WO2023109471A1 - Spiro pyrimidinone derivative, preparation method therefor, and pharmaceutical composition and use thereof - Google Patents

Spiro pyrimidinone derivative, preparation method therefor, and pharmaceutical composition and use thereof Download PDF

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WO2023109471A1
WO2023109471A1 PCT/CN2022/134253 CN2022134253W WO2023109471A1 WO 2023109471 A1 WO2023109471 A1 WO 2023109471A1 CN 2022134253 W CN2022134253 W CN 2022134253W WO 2023109471 A1 WO2023109471 A1 WO 2023109471A1
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compound
room temperature
added
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concentrated
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金贇
彭军
吴金华
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上海赛默罗生物科技有限公司
上海赛默罗德生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—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 three hetero rings
    • C07D471/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel pyrimidinone compounds, their preparation methods and pharmaceutical compositions containing the compounds and their use in the treatment of diseases mediated by Lp-PLA 2 .
  • Lipoprotein-associated phospholipase A 2 is a phospholipase A 2 enzyme involved in the hydrolysis of lipoprotein lipids or phospholipids, also known as platelet-activating factor acetylhydrolase (PAF-AH).
  • Lp-PLA 2 moves with low-density lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules resulting from LDL oxidation.
  • Lp-PLA 2 hydrolyzes the sn-2 ester of oxidized phosphatidylcholine to yield the lipid mediator lysophosphatidylcholine (lysoPC) and oxidized non-esterified fatty acids (NEFA).
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia
  • various neuropsychiatric diseases such as schizophrenia and autism, peripheral and cerebral atherosclerosis , stroke, metabolic bone disease (eg, bone marrow abnormalities), dyslipidemia, Paget's disease, type II diabetes, hypertension, angina, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance, and parathyroid Hyperfunction, diabetic complications (such as macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcer and diabetic nephropathy), diabetic peripheral neuropathic pain, inflammatory pain, neuropathic pain, various types of cancer (such as prostate cancer , colon cancer, breast cancer, kidney cancer, lung cancer and ovarian cancer, etc.), macular edema, wound healing, male erectile dysfunction, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), sepsis, acute
  • Lp-PLA 2 inhibitors can be used to treat atherosclerosis.
  • Wilensky et al demonstrated the effect of Lp-PLA 2 inhibitors on atherosclerotic plaque components in a diabetic and hypercholesterolemic pig model of accelerated coronary atherosclerosis (Wilensky et al., Nature Medicine, 10, 1015-1016 (2008)).
  • Clinical studies have also found that Lp-PLA 2 inhibitors can stabilize hardened plaques in patients with atherosclerotic plaques and prevent further development of plaques and rupture (Serruys et al., Circulation 118: 1172-1182 (2008)).
  • AD Alzheimer's disease
  • mixed dementia Van Oijen et al., Annals of Neurology, 59, 139 (2006); Fitzpatrick et al., Atherosclerosis 235 : 384-391 (2014).
  • AD patients Kassner et al., Current Alzheimer Research, 5, 358-366 (2008); Dildar et al., Alzheimer Dis Assoc Disord, 24, April-June (2010); Sinem et al., Current Alzheimer Research, 7, 463-469 (2010)).
  • Lp-PLA 2 inhibitors reduce blood-brain barrier leakage and brain amyloid (Abeta) load, which can be used to treat diseases associated with blood-brain barrier leakage, such as Alzheimer's disease and vascular dementia.
  • Abeta brain amyloid
  • Lp-PLA 2 inhibitors have a significant effect on preventing further deterioration of cognitive function in Alzheimer's patients (Maher-Edwards et al., Alzheimer's&Dementia: Translational Research&Clinical Interventions 1, 131-140(2015)) .
  • Lp-PLA 2 inhibitors reduce the release of various cytokines by inhibiting lysoPC production (Shi et al., Atherosclerosis 191, 54-62 (2007)). Therefore, inhibition of Lp-PLA 2 is a potential treatment for neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, etc.
  • LysoPC is also involved in leukocyte activation, induction of apoptosis and mediation of vascular endothelial cell dysfunction (Wilensky et al., Current Opinion in Lipidology, 20, 415-420, (2009)). Therefore, it is thought that Lp-PLA 2 inhibitors may be useful in the treatment of tissue damage associated with diabetes by reducing the production of lysoPC. High Lp-PLA 2 activity is associated with a high risk of developing diabetic retinopathy (Siddiqui et al., Diabetologia, 61, 1344-1353 (2016)).
  • Lp-PLA 2 inhibitors can inhibit the main pathological changes of retinopathy in diabetic rat models (Canning et al., PNAS113, 7213-7218 (2016). Clinical studies also show that Lp-PLA 2 inhibitors can improve diabetic retinopathy Macular edema symptoms and visual acuity (Staurenghi et al., Ophthalmology 122, 990-996 (2015). These studies demonstrate that Lp-PLA 2 inhibitors can be used in diabetic retinopathy.
  • Lp-PLA 2 activity in diabetic patients is higher than that of normal people (Serban et al. J.Cell.Mol.Med.6:643-647, (2002); Garg et al. Indian J.Med.Res.141:107 -114, (2015)).
  • the activity of Lp-PLA 2 mediates oxidative inflammatory reactions, and it is speculated that inhibiting the activity of Lp-PLA 2 can be used to treat various complications caused by oxidative inflammatory reactions in diabetic patients, such as diabetic nephropathy, diabetes Peripheral neuropathy and diabetic skin ulceration.
  • Glaucoma and age-related macular degeneration are retinal neurodegenerative diseases. Inflammation plays an important role in the pathogenesis of glaucoma and AMD (Buschini et al., Progress in Neurobiology, 95, 14-25 (2011); Tezel, Progress in Brain Research, vol. 173, ISSN 0079-6123, Chapter 28). Therefore, Lp-PLA 2 inhibitors may offer potential therapeutic applications for glaucoma and AMD.
  • Lp-PLA 2 In male erectile dysfunction patients, the activity of Lp-PLA 2 in the body is significantly higher than that of normal people, and it is believed that high Lp-PLA 2 activity can predict early male erectile dysfunction (Otunctemur et al., Andrologia 47: 706-710 (2015)), Tip inhibitors can be used to treat male erectile dysfunction.
  • Lp-PLA 2 is highly expressed in prostate cancer tissues, and reducing Lp-PLA 2 can reduce prostate cell carcinogenesis and promote prostate cancer cell apoptosis in vitro (Vainio et al., Oncotarget, 2: 1176-1190 (2011)) , suggesting that Lp-PLA 2 inhibitors can be used in the treatment of prostate cancer.
  • Lp-PLA 2 inhibitors can treat or prevent various diseases associated with inhibition of Lp-PLA 2 activity.
  • the present invention discovers a new Lp-PLA 2 inhibitor.
  • One object of the present invention is to provide the compound represented by general formula (I), its cis-trans isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates, or Its pharmaceutically acceptable salt or ester, or its prodrug.
  • Another object of the present invention is to provide a preparation method of the compound represented by general formula (I).
  • Another object of the present invention is to provide the compound shown in general formula (I) as the purposes of Lp- PLA2 inhibitor, thus in the application in the medicine that is used for preventing, treating or improving the disease relevant with Lp-PLA2 inhibition,
  • the disease is such as diabetic complications, neuroinflammation-related diseases or/and atherosclerosis, and the diabetic complications are diabetic retinopathy/diabetic macular edema, diabetic nephropathy, diabetic neuropathy, diabetic peripheral neuropathic pain or/and diabetes foot, neuroinflammation-associated diseases are Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or/and Parkinson's disease.
  • Another object of the present invention is to provide a pharmaceutical composition, which comprises one or more therapeutically effective doses of compounds represented by general formula (I), its cis-trans isomers, enantiomers, diastereomers Isomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts or esters thereof, or prodrugs thereof, and pharmaceutically acceptable carriers and/or adjuvants.
  • compounds represented by general formula (I) their cis-trans isomers, enantiomers, diastereomers Isomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts or esters thereof, or prodrugs thereof, and pharmaceutically acceptable carriers and/or adjuvants.
  • Another object of the present invention is to provide a method for preventing, treating or improving diseases related to Lp-PLA2 inhibition, comprising administering the compound represented by the general formula (I) of the present invention, its cis-trans isomers, Enantiomers, diastereoisomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts or esters thereof, or prodrugs thereof, or compositions of the present invention.
  • a compound represented by formula I its cis-trans isomers, its enantiomers, its diastereoisomers, its racemates, its solvates, and its hydrates or a pharmaceutically acceptable salt thereof or a prodrug thereof,
  • n 1 or 2; preferably, m is 1;
  • n, u are 0, 1 or 2; preferably, n, u are 0 or 1;
  • Q is -O-, -S- or -NR a -, preferably Q is -O-;
  • R a is H, C 1-6 alkyl, C 1-3 haloalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl;
  • R 1 is H, halogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclic group , R can be substituted by one or more of the following substituents: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl ;
  • (R 2 ) p represents that the hydrogen on the ring is replaced by p R 2s , and each R 2 is the same or different;
  • p 2, 3, 4, 5 or 6;
  • R 2 , R x , R y are independently selected from the following substituents: H, halogen, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl group, 3-8 membered heteroaryl group, -C(O)NR b R c , -S(O) 2 NR b R c , and can be replaced by one or more
  • the following substituents are substituted: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl;
  • R x , R y together with their connected carbon atoms can form a 3-6 membered saturated ring, which is a full carbon ring or contains one or more heterocyclic rings selected from N, O and S atoms, and can be surrounded by one or more R m replacement;
  • R 2 On the ring substituted by p independent R 2 , at least two R 2 are connected to the same carbon atom, and form a 3-6 membered saturated ring together with the carbon atoms they are connected to, and the ring is a full carbon ring or contains One or more heterocyclic rings selected from N, O and S atoms, and may be substituted by one or more R m ;
  • R m is C 1-6 alkyl, C 1-3 haloalkyl, halogen, cyano, -OR c , -NR b R c , C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6 -10 aryl or 3-8 membered heteroaryl;
  • R b is H, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group
  • R c is L, LC(O)-, L-CH 2 - or LS(O) 2 -,
  • L is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 3-8 membered heteroaryl, L can be replaced by one or more The following groups are substituted: halogen, hydroxyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 3-8 membered heteroaryl ;
  • Z is N or CR 3 ; preferably, Z is CR 3 ;
  • Z' is N or CR 4 ; preferably Z' is CR 4 ;
  • R 3 , R 4 , R 5 , R 6 are independently H, CN, halogen, C 1-3 alkyl or C 1-3 haloalkyl;
  • V is N or CR 9 , preferably, V is CR 9 , wherein R 9 is H, CN, halogen, C 1-3 alkyl, C 1-3 haloalkyl or -OW;
  • W is a 5- or 6-membered heteroaryl or phenyl group, preferably pyridyl , pyrimidinyl, pyrazolyl or phenyl, which may be optionally substituted by one or more of the following substituents: halogen, cyano, C -6 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and C 1-3 haloalkoxy.
  • the compound of formula (I) has one of the following 12 structures:
  • n 1 or 2; preferably, m is 1;
  • Q is -O-, -S- or -NR a -; preferred Q is -O-;
  • R a is H, C 1-6 alkyl, C 1-3 haloalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl;
  • R x , R y are independently selected from the following substituents: H, halogen, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 3-8 membered heteroaryl, -C(O)NR b R c , -S(O) 2 NR b R c , and may be substituted by one or more of the following Base substitution: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl;
  • R x , R y together with their connected carbon atoms can form a 3-6 membered saturated ring, which is a full carbon ring or contains one or more heterocyclic rings selected from N, O and S atoms, and can be surrounded by one or more
  • u is 0 or 1, preferably u is 0, and R x and R y are both H;
  • R 1 is H, halogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclic group , R 1 is optionally substituted by one or more of the following substituents: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl group; preferably, R 1 is H, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; preferably, R 1 is H, halogen, cyano, C 1-3 alkyl or C 1-3 alkoxy; more preferably, R is H, fluorine, chlorine, cyano, methyl, ethyl or methoxy; most preferably, R is H or methoxy;
  • R b is H, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group
  • R c is L, LC(O)-, L-CH 2 - or LS(O) 2 -,
  • L is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 3-8 membered heteroaryl, L is optionally replaced by one or more The following groups are substituted: halogen, hydroxyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 3-8 membered heteroaryl base;
  • Z is N or CR 3 ; preferably, Z is CR 3 ;
  • Z' is N or CR 4 ; preferably Z' is CR 4 ;
  • R 3 , R 4 , R 5 , R 6 are independently H, CN, halogen or C 1-3 haloalkyl
  • V is N or CR 9 , preferably, V is CR 9 , wherein R 9 is H, CN, halogen, C 1-3 alkyl, C 1-3 haloalkyl or -OW;
  • W is 5 or 6 membered heteroaryl or phenyl, preferably pyridyl, pyrimidyl, pyrazolyl or phenyl, which may be optionally substituted by one or more of the following substituents : halogen, cyano, C -6 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and C 1-3 haloalkoxy;
  • R 5 , R 6 , R 7 , R 8 , R 9 are independently H, F or CN;
  • R 5 , R 6 , R 7 , R 8 are independently H, F or CN;
  • R 9 is -OW
  • W is 5 or 6 membered heteroaryl or phenyl, preferably pyridyl, pyrimidyl, pyrazolyl or phenyl, which can be optionally substituted by one or more of the following substituents: C 1-3 haloalkyl, C 1-3 haloalkoxy, CN, halogen and C 1-6 alkyl.
  • A is
  • R 7 , R 8 are independently H, F or CN;
  • R 9 is -OW
  • W is pyridyl, pyrimidyl, pyrazolyl or phenyl, which may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, CF 3 , -OCF 3 , CHF 2 and CH 3 ;
  • A is selected from the following groups:
  • the compound is any one of the following compounds:
  • the compounds of the above formulas, salts thereof may exist in stereoisomeric forms (eg, which contain one or more asymmetric carbon atoms). Both the individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the present invention.
  • the invention also includes various deuterated forms of the compounds of the above formulas, salts (eg, pharmaceutically acceptable salts) thereof.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom.
  • Those of ordinary skill in the art will understand how to synthesize deuterated forms of the compounds of the above formulas, their salts (eg, pharmaceutically acceptable salts).
  • Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of the above formula, salts thereof (e.g., pharmaceutically acceptable salts), or conventional methods using deuterated reagents (such as lithium aluminum deuteride) can be used. technology to synthesize these compounds.
  • salt forms of the compounds are also within the scope of the present invention.
  • Salts or pharmaceutically acceptable salts of the compounds of the present invention can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in free acid or free base form with a suitable base or acid, respectively. preparation.
  • suitable pharmaceutical salts see Berge et al., J. Pharm, Sci., 66, 1-19, 1977; P L Gould, International Journal of Pharmaceuticals, 33 (1986), 201-217; and Bighley et al. People, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, pages 453-497.
  • the present invention provides a polymorphic form of a compound as defined herein, a salt thereof (e.g., a pharmaceutically acceptable salt), or a compound described herein, or a salt thereof (e.g., a pharmaceutically acceptable salt). Polymorphs of solvates or hydrates of acceptable salts above.
  • the invention also includes isotopically labeled compounds and salts which are equivalent to the compounds of the above formulas or salts thereof, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from that most frequently found in nature .
  • isotopes that can be incorporated into the compound of the above formula or its salt are isotopes of hydrogen, carbon, nitrogen, deuterium, such as 3 H, 11 C, 14 C and 18 F.
  • the compound of the above formula or its salt labeled with these isotopes can be used for Drug and/or substrate tissue distribution testing.
  • 11 C and 18 F isotopes can be used in PET (Positron Emission Tomography). PET can be used for brain imaging.
  • the compound of the above formula or salt thereof is non-isotopically labeled.
  • the compounds of the present invention include compounds of the above formulas, or salts thereof, such as pharmaceutically acceptable salts thereof.
  • Representative compounds of the invention include the specific compounds described.
  • the present invention also relates to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient.
  • the present invention also relates to a method for treating or preventing a disease associated with the activity of Lp-PLA 2 , comprising administering a therapeutically effective amount of the compound of the present invention described herein to a subject in need thereof.
  • the disease may be associated with the involvement of monocytes, macrophages or lymphocytes, increased formation of lysophosphatidylcholine and oxidized free fatty acids, oxidation of lipids associated with Lp-PLA 2 activity or endothelial dysfunction.
  • the present invention also provides methods for treating or preventing diseases by inhibiting the activity of Lp- PLA2 .
  • diseases include, but are not limited to: neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia), various neuropsychiatric diseases such as schizophrenia and autism, peripheral and cerebral Atherosclerosis, stroke, metabolic bone disease (eg, bone marrow abnormalities), dyslipidemia, Paget's disease, type 2 diabetes, hypertension, angina, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance and hyperparathyroidism, diabetic complications (such as macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcer and diabetic nephropathy), diabetic peripheral neuropathic pain, inflammatory pain, neuropathic pain, various types of cancer (such as prostate cancer, colon cancer, breast cancer, kidney cancer, lung cancer and ovarian cancer, etc.), macular edema, wound healing, male erectile dysfunction
  • the present invention also provides methods for treating or preventing Alzheimer's disease.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • the present invention also provides methods for treating or preventing atherosclerosis.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • the present invention also provides methods of treating or preventing ocular diseases by administering a compound of the present invention.
  • the invention provides a method of treating macular edema comprising administering to a subject a therapeutically effective amount of a compound of the invention.
  • the macular edema is associated with diabetic eye disease (eg, diabetic macular edema or diabetic retinopathy).
  • the macular edema is associated with posterior uveitis.
  • the present invention also provides the use of the compound of the present invention in the preparation of a medicament for the treatment or prevention of the diseases described in this application.
  • the invention also provides compounds of the invention for use in the treatment or prevention described herein.
  • disease refers to any change in the state of the body or some organ that interrupts or interferes with the performance of function and/or causes symptoms in a person who is afflicted or who is in contact with it (such as discomfort, dysfunction, adverse stress and even death).
  • diabetic retinopathy refers to the chronically progressive leakage and obstruction of retinal microvessels as a result of diabetes.
  • Diabetic macular edema refers to retinal thickening or hard exudative deposits due to the accumulation of extracellular fluid in the fovea of the macula within one optic disc diameter due to diabetes.
  • neurodegenerative disease refers to a variety of disorders of the central nervous system characterized by a gradual, progressive loss of nervous tissue and/or nervous tissue function.
  • Neurodegenerative disease is a class of neurological disorders characterized by gradual, progressive loss of neural tissue and/or altered neurological function, usually neurological Reduced functionality.
  • neurodegenerative diseases described herein include neurodegenerative diseases in which a defective blood-brain barrier (e.g., a permeable blood-brain barrier) is present. Examples of neurodegenerative diseases in which a defective blood-brain barrier is present include, but are not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, and vascular dementia, among others.
  • vascular dementia also known as “multi-infarct dementia” refers to a group of syndrome.
  • the main subtypes of vascular dementia are vascular mild cognitive impairment, multi-infarct dementia, vascular dementia due to a major single infarct affecting the thalamus, anterior cerebral artery, parietal lobe, or cingulate gyrus , vascular dementia due to hemorrhagic lesions, small vessel disease (including, for example, vascular dementia due to lacunar lesions and Binswanger disease) and mixed dementias.
  • neuroopathic pain is pain provoked or caused by primary damage and dysfunction of the nervous system.
  • inflammatory pain is pain resulting from localized acute inflammation or chronic inflammation that stimulates a nerve.
  • diabetic peripheral neuropathic pain refers to pain caused by nerve damage complicated by diabetes mellitus, at least in part due to reduced blood flow and hyperglycemia.
  • blood-brain barrier or “BBB” are used interchangeably herein to refer to the permeable barrier present in blood vessels passing through brain tissue that strictly limits and closely regulates the exchange of substances between blood and brain tissue.
  • BBB components include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that serve as structural associates of the BBB, the basement membrane of the endothelial cells, and the extracellular membrane that covers nearly all exposed blood vessels. Enlarged foot processes of astrocytes near the surface.
  • metabolic bone disease refers to the different classes of bone disease characterized by a gradual and progressive loss of bone tissue.
  • a metabolic bone disease as described herein is a bone metabolic disease in which there is a condition of diffuse decreased bone density and/or decreased bone strength. Such diseases are characterized by histological appearance.
  • Exemplary metabolic bone diseases include, but are not limited to, osteoporosis characterized by decreased mineral and bone matrix and osteomalacia characterized by decreased mineral and intact bone matrix.
  • osteoopenic disease or “osteopenia” are used interchangeably in this application to refer to a condition with decreased calcification and/or bone density, to mean A descriptive term for all skeletal systems in which calcification and/or decreased bone density are observed. Osteopenia also refers to a decrease in bone mass due to insufficient synthesis of osteoid.
  • osteoporosis refers to a condition in which mineral and/or bone matrix is reduced and/or bone matrix is reduced.
  • alkyl is a monovalent, saturated hydrocarbon chain having the indicated number of carbon atoms.
  • C 1-3 alkyl refers to an alkyl group having 1 to 3 carbon atoms.
  • C 1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms.
  • Alkyl groups can be straight or branched. In some embodiments, a branched alkyl group can have one, two, or three branches. Exemplary alkyl groups include, but are not limited to, methyl, methylethyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl).
  • an "alkoxy" substituent is a group of the formula "RO-", wherein R is alkyl as defined above.
  • C 1-3 alkoxy refers to such alkoxy substituents containing 1 to 3 carbons.
  • Exemplary alkoxy substituents include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropoxy, isobutoxy , sec-butoxy, tert-butoxy, isopentyloxy and neopentyloxy.
  • cycloalkyl refers to monovalent saturated cyclic hydrocarbon groups including bridged rings and spiro rings, preferably with 3-7 ring carbon atoms, such as cyclopropyl, cyclobutyl, Cyclopentyl or [1.1.1] propane, and those groups specifically exemplified hereinafter.
  • aryl means a hydrocarbon group containing one or more aromatic rings, such as phenyl or naphthyl and the like.
  • heteroaryl means a stable monocyclic, bicyclic, or tricyclic ring having up to 8 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H ,3H-1-oxoisoindolyl, benzotriazolyl, furyl, thienyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl, benzothienyl, benzofuran Base, benzodioxane, benzodioxine, quinolinyl, isoquinolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, Pyridyl, pyrimidyl, pyrrolyl, tetrahydroquinolyl
  • heteroaryls have a 5- or 6-membered ring, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl , pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl.
  • heterocycle or “heterocyclyl” means that 1 to 4 carbon atoms have been independently selected from N, N(R), S, S(O), S (O) and cyclic hydrocarbons substituted by heteroatoms of O.
  • Heterocycles can be saturated or unsaturated, but are not aromatic.
  • the heterocyclic group can also contain 1, 2 or 3 rings, including bridged and spiro ring structures.
  • heterocyclyl groups include, but are not limited to: azetidine, oxetane, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrrolinyl, pyranyl Base, dioxolanyl, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiocyclopentadienyl, oxathiolanyl Base, dioxanyl, dioxenyl, dioxazolyl, oxathiazolyl (oxathiozolyl), oxazolone, piperazinyl, morpholino, thiomorpholinyl, 3-oxomorpholinyl , dithianyl, trithianyl and oxazinyl.
  • bridged ring compound refers to the linking of one or more atoms (ie, C, O, N, or S) to two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In bridged rings, substituents on the ring may also be present on the bridge.
  • spirocyclic compound refers to a polycyclic compound in which two monocyclic rings share one carbon atom, which is called a spiroatom.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • Halo refers to a halogen group: fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).
  • haloalkyl is an alkyl group substituted with one or more halogen substituents, which may be the same or different.
  • C 1-3 haloalkyl refers to a haloalkyl substituent containing 1 to 3 carbons.
  • Exemplary haloalkyl substituents include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, trifluoropropyl, 3-fluoropropyl, and 2- Fluoroethyl.
  • ring when two substituents on a ring, together with their interconnected atoms, combine to form another ring, the ring may be spirofused or unilaterally fused.
  • a spiro-fused ring system consists of two rings which have only one carbon atom in common.
  • Unilateral-fused ring systems consist of two rings that share only two atoms and one bond.
  • 4, 5 or 6 membered saturated ring, which ring optionally contains a heteroatom selected from N or O means 4, 5 or 6 membered saturated carbocyclic ring and one carbon Atomic ring members may optionally be replaced by a heteroatom selected from N or O, for example, cyclobutyl, cyclopentyl, cyclohexane, azitidinyl, pyrrolidinyl, piperidine group, oxetanyl group, tetrahydrofuranyl group and tetrahydro-2H-pyranyl group.
  • treating means: (1) alleviating the disease or alleviating one or more biological manifestations of the disease, (2) interfering with (a) leading to or contributing to one or more points in the biological cascade of a disease or (b) one or more biological manifestations of a disease, (3) alleviating one or more symptoms or effects associated with a disease , and/or (4) slowing the progression of the disease or one or more biological manifestations of the disease, and/or (5) reducing the likelihood of the severity of the disease or the biological manifestations of the disease.
  • prevention refers to the prophylactic administration of a drug to reduce the likelihood of or delay the occurrence of a disease or its biological manifestations.
  • subject refers to mammalian subjects (eg, dogs, cats, horses, cows, sheep, goats, monkeys, etc.), and especially human subjects.
  • pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxicological effects.
  • pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with an appropriate base or acid, respectively.
  • the term "therapeutically effective amount” means an amount that results in the treatment or prevention of a disease compared to a corresponding subject not receiving that amount, but is within the scope of sound medical judgment Low enough to avoid serious side effects (with a reasonable benefit/risk ratio).
  • the therapeutically effective amount of a compound will vary with the particular compound selected (e.g., taking into account the potency, potency, and half-life of the compound): the route of administration chosen; the disease being treated; the severity of the disease being treated; the age, size, weight of the patient being treated. and physical condition: the medical history of the patient being treated; the duration of the treatment; the nature of concurrent treatment; the desired effect of the treatment, etc.
  • substituents described in this application can be protected with a suitable protecting group that is stable under the reaction conditions.
  • Protecting groups can be removed at appropriate points in the reaction sequence to afford the desired intermediate or target compound.
  • Suitable protecting groups and methods of using such suitable protecting groups for protection and deprotection of various substituents are well known to those skilled in the art; examples in this regard can be found in I. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (Third Edition), John Wiley & Sons, NY (1999).
  • substituents can be specifically selected to be reactive under the reaction conditions employed. In these cases, the reaction conditions transform the selected substituent into another substituent useful as an intermediate compound or as another substituent that is the desired substituent in the target compound.
  • R 1 , R 2 , R x , R y , Q, m, n, p, u, A are as defined in this application.
  • the preparation of the final compound 1.8 can be obtained through steps i, ii, iv, v, or steps i, iii, iv, v.
  • Step (i) can generate compound 1.2 by removing the Boc protecting group from compound 1.1 in a suitable acidic reagent, such as hydrogen chloride/1,4-dioxane solution, at a suitable temperature, such as room temperature.
  • a suitable acidic reagent such as hydrogen chloride/1,4-dioxane solution
  • Step (ii) or (iii) can be used as a SNAr reaction, using a suitable basic reagent, such as triethylamine, in a suitable solvent, such as acetonitrile, at a suitable temperature, such as room temperature, to react compound 1.2 with 1.3 to generate Compound 1.5 or compound 1.2 is reacted with 1.4 to give compound 1.6.
  • a suitable basic reagent such as triethylamine
  • a suitable solvent such as acetonitrile
  • Compound 1.5 or 1.6 can obtain the same intermediate 1.7 through the same operation step (iv), and step (iv) can be obtained by combining compound 1.5 or 1.6 with a suitable reagent, such as triethylamine/methanesulfonyl chloride, or thionyl chloride , at a suitable temperature such as 0 ° C or room temperature, the hydroxyl group is converted into mesylate or chlorination, and then the reaction is further heated in an alkaline reagent such as potassium carbonate or sodium carbonate and a suitable solvent such as acetonitrile without purification, Ring closure affords compound 1.7.
  • a suitable reagent such as triethylamine/methanesulfonyl chloride, or thionyl chloride
  • Step (v) Combine 1.7 with the corresponding alcohol, thiol, amine HQ-(CH 2 ) m -A (Q is -O-, -S-, -NR a -) in a suitable base such as NaH The reaction in a solvent such as acetonitrile gives the final product 1.8.
  • the compounds of the present invention are Lp-PLA 2 inhibitors. Accordingly, these compounds are useful in the treatment, eg, treatment or prevention of diseases associated with the activity of Lp- PLA2 comprising treating a subject in need of such treatment with a therapeutically effective amount of an Lp- PLA2 inhibitor. Accordingly, one aspect of the present invention pertains to methods of treating or preventing diseases associated with Lp- PLA2 activity. Those skilled in the art will understand that a particular disease or its treatment may involve one or more underlying mechanisms related to Lp-PLA 2 activity, including one or more of the mechanisms described in this application.
  • the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of any of the diseases disclosed in the following published patent applications: WO96/13484, WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805, WO02/30904, WO02/30911, WO 03/ 015786, WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO03/87088, WO08/048867, US2008/0103156, US2008/0090851 , US2008/0090852, WO08/048866, WO05/
  • the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of an eye disease.
  • Ocular diseases applicable in the present invention may be related to disruption of the inner blood-retinal barrier (iBRB).
  • Exemplary eye diseases relate to diabetic eye disease, which includes macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion, and the like.
  • Additional eye diseases include, but are not limited to, central retinal vein occlusion, branch retinal vein occlusion, I-Garr syndrome (post-cataract and post-surgery), retinitis pigmentosa, planaritis, shotgun retinochoroidopathy, retinal Outer layer membrane, choroidal tumor, cystic macular edema, parafoveal telangiectasia, traction maculopathy, vitreomacular traction syndrome, retinal detachment, neuroretinitis, idiopathic macular edema, etc. Further details of the use of Lp-PLA 2 inhibitors for the treatment of eye diseases are provided in WO2012/080497, which is incorporated herein by reference.
  • some embodiments of the present invention provide the use of a compound of the present invention in the manufacture of a medicament for treating or preventing diabetic macular edema in a subject.
  • the invention provides the use of a compound of the invention for treating diabetic macular edema in a subject.
  • the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of a subject suffering from or at risk of developing macular edema. In some embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for treating a subject suffering from or at risk of developing macular edema. In another embodiment, the macular edema is associated with diabetic eye disease, such as diabetic macular edema or diabetic retinopathy. In another embodiment, the macular edema is associated with posterior uveitis.
  • the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of glaucoma or macular degeneration. In some embodiments, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of glaucoma or macular degeneration.
  • the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of a disease associated with disruption of the blood retinal barrier in a subject in need thereof. In one embodiment, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a disease associated with disruption of the blood retinal barrier in a subject in need thereof.
  • the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of any disease involving endothelial dysfunction, e.g., atherosclerosis (e.g., peripheral vascular atherosclerosis sclerosis and cerebrovascular atherosclerosis), diabetes mellitus, hypertension, angina pectoris, ischemia and post-reperfusion conditions.
  • atherosclerosis e.g., peripheral vascular atherosclerosis sclerosis and cerebrovascular atherosclerosis
  • diabetes mellitus e.g., hypertension, angina pectoris, ischemia and post-reperfusion conditions.
  • the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of any disease involving lipid oxidation associated with enzymatic activity, for example, other than, for example, atherosclerosis and conditions other than diabetes, such as rheumatoid arthritis, stroke, inflammatory disorders of the brain (such as Alzheimer's disease), various neuropsychiatric conditions (such as schizophrenia, autism), myocardial infarction , ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.
  • any disease involving lipid oxidation associated with enzymatic activity for example, other than, for example, atherosclerosis and conditions other than diabetes, such as rheumatoid arthritis, stroke, inflammatory disorders of the brain (such as Alzheimer's disease), various neuropsychiatric conditions (such as schizophrenia, autism), myocardial infarction , ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.
  • the present invention provides the use of a compound of the present invention in the manufacture of a medicament for reducing the chance of a cardiovascular event such as heart attack, myocardial infarction or stroke in a patient suffering from coronary heart disease.
  • the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease involving activated monocytes, macrophages or lymphocytes, since all of these cell types express Lp- PLA2 , including diseases involving activated macrophages such as M1, dendritic and/or other oxidative stress producing macrophages.
  • Exemplary conditions include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD), cirrhosis, atopic dermatitis, emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm , atherosclerosis, multiple sclerosis, Alzheimer's disease and autoimmune diseases such as lupus.
  • COPD chronic obstructive pulmonary disease
  • the invention provides the use of a compound of the invention for the manufacture of a medicament for primary or secondary prophylaxis of acute coronary events (eg, caused by atherosclerosis); prophylaxis of restenosis Adjuvant therapy; or to delay the development of diabetic or hypertensive renal insufficiency. Prevention includes treatment of subjects at risk for such conditions.
  • the present invention provides methods of treating or preventing neurological disorders associated with abnormal blood-brain barrier (BBB) function, inflammation, and/or microglial activation in a subject in need thereof.
  • BBB blood-brain barrier
  • the present invention provides methods of treating or preventing neurological disorders associated with abnormal blood-brain barrier (BBB) function, inflammation, and/or microglial activation in a subject in need thereof.
  • the method comprises administering to a subject a therapeutically effective amount of a compound of the invention.
  • the abnormal BBB is an osmotic BBB.
  • the disease is a neurodegenerative disease.
  • Such neurodegenerative diseases are for example, but not limited to, vascular dementia, Alzheimer's disease, Parkinson's disease and Huntington's disease.
  • the present invention provides a method of treating or preventing a disease associated with blood-brain barrier (BBB) leakage in a subject.
  • BBB blood-brain barrier
  • the present invention provides methods of treating a subject for a disease associated with a blood-brain barrier (BBB) leak.
  • Exemplary diseases include, but are not limited to, cerebral hemorrhage, cerebral amyloid angiopathy.
  • the neurodegenerative disease is Alzheimer's disease.
  • the neurodegenerative disease is vascular dementia.
  • the neurodegenerative disease is multiple sclerosis (MS).
  • the compounds of the invention are useful for treating or preventing a neurodegenerative disease in a subject.
  • the methods comprise administering a compound of the invention (eg, in the form of a pharmaceutical composition comprising the compound of the invention) to a subject in need of such treatment.
  • compounds of the invention are useful for treating a neurodegenerative disease in a subject.
  • Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease.
  • the neurodegenerative diseases of the invention are associated with an abnormal blood-brain barrier.
  • the subject administered an agent that inhibits Lp- PLA2 activity is a human.
  • the invention provides a method of treating or preventing a subject suffering from or at risk of developing vascular dementia.
  • the methods comprise administering a compound of the invention (eg, a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention) to a subject.
  • a compound of the invention eg, a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention
  • the invention provides a method of treating a subject having or at risk of developing vascular dementia.
  • said vascular dementia is associated with Alzheimer's disease.
  • the present invention relates to methods of treating or preventing metabolic bone disease by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention.
  • the present invention relates to methods of treating metabolic bone disease by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention.
  • Exemplary metabolic bone diseases include diseases associated with loss of bone mass and bone density, including but not limited to osteoporosis and osteopenic diseases.
  • Exemplary osteoporotic and osteopenic diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Paget's disease, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, and related diseases.
  • the subject in need of such treatment is a human.
  • methods of preventing osteoporosis and/or osteopenic diseases described herein may be affected by inhibiting the expression of Lp- PLA2 and/or inhibiting the protein activity of Lp- PLA2 . Accordingly, some embodiments of the invention provide methods of inhibiting Lp- PLA2 by blocking enzymatic activity. In another embodiment, a method of inhibiting Lp- PLA2 by reducing and/or down-regulating the expression of Lp- PLA2 RNA is provided. In another embodiment, preventing and/or reducing bone mass loss and I or loss of bone density results in preventing or reducing symptoms associated with metabolic bone diseases such as osteoporosis and/or osteopenic diseases.
  • the method further comprises administering to the subject in need thereof an additional therapeutic agent for the treatment of metabolic bone disease.
  • an additional therapeutic agent for the treatment of metabolic bone disease for example, when the metabolic bone disease is osteoporosis, other therapeutic agents, such as bisphosphates (e.g., alendronate, ibanronate, risedronate, antihypertensive Calcitonin, raloxifene), selective estrogen modulators (SERMs), estrogen therapy, hormone replacement therapy (ET/HRT), and teriparamide.
  • bisphosphates e.g., alendronate, ibanronate, risedronate, antihypertensive Calcitonin, raloxifene
  • SERMs selective estrogen modulators
  • E/HRT hormone replacement therapy
  • teriparamide teriparamide
  • systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic Lupus erythematosus, V-Koyanagi-Harada syndrome, Lyme disease, Behcet's disease, ankylosing spondylitis, chronic granulomatous disease, enthesitis may be at the root of posterior uveitis affecting the retina cause, and it can lead to macular edema.
  • systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic Lupus erythematosus, V-Koyanagi-Harada syndrome, Lyme disease, Behcet's disease, ankylosing spondylitis, chronic
  • the present invention relates to methods of treating or preventing posterior uveitis, or any of these systemic inflammatory diseases, by administering a therapeutically effective amount of a compound of the present invention.
  • the invention provides a method of treating post uveitis, or any of these systemic inflammatory diseases, by administering a therapeutically effective amount of a compound of the invention.
  • Treatment and/or prevention of diseases associated with Lp-PLA 2 activity can be obtained using the compounds of the invention in monotherapy or in dual or multiple combination therapy.
  • the compounds of the present invention can be used in combination with antihyperlipidemic agents, antiatherosclerotic agents, antidiabetic agents, antianginal agents, antiinflammatory agents or antihypertensive agents or for lowering lipoprotein (a) (Lp(a)) Combination of agents to treat or prevent the diseases described in this invention.
  • agents include, but are not limited to, cholesterol synthesis inhibitors such as statins; antioxidants such as probucol; insulin sensitizers; calcium channel antagonists and anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Agents useful for lowering Lp(a) include phosphoramidates as described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312.
  • the compounds of the invention may be used together with one or more statins.
  • Statins are well known cholesterol lowering agents and include atorvastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin and rosuvastatin.
  • compounds of the invention may be used with antidiabetic or insulin sensitizing agents.
  • compounds of the invention may be used with PPAR gamma activators, such as GI262570 (GlaxoSmithKline), and gli tazone compounds such as rosiglitazone, troglitazone, and pioglitazone.
  • PPAR gamma activators such as GI262570 (GlaxoSmithKline)
  • gli tazone compounds such as rosiglitazone, troglitazone, and pioglitazone.
  • the agent may be administered, for example, in a therapeutically effective amount known in the art or in a smaller or greater amount than is known in the art to be administered to provide a therapeutically effective amount.
  • Combination therapy involves administering the therapeutic agents together, either in separate dosage forms or in a single dosage form.
  • Combination therapy may involve simultaneous or separate administration of the therapeutic agents, which may be administered substantially simultaneously or substantially separately.
  • combination therapy involves administering each agent such that a therapeutically effective amount of each agent is present in the subject's body for at least an overlapping period of time.
  • a therapeutically effective amount of a compound of the invention will depend on a number of factors including, for example, the age and weight of the intended recipient, the precise condition to be treated and its severity, the nature of the formulation, and the route of administration, and will ultimately depend on the preference of the prescribing physician. judge.
  • a therapeutically effective amount of a compound of the invention for use in the treatment of the diseases described herein will generally be in the range of 0.1 to 100 mg/kg body weight of the recipient per day, more usually in the range of 1 to 10 mg/kg body weight/day.
  • the actual amount per day will generally be 70 to 700 mg, and this amount may be administered in a single dose per day or in multiple sub-doses per day, such as two, three, four, five or six doses per day . Or the administration can be done intermittently, for example every other day, once a week or once a month. It is contemplated that similar dosages may be suitable for the treatment of other conditions mentioned above.
  • compositions of the invention may contain one or more compounds of the invention.
  • the pharmaceutical composition may contain more than one compound of the invention.
  • the pharmaceutical composition may contain two or more compounds of the invention.
  • the pharmaceutical compositions may optionally comprise one or more additional pharmaceutically active compounds.
  • a "pharmaceutically acceptable excipient” as used herein refers to a pharmaceutically acceptable raw material, component or carrier that participates in imparting form or consistency to the pharmaceutical composition. When mixed, each excipient is compatible with the other ingredients of the pharmaceutical composition, thereby avoiding interactions that would significantly reduce the efficacy of the compounds of the invention when administered to a subject and avoiding interactions that would result in pharmaceutically unacceptable drugs. Component interactions.
  • a compound of the invention and one or more pharmaceutically acceptable excipients can be formulated into a dosage form suitable for administration to a subject by the desired route of administration.
  • dosage forms include those suitable for the following routes of administration: (1) Oral administration (including buccal or sublingual), such as tablets, capsules, capsules, pills, lozenges, powders, syrups, brews, mixes; suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration (including subcutaneous, intramuscular, intravenous, or intradermal), such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration, such as transdermal patch; (4) rectal administration, such as suppository; (5) nasal inhalation, such as dry powder, aerosol, suspension and solution; and (6) topical administration Drugs (including buccal, sublingual or transdermal), such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
  • Such compositions
  • compositions suitable for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquid forms; edible foams or whips; or water packets.
  • Suitable pharmaceutically acceptable excipients may vary depending on the particular dosage form chosen. Furthermore, appropriate pharmaceutically acceptable excipients can be selected according to the specific function they perform in the composition. For example, some pharmaceutically acceptable excipients may be selected for their ability to facilitate the production of a uniform dosage form. Some pharmaceutically acceptable excipients can be selected for their ability to facilitate the production of stable dosage forms. Some pharmaceutically acceptable excipients may be selected for their ability to facilitate the delivery or transport of one or more compounds of the invention from one organ or part of the body to another organ or part of the body when administered to a subject . Some pharmaceutically acceptable excipients may be selected for their ability to increase patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives , stabilizers, surfactants and buffers. It will be appreciated by those skilled in the art that some pharmaceutically acceptable excipients can serve more than one function and may provide other functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. function.
  • compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington Pharmaceutical Sciences (Mack Press).
  • the invention is directed to solid oral dosage forms, such as tablets or capsules, comprising a therapeutically effective amount of a compound of the invention and a release or filler agent.
  • suitable diluents and fillers include lactose, glucosamine, dextrose, mannitol, sorbitol, starches (such as corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (such as microcrystalline cellulose), Calcium Sulfate and Dibasic Calcium Phosphate.
  • Oral solid dosage forms may also include binders.
  • Suitable binders include starches (such as corn starch, potato starch, and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, xanthan gum, guar gum, povidone, and cellulose and its derivatives (eg microcrystalline cellulose).
  • Oral solid dosage forms may also contain disintegrants. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid and sodium carboxymethylcellulose.
  • Oral solid dosage forms may also contain lubricants. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.
  • the present invention relates to a compound containing 0.01mg to 1000mg of one or more compounds of the above formula described herein or a pharmaceutically acceptable salt thereof and 0.01g to 5g of one or more pharmaceutically acceptable Excipients for pharmaceutical compositions.
  • triphenylphosphine (26.0g, 99.0mmol) and imidazole (6.5g, 96.0mmol) were added into dichloromethane (30mL), the temperature was lowered to 0°C under the protection of argon, and iodine (25.0g, 99.0mmol) was added ), stirred at 0°C for 1 hour.
  • iodine (25.0g, 99.0mmol) was added ), stirred at 0°C for 1 hour.
  • a solution of 1,1-cyclopropane-dimethanol (5.0 g, 48.0 mmol) in dichloromethane (20 mL) was added to the reaction solution, and stirred at this temperature for 3 hours.
  • Triethylamine (1.3 g, 12.7 mmol) was added to the reaction solution and stirred overnight at room temperature.
  • methyl triphenylphosphine bromide (407mg, 1.14mmol) was added into anhydrous tetrahydrofuran (10mL), the temperature was lowered to 0°C under the protection of argon, and n-butyllithium in n-hexane (2.5M, 0.456mL, 1.14mmL), stirred at 0°C for 0.5 hours.
  • tert-butyl 3-azaspiro[5.5]undecane-3-carboxylate (1g, 3.95mmol) and tetramethylethylenediamine (458mg, 3.95mmol) were added into anhydrous tetrahydrofuran (10mL ), the temperature was lowered to -60°C under the protection of argon, a n-hexane solution of sec-butyllithium (1.3M, 3.03mL, 3.95mmol) was added dropwise, and stirred at -50°C to -20°C for 0.5 hours.
  • tert-butyl 2-formyl-3-azaspiro[5.5]undecane-3-carboxylate (460 mg, 1.64 mmol) was added to ethanol (5 mL), and sodium borohydride (124 mg, 3.27mmol), stirred at room temperature for 2 hours.
  • the reaction solution was quenched with saturated ammonium chloride aqueous solution, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (430 mg, 93%).
  • MS: m/z [M+H-tBu] + 228.
  • tert-butyl 2-(hydroxymethyl)-3-azaspiro[5.5]undecane-3-carboxylate 430 mg, 1.52 mmol
  • dichloromethane 3 mL
  • hydrogen chloride was added under stirring
  • a solution of ethyl acetate (4M, 1.9 mL) was stirred at room temperature for 2 hours.
  • the reaction solution was concentrated, and acetonitrile (5 mL) and sodium carbonate (483 mg, 4.56 mmol) were successively added to the residue, and stirred overnight at 85°C.
  • tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate 5 g, 20.92 mmol was added to polyethylene glycol (50 mL), and hydrazine hydrate ( 7.32g, 146.44mmol) and potassium hydroxide solid (7.03g, 125.52mmol), stirred at 200°C for 4 hours.
  • the reaction solution was cooled to room temperature and poured into water, extracted with ether, and the organic phase was concentrated to obtain the title compound (3.32 g, 126%).
  • MS: m/z [M+H] + 126.
  • tetramethylethylenediamine (1.03g, 8.89mmol) and tert-butyl 7-azaspiro[3.5]nonane-7-carboxylate (2g, 8.89mmol) were successively added into anhydrous THF (20mL) , the temperature was lowered to -60°C under the protection of argon, and a n-hexane solution of sec-butyllithium (1.3M, 6.84mL, 8.89mmol) was added dropwise with stirring, and the addition was completed and stirred at -20°C for 30 minutes.
  • reaction solution was cooled to -60°C, N,N-dimethylformamide (973mg, 13.3mmol) was added dropwise, and the mixture was stirred at -60°C for 1 hour and at room temperature for 2 hours after the addition.
  • the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (0.83 g, 37%).
  • MS: m/z [M+H-tBu] + 198.
  • tert-butyl 6-formyl-7-azaspiro[3.5]nonane-7-carboxylate (1.63 g, 6.4 mmol) was added into absolute ethanol (10 mL), and sodium borohydride ( 487mg, 12.8mmol), stirred at room temperature for 2 hours.
  • the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (1.43 g, 87%).
  • MS: m/z [M+H-tBu] + 200.
  • tert-butyl 7-formyl-8-azaspiro[4.5]decane-8-carboxylate 132 mg, 0.49 mmol
  • sodium borohydride 92.68mg, 2.45mmol
  • the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (130 mg, 98%).
  • MS: m/z [M+H-tBu] + 214.
  • tert-butyl 6-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate 51 mg, 0.19 mmol was added into dichloromethane (3 mL), and hydrogen chloride was added under stirring Ethyl acetate solution (4M, 0.25 mL), stirred at room temperature for 3 hours.
  • the reaction solution was concentrated, and acetonitrile (10 mL), 4,6-dichloro-2-methoxypyrimidine (68 mg, 0.38 mmol) and sodium carbonate (165 mg, 1.56 mmol) were successively added to the residue, and stirred overnight at 85°C.
  • tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate 5g, 20.89mmol was added into methanol (50mL), and sodium borohydride (2.37g , 62.67mmol), stirred at room temperature for 5 hours.
  • the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (4.93 g, 98%).
  • MS: m/z [M+H-tBu] + 186.
  • tert-butyl 2-(tert-butyldimethylsilyl)oxy)-6-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (296 mg, 0.77 mmol) was added to dichloromethane (10 mL) and trifluoroacetic acid (1 mL), and stirred at room temperature for 1 hour.
  • Potassium carbonate (320 mg, 2.31 mmol) was added and stirred at room temperature for 0.5 hours.
  • the reaction solution was filtered, the filter cake was rinsed with dichloromethane, and the filtrate was concentrated.
  • tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate 5g, 20.89mmol was added into methanol (50mL), and sodium borohydride (2.37g , 62.67mmol), stirred at room temperature for 5 hours.
  • the reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organic phase was concentrated.
  • Acetonitrile (30 mL) and methyl iodide (8.96 g, 62.67 mmol) were sequentially added to the residue, and sodium hydride (60%, 2.51g, 62.67mmol), stirred at room temperature for 3 hours.
  • tert-butyl 6-formyl-2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate (380 mg, 1.34 mmol) was added into anhydrous methanol (5 mL), stirred Sodium borohydride (150mg, 4.02mmol) was added, stirred at room temperature for 3 hours, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (365mg, 95%).
  • MS: m/z [M+H-tBu] + 230.
  • tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate 5g, 20.89mmol
  • ethylene glycol 1.94g, 31.34mmol
  • 4-methyl Pyridine benzenesulfonate (1.05 g, 4.18 mmol) was successively added to toluene (50 mL), and stirred overnight at 120°C.
  • the reaction solution was concentrated and purified by column chromatography to obtain the title compound (3.6 g, 61%).
  • MS: m/z [M+H-tBu] + 228.
  • tert-butyl 9-(hydroxymethyl)-1,4-dioxa-10-azabispiro[4.1.5 7 .1 5 ]tridecane-10-carboxylate (1.1 g, 3.51 mmol) was added to dichloromethane (10 mL), hydrogen chloride in ethyl acetate solution (4M, 0.32 mL) was added with stirring, and stirred at room temperature for 3 hours.
  • the reaction solution was concentrated, and acetonitrile (10 mL), 4,6-dichloro-2-methoxypyrimidine (942 mg, 5.27 mmol) and sodium carbonate (2.07 g, 19.5 mmol) were successively added to the residue, and stirred overnight at 85°C.
  • tert-butyl 6-formyl-2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate (2.4 g, 8.47 mmol) was added into anhydrous tetrahydrofuran (80 mL), Add methyltriphenylphosphine bromide (3.63g, 10.16mmol) under stirring, lower the temperature to 0°C under the protection of argon, add sodium hydride (60%, 1.02g, 25.41mmol) in batches, and stir at room temperature for 3 Hour.
  • tert-butyl 6-(2-hydroxyethyl)-2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate 750 mg, 2.50 mmol
  • 1,4 - Dioxane solution 10 mL
  • the reaction solution was concentrated to obtain the crude product of the title compound (590 mg, 100%).
  • MS: m/z [M+H] + 200.
  • methyl 6-oxopiperidinyl-2-carboxylate 850 mg, 5.4 mmol
  • sodium borohydride 307 mg, 8.1 mmol
  • the reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated.
  • the residue was added to dimethyl sulfoxide (20 mL), the temperature was lowered to 0° C. under the protection of argon, and sodium hydride (3.6 g, 21 mmol) was slowly added with stirring, and stirred at room temperature for 30 minutes.
  • anhydrous tetrahydrofuran 60mL was cooled to -40°C, ethylmagnesium bromide solution in tetrahydrofuran (1M, 20mL, 19.4mmol) and tetraisopropyl titanate (2g, 7.2mmol) were added successively under stirring ), stirred at room temperature for 5 minutes.
  • dichloromethane 60mL was cooled to 0°C, diethylzinc n-hexane solution (1M, 60mL, 60mmol) was added under stirring, and trifluoroacetic acid (6.8g, 60 mmol), stirred at 0°C for 0.5 hours.
  • Diiodomethane (16 g, 60 mmol) was added to the reaction solution and stirred at room temperature for 30 minutes.
  • Benzyl 4-methylenepiperidine-1-carboxylate 7 g, 30 mmol was added to the reaction solution and reacted at room temperature overnight.
  • tert-butyl 6-azaspiro[2.5]octane-6-carboxylate 400mg, 1.9mmol was added into anhydrous tetrahydrofuran (5mL), the temperature was lowered to -78°C under the protection of argon, and the temperature was controlled to - Below 50°C, tetramethylethylenediamine (660mg, 5.7mmol) and sec-butyl lithium in n-hexane (1.3M, 2.2mL 2.9mmol) were successively added dropwise, and stirred at -30°C for 15 minutes.
  • tert-butyl 5-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate 360 mg, 1.5 mmol was added to a solution of hydrogen chloride in ethyl acetate (4M, 5 mL) and di Chloromethane (5 mL), stirred at room temperature for 1 hour.
  • the reaction solution was concentrated, solid sodium carbonate (318mg, 3.0mmol), 2,4,6-trichloropyrimidine (366mg, 3.0mmol) and acetonitrile (5mL) were sequentially added to the residue, and stirred overnight at room temperature.
  • tert-butyl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate 750 mg, 2.94 mmol
  • tetramethylethylenediamine 0.51 g, 4.41 mmol
  • a n-hexane solution of sec-butyllithium 1.3M, 4.5mL, 5.88mmol
  • N,N-dimethyl Dimethylformamide 0.32g, 4.41mmol
  • tert-butyl 8-formyl-3-oxa-9-azaspiro[5.5]undecane-9-carboxylate (340 mg, 1.2 mmol) was added into tetrahydrofuran (10 mL), and boron was added under stirring Sodium hydride (40mg, 1.2mmol), stirred at room temperature for 0.5 hours.
  • the reaction solution was quenched with saturated ammonium chloride aqueous solution, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (340 mg, 99%).
  • MS: m/z [M+H-Boc] + 186.
  • tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate 45.0g, 183mmol
  • imidazole 37.9g, 549mmol
  • tert-butyldimethylsilyl chloride 55.2 g, 366 mmol
  • MS: m/z [M+H-Boc] + 373.
  • tert-butyl 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-carboxylate (20.0 g, 42.28 mmol) and tetramethylethyl Diamine (7.35g, 64.42mmol) was added to anhydrous tetrahydrofuran (120mL), the temperature was lowered to -60°C under the protection of argon, and the cyclohexane solution of sec-butyllithium (1.3 M, 71.5 mL, 93.0mmol), stirred at -50°C for 1 hour, added N,N-dimethylformamide (4.56g, 63.42mmol), stirred at -50°C for 1h, and stirred at room temperature for 2 hours.
  • tert-butyl 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-2-formylpiperidine-1-carboxylate (4.0 g, 8.0 mmol)
  • dichloromethane solution 10%, 40 mL
  • the reaction solution was adjusted to 8-9 with solid potassium carbonate, filtered, and the filtrate was concentrated.
  • the residue was added to methanol (20 mL), sodium borohydride (907 mg, 24.0 mmol) was added with stirring, and stirred at room temperature for 1 hour.
  • reaction solution was quenched with saturated ammonium chloride aqueous solution and poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by preparative thin-layer chromatography to obtain the title compound (9 mg, 15%).
  • the compound of the present invention is an Lp-PLA 2 inhibitor, and can be used for treating and preventing diseases mediated by Lp-PLA 2 .
  • the biological activity of the compounds of the invention can be determined using any suitable assay for determining the activity of the compounds as Lp- PLA2 inhibitors, as well as tissue and in vivo models.
  • Lipoprotein-associated phospholipase A2 (Lp- PLA2 ) human plasma assay.
  • the human plasma assay utilizes a thioester analog of PAF (phosphatidylcholine), where hydrolysis results in the formation of phospholipids containing free sulfhydryl groups.
  • PAF phosphatidylcholine
  • the amount of sulfhydryl groups was continuously determined by reaction with CPM (7-diethylamino-3-(4'-maleimidophenyl)-4-methylcoumarin), which is a Fluorescence increases after Michael addition to maleimides.
  • This assay can detect the activity of Lp- PLA2 in human plasma, as determined by specific inhibition of Lp- PLA2 inhibitors.
  • Thio-PAF assays were performed as quenched 75 ⁇ L assays.
  • Compound source plates were prepared by making serial 1 :3 (volume) dilutions of the individual compounds in neat DMSO in 96-well microplates. Transfer 3 ⁇ L of the compound on the compound source plate into a 96-well microplate pre-added with 57 ⁇ L of assay buffer by a Rainin multichannel pipette, and perform a 20-fold dilution of the compound on the source plate.
  • the above test buffer contains 50mM HEPES, pH 7.4, 150mM NaCl, 1mM CHAPS.
  • 1 ⁇ L of the 20-fold diluted compound was transferred by Rainin multichannel pipette into a 96-well Greiner 655076 (black) microplate to which 40 ⁇ L of pooled human plasma had previously been aliquoted and thawed. Mix the plate by shaking for 20 seconds on a microplate shaker.
  • Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) 1 4.9 2 19.2 3 1.4 4 3.8 5 3.5 6 6.7 7 14.7 8 14.9 9 19.9 10 268.4 11 16.6 12 81.7 13 97.5 14 4.6 15 12.7 16 27.7 17 6.4 18 95.2 19 10.8 20 20.3 twenty one 8.9 twenty two 17.7 twenty three 6.4 twenty four 4.9 25 7.4 26 16.3 27 11.2 28 6.9 29 12.3 30 17.4 31 7.2 32 5.8 33 7.0

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Abstract

Provided are a compound as represented in general formula (I), and a cis-trans isomer, an enantiomer, a diastereoisomer, a racemate, a solvate, a hydrate or a pharmaceutically acceptable salt or a precursor drug thereof, and a preparation method therefor, a pharmaceutical composition containing the compound and the use thereof as an inhibitor of Lp-PLA2, wherein R1, R2, Rx, Ry, Q, m, n, p, u and A are as defined in the present application.

Description

螺环嘧啶酮衍生物、其制备方法、药物组合物和用途Spirocyclic pyrimidinone derivatives, preparation methods, pharmaceutical compositions and uses thereof 技术领域technical field
本发明涉及新的嘧啶酮化合物、其制备方法及包含该化合物的药物组合物以及它们在治疗由Lp-PLA 2介导的疾病中的用途。 The present invention relates to novel pyrimidinone compounds, their preparation methods and pharmaceutical compositions containing the compounds and their use in the treatment of diseases mediated by Lp-PLA 2 .
背景技术Background technique
脂蛋白相关磷脂酶A 2(Lp-PLA 2)是参与脂蛋白脂质或磷脂的水解的磷脂酶A 2酶，亦被称为血小板活化因子乙酰水解酶(PAF-AH)。Lp-PLA 2随低密度脂蛋白(LDL)移动，并迅速裂解从LDL氧化得到的氧化的磷脂酰胆碱分子。Lp-PLA 2水解氧化的磷脂酰胆碱的sn-2酯得到脂质介体溶血磷脂酰胆碱(lysoPC)和氧化的非酯化脂肪酸(NEFA)。文献报道lysoPC和NEFA能引起炎性反应，因此Lp-PLA 2介导了体内的氧化炎性反应。(Zalewski A等人，Arterioscler.Thromb.Vasc.Biol.,25,5,923-31(2005))。 Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is a phospholipase A 2 enzyme involved in the hydrolysis of lipoprotein lipids or phospholipids, also known as platelet-activating factor acetylhydrolase (PAF-AH). Lp-PLA 2 moves with low-density lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules resulting from LDL oxidation. Lp-PLA 2 hydrolyzes the sn-2 ester of oxidized phosphatidylcholine to yield the lipid mediator lysophosphatidylcholine (lysoPC) and oxidized non-esterified fatty acids (NEFA). Literature reports that lysoPC and NEFA can cause inflammatory response, so Lp-PLA 2 mediates oxidative inflammatory response in vivo. (Zalewski A et al., Arterioscler. Thromb. Vasc. Biol., 25, 5, 923-31 (2005)).
文献(WO96/13484、WO96/19451、WO97/02242、WO97/12963、WO97/21675、WO97/21676、WO97/41098、WO97/41099、WO99/2442、WO00/10980、WO00/66566、WO00/66567、WO00/68208、WO01/60805、WO02/30904、WO02/30911、WO03/015786、WO03/016287、WO03/041712、WO03/042179、WO03/042206、WO03/042218、WO03/086400、WO03/87088、WO08/04886、US2008/0103156、US2008/0090851、US2008/0090852、WO08/048866、W005/003118、W006/063811、W006/063813、WO2008/141176、WO2013013503A1、WO2013014185A1、WO2014114248A1、WO2014114694A1、WO2016011930A1、JP200188847US2008/0279846A1、US 2010/0239565A1、US 2008/0280829A1)描述了许多的Lp-PLA 2抑制剂和/或其用途，治疗涉及血管内皮功能异常或与其相关的疾病、涉及与Lp-PLA 2活性关联的(例如，与溶血磷脂酰胆碱和氧化的游离脂肪酸的形成相关的)脂质氧化的疾病及涉及活化的单核细胞、巨噬细胞或淋巴细胞的或者与单核细胞、巨噬细胞或淋巴细胞的参与增加相关的疾病。具体疾病的例子包括神经退行性疾病(例如阿兹海默症、帕金森病、亨廷顿病、血管性痴呆)、各种神经精神疾病如精神***症和自闭症、外周以及脑动脉粥样硬化、中 风、代谢性骨病(例如骨髓异常)、血脂异常、佩吉特病、II型糖尿病、高血压、心绞痛、心肌梗塞、缺血、再灌注损伤、代谢综合征、胰岛素抵抗和甲状旁腺功能亢进、糖尿病性并发症(例如黄斑水肿、糖尿病性视网膜病变和后葡萄膜炎、糖尿病溃疡和糖尿病肾病)、糖尿病外周神经病变性疼痛、炎性疼痛、神经病理性痛、各类癌症(例如***癌、结肠癌、乳腺癌、肾癌、肺癌和卵巢癌等)、黄斑水肿、伤口愈合、男性***障碍、类风湿性关节炎、慢性阻塞性肺病(COPD)、败血症、急慢性炎症、牛皮癣和多发性硬化。 Literature (WO96/13484, WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO97/41098, WO97/41099, WO99/2442, WO00/665666, WO00/66 6 6567, WO00/68208, WO01/60805, WO02/30904, WO02/30911, WO03/015786, WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO03/ 87088, WO08/ 04886, US2008/0103156, US2008/0090851, US2008/0090852, WO08/048866, W005/003118, W006/063811, W006/063813, WO2008/141176, WO2013013503A1 , WO2013014185A1, WO2014114248A1, WO2014114694A1, WO2016011930A1, JP200188847US2008/0279846A1, US 2010 /0239565A1, US 2008/0280829A1) have described a lot of Lp-PLA 2 inhibitors and/or its use, treatment involves the abnormality of vascular endothelial function or related diseases, involves the activity associated with Lp-PLA 2 (for example, with hemolysis Diseases of lipid oxidation associated with the formation of phosphatidylcholine and oxidized free fatty acids) and involving activated monocytes, macrophages, or lymphocytes or associated with increased involvement of monocytes, macrophages, or lymphocytes disease. Examples of specific diseases include neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia), various neuropsychiatric diseases such as schizophrenia and autism, peripheral and cerebral atherosclerosis , stroke, metabolic bone disease (eg, bone marrow abnormalities), dyslipidemia, Paget's disease, type II diabetes, hypertension, angina, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance, and parathyroid Hyperfunction, diabetic complications (such as macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcer and diabetic nephropathy), diabetic peripheral neuropathic pain, inflammatory pain, neuropathic pain, various types of cancer (such as prostate cancer , colon cancer, breast cancer, kidney cancer, lung cancer and ovarian cancer, etc.), macular edema, wound healing, male erectile dysfunction, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), sepsis, acute and chronic inflammation, psoriasis and multiple sexual sclerosis.
科学研究结果进一步证明Lp-PLA 2抑制剂可以用于治疗动脉粥样硬化。Wilensky等人在加速冠状动脉粥样硬化的糖尿病和高胆固醇血症猪模型中证明Lp-PLA 2抑制剂对于动脉粥样硬化斑块成分的作用(Wilensky等人，Nature Medicine,10,1015-1016(2008))。临床研究也发现Lp-PLA 2抑制剂能稳定动脉粥样硬化斑块的病人的硬化斑块，阻止斑块进一步发展而发生破裂(Serruys等人，Circulation 118：1172-1182(2008))。 Scientific research results further prove that Lp-PLA 2 inhibitors can be used to treat atherosclerosis. Wilensky et al demonstrated the effect of Lp-PLA 2 inhibitors on atherosclerotic plaque components in a diabetic and hypercholesterolemic pig model of accelerated coronary atherosclerosis (Wilensky et al., Nature Medicine, 10, 1015-1016 (2008)). Clinical studies have also found that Lp-PLA 2 inhibitors can stabilize hardened plaques in patients with atherosclerotic plaques and prevent further development of plaques and rupture (Serruys et al., Circulation 118: 1172-1182 (2008)).
研究表明高Lp-PLA 2活性与高痴呆症(包括阿尔茨海默病(AD)和混合性痴呆)风险相关(Van Oijen等人，Annals of Neurology,59,139(2006)；Fitzpatrick等人，Atherosclerosis 235：384-391(2014))。在AD患者中观察到较高的氧化LDL的水平(Kassner等人，Current Alzheimer Research，5，358-366(2008)；Dildar等人，Alzheimer Dis Assoc Disord，24，April-June(2010)；Sinem等人，Current Alzheimer Research,7,463-469(2010))。 Studies have shown that high Lp-PLA 2 activity is associated with high risk of dementia, including Alzheimer's disease (AD) and mixed dementia (Van Oijen et al., Annals of Neurology, 59, 139 (2006); Fitzpatrick et al., Atherosclerosis 235 : 384-391 (2014)). Higher levels of oxidized LDL were observed in AD patients (Kassner et al., Current Alzheimer Research, 5, 358-366 (2008); Dildar et al., Alzheimer Dis Assoc Disord, 24, April-June (2010); Sinem et al., Current Alzheimer Research, 7, 463-469 (2010)).
此外，US2008/0279846描述了Lp-PLA 2抑制剂减少了血脑屏障渗漏和大脑淀粉样蛋白(Abeta)负载,可以用于治疗与血脑屏障渗漏相关的疾病，例如阿尔茨海默病和血管性痴呆。在临床研究中，Lp-PLA 2抑制剂对阿尔茨海默病人能起到阻止认知功能进一步恶化的显著效果(Maher-Edwards等人，Alzheimer’s&Dementia：Translational Research&Clinical Interventions 1，131-140(2015))。 Furthermore, US2008/0279846 describes that Lp-PLA 2 inhibitors reduce blood-brain barrier leakage and brain amyloid (Abeta) load, which can be used to treat diseases associated with blood-brain barrier leakage, such as Alzheimer's disease and vascular dementia. In clinical studies, Lp-PLA 2 inhibitors have a significant effect on preventing further deterioration of cognitive function in Alzheimer's patients (Maher-Edwards et al., Alzheimer's&Dementia: Translational Research&Clinical Interventions 1, 131-140(2015)) .
神经炎症(包括多种细胞毒性细胞因子的释放)为所有神经退行性疾病(包括多发性硬化、肌萎缩性侧索硬化、帕金森病、阿尔茨海默病等)的共同特征(Perry,Acta Neuropathol,120,277-286(2010))。Lp-PLA 2抑制剂通过抑制lysoPC产生来减少多种细胞因子的释放(Shi等人，Atherosclerosis 191,54-62(2007))。因此，抑制Lp-PLA 2是神经退行性疾病(包括多发性硬化、肌萎缩性侧索硬化、 帕金森病等)的潜在治疗方法。 Neuroinflammation (including the release of multiple cytotoxic cytokines) is a common feature of all neurodegenerative diseases (including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc.) (Perry, Acta Neuropathol, 120, 277-286 (2010)). Lp-PLA 2 inhibitors reduce the release of various cytokines by inhibiting lysoPC production (Shi et al., Atherosclerosis 191, 54-62 (2007)). Therefore, inhibition of Lp-PLA 2 is a potential treatment for neurodegenerative diseases including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, etc.
LysoPC也参与白细胞活化、诱导细胞凋亡和介导血管内皮细胞功能障碍(Wilensky等人，Current Opinion in Lipidology,20,415-420,(2009))。因此，据认为Lp-PLA 2抑制剂可以用于通过减少lysoPC的产生而治疗与糖尿病相关的组织损伤。高Lp-PLA 2活性与高糖尿病视网膜病变发病风险有相关性(Siddiqui等人，Diabetologia，61，1344-1353(2018))。Lp-PLA 2抑制剂可以抑制糖尿病大鼠模型的视网膜病变的主要病理变化(Canning等人，P.N.A.S.113，7213-7218(2016)。临床研究也显示Lp-PLA 2抑制剂可以改善糖尿病视网膜病变病人的视网膜黄斑水肿症状和视力(Staurenghi等人，Ophthalmology 122,990-996(2015)。这些研究证明Lp-PLA 2抑制剂可以用于糖尿病视网膜病变。 LysoPC is also involved in leukocyte activation, induction of apoptosis and mediation of vascular endothelial cell dysfunction (Wilensky et al., Current Opinion in Lipidology, 20, 415-420, (2009)). Therefore, it is thought that Lp-PLA 2 inhibitors may be useful in the treatment of tissue damage associated with diabetes by reducing the production of lysoPC. High Lp-PLA 2 activity is associated with a high risk of developing diabetic retinopathy (Siddiqui et al., Diabetologia, 61, 1344-1353 (2018)). Lp-PLA 2 inhibitors can inhibit the main pathological changes of retinopathy in diabetic rat models (Canning et al., PNAS113, 7213-7218 (2016). Clinical studies also show that Lp-PLA 2 inhibitors can improve diabetic retinopathy Macular edema symptoms and visual acuity (Staurenghi et al., Ophthalmology 122, 990-996 (2015). These studies demonstrate that Lp-PLA 2 inhibitors can be used in diabetic retinopathy.
研究表明糖尿病病人体内的Lp-PLA 2活性高于正常人(Serban等人J.Cell.Mol.Med.6:643-647，(2002)；Garg等人Indian J.Med.Res.141:107-114,(2015))。而如上所述，Lp-PLA 2的活性介导了氧化炎性反应，推测抑制Lp-PLA 2活性可以用于治疗糖尿病病人由于体内氧化炎性反应引起的各种并发症，如糖尿病肾病、糖尿病周围神经病变和糖尿病皮肤溃烂等。 Studies have shown that the Lp-PLA 2 activity in diabetic patients is higher than that of normal people (Serban et al. J.Cell.Mol.Med.6:643-647, (2002); Garg et al. Indian J.Med.Res.141:107 -114, (2015)). As mentioned above, the activity of Lp-PLA 2 mediates oxidative inflammatory reactions, and it is speculated that inhibiting the activity of Lp-PLA 2 can be used to treat various complications caused by oxidative inflammatory reactions in diabetic patients, such as diabetic nephropathy, diabetes Peripheral neuropathy and diabetic skin ulceration.
青光眼和年龄相关性黄斑变性(AMD)为视网膜神经退行性疾病。炎症在青光眼和AMD的发病机制中起重要作用(Buschini等人，Progress in Neurobiology,95,14-25(2011)；Tezel,Progress in Brain Research,vol.173,ISSN0079—6123,第28章)。因此，Lp-PLA 2抑制剂可以提供对于青光眼和AMD的潜在治疗应用。 Glaucoma and age-related macular degeneration (AMD) are retinal neurodegenerative diseases. Inflammation plays an important role in the pathogenesis of glaucoma and AMD (Buschini et al., Progress in Neurobiology, 95, 14-25 (2011); Tezel, Progress in Brain Research, vol. 173, ISSN 0079-6123, Chapter 28). Therefore, Lp-PLA 2 inhibitors may offer potential therapeutic applications for glaucoma and AMD.
在男性***障碍病人中，体内Lp-PLA 2的活性显著高于正常人，并认为高Lp-PLA 2活性可以预测早期男性***障碍(Otunctemur等人，Andrologia 47：706-710(2015))，提示抑制剂可用于治疗男性***障碍。 In male erectile dysfunction patients, the activity of Lp-PLA 2 in the body is significantly higher than that of normal people, and it is believed that high Lp-PLA 2 activity can predict early male erectile dysfunction (Otunctemur et al., Andrologia 47: 706-710 (2015)), Tip inhibitors can be used to treat male erectile dysfunction.
在***癌组织中有Lp-PLA 2高表达，降低Lp-PLA 2可以在体外实验中减少***细胞癌变并促进***癌细胞凋亡(Vainio等人，Oncotarget，2：1176-1190(2011))，提示Lp-PLA 2抑制剂可以用于治疗***癌。 Lp-PLA 2 is highly expressed in prostate cancer tissues, and reducing Lp-PLA 2 can reduce prostate cell carcinogenesis and promote prostate cancer cell apoptosis in vitro (Vainio et al., Oncotarget, 2: 1176-1190 (2011)) , suggesting that Lp-PLA 2 inhibitors can be used in the treatment of prostate cancer.
因此，Lp-PLA 2抑制剂可以治疗或预防与Lp-PLA 2活性抑制相关的各种疾病。本发明发现了一种新的Lp-PLA 2抑制剂。 Therefore, Lp-PLA 2 inhibitors can treat or prevent various diseases associated with inhibition of Lp-PLA 2 activity. The present invention discovers a new Lp-PLA 2 inhibitor.
发明内容Contents of the invention
本发明的一个目的在于提供通式(I)所示的化合物、其顺反异构体、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、或其药学上可以接受的盐或酯、或其前体药物。One object of the present invention is to provide the compound represented by general formula (I), its cis-trans isomers, enantiomers, diastereoisomers, racemates, solvates, hydrates, or Its pharmaceutically acceptable salt or ester, or its prodrug.
本发明的另一个目的在于提供通式(I)所示化合物的制备方法。Another object of the present invention is to provide a preparation method of the compound represented by general formula (I).
本发明的另一个目的在于提供通式(I)所示化合物作为Lp-PLA 2抑制剂的用途，从而在制备用于预防、治疗或改善与Lp-PLA2抑制有关的疾病的药物中的应用，所述疾病如糖尿病并发症、神经炎症相关疾病或/和动脉粥样硬化，所述糖尿病并发症为糖尿病视网膜病变/糖尿病黄斑水肿、糖尿病肾病、糖尿病神经病变、糖尿病外周神经病变性疼痛或/和糖尿病足，神经炎症相关疾病为阿兹海默症、多发性硬化、肌萎缩性侧索硬化或/和帕金森病。 Another object of the present invention is to provide the compound shown in general formula (I) as the purposes of Lp- PLA2 inhibitor, thus in the application in the medicine that is used for preventing, treating or improving the disease relevant with Lp-PLA2 inhibition, The disease is such as diabetic complications, neuroinflammation-related diseases or/and atherosclerosis, and the diabetic complications are diabetic retinopathy/diabetic macular edema, diabetic nephropathy, diabetic neuropathy, diabetic peripheral neuropathic pain or/and diabetes foot, neuroinflammation-associated diseases are Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or/and Parkinson's disease.
本发明的另一个目的在于提供一种药物组合物，其包含一种或多种有效治疗剂量的通式(I)所示化合物、其顺反异构体、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、或其药学上可以接受的盐或酯、或其前体药物，以及药学上可以接受的载体和/或辅助剂。Another object of the present invention is to provide a pharmaceutical composition, which comprises one or more therapeutically effective doses of compounds represented by general formula (I), its cis-trans isomers, enantiomers, diastereomers Isomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts or esters thereof, or prodrugs thereof, and pharmaceutically acceptable carriers and/or adjuvants.
本发明的另一个目的在于提供一种预防、治疗或改善与Lp-PLA2抑制有关的疾病的方法，包括给予本发明所述的通式(I)所示化合物、其顺反异构体、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、或其药学上可以接受的盐或酯、或其前体药物或本发明所述的组合物。Another object of the present invention is to provide a method for preventing, treating or improving diseases related to Lp-PLA2 inhibition, comprising administering the compound represented by the general formula (I) of the present invention, its cis-trans isomers, Enantiomers, diastereoisomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts or esters thereof, or prodrugs thereof, or compositions of the present invention.
在第一方面，一种式I所示的化合物、其顺反异构体、其对映异构体、其非对映异构体、其外消旋体、其溶剂合物、其水合物或其药学上可以接受的盐或其前体药物，In the first aspect, a compound represented by formula I, its cis-trans isomers, its enantiomers, its diastereoisomers, its racemates, its solvates, and its hydrates or a pharmaceutically acceptable salt thereof or a prodrug thereof,
Figure PCTCN2022134253-appb-000001
Figure PCTCN2022134253-appb-000001
其中in
m为1或2；优选地，m为1；m is 1 or 2; preferably, m is 1;
n，u为0，1或2；优选地，n，u为0或1；n, u are 0, 1 or 2; preferably, n, u are 0 or 1;
Q为-O-，-S-或-NR a-，优选的Q为-O-； Q is -O-, -S- or -NR a -, preferably Q is -O-;
R a为H，C 1-6烷基，C 1-3卤代烷基，C 3-8环烷基或3-8元杂环基； R a is H, C 1-6 alkyl, C 1-3 haloalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl;
R 1为H，卤素，氰基，氨基，C 1-6烷基，C 1-6烷氧基，C 1-6烷基氨基，C 3-8环烷基或3-8元杂环基，R 1可以被一个或多个以下取代基取代：卤素，氰基，C 1-6烷氧基，C 3-8环烷基、3-8元杂环基或3-8元杂芳基； R 1 is H, halogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclic group , R can be substituted by one or more of the following substituents: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl ;
(R 2) p代表环上的氢被p个R 2取代，每个R 2相同或者不同； (R 2 ) p represents that the hydrogen on the ring is replaced by p R 2s , and each R 2 is the same or different;
p为2，3，4，5或6；p is 2, 3, 4, 5 or 6;
R 2，R x，R y独立地选自以下取代基：H，卤素，羟基，羧基，氰基，C 1-6烷基，C 1-6烷氧基，C 3-8环烷基，3-8元杂环基，C 6-10芳基，3-8元杂芳基，-C(O)NR bR c，-S(O) 2NR bR c，并且可以被一个或多个以下取代基取代：卤素，氰基，C 1-6烷氧基，C 3-8环烷基、3-8元杂环基或3-8元杂芳基； R 2 , R x , R y are independently selected from the following substituents: H, halogen, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl group, 3-8 membered heteroaryl group, -C(O)NR b R c , -S(O) 2 NR b R c , and can be replaced by one or more The following substituents are substituted: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl;
R x，R y连同它们连接的碳原子能够形成3-6元饱和环，该环为全碳环或包含一个或多个选自N，O和S原子的杂环，并且可以被一个或多个R m取代； R x , R y together with their connected carbon atoms can form a 3-6 membered saturated ring, which is a full carbon ring or contains one or more heterocyclic rings selected from N, O and S atoms, and can be surrounded by one or more R m replacement;
在被p个独立地R 2取代的环上，至少有两个R 2连接在同一碳原子上，且连同它们共同连接的碳原子形成3-6元饱和环，该环为全碳环或包含一个或多个选自N，O和S原子的杂环，并且可以被一个或多个R m取代； On the ring substituted by p independent R 2 , at least two R 2 are connected to the same carbon atom, and form a 3-6 membered saturated ring together with the carbon atoms they are connected to, and the ring is a full carbon ring or contains One or more heterocyclic rings selected from N, O and S atoms, and may be substituted by one or more R m ;
R m为C 1-6烷基、C 1-3卤代烷基、卤素，氰基，-OR c，-NR bR c，C 3-6环烷基、3-8元杂环基、C 6-10芳基或3-8元杂芳基； R m is C 1-6 alkyl, C 1-3 haloalkyl, halogen, cyano, -OR c , -NR b R c , C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6 -10 aryl or 3-8 membered heteroaryl;
R b为H，C 1-6烷基，C 3-8环烷基或3-8元杂环基； R b is H, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group;
R c为L，L-C(O)-，L-CH 2-或L-S(O) 2-， R c is L, LC(O)-, L-CH 2 - or LS(O) 2 -,
其中L为H，C 1-6烷基，C 3-6环烷基，3-8元杂环基，C 6-10芳基或3-8元杂芳基，L可以被一个或多个以下基团取代：卤素，羟基，C 1-6烷氧基，氰基，C 3-8环烷基，3-8元杂环基，C 6-10芳基或3-8元杂芳基； Wherein L is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 3-8 membered heteroaryl, L can be replaced by one or more The following groups are substituted: halogen, hydroxyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 3-8 membered heteroaryl ;
A为
Figure PCTCN2022134253-appb-000002
A is
Figure PCTCN2022134253-appb-000002
Z为N或CR 3；优选地，Z为CR 3； Z is N or CR 3 ; preferably, Z is CR 3 ;
Z’为N或CR 4；优选地Z’为CR 4； Z' is N or CR 4 ; preferably Z' is CR 4 ;
R 3,R 4,R 5,R 6独立地为H，CN，卤素、C 1-3烷基或C 1-3卤代烷基； R 3 , R 4 , R 5 , R 6 are independently H, CN, halogen, C 1-3 alkyl or C 1-3 haloalkyl;
V为N或CR 9，优选地，V为CR 9，其中R 9为H，CN，卤素，C 1-3烷基， C 1-3卤代烷基或-O-W； V is N or CR 9 , preferably, V is CR 9 , wherein R 9 is H, CN, halogen, C 1-3 alkyl, C 1-3 haloalkyl or -OW;
W为5或6元杂芳基或苯基，优选为吡啶基、嘧啶基、吡唑基或苯基，其可以任选由一个或多个下列的取代基取代：卤素，氰基，C 1-6烷基，C 1-3烷氧基，C 1-3卤代烷基和C 1-3卤代烷氧基。 W is a 5- or 6-membered heteroaryl or phenyl group, preferably pyridyl , pyrimidinyl, pyrazolyl or phenyl, which may be optionally substituted by one or more of the following substituents: halogen, cyano, C -6 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and C 1-3 haloalkoxy.
具体实施方式Detailed ways
在优选的实施方式中，所述式(I)化合物具有以下12个结构中的一个：In a preferred embodiment, the compound of formula (I) has one of the following 12 structures:
Figure PCTCN2022134253-appb-000003
Figure PCTCN2022134253-appb-000003
其中in
m为1或2；优选地，m为1；m is 1 or 2; preferably, m is 1;
Q为-O-，-S-或-NR a-；优选的Q为-O-； Q is -O-, -S- or -NR a -; preferred Q is -O-;
R a为H，C 1-6烷基，C 1-3卤代烷基，C 3-8环烷基或3-8元杂环基； R a is H, C 1-6 alkyl, C 1-3 haloalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl;
R x，R y独立地选自以下取代基：H，卤素，羟基，羧基，氰基，C 1-6烷基， C 1-6烷氧基，C 3-8环烷基，3-8元杂环基，C 6-10芳基，3-8元杂芳基，-C(O)NR bR c，-S(O) 2NR bR c，并且可以被一个或多个以下取代基取代：卤素，氰基，C 1-6烷氧基，C 3-8环烷基、3-8元杂环基或3-8元杂芳基； R x , R y are independently selected from the following substituents: H, halogen, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 3-8 membered heteroaryl, -C(O)NR b R c , -S(O) 2 NR b R c , and may be substituted by one or more of the following Base substitution: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl;
R x，R y连同它们连接的碳原子能够形成3-6元饱和环，该环为全碳环或包含一个或多个选自N，O和S原子的杂环，并且可以被一个或多个以下取代基取代：C 1-6烷基、C 1-3卤代烷基、卤素，氰基，氧代(＝O)，-OR c，-NR bR c，C 3-6环烷基、3-8元杂环基、C 6-10芳基或3-8元杂芳基； R x , R y together with their connected carbon atoms can form a 3-6 membered saturated ring, which is a full carbon ring or contains one or more heterocyclic rings selected from N, O and S atoms, and can be surrounded by one or more The following substituents are substituted: C 1-6 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo (=O), -OR c , -NR b R c , C 3-6 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl group or 3-8 membered heteroaryl group;
u为0或1，优选的u为0，同时R x，R y均为H； u is 0 or 1, preferably u is 0, and R x and R y are both H;
R 1为H，卤素，氰基，氨基，C 1-6烷基，C 1-6烷氧基，C 1-6烷基氨基，C 3-8环烷基或3-8元杂环基，R 1任选被一个或多个以下取代基取代：卤素，氰基，C 1-6烷氧基，C 3-8环烷基、3-8元杂环基或3-8元杂芳基；优选地，R 1为H，卤素，氰基，C 1-6烷基或C 1-6烷氧基；优选地，R 1为H，卤素，氰基，C 1-3烷基或C 1-3烷氧基；更优选地，R 1为H，氟，氯，氰基，甲基，乙基或甲氧基；最优选地，R 1为H或甲氧基； R 1 is H, halogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclic group , R 1 is optionally substituted by one or more of the following substituents: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl group; preferably, R 1 is H, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; preferably, R 1 is H, halogen, cyano, C 1-3 alkyl or C 1-3 alkoxy; more preferably, R is H, fluorine, chlorine, cyano, methyl, ethyl or methoxy; most preferably, R is H or methoxy;
R m为C 1-6烷基、C 1-3卤代烷基、卤素，氰基，氧代(＝O)，-OR c，-NR bR c，C 3-6环烷基、3-8元杂环基、C 6-10芳基或3-8元杂芳基； R m is C 1-6 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo (=O), -OR c , -NR b R c , C 3-6 cycloalkyl, 3-8 Membered heterocyclic group, C 6-10 aryl or 3-8 membered heteroaryl;
R b为H，C 1-6烷基，C 3-8环烷基或3-8元杂环基； R b is H, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group;
R c为L，L-C(O)-，L-CH 2-或L-S(O) 2-， R c is L, LC(O)-, L-CH 2 - or LS(O) 2 -,
其中L为H，C 1-6烷基，C 3-6环烷基，3-8元杂环基，C 6-10芳基或3-8元杂芳基，L任选被一个或多个以下基团取代：卤素，羟基，C 1-6烷氧基，氰基，C 3-8环烷基，3-8元杂环基，C 6-10芳基或3-8元杂芳基； Wherein L is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 3-8 membered heteroaryl, L is optionally replaced by one or more The following groups are substituted: halogen, hydroxyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 3-8 membered heteroaryl base;
A为A is
Figure PCTCN2022134253-appb-000004
Figure PCTCN2022134253-appb-000004
Z为N或CR 3；优选地，Z为CR 3； Z is N or CR 3 ; preferably, Z is CR 3 ;
Z’为N或CR 4；优选地Z’为CR 4； Z' is N or CR 4 ; preferably Z' is CR 4 ;
R 3,R 4,R 5,R 6独立地为H，CN，卤素或C 1-3卤代烷基； R 3 , R 4 , R 5 , R 6 are independently H, CN, halogen or C 1-3 haloalkyl;
V为N或CR 9，优选地，V为CR 9，其中R 9为H，CN，卤素，C 1-3烷基，C 1-3卤代烷基或-O-W； V is N or CR 9 , preferably, V is CR 9 , wherein R 9 is H, CN, halogen, C 1-3 alkyl, C 1-3 haloalkyl or -OW;
W为5或6元杂芳基或苯基，优选为吡啶基、嘧啶基、吡唑基或苯基，其可以任选由一个或多个以下的取代基取代：卤素，氰基，C 1-6烷基，C 1-3烷氧基，C 1-3卤代烷基和C 1-3卤代烷氧基； W is 5 or 6 membered heteroaryl or phenyl, preferably pyridyl, pyrimidyl, pyrazolyl or phenyl, which may be optionally substituted by one or more of the following substituents : halogen, cyano, C -6 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and C 1-3 haloalkoxy;
在式(I)和上述12个结构式中，优选地，A为In formula (I) and the above 12 structural formulas, preferably, A is
Figure PCTCN2022134253-appb-000005
Figure PCTCN2022134253-appb-000005
R 5,R 6,R 7,R 8,R 9独立地为H、F或CN； R 5 , R 6 , R 7 , R 8 , R 9 are independently H, F or CN;
或A为or A for
Figure PCTCN2022134253-appb-000006
Figure PCTCN2022134253-appb-000006
R 5,R 6,R 7,R 8独立地为H、F或CN； R 5 , R 6 , R 7 , R 8 are independently H, F or CN;
R 9为-O-W； R 9 is -OW;
W为5或6元杂芳基或苯基，优选为吡啶基、嘧啶基、吡唑基或苯基，其可以任选由一个或多个下列的取代基取代:C 1-3卤代烷基、C 1-3卤代烷氧基、CN、卤素和C 1-6烷基。 W is 5 or 6 membered heteroaryl or phenyl, preferably pyridyl, pyrimidyl, pyrazolyl or phenyl, which can be optionally substituted by one or more of the following substituents: C 1-3 haloalkyl, C 1-3 haloalkoxy, CN, halogen and C 1-6 alkyl.
更优选地，A为More preferably, A is
Figure PCTCN2022134253-appb-000007
Figure PCTCN2022134253-appb-000007
R 7,R 8独立地为H、F或CN； R 7 , R 8 are independently H, F or CN;
R 9为-O-W； R 9 is -OW;
W为吡啶基、嘧啶基、吡唑基或苯基，其可以任选由一个或多个独立选自以下的取代基取代：卤素、CN、CF 3、-OCF 3、CHF 2和CH 3； W is pyridyl, pyrimidyl, pyrazolyl or phenyl, which may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, CF 3 , -OCF 3 , CHF 2 and CH 3 ;
最优选地，A选自下列基团：Most preferably, A is selected from the following groups:
Figure PCTCN2022134253-appb-000008
Figure PCTCN2022134253-appb-000008
Figure PCTCN2022134253-appb-000009
Figure PCTCN2022134253-appb-000009
在一个实施方案中，所述的化合物为以下化合物任一个化合物：In one embodiment, the compound is any one of the following compounds:
Figure PCTCN2022134253-appb-000010
Figure PCTCN2022134253-appb-000010
Figure PCTCN2022134253-appb-000011
Figure PCTCN2022134253-appb-000011
Figure PCTCN2022134253-appb-000012
Figure PCTCN2022134253-appb-000012
上述式的化合物、其盐(例如，药学上可接受的盐)可以立体异构体形式存在(例如，它包含一个或多个不对称碳原子)。所述单个立体异构体(对映异构体和非对映异构体)及它们的混合物均包括在本发明的范围内。The compounds of the above formulas, salts thereof (eg, pharmaceutically acceptable salts) may exist in stereoisomeric forms (eg, which contain one or more asymmetric carbon atoms). Both the individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the present invention.
本发明还包括上述式的化合物、其盐(例如，药学上可接受的盐)的各种氘代形式。连接到碳原子上的各可用的氢原子可以独立地被氘原子取代。本领域的普通技术人员将了解如何合成上述式的化合物、其盐(例如，药学上可接受的盐)的氘代形式。市售的氘代原料可以用于氘代形式的上述式的化合物、其盐(例如，药学上可接受的盐)的制备中，或可以使用采用氘代试剂(如氘化铝锂)的常规技术来合成这些化合物。The invention also includes various deuterated forms of the compounds of the above formulas, salts (eg, pharmaceutically acceptable salts) thereof. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. Those of ordinary skill in the art will understand how to synthesize deuterated forms of the compounds of the above formulas, their salts (eg, pharmaceutically acceptable salts). Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of the above formula, salts thereof (e.g., pharmaceutically acceptable salts), or conventional methods using deuterated reagents (such as lithium aluminum deuteride) can be used. technology to synthesize these compounds.
除了本申请所述化合物的游离碱或游离酸形式，化合物的盐形式也在本发明的范围内。本发明化合物的盐或药学上可接受的盐可以在化合物的最后分离和纯化过程中在原位制备，或通过单独将游离酸或游离碱形式的纯化的化合物分别与合适的碱或酸反应来制备。对于合适的药学上的盐的综述参见Berge等人，J.Pharm,Sci.,66,1-19,1977；P L Gould,International Journal of Pharmaceutics,33(1986),201-217；和Bighley等人，Encyclopedia of Pharmaceutical Technology,Marcel Dekker Inc,New York 1996,Volume 13,page 453-497。In addition to the free base or free acid forms of the compounds described herein, the salt forms of the compounds are also within the scope of the present invention. Salts or pharmaceutically acceptable salts of the compounds of the present invention can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in free acid or free base form with a suitable base or acid, respectively. preparation. For a review of suitable pharmaceutical salts see Berge et al., J. Pharm, Sci., 66, 1-19, 1977; P L Gould, International Journal of Pharmaceuticals, 33 (1986), 201-217; and Bighley et al. People, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, pages 453-497.
本申请所描述的化合物、其盐(例如，药学上可接受的盐)、氘化形式、其溶剂化物或水合物可以以一种或多种多晶型物形式存在。因此，在另一个方面，本发明提供了本申请所定义的化合物、其盐(例如，药学上可接受的盐)的多晶型物，或本申请所述的化合物或其盐(例如，药学上可接受的盐)的溶剂化物或水合物的多晶型物。The compounds described herein, their salts (eg, pharmaceutically acceptable salts), deuterated forms, solvates or hydrates thereof, may exist in one or more polymorphic forms. Therefore, in another aspect, the present invention provides a polymorphic form of a compound as defined herein, a salt thereof (e.g., a pharmaceutically acceptable salt), or a compound described herein, or a salt thereof (e.g., a pharmaceutically acceptable salt). Polymorphs of solvates or hydrates of acceptable salts above.
本发明还包括同位素标记的化合物和盐，其等同于上述式的化合物或其盐，但一个或多个原子被原子质量或质量数不同于自然中最经常发现的原子质量或 质量数的原子代替。可掺入上述式的化合物或其盐的同位素的实例为氢、碳、氮、氘的同位素，如 3H、 11C、 14C和 18F这些同位素标记的上述式的化合物或其盐可用于药物和/或底物组织分布测试。例如， 11C和 18F同位素可用于PET(正电子发射断层摄影术)。PET可用于脑成像。在一个实施方案中，上述式的化合物或其盐为非同位素标记的。 The invention also includes isotopically labeled compounds and salts which are equivalent to the compounds of the above formulas or salts thereof, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from that most frequently found in nature . Examples of isotopes that can be incorporated into the compound of the above formula or its salt are isotopes of hydrogen, carbon, nitrogen, deuterium, such as 3 H, 11 C, 14 C and 18 F. The compound of the above formula or its salt labeled with these isotopes can be used for Drug and/or substrate tissue distribution testing. For example, 11 C and 18 F isotopes can be used in PET (Positron Emission Tomography). PET can be used for brain imaging. In one embodiment, the compound of the above formula or salt thereof is non-isotopically labeled.
因此，本发明的化合物包括上述式的化合物，或其盐，例如其药学上可接受的盐。本发明代表性化合物包括所述具体的化合物。Accordingly, the compounds of the present invention include compounds of the above formulas, or salts thereof, such as pharmaceutically acceptable salts thereof. Representative compounds of the invention include the specific compounds described.
本发明还涉及包含本发明的化合物和药学上可接受的赋形剂的药物组合物。The present invention also relates to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient.
本发明还涉及治疗或预防与Lp-PLA 2的活性相关的疾病的方法，包括向有需要的受试者给药治疗有效量的本申请所述的本发明的化合物。该疾病可以与以下相关：单核细胞、巨噬细胞或淋巴细胞的参与增加溶血磷脂酰胆碱和氧化的游离脂肪酸的形成与Lp-PLA 2活性关联的脂质的氧化或内皮功能障碍。 The present invention also relates to a method for treating or preventing a disease associated with the activity of Lp-PLA 2 , comprising administering a therapeutically effective amount of the compound of the present invention described herein to a subject in need thereof. The disease may be associated with the involvement of monocytes, macrophages or lymphocytes, increased formation of lysophosphatidylcholine and oxidized free fatty acids, oxidation of lipids associated with Lp-PLA 2 activity or endothelial dysfunction.
本发明还提供通过抑制Lp-PLA 2活性治疗或预防疾病的方法。示例性的疾病包括但不限于：神经退行性疾病(例如阿兹海默症、帕金森病、亨廷顿病、血管性痴呆)、各种神经精神疾病如精神***症和自闭症、外周以及脑动脉粥样硬化、中风、代谢性骨病(例如骨髓异常)、血脂异常、佩吉特病、II型糖尿病、高血压、心绞痛、心肌梗塞、缺血、再灌注损伤、代谢综合征、胰岛素抵抗和甲状旁腺功能亢进、糖尿病性并发症(例如黄斑水肿、糖尿病性视网膜病变和后葡萄膜炎、糖尿病溃疡和糖尿病肾病)、糖尿病外周神经病变性疼痛、炎性疼痛、神经病理性痛、各类癌症(例如***癌、结肠癌、乳腺癌、肾癌、肺癌和卵巢癌等)、黄斑水肿、伤口愈合、男性***障碍、类风湿性关节炎、慢性阻塞性肺病(COPD)、败血症、急慢性炎症、牛皮癣和多发性硬化。该方法包括向有需要的受试者给药治疗有效量的本发明的化合物。本发明并不意图限制于疾病的任何特定阶段(如早期或晚期)。 The present invention also provides methods for treating or preventing diseases by inhibiting the activity of Lp- PLA2 . Exemplary diseases include, but are not limited to: neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia), various neuropsychiatric diseases such as schizophrenia and autism, peripheral and cerebral Atherosclerosis, stroke, metabolic bone disease (eg, bone marrow abnormalities), dyslipidemia, Paget's disease, type 2 diabetes, hypertension, angina, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance and hyperparathyroidism, diabetic complications (such as macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcer and diabetic nephropathy), diabetic peripheral neuropathic pain, inflammatory pain, neuropathic pain, various types of cancer (such as prostate cancer, colon cancer, breast cancer, kidney cancer, lung cancer and ovarian cancer, etc.), macular edema, wound healing, male erectile dysfunction, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), sepsis, acute and chronic inflammation , psoriasis and multiple sclerosis. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. It is not intended that the present invention be limited to any particular stage of disease (eg, early or late).
本发明还提供治疗或预防阿兹海默症的方法。该方法包括向有需要的受试者给药治疗有效量的本发明的化合物。The present invention also provides methods for treating or preventing Alzheimer's disease. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
本发明还提供治疗或预防动脉粥样硬化的方法。该方法包括向有需要的受试者给药治疗有效量的本发明的化合物。The present invention also provides methods for treating or preventing atherosclerosis. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
本发明还提供了通过给药本发明的化合物治疗或预防眼部疾病的方法。在 一些实施方式中，本发明提供了治疗黄斑水肿的方法，其包括向受试者给药治疗有效量的本发明的化合物。在一些实施方式中，该黄斑水肿与糖尿病性眼病(例如糖尿病性黄斑水肿或糖尿病性视网膜病)有关。在一个实施方式中，该黄斑水肿与后葡萄膜炎有关。The present invention also provides methods of treating or preventing ocular diseases by administering a compound of the present invention. In some embodiments, the invention provides a method of treating macular edema comprising administering to a subject a therapeutically effective amount of a compound of the invention. In some embodiments, the macular edema is associated with diabetic eye disease (eg, diabetic macular edema or diabetic retinopathy). In one embodiment, the macular edema is associated with posterior uveitis.
本发明还提供了本发明的化合物在制备用于治疗或预防本申请所述的疾病的药物中的用途。The present invention also provides the use of the compound of the present invention in the preparation of a medicament for the treatment or prevention of the diseases described in this application.
本发明还提供了本发明化合物，其用于本申请所述的治疗或预防。The invention also provides compounds of the invention for use in the treatment or prevention described herein.
本申请使用的“和/或”是指包括一个或多个关联的列举项目的任何和所有可能的组合。可以进一步理解，本说明书中使用的术语“包含”和/或“包括”指明所指的特征、整体、步骤、操作、元素和/或组分的存在，但不排除一个或多个其他特征、整体、步骤、操作、元素、组分和/或其组合的存在或加入。As used herein, "and/or" is meant to include any and all possible combinations of one or more of the associated listed items. It can be further understood that the terms "comprising" and/or "comprising" used in this specification indicate the presence of the indicated features, integers, steps, operations, elements and/or components, but do not exclude one or more other features, Presence or addition of integers, steps, operations, elements, components and/or combinations thereof.
一般而言，本申请使用的命名和本申请所描述的有机化学、药物化学、生物学的实验操作是本领域公知的，而且在本领域中普遍采用。除非另有定义，本申请使用的所有技术和科学术语一般具有本公开所属领域的普通技术人员通常理解的相同含义。在本申请使用的术语存在多个定义的情况下，除非另有说明，以本部分的定义为准。In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and biology described herein are those well known and commonly employed in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Where there is more than one definition for a term used in this application, unless otherwise stated, the definition in this section controls.
定义definition
如本申请使用的，除非另有所述，术语“疾病”是指机体或一些器官的状态的任何改变，其中断或干扰功能的执行和/或引起患病的人或与其接触的人的症状(如不适、功能障碍、不良应激乃至死亡)。As used in this application, unless otherwise stated, the term "disease" refers to any change in the state of the body or some organ that interrupts or interferes with the performance of function and/or causes symptoms in a person who is afflicted or who is in contact with it (such as discomfort, dysfunction, adverse stress and even death).
如本申请使用的，除非另有所述，“糖尿病视网膜病变”是指糖尿病导致的慢性进展性视网膜微血管渗漏和梗阻的结果。“糖尿病性黄斑水肿”是指由于糖尿病引起的黄斑中心凹一个视盘直径范围内的细胞外液积聚所致的视网膜增厚或硬性渗出沉积。As used herein, unless otherwise stated, "diabetic retinopathy" refers to the chronically progressive leakage and obstruction of retinal microvessels as a result of diabetes. "Diabetic macular edema" refers to retinal thickening or hard exudative deposits due to the accumulation of extracellular fluid in the fovea of the macula within one optic disc diameter due to diabetes.
如本申请使用的，除非另有所述，“神经退行性疾病”是指特征为神经组织和/或神经组织功能的逐步的、进行性损失的不同种类的中枢神经***障碍。神经退行性疾病为一类神经***疾病，其中神经***疾病的特征为神经组织的逐步的、进行性损失和/或改变的神经功能，通常为由于逐步的、进行性的神经组织损失而导致神经功能的降低。在一些实施方式中，本申请所述神经退行性疾病包 括其中存在有缺陷的血脑屏障(例如渗透性血脑屏障)的神经退行性疾病。其中存在缺陷性血脑屏障的神经退行性疾病的例子包括但不限于，阿兹海默症、亨廷顿病、帕金森病和血管性痴呆等。As used herein, and unless otherwise stated, "neurodegenerative disease" refers to a variety of disorders of the central nervous system characterized by a gradual, progressive loss of nervous tissue and/or nervous tissue function. Neurodegenerative disease is a class of neurological disorders characterized by gradual, progressive loss of neural tissue and/or altered neurological function, usually neurological Reduced functionality. In some embodiments, neurodegenerative diseases described herein include neurodegenerative diseases in which a defective blood-brain barrier (e.g., a permeable blood-brain barrier) is present. Examples of neurodegenerative diseases in which a defective blood-brain barrier is present include, but are not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, and vascular dementia, among others.
如本申请使用的，除非另有所述，“血管性痴呆”也被称为“多发性梗塞性痴呆＂，其是指一组由不同的机制(其都导致脑中的血管损害)引起的综合征。例如，血管性痴呆的主要亚型为血管性轻度认知功能障碍、多发性梗塞性痴呆、由于重大的单梗塞(影响丘脑、大脑前动脉、顶叶或扣带回)导致的血管性痴呆、由于出血性损害导致的血管性痴呆、小血管疾病(包括，例如由于腔隙性损害和宾斯旺格病(Binswanger disease)导致的血管性痴呆)及混合型痴呆。As used in this application, unless otherwise stated, "vascular dementia", also known as "multi-infarct dementia", refers to a group of syndrome. For example, the main subtypes of vascular dementia are vascular mild cognitive impairment, multi-infarct dementia, vascular dementia due to a major single infarct affecting the thalamus, anterior cerebral artery, parietal lobe, or cingulate gyrus , vascular dementia due to hemorrhagic lesions, small vessel disease (including, for example, vascular dementia due to lacunar lesions and Binswanger disease) and mixed dementias.
如本申请使用的，除非另有所述，“神经病理性痛”是为由神经***原发性损害和功能障碍所激发或引起的疼痛。As used herein, unless otherwise stated, "neuropathic pain" is pain provoked or caused by primary damage and dysfunction of the nervous system.
如本申请使用的，除非另有所述，“炎性疼痛”是局部急性炎症或是慢性炎症刺激神经所致的疼痛。As used herein, unless otherwise stated, "inflammatory pain" is pain resulting from localized acute inflammation or chronic inflammation that stimulates a nerve.
如本申请使用的，除非另有所述，“糖尿病外周神经病变性疼痛”是指糖尿病并发的神经损伤而引起的疼痛，糖尿病中的神经损伤至少部分是由于血流减少和高血糖引起的。As used herein, unless otherwise stated, "diabetic peripheral neuropathic pain" refers to pain caused by nerve damage complicated by diabetes mellitus, at least in part due to reduced blood flow and hyperglycemia.
如本申请使用的，除非另有所述，“血脑屏障”或"BBB"在本申请可互换使用，用于指存在于穿过脑组织的血管中的可渗透屏障，其严格地限制和密切地调节物质在血液和脑组织之间的交换。血脑屏障组分包括形成所有血管的最内层衬里的内皮细胞、作为BBB的结构性关联物的相邻内皮细胞之间的紧密连接物、内皮细胞的基底膜和覆盖几乎所有暴露的血管外表面的附近星形胶质细胞的扩大的足突。As used herein, unless stated otherwise, "blood-brain barrier" or "BBB" are used interchangeably herein to refer to the permeable barrier present in blood vessels passing through brain tissue that strictly limits and closely regulates the exchange of substances between blood and brain tissue. BBB components include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that serve as structural associates of the BBB, the basement membrane of the endothelial cells, and the extracellular membrane that covers nearly all exposed blood vessels. Enlarged foot processes of astrocytes near the surface.
如本申请使用的，除非另有所述，“代谢性骨病”是指特征为骨组织的逐步和进行性损失的不同种类的骨疾病。本申请所述的代谢性骨病为其中存在扩散性骨密度下降和/或骨强度降低的状况的骨代谢疾病。这类疾病通过组织学外观来表征。示例性的代谢性骨病包括但不限于，特征为矿物质和骨基质减少的骨质疏松症和特征为矿物质减少但具有完整的骨基质的骨软化症。As used herein, and unless otherwise stated, "metabolic bone disease" refers to the different classes of bone disease characterized by a gradual and progressive loss of bone tissue. A metabolic bone disease as described herein is a bone metabolic disease in which there is a condition of diffuse decreased bone density and/or decreased bone strength. Such diseases are characterized by histological appearance. Exemplary metabolic bone diseases include, but are not limited to, osteoporosis characterized by decreased mineral and bone matrix and osteomalacia characterized by decreased mineral and intact bone matrix.
如本申请使用的，除非另有所述，“骨质减少疾病”或“骨质减少”可以在本申请中互换使用，涉及具有下降的钙化和/或骨密度的状况，为用来表示在其 中观察到钙化和/或骨密度下降的所有骨骼***的描述性术语。骨质减少也是指由于类骨质(osteoid)合成不足导致的骨质减少。As used herein, unless otherwise stated, "osteopenic disease" or "osteopenia" are used interchangeably in this application to refer to a condition with decreased calcification and/or bone density, to mean A descriptive term for all skeletal systems in which calcification and/or decreased bone density are observed. Osteopenia also refers to a decrease in bone mass due to insufficient synthesis of osteoid.
如本申请使用的，除非另有所述，“骨质疏松症”是指其中矿物质和/或骨基质减少和/或骨基质减少的病症。As used herein, unless stated otherwise, "osteoporosis" refers to a condition in which mineral and/or bone matrix is reduced and/or bone matrix is reduced.
如本申请所用，除非另有所述，“烷基”是具有指定碳原子数的一价、饱和经链。例如，C 1-3烷基是指具有1至3个碳原子的烷基。C 1-6烷基是指具有1至6个碳原子的烷基。烷基可为直链或支链的。在一些实施方案中，支链的烷基可具有一个、两个或三个支链。示例性烷基包括，但不限于，甲基、甲基乙基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)。 As used herein, unless otherwise stated, "alkyl" is a monovalent, saturated hydrocarbon chain having the indicated number of carbon atoms. For example, C 1-3 alkyl refers to an alkyl group having 1 to 3 carbon atoms. C 1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms. Alkyl groups can be straight or branched. In some embodiments, a branched alkyl group can have one, two, or three branches. Exemplary alkyl groups include, but are not limited to, methyl, methylethyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl).
如本申请所用，除非另有所述，“烷氧基”取代基为式“R-O-”的基团，其中R为如上定义的烷基。例如，C 1-3烷氧基是指包含1至3个碳的这种烷氧基取代基。示例性烷氧基取代基包括但不限于，甲氧基、乙氧基、正丙氧基、正丁氧基、正戊氧基、正已基氧基、异丙氧基、异丁氧基、仲丁氧基、叔丁氧基、异戊氧基和新戊氧基。 As used herein, unless otherwise stated, an "alkoxy" substituent is a group of the formula "RO-", wherein R is alkyl as defined above. For example, C 1-3 alkoxy refers to such alkoxy substituents containing 1 to 3 carbons. Exemplary alkoxy substituents include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropoxy, isobutoxy , sec-butoxy, tert-butoxy, isopentyloxy and neopentyloxy.
如本申请所用，除非另有所述，“环烷基”是指单价饱和的环状烃基包括桥环及螺环，优选具有3-7个环碳原子，例如环丙基、环丁基、环戊基或[1.1.1]螺桨烷，以及下文中特别示例的那些基团。As used in this application, unless otherwise stated, "cycloalkyl" refers to monovalent saturated cyclic hydrocarbon groups including bridged rings and spiro rings, preferably with 3-7 ring carbon atoms, such as cyclopropyl, cyclobutyl, Cyclopentyl or [1.1.1] propane, and those groups specifically exemplified hereinafter.
如本申请所用，除非另有所述，“芳基”表示包含一个或多个芳环的烃基，如苯基或萘基等。As used herein, unless otherwise stated, "aryl" means a hydrocarbon group containing one or more aromatic rings, such as phenyl or naphthyl and the like.
如本申请所用，除非另有所述，“杂芳基”表示在各环中具有至多8个原子的稳定单环、双环、或三环，其中至少一个环是芳族的并且至少一个环含有1至4个选自O、N和S的杂原子。在该定义的范围内的杂芳基包括但不限于吖啶基、咔唑基、噌啉基、喹喔啉基、喹唑啉基、吡唑基、吲哚基、异吲哚基、1H,3H-1-氧代异吲哚基、苯并***基、呋喃基、噻吩基、吡啶并吗啉基、吡啶并哌啶基、吡啶并吡咯烷基、苯并噻吩基、苯并呋喃基、苯并二噁烷、苯并二氧杂苯、喹啉基、异喹啉基、噁唑基、异噁唑基、苯并噁唑基、咪唑基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉基、噻唑基、异噻唑基、1,2,3-***基、1,2,4—***基、1,2,4-噁二唑基、1,2,4-噻二唑基、1,3,5-三嗪基、1,2,4-三嗪基、1,2,4,5-四嗪基、四唑基、呫吨基、吩嗪基、吩噻嗪基、吩噁嗪基、氮杂
Figure PCTCN2022134253-appb-000013
基、 氧杂
Figure PCTCN2022134253-appb-000014
基和硫杂
Figure PCTCN2022134253-appb-000015
基。特别的杂芳基具有5或6元环，例如呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、***基、四唑基、噻唑基、异噻唑基、噻二唑基，吡啶并吗啉基、吡啶并哌啶基、吡啶并吡咯烷基。 As used herein, unless otherwise stated, "heteroaryl" means a stable monocyclic, bicyclic, or tricyclic ring having up to 8 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H ,3H-1-oxoisoindolyl, benzotriazolyl, furyl, thienyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl, benzothienyl, benzofuran Base, benzodioxane, benzodioxine, quinolinyl, isoquinolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, Pyridyl, pyrimidyl, pyrrolyl, tetrahydroquinolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadio Azolyl, 1,2,4-thiadiazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,4,5-tetrazinyl, tetrazolyl, Xanthenyl, phenazinyl, phenothiazinyl, phenoxazinyl, aza
Figure PCTCN2022134253-appb-000013
base, oxa
Figure PCTCN2022134253-appb-000014
base and thia
Figure PCTCN2022134253-appb-000015
base. Particular heteroaryls have a 5- or 6-membered ring, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl , pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl.
如本申请所用，除非另有所述，“杂环”或“杂环基”是指1至4个碳原子已被独立地选自N、N(R)、S、S(O)、S(O)和O的杂原子代替的环烃。杂环可以是饱和或不饱和的，但不是芳族的。杂环基也可以是含有1、2或3个环，包括桥环及螺环结构。适合的杂环基的实例包括但不限于：氮杂环丁烷、氧杂环丁烷、四氢呋喃基、四氢噻吩基、吡咯烷基、2-氧代吡咯烷基、吡咯啉基、吡喃基、二氧戊环基、哌啶基、2-氧代哌啶基、吡唑啉基、咪唑啉基、噻唑啉基、二硫杂环戊二烯基、氧杂硫杂环戊二烯基、二噁烷基、二噁烯基、二噁唑基、噁噻唑基(oxathiozolyl)、噁唑酮基、哌嗪基、吗啉代、硫代吗啉基、3-氧代吗啉基、二噻烷基、三噻烷基和噁嗪基。As used herein, unless otherwise stated, "heterocycle" or "heterocyclyl" means that 1 to 4 carbon atoms have been independently selected from N, N(R), S, S(O), S (O) and cyclic hydrocarbons substituted by heteroatoms of O. Heterocycles can be saturated or unsaturated, but are not aromatic. The heterocyclic group can also contain 1, 2 or 3 rings, including bridged and spiro ring structures. Examples of suitable heterocyclyl groups include, but are not limited to: azetidine, oxetane, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrrolinyl, pyranyl Base, dioxolanyl, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiocyclopentadienyl, oxathiolanyl Base, dioxanyl, dioxenyl, dioxazolyl, oxathiazolyl (oxathiozolyl), oxazolone, piperazinyl, morpholino, thiomorpholinyl, 3-oxomorpholinyl , dithianyl, trithianyl and oxazinyl.
“桥环化合物”术语指一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳－氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。The term "bridged ring compound" refers to the linking of one or more atoms (ie, C, O, N, or S) to two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In bridged rings, substituents on the ring may also be present on the bridge.
“螺环化合物”术语是指两个单环共用一个碳原子的多环化合物，共用的碳原子称为螺原子。The term "spirocyclic compound" refers to a polycyclic compound in which two monocyclic rings share one carbon atom, which is called a spiroatom.
如本申请所用，除非另有所述，“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。卤代是指卤素基团：氟(-F)、氯(-Cl)、溴(-Br)、或碘(-I)。As used herein, unless otherwise stated, "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Halo refers to a halogen group: fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).
如本申请所用，除非另有所述，“卤代烷基”为取代有一个或多个卤素取代基的烷基，该卤素取代基可相同或不同。例如，C 1-3卤代烷基是指包含1至3个碳的卤代烷基取代基。示例性卤代烷基取代基包括，但不限于，单氟甲基、二氟甲基、三氟甲基、1-氯-2-氟乙基、三氟丙基、3-氟丙基和2-氟乙基。 As used herein, unless otherwise stated, a "haloalkyl" is an alkyl group substituted with one or more halogen substituents, which may be the same or different. For example, C 1-3 haloalkyl refers to a haloalkyl substituent containing 1 to 3 carbons. Exemplary haloalkyl substituents include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, trifluoropropyl, 3-fluoropropyl, and 2- Fluoroethyl.
如本申请所用，除非另有所述，当环上两个取代基连同它们的互相连接的原子一起结合形成另一环时，该环可为螺环稠合或单边稠合的。螺环-稠合的环体系由两个环组成，该两个环仅具有一个共同的碳原子。单边-稠合的环体系由两个环组成，该两个环仅共享两个原子和一个键。As used herein, unless otherwise stated, when two substituents on a ring, together with their interconnected atoms, combine to form another ring, the ring may be spirofused or unilaterally fused. A spiro-fused ring system consists of two rings which have only one carbon atom in common. Unilateral-fused ring systems consist of two rings that share only two atoms and one bond.
如本申请所用，除非另有所述，“任选取代的”表示基团或环可为未取代的，或该基团或环可取代有一个或多个本申请定义的取代基。As used herein, unless otherwise stated, "optionally substituted" means that a group or ring may be unsubstituted, or that group or ring may be substituted with one or more substituents as defined herein.
如本申请所用，除非另有所述，“4、5或6元饱和环，该环任选包含一个选自N或O的杂原子”是指4、5或6元饱和碳环且一个碳原子环成员可任选被一个选自N或O的杂原子代替，例如、环丁基、环戊烷基、环己烷基、氮杂环丁烷基(azitidinyl)、吡咯烷基、哌啶基、氧杂环丁烷基、四氢呋喃基和四氢-2H-吡喃基。As used in this application, unless otherwise stated, "4, 5 or 6 membered saturated ring, which ring optionally contains a heteroatom selected from N or O" means 4, 5 or 6 membered saturated carbocyclic ring and one carbon Atomic ring members may optionally be replaced by a heteroatom selected from N or O, for example, cyclobutyl, cyclopentyl, cyclohexane, azitidinyl, pyrrolidinyl, piperidine group, oxetanyl group, tetrahydrofuranyl group and tetrahydro-2H-pyranyl group.
如本申请所用，除非另有所述，涉及疾病的“治疗”、“治”或“处理”是指：(1)减轻疾病或减轻疾病的一种或多种生物学表现，(2)干扰(a)导致或造成疾病的生物学级联中的一个或多个点或(b)疾病的一种或多种生物学表现，(3)缓和与疾病相关的一种或多种症状或效应，和/或(4)减缓疾病的进展或疾病的一种或多种生物学表现，和/或(5)减少疾病严重性或疾病生物表现的可能性。As used in this application, unless otherwise stated, "treating", "treating" or "treating" with respect to a disease means: (1) alleviating the disease or alleviating one or more biological manifestations of the disease, (2) interfering with (a) leading to or contributing to one or more points in the biological cascade of a disease or (b) one or more biological manifestations of a disease, (3) alleviating one or more symptoms or effects associated with a disease , and/or (4) slowing the progression of the disease or one or more biological manifestations of the disease, and/or (5) reducing the likelihood of the severity of the disease or the biological manifestations of the disease.
如本申请所用，除非另有所述，“预防”是指预防性给药药物以减少疾病或其生物表现的发生的可能性或延迟该发生。As used herein, unless otherwise stated, "prevention" refers to the prophylactic administration of a drug to reduce the likelihood of or delay the occurrence of a disease or its biological manifestations.
如本申请所用，除非另有所述，“受试者”是指哺乳动物受试者(例如，狗、猫、马、牛、绵羊、山羊、猴等)，和尤其是人类受试者。As used herein, unless otherwise stated, "subject" refers to mammalian subjects (eg, dogs, cats, horses, cows, sheep, goats, monkeys, etc.), and especially human subjects.
如本申请所用，除非另有所述，“药学上可接受的盐”是指保留所述主题化合物所需的生物活性，并显示出最低的不希望的毒理效应的盐。这些药学上可接受的盐可以在化合物的最后分离和纯化过程中原位制备，或通过单独地将游离酸或游离碱形式的纯化化合物分别与合适的碱或酸反应来制备。As used herein, unless otherwise stated, "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with an appropriate base or acid, respectively.
如本申请所用，除非另有所述，术语“治疗有效量”是指相比于未接受该量的相应受试者，导致治疗或预防疾病的量，但该量在合理医学判断的范围内足够低以避免严重副作用(以合理的益处/风险比)。化合物的治疗有效量将随着选择的具体化合物(例如考虑到化合物的效力、功效和半衰期)：选择的给药途径；治疗的疾病；治疗的疾病的严重性；治疗患者的年龄、体型、体重和身体状况：治疗患者的医疗史；治疗的持续时间；并行治疗的性质；所需治疗效果等因素而改变，但仍可通过本领域技术人员以常规方式确定。As used herein, unless otherwise stated, the term "therapeutically effective amount" means an amount that results in the treatment or prevention of a disease compared to a corresponding subject not receiving that amount, but is within the scope of sound medical judgment Low enough to avoid serious side effects (with a reasonable benefit/risk ratio). The therapeutically effective amount of a compound will vary with the particular compound selected (e.g., taking into account the potency, potency, and half-life of the compound): the route of administration chosen; the disease being treated; the severity of the disease being treated; the age, size, weight of the patient being treated. and physical condition: the medical history of the patient being treated; the duration of the treatment; the nature of concurrent treatment; the desired effect of the treatment, etc.
化合物合成compound synthesis
本领域的技术人员可以理解，如果本申请描述的取代基与本申请描述的合成方法不相容，该取代基可以用在反应条件下稳定的合适的保护基进行保护。保护基可以在反应顺序中合适的点脱除，以得到所需的中间体或目标化合物。合适的保护基和使用这类合适保护基对不同的取代基进行保护和去保护的方法对于本领域技术人员是公知的；这方面的例子可以在I.Greene和P.Wuts,Protecting Groups in Chemical Synthesis(第三版)，JohnWiley&Sons,NY(1999)中找到。在一些情况下，可以具体地选择在使用的反应条件下具有反应性的取代基。在这些情况下，反应条件转化所选择的取代基成为可用作中间化合物的另一种取代基或者为目标化合物中的需要的取代基的另一种取代基。Those skilled in the art can understand that if a substituent described in this application is not compatible with the synthesis method described in this application, the substituent can be protected with a suitable protecting group that is stable under the reaction conditions. Protecting groups can be removed at appropriate points in the reaction sequence to afford the desired intermediate or target compound. Suitable protecting groups and methods of using such suitable protecting groups for protection and deprotection of various substituents are well known to those skilled in the art; examples in this regard can be found in I. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (Third Edition), John Wiley & Sons, NY (1999). In some cases, substituents can be specifically selected to be reactive under the reaction conditions employed. In these cases, the reaction conditions transform the selected substituent into another substituent useful as an intermediate compound or as another substituent that is the desired substituent in the target compound.
一般方案general plan
一般方案提供式1.8化合物的一般合成路线，其中R 1，R 2，R x，R y，Q,m,n,p,u,A如关于式(I)中所定义。所述路线包括以下步骤： General Scheme A general synthetic route is provided for compounds of formula 1.8, wherein R 1 , R 2 , R x , R y , Q, m, n, p, u, A are as defined for formula (I). The route includes the following steps:
步骤(i)：通过将化合物(1.1)脱除Boc保护基生成化合物(1.2)；Step (i): generating compound (1.2) by removing the Boc protecting group from compound (1.1);
步骤(ii):将化合物(1.2)与化合物(1.3)反应生成化合物(1.5)；Step (ii): reacting compound (1.2) with compound (1.3) to generate compound (1.5);
步骤(iv)：通过将化合物(1.5)关环得到化合物(1.7)；Step (iv): compound (1.7) is obtained by ring-closing compound (1.5);
步骤(v):化合物(1.7)与HQ-(CH 2) m-A反应得到最终产物(1.8)，即为式I的化合物； Step (v): react compound (1.7) with HQ-(CH 2 ) m -A to obtain final product (1.8), which is the compound of formula I;
或包含以下步骤：or include the following steps:
步骤(i)：通过将化合物(1.1)脱除Boc保护基生成化合物(1.2)；Step (i): generating compound (1.2) by removing the Boc protecting group from compound (1.1);
步骤(iii)：将化合物(1.2)与化合物(1.4)反应生成化合物(1.6)；Step (iii): reacting compound (1.2) with compound (1.4) to generate compound (1.6);
步骤(iv’)：通过将化合物(1.6)关环得到化合物(1.7)；Step (iv'): obtain compound (1.7) by ring-closing compound (1.6);
步骤(v):化合物(1.7)与HQ-(CH 2) m-A反应得到最终产物(1.8)，即为式I的化合物； Step (v): react compound (1.7) with HQ-(CH 2 ) m -A to obtain final product (1.8), which is the compound of formula I;
Figure PCTCN2022134253-appb-000016
Figure PCTCN2022134253-appb-000016
其中，R 1，R 2，R x，R y，Q,m,n,p,u,A如本申请中所定义。 Wherein, R 1 , R 2 , R x , R y , Q, m, n, p, u, A are as defined in this application.
具体地，最终化合物1.8的制备可以通过i,ii,iv,v的步骤也可以通过i,iii,iv,v的步骤获得。步骤(i)可以通过将化合物1.1在合适的酸性试剂，例如氯化氢/1,4-二氧六环溶液中，在合适温度，例如室温，脱除Boc保护基生成化合物1.2。步骤(ii)或(iii)可作为SN Ar反应，使用合适的碱性试剂，例如三乙胺，在合适的溶剂，例如乙腈中，在合适的温度，例如室温，将化合物1.2与1.3反应生成化合物1.5或者将化合物1.2与1.4反应生成化合物1.6。化合物1.5或1.6均可以通过相同的操作步骤(iv)得到同样的中间体1.7，步骤(iv)可以通过将化合物1.5或1.6与合适试剂，如三乙胺/甲磺酰氯，或者二氯亚砜，在合适的温度如0℃或室温，将羟基转化为甲磺酸酯或氯代，然后不经纯化进一步在碱性试剂，例如碳酸钾或碳酸钠和合适溶剂，例如乙腈中，加热反应，关环得到化合物1.7。步骤(v)将1.7与对应的醇，硫醇，胺HQ-(CH 2) m-A(Q为-O-，-S-，-NR a-)在合适的碱如NaH条件下在合适的溶剂如乙腈中反应得到最终产物1.8。 Specifically, the preparation of the final compound 1.8 can be obtained through steps i, ii, iv, v, or steps i, iii, iv, v. Step (i) can generate compound 1.2 by removing the Boc protecting group from compound 1.1 in a suitable acidic reagent, such as hydrogen chloride/1,4-dioxane solution, at a suitable temperature, such as room temperature. Step (ii) or (iii) can be used as a SNAr reaction, using a suitable basic reagent, such as triethylamine, in a suitable solvent, such as acetonitrile, at a suitable temperature, such as room temperature, to react compound 1.2 with 1.3 to generate Compound 1.5 or compound 1.2 is reacted with 1.4 to give compound 1.6. Compound 1.5 or 1.6 can obtain the same intermediate 1.7 through the same operation step (iv), and step (iv) can be obtained by combining compound 1.5 or 1.6 with a suitable reagent, such as triethylamine/methanesulfonyl chloride, or thionyl chloride , at a suitable temperature such as 0 ° C or room temperature, the hydroxyl group is converted into mesylate or chlorination, and then the reaction is further heated in an alkaline reagent such as potassium carbonate or sodium carbonate and a suitable solvent such as acetonitrile without purification, Ring closure affords compound 1.7. Step (v) Combine 1.7 with the corresponding alcohol, thiol, amine HQ-(CH 2 ) m -A (Q is -O-, -S-, -NR a -) in a suitable base such as NaH The reaction in a solvent such as acetonitrile gives the final product 1.8.
用途use
本发明化合物是Lp-PLA 2抑制剂。因此，这些化合物可用于治疗，例如治疗或预防与Lp-PLA 2的活性有关的疾病，其包括使用治疗有效量的Lp-PLA 2抑制剂治疗需要该治疗的受试者。因此，本发明的一方面涉及治疗或预防与Lp-PLA 2活性有关的疾病的方法。本领域技术人员可以理解，特定的疾病或其治 疗可以涉及与Lp-PLA 2活性有关的一种或多种潜在机制，包括一种或多种本申请中描述的机制。 The compounds of the present invention are Lp-PLA 2 inhibitors. Accordingly, these compounds are useful in the treatment, eg, treatment or prevention of diseases associated with the activity of Lp- PLA2 comprising treating a subject in need of such treatment with a therapeutically effective amount of an Lp- PLA2 inhibitor. Accordingly, one aspect of the present invention pertains to methods of treating or preventing diseases associated with Lp- PLA2 activity. Those skilled in the art will understand that a particular disease or its treatment may involve one or more underlying mechanisms related to Lp-PLA 2 activity, including one or more of the mechanisms described in this application.
在一些实施方案中，本发明提供本发明的化合物在制备用于治疗或预防以下公开的专利申请公开任意疾病的药物中的用途：WO96/13484，WO96/19451，WO97/02242，WO97/12963，WO97/21675，WO97/21676，WO97/41098，WO97/41099，WO99/24420，WO00/10980，WO00/66566，WO00/66567，WO00/68208，WO01/60805，WO02/30904，WO02/30911，WO03/015786，WO03/016287，WO03/041712，WO03/042179，WO03/042206，WO03/042218，WO03/086400，WO03/87088，WO08/048867，US2008/0103156，US2008/0090851，US2008/0090852、WO08/048866、WO05/003118(CA 2530816Al)、WO06/063811、WO06/063813、WO2008/141176、WO2013013503A1、WO2013014185A1、WO2014114248A1、WO2014114694A1、WO2016011930A1、JP 200188847、US 2008/0279846 A1、US 2010/0239565 A1、和US 2008/0280829 A1。In some embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of any of the diseases disclosed in the following published patent applications: WO96/13484, WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805, WO02/30904, WO02/30911, WO 03/ 015786, WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO03/87088, WO08/048867, US2008/0103156, US2008/0090851 , US2008/0090852, WO08/048866, WO05/003118 (CA 2530816Al), WO06/063811, WO06/063813, WO2008/141176, WO2013013503A1, WO2013014185A1, WO2014114248A1, WO2014114694A1, WO201601 1930A1, JP 200188847, US 2008/0279846 A1, US 2010/0239565 A1, and US 2008/0280829 A1.
在一些实施方案中，本发明提供本发明的化合物在制备用于治疗眼病的药物中的用途。本发明中适用的眼病可能与血视网膜内屏障(iBRB)的破坏有关。示例性的眼病涉及糖尿病性眼病，其包括黄斑水肿、糖尿病性视网膜病、后葡萄膜炎、视网膜静脉闭塞等。更多的眼病包括但不限于，视网膜中央静脉阻塞、视网膜分枝静脉阻塞、伊-加综合征(白内障后和手术后)、色素性视网膜炎、平坦部炎、鸟枪弹样视网膜脉络膜病变、视网膜外层膜、脉络膜肿瘤、囊性黄斑水肿、旁中心凹毛细血管扩张、牵引性黄斑病、玻璃体黄斑牵引综合征、视网膜剥离、视神经视网膜炎、特发性黄斑水肿等。使用Lp-PLA 2抑制剂治疗眼病的更详细内容提供在WO2012/080497中，将其引入本申请作为参考。 In some embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of an eye disease. Ocular diseases applicable in the present invention may be related to disruption of the inner blood-retinal barrier (iBRB). Exemplary eye diseases relate to diabetic eye disease, which includes macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion, and the like. Additional eye diseases include, but are not limited to, central retinal vein occlusion, branch retinal vein occlusion, I-Garr syndrome (post-cataract and post-surgery), retinitis pigmentosa, planaritis, shotgun retinochoroidopathy, retinal Outer layer membrane, choroidal tumor, cystic macular edema, parafoveal telangiectasia, traction maculopathy, vitreomacular traction syndrome, retinal detachment, neuroretinitis, idiopathic macular edema, etc. Further details of the use of Lp-PLA 2 inhibitors for the treatment of eye diseases are provided in WO2012/080497, which is incorporated herein by reference.
此外，本发明一些实施方案提供本发明的化合物在制备用于治疗或预防受试者的糖尿病性黄斑水肿的药物中的用途。在一些实施方案中，本发明提供了本发明的化合物在用于治疗受试者的糖尿病性黄斑水肿的用途。Furthermore, some embodiments of the present invention provide the use of a compound of the present invention in the manufacture of a medicament for treating or preventing diabetic macular edema in a subject. In some embodiments, the invention provides the use of a compound of the invention for treating diabetic macular edema in a subject.
在某些实施方案中，本发明提供本发明的化合物在制备用于治疗或预防患有黄斑水肿或具有患黄斑水肿风险的受试者的药物中的用途。在一些实施方案中，本发明提供本发明的化合物在制备用于治疗患有黄斑水肿或具有患黄斑水肿风险的受试者的药物中的用途。在另一个实施方案中，所述黄斑水肿与糖尿病性眼 病有关，例如糖尿病黄斑水肿或糖尿病性视网膜病。在另一个实施方案中，所述黄斑水肿与后葡萄膜炎有关。In certain embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of a subject suffering from or at risk of developing macular edema. In some embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for treating a subject suffering from or at risk of developing macular edema. In another embodiment, the macular edema is associated with diabetic eye disease, such as diabetic macular edema or diabetic retinopathy. In another embodiment, the macular edema is associated with posterior uveitis.
在某些实施方案中，本发明提供本发明的化合物在制备用于治疗或预防青光眼或黄斑变性的药物中的用途。在一些实施方案中，本发明提供本发明的化合物在制备用于治疗青光眼或黄斑变性的药物中的用途。In certain embodiments, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of glaucoma or macular degeneration. In some embodiments, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of glaucoma or macular degeneration.
在一个实施方案中，本发明提供本发明的化合物在制备用于治疗或预防需要此治疗的受试者中的与血视网膜内屏障破坏有关的疾病的药物中的用途。在一个实施方案中，本发明提供本发明的化合物在制备用于治疗在需要此治疗的受试者中的与血视网膜内屏障破坏有关的疾病的药物中的用途。In one embodiment, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of a disease associated with disruption of the blood retinal barrier in a subject in need thereof. In one embodiment, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a disease associated with disruption of the blood retinal barrier in a subject in need thereof.
在一些实施方案中，本发明提供本发明的化合物在制备用于治疗或预防以下任意疾病的药物中的用途，该疾病涉及内皮机能障碍，例如，动脉粥样硬化(例如，外周血管动脉粥样硬化和脑血管动脉粥样硬化)、糖尿病、高血压、心绞痛、局部缺血和再灌注后的病症。In some embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of any disease involving endothelial dysfunction, e.g., atherosclerosis (e.g., peripheral vascular atherosclerosis sclerosis and cerebrovascular atherosclerosis), diabetes mellitus, hypertension, angina pectoris, ischemia and post-reperfusion conditions.
在一些实施方案中，本发明提供本发明的化合物在制备用于治疗或预防以下任意疾病的药物中的用途，该疾病涉及与酶活性相关联的脂质氧化，例如，除了例如动脉粥样硬化和糖尿病等病症外的其他病症，例如类风湿性关节炎、中风、脑的炎性病症(例如阿兹海默症)、各种神经精神病症(如精神***症、自闭症)、心肌梗死、局部缺血、再灌注损伤、败血症以及急性和慢性炎症。In some embodiments, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of any disease involving lipid oxidation associated with enzymatic activity, for example, other than, for example, atherosclerosis and conditions other than diabetes, such as rheumatoid arthritis, stroke, inflammatory disorders of the brain (such as Alzheimer's disease), various neuropsychiatric conditions (such as schizophrenia, autism), myocardial infarction , ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.
在一些实施方案中，本发明提供本发明的化合物在制备用于降低患有冠心病的患者中心血管事件(例如心脏病发作、心肌梗塞或中风)的几率的药物中的用途。In some embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for reducing the chance of a cardiovascular event such as heart attack, myocardial infarction or stroke in a patient suffering from coronary heart disease.
在一些实施方案中，本发明提供本发明的化合物在制备用于治疗或预防以下疾病的药物中的用途，该疾病涉及活化的单核细胞、巨噬细胞或淋巴细胞，因为所有这些细胞种类表达Lp-PLA 2，包括涉及活化的巨噬细胞(如M1、枝状和/或其它产生氧化应激的巨噬细胞)的疾病。示例性的病症包括但不限于牛皮癫、类风湿性关节炎、伤口愈合、慢性阻塞性肺病(COPD)、肝硬化、特应性皮炎、肺气肿、慢性胰腺炎、慢性胃炎、主动脉瘤、动脉粥样硬化、多发性硬化、阿兹海默症和自身免疫疾病如狼疮。 In some embodiments, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease involving activated monocytes, macrophages or lymphocytes, since all of these cell types express Lp- PLA2 , including diseases involving activated macrophages such as M1, dendritic and/or other oxidative stress producing macrophages. Exemplary conditions include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD), cirrhosis, atopic dermatitis, emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm , atherosclerosis, multiple sclerosis, Alzheimer's disease and autoimmune diseases such as lupus.
在其它实施方案中，本发明提供本发明的化合物在制备以下药物中的用途， 该药物用于急性冠状动脉事件(例如由动脉粥样硬化引起的)的初级或次级预防；预防再狭窄的辅助治疗；或延迟糖尿病或高血压性肾功能不全的发展。预防包括治疗具有这类病症风险的受试者。In other embodiments, the invention provides the use of a compound of the invention for the manufacture of a medicament for primary or secondary prophylaxis of acute coronary events (eg, caused by atherosclerosis); prophylaxis of restenosis Adjuvant therapy; or to delay the development of diabetic or hypertensive renal insufficiency. Prevention includes treatment of subjects at risk for such conditions.
在一些实施方案中，本发明提供在需要此治疗的受试者中治疗或预防与异常血脑屏障(BBB)功能、炎症和/或小神经胶质活化有关的神经***病症的方法。在一些实施方案中，本发明提供在需要此治疗的受试者中治疗或预防与异常血脑屏障(BBB)功能、炎症和/或小神经胶质活化有关的神经***病症的方法。所述方法包括将治疗有效量的本发明化合物给药至受试者。在另一个实施方案中，所述异常BBB是渗透性BBB。在另一个实施方案中，所述疾病是神经退行性疾病。这类神经退行性疾病例如是但不限于，血管性痴呆、阿兹海默症、帕金森病和亨廷顿舞蹈病。在一个实施方案中，本发明提供治疗或预防受试者的与血脑屏障(BBB)泄漏有关的疾病的方法。在一些实施方案中，本发明提供了治疗受试者的与血脑屏障(BBB)泄漏有关的疾病的方法。示例性的疾病包括但不限于，脑出血、脑淀粉样血管病。在一个实施方案中，所述神经退行性疾病是阿兹海默症。在具体实施方案中，所述神经退行性疾病是血管性痴呆。在一个实施方案中，所述神经退行性疾病是多发性硬化症(MS)。In some embodiments, the present invention provides methods of treating or preventing neurological disorders associated with abnormal blood-brain barrier (BBB) function, inflammation, and/or microglial activation in a subject in need thereof. In some embodiments, the present invention provides methods of treating or preventing neurological disorders associated with abnormal blood-brain barrier (BBB) function, inflammation, and/or microglial activation in a subject in need thereof. The method comprises administering to a subject a therapeutically effective amount of a compound of the invention. In another embodiment, the abnormal BBB is an osmotic BBB. In another embodiment, the disease is a neurodegenerative disease. Such neurodegenerative diseases are for example, but not limited to, vascular dementia, Alzheimer's disease, Parkinson's disease and Huntington's disease. In one embodiment, the present invention provides a method of treating or preventing a disease associated with blood-brain barrier (BBB) leakage in a subject. In some embodiments, the present invention provides methods of treating a subject for a disease associated with a blood-brain barrier (BBB) leak. Exemplary diseases include, but are not limited to, cerebral hemorrhage, cerebral amyloid angiopathy. In one embodiment, the neurodegenerative disease is Alzheimer's disease. In specific embodiments, the neurodegenerative disease is vascular dementia. In one embodiment, the neurodegenerative disease is multiple sclerosis (MS).
在一个实施方案中，本发明化合物可用于治疗或预防受试者的神经退行性疾病。所述方法包括将本发明化合物(例如为包含本发明化合物的药物组合物的形式)给药于需要此治疗的受试者。在一个实施方案中，本发明化合物可用于治疗受试者的神经退行性疾病。示例性的神经退行性疾病包括但不限于，阿兹海默症、血管性痴呆、帕金森病和亨廷顿舞蹈病。在一具体实施方案中，本发明所述神经退行性疾病与异常的血脑屏障有关。在一个实施方案中，被给药抑制Lp-PLA 2活性的药剂的受试者是人。 In one embodiment, the compounds of the invention are useful for treating or preventing a neurodegenerative disease in a subject. The methods comprise administering a compound of the invention (eg, in the form of a pharmaceutical composition comprising the compound of the invention) to a subject in need of such treatment. In one embodiment, compounds of the invention are useful for treating a neurodegenerative disease in a subject. Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. In a specific embodiment, the neurodegenerative diseases of the invention are associated with an abnormal blood-brain barrier. In one embodiment, the subject administered an agent that inhibits Lp- PLA2 activity is a human.
在一个实施方案中，本发明提供治疗或预防患有血管性痴呆或具有患血管性痴呆风险的受试者的方法。所述方法包括将本发明化合物(例如包含治疗有效量的本发明化合物的药物组合物)给药至受试者。在一个实施方案中，本发明提供治疗患有血管性痴呆或具有患血管性痴呆风险的受试者的方法。在一具体实施方案中，所述血管性痴呆与阿兹海默症有关。In one embodiment, the invention provides a method of treating or preventing a subject suffering from or at risk of developing vascular dementia. The methods comprise administering a compound of the invention (eg, a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention) to a subject. In one embodiment, the invention provides a method of treating a subject having or at risk of developing vascular dementia. In a specific embodiment, said vascular dementia is associated with Alzheimer's disease.
在某些实施方案中，本发明涉及通过将治疗有效量的本发明化合物给药于 需要此治疗的受试者以治疗或预防代谢性骨病的方法。在一些实施方案中，本发明涉及通过将治疗有效量的本发明化合物给药至需要此治疗的受试者以治疗代谢性骨病的方法。示例性的代谢性骨病包括与骨质和骨密度损失有关的疾病，包括但不限于骨质疏松症和骨质减少疾病。示例性的骨质疏松症和骨质减少疾病包括但不限于，骨髓异常、血脂异常、佩吉特氏病、II型糖尿病、代谢综合征、胰岛素抵抗、甲状旁腺功能亢进和相关疾病。在另一个实施方案中，需要此治疗的受试者是人。In certain embodiments, the present invention relates to methods of treating or preventing metabolic bone disease by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention. In some embodiments, the present invention relates to methods of treating metabolic bone disease by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention. Exemplary metabolic bone diseases include diseases associated with loss of bone mass and bone density, including but not limited to osteoporosis and osteopenic diseases. Exemplary osteoporotic and osteopenic diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Paget's disease, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, and related diseases. In another embodiment, the subject in need of such treatment is a human.
认为预防本申请描述的骨质疏松症和/或骨质减少疾病的方法可能受到抑制Lp-PLA 2的表达和/或抑制Lp-PLA 2的蛋白活性的影响。因此，本发明的一些实施方案提供通过阻断酶活性来抑制Lp-PLA 2的方法。在另一个实施方案中，提供了通过降低和/或下调Lp-PLA 2RNA的表达从而抑制Lp-PLA 2的方法。在另一个实施方案中，预防和/或降低骨质损失和I或骨密度损失导致预防或减少与代谢性骨病例如骨质疏松症和/或骨质减少疾病有关的症状。 It is believed that methods of preventing osteoporosis and/or osteopenic diseases described herein may be affected by inhibiting the expression of Lp- PLA2 and/or inhibiting the protein activity of Lp- PLA2 . Accordingly, some embodiments of the invention provide methods of inhibiting Lp- PLA2 by blocking enzymatic activity. In another embodiment, a method of inhibiting Lp- PLA2 by reducing and/or down-regulating the expression of Lp- PLA2 RNA is provided. In another embodiment, preventing and/or reducing bone mass loss and I or loss of bone density results in preventing or reducing symptoms associated with metabolic bone diseases such as osteoporosis and/or osteopenic diseases.
在具体实施方案中，所述方法还包括将用于治疗代谢性骨病的其他治疗剂给药于需要治疗的受试者。例如，当所述代谢性骨病是骨质疏松症时，可以使用其他治疗剂，例如双磷酸盐类(bisphosphates)(例如，阿仑磷酸盐、伊班磷酸盐、利塞磷酸盐、降血钙素、雷洛昔芬)、选择性***调节剂(SERM)、***疗法、激素替代疗法(ET/HRT)和特立帕肤。In specific embodiments, the method further comprises administering to the subject in need thereof an additional therapeutic agent for the treatment of metabolic bone disease. For example, when the metabolic bone disease is osteoporosis, other therapeutic agents, such as bisphosphates (e.g., alendronate, ibanronate, risedronate, antihypertensive Calcitonin, raloxifene), selective estrogen modulators (SERMs), estrogen therapy, hormone replacement therapy (ET/HRT), and teriparamide.
在一个实施方案中，全身性炎性疾病例如幼年型类风湿关节炎、炎性肠病、川崎病、多发性硬化、结节病、多动脉炎、牛皮癣性关节炎、反应性关节炎、***性红斑狼疮、伏-小柳-原田综合征、莱姆病、贝赫切特病、强直性脊柱炎、慢性肉芽肿性疾病、起止点炎(enthesitis)可能是影响视网膜的后葡萄膜炎的根本原因，且其可导致黄斑水肿。本发明涉及通过给药治疗有效量的本发明化合物治疗或预防后葡萄膜炎或这些全身炎性疾病中的任一种的方法。在一个实施方案中，本发明提供了通过给药治疗有效量的本发明化合物治疗后葡萄膜炎或这些全身炎性疾病中的任一种的方法。In one embodiment, systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic Lupus erythematosus, V-Koyanagi-Harada syndrome, Lyme disease, Behcet's disease, ankylosing spondylitis, chronic granulomatous disease, enthesitis may be at the root of posterior uveitis affecting the retina cause, and it can lead to macular edema. The present invention relates to methods of treating or preventing posterior uveitis, or any of these systemic inflammatory diseases, by administering a therapeutically effective amount of a compound of the present invention. In one embodiment, the invention provides a method of treating post uveitis, or any of these systemic inflammatory diseases, by administering a therapeutically effective amount of a compound of the invention.
与Lp-PLA 2活性相关的疾病的治疗和/或预防可在单一疗法或在双重或多重组合治疗中使用本发明化合物来获得。例如本发明化合物可用于与抗高血脂剂、抗动脉粥样硬化剂、抗糖尿病剂、抗心绞痛剂、抗炎剂或抗高血压剂或用于降低 脂蛋白(a)(Lp(a))的药剂结合来治疗或预防本发明描述的疾病。上述药剂的例子包括但不限于，胆固醇合成抑制剂，例如他汀类：抗氧化剂，例如丙丁酚；胰岛素致敏剂；钙通道拮抗剂和抗炎药，例如非甾体抗炎药(NSAID)。用于降低Lp(a)的药剂包括WO 97/02037、WO 98/28310、WO 98/28311和WO98/28312中所述的氨基磷酸醋。在一个实施方案中，本发明化合物可与一个或多个他汀－起使用。他汀类是众所周知的胆固醇降低剂，包括阿托伐他汀、辛伐他汀、普伐他汀、西立伐他汀、氟伐他汀、洛伐他汀和瑞舒伐他汀。在一些实施方案中，本发明化合物可与抗糖尿病药或胰岛素致敏剂一起使用。在一个实施方案中，本发明化合物可与PPARγ激活剂，例如GI262570(GlaxoSmithKline)和格列酮类(gli tazone)化合物例如罗格列酮、曲格列酮和吡格列酮一起使用。该药剂可以例如本领域已知的治疗有效量或以比本领域已知的可提供有效治疗的给药量更小或更多的量给药。 Treatment and/or prevention of diseases associated with Lp-PLA 2 activity can be obtained using the compounds of the invention in monotherapy or in dual or multiple combination therapy. For example, the compounds of the present invention can be used in combination with antihyperlipidemic agents, antiatherosclerotic agents, antidiabetic agents, antianginal agents, antiinflammatory agents or antihypertensive agents or for lowering lipoprotein (a) (Lp(a)) Combination of agents to treat or prevent the diseases described in this invention. Examples of such agents include, but are not limited to, cholesterol synthesis inhibitors such as statins; antioxidants such as probucol; insulin sensitizers; calcium channel antagonists and anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs). Agents useful for lowering Lp(a) include phosphoramidates as described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312. In one embodiment, the compounds of the invention may be used together with one or more statins. Statins are well known cholesterol lowering agents and include atorvastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin and rosuvastatin. In some embodiments, compounds of the invention may be used with antidiabetic or insulin sensitizing agents. In one embodiment, compounds of the invention may be used with PPAR gamma activators, such as GI262570 (GlaxoSmithKline), and gli tazone compounds such as rosiglitazone, troglitazone, and pioglitazone. The agent may be administered, for example, in a therapeutically effective amount known in the art or in a smaller or greater amount than is known in the art to be administered to provide a therapeutically effective amount.
组合治疗包括以分开的剂型或在单一剂型中一起给药治疗药剂。组合治疗可包括同时给药或分开给药治疗药剂，其可为基本上同时或基本上分开给药。典型地，组合治疗包括给予每个药剂使得每个药剂的治疗有效量在至少一段重叠的时间内存在于受试者的体内。Combination therapy involves administering the therapeutic agents together, either in separate dosage forms or in a single dosage form. Combination therapy may involve simultaneous or separate administration of the therapeutic agents, which may be administered substantially simultaneously or substantially separately. Typically, combination therapy involves administering each agent such that a therapeutically effective amount of each agent is present in the subject's body for at least an overlapping period of time.
使用方法Instructions
本发明化合物的治疗有效量将取决于许多因素，例如包括预期接受者的年龄和体重、需要治疗的精确病症及其严重性、制剂性质和给药途径，且将最终取决于开具处方的医生的判断。然而，用于治疗文中所述疾病的本发明化合物的治疗有效量将通常在0.1到100毫克/kg接受者体重/天的范围，更通常在1到10毫克/kg体重/天的范围。因此，例如，对于70kg的成年哺乳动物，每天的实际量通常为70到700毫克，且该量可以单剂量/天或多个亚剂量每天，如二、三、四、五或六剂量每天给予。或给药可以间断地进行，例如每隔一天一次、一周一次或一月一次。预期类似剂量可适用于治疗上述其他病症。A therapeutically effective amount of a compound of the invention will depend on a number of factors including, for example, the age and weight of the intended recipient, the precise condition to be treated and its severity, the nature of the formulation, and the route of administration, and will ultimately depend on the preference of the prescribing physician. judge. However, a therapeutically effective amount of a compound of the invention for use in the treatment of the diseases described herein will generally be in the range of 0.1 to 100 mg/kg body weight of the recipient per day, more usually in the range of 1 to 10 mg/kg body weight/day. Thus, for example, for a 70 kg adult mammal, the actual amount per day will generally be 70 to 700 mg, and this amount may be administered in a single dose per day or in multiple sub-doses per day, such as two, three, four, five or six doses per day . Or the administration can be done intermittently, for example every other day, once a week or once a month. It is contemplated that similar dosages may be suitable for the treatment of other conditions mentioned above.
本发明药物组合物可以包含一种或多个本发明化合物。在一些实施方式中，所述药物组合物可以包含一种以上的本发明化合物。例如，在一些实施方式中，所述药物组合物可以包含两种或两种以上的本发明化合物。此外，所述药物组合物还可以任选包含一种或多种另外的药物活性化合物。Pharmaceutical compositions of the invention may contain one or more compounds of the invention. In some embodiments, the pharmaceutical composition may contain more than one compound of the invention. For example, in some embodiments, the pharmaceutical composition may contain two or more compounds of the invention. Furthermore, the pharmaceutical compositions may optionally comprise one or more additional pharmaceutically active compounds.
如本发明所使用的“药学上可接受的赋形剂”是指参与赋予所述药物组合物形态或一致性的药学上可接受的原料、组分或载体。当混合时，各赋形剂可与所述药物组合物的其他成分相容，从而避免在给药至受试者时显著降低本发明化合物效力的相互作用以及避免将导致药学上不可接受的药物成分的相互作用。A "pharmaceutically acceptable excipient" as used herein refers to a pharmaceutically acceptable raw material, component or carrier that participates in imparting form or consistency to the pharmaceutical composition. When mixed, each excipient is compatible with the other ingredients of the pharmaceutical composition, thereby avoiding interactions that would significantly reduce the efficacy of the compounds of the invention when administered to a subject and avoiding interactions that would result in pharmaceutically unacceptable drugs. Component interactions.
可将本发明化合物和一种或多种药学上可接受的赋形剂配制成适于通过所需给药途径给药至受试者的剂型。例如，剂型包括适于以下给药途径的那些：(1)口服给药(包括含服或舌下)，例如片剂、胶囊、嚢片、药丸、锭剂、粉末、糖浆、酿剂、混悬液、溶液、乳剂、小袋和扁囊剂；(2)肠胃外给药(包括皮下、肌内、静脉内或真皮内)，例如无菌溶液、混悬液和用于重构的粉末；(3)透皮给药，例如透皮贴片；(4)直肠给药，例如栓剂；(5)经鼻吸入，例如干粉、气雾剂、混悬液和溶液；和(6)局部给药(包括含服、舌下或透皮)，例如霜剂、膏剂、洗液、溶液、糊剂、喷雾剂、泡沫和凝胶。这类组合物可通过制药领域任何已知方法制备，例如通过使上述式的化合物与载体或赋形剂结合。A compound of the invention and one or more pharmaceutically acceptable excipients can be formulated into a dosage form suitable for administration to a subject by the desired route of administration. For example, dosage forms include those suitable for the following routes of administration: (1) Oral administration (including buccal or sublingual), such as tablets, capsules, capsules, pills, lozenges, powders, syrups, brews, mixes; suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration (including subcutaneous, intramuscular, intravenous, or intradermal), such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration, such as transdermal patch; (4) rectal administration, such as suppository; (5) nasal inhalation, such as dry powder, aerosol, suspension and solution; and (6) topical administration Drugs (including buccal, sublingual or transdermal), such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association a compound of the above formula and a carrier or excipient.
适于口服给药的药物组合物可作为离散单元存在，例如胶囊或片剂；粉末或颗粒；水性或非水性液体形式的溶液或混悬液；可食用泡沫(foams或whips)；或水包油液体乳剂或油包水液体乳剂。Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquid forms; edible foams or whips; or water packets. Oil liquid emulsion or water-in-oil liquid emulsion.
合适的药学上可接受的赋形剂可根据所选的具体剂型变化。此外，可根据它们在组合物中所起的特定功能来选择适当的药学上可接受的赋形剂。例如，可因为一些药学上可接受的赋形剂具有促进产生均一剂型的能力而选择它们。可因为一些药学上可接受的赋形剂具有促进产生稳定剂型的能力而选择它们。可因为一些药学上可接受的赋形剂在给药受试者时促进本发明一种或多种化合物从一个器官或机体的一部分递送或转运到另一个器官或机体的一部分的能力而选择它们。可因为一些药学上可接受的赋形剂增加患者顺应性的能力而选择它们。Suitable pharmaceutically acceptable excipients may vary depending on the particular dosage form chosen. Furthermore, appropriate pharmaceutically acceptable excipients can be selected according to the specific function they perform in the composition. For example, some pharmaceutically acceptable excipients may be selected for their ability to facilitate the production of a uniform dosage form. Some pharmaceutically acceptable excipients can be selected for their ability to facilitate the production of stable dosage forms. Some pharmaceutically acceptable excipients may be selected for their ability to facilitate the delivery or transport of one or more compounds of the invention from one organ or part of the body to another organ or part of the body when administered to a subject . Some pharmaceutically acceptable excipients may be selected for their ability to increase patient compliance.
合适的药学上可接受的赋形剂包括以下类型的赋形剂：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、成粒剂、包衣剂、润湿剂、溶剂、共溶剂、悬浮剂、乳化剂、增甜剂、调味剂、掩味剂、着色剂、抗结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。本领域技术人员应理解一些药物上可接受赋形剂可以提供一种以上的功能，并且取决于该赋形剂存在于制剂中的多少以及还有什么其他成分存在于该制剂中而可提 供其他的功能。Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives , stabilizers, surfactants and buffers. It will be appreciated by those skilled in the art that some pharmaceutically acceptable excipients can serve more than one function and may provide other functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. function.
技术熟练人员拥有本领域知识和技术，从而能够选择适当量的适当的药物上可接受赋形剂用于本发明。此外，技术熟练人员可获得描述药学上可接受的赋形剂并可用于选择适当的药学上可接受的赋形剂的许多资源。例子包括Remington药物科学(Remington's Pharmaceutical Sciences,Mack出版公司)、药物添加剂手册(The Hand book of Pharmaceutical Additives,Gower出版有限公司)和药物赋形剂手册(Handbook of Pharmaceutical Excipients,美国药物协会和药物出版社)。A skilled person possesses the knowledge and skill in the art to be able to select appropriate pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. In addition, many resources are available to the skilled artisan that describe pharmaceutically acceptable excipients and can be used to select an appropriate pharmaceutically acceptable excipient. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Co.), The Handbook of Pharmaceutical Additives (Gower Publishing Ltd.), and Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and Pharmaceutical Press ).
使用本领域技术人员已知的技术和方法制备本发明药物组合物。常用于本领域的一些方法描述在Remington药物科学(Mack出版社)中。The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington Pharmaceutical Sciences (Mack Press).
一个方面，本发明涉及包含治疗有效量的本发明化合物和桸释剂或填充剂的固体口服剂型，例如片剂或胶囊。合适的稀释剂和填充剂包括乳糖、催糖、葡萄糖、甘露醇、山梨醇、淀粉(例如玉米淀粉、马铃薯淀粉和预胶化淀粉)、纤维素及其衍生物(例如微晶纤维素)、硫酸钙和磷酸氢钙。口服固体剂型还可包括粘合剂。合适的粘合剂包括淀粉(例如玉米淀粉、马铃薯淀粉和预胶化淀粉)、明胶、***胶、藻酸钠、藻酸、黄胶、瓜尔胶、聚维酮和纤维素及其衍生物(例如微晶纤维素)。口服固体剂型还可以包括含崩解剂。合适的崩解剂包括交聚维酮、淀粉羟基乙酸钠、交联羧甲纤维素(croscarmelose)、藻酸和羧甲基纤维素钠。口服固体剂型还可以包含润滑剂。适当的润滑剂包括硬脂酸、硬脂酸镁、硬脂酸钙和滑石。In one aspect, the invention is directed to solid oral dosage forms, such as tablets or capsules, comprising a therapeutically effective amount of a compound of the invention and a release or filler agent. Suitable diluents and fillers include lactose, glucosamine, dextrose, mannitol, sorbitol, starches (such as corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (such as microcrystalline cellulose), Calcium Sulfate and Dibasic Calcium Phosphate. Oral solid dosage forms may also include binders. Suitable binders include starches (such as corn starch, potato starch, and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, xanthan gum, guar gum, povidone, and cellulose and its derivatives (eg microcrystalline cellulose). Oral solid dosage forms may also contain disintegrants. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid and sodium carboxymethylcellulose. Oral solid dosage forms may also contain lubricants. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.
在具体实施方式中，本发明涉及含0.01mg至1000mg一种或多种文中所述的上述式的化合物或其药学上可接受的盐以及0.01g至5g的一种或多种药学上可接受的赋形剂的药物组合物。In a specific embodiment, the present invention relates to a compound containing 0.01mg to 1000mg of one or more compounds of the above formula described herein or a pharmaceutically acceptable salt thereof and 0.01g to 5g of one or more pharmaceutically acceptable Excipients for pharmaceutical compositions.
实施例制备Example preparation
中间体1Intermediate 1
(S)-2-(((叔丁氧羰基)氨基)-6-(二甲基(氧代)-λ 6-亚磺酰基)-5-氧代己酸甲酯 (S)-2-(((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-λ 6 -sulfinyl)-5-oxohexanoic acid methyl ester
Figure PCTCN2022134253-appb-000017
Figure PCTCN2022134253-appb-000017
室温下，将1-(叔丁基)2-甲基(S)-5-氧吡咯烷-1,2-二羧酸酯(49g，0.2mol)，叔丁醇钾(34g，0.3mol)加入二甲亚砜(500mL)中，室温搅拌1小时，加入三甲基碘化亚砜(75g，0.34mol)，室温搅拌3小时。反应液倒入水中，二氯甲烷提取，有机相浓缩，柱层析纯化得到标题化合物(41g，61％)。MS:m/z[M+H] +＝336。 At room temperature, 1-(tert-butyl) 2-methyl(S)-5-oxopyrrolidine-1,2-dicarboxylate (49g, 0.2mol), potassium tert-butoxide (34g, 0.3mol) Add dimethyl sulfoxide (500 mL), stir at room temperature for 1 hour, add trimethylsulfoxide iodide (75 g, 0.34 mol), and stir at room temperature for 3 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (41 g, 61%). MS: m/z [M+H] + = 336.
1-(叔丁基)2-甲基(S)-5-氧哌啶-1,2-二羧酸酯1-(tert-butyl)2-methyl(S)-5-oxopiperidine-1,2-dicarboxylate
Figure PCTCN2022134253-appb-000018
Figure PCTCN2022134253-appb-000018
室温下，(S)-2-(((叔丁氧羰基)氨基)-6-(二甲基(氧代)-λ 6-亚磺酰基)-5-氧代己酸甲酯(4.1g，12mmol)和Ir[COD] 2Cl(41mg，0.6mmol)加入1,2-二氯乙烷(50mL)中，氩气保护下，90℃搅拌2天。反应液浓缩，柱层析纯化得到标题化合物(1.3g，33％)。MS:m/z[M+H] +＝258。 At room temperature, (S)-2-(((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-λ 6 -sulfinyl)-5-oxohexanoic acid methyl ester (4.1g , 12mmol) and Ir[COD] 2 Cl (41mg, 0.6mmol) were added to 1,2-dichloroethane (50mL), and stirred at 90°C for 2 days under the protection of argon. The reaction solution was concentrated and purified by column chromatography to obtain The title compound (1.3 g, 33%). MS: m/z [M+H] + =258.
1-(叔丁基)2-甲基(S)-5-亚甲基哌啶-1,2-二羧酸酯1-(tert-butyl)2-methyl(S)-5-methylenepiperidine-1,2-dicarboxylate
Figure PCTCN2022134253-appb-000019
Figure PCTCN2022134253-appb-000019
室温下，将1-(叔丁基)2-甲基(S)-5-氧哌啶-1,2-二羧酸酯(500mg，1.9mmol)加入无水四氢呋喃(50mL)中，氩气保护下降温至0℃，滴加正丁基锂的正己烷溶液(2.5M，1mL，2.5mmol)，0℃搅拌1小时。将甲基三苯基溴化磷(500mg，1.9mmol)加入反应液，室温搅拌过夜。反应液用水淬灭，二氯甲烷提取，有机相浓缩，柱层析纯化得到化合物(250mg，50％)。MS:m/z[M+H] +＝256。 At room temperature, 1-(tert-butyl) 2-methyl(S)-5-oxopiperidine-1,2-dicarboxylate (500mg, 1.9mmol) was added into anhydrous tetrahydrofuran (50mL), and argon Protect and lower the temperature to 0°C, add n-butyllithium in n-hexane solution (2.5M, 1 mL, 2.5mmol) dropwise, and stir at 0°C for 1 hour. Methyltriphenylphosphine bromide (500mg, 1.9mmol) was added to the reaction solution and stirred overnight at room temperature. The reaction solution was quenched with water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to obtain the compound (250 mg, 50%). MS: m/z [M+H] + =256.
1-苄基2-甲基(S)-5-亚甲基哌啶-1,2-二羧酸酯1-Benzyl 2-methyl(S)-5-methylenepiperidine-1,2-dicarboxylate
Figure PCTCN2022134253-appb-000020
Figure PCTCN2022134253-appb-000020
室温下，将1-(叔丁基)2-甲基(S)-5-亚甲基哌啶-1,2-二羧酸酯(250mg，1.0mmol)和三氟乙酸(228mg，2.0mmol)加入二氯甲烷(5mL)中，室温搅拌1小时。 反应液浓缩，向残留物中依次加入水(5mL)、碳酸钾(414mg，3.0mmol)和氯甲酸苄酯(170mg，1.0mmol)，室温搅拌过夜。反应液倒入水中，二氯甲烷提取，有机相浓缩，制备薄层色谱分离得到标题化合物(110mg，38％)。MS:m/z[M+H] +＝290。 At room temperature, mix 1-(tert-butyl)2-methyl(S)-5-methylenepiperidine-1,2-dicarboxylate (250mg, 1.0mmol) and trifluoroacetic acid (228mg, 2.0mmol ) was added into dichloromethane (5 mL), and stirred at room temperature for 1 hour. The reaction solution was concentrated, and water (5 mL), potassium carbonate (414 mg, 3.0 mmol) and benzyl chloroformate (170 mg, 1.0 mmol) were successively added to the residue, and stirred overnight at room temperature. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and separated by preparative thin-layer chromatography to obtain the title compound (110 mg, 38%). MS: m/z [M+H] + =290.
5-苄基6-甲基(S)-5-氮杂螺[2.5]辛烷-5,6-二羧酸酯5-Benzyl 6-methyl(S)-5-azaspiro[2.5]octane-5,6-dicarboxylate
Figure PCTCN2022134253-appb-000021
Figure PCTCN2022134253-appb-000021
室温下，将二乙基锌的正己烷溶液(1M，7.6mL，7.6mmol)加入二氯甲烷(7mL)中，氩气保护下降温至0℃，将三氟乙酸(560μL，7.6mmol)加入反应液，0℃搅拌1小时。将二碘甲烷(2.0g，7.6mmol)加入反应液，0℃搅拌1小时。将1-苄基2-甲基(S)-5-亚甲基哌啶-1,2-二羧酸酯(1.1g，3.8mmol)加入反应液，室温搅拌过夜。反应液用二氯甲烷稀释后倒入饱和碳酸氢钠水溶液中，室温搅拌0.5小时。过滤，滤液用二氯甲烷提取，有机相浓缩，柱层析纯化得到标题化合物(300mg，27％)。MS:m/z[M+H] +＝304。 At room temperature, a n-hexane solution of diethylzinc (1M, 7.6mL, 7.6mmol) was added into dichloromethane (7mL), the temperature was lowered to 0°C under the protection of argon, and trifluoroacetic acid (560μL, 7.6mmol) was added The reaction solution was stirred at 0°C for 1 hour. Diiodomethane (2.0 g, 7.6 mmol) was added to the reaction solution, and stirred at 0° C. for 1 hour. 1-Benzyl 2-methyl(S)-5-methylenepiperidine-1,2-dicarboxylate (1.1 g, 3.8 mmol) was added to the reaction solution and stirred overnight at room temperature. The reaction solution was diluted with dichloromethane, poured into saturated aqueous sodium bicarbonate solution, and stirred at room temperature for 0.5 hours. After filtration, the filtrate was extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (300 mg, 27%). MS: m/z [M+H] + =304.
(S)-5-氮杂螺[2.5]辛烷-6-羧酸甲酯(S)-5-Azaspiro[2.5]octane-6-carboxylic acid methyl ester
Figure PCTCN2022134253-appb-000022
Figure PCTCN2022134253-appb-000022
室温下，将5-苄基6-甲基(S)-5-氮杂螺[2.5]辛烷-5,6-二羧酸酯(300mg，1.0mmol)和钯碳(10％，30mg)加入甲醇(10mL)中，室温常压氢化过夜。反应液过滤，滤液浓缩得到标题化合物粗品直接用于下一步反应。MS:m/z[M+H] +＝170。 At room temperature, mix 5-benzyl 6-methyl(S)-5-azaspiro[2.5]octane-5,6-dicarboxylate (300mg, 1.0mmol) and palladium on carbon (10%, 30mg) Add methanol (10 mL) and hydrogenate at room temperature and pressure overnight. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product of the title compound, which was directly used in the next reaction. MS: m/z [M+H] + =170.
(S)-(5-氮杂螺[2.5]辛烷-6-基)甲醇(S)-(5-Azaspiro[2.5]octane-6-yl)methanol
Figure PCTCN2022134253-appb-000023
Figure PCTCN2022134253-appb-000023
室温下，将(S)-5-氮杂螺[2.5]辛烷-6-羧酸甲酯(190mg，1.1mmol)加入无水四氢呋喃(2mL)中，搅拌下加入氢化铝锂(45mg，1.1mmol)，室温搅拌2小时。 反应液用十水硫酸钠淬灭，室温搅拌30分钟，过滤，滤饼用四氢呋喃淋洗，滤液浓缩得到标题化合物(100mg，2步收率：64％)。MS:m/z[M+H] +＝142。 At room temperature, (S)-methyl 5-azaspiro[2.5]octane-6-carboxylate (190 mg, 1.1 mmol) was added into anhydrous tetrahydrofuran (2 mL), and lithium aluminum hydride (45 mg, 1.1 mmol), stirred at room temperature for 2 hours. The reaction solution was quenched with sodium sulfate decahydrate, stirred at room temperature for 30 minutes, filtered, the filter cake was rinsed with THF, and the filtrate was concentrated to obtain the title compound (100 mg, 2-step yield: 64%). MS: m/z [M+H] + =142.
(S)-(5-(2,6-二氯嘧啶-4-基)-5-氮杂螺[2.5]辛烷-6-基)甲醇(S)-(5-(2,6-dichloropyrimidin-4-yl)-5-azaspiro[2.5]octane-6-yl)methanol
Figure PCTCN2022134253-appb-000024
Figure PCTCN2022134253-appb-000024
室温下，将(S)-(5-氮杂螺[2.5]辛烷-6-基)甲醇(100mg，0.7mmol)和碳酸钠固体(150mg，1.4mmol)加入乙腈(2mL)中，氩气保护下冷却至0℃，加入2,4,6-三氯嘧啶(130mg，0.7mmol)，室温搅拌过夜。反应液过滤，滤液浓缩，制备薄层色谱分离得到标题化合物(100mg，50％)。MS:m/z[M+H] +＝288。 (S)-(5-Azaspiro[2.5]octan-6-yl)methanol (100 mg, 0.7 mmol) and solid sodium carbonate (150 mg, 1.4 mmol) were added to acetonitrile (2 mL) at room temperature under argon Cool to 0°C under protection, add 2,4,6-trichloropyrimidine (130 mg, 0.7 mmol), and stir at room temperature overnight. The reaction liquid was filtered, the filtrate was concentrated, and the title compound (100 mg, 50%) was obtained by preparative thin-layer chromatography. MS: m/z [M+H] + =288.
(S)-3'-氯-8',9',9a',10'-四氢-1'H,6'H-螺[环丙烷-1,7'-吡啶[1',2':3,4]咪唑并[1,2-c]嘧啶]-1'-酮(S)-3'-chloro-8',9',9a',10'-tetrahydro-1'H,6'H-spiro[cyclopropane-1,7'-pyridine[1',2': 3,4]imidazo[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000025
Figure PCTCN2022134253-appb-000025
室温下，将(S)-(5-(2,6-二氯嘧啶-4-基)-5-氮杂螺[2.5]辛烷-6-基)甲醇(50mg，0.2mmol)和二氯亚砜(250mg，0.2mmol)加入二氯甲烷(2mL)中，室温搅拌过夜。反应液浓缩，向残留物中依次加入碳酸钾固体(50mg，0.3mmol)和乙腈(2mL)，80℃搅拌过夜。反应液过滤，滤液浓缩，制备薄层色谱分离得到标题化合物(20mg，45％)。MS:m/z[M+H] +＝252。 At room temperature, (S)-(5-(2,6-dichloropyrimidin-4-yl)-5-azaspiro[2.5]octane-6-yl)methanol (50 mg, 0.2 mmol) and dichloro Sulfoxide (250 mg, 0.2 mmol) was added into dichloromethane (2 mL), and stirred at room temperature overnight. The reaction solution was concentrated, solid potassium carbonate (50 mg, 0.3 mmol) and acetonitrile (2 mL) were successively added to the residue, and stirred overnight at 80°C. The reaction solution was filtered, the filtrate was concentrated, and the title compound (20 mg, 45%) was obtained by preparative thin-layer chromatography. MS: m/z [M+H] + =252.
中间体2Intermediate 2
1-苄基-5-氧吡咯烷-2-羧酸甲酯1-Benzyl-5-oxopyrrolidine-2-carboxylic acid methyl ester
Figure PCTCN2022134253-appb-000026
Figure PCTCN2022134253-appb-000026
室温下，将5-氧吡咯烷-2-羧酸甲酯(4.0g，28.0mmol)和氢化钠(60％，2.24g，56.0mmol)加入无水四氢呋喃(50mL)中，氩气保护下升温至60℃，加入溴化苄(5.7g，33.6mmol)，60℃搅拌2小时。反应液冷却至室温后倒饱和氯化铵水溶液中，乙酸乙酯萃取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝3/1)得到标题化合物(4.2g，64％)。MS:m/z[M+H] +＝234。 At room temperature, add methyl 5-oxopyrrolidine-2-carboxylate (4.0 g, 28.0 mmol) and sodium hydride (60%, 2.24 g, 56.0 mmol) into anhydrous tetrahydrofuran (50 mL), and raise the temperature under the protection of argon To 60°C, add benzyl bromide (5.7g, 33.6mmol), and stir at 60°C for 2 hours. After the reaction solution was cooled to room temperature, it was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=3/1) to obtain the title compound (4.2 g, 64%). MS: m/z [M+H] + =234.
1-苄基-5-(羟甲基)吡咯烷-2-酮1-Benzyl-5-(hydroxymethyl)pyrrolidin-2-one
Figure PCTCN2022134253-appb-000027
Figure PCTCN2022134253-appb-000027
室温下，将1-苄基-5-氧吡咯烷-2-羧酸甲酯(4.2g，18.02mmol)加入无水四氢呋喃(40mL)中，搅拌下加入硼氢化锂(800mg，36.0mmol)，室温搅拌1小时。反应液用十水硫酸钠淬灭，室温搅拌30分钟。过滤，滤液浓缩得到标题化合物粗品(3.6g，97％)。MS:m/z[M+H] +＝206。 At room temperature, 1-benzyl-5-oxopyrrolidine-2-carboxylic acid methyl ester (4.2g, 18.02mmol) was added into anhydrous tetrahydrofuran (40mL), and lithium borohydride (800mg, 36.0mmol) was added under stirring, Stir at room temperature for 1 hour. The reaction solution was quenched with sodium sulfate decahydrate and stirred at room temperature for 30 minutes. After filtration, the filtrate was concentrated to give the crude title compound (3.6 g, 97%). MS: m/z [M+H] + =206.
1-苄基-5-(((叔丁基二甲基硅烷基)氧基)甲基)吡咯烷-2-酮1-Benzyl-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one
Figure PCTCN2022134253-appb-000028
Figure PCTCN2022134253-appb-000028
室温下，将1-苄基-5-(羟甲基)吡咯烷-2-酮(3.6g，14.4mmol)溶于二氯甲烷(50mL)中，加入咪唑(2.9g，43.2mmol)和叔丁基二甲基氯硅烷(3.2g，21.6mmol)，室温搅拌30分钟。反应液倒入饱和氯化铵水溶液中，二氯甲烷提取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝10/1)得到标题化合物(3.6g，78％)。MS:m/z[M+H] +＝320。 At room temperature, 1-benzyl-5-(hydroxymethyl)pyrrolidin-2-one (3.6g, 14.4mmol) was dissolved in dichloromethane (50mL), imidazole (2.9g, 43.2mmol) and tert Butyldimethylsilyl chloride (3.2 g, 21.6 mmol), stirred at room temperature for 30 minutes. The reaction solution was poured into saturated aqueous ammonium chloride, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the title compound (3.6 g, 78%). MS: m/z [M+H] + = 320.
4-苄基5-(((叔丁基二甲基硅烷基)氧基)甲基)-4-氮杂螺[2.4]庚烷4-Benzyl 5-(((tert-butyldimethylsilyl)oxy)methyl)-4-azaspiro[2.4]heptane
Figure PCTCN2022134253-appb-000029
Figure PCTCN2022134253-appb-000029
室温下，将1-苄基-5-(((叔丁基二甲基硅烷基)氧基)甲基)吡咯烷-2-酮(2.0g，6.27mmol)加入无水四氢呋喃(30mL)中，氩气保护下降温至0℃，搅拌下加入钛酸四异丙酯(4.5mL，15.67mmol)和乙基溴化镁的四氢呋喃溶液(2M，15mL，30mmol)，室温过夜。反应液用水淬灭，反应液过滤，滤液浓缩，柱层析纯化(石油醚/乙酸乙酯＝20/1)得到标题化合物(1.3g，63％)。MS:m/z[M+H] +＝332。 Add 1-benzyl-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one (2.0 g, 6.27 mmol) into anhydrous THF (30 mL) at room temperature , the temperature was lowered to 0°C under the protection of argon, tetraisopropyl titanate (4.5 mL, 15.67 mmol) and tetrahydrofuran solution of ethylmagnesium bromide (2M, 15 mL, 30 mmol) were added under stirring, and the mixture was left overnight at room temperature. The reaction solution was quenched with water, the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=20/1) to obtain the title compound (1.3 g, 63%). MS: m/z [M+H] + =332.
(4-苄基-4-氮杂螺[2.4]庚烷-5-基)甲醇(4-Benzyl-4-azaspiro[2.4]heptane-5-yl)methanol
Figure PCTCN2022134253-appb-000030
Figure PCTCN2022134253-appb-000030
氩气保护下，将4-苄基5-(((叔丁基二甲基硅烷基)氧基)甲基)-4-氮杂螺[2.4]庚烷(3.1g，9.36mmol)加入无水四氢呋喃(40mL)和四丁基氟化铵的四氢呋喃溶液(1M，10.8mmol，10.8mL)中，室温搅拌3小时。反应液用饱和氯化铵水溶液淬灭，二氯甲烷萃取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝15/1～10/1)得到标题化合物(800mg，94％)。MS:m/z[M+H] +＝218。 Under argon protection, 4-benzyl 5-(((tert-butyldimethylsilyl)oxy)methyl)-4-azaspiro[2.4]heptane (3.1g, 9.36mmol) was added to the A solution of tetrahydrofuran (40 mL) in water and tetrabutylammonium fluoride in tetrahydrofuran (1M, 10.8 mmol, 10.8 mL) was stirred at room temperature for 3 hours. The reaction solution was quenched with saturated aqueous ammonium chloride, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=15/1-10/1) to obtain the title compound (800 mg, 94%). MS: m/z [M+H] + =218.
(4-氮杂螺[2.4]庚烷-5-基)甲醇(4-Azaspiro[2.4]heptan-5-yl)methanol
Figure PCTCN2022134253-appb-000031
Figure PCTCN2022134253-appb-000031
室温下，将(4-苄基-4-氮杂螺[2.4]庚烷-5-基)甲醇(700mg，3.22mmol)和钯碳(10％，105mg)加入甲醇(25mL)中，50℃常压氢化3天。反应液过滤，滤液浓缩得到标题化合物粗品(1.2g，256％)。MS:m/z[M+H] +＝128。 Add (4-benzyl-4-azaspiro[2.4]heptan-5-yl)methanol (700mg, 3.22mmol) and palladium on carbon (10%, 105mg) into methanol (25mL) at room temperature, 50°C Atmospheric pressure hydrogenation for 3 days. The reaction liquid was filtered, and the filtrate was concentrated to obtain the crude product of the title compound (1.2 g, 256%). MS: m/z [M+H] + =128.
(4-(2,6-二氯吡啶-4-基)-4-氮杂螺[2.4]庚烷-5-基)甲醇(4-(2,6-Dichloropyridin-4-yl)-4-azaspiro[2.4]heptane-5-yl)methanol
Figure PCTCN2022134253-appb-000032
Figure PCTCN2022134253-appb-000032
室温下，将2,4,6-三氯嘧啶(582mg，3.2mmol)加到乙腈(20mL)中，氩气保护下冷却至0℃。搅拌下依次加入碳酸钠固体(510mg，4.8mmol)和(4-氮杂螺[2.4]庚烷-5-基)甲醇的粗品(600mg，4.7mmol)，室温搅拌2小时。反应液过滤，滤液浓缩，制备薄层色谱分离(石油醚/乙酸乙酯＝5/1)得到标题化合物(160mg，12％)。MS:m/z[M+H] +＝274。 At room temperature, 2,4,6-trichloropyrimidine (582mg, 3.2mmol) was added into acetonitrile (20mL), and cooled to 0°C under the protection of argon. Solid sodium carbonate (510mg, 4.8mmol) and crude (4-azaspiro[2.4]heptan-5-yl)methanol (600mg, 4.7mmol) were added successively with stirring, and stirred at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and separated by preparative thin-layer chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound (160 mg, 12%). MS: m/z [M+H] + =274.
3'-氯-7',8',8a',9'-四氢-1'H-螺[环丙烷-1,6'-吡咯并[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3'-Chloro-7',8',8a',9'-tetrahydro-1'H-spiro[cyclopropane-1,6'-pyrrolo[1',2':3,4]imidazol[1 ,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000033
Figure PCTCN2022134253-appb-000033
室温下，将(4-(2,6-二氯吡啶-4-基)-4-氮杂螺[2.4]庚烷-5-基)甲醇(120mg，0.52mmol)加到二氯甲烷(8mL)中，室温下滴加氯化亚砜(120mg，1.04mmol)，室温搅拌10分钟。反应液浓缩，向残留物中依次加入碳酸钾(290mg，2.08mmol)和乙腈(12mL)，85℃搅拌过夜。反应液过滤，滤液浓缩,制备薄层色谱分离(二氯甲烷/甲醇＝20/1)得到标题化合物(80mg，65％)。MS:m/z[M+H] +＝238。 (4-(2,6-Dichloropyridin-4-yl)-4-azaspiro[2.4]heptan-5-yl)methanol (120 mg, 0.52 mmol) was added to dichloromethane (8 mL ), add thionyl chloride (120 mg, 1.04 mmol) dropwise at room temperature, and stir at room temperature for 10 minutes. The reaction solution was concentrated, and potassium carbonate (290 mg, 2.08 mmol) and acetonitrile (12 mL) were successively added to the residue, and stirred overnight at 85°C. The reaction solution was filtered, the filtrate was concentrated, and separated by preparative thin-layer chromatography (dichloromethane/methanol=20/1) to obtain the title compound (80 mg, 65%). MS: m/z [M+H] + =238.
中间体3Intermediate 3
1,1-双(碘甲基)环丙烷1,1-Bis(iodomethyl)cyclopropane
Figure PCTCN2022134253-appb-000034
Figure PCTCN2022134253-appb-000034
室温下，将三苯基膦(26.0g，99.0mmol)和咪唑(6.5g，96.0mmol)加入二氯甲烷(30mL)中，氩气保护下降温至0℃，加入碘(25.0g，99.0mmol)，0℃搅拌1小时。将1,1-环丙烷-二甲醇(5.0g，48.0mmol)的二氯甲烷(20mL)溶液加入反 应液，该温度下搅拌3小时。反应液倒入食盐水(15％)中，乙酸乙酯提取，有机相用饱和亚硫酸钠溶液洗涤，有机相浓缩，向残留物中依次加入石油醚(200mL)和乙酸乙酯(10mL)，室温搅拌30分钟，过滤，滤液浓缩得到标题化合物(12g，75％)。 1H NMR(400MHz,CDCl 3)δ3.34(br.s.,4H),1.02(br.s.,4H)。 At room temperature, triphenylphosphine (26.0g, 99.0mmol) and imidazole (6.5g, 96.0mmol) were added into dichloromethane (30mL), the temperature was lowered to 0°C under the protection of argon, and iodine (25.0g, 99.0mmol) was added ), stirred at 0°C for 1 hour. A solution of 1,1-cyclopropane-dimethanol (5.0 g, 48.0 mmol) in dichloromethane (20 mL) was added to the reaction solution, and stirred at this temperature for 3 hours. The reaction solution was poured into brine (15%), extracted with ethyl acetate, the organic phase was washed with saturated sodium sulfite solution, the organic phase was concentrated, petroleum ether (200 mL) and ethyl acetate (10 mL) were added successively to the residue, and stirred at room temperature After 30 minutes, it was filtered and the filtrate was concentrated to give the title compound (12 g, 75%). 1 H NMR (400 MHz, CDCl 3 ) δ 3.34 (br.s., 4H), 1.02 (br.s., 4H).
5-(叔丁基)6-乙基5-氮杂螺[2.4]庚烷-5,6-二羧酸酯5-(tert-butyl)6-ethyl 5-azaspiro[2.4]heptane-5,6-dicarboxylate
Figure PCTCN2022134253-appb-000035
Figure PCTCN2022134253-appb-000035
室温下，将氢化钠(60％，3.0g，75.0mmol)加入N,N-二甲基甲酰胺(40mL)中，氩气保护下降温至0℃，搅拌下滴入1,1-双(碘甲基)环丙烷(9.6g，28.9mmol)和(叔丁氧羰基)甘氨酸乙酯(6.2g，30.5mmol)的N,N-二甲基甲酰胺(40mL)溶液，0℃搅拌1.5小时。加入乙酸(2.5mL)，0℃搅拌2小时。反应液倒入水中，乙酸乙酯提取，有机相浓缩得到标题化合物(4.8g，62％)。MS:m/z[M+H-Boc] +＝170。 At room temperature, sodium hydride (60%, 3.0g, 75.0mmol) was added into N,N-dimethylformamide (40mL), the temperature was lowered to 0°C under the protection of argon, and 1,1-bis( Iodomethyl)cyclopropane (9.6g, 28.9mmol) and (tert-butoxycarbonyl)glycine ethyl ester (6.2g, 30.5mmol) in N,N-dimethylformamide (40mL) solution, stirred at 0°C for 1.5 hours . Acetic acid (2.5 mL) was added and stirred at 0°C for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (4.8 g, 62%). MS: m/z [M+H-Boc] + =170.
(5-氮杂螺[2.4]庚烷-6-基)甲醇盐酸盐(5-Azaspiro[2.4]heptan-6-yl)methanol hydrochloride
Figure PCTCN2022134253-appb-000036
Figure PCTCN2022134253-appb-000036
室温下，将5-(叔丁基)6-乙基5-氮杂螺[2.4]庚烷-5,6-二羧酸酯(540mg，2.0mmol)加入无水四氢呋喃(6mL)中，搅拌下加入硼氢化锂(88mg，4.0mmol)，室温搅拌过夜。反应液用十水硫酸钠淬灭，室温搅拌0.5小时，过滤，滤液浓缩，将残留物加入二氯甲烷(3mL)和氯化氢的乙酸乙酯溶液(4M，6mL)中。室温搅拌30分钟，反应液浓缩得到标题化合物粗品(350mg，107％)。MS:m/z[M+H] +＝128。 At room temperature, add 5-(tert-butyl) 6-ethyl 5-azaspiro[2.4]heptane-5,6-dicarboxylate (540mg, 2.0mmol) into anhydrous tetrahydrofuran (6mL), stir Lithium borohydride (88mg, 4.0mmol) was added under low temperature, and stirred at room temperature overnight. The reaction solution was quenched with sodium sulfate decahydrate, stirred at room temperature for 0.5 hours, filtered, the filtrate was concentrated, and the residue was added to a solution of dichloromethane (3 mL) and hydrogen chloride in ethyl acetate (4M, 6 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated to obtain the crude product of the title compound (350 mg, 107%). MS: m/z [M+H] + =128.
(5-(2,6-二氯嘧啶-4-基)-5-氮杂螺[2.4]庚烷-6-基)甲醇(5-(2,6-dichloropyrimidin-4-yl)-5-azaspiro[2.4]heptane-6-yl)methanol
Figure PCTCN2022134253-appb-000037
Figure PCTCN2022134253-appb-000037
室温下，将2,4,6-三氯嘧啶(760mg，4.18mmol)加入乙腈(12mL)中，氩气保护下冷却至0℃，搅拌下依次加入碳酸钠固体(680mg，6.42mmol)和(5-氮杂螺[2.4]庚烷-6-基)甲醇盐酸盐(350mg，2.14mmol)，室温搅拌1小时。反应液过滤，滤液浓缩，制备薄层色谱分离(石油醚/乙酸乙酯＝4/1)得到标题化合物(140mg，19％)。MS:m/z[M+H] +＝273。 At room temperature, 2,4,6-trichloropyrimidine (760mg, 4.18mmol) was added into acetonitrile (12mL), cooled to 0°C under the protection of argon, and solid sodium carbonate (680mg, 6.42mmol) and ( 5-Azaspiro[2.4]heptan-6-yl)methanol hydrochloride (350 mg, 2.14 mmol), stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was concentrated, and separated by preparative thin-layer chromatography (petroleum ether/ethyl acetate=4/1) to obtain the title compound (140 mg, 19%). MS: m/z [M+H] + =273.
3'-氯-8a',9'-二氢-1'H,6'H,8'H-螺[环丙烷-1,7'-吡咯并[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3'-Chloro-8a',9'-dihydro-1'H,6'H,8'H-spiro[cyclopropane-1,7'-pyrrolo[1',2':3,4]imidazole [1,2-c]pyrimidine]-1'-one
Figure PCTCN2022134253-appb-000038
Figure PCTCN2022134253-appb-000038
室温下，将(5-(2,6-二氯嘧啶-4-基)-5-氮杂螺[2.4]庚烷-6-基)甲醇(140mg，0.51mmol)加入二氯甲烷(6mL)中，搅拌下滴加氯化亚砜(184mg，1.53mmol)，室温搅拌10分钟。反应液浓缩，向残留物中依次加入碳酸钾固体(345mg，2.5mmol)和乙腈(8mL)，85℃搅拌过夜。反应液过滤，滤液浓缩，制备薄层色谱分离(二氯甲烷/甲醇＝20/1)得到标题化合物(80mg，66％)。MS:m/z[M+H] +＝238。 (5-(2,6-Dichloropyrimidin-4-yl)-5-azaspiro[2.4]heptan-6-yl)methanol (140 mg, 0.51 mmol) was added to dichloromethane (6 mL) at room temperature In, thionyl chloride (184mg, 1.53mmol) was added dropwise under stirring, and stirred at room temperature for 10 minutes. The reaction solution was concentrated, solid potassium carbonate (345 mg, 2.5 mmol) and acetonitrile (8 mL) were successively added to the residue, and stirred overnight at 85°C. The reaction solution was filtered, the filtrate was concentrated, and separated by preparative thin-layer chromatography (dichloromethane/methanol=20/1) to obtain the title compound (80 mg, 66%). MS: m/z [M+H] + =238.
中间体4Intermediate 4
5-羟基-6-氧杂-7-氮杂螺[3.5]壬基-7-烯-8-羧酸乙酯5-Hydroxy-6-oxa-7-azaspiro[3.5]nonyl-7-ene-8-carboxylic acid ethyl ester
Figure PCTCN2022134253-appb-000039
Figure PCTCN2022134253-appb-000039
室温下，将环丁烷甲醛(1g，11.9mmol)和吡咯烷(1.1g，15.5mmol)加到无水甲苯(12mL)中，搅拌下加入4A分子筛(0.1g)，室温搅拌2小时。将无水四氢呋喃(12mL)加入反应液，随后分批加入3-溴-2-(羟基亚氨基)丙酸乙酯(2.6g，12.6 mmol，J.Org.Chem.，1982，47，2147)，室温搅拌0.5小时。将三乙胺(1.3g，12.7mmol)加入反应液，室温搅拌过夜。反应液浓缩，柱层析纯化(石油醚/乙酸乙酯＝5/1)，制备薄层色谱纯化(石油醚/乙酸乙酯＝5/1)得到标题化合物(510mg，20％)。 1H NMR(400MHz,DMSO-d 6)δ7.44-7.14(m,1H),5.26(br.s.,1H),4.21(q,J＝6.8Hz,2H),2.56(m,1H),2.32(m,1H),2.09-1.95(m,1H),1.95-1.66(m,4H),1.59(d,J＝10.3Hz,1H),1.25(t,J＝7.1Hz,3H)；MS:m/z[M+H] +＝214。 At room temperature, cyclobutanecarbaldehyde (1 g, 11.9 mmol) and pyrrolidine (1.1 g, 15.5 mmol) were added to anhydrous toluene (12 mL), 4A molecular sieves (0.1 g) were added under stirring, and stirred at room temperature for 2 hours. Anhydrous tetrahydrofuran (12 mL) was added to the reaction solution, followed by adding ethyl 3-bromo-2-(hydroxyimino)propionate (2.6 g, 12.6 mmol, J.Org.Chem., 1982, 47, 2147) in batches , stirred at room temperature for 0.5 hours. Triethylamine (1.3 g, 12.7 mmol) was added to the reaction solution and stirred overnight at room temperature. The reaction solution was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=5/1) and preparative thin layer chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound (510 mg, 20%). 1 H NMR (400MHz,DMSO-d 6 )δ7.44-7.14(m,1H),5.26(br.s.,1H),4.21(q,J=6.8Hz,2H),2.56(m,1H) ,2.32(m,1H),2.09-1.95(m,1H),1.95-1.66(m,4H),1.59(d,J=10.3Hz,1H),1.25(t,J=7.1Hz,3H); MS: m/z [M+H] + =214.
6-氮杂螺[3.4]辛烷-7-羧酸乙酯Ethyl 6-azaspiro[3.4]octane-7-carboxylate
Figure PCTCN2022134253-appb-000040
Figure PCTCN2022134253-appb-000040
室温下，将5-羟基-6-氧杂-7-氮杂螺[3.5]壬基-7-烯-8-羧酸乙酯(510mg，2.4mmol)加入乙醇(30mL)中，氩气保护下加入Raney-Ni催化剂(510mg)，室温常压氢化过夜。过滤，滤液浓缩得到标题化合物粗品(460mg，102％)。 1H NMR(400MHz,DMSO-d 6)δ4.06(d,J＝6.4Hz,2H),3.63(br.s.,1H),2.86(br.s.,1H),2.76(br.s.,1H),2.04(d,J＝8.3Hz,1H),1.96-1.67(m,7H),1.23-1.11(m,3H)；MS:m/z[M+H] +＝184。 Add ethyl 5-hydroxy-6-oxa-7-azaspiro[3.5]nonyl-7-ene-8-carboxylate (510mg, 2.4mmol) into ethanol (30mL) at room temperature, and protect with argon Raney-Ni catalyst (510 mg) was added under low temperature, and the mixture was hydrogenated at room temperature and pressure overnight. After filtration, the filtrate was concentrated to obtain the crude product of the title compound (460 mg, 102%). 1 H NMR (400MHz, DMSO-d 6 ) δ4.06 (d, J=6.4Hz, 2H), 3.63 (br.s., 1H), 2.86 (br.s., 1H), 2.76 (br.s ., 1H), 2.04 (d, J=8.3Hz, 1H), 1.96-1.67 (m, 7H), 1.23-1.11 (m, 3H); MS: m/z[M+H] + =184.
(6-氮杂螺[3.4]辛基-7-基)甲醇(6-Azaspiro[3.4]octyl-7-yl)methanol
Figure PCTCN2022134253-appb-000041
Figure PCTCN2022134253-appb-000041
室温下，将6-氮杂螺[3.4]辛烷-7-羧酸乙酯粗品(360mg，1.97mmol)加到无水四氢呋喃(10mL)和甲醇(1mL)中，缓慢加入硼氢化锂(220mg，5.8mmol)，50℃搅拌2小时。反应液冷却到0℃，反应液用十水硫酸钠淬灭。过滤，滤饼用二氯甲烷淋洗，滤液浓缩得到标题化合物粗品(290mg，105％)。MS:m/z[M+H] +＝142。 At room temperature, crude ethyl 6-azaspiro[3.4]octane-7-carboxylate (360 mg, 1.97 mmol) was added to anhydrous tetrahydrofuran (10 mL) and methanol (1 mL), and lithium borohydride (220 mg , 5.8mmol), stirred at 50°C for 2 hours. The reaction solution was cooled to 0°C, and the reaction solution was quenched with sodium sulfate decahydrate. After filtration, the filter cake was rinsed with dichloromethane, and the filtrate was concentrated to obtain the crude product of the title compound (290 mg, 105%). MS: m/z [M+H] + =142.
(6-(6-氯-2-甲氧基嘧啶-4-基)-6-氮杂螺[3.4]辛基-7-基)甲醇(6-(6-Chloro-2-methoxypyrimidin-4-yl)-6-azaspiro[3.4]octyl-7-yl)methanol
Figure PCTCN2022134253-appb-000042
Figure PCTCN2022134253-appb-000042
室温下，将(6-氮杂螺[3.4]辛基-7-基)甲醇(290mg，2.06mmol)和4,6-二氯-2-甲氧基嘧啶(358mg，2mmol)溶解在异丙醇(20mL)中，搅拌下加入碳酸钠(848mg，8mmol)，80℃搅拌3小时。反应液冷却到室温，用二氯甲烷稀释反应混合物，硅藻土过滤，滤液浓缩，制备薄层色谱分离(石油醚/乙酸乙酯＝2/1)得到标题化合物(160mg，24％)。 1H NMR(400MHz,CDCl 3)δ6.05(br.s.,1H),5.55(br.s.,1H),4.29(br.s.,1H),3.93(s,3H),3.78-3.60(m,2H),3.53-3.42(m,1H),3.39(br.s.,1H),2.17-2.10(m,1H),2.10-1.85(m,7H)；MS:m/z[M+H] +＝284。 Dissolve (6-azaspiro[3.4]octyl-7-yl)methanol (290mg, 2.06mmol) and 4,6-dichloro-2-methoxypyrimidine (358mg, 2mmol) in isopropyl To alcohol (20 mL), sodium carbonate (848 mg, 8 mmol) was added with stirring, and stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature, the reaction mixture was diluted with dichloromethane, filtered through celite, the filtrate was concentrated, and separated by preparative thin-layer chromatography (petroleum ether/ethyl acetate=2/1) to obtain the title compound (160mg, 24%). 1 H NMR (400MHz, CDCl 3 )δ6.05(br.s.,1H),5.55(br.s.,1H),4.29(br.s.,1H),3.93(s,3H),3.78- 3.60(m,2H),3.53-3.42(m,1H),3.39(br.s.,1H),2.17-2.10(m,1H),2.10-1.85(m,7H); MS: m/z[ M+H] + = 284.
3'-氯-8a',9'-二氢-1'H,6'H,8'H-螺[环丁烷-1,7'-吡咯并[1',2':3,4]咪唑并[1,2-c]嘧啶]-1'-酮3'-chloro-8a',9'-dihydro-1'H,6'H,8'H-spiro[cyclobutane-1,7'-pyrrolo[1',2':3,4] imidazo[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000043
Figure PCTCN2022134253-appb-000043
室温下，将(6-(6-氯-2-甲氧基嘧啶-4-基)-6-氮杂螺[3.4]辛基-7-基)甲醇(140mg，0.49mmol)和氯化亚砜(176mg，1.48mmol)加入到二氯甲烷(3mL)中，室温搅拌过夜。反应液浓缩并溶解在水(2mL)中，0℃下加入氢氧化钠固体(78mg，1.96mmol)，0℃搅拌0.5小时。反应液倒入水中，用二氯甲烷萃取，有机相浓缩，制备薄层色谱分离(二氯甲烷/甲醇＝40/1)得到白色固体标题化合物(47mg，38％)。 1H NMR(400MHz,CDCl 3)δ5.60(s,1H),4.22(d,J＝7.8Hz,2H),4.09-3.97(m,1H),3.47(d,J＝10.8Hz,1H),3.23(d,J＝10.8Hz,1H),2.37-2.27(m,1H),2.18-1.88(m,7H)；MS:m/z[M+H] +＝252。 At room temperature, (6-(6-chloro-2-methoxypyrimidin-4-yl)-6-azaspiro[3.4]octyl-7-yl)methanol (140mg, 0.49mmol) and chlorinated Sulfone (176 mg, 1.48 mmol) was added into dichloromethane (3 mL), and stirred at room temperature overnight. The reaction solution was concentrated and dissolved in water (2 mL), and solid sodium hydroxide (78 mg, 1.96 mmol) was added at 0°C, and stirred at 0°C for 0.5 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and separated by preparative thin-layer chromatography (dichloromethane/methanol=40/1) to obtain the title compound (47 mg, 38%) as a white solid. 1 H NMR (400MHz, CDCl 3 ) δ5.60(s, 1H), 4.22(d, J=7.8Hz, 2H), 4.09-3.97(m, 1H), 3.47(d, J=10.8Hz, 1H) , 3.23 (d, J=10.8 Hz, 1H), 2.37-2.27 (m, 1H), 2.18-1.88 (m, 7H); MS: m/z[M+H] + =252.
中间体5Intermediate 5
2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3-甲烯基哌啶-1-羧酸叔丁酯2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methenylpiperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2022134253-appb-000044
Figure PCTCN2022134253-appb-000044
室温下，将甲基三苯基溴化磷(407mg，1.14mmol)加入无水四氢呋喃(10mL)中，氩气保护下降温至0℃，滴加正丁基锂的正己烷溶液(2.5M，0.456mL，1.14mmL)，0℃搅拌0.5小时。将2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3-氧代哌啶-1-羧酸叔丁酯(300mg，0.87mmol，Bioorganic and Medicinal Chemistry Letters,2017,27,2210-2215)的无水四氢呋喃(10mL)溶液缓慢滴入反应液中，室温搅拌过夜。反应液冷却到0℃，加入饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相浓缩，制备薄层色谱分离(二氯甲烷/甲醇＝100/1)得到标题化合物(92mg，29％)。MS:m/z[M+H-Boc] +＝242。 At room temperature, methyl triphenylphosphine bromide (407mg, 1.14mmol) was added into anhydrous tetrahydrofuran (10mL), the temperature was lowered to 0°C under the protection of argon, and n-butyllithium in n-hexane (2.5M, 0.456mL, 1.14mmL), stirred at 0°C for 0.5 hours. 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxopiperidine-1-carboxylic acid tert-butyl ester (300mg, 0.87mmol, Bioorganic and Medicinal Chemistry Letters, 2017 , 27,2210-2215) in anhydrous tetrahydrofuran (10 mL) was slowly dropped into the reaction solution, and stirred overnight at room temperature. The reaction solution was cooled to 0°C, quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, concentrated the organic phase, and separated by preparative thin-layer chromatography (dichloromethane/methanol=100/1) to obtain the title compound (92mg, 29%) . MS: m/z [M+H-Boc] + =242.
(5-氮杂螺[2.5]辛基-4-基)甲醇盐酸盐(5-Azaspiro[2.5]octyl-4-yl)methanol hydrochloride
Figure PCTCN2022134253-appb-000045
Figure PCTCN2022134253-appb-000045
室温下，将2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3-甲烯基哌啶-1-羧酸叔丁酯(82mg，0.24mmol)和二乙基锌的正己烷溶液(1M，2.4mL，2.4mmL)加入二氯甲烷(20mL)中，氩气保护下冷却到0℃，滴加二碘甲烷(1.3g，4.8mmol)，滴加完后室温搅拌过夜。反应液冷却到0℃，反应液用十水硫酸钠淬灭，过滤，滤饼用二氯甲烷淋洗，滤液浓缩，向残留物中依次加入甲醇(2mL)和氯化氢的乙酸乙酯溶液(4M，1mL)，室温搅拌5小时。反应液浓缩得到标题化合物粗品(90mg，211％)。MS:m/z[M+H] +＝142。 At room temperature, tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methenylpiperidine-1-carboxylate (82 mg, 0.24 mmol) and diethyl The n-hexane solution (1M, 2.4mL, 2.4mmL) of base zinc was added into dichloromethane (20mL), cooled to 0°C under the protection of argon, and diiodomethane (1.3g, 4.8mmol) was added dropwise. Stir overnight at room temperature. The reaction solution was cooled to 0°C, the reaction solution was quenched with sodium sulfate decahydrate, filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, methanol (2 mL) and hydrogen chloride in ethyl acetate (4M , 1 mL), stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain the crude product of the title compound (90 mg, 211%). MS: m/z [M+H] + =142.
(5-(6-氯-2-甲氧基嘧啶-4-基)-5-氮杂螺[2.5]辛基-4-基)甲醇(5-(6-Chloro-2-methoxypyrimidin-4-yl)-5-azaspiro[2.5]octyl-4-yl)methanol
Figure PCTCN2022134253-appb-000046
Figure PCTCN2022134253-appb-000046
室温下，将(5-氮杂螺[2.5]辛基-4-基)甲醇盐酸盐粗品(90mg，0.51mmol)、4,6-二氯-2-甲氧基嘧啶(90mg，0.39mmol)和碳酸钠固体(127mg，1.2mmol)加入异丙醇(5mL)中，80℃搅拌2天。反应液冷却到室温后倒入水中，二氯甲烷提取，有机相浓缩，制备薄层色谱分离(石油醚/乙酸乙酯＝2/1)得到标题化合物(20mg，14％)。 1H NMR(400MHz,CDCl 3)δ6.24(s,1H),4.79-4.50(m,2H),4.01(br.s.,1H),3.88(s,3H),3.81(d,J＝7.3Hz,1H),3.14(d,J＝7.3Hz,1H),2.19-1.93(m,2H),1.74(br.s.,1H),1.71-1.59(m,1H),0.88-0.76(m,1H),0.68-0.49(m,1H),0.47-0.36(m,1H),0.21(br.s.,1H)；MS:m/z[M+H] +＝284。 At room temperature, (5-azaspiro[2.5]octyl-4-yl)methanol hydrochloride crude product (90mg, 0.51mmol), 4,6-dichloro-2-methoxypyrimidine (90mg, 0.39mmol ) and solid sodium carbonate (127mg, 1.2mmol) were added to isopropanol (5mL), stirred at 80°C for 2 days. The reaction solution was cooled to room temperature and poured into water, extracted with dichloromethane, concentrated the organic phase, and separated by preparative thin-layer chromatography (petroleum ether/ethyl acetate=2/1) to obtain the title compound (20 mg, 14%). 1 H NMR (400MHz, CDCl 3 ) δ6.24(s, 1H), 4.79-4.50(m, 2H), 4.01(br.s., 1H), 3.88(s, 3H), 3.81(d, J= 7.3Hz, 1H), 3.14(d, J=7.3Hz, 1H), 2.19-1.93(m, 2H), 1.74(br.s., 1H), 1.71-1.59(m, 1H), 0.88-0.76( m,1H), 0.68-0.49(m,1H), 0.47-0.36(m,1H), 0.21(br.s.,1H); MS: m/z[M+H] + =284.
3'-氯-7',8',9a',10'-四氢-1'H,6'H-螺环[1,9'-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶]-1'-酮3'-Chloro-7',8',9a',10'-tetrahydro-1'H,6'H-spiro[1,9'-pyrido[1',2':3,4]imidazole And[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000047
Figure PCTCN2022134253-appb-000047
室温下，将(5-(6-氯-2-甲氧基嘧啶-4-基)-5-氮杂螺[2.5]辛基-4-基)甲醇(20mg，0.07mmol)和氯化亚砜(26mg，0.22mmol)加入到二氯甲烷(3mL)中，室温搅拌过夜。反应液浓缩，向残留物中加入水(2mL)，冷却至0℃，搅拌下加入氢氧化钠固体(11mg，0.28mmol)。0℃搅拌0.5小时。反应液倒入水中，二氯甲烷萃取，有机相浓缩得到标题化合物粗品(24mg，113％)。MS:m/z[M+H] +＝252。 At room temperature, (5-(6-chloro-2-methoxypyrimidin-4-yl)-5-azaspiro[2.5]octyl-4-yl)methanol (20mg, 0.07mmol) and chlorinated Sulfone (26 mg, 0.22 mmol) was added into dichloromethane (3 mL), and stirred at room temperature overnight. The reaction solution was concentrated, water (2 mL) was added to the residue, cooled to 0°C, and solid sodium hydroxide (11 mg, 0.28 mmol) was added with stirring. Stir at 0°C for 0.5 hours. The reaction solution was poured into water, extracted with dichloromethane, and the organic phase was concentrated to obtain the crude product of the title compound (24 mg, 113%). MS: m/z [M+H] + =252.
中间体6Intermediate 6
3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯tert-Butyl 3-azaspiro[5.5]undecane-3-carboxylate
Figure PCTCN2022134253-appb-000048
Figure PCTCN2022134253-appb-000048
室温下，将3-氮杂螺[5.5]十一烷(900mg，5.87mmol)、二碳酸二叔丁酯(1.92g，8.81mmol)和碳酸钠(1.87g，17.61mmol)依次加入二氯甲烷(10mL)中，室温下搅拌5小时。反应液倒入水中，二氯甲烷提取，有机相浓缩，柱层析纯化得到标题化合物(1.62g，94％)。MS:m/z[M+H-tBu] +＝198。 At room temperature, 3-azaspiro[5.5]undecane (900mg, 5.87mmol), di-tert-butyl dicarbonate (1.92g, 8.81mmol) and sodium carbonate (1.87g, 17.61mmol) were sequentially added to dichloromethane (10 mL), stirred at room temperature for 5 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (1.62 g, 94%). MS: m/z [M+H-tBu] + =198.
2-甲酰基-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯tert-Butyl 2-formyl-3-azaspiro[5.5]undecane-3-carboxylate
Figure PCTCN2022134253-appb-000049
Figure PCTCN2022134253-appb-000049
氩气保护下，将3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1g，3.95mmol)和四甲基乙二胺(458mg，3.95mmol)加入无水四氢呋喃(10mL)中，氩气保护下降温至-60℃，滴加仲丁基锂的正己烷溶液(1.3M，3.03mL，3.95mmol)，-50℃～-20℃搅拌0.5小时。反应液降温至-60℃，滴加N,N-二甲基甲酰胺(432mg，5.93mmol)，-50℃搅拌1小时，室温搅拌1小时。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(563mg，51％)。MS:m/z[M+H-tBu] +＝226。 Under the protection of argon, tert-butyl 3-azaspiro[5.5]undecane-3-carboxylate (1g, 3.95mmol) and tetramethylethylenediamine (458mg, 3.95mmol) were added into anhydrous tetrahydrofuran (10mL ), the temperature was lowered to -60°C under the protection of argon, a n-hexane solution of sec-butyllithium (1.3M, 3.03mL, 3.95mmol) was added dropwise, and stirred at -50°C to -20°C for 0.5 hours. The reaction solution was cooled to -60°C, N,N-dimethylformamide (432mg, 5.93mmol) was added dropwise, stirred at -50°C for 1 hour, and at room temperature for 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (563 mg, 51%). MS: m/z [M+H-tBu] + =226.
2-(羟甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯tert-butyl 2-(hydroxymethyl)-3-azaspiro[5.5]undecane-3-carboxylate
Figure PCTCN2022134253-appb-000050
Figure PCTCN2022134253-appb-000050
室温下，将2-甲酰基-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(460mg，1.64mmol)加入乙醇(5mL)中，搅拌下加入硼氢化钠(124mg，3.27mmol)，室温搅拌2小时。反应液用饱和氯化铵水溶液淬灭后倒入水中，乙酸乙酯提取，有机相浓缩得到标题化合物(430mg，93％)。MS:m/z[M+H-tBu] +＝228。 At room temperature, tert-butyl 2-formyl-3-azaspiro[5.5]undecane-3-carboxylate (460 mg, 1.64 mmol) was added to ethanol (5 mL), and sodium borohydride (124 mg, 3.27mmol), stirred at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (430 mg, 93%). MS: m/z [M+H-tBu] + =228.
(3-(2,6-二氯嘧啶-4-基)-3-氮杂螺环[5.5]十一烷-2-基)甲醇(3-(2,6-Dichloropyrimidin-4-yl)-3-azaspiro[5.5]undecane-2-yl)methanol
Figure PCTCN2022134253-appb-000051
Figure PCTCN2022134253-appb-000051
室温下，将2-(羟甲基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(430mg，1.52mmol)加入二氯甲烷(3mL)中，搅拌下加入氯化氢的乙酸乙酯溶液(4M，1.9mL)，室温搅拌2小时。反应液浓缩，向残留物中依次加入乙腈(5mL)和碳酸钠(483mg，4.56mmol)，85℃搅拌过夜。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，制备薄层色谱分离得到标题化合物(410mg，8 2％)。MS:m/z[M+H] +＝330。 At room temperature, tert-butyl 2-(hydroxymethyl)-3-azaspiro[5.5]undecane-3-carboxylate (430 mg, 1.52 mmol) was added into dichloromethane (3 mL), and hydrogen chloride was added under stirring A solution of ethyl acetate (4M, 1.9 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated, and acetonitrile (5 mL) and sodium carbonate (483 mg, 4.56 mmol) were successively added to the residue, and stirred overnight at 85°C. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and separated by preparative thin-layer chromatography to obtain the title compound (410 mg, 82%). MS: m/z [M+H] + = 330.
3'-氯-6',7',9a',10'-四氢-1'H,9'H-螺[环己烷-1,8'-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶]-1'-酮3'-chloro-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[cyclohexane-1,8'-pyrido[1',2':3, 4] imidazo[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000052
Figure PCTCN2022134253-appb-000052
室温下，将(3-(2,6-二氯嘧啶-4-基)-3-氮杂螺环[5.5]十一烷-2-基)甲醇(360mg，1.09mmol)加入二氯甲烷(5mL)中，搅拌下加入氯化亚砜(389mg，3.27mmol)，室温搅拌1小时。反应液浓缩，向残留物中依次加入乙腈(5mL)和碳酸钾(451mg，3.1mmol)，85℃搅拌过夜。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，制备薄层色谱纯化得到标题化合物(220mg，60％)。MS:m/z[M+H] +＝294。 (3-(2,6-Dichloropyrimidin-4-yl)-3-azaspiro[5.5]undec-2-yl)methanol (360 mg, 1.09 mmol) was added to dichloromethane ( 5 mL), thionyl chloride (389 mg, 3.27 mmol) was added under stirring, and stirred at room temperature for 1 hour. The reaction solution was concentrated, acetonitrile (5 mL) and potassium carbonate (451 mg, 3.1 mmol) were successively added to the residue, and stirred overnight at 85°C. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by preparative thin-layer chromatography to obtain the title compound (220 mg, 60%). MS: m/z [M+H] + =294.
中间体7Intermediate 7
1,1-二氯-2-氧代-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯tert-butyl 1,1-dichloro-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000053
Figure PCTCN2022134253-appb-000053
室温下，将4-亚甲基哌啶-1-羧酸叔丁酯(49g，248.4mmol)和锌铜试剂(49g) 依次加入无水乙二醇二甲醚(500mL)中，控温30℃-40℃，滴加三氯乙酰氯(49.4g，273.2mmol)，室温搅拌3小时。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，柱层析纯化得到标题化合物(38.6g，50％)。MS:m/z[M+H-tBu] +＝252。 At room temperature, tert-butyl 4-methylenepiperidine-1-carboxylate (49g, 248.4mmol) and zinc copper reagent (49g) were successively added to anhydrous ethylene glycol dimethyl ether (500mL), and the temperature was controlled for 30 From ℃ to 40℃, trichloroacetyl chloride (49.4 g, 273.2 mmol) was added dropwise, and stirred at room temperature for 3 hours. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by column chromatography to obtain the title compound (38.6 g, 50%). MS: m/z [M+H-tBu] + =252.
2-氧代-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000054
Figure PCTCN2022134253-appb-000054
室温下，依次将1,1-二氯-2-氧代-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(37g，120.1mmol)加入饱和氯化铵水溶液(200mL)和甲醇(200mL)中，氩气保护下降温至0℃，分批加入锌粉(37g，565.8mmol)，室温搅拌过夜。反应液过滤，滤饼用乙酸乙酯淋洗，有机相浓缩，柱层析纯化得到标题化合物(24.2g，84％)。MS:m/z[M+H-tBu] +＝184。 At room temperature, successively add tert-butyl 1,1-dichloro-2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (37g, 120.1mmol) into saturated aqueous ammonium chloride (200mL ) and methanol (200mL), the temperature was lowered to 0°C under the protection of argon, and zinc powder (37g, 565.8mmol) was added in batches, and stirred overnight at room temperature. The reaction solution was filtered, the filter cake was rinsed with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (24.2 g, 84%). MS: m/z [M+H-tBu] + =184.
7-氮杂螺[3.5]壬烷7-Azaspiro[3.5]nonane
Figure PCTCN2022134253-appb-000055
Figure PCTCN2022134253-appb-000055
室温下，将2-氧代-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(5g，20.92mmol)加入聚乙二醇(50mL)中，搅拌下加入水合肼(7.32g，146.44mmol)和氢氧化钾固体(7.03g，125.52mmol)，200℃搅拌4小时。反应液冷却至室温后倒入水中，***提取，有机相浓缩得到标题化合物(3.32g，126％)。MS:m/z[M+H] +＝126。 At room temperature, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5 g, 20.92 mmol) was added to polyethylene glycol (50 mL), and hydrazine hydrate ( 7.32g, 146.44mmol) and potassium hydroxide solid (7.03g, 125.52mmol), stirred at 200°C for 4 hours. The reaction solution was cooled to room temperature and poured into water, extracted with ether, and the organic phase was concentrated to obtain the title compound (3.32 g, 126%). MS: m/z [M+H] + =126.
7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯tert-Butyl 7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000056
Figure PCTCN2022134253-appb-000056
室温下，将7-氮杂螺[3.5]壬烷(2.8g，22.4mmol)加入二氯甲烷(50mL)中， 搅拌下依次加入二碳酸二叔丁酯(7.32g，33.6mmol)和碳酸钾(9.27g，67.3mmol)，室温下搅拌过夜。反应液倒入水中，二氯甲烷提取，有机相浓缩，柱层析纯化得到标题化合物(4.5g，89％)。MS:m/z[M+H-tBu] +＝170。 At room temperature, 7-azaspiro[3.5]nonane (2.8g, 22.4mmol) was added into dichloromethane (50mL), and di-tert-butyl dicarbonate (7.32g, 33.6mmol) and potassium carbonate were added successively under stirring (9.27g, 67.3mmol), stirred overnight at room temperature. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (4.5 g, 89%). MS: m/z [M+H-tBu] + =170.
6-甲酰基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯tert-butyl 6-formyl-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000057
Figure PCTCN2022134253-appb-000057
室温下，依次将四甲基乙二胺(1.03g，8.89mmol)和7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(2g，8.89mmol)加入无水四氢呋喃(20mL)中，氩气保护下降温至-60℃，搅拌下滴加仲丁基锂的正己烷溶液(1.3M，6.84mL，8.89mmol)，滴加结束-20℃搅拌30分钟。反应液降温至-60℃，滴加N,N-二甲基甲酰胺(973mg，13.3mmol)，滴加结束-60℃搅拌1小时，室温搅拌2小时。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(0.83g，37％)。MS:m/z[M+H-tBu] +＝198。 At room temperature, tetramethylethylenediamine (1.03g, 8.89mmol) and tert-butyl 7-azaspiro[3.5]nonane-7-carboxylate (2g, 8.89mmol) were successively added into anhydrous THF (20mL) , the temperature was lowered to -60°C under the protection of argon, and a n-hexane solution of sec-butyllithium (1.3M, 6.84mL, 8.89mmol) was added dropwise with stirring, and the addition was completed and stirred at -20°C for 30 minutes. The reaction solution was cooled to -60°C, N,N-dimethylformamide (973mg, 13.3mmol) was added dropwise, and the mixture was stirred at -60°C for 1 hour and at room temperature for 2 hours after the addition. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (0.83 g, 37%). MS: m/z [M+H-tBu] + =198.
6-(羟甲基)-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯tert-butyl 6-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000058
Figure PCTCN2022134253-appb-000058
室温下，将6-甲酰基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1.63g，6.4mmol)加入无水乙醇(10mL)中，搅拌下加入硼氢化钠(487mg，12.8mmol)，室温搅拌2小时。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯提取，有机相浓缩得到标题化合物(1.43g，87％)。MS:m/z[M+H-tBu] +＝200。 At room temperature, tert-butyl 6-formyl-7-azaspiro[3.5]nonane-7-carboxylate (1.63 g, 6.4 mmol) was added into absolute ethanol (10 mL), and sodium borohydride ( 487mg, 12.8mmol), stirred at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (1.43 g, 87%). MS: m/z [M+H-tBu] + =200.
(7-(6-氯-2-甲氧基嘧啶-4-基)-7-氮杂螺[3.5]壬烷-6-基)甲醇(7-(6-Chloro-2-methoxypyrimidin-4-yl)-7-azaspiro[3.5]nonan-6-yl)methanol
Figure PCTCN2022134253-appb-000059
Figure PCTCN2022134253-appb-000059
室温下，将6-(羟甲基)-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1.43g，6.4mmol)加入二氯甲烷(100mL)中，搅拌下加入氯化氢的乙酸乙酯溶液(4M，27.8mL)，室温搅拌1小时。反应液浓缩，向残留物中依次加入乙腈(10mL)、4,6-二氯-2-甲氧基嘧啶(2.29g，12.8mmol)和碳酸钠(2.32g,21.87mmol)，85℃搅拌16小时。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，柱层析纯化得到标题化合物(0.783g，35％)。MS:m/z[M+H] +＝298。 At room temperature, add tert-butyl 6-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.43g, 6.4mmol) into dichloromethane (100mL), and add hydrogen chloride under stirring A solution of ethyl acetate (4M, 27.8 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated, and acetonitrile (10 mL), 4,6-dichloro-2-methoxypyrimidine (2.29 g, 12.8 mmol) and sodium carbonate (2.32 g, 21.87 mmol) were successively added to the residue, and stirred at 85°C for 16 Hour. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by column chromatography to obtain the title compound (0.783 g, 35%). MS: m/z [M+H] + =298.
3'-氯-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3'-chloro-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[cyclobutane-1,8'-pyridine[1',2':3, 4] imidazol[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000060
Figure PCTCN2022134253-appb-000060
室温下，将(7-(6-氯-2-甲氧基嘧啶-4-基)-7-氮杂螺[3.5]壬烷-6-基)甲醇(100mg，0.33mmol)加入二氯甲烷(5mL)中，搅拌下加入氯化亚砜(118mg，0.99mmol)，室温搅拌1小时。反应液浓缩，向残留物中依次加入乙腈(5mL)和碳酸钾(182mg，1.32mmol)，85℃搅拌过夜。反应液过滤，滤液浓缩，制备薄层色谱纯化得到标题化合物(38mg，43％)。MS:m/z[M+H] +＝266。 (7-(6-Chloro-2-methoxypyrimidin-4-yl)-7-azaspiro[3.5]nonan-6-yl)methanol (100 mg, 0.33 mmol) was added to dichloromethane at room temperature (5 mL), add thionyl chloride (118 mg, 0.99 mmol) with stirring, and stir at room temperature for 1 hour. The reaction solution was concentrated, and acetonitrile (5 mL) and potassium carbonate (182 mg, 1.32 mmol) were successively added to the residue, and stirred overnight at 85°C. The reaction liquid was filtered, the filtrate was concentrated, and purified by preparative thin-layer chromatography to obtain the title compound (38 mg, 43%). MS: m/z [M+H] + = 266.
中间体8Intermediate 8
8-氮杂螺环[4.5]癸烷-8-羧酸叔丁酯8-Azaspiro[4.5]decane-8-carboxylate tert-butyl ester
Figure PCTCN2022134253-appb-000061
Figure PCTCN2022134253-appb-000061
室温下，将8-氮杂螺[4.5]癸烷盐酸盐(1g，7.18mmol)加入二氯甲烷(10mL)中，搅拌下依次加入二碳酸二叔丁酯(2.35g，10.77mmol)和碳酸钾(2.98g，21.54 mmol)，室温搅拌过夜。反应液倒入水中，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(1.41g，82％)。MS:m/z[M+H-tBu] +＝184。 At room temperature, 8-azaspiro[4.5]decane hydrochloride (1g, 7.18mmol) was added into dichloromethane (10mL), and di-tert-butyl dicarbonate (2.35g, 10.77mmol) and Potassium carbonate (2.98 g, 21.54 mmol), stirred overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (1.41 g, 82%). MS: m/z [M+H-tBu] + =184.
7-甲酰基-8-氮杂螺环[4.5]癸烷-8-羧酸叔丁酯tert-butyl 7-formyl-8-azaspiro[4.5]decane-8-carboxylate
Figure PCTCN2022134253-appb-000062
Figure PCTCN2022134253-appb-000062
室温下，依次将四甲基乙二胺(0.65g，5.56mmol)和8-氮杂螺环[4.5]癸烷-8-羧酸叔丁酯(1.33g，5.56mmol)加入无水四氢呋喃(10mL)中，氩气保护下降温至-60℃，搅拌下滴加仲丁基锂的正己烷溶液(1.3M，5.56mL，7.23mmol)，滴加结束-20℃搅拌30分钟。反应液降温至-60℃，滴加N,N-二甲基甲酰胺(610mg，8.34mmol)，-60℃搅拌1小时，室温搅拌2小时。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(0.132g，9％)。MS:m/z[M+H-tBu] +＝212。 At room temperature, sequentially add tetramethylethylenediamine (0.65g, 5.56mmol) and tert-butyl 8-azaspiro[4.5]decane-8-carboxylate (1.33g, 5.56mmol) into anhydrous tetrahydrofuran ( 10 mL), under the protection of argon, the temperature was lowered to -60°C, and a n-hexane solution of sec-butyllithium (1.3M, 5.56mL, 7.23mmol) was added dropwise with stirring, and the addition was completed and stirred at -20°C for 30 minutes. The reaction solution was cooled to -60°C, N,N-dimethylformamide (610mg, 8.34mmol) was added dropwise, stirred at -60°C for 1 hour, and at room temperature for 2 hours. The reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (0.132 g, 9%). MS: m/z [M+H-tBu] + =212.
7-(羟甲基)-8-氮杂螺环[4.5]癸烷-8-羧酸叔丁酯tert-butyl 7-(hydroxymethyl)-8-azaspiro[4.5]decane-8-carboxylate
Figure PCTCN2022134253-appb-000063
Figure PCTCN2022134253-appb-000063
室温下，将7-甲酰基-8-氮杂螺环[4.5]癸烷-8-羧酸叔丁酯(132mg，0.49mmol)加入无水甲醇(10mL)中，搅拌下加入硼氢化钠(92.68mg，2.45mmol)，室温搅拌3小时。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯提取，有机相浓缩得到标题化合物(130mg，98％)。MS:m/z[M+H-tBu] +＝214。 At room temperature, tert-butyl 7-formyl-8-azaspiro[4.5]decane-8-carboxylate (132 mg, 0.49 mmol) was added into anhydrous methanol (10 mL), and sodium borohydride ( 92.68mg, 2.45mmol), stirred at room temperature for 3 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (130 mg, 98%). MS: m/z [M+H-tBu] + =214.
(8-(6-氯-2-甲氧基嘧啶-4-基)-8-氮杂螺环[4.5]癸烷-7-基)甲醇(8-(6-Chloro-2-methoxypyrimidin-4-yl)-8-azaspiro[4.5]decane-7-yl)methanol
Figure PCTCN2022134253-appb-000064
Figure PCTCN2022134253-appb-000064
室温下，将6-(羟甲基)-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(51mg，0.19mmol)加入二氯甲烷(3mL)中，搅拌下加入氯化氢的乙酸乙酯溶液(4M，0.25mL)，室温搅拌3小时。反应液浓缩，向残留物中依次加入乙腈(10mL)、4,6-二氯-2-甲氧基嘧啶(68mg，0.38mmol)和碳酸钠(165mg，1.56mmol)，85℃搅拌过夜。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，制备薄层色谱分离得到标题化合物(55mg，93％)。MS:m/z[M+H] +＝312。 At room temperature, tert-butyl 6-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (51 mg, 0.19 mmol) was added into dichloromethane (3 mL), and hydrogen chloride was added under stirring Ethyl acetate solution (4M, 0.25 mL), stirred at room temperature for 3 hours. The reaction solution was concentrated, and acetonitrile (10 mL), 4,6-dichloro-2-methoxypyrimidine (68 mg, 0.38 mmol) and sodium carbonate (165 mg, 1.56 mmol) were successively added to the residue, and stirred overnight at 85°C. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and separated by preparative thin-layer chromatography to obtain the title compound (55 mg, 93%). MS: m/z [M+H] + = 312.
3'-氯-6',7',9a',10'-四氢-1'H,9'H-螺环[环戊烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3'-chloro-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[cyclopentane-1,8'-pyridine[1',2':3, 4] imidazol[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000065
Figure PCTCN2022134253-appb-000065
室温下，将(8-(6-氯-2-甲氧基嘧啶-4-基)-8-氮杂螺环[4.5]癸烷-7-基)甲醇(55mg，0.18mmol)加入二氯甲烷(5mL)中，搅拌下加入氯化亚砜(64mg，0.54mmol)，室温搅拌1小时。反应液浓缩，向残留物中依次加入水(5mL)和氢氧化钠水溶液(15％，186mg)，室温搅拌0.5小时。反应液用二氯甲烷提取，有机相浓缩得到标题化合物(28mg，72％)。MS:m/z[M+H] +＝280。 (8-(6-Chloro-2-methoxypyrimidin-4-yl)-8-azaspiro[4.5]decane-7-yl)methanol (55 mg, 0.18 mmol) was added to dichloro Thionyl chloride (64 mg, 0.54 mmol) was added to methane (5 mL) with stirring, and stirred at room temperature for 1 hour. The reaction solution was concentrated, water (5 mL) and aqueous sodium hydroxide solution (15%, 186 mg) were successively added to the residue, and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was extracted with dichloromethane, and the organic phase was concentrated to obtain the title compound (28 mg, 72%). MS: m/z [M+H] + =280.
中间体8Intermediate 8
2-羟基-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯tert-Butyl 2-Hydroxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000066
Figure PCTCN2022134253-appb-000066
室温下，将2-氧代-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(5g，20.89mmol)加 入甲醇(50mL)中，搅拌下加入硼氢化钠(2.37g，62.67mmol)，室温搅拌5小时。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯提取，有机相浓缩得到标题化合物(4.93g，98％)。MS:m/z[M+H-tBu] +＝186。 At room temperature, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5g, 20.89mmol) was added into methanol (50mL), and sodium borohydride (2.37g , 62.67mmol), stirred at room temperature for 5 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (4.93 g, 98%). MS: m/z [M+H-tBu] + =186.
2-((叔丁基二甲基甲硅烷基)氧基)-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯tert-butyl 2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000067
Figure PCTCN2022134253-appb-000067
室温下，依次将2-羟基-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(4.83g，20.01mmol)和咪唑(2.72g，40.02mmol)加入二氯甲烷(50mL)中，搅拌下加入叔丁基二甲基氯硅烷(4.52g，30.01mmol)，室温搅拌3小时。反应液倒入水中，二氯甲烷提取，有机相浓缩，柱层析纯化得到标题化合物(6.8g，96％)。MS:m/z[M+H-tBu] +＝300。 At room temperature, tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (4.83g, 20.01mmol) and imidazole (2.72g, 40.02mmol) were successively added into dichloromethane (50mL ), tert-butyldimethylsilyl chloride (4.52 g, 30.01 mmol) was added under stirring, and stirred at room temperature for 3 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (6.8 g, 96%). MS: m/z [M+H-tBu] + = 300.
2-((叔丁基二甲基硅基)氧基)-6-甲酰基-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯tert-butyl 2-((tert-butyldimethylsilyl)oxy)-6-formyl-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000068
Figure PCTCN2022134253-appb-000068
室温下，依次将四甲基乙二胺(0.69g，5.91mmol)和2-((叔丁基二甲基甲硅烷基)氧基)-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(2.1g，5.91mmol)加入无水四氢呋喃(15mL)中，氩气保护下降温至-60℃，搅拌下滴加仲丁基锂的正己烷溶液(1.3M，4.55mL，5.91mmol)，滴加结束-20℃搅拌30分钟。反应液降温至-60℃，滴加N,N-二甲基甲酰胺(650mg，8.87mmol)，滴加结束-60℃搅拌1小时，室温搅拌2小时。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(2.2g，97％)。MS:m/z[M+H-tBu] +＝328。 At room temperature, tetramethylethylenediamine (0.69g, 5.91mmol) and 2-((tert-butyldimethylsilyl)oxy)-7-azaspiro[3.5]nonane-7- Add tert-butyl carboxylate (2.1g, 5.91mmol) into anhydrous tetrahydrofuran (15mL), lower the temperature to -60°C under the protection of argon, and add a n-hexane solution of sec-butyllithium dropwise (1.3M, 4.55mL, 5.91 mmol), and stirred at -20°C for 30 minutes at the end of the dropwise addition. The reaction solution was cooled to -60°C, N,N-dimethylformamide (650mg, 8.87mmol) was added dropwise, and the mixture was stirred at -60°C for 1 hour and then at room temperature for 2 hours. The reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (2.2 g, 97%). MS: m/z [M+H-tBu] + =328.
2-(叔丁基二甲基硅基)氧基)-6-(羟甲基)-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯tert-butyl 2-(tert-butyldimethylsilyl)oxy)-6-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000069
Figure PCTCN2022134253-appb-000069
室温下，将2-((叔丁基二甲基硅基)氧基)-6-甲酰基-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(310mg，0.81mmol)加入无水甲醇(3mL)中，搅拌下加入硼氢化钠(91mg，2.43mmol)，室温搅拌3小时，反应液用饱和氯化铵水溶液淬灭，乙酸乙酯提取，有机相浓缩得到标题化合物(298mg，95％)。MS:m/z[M+H-tBu] +＝330。 At room temperature, tert-butyl 2-((tert-butyldimethylsilyl)oxy)-6-formyl-7-azaspiro[3.5]nonane-7-carboxylate (310mg, 0.81mmol ) was added into anhydrous methanol (3mL), sodium borohydride (91mg, 2.43mmol) was added under stirring, stirred at room temperature for 3 hours, the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (298 mg, 95%). MS: m/z [M+H-tBu] + =330.
(2-((叔丁基二甲基硅基)氧基)-7-(6-氯-2-甲氧基嘧啶-4-基)-7-氮杂螺环[3.5]壬烷-6-基)甲醇(2-((tert-butyldimethylsilyl)oxy)-7-(6-chloro-2-methoxypyrimidin-4-yl)-7-azaspiro[3.5]nonane-6 -yl)methanol
Figure PCTCN2022134253-appb-000070
Figure PCTCN2022134253-appb-000070
室温下，将2-(叔丁基二甲基硅基)氧基)-6-(羟甲基)-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(296mg，0.77mmol)加入二氯甲烷(10mL)和三氟乙酸(1mL)中，室温搅拌1小时。加入碳酸钾(320mg，2.31mmol)，室温搅拌0.5小时。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩。向残留物中依次加入乙腈(5mL)、4,6-二氯-2-甲氧基嘧啶(196mg，1.06mmol)和碳酸钠(169mg，1.59mmol)，85℃搅拌过夜。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，制备薄层色谱分离得到标题化合物(55mg，17％)。MS:m/z[M+H] +＝428。 At room temperature, tert-butyl 2-(tert-butyldimethylsilyl)oxy)-6-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (296 mg, 0.77 mmol) was added to dichloromethane (10 mL) and trifluoroacetic acid (1 mL), and stirred at room temperature for 1 hour. Potassium carbonate (320 mg, 2.31 mmol) was added and stirred at room temperature for 0.5 hours. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, and the filtrate was concentrated. Acetonitrile (5 mL), 4,6-dichloro-2-methoxypyrimidine (196 mg, 1.06 mmol) and sodium carbonate (169 mg, 1.59 mmol) were sequentially added to the residue, and stirred overnight at 85°C. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and separated by preparative thin-layer chromatography to obtain the title compound (55 mg, 17%). MS: m/z [M+H] + = 428.
3-((叔丁基二甲基硅基)氧基)-3'-氯-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3-((tert-Butyldimethylsilyl)oxy)-3'-chloro-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[cyclobutyl Alkane-1,8'-pyridin[1',2':3,4]imidazol[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000071
Figure PCTCN2022134253-appb-000071
室温下，将(2-((叔丁基二甲基硅基)氧基)-7-(6-氯-2-甲氧基嘧啶-4-基)-7-氮杂螺环[3.5]壬-6-基)甲醇(55mg，0.13mmol)和三乙胺(66mg，0.26mmol)加入二氯甲烷(5mL)中，搅拌下加入甲基磺酸酐(45mg，0.26mmol)，室温搅拌3小时。反应液倒入水中，二氯甲烷提取，有机相浓缩，向残留物中依次加入水(5mL)和氢氧化钠水溶液(15％，123mg)，室温搅拌0.5小时。反应液用二氯甲烷提取，有机相浓缩得到标题化合物(18mg，41％)。MS:m/z[M+H] +＝396。 At room temperature, (2-((tert-butyldimethylsilyl)oxy)-7-(6-chloro-2-methoxypyrimidin-4-yl)-7-azaspiro[3.5] Non-6-yl)methanol (55mg, 0.13mmol) and triethylamine (66mg, 0.26mmol) were added into dichloromethane (5mL), methanesulfonic anhydride (45mg, 0.26mmol) was added under stirring, and stirred at room temperature for 3 hours . The reaction solution was poured into water, extracted with dichloromethane, and the organic phase was concentrated. Water (5 mL) and aqueous sodium hydroxide solution (15%, 123 mg) were successively added to the residue, and stirred at room temperature for 0.5 hours. The reaction solution was extracted with dichloromethane, and the organic phase was concentrated to obtain the title compound (18 mg, 41%). MS: m/z [M+H] + = 396.
3-((叔丁基二甲基硅基)氧基)-3'-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3-((tert-butyldimethylsilyl)oxy)-3'-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl) Oxy)-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[cyclobutane-1,8'-pyridine[1',2':3,4 ]imidazol[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000072
Figure PCTCN2022134253-appb-000072
将3-((叔丁基二甲基硅基)氧基)-3'-氯-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮(17mg，0.043mmol)、(3-氟-4-(2-三氟甲基)吡啶-4-基)苯基)甲醇(37mg，0.13mmol)和碳酸铯(42mg，0.13mmol)加入甲苯(5mL)中，110℃搅拌过夜。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，制备薄层色谱纯化得到标题化合物(23mg，83％)。MS:m/z[M+H] +＝647。 3-((tert-butyldimethylsilyl)oxy)-3'-chloro-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[ring Butane-1,8'-pyridin[1',2':3,4]imidazol[1,2-c]pyrimidin]-1'-one (17mg, 0.043mmol), (3-fluoro-4-( 2-Trifluoromethyl)pyridin-4-yl)phenyl)methanol (37mg, 0.13mmol) and cesium carbonate (42mg, 0.13mmol) were added to toluene (5mL), stirred overnight at 110°C. The reaction liquid was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by preparative thin-layer chromatography to obtain the title compound (23 mg, 83%). MS: m/z [M+H] + = 647.
中间体9Intermediate 9
2-甲氧基-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯tert-Butyl 2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000073
Figure PCTCN2022134253-appb-000073
室温下，将2-氧代-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(5g，20.89mmol)加入甲醇(50mL)中，搅拌下加入硼氢化钠(2.37g，62.67mmol)，室温搅拌5小时。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯提取，有机相浓缩，向残留物中依次加入乙腈(30mL)和碘甲烷(8.96g，62.67mmol)，搅拌下加入氢化钠(60％，2.51g， 62.67mmol)，室温搅拌3小时。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(1.9g，36％)。MS:m/z[M+H-tBu] +＝200。 At room temperature, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5g, 20.89mmol) was added into methanol (50mL), and sodium borohydride (2.37g , 62.67mmol), stirred at room temperature for 5 hours. The reaction solution was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organic phase was concentrated. Acetonitrile (30 mL) and methyl iodide (8.96 g, 62.67 mmol) were sequentially added to the residue, and sodium hydride (60%, 2.51g, 62.67mmol), stirred at room temperature for 3 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (1.9 g, 36%). MS: m/z [M+H-tBu] + =200.
6-甲酰基-2-甲氧基-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯tert-butyl 6-formyl-2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000074
Figure PCTCN2022134253-appb-000074
室温下，依次将四甲基乙二胺(1.3g，11.16mmol)和2-甲氧基-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(1.9g，7.44mmol)加入无水四氢呋喃(20mL)中，氩气保护下降温至-60℃，搅拌下滴加仲丁基锂的正己烷溶液(1.3M，8.58mL，11.16mmol)，滴加结束-20℃搅拌30分钟。反应液降温至-60℃，滴加N,N-二甲基甲酰胺(1.63g，22.32mmol)，滴加结束-60℃搅拌1小时，室温搅拌2小时。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(0.57g，27％)。MS:m/z[M+H-tBu] +＝228。 At room temperature, tetramethylethylenediamine (1.3g, 11.16mmol) and tert-butyl 2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate (1.9g, 7.44mmol ) into anhydrous tetrahydrofuran (20mL), the temperature was lowered to -60°C under the protection of argon, and a n-hexane solution of sec-butyllithium (1.3M, 8.58mL, 11.16mmol) was added dropwise with stirring, and the addition was completed and stirred at -20°C 30 minutes. The temperature of the reaction solution was lowered to -60°C, and N,N-dimethylformamide (1.63 g, 22.32 mmol) was added dropwise. After the addition, the mixture was stirred at -60°C for 1 hour and at room temperature for 2 hours. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (0.57 g, 27%). MS: m/z [M+H-tBu] + =228.
6-(羟甲基)-2-甲氧基-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯tert-butyl 6-(hydroxymethyl)-2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000075
Figure PCTCN2022134253-appb-000075
室温下，将6-甲酰基-2-甲氧基-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(380mg，1.34mmol)加入无水甲醇(5mL)中，搅拌下加入硼氢化钠(150mg，4.02mmol)，室温搅拌3小时，反应液用饱和氯化铵水溶液淬灭，乙酸乙酯提取，有机相浓缩得到标题化合物(365mg，95％)。MS:m/z[M+H-tBu] +＝230。 At room temperature, tert-butyl 6-formyl-2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate (380 mg, 1.34 mmol) was added into anhydrous methanol (5 mL), stirred Sodium borohydride (150mg, 4.02mmol) was added, stirred at room temperature for 3 hours, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (365mg, 95%). MS: m/z [M+H-tBu] + =230.
(7-(6-氯-2-甲氧基嘧啶-4-基)-2-甲氧基-7-氮杂螺环[3.5]壬烷-6-基)甲醇(7-(6-Chloro-2-methoxypyrimidin-4-yl)-2-methoxy-7-azaspiro[3.5]nonan-6-yl)methanol
Figure PCTCN2022134253-appb-000076
Figure PCTCN2022134253-appb-000076
室温下，将6-(羟甲基)-2-甲氧基-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(365mg，1.28mmol)加入二氯甲烷(2mL)中，搅拌下加入氯化氢的乙酸乙酯溶液(4M，2mL)，室温搅拌1小时。反应液浓缩，向残留物中依次加入乙腈(10mL)、4,6-二氯-2-甲氧基嘧啶(344mg，1.92mmol)和碳酸钠(385mg，3.63mmol)，85℃搅拌过夜。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，制备薄层色谱分离得到标题化合物(310mg，74％)。MS:m/z[M+H] +＝328。 Add tert-butyl 6-(hydroxymethyl)-2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate (365 mg, 1.28 mmol) into dichloromethane (2 mL) at room temperature , hydrogen chloride in ethyl acetate solution (4M, 2 mL) was added with stirring, and stirred at room temperature for 1 hour. The reaction solution was concentrated, and acetonitrile (10 mL), 4,6-dichloro-2-methoxypyrimidine (344 mg, 1.92 mmol) and sodium carbonate (385 mg, 3.63 mmol) were sequentially added to the residue, and stirred overnight at 85°C. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and separated by preparative thin-layer chromatography to obtain the title compound (310 mg, 74%). MS: m/z [M+H] + = 328.
3'-氯-3-甲氧基-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3'-Chloro-3-methoxy-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[cyclobutane-1,8'-pyridine[1' ,2':3,4]imidazol[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000077
Figure PCTCN2022134253-appb-000077
室温下，将(7-(6-氯-2-甲氧基嘧啶-4-基)-2-甲氧基-7-氮杂螺环[3.5]壬烷-6-基)甲醇(270mg，0.82mmol)加入二氯甲烷(5mL)中，搅拌下加入氯化亚砜(118mg，0.99mmol)，室温搅拌1小时。反应液浓缩，向残留物中依次加入乙腈(5mL)和碳酸钾固体(298mg，2.16mmol)，85℃搅拌过夜。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，制备薄层色谱纯化得到标题化合物(198mg，93％)。MS:m/z[M+H] +＝296。 At room temperature, (7-(6-chloro-2-methoxypyrimidin-4-yl)-2-methoxy-7-azaspiro[3.5]nonan-6-yl)methanol (270 mg, 0.82mmol) was added to dichloromethane (5mL), thionyl chloride (118mg, 0.99mmol) was added under stirring, and stirred at room temperature for 1 hour. The reaction solution was concentrated, acetonitrile (5 mL) and solid potassium carbonate (298 mg, 2.16 mmol) were successively added to the residue, and stirred overnight at 85°C. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by preparative thin-layer chromatography to obtain the title compound (198 mg, 93%). MS: m/z [M+H] + = 296.
中间体10Intermediate 10
1,4-二氧杂-10-氮杂双螺[4.1.5 7.1 5]十三烷-10-羧酸叔丁酯 tert-butyl 1,4-dioxa-10-azabispiro[4.1.5 7 .1 5 ]tridecane-10-carboxylate
Figure PCTCN2022134253-appb-000078
Figure PCTCN2022134253-appb-000078
室温下，将2-氧代-7-氮杂螺环[3.5]壬烷-7-羧酸叔丁酯(5g，20.89mmol)、乙二醇(1.94g，31.34mmol)和4-甲基苯磺酸吡啶(1.05g，4.18mmol)依次加入甲苯(50mL)中，120℃搅拌过夜。反应液浓缩，柱层析纯化得到标题化合物(3.6g，61％)。MS:m/z[M+H-tBu] +＝228。 At room temperature, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5g, 20.89mmol), ethylene glycol (1.94g, 31.34mmol) and 4-methyl Pyridine benzenesulfonate (1.05 g, 4.18 mmol) was successively added to toluene (50 mL), and stirred overnight at 120°C. The reaction solution was concentrated and purified by column chromatography to obtain the title compound (3.6 g, 61%). MS: m/z [M+H-tBu] + =228.
9-甲酰基-1,4-二氧杂-10-氮杂双螺[4.1.5 7.1 5]十三烷-10-羧酸叔丁酯 tert-butyl 9-formyl-1,4-dioxa-10-azabispiro[4.1.5 7 .1 5 ]tridecane-10-carboxylate
Figure PCTCN2022134253-appb-000079
Figure PCTCN2022134253-appb-000079
室温下，依次将四甲基乙二胺(2.15g，18.52mmol)和1,4-二氧杂-10-氮杂双螺[4.1.5 7.1 5]十三烷-10-羧酸叔丁酯(3.5g，12.35mmol)加入无水四氢呋喃(40mL)中，氩气保护下降温至-60℃，搅拌下滴加仲丁基锂的正己烷溶液(1.3M，14.25mL，18.52mmol)，滴加结束-20℃搅拌30分钟。反应液降温至-60℃，滴加N,N-二甲基甲酰胺(2.71g，37.05mmol)，滴加结束-60℃搅拌1小时，室温搅拌2小时。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(1.23g，32％)。MS:m/z[M+H-tBu] +＝256。 At room temperature, sequentially add tetramethylethylenediamine (2.15g, 18.52mmol) and 1,4-dioxa-10-azabispiro[4.1.5 7 .1 5 ]tridecane-10-carboxylic acid Tert-butyl ester (3.5g, 12.35mmol) was added to anhydrous tetrahydrofuran (40mL), the temperature was lowered to -60°C under argon protection, and a n-hexane solution of sec-butyllithium (1.3M, 14.25mL, 18.52mmol) was added dropwise with stirring. ), stirring at -20°C for 30 minutes at the end of the dropwise addition. The temperature of the reaction solution was cooled to -60°C, and N,N-dimethylformamide (2.71 g, 37.05 mmol) was added dropwise, and the mixture was stirred at -60°C for 1 hour and at room temperature for 2 hours after the addition was completed. The reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (1.23 g, 32%). MS: m/z [M+H-tBu] + =256.
9-(羟甲基)-1,4-二氧杂-10-氮杂双螺[4.1.5 7.1 5]十三烷-10-羧酸叔丁酯 tert-butyl 9-(hydroxymethyl)-1,4-dioxa-10-azabispiro[4.1.5 7 .1 5 ]tridecane-10-carboxylate
Figure PCTCN2022134253-appb-000080
Figure PCTCN2022134253-appb-000080
室温下，将9-甲酰基-1,4-二氧杂-10-氮杂双螺[4.1.5 7.1 5]十三烷-10-羧酸叔丁酯 At room temperature, tert-butyl 9-formyl-1,4-dioxa-10-azabispiro[4.1.5 7 .1 5 ]tridecane-10-carboxylate
(1.13g，3.63mmol)加入无水甲醇(10mL)中，搅拌下加入硼氢化钠(270mg，7.26mmol)，室温搅拌3小时，反应液用饱和氯化铵水溶液淬灭，二氯甲烷提取，有机相浓缩得到标题化合物(1.1g，97％)。MS:m/z[M+H-tBu] +＝258。 (1.13g, 3.63mmol) was added into anhydrous methanol (10mL), sodium borohydride (270mg, 7.26mmol) was added under stirring, stirred at room temperature for 3 hours, the reaction solution was quenched with saturated aqueous ammonium chloride, extracted with dichloromethane, The organic phase was concentrated to give the title compound (1.1 g, 97%). MS: m/z [M+H-tBu] + =258.
7-(6-氯-2-甲氧基嘧啶-4-基)-6-(羟甲基)-7-氮杂螺环[3.5]壬-2-酮7-(6-Chloro-2-methoxypyrimidin-4-yl)-6-(hydroxymethyl)-7-azaspiro[3.5]nonan-2-one
Figure PCTCN2022134253-appb-000081
Figure PCTCN2022134253-appb-000081
室温下，将9-(羟甲基)-1,4-二氧杂-10-氮杂双螺[4.1.5 7.1 5]十三烷-10-羧酸叔丁酯(1.1g，3.51mmol)加入二氯甲烷(10mL)中，搅拌下加入氯化氢的乙酸乙酯溶液(4M，0.32mL)，室温搅拌3小时。反应液浓缩，向残留物中依次加入乙腈(10mL)、4,6-二氯-2-甲氧基嘧啶(942mg，5.27mmol)和碳酸钠(2.07g,19.5mmol)，85℃搅拌过夜。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，制备薄层色谱分离得到标题化合物(180mg，8％)。MS:m/z[M+H] +＝312。 At room temperature, tert-butyl 9-(hydroxymethyl)-1,4-dioxa-10-azabispiro[4.1.5 7 .1 5 ]tridecane-10-carboxylate (1.1 g, 3.51 mmol) was added to dichloromethane (10 mL), hydrogen chloride in ethyl acetate solution (4M, 0.32 mL) was added with stirring, and stirred at room temperature for 3 hours. The reaction solution was concentrated, and acetonitrile (10 mL), 4,6-dichloro-2-methoxypyrimidine (942 mg, 5.27 mmol) and sodium carbonate (2.07 g, 19.5 mmol) were successively added to the residue, and stirred overnight at 85°C. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and the title compound (180 mg, 8%) was obtained by preparative thin-layer chromatography. MS: m/z [M+H] + = 312.
3'-氯-6',7',9a',10'-四氢-1'H,9'H-螺环[1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1',3-二酮3'-Chloro-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[1,8'-pyridine[1',2':3,4]imidazol[ 1,2-c]pyrimidine]-1',3-dione
Figure PCTCN2022134253-appb-000082
Figure PCTCN2022134253-appb-000082
室温下，将7-(6-氯-2-甲氧基嘧啶-4-基)-6-(羟甲基)-7-氮杂螺环[3.5]壬烷-2-酮(58mg，0.19mmol)加入二氯甲烷(5mL)中，搅拌下加入氯化亚砜(67.8mg，0.57mmol)，室温搅拌3小时。反应液浓缩，向残留物中依次加入乙腈(3mL)和碳酸钾固体(62mg，0.45mmol)，85℃搅拌过夜。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，制备薄层色谱纯化得到标题化合物(37mg，88％)。MS:m/z[M+H] +＝280。 At room temperature, 7-(6-chloro-2-methoxypyrimidin-4-yl)-6-(hydroxymethyl)-7-azaspiro[3.5]nonan-2-one (58mg, 0.19 mmol) was added to dichloromethane (5 mL), and thionyl chloride (67.8 mg, 0.57 mmol) was added with stirring, and stirred at room temperature for 3 hours. The reaction solution was concentrated, acetonitrile (3 mL) and solid potassium carbonate (62 mg, 0.45 mmol) were successively added to the residue, and stirred overnight at 85°C. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by preparative thin-layer chromatography to obtain the title compound (37 mg, 88%). MS: m/z [M+H] + =280.
3'-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1',3-二酮3'-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6',7',9a',10'-tetra Hydrogen-1'H,9'H-spiro[cyclobutane-1,8'-pyridine[1',2':3,4]imidazol[1,2-c]pyrimidine]-1',3- diketone
Figure PCTCN2022134253-appb-000083
Figure PCTCN2022134253-appb-000083
室温下，依次将3'-氯-3-甲氧基-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮(33mg，0.12mmol)、(3-氟-4-(2-三氟甲基)吡啶-4-基)苯基)甲醇(51mg，0.18mmol)和碳酸铯(78mg，0.24mmol)加入甲苯(3mL)中，120℃搅拌过夜。反应液过滤，滤饼用二氯甲烷淋洗，滤液浓缩，制备薄层色谱纯化得到标题化合物(41mg，64％)。MS:m/z[M+H] +＝531。 At room temperature, 3'-chloro-3-methoxy-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[cyclobutane-1,8'-pyridin[1',2':3,4]imidazol[1,2-c]pyrimidin]-1'-one (33 mg, 0.12 mmol), (3-fluoro-4-(2-trifluoromethyl) Pyridin-4-yl)phenyl)methanol (51mg, 0.18mmol) and cesium carbonate (78mg, 0.24mmol) were added to toluene (3mL), and stirred overnight at 120°C. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by preparative thin-layer chromatography to obtain the title compound (41 mg, 64%). MS: m/z [M+H] + = 531.
中间体11Intermediate 11
2-甲氧基-6-乙烯基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯tert-Butyl 2-methoxy-6-vinyl-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000084
Figure PCTCN2022134253-appb-000084
室温下，将6-甲酰基-2-甲氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(2.4g，8.47mmol)加入无水四氢呋喃中(80mL)中，搅拌下加入甲基三苯基溴化磷(3.63g，10.16mmol)，氩气保护下降温至0℃，分批次加入氢化钠(60％，1.02g，25.41mmol)，加料结束室温搅拌3小时。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯提取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝10/1)得到标题化合物(700mg，29％)。MS:m/z[M+H-tBu] +＝226。 At room temperature, tert-butyl 6-formyl-2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate (2.4 g, 8.47 mmol) was added into anhydrous tetrahydrofuran (80 mL), Add methyltriphenylphosphine bromide (3.63g, 10.16mmol) under stirring, lower the temperature to 0°C under the protection of argon, add sodium hydride (60%, 1.02g, 25.41mmol) in batches, and stir at room temperature for 3 Hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the title compound (700 mg, 29%). MS: m/z [M+H-tBu] + =226.
6-(2-羟乙基)-2-甲氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯tert-butyl 6-(2-hydroxyethyl)-2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2022134253-appb-000085
Figure PCTCN2022134253-appb-000085
室温下，将2-甲氧基-6-乙烯基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(700mg，2.49mmol)加入9-硼双环[3.3.1]壬烷的四氢呋喃溶液(0.5M，20mL，9.96mmol)中，室温搅拌过夜。向反应液中依次加入水(2mL)、氢氧化钠水溶液(3M，10mL)和双氧水(37％，10mL)，反应液50℃搅拌2小时。将反应液降温至室温后用乙酸乙酯提取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝2/1)得到标题化合物(750mg，100％)。MS:m/z[M+H-tBu] +＝244。 Add tert-butyl 2-methoxy-6-vinyl-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 2.49 mmol) to 9-borabicyclo[3.3.1]nonane at room temperature Alkanes in tetrahydrofuran (0.5M, 20mL, 9.96mmol), stirred overnight at room temperature. Water (2 mL), aqueous sodium hydroxide solution (3M, 10 mL) and hydrogen peroxide (37%, 10 mL) were sequentially added to the reaction solution, and the reaction solution was stirred at 50° C. for 2 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=2/1) to obtain the title compound (750 mg, 100%). MS: m/z [M+H-tBu] + =244.
2-(2-甲氧基-7-氮杂螺[3.5]壬烷-6-基)乙基-1-醇盐酸盐2-(2-Methoxy-7-azaspiro[3.5]nonan-6-yl)ethyl-1-ol hydrochloride
Figure PCTCN2022134253-appb-000086
Figure PCTCN2022134253-appb-000086
室温下，将6-(2-羟乙基)-2-甲氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(750mg，2.50mmol)加入氯化氢的1，4-二氧六环溶液(10mL)中，室温搅拌2小时。反应液浓缩得到标题化合物粗品(590mg，100％)。MS:m/z[M+H] +＝200。 At room temperature, tert-butyl 6-(2-hydroxyethyl)-2-methoxy-7-azaspiro[3.5]nonane-7-carboxylate (750 mg, 2.50 mmol) was added to 1,4 - Dioxane solution (10 mL), stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the crude product of the title compound (590 mg, 100%). MS: m/z [M+H] + = 200.
2-(7-(2,6-二氯嘧啶-4-基)-2-甲氧基-7-氮杂螺[3.5]壬烷-6-基)乙基-1-醇2-(7-(2,6-Dichloropyrimidin-4-yl)-2-methoxy-7-azaspiro[3.5]nonan-6-yl)ethyl-1-ol
Figure PCTCN2022134253-appb-000087
Figure PCTCN2022134253-appb-000087
室温下，将2-(2-甲氧基-7-氮杂螺[3.5]壬烷-6-基)乙基-1-醇盐酸盐(570mg，2.86mmol)加入乙腈(10mL)中，搅拌下依次加入4,6-二氯-2-甲氧基嘧啶(512mg， 2.86mmol)和碳酸钠固体(909mg，8.58mmol)，反应液室温搅拌过夜。反应液倒入水中，乙酸乙酯提取，有机相浓缩，柱层析纯化(二氯甲烷/甲醇＝50/1)得到标题化合物(390mg，40％)。MS:m/z[M+H] +＝342。 Add 2-(2-methoxy-7-azaspiro[3.5]nonan-6-yl)ethyl-1-ol hydrochloride (570 mg, 2.86 mmol) into acetonitrile (10 mL) at room temperature, 4,6-dichloro-2-methoxypyrimidine (512mg, 2.86mmol) and solid sodium carbonate (909mg, 8.58mmol) were added successively with stirring, and the reaction solution was stirred overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (dichloromethane/methanol=50/1) to obtain the title compound (390 mg, 40%). MS: m/z [M+H] + =342.
7-(6-氯-2-甲氧基嘧啶-4-基)-6-(2-氯乙基)-2-甲氧基-7-氮杂螺[3.5]壬烷7-(6-Chloro-2-methoxypyrimidin-4-yl)-6-(2-chloroethyl)-2-methoxy-7-azaspiro[3.5]nonane
Figure PCTCN2022134253-appb-000088
Figure PCTCN2022134253-appb-000088
室温下，将2-(7-(2,6-二氯嘧啶-4-基)-2-甲氧基-7-氮杂螺[3.5]壬烷-6-基)乙-1-醇(350mg，1.02mmol)加入二氯甲烷(20mL)中，降温至0℃，加入氯化亚砜(394mg，3.06mmol)，回流搅拌2小时。反应液浓缩，得到标题化合物(350mg，95％)。MS:m/z[M+H] +＝360。 At room temperature, 2-(7-(2,6-dichloropyrimidin-4-yl)-2-methoxy-7-azaspiro[3.5]nonan-6-yl)ethan-1-ol ( 350mg, 1.02mmol) was added into dichloromethane (20mL), cooled to 0°C, thionyl chloride (394mg, 3.06mmol) was added, and stirred under reflux for 2 hours. The reaction solution was concentrated to obtain the title compound (350 mg, 95%). MS: m/z [M+H] + = 360.
2'-氯-3-甲氧基-6',7',7a',8',10',11'-六氢-4'H-螺[环丁烷-1,9'-吡啶并[1,2-c]嘧啶并[1,6-a]嘧啶]-4'-酮2'-Chloro-3-methoxy-6',7',7a',8',10',11'-hexahydro-4'H-spiro[cyclobutane-1,9'-pyrido[ 1,2-c]pyrimido[1,6-a]pyrimidin]-4'-one
Figure PCTCN2022134253-appb-000089
Figure PCTCN2022134253-appb-000089
氩气保护下，将7-(6-氯-2-甲氧基嘧啶-4-基)-6-(2-氯乙基)-2-甲氧基-7-氮杂螺[3.5]壬烷(350mg，0.97mmol)和碳酸钾(402mg，2.91mmol)加入乙腈(10mL)中，85℃搅拌过夜，反应液过滤，有机相浓缩，柱层析纯化(二氯甲烷/甲醇＝100/1～50/1)得到标题化合物(200mg，66％)。MS:m/z[M+H] +＝310。 Under argon protection, 7-(6-chloro-2-methoxypyrimidin-4-yl)-6-(2-chloroethyl)-2-methoxy-7-azaspiro[3.5]nonane Add alkane (350mg, 0.97mmol) and potassium carbonate (402mg, 2.91mmol) into acetonitrile (10mL), stir overnight at 85°C, filter the reaction solution, concentrate the organic phase, and purify by column chromatography (dichloromethane/methanol=100/1 ~50/1) afforded the title compound (200 mg, 66%). MS: m/z [M+H] + = 310.
中间体12Intermediate 12
6-氧哌啶-2-羧酸6-oxopiperidine-2-carboxylic acid
Figure PCTCN2022134253-appb-000090
Figure PCTCN2022134253-appb-000090
室温下，将6-氧代-1,6-二氢吡啶-2-羧酸(10g，72mmol)和钯碳(10％，1g)加入甲醇(100mL)中，室温常压氢化过夜。反应液过滤，滤液浓缩得到标题化合物(5g，50％)。LC-MS:m/z[M+H] +＝144。 At room temperature, 6-oxo-1,6-dihydropyridine-2-carboxylic acid (10 g, 72 mmol) and palladium on carbon (10%, 1 g) were added into methanol (100 mL), and hydrogenated at room temperature and pressure overnight. The reaction solution was filtered, and the filtrate was concentrated to obtain the title compound (5 g, 50%). LC-MS: m/z [M+H] + =144.
6-氧哌啶甲基-2-羧酸甲酯Methyl 6-oxopiperidinyl-2-carboxylate
Figure PCTCN2022134253-appb-000091
Figure PCTCN2022134253-appb-000091
氩气保护下，将甲醇(10mL)冷却至0℃，搅拌下滴入二氯亚砜(830mg，7.7mmol)，室温搅拌10分钟。将6-氧哌啶-2-羧酸(1g，7mmol)加入反应液，室温搅拌过夜。反应液浓缩，向残留物中依次加入甲苯(10mL)和三乙胺(1.4g，14mmol)，室温搅拌0.5小时，反应液过滤，滤液浓缩得到标题化合物(850mg，77％)。MS:m/z[M+H] +＝158。 Under the protection of argon, methanol (10 mL) was cooled to 0°C, thionyl chloride (830 mg, 7.7 mmol) was added dropwise with stirring, and stirred at room temperature for 10 minutes. 6-Oxypiperidine-2-carboxylic acid (1 g, 7 mmol) was added to the reaction solution and stirred overnight at room temperature. The reaction solution was concentrated, and toluene (10 mL) and triethylamine (1.4 g, 14 mmol) were sequentially added to the residue, stirred at room temperature for 0.5 hour, the reaction solution was filtered, and the filtrate was concentrated to obtain the title compound (850 mg, 77%). MS: m/z [M+H] + =158.
1-苄基-6-((苄氧基)甲基)哌啶-2-酮1-Benzyl-6-((benzyloxy)methyl)piperidin-2-one
Figure PCTCN2022134253-appb-000092
Figure PCTCN2022134253-appb-000092
室温下，将6-氧哌啶甲基-2-羧酸甲酯(850mg，5.4mmol)加入甲醇(10mL)中，搅拌下缓慢加入硼氢化钠(307mg，8.1mmol)，室温搅拌1小时。反应液用十水硫酸钠淬灭，过滤，滤液浓缩。将残留物加入二甲亚砜(20mL)中，氩气保护下降温至0℃，搅拌下缓慢加入氢化钠(3.6g，21mmol)，室温搅拌30分钟。将溴化苄(3.6g，21mmol)加入反应液，室温搅拌过夜。反应液用水淬灭后倒入水中，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(900mg，54％)。MS:m/z[M+H] +＝310。 At room temperature, methyl 6-oxopiperidinyl-2-carboxylate (850 mg, 5.4 mmol) was added to methanol (10 mL), and sodium borohydride (307 mg, 8.1 mmol) was slowly added with stirring, and stirred at room temperature for 1 hour. The reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated. The residue was added to dimethyl sulfoxide (20 mL), the temperature was lowered to 0° C. under the protection of argon, and sodium hydride (3.6 g, 21 mmol) was slowly added with stirring, and stirred at room temperature for 30 minutes. Benzyl bromide (3.6 g, 21 mmol) was added to the reaction solution and stirred overnight at room temperature. The reaction solution was quenched with water and poured into water, extracted with ethyl acetate, the organic phase was concentrated and purified by column chromatography to obtain the title compound (900 mg, 54%). MS: m/z [M+H] + = 310.
4-苄基-5-((苄氧基)甲基)-4-氮杂螺[2.5]辛烷4-Benzyl-5-((benzyloxy)methyl)-4-azaspiro[2.5]octane
Figure PCTCN2022134253-appb-000093
Figure PCTCN2022134253-appb-000093
氩气保护下，将无水四氢呋喃(60mL)降温至-40℃，搅拌下依次加入乙基溴化镁的四氢呋喃溶液(1M，20mL，19.4mmol)和钛酸四异丙酯(2g，7.2mmol)，室温搅拌5分钟。将1-苄基-6-((苄氧基)甲基)哌啶-2-酮(2.0g，6.5mmol)的无水四氢呋喃(1mL)溶液加入反应液，回流搅拌过夜。反应液用10％氢氧化钠水溶液淬灭，无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化得到标题化合物(1.1g，53％)。MS:m/z[M+H] +＝322。 Under the protection of argon, anhydrous tetrahydrofuran (60mL) was cooled to -40°C, ethylmagnesium bromide solution in tetrahydrofuran (1M, 20mL, 19.4mmol) and tetraisopropyl titanate (2g, 7.2mmol) were added successively under stirring ), stirred at room temperature for 5 minutes. A solution of 1-benzyl-6-((benzyloxy)methyl)piperidin-2-one (2.0 g, 6.5 mmol) in anhydrous tetrahydrofuran (1 mL) was added to the reaction solution, and stirred under reflux overnight. The reaction solution was quenched with 10% aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain the title compound (1.1 g, 53%). MS: m/z [M+H] + =322.
(4-氮杂螺[2.5]辛-5-基)甲醇盐酸盐(4-Azaspiro[2.5]oct-5-yl)methanol hydrochloride
Figure PCTCN2022134253-appb-000094
Figure PCTCN2022134253-appb-000094
室温下，将4-苄基-5-((苄氧基)甲基)-4-氮杂螺[2.5]辛烷(200mg，0.6mmol)和钯碳(10％，30mg)加入氯化氢的乙酸乙酯溶液(4M，5mL)和甲醇(5mL)中，40℃常压氢化过夜。反应液过滤，滤液浓缩得到标题化合物粗品(200mg，182％)。MS:m/z[M+H] +＝142。 Add 4-benzyl-5-((benzyloxy)methyl)-4-azaspiro[2.5]octane (200 mg, 0.6 mmol) and palladium on carbon (10%, 30 mg) to acetic acid with hydrogen chloride at room temperature Ethyl ester solution (4M, 5mL) and methanol (5mL) were hydrogenated overnight at 40°C under normal pressure. The reaction liquid was filtered, and the filtrate was concentrated to obtain the crude product of the title compound (200 mg, 182%). MS: m/z [M+H] + =142.
(4-(2,6-二氯嘧啶-4-基)-4-氮杂螺[2.5]辛基-5-基)甲醇(4-(2,6-Dichloropyrimidin-4-yl)-4-azaspiro[2.5]octyl-5-yl)methanol
Figure PCTCN2022134253-appb-000095
Figure PCTCN2022134253-appb-000095
室温下，依次将(4-氮杂螺[2.5]辛烷-5-基)甲醇盐酸盐(100mg，0.6mmol)、2,4,6-三氯嘧啶(146mg，0.8mmol)和碳酸钠固体(149mg，1.4mmol)加入乙腈(2mL)中，室温搅拌过夜。反应液过滤，滤液浓缩，制备薄层色谱分离得到标题化合物(100mg，62％)。MS:m/z[M+H] +＝288。 At room temperature, (4-azaspiro[2.5]octane-5-yl)methanol hydrochloride (100mg, 0.6mmol), 2,4,6-trichloropyrimidine (146mg, 0.8mmol) and sodium carbonate The solid (149 mg, 1.4 mmol) was added into acetonitrile (2 mL), and stirred at room temperature overnight. The reaction solution was filtered, the filtrate was concentrated, and the title compound (100 mg, 62%) was obtained by preparative thin-layer chromatography. MS: m/z [M+H] + =288.
3'-氯-8',9',9a',10'-四氢-1'H,7'H-螺[环丙烷-1,6'-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶]-1'-酮3'-chloro-8',9',9a',10'-tetrahydro-1'H,7'H-spiro[cyclopropane-1,6'-pyrido[1',2':3,4 ]imidazo[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000096
Figure PCTCN2022134253-appb-000096
室温下，将(4-(2,6-二氯嘧啶-4-基)-4-氮杂螺[2.5]辛基-5-基)甲醇(100mg，0.3mmol)和二氯亚砜(47mg，0.4mmol)加入二氯甲烷(2mL)中，室温搅拌过夜。反应液浓缩，向残留物中依次加入碳酸钾固体(83mg，0.6mmol)和乙腈(5mL)，80 oC搅拌过夜。反应液冷却至室温，过滤，滤液浓缩，制备色谱分离得到标题化合物(80mg，100％)。MS:m/z[M+H] +＝252。 At room temperature, (4-(2,6-dichloropyrimidin-4-yl)-4-azaspiro[2.5]octyl-5-yl)methanol (100mg, 0.3mmol) and thionyl chloride (47mg , 0.4mmol) was added into dichloromethane (2mL), and stirred overnight at room temperature. The reaction solution was concentrated, and solid potassium carbonate (83 mg, 0.6 mmol) and acetonitrile (5 mL) were successively added to the residue, and stirred overnight at 80 o C. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated, and separated by preparative chromatography to obtain the title compound (80 mg, 100%). MS: m/z [M+H] + =252.
中间体13Intermediate 13
4-亚甲基哌啶-1-羧酸苄酯Benzyl 4-methylenepiperidine-1-carboxylate
Figure PCTCN2022134253-appb-000097
Figure PCTCN2022134253-appb-000097
室温下，将甲基三苯基溴化磷(10g，27.8mmol)加入无水四氢呋喃(30mL)中，氩气保护下降温至0℃，控温0℃以下滴加正丁基锂的四氢呋喃溶液(2.5M，11mL，27.8mmol)，0℃搅拌1小时。控温0℃以下将4-氧哌啶-1-甲酸苄酯(5g，21.4mmol)的无水四氢呋喃(20mL)溶液滴入反应液，0℃搅拌1小时后室温搅拌过夜。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(3.8g，76％)。MS:m/z[M+H] +＝232。 At room temperature, add methyltriphenylphosphine bromide (10g, 27.8mmol) into anhydrous tetrahydrofuran (30mL), lower the temperature to 0°C under the protection of argon, and add n-butyllithium tetrahydrofuran solution dropwise under 0°C (2.5M, 11 mL, 27.8 mmol), stirred at 0°C for 1 hour. A solution of benzyl 4-oxopiperidine-1-carboxylate (5 g, 21.4 mmol) in anhydrous tetrahydrofuran (20 mL) was dropped into the reaction mixture at a temperature below 0 °C, stirred at 0 °C for 1 hour and then at room temperature overnight. The reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (3.8 g, 76%). MS: m/z [M+H] + =232.
6-氮杂螺并[2.5]辛烷-6-羧酸苄酯Benzyl 6-azaspiro[2.5]octane-6-carboxylate
Figure PCTCN2022134253-appb-000098
Figure PCTCN2022134253-appb-000098
氩气保护下，将二氯甲烷(60mL)降温至0℃，搅拌下加入二乙基锌的正己烷溶液(1M，60mL，60mmol)，控温0℃以下滴入三氟乙酸(6.8g，60mmol)，0℃搅拌0.5小时。将二碘甲烷(16g，60mmol)加入反应液，室温搅拌30分钟。将4-亚甲基哌啶-1-羧酸苄酯(7g，30mmol)加入反应液，室温反应过夜。反应液 倒入饱和碳酸氢钠水溶液中，二氯甲烷提取，有机相浓缩，柱层析纯化得到标题化合物(6.1g，82％)。MS:m/z[M+H] +＝246。 Under argon protection, dichloromethane (60mL) was cooled to 0°C, diethylzinc n-hexane solution (1M, 60mL, 60mmol) was added under stirring, and trifluoroacetic acid (6.8g, 60 mmol), stirred at 0°C for 0.5 hours. Diiodomethane (16 g, 60 mmol) was added to the reaction solution and stirred at room temperature for 30 minutes. Benzyl 4-methylenepiperidine-1-carboxylate (7 g, 30 mmol) was added to the reaction solution and reacted at room temperature overnight. The reaction solution was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (6.1 g, 82%). MS: m/z [M+H] + = 246.
6-氮杂螺[2.5]辛烷盐酸盐6-Azaspiro[2.5]octane hydrochloride
Figure PCTCN2022134253-appb-000099
Figure PCTCN2022134253-appb-000099
室温下，将6-氮杂螺并[2.5]辛烷-6-羧酸苄酯(8.3g，33.9mmol)和钯碳(10％，830mg)加入甲醇(30mL)中，室温常压氢化过夜。反应液过滤，向滤液中加入氯化氢的1,4-二氧六环溶液(4M，30mL)，室温搅拌30分钟，反应液浓缩，向残留物中加入四氢呋喃(15mL)，室温搅拌30分钟。过滤，将滤饼烘干得到标题化合物(4.3g，86％)。MS:m/z[M+H] +＝112。 Add benzyl 6-azaspiro[2.5]octane-6-carboxylate (8.3g, 33.9mmol) and palladium on carbon (10%, 830mg) into methanol (30mL) at room temperature, and hydrogenate at room temperature and pressure overnight . The reaction solution was filtered, hydrogen chloride solution in 1,4-dioxane (4M, 30 mL) was added to the filtrate, stirred at room temperature for 30 minutes, the reaction solution was concentrated, tetrahydrofuran (15 mL) was added to the residue, and stirred at room temperature for 30 minutes. After filtration, the filter cake was dried to obtain the title compound (4.3 g, 86%). MS: m/z [M+H] + =112.
6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯tert-Butyl 6-azaspiro[2.5]octane-6-carboxylate
Figure PCTCN2022134253-appb-000100
Figure PCTCN2022134253-appb-000100
室温下，依次将6-氮杂螺[2.5]辛烷盐酸盐(4.27g，29mmol)、三乙胺(6.2g，61mmol)和二碳酸二叔丁酯(7g，32mmol)加入二氯甲烷(50mL)中，室温搅拌过夜。反应液倒入饱和氯化铵水溶液中，二氯甲烷提取，有机相浓缩，柱层析纯化得到标题化合物(5.3g，87％)。MS:m/z[M+H] +＝212。 At room temperature, 6-azaspiro[2.5]octane hydrochloride (4.27g, 29mmol), triethylamine (6.2g, 61mmol) and di-tert-butyl dicarbonate (7g, 32mmol) were successively added to dichloromethane (50 mL), stirred overnight at room temperature. The reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (5.3 g, 87%). MS: m/z [M+H] + =212.
5-甲酰基-6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯tert-Butyl 5-formyl-6-azaspiro[2.5]octane-6-carboxylate
Figure PCTCN2022134253-appb-000101
Figure PCTCN2022134253-appb-000101
室温下，将6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯(400mg，1.9mmol)加入无水四氢呋喃(5mL)中，氩气保护下降温至-78℃，控温-50℃以下依次滴入四甲基乙二胺(660mg，5.7mmol)和仲丁基锂的正己烷溶液(1.3M，2.2mL 2.9mmol)，-30℃搅拌15分钟。降温至-78℃，滴入N,N-二甲基甲酰胺(416mg，5.7mmol)，室温搅拌过夜。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化得到标题化合物(110mg，24％)。MS:m/z[M+H] +＝240。 At room temperature, tert-butyl 6-azaspiro[2.5]octane-6-carboxylate (400mg, 1.9mmol) was added into anhydrous tetrahydrofuran (5mL), the temperature was lowered to -78°C under the protection of argon, and the temperature was controlled to - Below 50°C, tetramethylethylenediamine (660mg, 5.7mmol) and sec-butyl lithium in n-hexane (1.3M, 2.2mL 2.9mmol) were successively added dropwise, and stirred at -30°C for 15 minutes. Cool down to -78°C, add N,N-dimethylformamide (416 mg, 5.7 mmol) dropwise, and stir overnight at room temperature. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to obtain the title compound (110 mg, 24%). MS: m/z [M+H] + =240.
5-(羟甲基)-6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯tert-butyl 5-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate
Figure PCTCN2022134253-appb-000102
Figure PCTCN2022134253-appb-000102
室温下，将5-甲酰基-6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯(110mg，0.46mmol)加入无水乙醇(5mL)中，搅拌下加入硼氢化钠固体(17mg，0.46mmol)，室温搅拌2小时。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩得到标题化合物(110mg，100％)。MS:m/z[M+H] +＝242。 At room temperature, tert-butyl 5-formyl-6-azaspiro[2.5]octane-6-carboxylate (110 mg, 0.46 mmol) was added into absolute ethanol (5 mL), and solid sodium borohydride ( 17mg, 0.46mmol), stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (110 mg, 100%). MS: m/z [M+H] + =242.
(6-(2,6-二氯嘧啶-4-基)-6-氮杂螺[2.5]辛基-5-基)甲醇(6-(2,6-Dichloropyrimidin-4-yl)-6-azaspiro[2.5]octyl-5-yl)methanol
Figure PCTCN2022134253-appb-000103
Figure PCTCN2022134253-appb-000103
室温下，将5-(羟甲基)-6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯(360mg，1.5mmol)加入氯化氢的乙酸乙酯溶液(4M，5mL)和二氯甲烷(5mL)中，室温搅拌1小时。反应液浓缩，向残留物中依次加入碳酸钠固体(318mg，3.0mmol)、2,4,6-三氯嘧啶(366mg，3.0mmol)和乙腈(5mL)，室温搅拌过夜。反应液过滤，滤液浓缩，制备薄层色谱分离得到标题化合物(260mg，60％)。MS:m/z[M+H] +＝288。 At room temperature, tert-butyl 5-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (360 mg, 1.5 mmol) was added to a solution of hydrogen chloride in ethyl acetate (4M, 5 mL) and di Chloromethane (5 mL), stirred at room temperature for 1 hour. The reaction solution was concentrated, solid sodium carbonate (318mg, 3.0mmol), 2,4,6-trichloropyrimidine (366mg, 3.0mmol) and acetonitrile (5mL) were sequentially added to the residue, and stirred overnight at room temperature. The reaction liquid was filtered, the filtrate was concentrated, and the title compound (260 mg, 60%) was obtained by preparative thin-layer chromatography. MS: m/z [M+H] + =288.
3'-氯-6',7',9a',10'-四氢-1'H,9'H-螺[环丙烷-1,8'-吡啶基[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3'-chloro-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[cyclopropane-1,8'-pyridyl[1',2':3,4 ]imidazol[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000104
Figure PCTCN2022134253-appb-000104
室温下，依次将(6-(2,6-二氯嘧啶-4-基)-6-氮杂螺[2.5]辛基-5-基)甲醇(160mg，0.6mmol)和二氯亚砜(1mL)加入二氯甲烷(1mL)中，室温搅拌过夜。反应液浓缩，向残留物中依次加入碳酸钾固体(230mg，1.7mmol)和乙腈(5mL)，回流搅拌过夜。反应液冷却至室温后过滤，滤液浓缩，制备薄层色谱分离得到标题化合物(80mg，50％)。MS:m/z[M+H] +＝252。 At room temperature, (6-(2,6-dichloropyrimidin-4-yl)-6-azaspiro[2.5]octyl-5-yl)methanol (160mg, 0.6mmol) and thionyl chloride ( 1 mL) was added into dichloromethane (1 mL), and stirred overnight at room temperature. The reaction solution was concentrated, solid potassium carbonate (230 mg, 1.7 mmol) and acetonitrile (5 mL) were successively added to the residue, and the mixture was stirred under reflux overnight. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated and separated by preparative thin-layer chromatography to obtain the title compound (80 mg, 50%). MS: m/z [M+H] + =252.
中间体14Intermediate 14
8-甲酰基-3-氧杂-9-氮杂螺[5.5]十一烷-9-羧酸叔丁酯tert-Butyl 8-formyl-3-oxa-9-azaspiro[5.5]undecane-9-carboxylate
Figure PCTCN2022134253-appb-000105
Figure PCTCN2022134253-appb-000105
室温下，将3-氧杂-9-氮杂螺[5.5]十一烷-9-羧酸叔丁酯(750mg，2.94mmol)和四甲基乙二胺(0.51g，4.41mmol)加入四氢呋喃(10mL)中，氩气保护下降温至-60℃，滴加仲丁基锂的正己烷溶液(1.3M，4.5mL，5.88mmol)，-50℃搅拌1小时，加入N,N-二甲基甲酰胺(0.32g，4.41mmol)，-50℃搅拌1小时，室温搅拌1小时。反应液用饱和氯化铵水溶液淬灭后倒入水中，乙酸乙酯提取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝10/1)得到标题化合物(340mg，41％)。MS:m/z[M+H-Boc] +＝184。 tert-butyl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate (750 mg, 2.94 mmol) and tetramethylethylenediamine (0.51 g, 4.41 mmol) were added to THF at room temperature (10mL), the temperature was lowered to -60°C under the protection of argon, a n-hexane solution of sec-butyllithium (1.3M, 4.5mL, 5.88mmol) was added dropwise, stirred at -50°C for 1 hour, and N,N-dimethyl Dimethylformamide (0.32g, 4.41mmol), stirred at -50°C for 1 hour, and stirred at room temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution and poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the title compound (340 mg, 41%). MS: m/z [M+H-Boc] + =184.
8-(羟甲基)-3-氧杂-9-氮杂螺[5.5]十一烷-9-羧酸叔丁酯tert-butyl 8-(hydroxymethyl)-3-oxa-9-azaspiro[5.5]undecane-9-carboxylate
Figure PCTCN2022134253-appb-000106
Figure PCTCN2022134253-appb-000106
室温下，将8-甲酰基-3-氧杂-9-氮杂螺[5.5]十一烷-9-羧酸叔丁酯(340mg，1.2mmol)加入四氢呋喃(10mL)中，搅拌下加入硼氢化钠(40mg，1.2mmol)，室温搅拌0.5小时。反应液用饱和氯化铵水溶液淬灭后倒入水中，乙酸乙酯提取，有机相浓缩得到标题化合物(340mg，99％)。MS:m/z[M+H-Boc] +＝186。 At room temperature, tert-butyl 8-formyl-3-oxa-9-azaspiro[5.5]undecane-9-carboxylate (340 mg, 1.2 mmol) was added into tetrahydrofuran (10 mL), and boron was added under stirring Sodium hydride (40mg, 1.2mmol), stirred at room temperature for 0.5 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the title compound (340 mg, 99%). MS: m/z [M+H-Boc] + =186.
(9-(6-氯-2-甲氧基嘧啶-4-基)-3-氧杂-9-氮杂螺[5.5]十一烷-8-基)甲醇(9-(6-Chloro-2-methoxypyrimidin-4-yl)-3-oxa-9-azaspiro[5.5]undecane-8-yl)methanol
Figure PCTCN2022134253-appb-000107
Figure PCTCN2022134253-appb-000107
室温下，将8-(羟甲基)-3-氧杂-9-氮杂螺[5.5]十一烷-9-羧酸叔丁酯(340mg，1.2mmol)加入三氟乙酸(1mL)和二氯甲烷(4mL)中，室温搅拌5分钟。用碳酸钠固体将反应体系pH调节至8-9。反应液浓缩，向残留物中依次加入4,6-二氯-2-甲氧基嘧啶(0.32g，1.78mmol)、碳酸钠(0.63g，5.95mmol)和乙腈(30mL)中，85℃搅拌过夜。反应液过滤，滤液浓缩，柱层析纯化(二氯甲烷/甲醇＝20/1)得到标题化合物(210mg，54％)。MS:m/z[M+H] +＝328。 At room temperature, tert-butyl 8-(hydroxymethyl)-3-oxa-9-azaspiro[5.5]undecane-9-carboxylate (340 mg, 1.2 mmol) was added to trifluoroacetic acid (1 mL) and In dichloromethane (4 mL), stir at room temperature for 5 minutes. The pH of the reaction system was adjusted to 8-9 with solid sodium carbonate. The reaction solution was concentrated, and 4,6-dichloro-2-methoxypyrimidine (0.32g, 1.78mmol), sodium carbonate (0.63g, 5.95mmol) and acetonitrile (30mL) were successively added to the residue, and stirred at 85°C overnight. The reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (dichloromethane/methanol=20/1) to obtain the title compound (210 mg, 54%). MS: m/z [M+H] + = 328.
3'-氯-2,3,5,6,6',7',9a',10'-八氢-1'H,9'H-螺[吡喃-4,8'-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶]-1'-酮3'-chloro-2,3,5,6,6',7',9a',10'-octahydro-1'H,9'H-spiro[pyran-4,8'-pyrido[1 ',2':3,4]imidazo[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000108
Figure PCTCN2022134253-appb-000108
室温下，将(9-(6-氯-2-甲氧基嘧啶-4-基)-3-氧杂-9-氮杂螺[5.5]十一烷-8-基)甲醇(141mg，0.43mmol)和三乙胺(0.13g，1.29mmol)加入二氯甲烷(12mL)中，搅拌下加入甲磺酰酐(74mg，0.65mmol)，室温搅拌20分钟。用碳酸钠固体将反应液pH调节至8-9。反应液浓缩，向残留物中依次加入水(8mL)和碳酸钾(0.29g，2.1mmol)。室温搅拌30分钟。二氯甲烷提取，有机相浓缩，制备薄层色谱分离(二氯甲烷/甲醇＝20/1)得到标题化合物(60mg，47％)。MS:m/z[M+H] +＝296。 At room temperature, (9-(6-chloro-2-methoxypyrimidin-4-yl)-3-oxa-9-azaspiro[5.5]undecane-8-yl)methanol (141 mg, 0.43 mmol) and triethylamine (0.13g, 1.29mmol) were added into dichloromethane (12mL), methanesulfonyl anhydride (74mg, 0.65mmol) was added under stirring, and stirred at room temperature for 20 minutes. The pH of the reaction solution was adjusted to 8-9 with solid sodium carbonate. The reaction solution was concentrated, and water (8 mL) and potassium carbonate (0.29 g, 2.1 mmol) were successively added to the residue. Stir at room temperature for 30 minutes. Extract with dichloromethane, concentrate the organic phase, and separate by preparative thin-layer chromatography (dichloromethane/methanol=20/1) to obtain the title compound (60 mg, 47%). MS: m/z [M+H] + = 296.
中间体15Intermediate 15
1-(叔丁基)4-乙基4-甲基哌啶-1,4,4-三羧酸1-(tert-butyl)4-ethyl 4-methylpiperidine-1,4,4-tricarboxylic acid
Figure PCTCN2022134253-appb-000109
Figure PCTCN2022134253-appb-000109
室温下，将1-(叔丁基)4-乙基哌啶-1,4-二羧酸酯(45.0g，175.1mmol)加入无水四氢呋喃(180mL)中，氩气保护下降温至-60℃，搅拌下加入二异丙基氨基锂的四氢呋喃溶液/正庚烷溶液(2M，131mL，262mmol)，-60℃搅拌0.5小时，加入氯甲酸甲酯(18.2g，192.6mmol)，-60℃搅拌30分钟，室温搅拌两小时。 反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝5/1)得到标题化合物(41g，91％)。MS:m/z[M+H-Boc] +＝216。 At room temperature, 1-(tert-butyl) 4-ethylpiperidine-1,4-dicarboxylate (45.0 g, 175.1 mmol) was added into anhydrous tetrahydrofuran (180 mL), and the temperature was lowered to -60 °C under the protection of argon. ℃, add lithium diisopropylamide tetrahydrofuran solution/n-heptane solution (2M, 131mL, 262mmol) under stirring, stir at -60°C for 0.5 hours, add methyl chloroformate (18.2g, 192.6mmol), -60°C Stir for 30 minutes and for two hours at room temperature. The reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound (41 g, 91%). MS: m/z [M+H-Boc] + =216.
4,4-双(羟甲基)哌啶-1-羧酸叔丁酯tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate
Figure PCTCN2022134253-appb-000110
Figure PCTCN2022134253-appb-000110
室温下，将1-(叔丁基)4-乙基4-甲基哌啶-1,4,4-三羧酸(10.0g，31.7mmol)加入四氢呋喃(50mL)和甲醇(50mL)中，反应升温至50℃，控温50℃-60℃分批次加入硼氢化钠(6.0g，158.5mmol)，60℃搅拌1小时。反应液用饱和氯化铵水溶液淬灭后倒入水中，乙酸乙酯提取，有机相浓缩得到标题化合物粗品(8g，103％)。MS:m/z[M+H-Boc] +＝146。 Add 1-(tert-butyl)4-ethyl4-methylpiperidine-1,4,4-tricarboxylic acid (10.0 g, 31.7 mmol) into tetrahydrofuran (50 mL) and methanol (50 mL) at room temperature, The reaction temperature was raised to 50°C, and sodium borohydride (6.0 g, 158.5 mmol) was added in batches under temperature control at 50°C-60°C, and stirred at 60°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude product of the title compound (8 g, 103%). MS: m/z [M+H-Boc] + =146.
4,4-双(((叔丁基二甲基甲硅烷基)氧基)甲基)哌啶-1-羧酸叔丁酯tert-butyl 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-carboxylate
Figure PCTCN2022134253-appb-000111
Figure PCTCN2022134253-appb-000111
室温下，将4,4-双(羟甲基)哌啶-1-羧酸叔丁酯(45.0g，183mmol)和咪唑(37.9g，549mmol)依次加入二氯甲烷(100mL)中，搅拌下加入叔丁基二甲基氯硅烷(55.2g，366mmol)，室温搅拌2小时。反应液倒入水中，二氯甲烷提取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝10/1)得到标题化合物(66g，77％)。MS:m/z[M+H-Boc] +＝373。 At room temperature, tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate (45.0g, 183mmol) and imidazole (37.9g, 549mmol) were successively added to dichloromethane (100mL), and stirred Add tert-butyldimethylsilyl chloride (55.2 g, 366 mmol), and stir at room temperature for 2 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the title compound (66 g, 77%). MS: m/z [M+H-Boc] + =373.
4,4-双(((叔丁基二甲基甲硅烷基)氧基)甲基)-2-甲酰基哌啶-1-羧酸叔丁酯tert-butyl 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-2-formylpiperidine-1-carboxylate
Figure PCTCN2022134253-appb-000112
Figure PCTCN2022134253-appb-000112
室温下，将4,4-双(((叔丁基二甲基甲硅烷基)氧基)甲基)哌啶-1-羧酸叔丁酯(20.0g，42.28mmol)和四甲基乙二胺(7.35g，64.42mmol)加入无水四氢呋喃(120mL)中，氩气保护下降温至-60℃，控温-50℃以下滴加仲丁基锂的环己烷溶液(1.3 M，71.5mL，93.0mmol)，-50℃搅拌1小时，加入N,N-二甲基甲酰胺(4.56g，63.42mmol)，-50℃搅拌1h，室温搅拌2小时。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝10/1)得到标题化合物(12g，57％)。MS:m/z[M+H-Boc] +＝402。 At room temperature, tert-butyl 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-carboxylate (20.0 g, 42.28 mmol) and tetramethylethyl Diamine (7.35g, 64.42mmol) was added to anhydrous tetrahydrofuran (120mL), the temperature was lowered to -60°C under the protection of argon, and the cyclohexane solution of sec-butyllithium (1.3 M, 71.5 mL, 93.0mmol), stirred at -50°C for 1 hour, added N,N-dimethylformamide (4.56g, 63.42mmol), stirred at -50°C for 1h, and stirred at room temperature for 2 hours. The reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the title compound (12 g, 57%). MS: m/z [M+H-Boc] + =402.
(4,4-双(((叔丁基二甲基甲硅烷基)氧基)甲基)哌啶-2-基)甲醇(4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)piperidin-2-yl)methanol
Figure PCTCN2022134253-appb-000113
Figure PCTCN2022134253-appb-000113
室温下，将4,4-双(((叔丁基二甲基甲硅烷基)氧基)甲基)-2-甲酰基哌啶-1-羧酸叔丁酯(4.0g，8.0mmol)加入三氟乙酸的二氯甲烷溶液(10％，40mL)中，室温搅拌5分钟。反应液用碳酸钾固体调节至8-9，过滤，滤液浓缩。将残留物加入甲醇(20mL)中，搅拌下加入硼氢化钠(907mg，24.0mmol)，室温搅拌1小时。反应液用饱和氯化铵水溶液淬灭后倒入水中，乙酸乙酯提取，有机相浓缩得到标题化合物粗品(4g，124％)。MS:m/z[M+H] +＝404。 At room temperature, tert-butyl 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-2-formylpiperidine-1-carboxylate (4.0 g, 8.0 mmol) Add trifluoroacetic acid in dichloromethane solution (10%, 40 mL), and stir at room temperature for 5 minutes. The reaction solution was adjusted to 8-9 with solid potassium carbonate, filtered, and the filtrate was concentrated. The residue was added to methanol (20 mL), sodium borohydride (907 mg, 24.0 mmol) was added with stirring, and stirred at room temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude product of the title compound (4 g, 124%). MS: m/z [M+H] + = 404.
(4,4-双(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-(6-氯-2-甲氧基嘧啶-4-基)哌啶-2-基)甲醇(4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-1-(6-chloro-2-methoxypyrimidin-4-yl)piperidin-2-yl ) Methanol
Figure PCTCN2022134253-appb-000114
Figure PCTCN2022134253-appb-000114
室温下，将(4,4-双(((叔丁基二甲基甲硅烷基)氧基)甲基)哌啶-2-基)甲醇的粗品(3.0g，7.44mmol)、4,6-二氯-2-甲氧基嘧啶(1.32g，7.44mmol)和碳酸钠固体(1.58g，14.88mmol)加入乙腈(30mL)中，90℃搅拌过夜。过滤，滤液浓缩，柱层析纯化(石油醚/乙酸乙酯＝10/1～5/1)得到标题化合物(1g，25％)。MS:m/z[M+H] +＝546。 At room temperature, the crude product of (4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)piperidin-2-yl)methanol (3.0 g, 7.44 mmol), 4,6 -Dichloro-2-methoxypyrimidine (1.32g, 7.44mmol) and solid sodium carbonate (1.58g, 14.88mmol) were added to acetonitrile (30mL), stirred at 90°C overnight. After filtration, the filtrate was concentrated and purified by column chromatography (petroleum ether/ethyl acetate=10/1-5/1) to obtain the title compound (1 g, 25%). MS: m/z [M+H] + = 546.
8,8-双(((叔丁基二甲基甲硅烷基)氧基)甲基)-3-氯-6,7,8,9,9a,10-六氢-1H- 吡啶并[1',2':3,4]咪唑[1,2-c]嘧啶-1-酮8,8-bis(((tert-butyldimethylsilyl)oxy)methyl)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1 ',2':3,4]imidazol[1,2-c]pyrimidin-1-one
Figure PCTCN2022134253-appb-000115
Figure PCTCN2022134253-appb-000115
室温下，将(4,4-双(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-(6-氯-2-甲氧基嘧啶-4-基)哌啶-2-基)甲醇(1.0g，2.0mmol)加入二氯甲烷(20mL)中，搅拌下将三乙胺(303mg，3.0mmol)和甲基磺酰氯(273mg，2.4mmol)依次加入反应液，室温搅拌20分钟。反应液浓缩，向残留物中加入水(16mL)，搅拌下用碳酸钾固体将体系pH调节至9-10，室温搅拌30分钟。二氯甲烷提取，有机相浓缩，柱层析纯化(二氯甲烷/甲醇＝20/1)得到标题化合物(450mg，48％)。MS:m/z[M+H] +＝514。 At room temperature, (4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-1-(6-chloro-2-methoxypyrimidin-4-yl)piperidine -2-yl)methanol (1.0g, 2.0mmol) was added into dichloromethane (20mL), and triethylamine (303mg, 3.0mmol) and methanesulfonyl chloride (273mg, 2.4mmol) were added to the reaction solution in turn under stirring, Stir at room temperature for 20 minutes. The reaction solution was concentrated, water (16 mL) was added to the residue, and the pH of the system was adjusted to 9-10 with solid potassium carbonate while stirring, and stirred at room temperature for 30 minutes. Extract with dichloromethane, concentrate the organic phase, and purify by column chromatography (dichloromethane/methanol=20/1) to obtain the title compound (450 mg, 48%). MS: m/z [M+H] + = 514.
8,8-双(((叔丁基二甲基甲硅烷基)氧基)甲基)-3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-6,7,8,9,9a,10-六氢-1H-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮8,8-bis(((tert-butyldimethylsilyl)oxy)methyl)-3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl )oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1',2':3,4]imidazo[1,2-c] pyrimidin-1-one
Figure PCTCN2022134253-appb-000116
Figure PCTCN2022134253-appb-000116
室温下，依次将8,8-双(((叔丁基二甲基甲硅烷基)氧基)甲基)-3-氯-6,7,8,9,9a,10-六氢-1H-吡啶并[1',2':3,4]咪唑[1,2-c]嘧啶-1-酮(450mg，0.88mmol)、(3-氟-4-[(2-(三氟甲基)吡啶-4-基)氧基]苯基)甲醇(0.28g，0.97mmol)和碳酸铯(0.86g，2.64mmol)加入甲苯(20mL)中，110℃搅拌过夜。反应液浓缩后倒入水中，二氯甲烷提取，有机相浓缩，柱层析纯化(二氯甲烷/甲醇＝20/1)得到标题化合物(670mg，99％)。MS:m/z[M+H] +＝765。 At room temperature, 8,8-bis(((tert-butyldimethylsilyl)oxy)methyl)-3-chloro-6,7,8,9,9a,10-hexahydro-1H -pyrido[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (450 mg, 0.88 mmol), (3-fluoro-4-[(2-(trifluoromethyl )pyridin-4-yl)oxy]phenyl)methanol (0.28g, 0.97mmol) and cesium carbonate (0.86g, 2.64mmol) were added into toluene (20mL), and stirred overnight at 110°C. The reaction solution was concentrated and poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (dichloromethane/methanol=20/1) to obtain the title compound (670mg, 99%). MS: m/z [M+H] + = 765.
3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-8,8-双(羟甲基)-6,7,8,9,9a,10-六氢-1H-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-8,8-bis(hydroxymethyl)-6,7 ,8,9,9a,10-Hexahydro-1H-pyrido[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one
Figure PCTCN2022134253-appb-000117
Figure PCTCN2022134253-appb-000117
室温下，将8,8-双(((叔丁基二甲基甲硅烷基)氧基)甲基)-3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-6,7,8,9,9a,10-六氢-1H-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮(670mg，0.88mmol)加入无水四氢呋喃(10mL)中，搅拌下加入四丁基氟化铵的四氢呋喃溶液(1M，2.2mL，2.2mmol)，室温搅拌1小时。反应液倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，柱层析纯化(二氯甲烷/甲醇＝20/1～10/1)得到标题化合物(350mg，74％)。MS:m/z[M+H] +＝537。 At room temperature, 8,8-bis(((tert-butyldimethylsilyl)oxy)methyl)-3-((3-fluoro-4-((2-(trifluoromethyl)pyridine -4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1',2':3,4]imidazo[1, 2-c] Pyrimidin-1-one (670mg, 0.88mmol) was added to anhydrous tetrahydrofuran (10mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 2.2mL, 2.2mmol) was added under stirring, and stirred at room temperature for 1 hour . The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (dichloromethane/methanol=20/1-10/1) to obtain the title compound (350 mg, 74%). MS: m/z [M+H] + = 537.
(3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-8-(羟甲基)-1-氧代-6,7,8,9,9a,10-六氢-1H-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶-8-基)甲磺酸甲酯(3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-8-(hydroxymethyl)-1-oxo- 6,7,8,9,9a,10-Hexahydro-1H-pyrido[1',2':3,4]imidazo[1,2-c]pyrimidin-8-yl)methylsulfonate
Figure PCTCN2022134253-appb-000118
Figure PCTCN2022134253-appb-000118
室温下，将3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-8,8-双(羟甲基)-6,7,8,9,9a,10-六氢-1H-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮(100mg，0.19mmol)加入二氯甲烷(10mL)中，氩气保护下降温至0℃，搅拌下依次加入三乙胺(23.07mg，0.23mmol)和甲基磺酰氯(13.06mg，0.11mmol)的二氯甲烷(1mL)溶液，室温搅拌15分钟。反应液倒入水中，二氯甲烷提取，有机相浓缩，制备薄层色谱分离(二氯甲烷/甲醇＝10/1)得到标题化合物(60mg，51％)。MS:m/z[M+H] +＝615。 At room temperature, 3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-8,8-bis(hydroxymethyl) -6,7,8,9,9a,10-Hexahydro-1H-pyrido[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (100mg, 0.19mmol ) was added into dichloromethane (10mL), the temperature was lowered to 0°C under the protection of argon, and triethylamine (23.07mg, 0.23mmol) and methanesulfonyl chloride (13.06mg, 0.11mmol) were added successively under stirring in dichloromethane ( 1 mL) solution, stirred at room temperature for 15 minutes. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and separated by preparative thin-layer chromatography (dichloromethane/methanol=10/1) to obtain the title compound (60 mg, 51%). MS: m/z [M+H] + = 615.
中间体16Intermediate 16
5-甲酰基-2-(3-(三氟甲基)苯氧基)苄腈5-Formyl-2-(3-(trifluoromethyl)phenoxy)benzonitrile
Figure PCTCN2022134253-appb-000119
Figure PCTCN2022134253-appb-000119
室温下，将2-氟-5-甲酰基苄腈(15.0g，0.1mol)、3-(三氟甲基)苯酚(16.0g，0.1mol)和碳酸钾(13.8g，0.1mol)加到DMF(100mL)中，105℃搅拌8小时，反 应液倒入水中，用二氯甲烷萃取，有机相浓缩，向残留物中加入乙醇(50mL)，室温搅拌30分钟，过滤，滤饼浓缩干得到标题化合物(22.1g，76％)。 1H NMR(400MHz,DMSO-d 6)δ9.96(s,1H),8.49(s,1H),8.14(br.s,1H),7.88(d,2H),7.47(d,2H),7.19(d,1H)。 At room temperature, 2-fluoro-5-formylbenzonitrile (15.0 g, 0.1 mol), 3-(trifluoromethyl)phenol (16.0 g, 0.1 mol) and potassium carbonate (13.8 g, 0.1 mol) were added to In DMF (100mL), stirred at 105°C for 8 hours, the reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, ethanol (50mL) was added to the residue, stirred at room temperature for 30 minutes, filtered, and the filter cake was concentrated to dryness to obtain The title compound (22.1 g, 76%). 1 H NMR (400MHz,DMSO-d 6 )δ9.96(s,1H),8.49(s,1H),8.14(br.s,1H),7.88(d,2H),7.47(d,2H), 7.19(d,1H).
5-(羟甲基)-2-(3-(三氟甲基)苯氧基)苄腈5-(Hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile
Figure PCTCN2022134253-appb-000120
Figure PCTCN2022134253-appb-000120
室温下，将5-甲酰基-2-(3-(三氟甲基)苯氧基)苄腈(24.3g，83.44mmol)加入甲醇(250mL)中，分批加入硼氢化钠(4.86g，127.9mmol)，室温反应0.5小时。反应液倒入水中，用二氯甲烷萃取，有机相浓缩得到标题化合物(24.2g，99％)。 1H NMR(400MHz,DMSO-d 6)δ7.80(s,1H),7.73-7.53(m,3H),7.52-7.27(m,2H),7.09(br.s,1H),5.41(s,1H),4.51(s,2H)。 At room temperature, 5-formyl-2-(3-(trifluoromethyl)phenoxy)benzonitrile (24.3 g, 83.44 mmol) was added into methanol (250 mL), and sodium borohydride (4.86 g, 127.9mmol), reacted at room temperature for 0.5 hours. The reaction solution was poured into water, extracted with dichloromethane, and the organic phase was concentrated to obtain the title compound (24.2 g, 99%). 1 H NMR (400MHz,DMSO-d 6 )δ7.80(s,1H),7.73-7.53(m,3H),7.52-7.27(m,2H),7.09(br.s,1H),5.41(s ,1H), 4.51(s,2H).
参考下表，采用“原料”一栏所述化合物为原料，参照中间体16的制备方法制备以下中间体17～23。Referring to the table below, the following intermediates 17-23 were prepared by using the compounds described in the "raw material" column as raw materials and referring to the preparation method of intermediate 16.
Figure PCTCN2022134253-appb-000121
Figure PCTCN2022134253-appb-000121
Figure PCTCN2022134253-appb-000122
Figure PCTCN2022134253-appb-000122
中间体24Intermediate 24
4-(苄氧基)-2-(三氟甲氧基)吡啶4-(Benzyloxy)-2-(trifluoromethoxy)pyridine
Figure PCTCN2022134253-appb-000123
Figure PCTCN2022134253-appb-000123
将4-(苄氧基)吡啶-2-醇(1.91g，9.48mmol)和1-三氟甲基-1,2-苯碘酰-3(H)-酮(1g，3.16mmol)加到硝基甲烷(25mL)中，在100℃搅拌过夜。反应液浓缩， 残留物柱层析纯化(石油醚/乙酸乙酯＝10/1)得到标题化合物(530mg，47％)。MS:m/z[M+H] +＝270。 4-(Benzyloxy)pyridin-2-ol (1.91 g, 9.48 mmol) and 1-trifluoromethyl-1,2-phenyliodyl-3(H)-one (1 g, 3.16 mmol) were added to Nitromethane (25 mL), stirred overnight at 100°C. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the title compound (530 mg, 47%). MS: m/z [M+H] + =270.
2-(三氟甲氧基)吡啶-4-醇2-(Trifluoromethoxy)pyridin-4-ol
Figure PCTCN2022134253-appb-000124
Figure PCTCN2022134253-appb-000124
将4-(苄氧基)-2-(三氟甲氧基)吡啶(530mg，1.97mmol)和Pd/C(10％，125mg)加到甲醇(20mL)中，在60℃，3bar压力的氢气下搅拌过夜。反应液过滤，滤液浓缩得到粗品标题化合物(330mg，94％)。MS:m/z[M+H] +＝180。 Add 4-(benzyloxy)-2-(trifluoromethoxy)pyridine (530mg, 1.97mmol) and Pd/C (10%, 125mg) into methanol (20mL) at 60°C under 3bar pressure Stir overnight under hydrogen. The reaction liquid was filtered, and the filtrate was concentrated to obtain the crude title compound (330 mg, 94%). MS: m/z [M+H] + =180.
(3,5-二氟-4-((2-(三氟甲氧基)吡啶-4-基)氧基)苯基)甲醇(3,5-Difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)phenyl)methanol
Figure PCTCN2022134253-appb-000125
Figure PCTCN2022134253-appb-000125
将3,4,5-三氟苯甲醛(294.4mg，1.84mol)，2-(三氟甲氧基)吡啶-4-醇(330mg，1.84mol)和碳酸钾(330.6mg，2.39mol)加到DMF(10mL)中，在120℃搅拌2小时，反应液倒入水中，用乙酸乙酯萃取，有机相浓缩得到3,5-二氟-4-((2-(三氟甲氧基)吡啶-4-基)氧基)苯甲醛粗品，将该粗品加到乙醇(250.0mL)中，加入硼氢化钠(69.61mg，1.84mmol)室温搅拌1小时。反应用水淬灭，乙酸乙酯萃取，有机相干燥浓缩得到标题化合物(400mg，68％)。 1H NMR(400MHz，DMSO-d 6)δ8.30(d，J＝5.9Hz，1H)，7.29(d，J＝9.3Hz，2H)，7.07(d，J＝3.9Hz，1H)，6.95(s，1H)，5.56(br.s.，1H)，4.56(d，J＝4.9Hz，2H)；MS:m/z[M+H] +＝322。 3,4,5-Trifluorobenzaldehyde (294.4 mg, 1.84 mol), 2-(trifluoromethoxy)pyridin-4-ol (330 mg, 1.84 mol) and potassium carbonate (330.6 mg, 2.39 mol) were added into DMF (10mL), stirred at 120°C for 2 hours, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated to obtain 3,5-difluoro-4-((2-(trifluoromethoxy) Add the crude product of pyridin-4-yl)oxy)benzaldehyde to ethanol (250.0 mL), add sodium borohydride (69.61 mg, 1.84 mmol) and stir at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the title compound (400 mg, 68%). 1 H NMR (400MHz, DMSO-d 6 ) δ8.30(d, J=5.9Hz, 1H), 7.29(d, J=9.3Hz, 2H), 7.07(d, J=3.9Hz, 1H), 6.95 (s, 1H), 5.56 (br.s., 1H), 4.56 (d, J = 4.9 Hz, 2H); MS: m/z [M+H] + = 322.
中间体25Intermediate 25
4-(4-氯-3-(三氟甲基)苯氧基)苯甲醛4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzaldehyde
Figure PCTCN2022134253-appb-000126
Figure PCTCN2022134253-appb-000126
将2-氯-5-羟基三氟甲苯(15g，76.53mmol)，4-氟苯甲醛(9.50g，76.53mmol)和碳酸钾(21.12g，153.06mmol)加到DMF(150mL)中，120℃搅拌过夜，反应 液倒入水中，乙酸乙酯提取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝50/1～5/1)得到标题化合物(14.6g，64％)。MS:m/z[M+H] +＝301。 2-Chloro-5-hydroxybenzotrifluoride (15g, 76.53mmol), 4-fluorobenzaldehyde (9.50g, 76.53mmol) and potassium carbonate (21.12g, 153.06mmol) were added to DMF (150mL), 120°C After stirring overnight, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=50/1-5/1) to obtain the title compound (14.6 g, 64%). MS: m/z [M+H] + = 301.
1-氯-2-(三氟甲基)-4-(4-乙烯基苯氧基)苯1-Chloro-2-(trifluoromethyl)-4-(4-vinylphenoxy)benzene
Figure PCTCN2022134253-appb-000127
Figure PCTCN2022134253-appb-000127
将4-(4-氯-3-(三氟甲基)苯氧基)苯甲醛(14.6g，48.67mmol)，甲基三苯基溴化磷(19.12g，53.53mmol)加入到THF(150mL)中，氩气保护下降温至0℃，搅拌下缓慢加入氢化钠(60％，9.73g，243.35mmol)，室温搅拌过夜。反应液用水淬灭后倒入冰水中，二氯甲烷提取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝50/1～5/1)得到标题化合物(13.6g，94％)。MS:m/z[M+H] +＝299。 4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzaldehyde (14.6 g, 48.67 mmol), methyltriphenylphosphine bromide (19.12 g, 53.53 mmol) were added to THF (150 mL ), the temperature was lowered to 0°C under the protection of argon, and sodium hydride (60%, 9.73 g, 243.35 mmol) was slowly added with stirring, and stirred at room temperature overnight. The reaction solution was quenched with water and poured into ice water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=50/1～5/1) to obtain the title compound (13.6g, 94%) . MS: m/z [M+H] + = 299.
2-(4-(4-氯-3-(三氟甲基)苯氧基)苯基)乙基-1-醇2-(4-(4-Chloro-3-(trifluoromethyl)phenoxy)phenyl)ethyl-1-ol
Figure PCTCN2022134253-appb-000128
Figure PCTCN2022134253-appb-000128
室温下，将1-氯-2-(三氟甲基)-4-(4-乙烯基苯氧基)苯(13.6g，45.48mmol)溶解到无水四氢呋喃(150mL)中，降温至0℃加入9-硼双环[3.3.1]壬烷的四氢呋喃溶液(0.5M，136mL，68.00mmol)，室温搅拌过夜。向反应液中依次加入水(14mL)、氢氧化钠水溶液(3M，70mL)和双氧水(30％，70mL)，50℃搅拌2小时。反应液用饱和硫代硫酸钠水溶液淬灭后倒入水中，二氯甲烷提取，有机相浓缩，柱层析纯化(二氯甲烷/甲醇＝30/1)得到标题化合物(10.6g，74％)。MS:m/z[M+H] +＝317。 Dissolve 1-chloro-2-(trifluoromethyl)-4-(4-vinylphenoxy)benzene (13.6g, 45.48mmol) in anhydrous tetrahydrofuran (150mL) at room temperature and cool to 0°C Add a solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (0.5M, 136 mL, 68.00 mmol), and stir at room temperature overnight. Water (14 mL), sodium hydroxide aqueous solution (3M, 70 mL) and hydrogen peroxide (30%, 70 mL) were sequentially added to the reaction liquid, and stirred at 50° C. for 2 hours. The reaction solution was quenched with saturated aqueous sodium thiosulfate solution and poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (dichloromethane/methanol=30/1) to obtain the title compound (10.6 g, 74%) . MS: m/z [M+H] + = 317.
中间体26Intermediate 26
4-溴-2-(二氟甲基)吡啶4-Bromo-2-(difluoromethyl)pyridine
Figure PCTCN2022134253-appb-000129
Figure PCTCN2022134253-appb-000129
将4-溴吡啶甲醛(10g，53.76mmol)加入二氯甲烷(100mL)中，降温至0℃。搅拌下将二乙胺基三氟化硫(17.3g，107.52mmol)滴入反应液，室温搅拌过夜。将反应液缓慢滴入水中，二氯甲烷提取，有机相浓缩得到标题化合物粗品直接用于下一步反应。MS:m/z[M+H] +＝208。 4-Bromopicolinaldehyde (10 g, 53.76 mmol) was added into dichloromethane (100 mL), and the temperature was lowered to 0°C. Diethylaminosulfur trifluoride (17.3 g, 107.52 mmol) was dropped into the reaction solution under stirring, and stirred overnight at room temperature. The reaction solution was slowly dropped into water, extracted with dichloromethane, and the organic phase was concentrated to obtain the crude product of the title compound, which was directly used in the next reaction. MS: m/z [M+H] + =208.
2-(二氟甲基)-4-甲氧基吡啶2-(Difluoromethyl)-4-methoxypyridine
Figure PCTCN2022134253-appb-000130
Figure PCTCN2022134253-appb-000130
将4-溴-2-(二氟甲基)吡啶(11.18g，53.76mmol)、甲醇钠(5.81g，107.52mmol)加入甲醇(100mL)中。90℃搅拌过夜。反应液降温至室温并倒入水(300mL)中，乙酸乙酯提取。有机相浓缩得到标题化合物粗品直接用于下一步反应。MS:m/z[M+H] +＝160。 4-Bromo-2-(difluoromethyl)pyridine (11.18 g, 53.76 mmol), sodium methoxide (5.81 g, 107.52 mmol) were added to methanol (100 mL). Stir overnight at 90°C. The reaction solution was cooled to room temperature and poured into water (300 mL), extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product of the title compound which was directly used in the next reaction. MS: m/z [M+H] + =160.
2-(二氟甲基)吡啶-4-醇2-(Difluoromethyl)pyridin-4-ol
Figure PCTCN2022134253-appb-000131
Figure PCTCN2022134253-appb-000131
将2-(二氟甲基)-4-甲氧基吡啶(9.54g，59.95mmol)加入氢溴酸(40％水溶液，58mL)中。90℃搅拌2天。反应液浓缩，将残留物加水稀释，搅拌下加入碳酸氢钠固体直到体系没有气泡产生为止，乙酸乙酯提取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝10/1～1/1)得到标题化合物(2.5g，三步总收率26％)。MS:m/z[M+H] +＝146。 2-(Difluoromethyl)-4-methoxypyridine (9.54 g, 59.95 mmol) was added to hydrobromic acid (40% in water, 58 mL). Stir at 90°C for 2 days. The reaction solution was concentrated, the residue was diluted with water, solid sodium bicarbonate was added under stirring until no bubbles were generated in the system, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate=10/1～1 /1) The title compound (2.5 g, 26% overall yield in three steps) was obtained. MS: m/z [M+H] + =146.
4-((2-(二氟甲基)吡啶-4-基)氧基)-3-氟苯甲醛4-((2-(Difluoromethyl)pyridin-4-yl)oxy)-3-fluorobenzaldehyde
Figure PCTCN2022134253-appb-000132
Figure PCTCN2022134253-appb-000132
将3,4-二氟苯甲醛(350mg，2.46mmol)、2-(二氟甲基)吡啶-4-醇(357mg，2.46mmol)和碳酸钾固体(1019mg，7.38mmol)加入到N，N-二甲基甲酰胺(5mL)中，120℃搅拌3小时。反应液倒入水中，乙酸乙酯提取，有机相浓缩，制备薄层色谱分离得到标题化合物(510mg，78％)。MS:m/z[M+H] +＝268。 3,4-Difluorobenzaldehyde (350mg, 2.46mmol), 2-(difluoromethyl)pyridin-4-ol (357mg, 2.46mmol) and solid potassium carbonate (1019mg, 7.38mmol) were added to N,N - Dimethylformamide (5 mL), stirred at 120°C for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and separated by preparative thin-layer chromatography to obtain the title compound (510 mg, 78%). MS: m/z [M+H] + =268.
(4-((2-(二氟甲基)吡啶-4-基)氧基)-3-氟苯基)甲醇(4-((2-(Difluoromethyl)pyridin-4-yl)oxy)-3-fluorophenyl)methanol
Figure PCTCN2022134253-appb-000133
Figure PCTCN2022134253-appb-000133
将4-((2-(二氟甲基)吡啶-4-基)氧基)-3-氟苯甲醛(505mg，1.89mmol)加入无水乙醇(5mL)中，搅拌下加入NaBH 4(140mg，3.78mmol)，室温搅拌2小时。反应液倒入水中，二氯甲烷提取，有机相浓缩得到标题化合物(381mg，75％)。MS:m/z[M+H] +＝271。 Add 4-((2-(difluoromethyl)pyridin-4-yl)oxy)-3-fluorobenzaldehyde (505 mg, 1.89 mmol) into absolute ethanol (5 mL), add NaBH 4 ( 140 mg , 3.78mmol), stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted with dichloromethane, and the organic phase was concentrated to obtain the title compound (381 mg, 75%). MS: m/z [M+H] + =271.
实施例Example
实施例1Example 1
方法AMethod A
3'-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-6',7',9a',10'-四氢-1'H,9'H-螺[环丙烷-1,8'-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶]-1'-酮3'-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6',7',9a',10'-tetra Hydrogen-1'H,9'H-spiro[cyclopropane-1,8'-pyrido[1',2':3,4]imidazo[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000134
Figure PCTCN2022134253-appb-000134
室温下，将3'-氯-6',7',9a',10'-四氢-1'H,9'H-螺[环丙烷-1,8'-吡啶基[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮(30mg，0.12mmol)、(3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苯基)甲醇(50mg，0.17mmol)和氢化钠(7mg，0.18mmol)加入乙腈(5mL)中，室温搅拌1小时。反应液饱和氯化铵水溶液淬灭后倒入水中，乙酸乙酯提取，有机相浓缩，制备薄层色谱纯化得到标题化合物(9mg，15％)。 1H NMR(400MHz,CDCl 3)δ8.56(d,J＝5.4Hz,1H),7.32(d,J＝11.2Hz,1H),7.28-7.14(m,3H),6.95(d,J＝3.4Hz,1H),5.43(s,2H),5.04(s,1H),4.35-4.13(m,1H),4.01-3.84(m,1H),3.67(dd,J＝7.3,11.2Hz,1H),3.53(dd,J＝3.9,12.7Hz,1H),3.22-3.07(m,1H),2.09-1.92(m,2H),1.11(d,J＝12.7Hz,1H),0.88(d,J＝12.7Hz,1H),0.53-0.38(m,4H)；MS:m/z[M+H] +＝503。 At room temperature, 3'-chloro-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[cyclopropane-1,8'-pyridyl[1',2':3,4]imidazo[1,2-c]pyrimidin]-1'-one (30mg, 0.12mmol), (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl) Oxy)phenyl)methanol (50mg, 0.17mmol) and sodium hydride (7mg, 0.18mmol) were added into acetonitrile (5mL), and stirred at room temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution and poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by preparative thin-layer chromatography to obtain the title compound (9 mg, 15%). 1 H NMR (400MHz, CDCl 3 ) δ8.56 (d, J = 5.4Hz, 1H), 7.32 (d, J = 11.2Hz, 1H), 7.28-7.14 (m, 3H), 6.95 (d, J = 3.4Hz, 1H), 5.43(s, 2H), 5.04(s, 1H), 4.35-4.13(m, 1H), 4.01-3.84(m, 1H), 3.67(dd, J＝7.3, 11.2Hz, 1H ),3.53(dd,J=3.9,12.7Hz,1H),3.22-3.07(m,1H),2.09-1.92(m,2H),1.11(d,J=12.7Hz,1H),0.88(d, J=12.7Hz, 1H), 0.53-0.38(m, 4H); MS: m/z[M+H] + =503.
实施例2Example 2
方法BMethod B
3'-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-8',9',9a',10'-四氢-1'H,7'H-螺[环丙烷-1,6'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3'-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-8',9',9a',10'-tetra Hydrogen-1'H,7'H-spiro[cyclopropane-1,6'-pyridin[1',2':3,4]imidazol[1,2-c]pyrimidin]-1'-one
Figure PCTCN2022134253-appb-000135
Figure PCTCN2022134253-appb-000135
室温下，将3'-氯-8',9',9a',10'-四氢-1'H,7'H-螺[环丙烷-1,6'-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶]-1'-酮(80mg，0.3mmol)、(3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苯基)甲醇(86mg，0.3mmol)和碳酸铯固体(195mg，0.6mmol)加入甲苯(10mL)中，100℃搅拌过夜。反应液过滤，滤液浓缩，制备薄层色谱分离得到标题化合物(50mg，33％)。 1H NMR(400MHz,CDCl 3)δ8.55(d,J＝5.4Hz,1H),7.34(d,J＝10.8Hz,1H),7.27-7.25(m,1H),7.23-7.12(m,2H),6.95(d,J＝5.4Hz,1H),5.41(s,2H),5.35(s,1H),3.94-3.84(m,3H),2.04(t,J＝12.5Hz,1H),1.85(br.s.,1H),1.79-1.71(m,1H),1.53(br.s.,1H),1.41-1.29(m,1H),1.20-1.13(m,1H),0.96-0.84(m,2H),0.78-0.68(m,1H),0.58-0.48(m,1H)；MS:m/z[M+H] +＝503。 At room temperature, 3'-chloro-8',9',9a',10'-tetrahydro-1'H,7'H-spiro[cyclopropane-1,6'-pyrido[1',2':3,4]imidazo[1,2-c]pyrimidin]-1'-one (80mg, 0.3mmol), (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl )oxy)phenyl)methanol (86mg, 0.3mmol) and cesium carbonate solid (195mg, 0.6mmol) were added into toluene (10mL), and stirred overnight at 100°C. The reaction solution was filtered, the filtrate was concentrated, and the title compound (50 mg, 33%) was obtained by preparative thin-layer chromatography. 1 H NMR (400MHz, CDCl 3 ) δ8.55(d, J=5.4Hz, 1H), 7.34(d, J=10.8Hz, 1H), 7.27-7.25(m, 1H), 7.23-7.12(m, 2H), 6.95(d, J=5.4Hz, 1H), 5.41(s, 2H), 5.35(s, 1H), 3.94-3.84(m, 3H), 2.04(t, J=12.5Hz, 1H), 1.85(br.s.,1H),1.79-1.71(m,1H),1.53(br.s.,1H),1.41-1.29(m,1H),1.20-1.13(m,1H),0.96-0.84 (m,2H), 0.78-0.68(m,1H), 0.58-0.48(m,1H); MS: m/z[M+H] + =503.
实施例3Example 3
方法CMethod C
3'-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-6',7',9a',10'-四氢-1'H,9'H-螺[氧杂环丁烷-3,8'-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶]-1'-酮3'-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6',7',9a',10'-tetra Hydrogen-1'H,9'H-spiro[oxetane-3,8'-pyrido[1',2':3,4]imidazo[1,2-c]pyrimidine]-1' -ketone
Figure PCTCN2022134253-appb-000136
Figure PCTCN2022134253-appb-000136
室温下，将(3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-8-(羟甲基)-1-氧代-6,7,8,9,9a,10-六氢-1H-吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶-8-基)甲磺酸甲酯(60mg，0.098mmol)加入无水四氢呋喃(20mL)中，加入氢化钠(60％，19.6mg，0.49mmol)，50℃搅拌24小时。反应液用饱和氯化铵水溶液淬灭后倒入水中，乙酸乙酯提取，有机相浓缩，制备薄层色谱分离(二氯甲烷/甲醇＝10/1) 得到标题化合物(15mg，30％)。 1H NMR(400MHz,CDCl 3)δ8.58(d,J＝5.4Hz,1H),7.33(d,J＝11.2Hz,1H),7.24(d,J＝9.3Hz,2H),7.22-7.16(m,1H),6.96(d,J＝5.4Hz,1H),5.46(s,2H),5.05(s,1H),4.69-4.52(m,2H),4.43(s,2H),4.33-4.17(m,1H),3.74(d,J＝7.3Hz,2H),3.62-3.49(m,1H),3.15-2.93(m,1H),2.44(d,J＝12.2Hz,1H),2.26(d,J＝12.7Hz,1H),1.74(br.s.,1H),1.64-1.56(m,1H)；MS:m/z[M+H] +＝519。 At room temperature, (3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-8-(hydroxymethyl)-1 -oxo-6,7,8,9,9a,10-hexahydro-1H-pyrido[1',2':3,4]imidazo[1,2-c]pyrimidin-8-yl)methanol Add methyl sulfonate (60 mg, 0.098 mmol) into anhydrous tetrahydrofuran (20 mL), add sodium hydride (60%, 19.6 mg, 0.49 mmol), and stir at 50°C for 24 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, poured into water, extracted with ethyl acetate, the organic phase was concentrated, and separated by preparative thin-layer chromatography (dichloromethane/methanol=10/1) to obtain the title compound (15 mg, 30%). 1 H NMR (400MHz, CDCl 3 ) δ8.58(d, J=5.4Hz, 1H), 7.33(d, J=11.2Hz, 1H), 7.24(d, J=9.3Hz, 2H), 7.22-7.16 (m,1H),6.96(d,J=5.4Hz,1H),5.46(s,2H),5.05(s,1H),4.69-4.52(m,2H),4.43(s,2H),4.33- 4.17(m,1H),3.74(d,J=7.3Hz,2H),3.62-3.49(m,1H),3.15-2.93(m,1H),2.44(d,J=12.2Hz,1H),2.26 (d, J = 12.7 Hz, 1H), 1.74 (br.s., 1H), 1.64-1.56 (m, 1H); MS: m/z [M+H] + = 519.
实施例4Example 4
方法DMethod D
3'-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-3-羟基-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3'-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3-hydroxy-6',7',9a', 10'-tetrahydro-1'H,9'H-spiro[cyclobutane-1,8'-pyridine[1',2':3,4]imidazol[1,2-c]pyrimidine]-1 '-ketone
Figure PCTCN2022134253-appb-000137
Figure PCTCN2022134253-appb-000137
室温下，将3-((叔丁基二甲基硅基)氧基)-3'-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮(16mg，0.026mmol)加入无水四氢呋喃(2mL)中，搅拌下加入四丁基氟化氨(20.39mg，0.078mmol)，室温搅拌5小时。反应液倒入水中，二氯甲烷提取，有机相浓缩，制备薄层色谱纯化得到标题化合物(5.5mg，40％)。 1H NMR(400MHz,CDCl 3)δ8.57(d,J＝5.4Hz,1H),7.32(d,J＝10.8Hz,1H),7.25-7.14(m,3H),6.95(d,J＝4.4Hz,1H),5.42(s,2H),5.02(s,1H),4.48-4.33(m,1H),4.26-4.15(m,1H),3.82(br.s.,1H),3.72-3.63(m,1H),3.42(d,J＝10.3Hz,1H),3.15-2.99(m,1H),2.44(d,J＝5.4Hz,1H),2.25(d,J＝4.9Hz,1H),2.04(br.s.,1H),1.92(d,J＝13.2Hz,1H),1.72-1.62(m,4H)；MS:m/z[M+H] +＝533。 At room temperature, 3-((tert-butyldimethylsilyl)oxy)-3'-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy )benzyl)oxy)-6',7',9a',10'-tetrahydro-1'H,9'H-spiro[cyclobutane-1,8'-pyridine[1',2':3,4]imidazol[1,2-c]pyrimidine]-1'-one (16mg, 0.026mmol) was added into anhydrous tetrahydrofuran (2mL), and tetrabutylammonium fluoride (20.39mg, 0.078mmol ), stirred at room temperature for 5 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by preparative thin-layer chromatography to obtain the title compound (5.5 mg, 40%). 1 H NMR (400MHz, CDCl 3 ) δ8.57(d, J=5.4Hz, 1H), 7.32(d, J=10.8Hz, 1H), 7.25-7.14(m, 3H), 6.95(d, J= 4.4Hz,1H),5.42(s,2H),5.02(s,1H),4.48-4.33(m,1H),4.26-4.15(m,1H),3.82(br.s.,1H),3.72- 3.63(m,1H),3.42(d,J=10.3Hz,1H),3.15-2.99(m,1H),2.44(d,J=5.4Hz,1H),2.25(d,J=4.9Hz,1H ), 2.04 (br.s., 1H), 1.92 (d, J=13.2Hz, 1H), 1.72-1.62 (m, 4H); MS: m/z[M+H] + =533.
实施例5Example 5
方法EMethod E
3-氨基-3'-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1'-酮3-amino-3'-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6',7',9a', 10'-tetrahydro-1'H,9'H-spiro[cyclobutane-1,8'-pyridine[1',2':3,4]imidazol[1,2-c]pyrimidine]-1 '-ketone
Figure PCTCN2022134253-appb-000138
Figure PCTCN2022134253-appb-000138
室温下，将3'-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-6',7',9a',10'-四氢-1'H,9'H-螺环[环丁烷-1,8'-吡啶[1',2':3,4]咪唑[1,2-c]嘧啶]-1',3-二酮(33mg，0.12mmol)和甲胺盐酸盐(13mg，0.2mmol)加入甲醇(3mL)中，搅拌下加入氰基硼氢化钠(21mg，0.33mmol)，室温搅拌过夜。反应液用水淬灭，二氯甲烷萃取，有机相浓缩，制备薄层色谱纯化得到标题化合物(9mg，25％)。 1H NMR(400MHz,CDCl 3)δ8.58(d,J＝5.4Hz,1H),7.33(d,J＝10.8Hz,1H),7.27-7.25(m,1H),7.23-7.15(m,2H),6.97(br.s.,1H),5.42(br.s.,2H),5.05(s,1H),4.29-4.19(m,1H),3.83(br.s.,1H),3.76-3.61(m,2H),3.51(d,J＝12.2Hz,1H),3.16-2.97(m,1H),2.58(br.s.,3H),2.52-2.34(m,3H),2.30-2.16(m,2H),2.12-1.97(m,2H),1.67-1.59(m,1H)；MS:m/z[M+H] +＝546。 At room temperature, 3'-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6',7',9a', 10'-tetrahydro-1'H,9'H-spiro[cyclobutane-1,8'-pyridine[1',2':3,4]imidazol[1,2-c]pyrimidine]-1 ', 3-diketone (33mg, 0.12mmol) and methylamine hydrochloride (13mg, 0.2mmol) were added to methanol (3mL), and sodium cyanoborohydride (21mg, 0.33mmol) was added with stirring, and stirred overnight at room temperature. The reaction solution was quenched with water, extracted with dichloromethane, the organic phase was concentrated, and purified by preparative thin-layer chromatography to obtain the title compound (9 mg, 25%). 1 H NMR (400MHz, CDCl 3 ) δ8.58(d, J=5.4Hz, 1H), 7.33(d, J=10.8Hz, 1H), 7.27-7.25(m, 1H), 7.23-7.15(m, 2H),6.97(br.s.,1H),5.42(br.s.,2H),5.05(s,1H),4.29-4.19(m,1H),3.83(br.s.,1H),3.76 -3.61(m,2H),3.51(d,J＝12.2Hz,1H),3.16-2.97(m,1H),2.58(br.s.,3H),2.52-2.34(m,3H),2.30- 2.16 (m, 2H), 2.12-1.97 (m, 2H), 1.67-1.59 (m, 1H); MS: m/z [M+H] + = 546.
下表所列的实施例6-34通过类似于实施例1-5所述的步骤制备，起始于相应的中间体：Examples 6-34 listed in the table below were prepared by procedures analogous to those described for Examples 1-5, starting from the corresponding intermediates:
Figure PCTCN2022134253-appb-000139
Figure PCTCN2022134253-appb-000139
Figure PCTCN2022134253-appb-000140
Figure PCTCN2022134253-appb-000140
Figure PCTCN2022134253-appb-000141
Figure PCTCN2022134253-appb-000141
Figure PCTCN2022134253-appb-000142
Figure PCTCN2022134253-appb-000142
Figure PCTCN2022134253-appb-000143
Figure PCTCN2022134253-appb-000143
Figure PCTCN2022134253-appb-000144
Figure PCTCN2022134253-appb-000144
Figure PCTCN2022134253-appb-000145
Figure PCTCN2022134253-appb-000145
Figure PCTCN2022134253-appb-000146
Figure PCTCN2022134253-appb-000146
Figure PCTCN2022134253-appb-000147
Figure PCTCN2022134253-appb-000147
Figure PCTCN2022134253-appb-000148
Figure PCTCN2022134253-appb-000148
生物测试和数据Biological Tests and Data
本发明的化合物为Lp-PLA 2抑制剂，可用于治疗和预防Lp-PLA 2介导的疾病。本发明的化合物的生物活性可使用用于确定化合物作为Lp-PLA 2抑制剂的活性的任何合适的测试，以及组织和体内模型进行测定。 The compound of the present invention is an Lp-PLA 2 inhibitor, and can be used for treating and preventing diseases mediated by Lp-PLA 2 . The biological activity of the compounds of the invention can be determined using any suitable assay for determining the activity of the compounds as Lp- PLA2 inhibitors, as well as tissue and in vivo models.
各化合物的生物活性数据以至少一个实验或多个实验的平均值报告。应理解本发明描述的数据可根据实施实验的人所使用的具体条件和方法而存在合理的变化。Biological activity data for each compound are reported as the average of at least one experiment or multiple experiments. It is to be understood that the data described herein may vary reasonably depending on the particular conditions and methods employed by one who performs the experiments.
脂蛋白-相关磷脂酶A2(Lp-PLA 2)人血浆测定。 Lipoprotein-associated phospholipase A2 (Lp- PLA2 ) human plasma assay.
人血浆测定利用PAF(磷脂酰胆碱)的硫酯类似物，其中水解导致形成包 含游离巯基的磷脂。通过与CPM(7-二乙基氨基-3-(4’-马来酰亚胺基苯基)-4-甲基香豆素)反应来连续测定巯基的量，该CPM为一种在巯基的Michael加成后荧光增加的马来酰亚胺。该测定可以检测在人血浆的Lp-PLA 2的活性，如通过Lp-PLA 2抑制剂的特异性抑制所确定。 The human plasma assay utilizes a thioester analog of PAF (phosphatidylcholine), where hydrolysis results in the formation of phospholipids containing free sulfhydryl groups. The amount of sulfhydryl groups was continuously determined by reaction with CPM (7-diethylamino-3-(4'-maleimidophenyl)-4-methylcoumarin), which is a Fluorescence increases after Michael addition to maleimides. This assay can detect the activity of Lp- PLA2 in human plasma, as determined by specific inhibition of Lp- PLA2 inhibitors.
Thio-PAF测定作为淬灭的75μL测定进行。通过在96孔微量板上在纯DMSO中制备所述各个化合物的1:3(体积)系列稀释液来准备化合物源板。通过Rainin多道移液器将化合物源板上的3μL化合物转移入预先添加57μL测定缓冲液的96孔微量板中，将源板上的化合物进行20倍稀释。上述测试缓冲液含有由50mM HEPES，pH 7.4、150mM NaCl、1mM CHAPS组成。通过Rainin多道移液器将进行20倍稀释后的化合物转移1μL入预先添加等分和解冻的40μL混合人血浆的96孔Greiner 655076(黑色)微量板中。板在酶标板振荡器振荡20秒混匀。室温下30分钟的预孵育后，通过Rainin多道移液器将10μL的底物溶液添加到96孔Greiner 655076(黑色)微量板中，所述底物溶液含有由50mM HEPES，pH 7.4、150mM NaCl、1mM CHAPS组成的测定缓冲液中的2.5mM 2-thio-PAF[来自乙醇母液]、32μM CPM[来自DMSO母液]和3.2mM NEM(N-乙基马来酰亚胺)[每次实验在DMSO中新制备]。2分钟后，用25μL的5％三氟乙酸(TFA)水溶液淬灭反应。板以2000rpm离心1分钟。使用Biotek Synergy H1(H1MF)酶标仪以ex:380/em:485读板。使用GraphPad Prism 6.0和Excel进行IC 50数据、曲线和QC分析。 Thio-PAF assays were performed as quenched 75 μL assays. Compound source plates were prepared by making serial 1 :3 (volume) dilutions of the individual compounds in neat DMSO in 96-well microplates. Transfer 3 μL of the compound on the compound source plate into a 96-well microplate pre-added with 57 μL of assay buffer by a Rainin multichannel pipette, and perform a 20-fold dilution of the compound on the source plate. The above test buffer contains 50mM HEPES, pH 7.4, 150mM NaCl, 1mM CHAPS. 1 μL of the 20-fold diluted compound was transferred by Rainin multichannel pipette into a 96-well Greiner 655076 (black) microplate to which 40 μL of pooled human plasma had previously been aliquoted and thawed. Mix the plate by shaking for 20 seconds on a microplate shaker. After 30 minutes of pre-incubation at room temperature, 10 μL of the substrate solution containing 50 mM HEPES, pH 7.4, 150 mM NaCl , 2.5 mM 2-thio-PAF [from ethanol stock solution], 32 μM CPM [from DMSO stock solution] and 3.2 mM NEM (N-ethylmaleimide) in assay buffer consisting of 1 mM CHAPS [each experiment at Freshly prepared in DMSO]. After 2 minutes, the reaction was quenched with 25 μL of 5% trifluoroacetic acid (TFA) in water. Plates were centrifuged at 2000 rpm for 1 minute. Plates were read at ex:380/em:485 using a Biotek Synergy H1 (H1MF) microplate reader. IC50 data, curves and QC analysis were performed using GraphPad Prism 6.0 and Excel.
实施例测定活性Example Determination of activity
实施例Example IC 50(nM) IC 50 (nM) 实施例Example IC 50(nM) IC 50 (nM) 实施例Example IC 50(nM) IC 50 (nM)
11 4.94.9 22 19.219.2 33 1.41.4
44 3.83.8 55 3.53.5 66 6.76.7
77 14.714.7 88 14.914.9 99 19.919.9
1010 268.4268.4 1111 16.616.6 1212 81.781.7
1313 97.597.5 1414 4.64.6 1515 12.712.7
1616 27.727.7 1717 6.46.4 1818 95.295.2
1919 10.810.8 2020 20.320.3 21twenty one 8.98.9
22twenty two 17.717.7 23twenty three 6.46.4 24twenty four 4.94.9
2525 7.47.4 2626 16.316.3 2727 11.211.2
2828 6.96.9 2929 12.312.3 3030 17.417.4
3131 7.27.2 3232 5.85.8 3333 7.07.0

Claims (18)

  1. 式I所示的化合物或其药学上可以接受的盐：The compound shown in formula I or its pharmaceutically acceptable salt:
    Figure PCTCN2022134253-appb-100001
    Figure PCTCN2022134253-appb-100001
    其中in
    m为1或2；m is 1 or 2;
    n，u独立地为0，1或2；n, u are independently 0, 1 or 2;
    Q为-O-，-S-或-NR a-； Q is -O-, -S- or -NR a -;
    R a为H，C 1-6烷基，C 1-3卤代烷基，C 3-8环烷基或3-8元杂环基； R a is H, C 1-6 alkyl, C 1-3 haloalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl;
    R 1为H，卤素，氰基，氨基，C 1-6烷基，C 1-6烷氧基，C 1-6烷基氨基，C 3-8环烷基或3-8元杂环基，R 1任选被一个或多个以下取代基取代：卤素，氰基，C 1-6烷氧基，C 3-8环烷基、3-8元杂环基或3-8元杂芳基； R 1 is H, halogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclic group , R 1 is optionally substituted by one or more of the following substituents: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl base;
    (R 2) p代表环上的氢被p个R 2取代，每个R 2相同或者不同； (R 2 ) p represents that the hydrogen on the ring is replaced by p R 2s , and each R 2 is the same or different;
    p为2，3，4，5或6；p is 2, 3, 4, 5 or 6;
    R 2，R x，R y独立地选自以下取代基：H，卤素，羟基，羧基，氰基，C 1-6烷基，C 1-6烷氧基，C 3-8环烷基，3-8元杂环基，C 6-10芳基，3-8元杂芳基，-C(O)NR bR c，-S(O) 2NR bR c，并且任选被一个或多个以下取代基取代：卤素，氰基，C 1-6烷氧基，C 3-8环烷基、3-8元杂环基或3-8元杂芳基； R 2 , R x , R y are independently selected from the following substituents: H, halogen, hydroxyl, carboxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl group, 3-8 membered heteroaryl group, -C(O)NR b R c , -S(O) 2 NR b R c , and optionally replaced by one or A plurality of the following substituents are substituted: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl;
    R x，R y连同它们连接的碳原子能够形成3-6元饱和环，该环为全碳环或包含一个或多个选自N，O和S原子的杂环，并且可以被一个或多个R m取代； R x , R y together with their connected carbon atoms can form a 3-6 membered saturated ring, which is a full carbon ring or contains one or more heterocyclic rings selected from N, O and S atoms, and can be surrounded by one or more R m replacement;
    在被p个独立的R 2取代的环上，至少有两个R 2连接在同一碳原子上，且连同它们共同连接的碳原子形成3-6元饱和环，该环为全碳环或包含一个或多个选自N，O和S原子的杂环，并且任选被一个或多个R m取代； On the ring substituted by p independent R 2 , at least two R 2 are connected to the same carbon atom, and form a 3-6 membered saturated ring together with the carbon atoms they are connected to, and the ring is a full carbon ring or contains One or more heterocyclic rings selected from N, O and S atoms, and optionally substituted by one or more R m ;
    R m为C 1-6烷基、C 1-3卤代烷基、卤素，氰基，-OR c，-NR bR c，C 3-6环烷基、3-8元杂环基、C 6-10芳基或3-8元杂芳基； R m is C 1-6 alkyl, C 1-3 haloalkyl, halogen, cyano, -OR c , -NR b R c , C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6 -10 aryl or 3-8 membered heteroaryl;
    R b为H，C 1-6烷基，C 3-8环烷基或3-8元杂环基； R b is H, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group;
    R c为L，L-C(O)-，L-CH 2-或L-S(O) 2-， R c is L, LC(O)-, L-CH 2 - or LS(O) 2 -,
    其中L为H，C 1-6烷基，C 3-6环烷基，3-8元杂环基，C 6-10芳基或3-8元杂芳基，L任选被一个或多个以下基团取代：卤素，羟基，C 1-6烷氧基，氰基，C 3-8环烷基，3-8元杂环基，C 6-10芳基或3-8元杂芳基； Wherein L is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 3-8 membered heteroaryl, L is optionally replaced by one or more The following groups are substituted: halogen, hydroxyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 3-8 membered heteroaryl base;
    A为
    Figure PCTCN2022134253-appb-100002
    A is
    Figure PCTCN2022134253-appb-100002
    Z为N或CR 3； Z is N or CR 3 ;
    Z’为N或CR 4； Z' is N or CR 4 ;
    R 3,R 4,R 5,R 6独立地为H，CN，卤素、C 1-3烷基或C 1-3卤代烷基； R 3 , R 4 , R 5 , R 6 are independently H, CN, halogen, C 1-3 alkyl or C 1-3 haloalkyl;
    V为N或CR 9，其中R 9为H，CN，卤素，C 1-3烷基，C 1-3卤代烷基或-O-W； V is N or CR 9 , wherein R 9 is H, CN, halogen, C 1-3 alkyl, C 1-3 haloalkyl or -OW;
    W为5或6元杂芳基或苯基，其可以任选由一个或多个下列的取代基取代：卤素，氰基，C 1-6烷基，C 1-3烷氧基，C 1-3卤代烷基和C 1-3卤代烷氧基。 W is 5 or 6 membered heteroaryl or phenyl, which can be optionally substituted by one or more of the following substituents: halogen, cyano, C 1-6 alkyl, C 1-3 alkoxy, C 1 -3 haloalkyl and C 1-3 haloalkoxy.
  2. 如权利要求1所述的化合物，其具有以下结构：The compound of claim 1, which has the following structure:
    Figure PCTCN2022134253-appb-100003
    Figure PCTCN2022134253-appb-100003
    其中，取代基R 1，R x，R y，R m，Q，m，u和A如权利要求1中所定义。 Wherein, the substituents R 1 , R x , R y , R m , Q, m, u and A are as defined in claim 1 .
  3. 如权利要求1所述的化合物，其中compound as claimed in claim 1, wherein
    Q为-O-，p为2；Q is -O-, p is 2;
    两个独立的R 2连接在同一碳原子上，且连同它们共同连接的碳原子形成3-6元饱和环，该环为全碳环或包含一个或多个选自N，O和S原子的杂环，并且可以被一个或多个R m取代； Two independent R2 are connected on the same carbon atom, and form 3-6 membered saturated ring together with the carbon atom that they are connected together, and this ring is full carbon ring or contains one or more selected from N, O and S atom Heterocycle, and may be substituted by one or more R m ;
    R 1为H，卤素，氰基，氨基，C 1-6烷基，C 1-3烷氧基，C 1-3烷基氨基，C 1-3卤代烷基。 R 1 is H, halogen, cyano, amino, C 1-6 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 haloalkyl.
  4. 如权利要求1或2所述的化合物，其中u为0，R x,R y为H。 The compound as claimed in claim 1 or 2, wherein u is 0, R x , R y are H.
  5. 如权利要求1或2所述的化合物，其中R 1为H，卤素，C 1-6烷基或C 1-6烷氧基。 The compound as claimed in claim 1 or 2, wherein R is H , halogen, C 1-6 alkyl or C 1-6 alkoxy.
  6. 如权利要求1或2所述的化合物，其中m为1。The compound of claim 1 or 2, wherein m is 1.
  7. 如权利要求l或2所述的化合物，其中A为The compound as claimed in claim 1 or 2, wherein A is
    Figure PCTCN2022134253-appb-100004
    Figure PCTCN2022134253-appb-100004
    R 5,R 6,R 7,R 8,R 9独立地为H、F或CN。 R 5 , R 6 , R 7 , R 8 , R 9 are independently H, F or CN.
  8. 如权利要求l或2所述的化合物或其药学上可以接受的盐，其中A为The compound or pharmaceutically acceptable salt thereof as claimed in claim 1 or 2, wherein A is
    Figure PCTCN2022134253-appb-100005
    Figure PCTCN2022134253-appb-100005
    R 5,R 6,R 7,R 8独立地为H、F或CN； R 5 , R 6 , R 7 , R 8 are independently H, F or CN;
    R 9为-O-W； R 9 is -OW;
    W为5或6元杂芳基或苯基，其可以任选由一个或多个下列的取代基取代:C 1-3卤代烷基、C 1-3卤代烷氧基、CN、卤素和C 1-6烷基。 W is 5 or 6 membered heteroaryl or phenyl, which can be optionally substituted by one or more of the following substituents: C 1-3 haloalkyl, C 1-3 haloalkoxy, CN, halogen and C 1- 6 alkyl.
  9. 如权利要求l或2所述的化合物，其中A为The compound as claimed in claim 1 or 2, wherein A is
    Figure PCTCN2022134253-appb-100006
    Figure PCTCN2022134253-appb-100006
    R 7,R 8独立地为H、F或CN； R 7 , R 8 are independently H, F or CN;
    R 9为-O-W； R 9 is -OW;
    W为吡啶基、嘧啶基、吡唑基或苯基，其任选由一个或多个独立选自以下的取代基所取代：卤素、CN、CF 3、-OCF 3、CHF 2和CH 3。 W is pyridyl, pyrimidinyl, pyrazolyl or phenyl, optionally substituted by one or more substituents independently selected from halogen, CN, CF3 , -OCF3 , CHF2 and CH3 .
  10. 如权利要求1或2所述的化合物，其中R m为H，羟基，甲氧基或甲胺基。 The compound of claim 1 or 2, wherein R m is H, hydroxyl, methoxy or methylamino.
  11. 如权利要求l或2所述的化合物，其中A选自以下基团：The compound as claimed in claim 1 or 2, wherein A is selected from the following groups:
    Figure PCTCN2022134253-appb-100007
    Figure PCTCN2022134253-appb-100007
  12. 如权利要求1或2所述的化合物，其具有以下结构之一：The compound as claimed in claim 1 or 2, which has one of the following structures:
    Figure PCTCN2022134253-appb-100008
    Figure PCTCN2022134253-appb-100008
    Figure PCTCN2022134253-appb-100009
    Figure PCTCN2022134253-appb-100009
    Figure PCTCN2022134253-appb-100010
    Figure PCTCN2022134253-appb-100010
  13. 一种组合物，其包含如权利要求1至12中任一项所述的化合物或其药学上可接受的盐和药学上可接受的赋形剂。A composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  14. 如权利要求1至12中任一项所述的化合物或如权利要求13所述的组合物在制备药物中的用途。Use of the compound according to any one of claims 1 to 12 or the composition according to claim 13 in the preparation of medicaments.
  15. 如权利要求1至12中任一项所述的化合物或如权利要求13所述的组合物在制备治疗、预防或改善与Lp-PLA 2抑制有关的疾病的药物中的用途。 Use of the compound as described in any one of claims 1 to 12 or the composition as claimed in claim 13 in the preparation of medicines for treating, preventing or improving diseases related to Lp- PLA2 inhibition.
  16. 如权利要求1至12中任一项所述的化合物或如权利要求13所述的组合物在制备治疗、预防或改善下列疾病的药物中的用途：糖尿病并发症、神经炎症相关疾病或/和动脉粥样硬化。Use of the compound as described in any one of claims 1 to 12 or the composition as claimed in claim 13 in the preparation of a medicament for the treatment, prevention or improvement of the following diseases: diabetic complications, neuroinflammation-related diseases or/and Atherosclerosis.
  17. 如权利要求16所述的用途，其特征在于所述糖尿病并发症为糖尿病视网膜病变/糖尿病黄斑水肿、糖尿病肾病、糖尿病神经病变、糖尿病外周神经病 变性疼痛或/和糖尿病足，神经炎症相关疾病为阿兹海默症、多发性硬化、肌萎缩性侧索硬化或/和帕金森病。purposes as claimed in claim 16, it is characterized in that described diabetic complication is diabetic retinopathy/diabetic macular edema, diabetic nephropathy, diabetic neuropathy, diabetic peripheral neuropathic pain or/and diabetic foot, neuroinflammation related disease is A Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, or/and Parkinson's disease.
  18. 一种制备权利要求1-12中任一项所述化合物的方法，所述方法包括以下步骤：A method for preparing the compound according to any one of claims 1-12, said method comprising the steps of:
    Figure PCTCN2022134253-appb-100011
    Figure PCTCN2022134253-appb-100011
    步骤(i)：通过将化合物(1.1)脱除Boc保护基生成化合物(1.2)；Step (i): generating compound (1.2) by removing the Boc protecting group from compound (1.1);
    步骤(ii):将化合物(1.2)与化合物(1.3)反应生成化合物(1.5)；Step (ii): reacting compound (1.2) with compound (1.3) to generate compound (1.5);
    步骤(iv)：通过将化合物(1.5)关环得到化合物(1.7)；Step (iv): compound (1.7) is obtained by ring-closing compound (1.5);
    步骤(v):化合物(1.7)与HQ-(CH 2) m-A反应得到最终产物(1.8)，即为式I的化合物； Step (v): react compound (1.7) with HQ-(CH 2 ) m -A to obtain final product (1.8), which is the compound of formula I;
    或包含以下步骤：or include the following steps:
    步骤(i)：通过将化合物(1.1)脱除Boc保护基生成化合物(1.2)；Step (i): generating compound (1.2) by removing the Boc protecting group from compound (1.1);
    步骤(iii)：将化合物(1.2)与化合物(1.4)反应生成化合物(1.6)；Step (iii): reacting compound (1.2) with compound (1.4) to generate compound (1.6);
    步骤(iv’)：通过将化合物(1.6)关环得到化合物(1.7)；Step (iv'): obtain compound (1.7) by ring-closing compound (1.6);
    步骤(v):化合物(1.7)与HQ-(CH 2) m-A反应得到最终产物(1.8)，即为式I的化合物； Step (v): react compound (1.7) with HQ-(CH 2 ) m -A to obtain final product (1.8), which is the compound of formula I;
    其中，R 1，R 2，R x，R y，Q,m,n,p,u,A如权利要求1-12任一项中所定义。 Wherein, R 1 , R 2 , R x , R y , Q, m, n, p, u, A are as defined in any one of claims 1-12.
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