2020078215-appb-100004
    Figure PCTCN2020078215-appb-100005
  3. 如权利要求1或2所述的用途，其特征在于，所述的治疗心衰疾病的药物还包括第二种或多种治疗剂。
  4. 如权利要求1或2所述的用途，其特征在于，所述治疗心衰疾病的药物可以与药用载体制成药学上可接受的任意药物制剂。
  5. 如权利要求1或2所述的用途，其特征在于，所述的药物通过口服、肠胃外、透皮、直肠、经鼻、经肺、植入、局部给药方式施用于需要治疗的患者或受试者。
  6. 如权利要求1或2所述的用途，其特征在于，所述心衰疾病为不同分类依据下的各种心衰，包括左心衰竭、右心衰竭、全心衰竭；急性心衰、慢性心衰、失代偿性心衰；收缩性和舒张性心力衰竭；前心衰阶段、前临床心衰阶段、临床心衰阶段、难治性终末期心衰阶段；纽约心脏协会(NYHA)心功能分级I级、II级、III级、IV级的心衰；左心室射血分数降低型心衰、左心室射血分数中间值心衰、左心室射血分数保留型心衰。
  7. 如权利要求1或2所述的用途，其特征在于，所述心衰疾病选自缺血性心脏病导致的心衰、毒性损害导致的心衰、免疫介导的和炎症损害导致的心衰、浸润性病变导致的心衰、代谢紊乱导致的心衰、遗传异常导致的心衰、异常负荷导致的心衰、心律失常导致的心衰。
  8. 如权利要求1或2所述的用途，其特征在于，所述心衰疾病选自收缩性心力衰竭和舒 张性心力衰竭。
  9. 如权利要求1所述的用途，所述的哺乳动物是人类和动物类。
  10. 如权利要求1或2所述的用途，其特征在于，通式(I)化合物及其药学上可接受的盐、异构体和氘代化合物通过抑制PDE9活性，提高环磷酸鸟苷酸的水平，起到治疗心衰的作用效果。
  11. 如权利要求1或2所述的用途，其特征在于，通式(I)化合物及其药学上可接受的盐、异构体和氘代化合物通过改善心衰患者或受试者的心脏功能，逆转心衰患者或受试者的心肌重构，起到治疗心衰的作用效果。
  12. 一个药盒，包含(a)通式(I)所示的磷酸二酯酶9(PDE9)抑制剂化合物及其药学上可接受的盐、异构体和氘代化合物和(b)使用所述化合物或其药学上可接受的盐或其异构体或其氘代化合物用于治疗哺乳动物心衰疾病的说明书：
    Figure PCTCN2020078215-appb-100006
    其中，X 1、X 2、X 3、X 4分别独立地选自CR 3或N，N杂原子可以任选被氧化为
    Figure PCTCN2020078215-appb-100007
    R 3在每次出现时独立地选自氢、氘、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、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、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3-12元杂环基、芳基、5-10元杂芳基、3-12元环烷基、3-12元环烯基，其中所述3-12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)，N杂原子可以任选被氧化为
    Figure PCTCN2020078215-appb-100008
    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、氘、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为0、1、2或3；
    R 2选自氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、卤代C 1-6烷基。
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CHINESE JOURNAL OF CARDIOLOGY, vol. 46, no. 10, 2018, pages 760 - 789
See also references of EP3939588A4
WU YUE; ZHANG YAO: "Advances in Heart Failure using Phosphodiesterase 9", JOURNAL OF SOUTHEAST UNIVERSITY (MEDICAL SCIENCE EDITION), vol. 35, no. 1,, 29 February 2016 (2016-02-29), pages 162 - 164, XP009523117 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021105115A1 (en) 2019-11-28 2021-06-03 Bayer Aktiengesellschaft Substituted aminoquinolones as dgkalpha inhibitors for immune activation
WO2021105117A1 (en) 2019-11-28 2021-06-03 Bayer Aktiengesellschaft Substituted aminoquinolones as dgkalpha inhibitors for immune activation
WO2022206936A1 (zh) 2021-04-01 2022-10-06 药捷安康(南京)科技股份有限公司 磷酸二酯酶抑制剂的制备方法

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CN111658653A (zh) 2020-09-15
SG11202109781QA (en) 2021-10-28
TWI816026B (zh) 2023-09-21
CA3132895A1 (en) 2020-09-17
AU2020235187B2 (en) 2023-09-07
EP3939588A4 (en) 2023-01-11
AU2020235187A1 (en) 2021-10-07
KR20210136104A (ko) 2021-11-16
AU2020235187B8 (en) 2024-02-08
CN111658653B (zh) 2022-09-09
EP3939588A1 (en) 2022-01-19
JP2022533879A (ja) 2022-07-27
TW202100151A (zh) 2021-01-01
JP7404616B2 (ja) 2023-12-26
AU2020235187A8 (en) 2024-02-08

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