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WO2021089032A1 - 三环二氢咪唑并嘧啶酮衍生物、其制备方法、药物组合物和用途 - Google Patents

三环二氢咪唑并嘧啶酮衍生物、其制备方法、药物组合物和用途 Download PDF

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Publication number
WO2021089032A1
WO2021089032A1 PCT/CN2020/127426 CN2020127426W WO2021089032A1 WO 2021089032 A1 WO2021089032 A1 WO 2021089032A1 CN 2020127426 W CN2020127426 W CN 2020127426W WO 2021089032 A1 WO2021089032 A1 WO 2021089032A1
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Prior art keywords
compound
cyano
halogen
reaction solution
concentrated
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PCT/CN2020/127426
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English (en)
French (fr)
Inventor
金赟
吴金华
彭军
孙勇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Simr Biotechnology Co Ltd
Shanghai Simrd Biotechnology Co Ltd
Original Assignee
Shanghai Simr Biotechnology Co Ltd
Shanghai Simrd Biotechnology Co Ltd
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=75750506&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2021089032(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to NZ789146A priority Critical patent/NZ789146A/en
Priority to CA3156783A priority patent/CA3156783A1/en
Priority to BR112022008786A priority patent/BR112022008786A2/pt
Priority to KR1020227019154A priority patent/KR102816614B1/ko
Priority to MX2022005615A priority patent/MX2022005615A/es
Priority to US17/775,108 priority patent/US20230044787A1/en
Priority to AU2020379796A priority patent/AU2020379796C1/en
Application filed by Shanghai Simr Biotechnology Co Ltd, Shanghai Simrd Biotechnology Co Ltd filed Critical Shanghai Simr Biotechnology Co Ltd
Priority to PE2022000742A priority patent/PE20230092A1/es
Priority to JP2022526201A priority patent/JP7564872B2/ja
Priority to EP20885448.9A priority patent/EP4056571A4/en
Priority to IL292668A priority patent/IL292668A/en
Priority to PH1/2022/551104A priority patent/PH12022551104A1/en
Publication of WO2021089032A1 publication Critical patent/WO2021089032A1/zh
Anticipated expiration legal-status Critical
Priority to CONC2022/0008171A priority patent/CO2022008171A2/es
Priority to JP2024092300A priority patent/JP2024116262A/ja
Ceased legal-status Critical Current

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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • the present invention relates to a new tricyclic dihydroimidazopyrimidinone compound, a preparation method thereof, a pharmaceutical composition containing the compound, 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, and is also known as platelet activating factor acetylhydrolase (PAF-AH).
  • Lp-PLA 2 moves with low-density lipoprotein (LDL) and rapidly cleaves the oxidized phosphatidylcholine molecule obtained from the oxidation of LDL.
  • Lp-PLA 2 hydrolyzes the sn-2 ester of oxidized phosphatidylcholine to obtain the lipid mediator lysophosphatidylcholine (lysoPC) and oxidized non-esterified fatty acid (NEFA). It is reported in the literature that lysoPC and NEFA can cause inflammatory response, so Lp-PLA 2 mediates the oxidative inflammatory response in the body. (Zalewski A et al., Arterioscler. Thromb. Vasc. Biol., 25, 5, 923-31 (2005))
  • 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 (e.g.
  • diabetes bone marrow abnormalities
  • dyslipidemia Paget's disease
  • type II diabetes hypertension
  • angina pectoris myocardial infarction
  • ischemia reperfusion injury
  • metabolic syndrome insulin resistance
  • parathyroid glands Hyperfunction
  • diabetic complications such as macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcers and diabetic nephropathy
  • diabetic peripheral neuropathic pain inflammatory pain, neuropathic pain
  • various cancers 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.
  • 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 pig model of diabetes and hypercholesterolemia that accelerates coronary atherosclerosis (Wilensky et al., Nature Medicine, 10, 1015-1016 (2008)).
  • Clinical studies have also found that Lp-PLA 2 inhibitors can stabilize atherosclerotic plaques in patients with atherosclerotic plaques and prevent the plaques from further development and rupture (Serruys et al., Circulation 118: 1172-1182 (2008)).
  • Lp-PLA 2 activity is associated with high dementia (including Alzheimer’s disease (AD) and mixed dementia) risk (Van Oijen et al., Annals of Neurology, 59, 139 (2006); Fitzpatrick et al., Atherosclerosis 235 : 384-391 (2014)).
  • AD Alzheimer’s disease
  • Higher levels of oxidized LDL are 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)).
  • Lp-PLA 2 inhibitors reduce blood-brain barrier leakage and brain amyloid (Abeta) load, and can be used to treat diseases related to blood-brain barrier leakage, such as Alzheimer's disease And vascular dementia.
  • Abeta brain amyloid
  • Lp-PLA 2 inhibitors can prevent the 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 the production of lysoPC (Shi et al., Atherosclerosis 191, 54-62 (2007)). Therefore, the inhibition of Lp-PLA 2 is a potential treatment method for neurodegenerative diseases (including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, etc.).
  • LysoPC is also involved in leukocyte activation, inducing apoptosis and mediating vascular endothelial cell dysfunction (Wilensky et al., Current Opinion in Lipidology, 20, 415-420, (2009)). Therefore, it is believed that Lp-PLA 2 inhibitors can be used to treat tissue damage related to diabetes by reducing the production of lysoPC. High Lp-PLA 2 activity is associated with a high risk of 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 have also shown that Lp-PLA 2 inhibitors can improve diabetic retinopathy patients Retinal macular edema symptoms and vision (Staurenghi et al., Ophthalmology 122, 990-996 (2015). These studies demonstrate that Lp-PLA 2 inhibitors can be used for diabetic retinopathy.
  • Lp-PLA 2 Studies have shown that the activity of Lp-PLA 2 in diabetic patients is higher than that in 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 the oxidative inflammatory response. It is speculated that inhibiting the activity of Lp-PLA 2 can be used to treat various complications caused by the oxidative inflammatory response in the body in diabetic patients, such as diabetic nephropathy and diabetes. Peripheral neuropathy and diabetic skin ulcers, etc.
  • Glaucoma and age-related macular degeneration are neurodegenerative diseases of the retina. 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, ISSN0079-6123, Chapter 28). Therefore, Lp-PLA 2 inhibitors can provide potential therapeutic applications for glaucoma and AMD.
  • Lp-PLA 2 inhibitors can be used to treat male erectile dysfunction.
  • Lp-PLA 2 There prostate carcinoma Lp-PLA 2 expression, reduced Lp-PLA 2 can be reduced prostate cancer cells in vitro and promotes apoptosis in prostate cancer (Vainio et al., Oncotarget, 2: 1176-1190 (2011 )) , Suggesting that Lp-PLA 2 inhibitors can be used to treat prostate cancer.
  • the purpose of the present invention is to provide a pyrimidinone compound and a pharmaceutical composition thereof, which can be used as an Lp-PLA 2 inhibitor.
  • the present invention relates to a compound represented by formula I, its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, Its hydrate or its pharmaceutically acceptable salt or its prodrug,
  • n 0, 1 or 2
  • R 2 is methyl or ethyl, and when n is 1 or 2, R 2 does not exist;
  • R 1 is H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, R 1 may be optionally substituted by one or more Substitution with one of the following substituents: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 6-10 membered heteroaryl;
  • R a is H or D independently
  • n 1 or 2;
  • R x is H, halogen, hydroxy, carboxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 6-10 Membered aryl group, 6-10 membered heteroaryl group, -C(O)NR b R c , -S(O) 2 NR b R c , R x may be optionally substituted by one or more of the following substituents: halogen, Hydroxy, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 6-10 membered heteroaryl;
  • Q is -O-, -S-, -CH 2 -or -NR b -;
  • X is -O-, -CH 2 -, -NR c -, -OCH 2 -or not present;
  • R b is H, C 1-6 alkyl or C 3-8 cycloalkyl or 3-8 membered heterocyclic group
  • R c is L, LC(O)-, L-CH 2 -or LS(O) 2 -, where L is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocycle Group, 6-10 membered aryl group or 6-10 membered heteroaryl group, L may be optionally substituted by one or more of the following groups: halogen, hydroxyl, C 1-6 alkoxy, cyano, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 6-10 membered heteroaryl;
  • Y is -CH 2 -, -CH 2 CH 2 -or does not exist
  • U is -CH 2 -, -C(O)- or does not exist;
  • Y and U may be optionally substituted by one or more of the following substituents: halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, 3-8 membered Heterocyclyl, 6-10 membered aryl or 6-10 membered heteroaryl;
  • Z is N or CR 3
  • R 3 , R 4 , R 5 , and R 6 are independently H, cyano, halogen or C 1-3 haloalkyl; V is N or CR 9 , wherein R 9 is H, cyano, halogen, C 1-3 Alkyl, C 1-3 haloalkyl or -OW; W is phenyl or 5 or 6-membered heteroaryl, which may 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.
  • R 1 is H and Rx is H.
  • R 2 is not present.
  • R x is H.
  • X is -O- or -CH 2 -.
  • U is -CH 2 -;
  • X is -NR c -, R c is methyl, oxetanyl, trifluoroethyl, benzoyl, cyclobutyl, benzyl,
  • U is -C(O)-; R 1 and R x are both H, Y is -CH 2 -; X is -NR c -, R c is L or LC(O)-, Where L is methyl, trifluoroethyl, benzoyl, oxetane, cyclobutane, benzyl, Further, L is a methyl group.
  • Y is -CH 2 -;
  • R 1 is H, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-6 alkoxy;
  • Q is -O -.
  • R x is H, halogen, cyano, amino, difluoromethyl
  • R x is H, halogen, cyano, amino, difluoromethyl
  • R 1 is H, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 1-6 alkoxy
  • Q is -O-.
  • Rx is H.
  • n 2; U is -CH 2 -; X is -CH 2 -or -O-; Y is -CH 2 -or not present; R x is H, halogen, cyano, amino , Difluoromethyl, R 1 is H, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 1-6 alkoxy; and Q is -O-. Further, Rx is H and R 1 is H.
  • R 1 is H, cyano or C 1-3 haloalkyl; and R x is H.
  • R 1 is H, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-6 alkoxy; and R x is H.
  • R 5 , R 6, R 7 , R 8 , and R 9 are independently H, F or cyano.
  • R 5 , R 6, R 7 and R 8 are independently H, F or cyano; R 9 is -OW, W is 5 or 6-membered heteroaryl or phenyl, which may optionally consist of one or more of the following Substituents for substitution: C 1-3 haloalkyl, C 1-3 haloalkoxy, cyanohalogen and C 1-6 alkyl.
  • the compound has formula I'
  • R 1 is H, cyano, halogen, C 1-6 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl;
  • X is -O-, -CH 2 -, -NRc- or not present ;
  • R c is L or LC(O)-, where L is H, C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 1-3 haloalkyl, or benzyl ;
  • Y is -CH 2 - or absent;
  • n, R 2, R a , A, m are as defined in formula (I).
  • n 0, R 2 is methyl or ethyl; R 1 is H; R a is H; m is 1; X is -O- or -CH 2 -.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • R 1 is H, halogen, cyano, C 1-6 alkyl, C 1-3 haloalkyl or C 1-6 alkoxy (further, the halogen is fluorine or chlorine, and the C 1- 6 alkyl is methyl, ethyl or isopropyl, said C 1-3 haloalkyl is trifluoromethyl, and said C 1-6 alkoxy is methoxy);
  • R 2 is methyl or Ethyl;
  • R c is C 1-6 alkyl, 3-8 membered heterocyclic group, C 1-3 haloalkyl, benzoyl, C 3-8 cycloalkyl, benzyl or (Further, the C 1-6 alkyl group is a methyl group, the 3-8 membered heterocyclic group is an oxetanyl group, the C 1-3 haloalkyl group is a trifluoroethyl group, and the C 3 -8 cycloalkyl is cyclo
  • R 1 is H, halogen, cyano, C 1-6 alkyl, C 1-3 haloalkyl or C 1-6 alkoxy (further, the halogen is fluorine or chlorine, and the C 1- 6 alkyl is methyl, ethyl or isopropyl, said C 1-3 haloalkyl is trifluoromethyl, and said C 1-6 alkoxy is methoxy);
  • R 2 is methyl or Ethyl;
  • R c is C 1-6 alkyl, 3-8 membered heterocyclic group, C 1-3 haloalkyl, benzoyl, C 3-8 cycloalkyl, benzyl or (Further, the C 1-6 alkyl group is a methyl group, the 3-8 membered heterocyclic group is an oxetanyl group, the C 1-3 haloalkyl group is a trifluoroethyl group, and the C 3 -8 cycloalkyl is cyclo
  • A is selected from the following groups:
  • the compound of general formula (I) above is the following compound:
  • the present invention relates to a compound represented by formula I', its cis-trans isomers, its enantiomers, its diastereomers, its racemates, and its solvates , Its hydrate or its pharmaceutically acceptable salt or its prodrug,
  • R 2 is methyl or ethyl, and when n is not 0, R 2 does not exist;
  • R 1 is H, halogen, C 1-6 alkyl or C 3-6 cycloalkyl
  • R a is H or D independently
  • n 1 or 2;
  • X is -O-, -CH 2 -, -NR- or not present;
  • R is LC(O)-, L-CH 2 -or LS(O) 2 -, where L is H, C 1-3 alkyl, C 3-6 cycloalkyl or phenyl;
  • Y is -CH 2 -or does not exist
  • Z is N or CR 3
  • R 3 , R 4 , R 5 , and R 6 are independently H, CN, halogen or C 1-3 haloalkyl;
  • V is N or 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 heteroaromatic ring or phenyl, which may be optionally substituted by one or more of the following substituents: C 1-3 haloalkyl, C 1-3 haloalkoxy, CN, halogen, and C 1- 5 Alkyl.
  • n in the compound of general formula (I') above is not 0 and has one or more of the following characteristics:
  • R 1 is H, R a is H;
  • n in the compound of general formula (I') is 0 and has one or more of the following characteristics:
  • R 1 is H, R a is H;
  • R 2 is methyl
  • A is wherein R 5 , R 6, R 7 , R 8 , and R 9 are independently H, F or CN.
  • A is Wherein R 5 , R 6, R 7 , and R 8 are independently H, F or CN; R 9 is -OW; W is 5 or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is either Optionally substituted by one or more of the following substituents: C 1-3 haloalkyl, C 1-3 haloalkoxy, CN, halogen, and C 1-5 alkyl.
  • A is Wherein R 7 and R 8 are independently H, F or CN; R 9 is -OW; W is pyridyl, pyrimidinyl, pyrazolyl and phenyl, wherein the pyridyl, pyrimidinyl, pyrazolyl or benzene The group is optionally substituted by one or more of the following substituents: halogen, CN, CF 3 , -OCF 3 and CH 3 . In some embodiments, A is
  • the compound is any one of the following compounds:
  • the compound of the above formula and its salt may exist in the form of stereoisomers (for example, it contains one or more asymmetric carbon atoms).
  • stereoisomers for example, it contains one or more asymmetric carbon atoms.
  • the single stereoisomers (enantiomers and diastereomers) and their mixtures are all included in the scope of the present invention.
  • the present invention also includes various deuterated forms of the compound of the above formula, and salts thereof (for example, pharmaceutically acceptable salts).
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those of ordinary skill in the art will know how to synthesize the deuterated form of the compound of the above formula, its salt (for example, a pharmaceutically acceptable salt).
  • Commercially available deuterated raw materials can be used in the preparation of deuterated forms of the compounds of the above formula and their salts (for example, pharmaceutically acceptable salts), or conventional deuterated reagents (such as lithium aluminum deuteride) can be used. Technology to synthesize these compounds.
  • the salt forms of the compounds are also within the scope of the present invention.
  • the salt or pharmaceutically acceptable salt of the compound of the present invention can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in free acid or free base form with a suitable base or acid. 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, page 453-497.
  • the present invention provides a compound as defined herein, a polymorph of a salt thereof (e.g., a pharmaceutically acceptable salt), or a compound described herein or a salt thereof (e.g., a pharmaceutically acceptable salt). Accepted salt) solvates or polymorphs of hydrates.
  • the present invention also includes isotopically-labeled compounds and salts, which are equivalent to the compounds of the above formula or their salts, but one or more atoms are replaced by an atom whose atomic mass or mass number is different from the atomic mass or mass number most often found in nature .
  • isotopes that can be incorporated into the compound of the above formula or its salt are isotopes of hydrogen, carbon, nitrogen, and deuterium.
  • 3 H, 11 C, 14 C, and 18 F labeled compounds of the above formula or their salts can be used Drug and/or substrate tissue distribution test.
  • 11 C and 18 F isotopes can be used for 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 compound of the present invention includes a compound of the above formula, or a salt thereof, for example, a pharmaceutically acceptable salt thereof.
  • the representative compound of the present invention includes the specific compound.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable excipient.
  • the present invention also relates to a method for treating or preventing diseases related to the activity of Lp-PLA 2 , comprising administering to a subject in need a therapeutically effective amount of the compound of the present invention described herein.
  • the disease can be associated with the involvement of monocytes, macrophages or lymphocytes in increasing the formation of lysophosphatidylcholine and oxidized free fatty acids, oxidation of lipids or endothelial dysfunction associated with Lp-PLA 2 activity.
  • the present invention also provides methods for treating or preventing diseases by inhibiting Lp-PLA 2 activity.
  • 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 brain Atherosclerosis, stroke, metabolic bone disease (e.g.
  • dyslipidemia Paget's disease, type II diabetes, hypertension, angina pectoris, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance And hyperparathyroidism, diabetic complications (such as macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcers and diabetic nephropathy), diabetic peripheral neuropathic pain, inflammatory pain, neuropathic pain, various cancers (E.g.
  • the method includes administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • the present invention is not intended to be limited to any specific stage (such as early or late) of the disease.
  • the present invention also provides methods for treating or preventing Alzheimer's disease.
  • the method includes 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 includes 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 ocular diseases by administering the compounds of the present invention.
  • the present invention provides a method of treating macular edema, which comprises administering to a subject a therapeutically effective amount of a compound of the present invention.
  • the macular edema is related to diabetic eye disease (eg, diabetic macular edema or diabetic retinopathy).
  • the macular edema is related to 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 diseases related to Lp-PLA 2.
  • 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 brain Atherosclerosis, stroke, metabolic bone disease (e.g.
  • dyslipidemia Paget's disease, type II diabetes, hypertension, angina pectoris, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance And hyperparathyroidism, diabetic complications (such as macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcers and diabetic nephropathy), diabetic peripheral neuropathic pain, inflammatory pain, neuropathic pain, various cancers (E.g.
  • the method includes administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • the present invention is not intended to be limited to any specific stage (such as early or late) of the disease.
  • the present invention also provides a compound of the present invention for use in the treatment or prevention of the diseases described herein.
  • disease refers to any change in the state of the body or some organs that interrupts or interferes with the performance of functions and/or causes symptoms in a person who is ill or in contact with (such as discomfort, dysfunction, adverse stress and even death).
  • diabetic retinopathy refers to the result of chronic progressive retinal microvascular leakage and obstruction caused by diabetes.
  • Diabetic macular edema refers to the thickening or hard exudation of the retina caused by the accumulation of extracellular fluid within a diameter of the optic disc in the fovea of the macula caused by diabetes.
  • neurodegenerative diseases refer to different kinds of central nervous system disorders characterized by a gradual and progressive loss of nerve tissue and/or nerve tissue function.
  • Neurodegenerative diseases are a type of neurological diseases, in which the neurological diseases are characterized by the gradual and progressive loss of nerve tissue and/or altered nerve function, usually due to the gradual and progressive loss of nerve tissue. Reduced functionality.
  • the neurodegenerative diseases described herein include neurodegenerative diseases in which there is a defective blood-brain barrier (e.g., a permeable blood-brain barrier). Examples of neurodegenerative diseases with defective blood-brain barriers include, but are not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, and vascular dementia.
  • vascular dementia is also referred to as “multi-infarct dementia”, which refers to a group of different mechanisms (all of which cause damage to blood vessels in the brain).
  • vascular dementia is also referred to as “multi-infarct dementia”, which refers to a group of different mechanisms (all of which cause damage to blood vessels in the brain).
  • the main subtypes of vascular dementia are vascular mild cognitive impairment, multiple infarct dementia, and vascular dementia due to a major single infarction (affecting the thalamus, anterior cerebral artery, parietal lobe, or cingulate gyrus) , Vascular dementia due to hemorrhagic damage, small vessel diseases (including, for example, vascular dementia due to lacunar damage and Binswanger disease) and mixed dementia.
  • neuroopathic pain is pain that is triggered or caused by primary damage and dysfunction of the nervous system.
  • inflammatory pain is pain caused by local acute inflammation or chronic inflammation that stimulates nerves.
  • diabetic peripheral neuropathic pain refers to pain caused by nerve damage complicated by diabetes, which is caused at least in part by reduced blood flow and hyperglycemia.
  • blood-brain barrier or “BBB” are used interchangeably herein to refer to a permeable barrier that exists in blood vessels that pass through brain tissue, which strictly limits and closes To regulate the exchange of substances between blood and brain tissue.
  • the blood-brain barrier components include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that are structurally related to BBB, the basement membrane of endothelial cells, and the extravascular covering almost all exposed blood vessels. Enlarged foot processes of astrocytes near the surface.
  • metabolic bone disease refers to a different kind of bone disease characterized by the gradual and progressive loss of bone tissue.
  • the metabolic bone disease described herein is a bone metabolic disease in which there is a condition of diffuse decrease in bone density and/or decrease in bone strength. Such diseases are characterized by histological appearance.
  • Exemplary metabolic bone diseases include, but are not limited to, osteoporosis characterized by reduced minerals and bone matrix and osteomalacia characterized by reduced minerals but with intact bone matrix.
  • osteoopenia disease or “osteopenia” may be used interchangeably herein, and refers to a condition with decreased calcification and/or bone density, and is used to indicate in which Descriptive term for all skeletal systems where calcification and/or decreased bone density are observed. Osteopenia also refers to osteopenia due to insufficient osteoid synthesis.
  • osteoporosis refers to a condition in which minerals and/or bone matrix are reduced and/or bone matrix is reduced.
  • alkyl is a monovalent, saturated chain with the specified number of carbon atoms.
  • C 1-3 alkyl refers to an alkyl group having 1 to 3 carbon atoms.
  • the C 1-5 alkyl group refers to an alkyl group having 1 to 5 carbon atoms.
  • the C 1-6 alkyl group refers to an alkyl group having 1 to 6 carbon atoms.
  • Alkyl groups can be straight or branched. In some embodiments, the branched alkyl group may have one, two, or three branches.
  • alkyl groups include, but are not limited to, methyl, methylethyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl Base, hexyl.
  • alkoxy substituents are groups of the formula "RO-", where R is an alkyl group as defined above.
  • R is an alkyl group 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-pentoxy, n-hexyloxy, isopropoxy, isobutoxy , Sec-butoxy, tert-butoxy, isopentoxy and neopentoxy.
  • cycloalkyl refers to a monovalent saturated cyclic hydrocarbon group including bridged rings and spiro rings, preferably having 3-8 ring carbon atoms (C 3-8 cycloalkyl), 3-7 ring carbons Atom (C 3-7 cycloalkyl) or 3-6 ring carbon atoms (C 3-6 cycloalkyl), such as cyclopropyl, cyclobutyl, cyclopentyl or [1,1,1] propeller Alkanes, and those groups specifically exemplified below.
  • C 3-6 cycloalkyl is a monovalent group obtained by removing one hydrogen atom from a 3-, 4-, 5-, or 6-membered monocyclic cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl means a hydrocarbon group containing one or more aromatic rings, such as phenyl or naphthyl and the like.
  • heteroaryl is a monovalent group obtained by removing one hydrogen atom from a monocyclic 5- or 6-membered heteroaromatic ring consisting of a ring-carbon atom and selected from nitrogen, The ring-heteroatom composition of oxygen and sulfur, and the ring is aromatic.
  • a heteroaryl group is a monocyclic heteroaryl group composed of 5 or 6 ring atoms, of which 1 to 3 are ring-heteroatoms.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazole Group, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, aza Oxazepine Base, thiazepine Diaza base.
  • heteroaryl means a stable monocyclic, bicyclic, or tricyclic ring having up to 7 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, furanyl, thienyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl, benzothienyl, benzofuran Group, benzodioxane, benzodioxabenzene, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, Pyridyl, pyrimidinyl, pyrrolyl, te
  • heteroaryl groups have 5- or 6-membered rings, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl , Pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl.
  • heterocyclic group is a monovalent group obtained by removing one hydrogen atom from a 3-, 4-, 5-, or 6-membered saturated monocyclic heterocyclic ring, the ring consisting of a ring-carbon atom and Ring-heteroatom composition selected from nitrogen, oxygen and sulfur.
  • exemplary monocyclic saturated heterocyclyl substituents include, but are not limited to, pyrrolidinyl, dioxolane, imidazolidinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholino, Dithiaalkyl, thiomorpholino and piperazinyl.
  • 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 replaced by O heteroatoms.
  • Heterocycles can be saturated or unsaturated, but are not aromatic.
  • the heterocyclic group can also contain 1, 2 or 3 rings, including bridged rings and spiro ring structures.
  • heterocyclic groups include, but are not limited to: azetidine, oxetane, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrrolinyl, pyran Group, dioxolane, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiolanyl, oxathiolanyl Group, dioxanyl group, dioxenyl group, dioxazolyl group, oxathiozolyl group (oxathiozolyl), oxazolone group, piperazinyl group, morpholino group, thiomorpholinyl group, 3-oxomorpholinyl group , Dithiaalkyl, trithiaalkyl and oxazinyl.
  • bridged ring compound refers to one or more atoms (ie, C, O, N, or S) connecting two non-adjacent carbon atoms 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 one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In bridged rings, substituents on the ring can also appear on the bridge.
  • spiro compound refers to a polycyclic compound in which two monocyclic rings share one carbon atom, and the shared carbon atom is called a spiro atom.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • Halo refers to halogen groups: 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.
  • the ring when two substituents on a ring together with their interconnected atoms combine to form another ring, the ring may be spiro-fused or unilaterally fused.
  • the spiro-fused ring system consists of two rings that have only one carbon atom in common.
  • a unilateral-fused ring system consists of two rings that share only two atoms and one bond.
  • 4-, 5-, or 6-membered saturated ring which optionally contains one heteroatom selected from N or O
  • treatment refers to: (1) alleviating the disease or alleviating one or more biological manifestations of the disease, (2) interference (a) One or more points in the biological cascade that cause or cause the disease or (b) one or more biological manifestations of the disease, (3) alleviate one or more symptoms or effects related to the disease , And/or (4) slow the progression of the disease or one or more of the biological manifestations of the disease, and/or (5) reduce the severity of the disease or the possibility of the biological manifestations of the disease.
  • prevention refers to the prophylactic administration of drugs to reduce the likelihood 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 the lowest undesirable 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 free acid or free base form with a suitable base or acid, respectively.
  • the term "therapeutically effective amount” refers to an amount that causes treatment or prevention of disease compared to a corresponding subject who did not receive the amount, but the amount is within the range of reasonable medical judgment Low enough to avoid serious side effects (with a reasonable benefit/risk ratio).
  • the therapeutically effective amount of the compound will depend on the specific compound selected (for example, taking into account the potency, efficacy and half-life of the compound): the chosen route of administration; the disease to be treated; the severity of the disease to be treated; the age, size, and weight of the patient to be treated And physical condition: the medical history of the treated patient; the duration of the treatment; the nature of the concurrent treatment; the required treatment effect and other factors may change, but it can still be determined by those skilled in the art in a conventional manner.
  • the substituents described herein are incompatible with the synthetic methods described herein, the substituents can be protected with suitable protecting groups that are stable under the reaction conditions.
  • the protecting group can be removed at a suitable point in the reaction sequence to obtain the desired intermediate or target compound.
  • suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of this can be found in I. Greene and P. Wuts, Protecting Groups in Chemical Found in Synthesis (third edition), John Wiley & Sons, NY (1999).
  • substituents that are reactive under the reaction conditions used can be specifically selected. In these cases, the reaction conditions transform the selected substituent into another substituent that can be used as an intermediate compound or another substituent that is a desired substituent in the target compound.
  • Step (i) can be used as a S N Ar reaction, using a suitable reagent, such as triethylamine in a suitable solvent such as acetonitrile at a suitable temperature, such as room temperature, to react compound 1.1 with 1.2 to produce compound 1.3.
  • Step (ii) can be achieved by combining compound 1.3 with a suitable reagent such as triethylamine and methanesulfonyl chloride or thionyl chloride at a suitable temperature, such as 0°C or room temperature, to convert the hydroxyl group into a methanesulfonate or chlorinated compound.
  • Step (iii) combine 1.4 with the corresponding alcohol or amine HQ-(CH 2 ) m -A (Q is -O- or -NR b -) in a suitable base such as NaH or DIPEA in a suitable solvent such as acetonitrile or
  • a suitable base such as NaH or DIPEA
  • a suitable solvent such as acetonitrile or
  • the reaction in 1,4-dioxane gives the final product 1.5.
  • Compound 2.5 is prepared starting from alcohol 2.1 and trichloropyrimidine substituted with R 1. The changes in reaction conditions and reactants are obvious to those skilled in the art.
  • Q is -CH 2 -, please refer to Example 170 for the specific synthesis scheme.
  • Step (i) can be used as a S N Ar reaction, using a suitable reagent, such as triethylamine in a suitable solvent such as acetonitrile at a suitable temperature, such as room temperature, to react compound 1.1 with 1.2 to produce compound 1.3.
  • Step (ii) can be achieved by combining compound 1.3 with a suitable reagent such as triethylamine and methanesulfonyl chloride or thionyl chloride at a suitable temperature, such as 0°C or room temperature, to convert the hydroxyl group into a methanesulfonate or chlorinated compound.
  • Step (iii) react 1.4 with the corresponding alcohol HO-(CH 2 ) m -A in a suitable base such as NaH in a suitable solvent such as acetonitrile to obtain the final product 1.5.
  • Compound 2.5 is prepared starting from alcohol 2.1 and trichloropyrimidine substituted with R 1. The changes in reaction conditions and reactants are obvious to those skilled in the art.
  • the compounds of the present invention are Lp-PLA 2 inhibitors. Therefore, these compounds can be used to treat, for example, treat or prevent diseases related to the activity of Lp-PLA 2 , which includes treating a subject in need of such treatment with a therapeutically effective amount of an Lp-PLA 2 inhibitor. Therefore, one aspect of the present invention relates to a method of treating or preventing diseases related to Lp-PLA 2 activity.
  • a particular disease or its treatment may involve one or more potential mechanisms related to Lp-PLA 2 activity, including one or more of the mechanisms described herein.
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment or prevention of any disease 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, 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
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment of eye diseases.
  • the ophthalmopathy applicable in the present invention may be related to the destruction of the blood-retinal barrier (iBRB).
  • Exemplary eye diseases involve diabetic eye diseases, which include macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion, and the like.
  • More eye diseases include, but are not limited to, central retinal vein occlusion, branch retinal vein occlusion, I-Ga syndrome (post-cataract and post-surgery), retinitis pigmentosa, planitis, shotgun retinal choroidopathy, retina Outer membrane, choroidal tumors, cystic macular edema, parafoveal telangiectasia, traction macular disease, vitreous macular traction syndrome, retinal detachment, optic neuroretinitis, idiopathic macular edema, etc. More details on the use of Lp-PLA 2 inhibitors to treat eye diseases are provided in WO2012/080497, which is incorporated herein by reference.
  • some embodiments of the present invention provide the use of the compound of the present invention in the preparation of a medicament for treating or preventing diabetic macular edema in a subject.
  • the present invention provides the use of a compound of the present invention for the treatment of diabetic macular edema in a subject.
  • the present invention provides the use of a compound of the present invention in the preparation of a medicament for the treatment or prevention of subjects suffering from or at risk of developing macular edema. In some embodiments, the present invention provides the use of the compound of the present invention in the preparation of a medicament for treating subjects suffering from or at risk of suffering from macular edema. In other embodiments, the macular edema is related to diabetic eye disease, such as diabetic macular edema or diabetic retinopathy. In other embodiments, the macular edema is related to posterior uveitis.
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment or prevention of glaucoma or macular degeneration. In some embodiments, the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment of glaucoma or macular degeneration.
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment or prevention of diseases related to the destruction of the blood-retinal barrier in a subject in need of such treatment. In some embodiments, the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment of diseases related to the destruction of the blood-retinal inner barrier in a subject in need of such treatment.
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment or prevention of any of the following diseases involving endothelial dysfunction, for example, atherosclerosis (eg, peripheral vascular atherosclerosis) Sclerosis and cerebrovascular atherosclerosis), diabetes, hypertension, angina pectoris, ischemia and conditions after reperfusion.
  • atherosclerosis eg, peripheral vascular atherosclerosis
  • Sclerosis peripheral vascular atherosclerosis
  • cerebrovascular atherosclerosis cerebrovascular atherosclerosis
  • diabetes e.g, hypertension, angina pectoris, ischemia and conditions after reperfusion.
  • the present invention provides the use of a compound of the present invention in the preparation of a medicament for the treatment or prevention of any of the following diseases involving lipid oxidation associated with enzyme activity, for example, in addition to, for example, atherosclerosis Diseases other than diabetes and other diseases, such as rheumatoid arthritis, stroke, inflammatory diseases of the brain (such as Alzheimer's disease), various neuropsychiatric disorders (such as schizophrenia, autism), and myocardial infarction , Ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.
  • atherosclerosis Diseases other than diabetes and other diseases such as rheumatoid arthritis, stroke, inflammatory diseases of the brain (such as Alzheimer's disease), various neuropsychiatric disorders (such as schizophrenia, autism), and myocardial infarction , Ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for reducing the probability of cardiovascular events (eg, heart attack, myocardial infarction, or stroke) in patients suffering from coronary heart disease.
  • cardiovascular events eg, heart attack, myocardial infarction, or stroke
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment or prevention of diseases involving activated monocytes, macrophages or lymphocytes, because all these cell types express Lp-PLA 2 includes diseases involving activated macrophages (such as M1, dendrites and/or other oxidative stress-producing macrophages).
  • Exemplary disorders include, but are not limited to, epilepsy, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease (COPD), liver 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 present invention provides the use of the compound of the present invention in the preparation of a medicament for primary or secondary prevention of acute coronary events (for example, caused by atherosclerosis); prevention of restenosis Adjuvant treatment; or delay the development of diabetes or hypertensive renal insufficiency. Prevention includes treating subjects who are at risk for such conditions.
  • the present invention provides methods for treating or preventing neurological disorders related to abnormal blood-brain barrier (BBB) function, inflammation, and/or microglial activation in a subject in need of such treatment.
  • BBB blood-brain barrier
  • the present invention provides methods for treating or preventing neurological disorders related to abnormal blood-brain barrier (BBB) function, inflammation, and/or microglial activation in a subject in need of such treatment.
  • the method includes administering to the 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 methods for treating or preventing diseases related to blood-brain barrier (BBB) leakage in a subject.
  • BBB blood-brain barrier
  • the present invention provides methods for treating diseases related to blood-brain barrier (BBB) leakage in a subject.
  • 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 present invention can be used to treat or prevent neurodegenerative diseases in a subject.
  • the method includes administering a compound of the invention (e.g., in the form of a pharmaceutical composition comprising the compound of the invention) to a subject in need of such treatment.
  • the compounds of the invention can be used to treat neurodegenerative diseases in a subject.
  • neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease.
  • the neurodegenerative disease of the present invention is related to an abnormal blood-brain barrier.
  • the subject to which the agent that inhibits Lp-PLA 2 activity is administered is a human.
  • the present invention provides methods of treating or preventing subjects suffering from or at risk of vascular dementia.
  • the method includes administering a compound of the invention (e.g., a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention) to a subject.
  • a compound of the invention e.g., a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention
  • the present invention provides methods of treating subjects suffering from or at risk of vascular dementia.
  • the vascular dementia is related to Alzheimer's disease.
  • the present invention relates to a method of treating or preventing metabolic bone disease by administering a therapeutically effective amount of the compound of the present invention to a subject in need of such treatment.
  • the present invention relates to a method of treating metabolic bone disease by administering a therapeutically effective amount of the compound of the present invention to a subject in need of such treatment.
  • Exemplary metabolic bone diseases include diseases related to the loss of bone mass and bone density, including but not limited to osteoporosis and osteopenia diseases.
  • Exemplary osteoporosis and osteopenia 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 this treatment is a human.
  • some embodiments of the present invention provide methods for inhibiting Lp-PLA 2 by blocking enzyme activity. In other embodiments, methods for inhibiting Lp-PLA 2 by reducing and/or down-regulating the expression of Lp-PLA 2 RNA are provided. In other embodiments, preventing and/or reducing bone loss and I or bone density loss results in preventing or reducing symptoms associated with metabolic bone diseases such as osteoporosis and/or osteopenic diseases.
  • the method further comprises administering other therapeutic agents for the treatment of metabolic bone disease to the subject in need of treatment.
  • other therapeutic agents can be used, such as bisphosphates (for example, alendronate, iban phosphate, risen phosphate, hypotensive Calcin, raloxifene), selective estrogen modulators (SERM), estrogen therapy, hormone replacement therapy (ET/HRT) and teriparaseptide.
  • bisphosphates for example, alendronate, iban phosphate, risen phosphate, hypotensive Calcin, raloxifene
  • SERM selective estrogen modulators
  • E/HRT hormone replacement therapy
  • teriparaseptide teriparaseptide
  • systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic Lupus erythematosus, Fu-Koyanagi-Harada syndrome, Lyme disease, Behcet's disease, ankylosing spondylitis, chronic granulomatous disease, enthesitis may be the root cause of posterior uveitis affecting the retina Reason, 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, Fu-Koyanagi-Harada syndrome, Lyme disease, Behcet's disease, ankylosing spondylitis, chronic
  • the present invention relates to a method for treating or preventing posterior uveitis or any of these systemic inflammatory diseases by administering a therapeutically effective amount of the compound of the present invention.
  • the present invention provides methods for treating post uveitis or any of these systemic inflammatory diseases by administering a therapeutically effective amount of a compound of the present invention.
  • the treatment and/or prevention of diseases related to Lp-PLA 2 activity can be obtained by using the compounds of the present invention in monotherapy or in dual or multiple combination therapy.
  • the compounds of the present invention can be used in combination with anti-hyperlipidemic agents, anti-atherosclerotic agents, anti-diabetic agents, anti-angina pectoris agents, anti-inflammatory agents or anti-hypertensive agents or for lowering lipoprotein (a) (Lp(a)) Combination of medicaments to treat or prevent the diseases described in this invention.
  • agents for lowering Lp(a) include phosphoramidates described in WO 97/02037, WO 98/28310, WO 98/28311, and WO 98/28312.
  • the compounds of the present invention can be used with one or more statins.
  • Statins are well-known cholesterol lowering agents and include atorvastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin, and rosuvastatin.
  • the compounds of the present invention can be used with antidiabetic drugs or insulin sensitizers.
  • the compounds of the present invention may be used with PPAR ⁇ activators such as GI262570 (GlaxoSmithKline) and glitazone 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 larger amount than the dosage known in the art to provide effective treatment.
  • Combination therapy includes the administration of therapeutic agents in separate dosage forms or together in a single dosage form.
  • Combination therapy may include simultaneous or separate administration of the therapeutic agents, which may be substantially simultaneous or substantially separate administration.
  • the combination therapy involves administering each agent so that the therapeutically effective amount of each agent resides in the subject's body for at least an overlapping period of time.
  • the therapeutically effective amount of the compound of the present invention will depend on many 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 prescribing doctor’s judgment.
  • the therapeutically effective amount of the compound of the present invention for the treatment of the diseases described herein will generally be in the range of 0.1 to 100 mg/kg recipient body weight/day, and more usually in the range of 1 to 10 mg/kg body weight/day.
  • the actual daily amount is usually 70 to 700 mg, and the amount can be given in a single dose per day or multiple sub-doses per day, such as two, three, four, five or six doses per day .
  • the administration can be performed intermittently, for example, once every other day, once a week, or once a month. It is expected that similar dosages may be suitable for the treatment of other conditions mentioned above.
  • the pharmaceutical composition of the present invention may contain one or more compounds of the present invention.
  • the pharmaceutical composition may include more than one compound of the invention.
  • the pharmaceutical composition may include two or more compounds of the present invention.
  • the pharmaceutical composition may optionally contain one or more additional pharmaceutically active compounds.
  • the "pharmaceutically acceptable excipient" as used in the present invention refers to a pharmaceutically acceptable raw material, component or carrier that participates in imparting the shape or consistency of the pharmaceutical composition. When mixed, each excipient is compatible with the other ingredients of the pharmaceutical composition, thereby avoiding interactions that significantly reduce the effectiveness of the compound of the present invention when administered to a subject and avoiding drugs that would result in pharmaceutically unacceptable drugs. Interaction of ingredients.
  • 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, mixtures 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 patches; (4) rectal administration, such as suppositories; (5) nasal inhalation, such as dry powder, aerosol, suspension and solution; and (6) topical administration Medicines (including buccal, sublingual or transdermal), such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
  • Oral administration including buccal or sublingual
  • parenteral administration including subcutaneous, intramuscular, intravenous or intradermal
  • transdermal administration such as transdermal patches
  • compositions suitable for oral administration may exist as discrete units, such as capsules or tablets; powder or granules; solutions or suspensions in aqueous or non-aqueous liquid form; edible foams (foams or whips); or water packets Oil liquid emulsion or water-in-oil liquid emulsion.
  • Suitable pharmaceutically acceptable excipients can vary according to the specific dosage form selected.
  • appropriate pharmaceutically acceptable excipients can be selected according to their specific functions in the composition. For example, some pharmaceutically acceptable excipients may be selected because they have the ability to promote the production of a uniform dosage form. Some pharmaceutically acceptable excipients may be selected because they have the ability to promote the production of stable dosage forms. Some pharmaceutically acceptable excipients may be selected because of 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 because of 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, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives , Stabilizers, surfactants and buffers.
  • excipients can provide more than one function, and depend on how much of the excipient is present in the formulation and what other ingredients are present in the formulation to provide other functions. Function.
  • composition of the present invention is prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the field are described in Remington Pharmaceutical Sciences (Mack Press).
  • the present invention relates to a solid oral dosage form, such as a tablet or capsule, comprising a therapeutically effective amount of a compound of the present invention and a release agent or filler.
  • Suitable diluents and fillers include lactose, sugar, glucose, mannitol, sorbitol, starch (such as corn starch, potato starch and pregelatinized starch), cellulose and its derivatives (such as microcrystalline cellulose), Calcium sulfate and calcium hydrogen phosphate.
  • the oral solid dosage form may also include a binder. Suitable binders include starch (e.g.
  • Oral solid dosage forms may also include disintegrants. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may also contain lubricants. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.
  • the present invention relates to a compound containing 0.01 mg to 1000 mg of one or more of the above formulae described in the text or a pharmaceutically acceptable salt thereof and 0.01 g to 5 g of one or more pharmaceutically acceptable Pharmaceutical composition of excipients.
  • reaction solution was poured into dichloromethane, dried with anhydrous sodium sulfate, filtered, the filter cake was washed with dichloromethane/methanol (20/1), and the filtrate was concentrated to obtain the crude title compound (1.5 g).
  • 2,4,6-Trichloropyrimidine (1055mg, 5.76mmol) was added to acetonitrile (30mL) and cooled to 0°C.
  • ((1R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-4-yl)methanol 700mg, 2.88mmol
  • triethylamine 872mg, 8.64mmol
  • 2,4,6-Trichloropyrimidine (584mg, 3.19mmol) was added to acetonitrile (5mL) and cooled to 0°C.
  • (2-Azabicyclo[2.2.2]oct-1-yl)methanol 300mg, 2.12mmol, J.Org.Chem., 2007,72,3112-3115
  • triethylamine 429mg, 4.25mmol
  • Methyl 1-Boc-2-pyrrolidinecarboxylate (25 g, 109.04 mmol) was added to the ethyl acetate solution of hydrogen chloride (4.0M, 100 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue, benzyl bromide (22.38 g, 130.85 mmol), and anhydrous potassium carbonate (30.1 g, 218.08 mmol) were added to acetonitrile (100 mL), and the temperature was raised to reflux and stirred overnight.
  • Benzylproline methyl ester (8g, 36.48mmol) was added to tetrahydrofuran (100mL) and cooled to -20°C under argon protection.
  • methyl iodide (15.5g, 109.44mmol) to the reaction solution, lower the temperature to -50°C, and control the temperature from -50°C to -40°C and add dropwise a solution of lithium diisopropylamide in tetrahydrofuran (2.0M, 63.84mL, 127.68mmol) , After dropping, control the temperature at -50°C ⁇ -40°C and stir for 3 hours.
  • Lithium aluminum hydride (1.63g, 42.90mmol) was added to anhydrous tetrahydrofuran (25mL), and the temperature was reduced to 0°C under argon protection.
  • Sodium sulfate decahydrate (20 g) was added to the reaction solution to quench the reaction, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude title compound (3.8 g, 86%).
  • Benzylproline methyl ester (8g, 36.48mmol) was added to tetrahydrofuran (100mL) and cooled to -20°C under argon protection.
  • iodoethane (17.1g, 109.45mmol) to the reaction solution, cool to -50°C, control the temperature from -50°C to -40°C, add dropwise a solution of lithium diisopropylamide in tetrahydrofuran (2.0M, 63.84mL, 127.68mmol) ), the dripping is over, the temperature is controlled at -50°C to -40°C and stirred for 3 hours.
  • Lithium aluminum hydride (1.51 g, 39.66 mmol) was added to anhydrous tetrahydrofuran (25 mL) and cooled to 0° C. under argon protection.
  • Sodium sulfate decahydrate (5 g) was added to the reaction solution to quench the reaction, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude title compound (3.5 g, 81%).
  • 2,4,6-Trichloropyrimidine (3.5g, 19.16mmol) and triethylamine (3.23g, 31.94mmol) were added to acetonitrile (80mL) and cooled to 0°C.
  • (2-Ethylpyrrolidin-2-yl)methanol (2.1 g, 15.97 mmol) was added to the reaction solution and stirred at 0°C for 2 hours.
  • N-BOC-piperidine-2-carboxylic acid methyl ester (5.1g, 20.98mmol) and iodoethane (3.2mL, 41.0mmol) were added to tetrahydrofuran (60mL), cooled to 0°C, and lithium diisopropylamide was added ⁇ tetrahydrofuran solution (21.0mL, 2.0M, 42.0mmol).
  • Methyl N-Boc-morpholine-3-carboxylate (11g, 44.9mmol) was dissolved in tetrahydrofuran (120mL). Under argon protection, methyl iodide (10.5g, 67.3mmol) was added, and the temperature of the reaction solution was cooled to 0 Below °C, add dropwise a tetrahydrofuran solution (2.0M, 45mL, 89.8mmol) of sodium bis(trimethylsilyl)amide, and stir at room temperature for 3 hours after the addition.
  • tetrahydrofuran solution 2.0M, 45mL, 89.8mmol
  • Methyl N-Boc-3-methylmorpholine-3-carboxylate (1g, 3.86mmol) was dissolved in tetrahydrofuran (10mL), the reaction solution was cooled to below 0°C, and lithium aluminum hydride (220mg, 5.8mmol) was added in batches. ), stirring at room temperature for 30 minutes. The reaction solution was quenched with sodium sulfate decahydrate, stirred at room temperature for 0.5 hours, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain the title compound (550 mg, 61%).
  • Triethylamine (307mg, 3.04mmol) and 2,4,6-trichloropyrimidine (335.6mg, 1.83mmol) were added to acetonitrile (20mL) and cooled to 0°C.
  • ((1S,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-4-yl)methane-d2-ol 200mg, 1.52mmol
  • the reaction solution was concentrated and purified by silica gel column chromatography to obtain the title compound (130 mg, 31%).
  • reaction solution was concentrated, tetrahydrofuran (40 mL) and sodium hydroxide aqueous solution (5%, 35 mL) were added to the residue, di-tert-butyl dicarbonate (10.6 g, 48.9 mmol) was added with stirring, and the mixture was stirred at room temperature overnight.
  • reaction solution was concentrated, and di-tert-butyl dicarbonate (1.35 g, 6.21 mmol) and tert-butanol (20 mL) were sequentially added to the residue, and the mixture was stirred at 90° C. overnight.
  • reaction solution was concentrated to dryness, HATU (112.26 g, 0.296 mol), triethylamine (59.8 g, 0.592 mol) and N,N-dimethylformamide (90 mL) were sequentially added to the residue, and the mixture was stirred at room temperature overnight.
  • Example 4-168 listed in the following table was prepared by a procedure similar to that described in Example 1-2, starting from the corresponding intermediate:
  • reaction solution was concentrated, and an aqueous formaldehyde solution (37%, 5mg, 0.06 mmol), sodium cyanoborohydride (12mg, 0.18mmol) and methanol (1mL), stirred at room temperature for 1 hour.
  • the reaction solution was concentrated and purified by preparative thin-layer chromatography to obtain (13mg, 41%).
  • reaction solution was concentrated, and oxetanone (20mg, 0.28mmol), sodium cyanoborohydride (17mg, 0.28mmol) and methanol (1mL), stirred at room temperature for 1 hour.
  • the reaction solution was concentrated and purified by preparative thin-layer chromatography (60mg, 81%).

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Abstract

一种通式(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，其制备方法，含有该化合物的药物组合物以及所述化合物作为Lp-PLA 2抑制剂的用途。

Description

三环二氢咪唑并嘧啶酮衍生物、其制备方法、药物组合物和用途 技术领域:
本发明涉及新的三环二氢咪唑并嘧啶酮化合物、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。
背景技术:
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))
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、JP200188847 US2008/0279846A1、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分裂症和自闭症、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(例如前列腺癌、结肠癌、乳腺癌、肾癌、肺癌和卵巢癌等)、黄斑水肿、伤口愈合、男性勃起障碍、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。
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))。
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))。
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))。
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。
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。
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。
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。
在男性勃起障碍病人中，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勃起障碍(Otunctemur等人，Andrologia 47：706-710(2015))，提示Lp-PLA 2抑制剂可用于治疗男性勃起障碍。
在前列腺癌组织中有Lp-PLA 2高表达，降低Lp-PLA 2可以在体外实验中减少前列腺细胞癌变并促进前列腺癌细胞凋亡(Vainio等人，Oncotarget，2：1176-1190(2011))，提示Lp-PLA 2抑制剂可以用于治疗前列腺癌。
但是，现有技术中仍然对新的Lp-PLA 2抑制剂存在强烈的需求。
发明内容
本发明的目的在于提供一种嘧啶酮类化合物及其药物组合物，其可被用作Lp-PLA 2抑制剂。
在第一方面，本发明涉及一种式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，
Figure PCTCN2020127426-appb-000001
其中
n为0，1或2，且当n为0时，R 2为甲基或乙基，当n为1或2时，R 2不存在；
R 1为H，卤素，氰基，C 1-6烷基，C 1-6烷氧基，C 3-8环烷基或3-8元杂环基，R 1可以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6-10元杂芳基；
R a独立的为H或D；
m为1或2；
R x为H，卤素，羟基，羧基，氰基，氨基，C 1-6烷基，C 1-6烷氧基，C 3-8环烷基，3-8元杂环基，6-10元芳基，6-10元杂芳基，-C(O)NR bR c，-S(O) 2NR bR c，R x可以任选被一个或多个以下取代基取代：卤素，羟基，C 1-6烷氧基，氰基，C 3-8环烷基，3-8元杂环基，6-10元芳基或6-10元杂芳基；
Q为-O-，-S-，-CH 2-或-NR b-；
X为-O-，-CH 2-,-NR c-，-OCH 2-或不存在；
R b为H，C 1-6烷基或C 3-8环烷基或3-8元杂环基；
R c为L，L-C(O)-，L-CH 2-或L-S(O) 2-，其中L为H、C 1-6烷基、C 3-6环烷基、3-8元杂环基，6-10元芳基或6-10元杂芳基，L可以任选被一个或多个下基团取代：卤素，羟基，C 1-6烷氧基，氰基，C 3-8环烷基，3-8元杂环基，6-10元芳基或6-10元杂芳基；
Y为-CH 2-，-CH 2CH 2-或者不存在；
U为-CH 2-，-C(O)-或者不存在；
X与U不同时为不存在；
Y和U可以任选被一个或多个以下取代基取代：卤素，羟基，C 1-6烷基，C 1-6烷氧基，氰基，C 3-8环烷基，3-8元杂环基，6-10元芳基或6-10元杂芳基；
A为
Figure PCTCN2020127426-appb-000002
Z为N或CR 3；
Z’为N或CR 4；
R 3,R 4,R 5,R 6独立的为H、氰基、卤素或C 1-3卤代烷基；V为N或CR 9，其中R 9为H、氰基、卤素、C 1-3烷基、C 1-3卤代烷基或-O-W；W为苯基或5或6元杂芳基，其可以任选被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。
在一些实施方案中，其中n为0；R 1为H、氰基、卤素、C 1-6烷基，C 1-6烷氧基或C 1-3卤代烷基；R a为H；Rx为H，氰基，氟，二氟甲基，氨基，
Figure PCTCN2020127426-appb-000003
Figure PCTCN2020127426-appb-000004
R 2为甲基或乙基；Q为-O-；X为-O-，-CH 2或者不存在-；Y为-CH 2-；U为-CH 2-，或者不存在；X与U不同时为不存在。
进一步地，R 1为H和Rx为H。
在一些实施方案中，其中n＝1或2，R 2不存在。进一步地，其中R x为H。进一步地，其中X为-O-或-CH 2-。
在一些实施方案中，其中n为1；R x为H；R 1为H，氰基，氨基，卤素，C 1-3烷基，C 1-3卤代烷基或C 1-6烷氧基。
在一些实施方案中，其中U为-CH 2-；X为-CH 2-或-O-且Q为-O-。
在一些实施方案中，其中U为-CH 2-；X为-NR c-，R c为甲基，氧杂环丁基，三氟乙基，苯甲酰基，环丁基，苄基，
Figure PCTCN2020127426-appb-000005
在一些实施方案中，其中U为-C(O)-；R 1和R x均为H，Y为-CH 2-；X为-NR c-，R c为L或L-C(O)-，其中L为甲基，三氟乙基,苯甲酰基，氧杂环丁烷，环丁烷， 苄基，
Figure PCTCN2020127426-appb-000006
进一步地，L为甲基。
在一些实施方案中，其中n为1；X为-CH 2-；U不存在；R x为H，羟基，卤素，氰基，氨基，C 1-3烷氧基，C 1-3卤代烷基，3-8元杂环基，R x可以任选被一个或多个以下取代基取代：卤素，羟基，C 1-6烷氧基，氰基，3-8元杂环基，6-10元芳基或6-10元杂芳基。
在一些实施方案中，其中Y为-CH 2-；R 1为H，氰基，卤素，C 1-3烷基，C 1-3卤代烷基，C 1-6烷氧基；Q为-O-。
在一些实施方案中，其中R x为H，卤素，氰基，氨基，二氟甲基，
Figure PCTCN2020127426-appb-000007
Figure PCTCN2020127426-appb-000008
在一些实施方案中，其中Y为-CH 2CH 2-；R x为H，卤素，氰基，氨基，二氟甲基，
Figure PCTCN2020127426-appb-000009
R 1为H，氰基，卤素，C 1-3烷基，C 1-3卤代烷基或C 1-6烷氧基；Q为-O-。进一步地，Rx为H。
在一些实施方案中，其中n为2；U为-CH 2-；X为-CH 2-或-O-；Y为-CH 2-或不存在；R x为H，卤素，氰基，氨基，二氟甲基，
Figure PCTCN2020127426-appb-000010
Figure PCTCN2020127426-appb-000011
R 1为H，氰基，卤素，C 1-3烷基，C 1-3卤代烷基或C 1-6烷氧基；且Q为-O-。进一步地，Rx为H且R 1为H。
在一些实施方案中，其中m＝2；R 1为H，氰基或C 1-3卤代烷基；且R x为H。
在一些实施方案中，其中m＝1，R 1为H，氰基，卤素，C 1-3烷基，C 1-3卤代烷基或C 1-6烷氧基；且R x为H。
在一些实施方案中，其中A为
Figure PCTCN2020127426-appb-000012
R 5,R 6,R 7,R 8,R 9独立的为H，F或氰基。
在一些实施方案中，其中A为
Figure PCTCN2020127426-appb-000013
R 5,R 6,R 7和R 8独立的为H，F或氰基；R 9为-O-W，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、氰基卤素和C 1-6烷基。
在一些实施方案中，其中A为
Figure PCTCN2020127426-appb-000014
R 7和R 8独立的为H，F或氰基；R 9为-O-W；W为吡啶基、嘧啶基、吡唑基或苯基，其可以任选被一个或多个独立选自以下的取代基取代：卤素、氰基、CF 3、-OCF 3、CHF 2和CH 3。
在一些实施方案中，化合物具有式I’
Figure PCTCN2020127426-appb-000015
其中R 1为H，氰基,卤素，C 1-6烷基,C 1-3烷氧基或C 1-3卤代烷基；X为-O-，-CH 2-,-NRc-或不存在；R c为L或L-C(O)-，其中L为H、C 1-3烷基、C 3-6环烷基，C 3-6杂环烷基，C1-3卤代烷基、或苄基；Y为-CH 2-或者不存在；n，R 2，R a，A，m如在上述式(I)中所定义。
在一些实施方案中，n为0，R 2为甲基或乙基；R 1为H；R a为H；m为1；X为-O-或-CH 2-。
在一些实施方案中，化合物是下述化合物
Figure PCTCN2020127426-appb-000016
其中，R 1为H，卤素，氰基，C 1-6烷基，C 1-3卤代烷基或C 1-6烷氧基(进一步地，所述卤素为氟或氯，所述C 1-6烷基是甲基、乙基或异丙基，所述C 1-3卤代烷基是三氟甲基，且所述C 1-6烷氧基是甲氧基)；R 2为甲基或乙基；R c为C 1-6烷基，3-8元杂环基，C 1-3卤代烷基，苯甲酰基，C 3-8环烷基，苄基或
Figure PCTCN2020127426-appb-000017
(进一步地，所述C 1-6烷基是甲基，所述3-8元杂环基是氧杂环丁基，所述C 1-3卤代烷基是三氟乙基且所述C 3-8环烷基是环丁基)；R x为H，氰基，卤素，C 1-3卤代烷基，氨基，
Figure PCTCN2020127426-appb-000018
(进一步地，所述卤素为氟且所述C 1-3卤代烷基是二氟甲基)。
进一步地，化合物是下述化合物
Figure PCTCN2020127426-appb-000019
其中，R 1为H，卤素，氰基，C 1-6烷基，C 1-3卤代烷基或C 1-6烷氧基(进一步地，所述卤素为氟或氯，所述C 1-6烷基是甲基、乙基或异丙基，所述C 1-3卤代烷基是三氟甲基，且所述C 1-6烷氧基是甲氧基)；R 2为甲基或乙基；R c为C 1-6烷基，3-8元杂环基，C 1-3卤代烷基，苯甲酰基，C 3-8环烷基，苄基或
Figure PCTCN2020127426-appb-000020
(进一步地，所述C 1-6烷基是甲基，所述3-8元杂环基是氧杂环丁基，所述C 1-3卤代烷基是三氟乙基且所述C 3-8环烷基是环丁基)；R x为H，氰基，卤素，C 1-3卤代烷基，氨基，
Figure PCTCN2020127426-appb-000021
(进一步地，所述卤素为氟且所述C 1-3卤代烷基是二氟甲基)。
在一些实施方案中，上述通式(I)化合物中，A选自下述基团：
Figure PCTCN2020127426-appb-000022
Figure PCTCN2020127426-appb-000023
在一些实施方案中，上述通式(I)化合物是下述化合物：
Figure PCTCN2020127426-appb-000024
Figure PCTCN2020127426-appb-000025
Figure PCTCN2020127426-appb-000026
Figure PCTCN2020127426-appb-000027
Figure PCTCN2020127426-appb-000028
Figure PCTCN2020127426-appb-000029
Figure PCTCN2020127426-appb-000030
Figure PCTCN2020127426-appb-000031
Figure PCTCN2020127426-appb-000032
Figure PCTCN2020127426-appb-000033
Figure PCTCN2020127426-appb-000034
Figure PCTCN2020127426-appb-000035
Figure PCTCN2020127426-appb-000036
在第二方面，本发明涉及一种式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，
Figure PCTCN2020127426-appb-000037
其中
n为0，1或2，且n为0时，R 2为甲基或乙基，n不为0时，R 2不存在；
R 1为H，卤素，C 1-6烷基或C 3-6环烷基；
R a独立的为H或D；
m为1或2；
X为-O-，-CH 2-,-NR-或不存在；
R为L-C(O)-，L-CH 2-或L-S(O) 2-，其中L为H、C 1-3烷基、C 3-6环烷基或苯基；
Y为-CH 2-或者不存在；
A为
Figure PCTCN2020127426-appb-000038
Z为N或CR 3；
Z’为N或CR 4；
R 3,R 4,R 5,R 6独立的为H、CN、卤素或C 1-3卤代烷基；
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；
W为5或6元杂芳环或苯基，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 1-5烷基。
在一些实施方案中，上述通式(I’)化合物中n不为0且具有以下一个或多个特征：
(1)R 1为H，R a为H；
(2)X为O或不存在，Y为-CH 2-,n为1；
(3)X为-CH 2-,Y为-CH 2-或不存在,n为2；
(4)m为1。
在一些实施方案中，所述通式(I’)化合物中n为0且具有以下一个或多个特征：
(1)R 1为H，R a为H；
(2)R 2为甲基；
(3)X为不存在，-O-，-CH 2-；
(4)m为1。
在一个实施方案中，A为
Figure PCTCN2020127426-appb-000039
其中R 5,R 6,R 7,R 8,R 9独立的为H、F或CN。
在一个实施例中，A为
Figure PCTCN2020127426-appb-000040
其中R 5,R 6,R 7,R 8独立的为H、F或CN；R 9为-O-W；W为5或6元杂芳基或苯基，其中所述杂芳基或苯基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 1-5烷基。
在一个实施例中，A为
Figure PCTCN2020127426-appb-000041
其中R 7,R 8独立的为H、F或CN；R 9为-O-W；W为吡啶基、嘧啶基、吡唑基和苯基，其中所述吡啶基、嘧啶基、吡唑基或苯基任选由一个或多个下列的取代基取代：卤素,CN,CF 3，-OCF 3和CH 3。在一些实施方案中，A为
Figure PCTCN2020127426-appb-000042
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：
Figure PCTCN2020127426-appb-000043
Figure PCTCN2020127426-appb-000044
Figure PCTCN2020127426-appb-000045
Figure PCTCN2020127426-appb-000046
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。
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。
除了本文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。
本文所描述的化合物、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，本发明提供了本文所定义的化合物、其盐(例如，药学上可接受的盐)的多晶型物，或本文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。
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。在一些实施方案中，上述式的化合物或其盐为非同位素标记的。
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。
在第三方面，本发明还涉及包含本发明所述的化合物和药学上可接受的赋形剂的药物组合物。
在第四方面，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文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。
在一些实施方案中，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分裂症和自闭症、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(例如前列腺癌、结肠癌、乳腺癌、肾癌、肺癌和卵巢癌等)、黄斑水肿、伤口愈合、男性勃起障碍、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)。
在一些实施中，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。
在一些实施中，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。
在一些实施中，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。
在第五方面，本发明还提供了本发明的化合物在制备用于治疗或预防与Lp-PLA 2相关的疾病的药物中的用途。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分裂症和自闭症、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(例如前列腺癌、结肠癌、乳腺癌、肾癌、肺癌和卵巢癌等)、黄斑水肿、伤口愈合、男性勃起障碍、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)。
在第六方面，本发明还提供了本发明化合物，其用于本文所述的疾病的治疗或预防。
本文使用的“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。
一般而言，本文使用的命名和本文所描述的有机化学、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，本文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。在本文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。
发明详述
定义
如本文使用的，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)。
如本文使用的，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。
如本文使用的，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系统障碍。神经退行性疾病为一类神经系统疾病，其中神经系统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，本文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。
如本文使用的，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。
如本文使用的，除非另有所述，“神经病理性痛”是为由神经系统原发性损害和功能障碍所激发或引起的疼痛。
如本文使用的，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。
如本文使用的，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。
如本文使用的，除非另有所述，“血脑屏障”或"BBB"在本文可互换使用，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。
如本文使用的，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。本文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。
如本文使用的，除非另有所述，“骨质减少疾病”或“骨质减少”可以在本文中互换使用，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系统的描述性术语。骨质减少也是指由于类骨质(osteoid)合成不足导致的骨质减少。
如本文使用的，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。
如本文使用的，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 1-5烷基是指具有1至5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)、戊基、己基。
如本文使用的，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。
如本文使用的，“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3-8个环碳原子(C 3-8环烷基)、3-7个环碳原子(C 3-7环烷基)或3-6个环碳原子(C 3-6环烷基)，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。除非另有所述，“C 3-6环烷基”为通过从3、4、5或6元单环环烷烃去除一个氢原子得到的一价基团。示例性环烷基包括，但不限于，环丙基、环丁基、环戊基和环己基。
如本文使用的，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。
如本文使用的，在一些实施方案中，“杂芳基”为从单环5或6元杂芳环去除一个氢原子得到的一价基团，该环由环-碳原子和选自氮、氧和硫的环-杂原子组成，且该环为芳族的。例如，杂芳基为由5或6个环原子组成的单环杂芳基，其中1至3个为环-杂原子。示例性杂芳基包括，但不限于，呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、氮杂
Figure PCTCN2020127426-appb-000047
基、氧氮杂
Figure PCTCN2020127426-appb-000048
基、硫氮杂
Figure PCTCN2020127426-appb-000049
基和二氮杂
Figure PCTCN2020127426-appb-000050
基。在另一些实施方案中，“杂芳基”表示在各环中具有至多7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、苯并三唑基、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、1,2,3-三唑基、1,2,4-三唑基、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、氮杂卓基、氧杂卓基和硫杂卓基。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、三唑基、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。如本文所用，在一些实施方案中，“杂环基”为从3、4、5或6—元饱和单环杂环去除一个氢原子得到的一价基团，该环由环—碳原子和选自氮、氧和硫的环-杂原子组成。示例性单环饱和杂环基取代基包括，但不限于，吡咯烷基、二氧杂环戊烷基、咪唑烷基、吡唑烷基、哌啶基、二噁烷基、吗啉代、二噻烷基、硫吗啉代和哌嗪基。在另一些实施方案中，“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。
如本文使用的，除非另有所述，“桥环化合物”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。
“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。
如本文使用的，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)。
如本文使用的，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。
如本文使用的，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。
如本文使用的，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文定义的取代基。
如本文使用的，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。
如本文使用的，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。
如本文使用的，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。
如本文使用的，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。
如本文使用的，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。
如本文使用的，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。
化合物合成
本领域的技术人员可以理解，如果本文描述的取代基与本文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。
一般方案：
一般方案提供式1.5及2.5化合物的一般合成路线，其中R 1,R 2,R x,U,X,Y,m,n,Q,A如式(I)所定义
Figure PCTCN2020127426-appb-000051
步骤(i)可作为S NAr反应，使用合适的试剂，例如三乙胺在合适的溶剂例如乙腈中在合适的温度如室温将化合物1.1与1.2反应生成化合物1.3。步骤(ii)可以通过将化合物1.3与合适试剂如三乙胺和甲磺酰氯或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化合物后，不经纯化进一步在碱例如碳酸钾和合适溶剂例如乙腈中回流反应关环得到化合物1.4。步骤(iii)将1.4与对应的醇 或胺HQ-(CH 2) m-A(Q为-O-或-NR b-)在合适的碱如NaH或DIPEA条件下在合适的溶剂如乙腈或1，4-二氧六环中反应得到最终产物1.5。化合物2.5从醇2.1和R 1取代的三氯嘧啶开始制备获得。反应条件和反应物的变化对于本领域技术人员式显而易见的。当Q为-CH 2-时，参看实施例170合成具体方案。
另外，一般方案提供式1.5及2.5化合物的一般合成路线，其中R 1,R 2,X,Y,m,n,A如式(I’)所定义
Figure PCTCN2020127426-appb-000052
步骤(i)可作为S NAr反应，使用合适的试剂，例如三乙胺在合适的溶剂例如乙腈中在合适的温度如室温将化合物1.1与1.2反应生成化合物1.3。步骤(ii)可以通过将化合物1.3与合适试剂如三乙胺和甲磺酰氯或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化合物后，不经纯化进一步在碱例如碳酸钾和合适溶剂例如乙腈中回流反应关环得到化合物1.4。步骤(iii)将1.4与对应的醇HO-(CH 2) m-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1.5。化合物2.5从醇2.1和R 1取代的三氯嘧啶开始制备获得。反应条件和反应物的变化对于本领域技术人员式显而易见的。
用途
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，包括一种或多种本文中描述的机制。
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.
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，将其引入本文作为参考。
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。
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。在另一些实施方案中，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。在另一些实施方案中，所述黄斑水肿与后葡萄膜炎有关。
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。
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。
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。
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(如精神分裂症、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。
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。
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。
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。
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系统病症的方法。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系统病症的方法。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。在另一些实施方案中，所述异常BBB是渗透性BBB。在另一些实施方案中，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。在一些实施方案中，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。在一些实施方案中，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。在一些实施方案中，所述神经退行性疾病是多发性硬化症(MS)。
在一些实施方案中，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。在一些实施方案中，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。在一些实施方案中，被给药抑制Lp-PLA 2活性的药剂的受试者是人。
在一些实施方案中，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。在一些实施方案中，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。
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。在另一些实施方案中，需要此治疗的受试者是人。
认为预防本文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。在另一些实施方案中，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。在另一些实施方案中，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。
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)、选择性雌激素调节剂(SERM)、雌激素疗法、激素替代疗法(ET/HRT)和特立帕肤。
在一些实施方案中，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、系统性红斑狼疮、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。在一些实施方案中，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。
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。在一些实施方案中，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。在一些实施方案中，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。
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。
使用方法
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。
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。
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。
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。
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。
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。
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。
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)。
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。
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、阿拉伯胶、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。
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。
中间体1
(1S,4R)-4-(羟甲基)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-羧酸叔丁酯
Figure PCTCN2020127426-appb-000053
(1S,4S)-5-叔丁氧基羰基-2-氧杂-5-氮杂双环[2.2.1]庚烷-4-羧酸甲酯(0.88g,3.4mmol,Chemistry Letters,2017,566-568)加入到无水四氢呋喃(30mL)中，冷却到0℃，缓慢加入硼氢化锂(222mg,10.2mmol)，室温搅拌过夜。反应液冷却到0℃， 加入十水硫酸钠淬灭。反应液倒入二氯甲烷中，加入无水硫酸钠干燥，过滤，滤饼用二氯甲烷/甲醇(20/1)洗涤，将滤液浓缩得到标题化合物粗品(1.5g)。
LC-MS:m/z[M+H-tBu] +＝174.
((1S,4R)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇盐酸盐
Figure PCTCN2020127426-appb-000054
(1S,4R)-4-(羟甲基)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-羧酸叔丁酯(1.5g粗品)溶解在混合溶剂二氯甲烷(5mL)和甲醇(5mL)中，加入氯化氢乙酸乙酯溶液(4.0M,5mL)，反应混合物40-50℃搅拌过夜。反应液浓缩到标题化合物粗品(900mg)。LC-MS:m/z[M+H] +＝130.
((1S,4R)-5-(2,6-二氯嘧啶-4-基)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇
Figure PCTCN2020127426-appb-000055
((1S,4R)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇盐酸盐(0.9g,5.4mmol)溶解在二氯甲烷(50mL)中，冷却到0℃，依次加入三乙胺(1.1g,1.5mL,10.8mmol)和2,4,6-三氯嘧啶(1.2g,5.76mmol)，室温搅拌4小时。饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，有机相浓缩，硅胶柱层析纯化得到标题化合物(0.36g,三步收率38％)。
LC-MS:m/z[M+H] +＝276.
(3S,11aR)-7-氯-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6',1':2,3]咪唑并[5, 1-C][1,4]恶嗪-9-酮
Figure PCTCN2020127426-appb-000056
((1S,4R)-5-(2,6-二氯嘧啶-4-基)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇(360mg,1.3mmol)和三乙胺(395mg,3.9mmol)加入到无水四氢呋喃(10mL)中，冷却到0℃。滴加甲基磺酰氯(229mg,2.0mmol)，0℃搅拌30分钟。将反应液浓缩并加入碳酸钾(898mg,6.5mmol)和乙腈(15mL)，80℃搅拌过夜。反应液浓缩，制备薄层色谱分离(二氯甲烷/甲醇＝20/1)得标题化合物(230mg,74％)。
LC-MS:m/z[M+H] +＝240.
1H NMR(400MHz,CDCl 3)δ5.60(s,1H),4.78(br.s,1H),4.49(d,J＝13.2Hz,1H),4.09-3.88(m,3H),3.61(d,J＝9.8Hz,1H),3.32(d,J＝9.8Hz,1H),2.10(d,J＝10.8Hz,1H),1.84(d,J＝10.3Hz,1H).
中间体2
(1R,4S)-4-(羟甲基)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-羧酸叔丁酯
Figure PCTCN2020127426-appb-000057
(1R,4R)-5-叔丁氧基羰基-2-氧杂-5-氮杂双环[2.2.1]庚烷-4-羧酸甲酯(430mg,1.67mmol,Chemistry Letters,2017,566-568)加入到无水四氢呋喃(10mL)中，冷却到0℃，缓慢加入硼氢化锂(430mg,1.67mmol)，室温搅拌过夜。反应液冷却到0℃，加水淬灭。用乙酸乙酯稀释反应液并加入无水硫酸钠干燥，过滤，滤饼用乙醇洗涤，将滤液浓缩。加入二氯甲烷溶解残留物，过滤，将滤液浓缩得到标题化合物粗品(380mg,99％)。
LC-MS:m/z[M+H-tBu] +＝174.
((1R,4S)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇
Figure PCTCN2020127426-appb-000058
(1R,4S)-4-(羟甲基)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-羧酸叔丁酯(380mg,1.67mmol)加入到二氯甲烷(10mL)和三氟乙酸(5mL)中，室温搅拌过夜。反应液浓缩，柱层析纯化(二氯甲烷/甲醇＝20/1～2/1)得到标题化合物粗品(800mg)。
LC-MS:m/z[M+H] +＝130.
((1R,4S)-5-(2,6-二氯嘧啶-4-基)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇
Figure PCTCN2020127426-appb-000059
2,4,6-三氯嘧啶(1055mg,5.76mmol)加到乙腈(30mL)中，冷却到0℃。滴加((1R,4S)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇(700mg,2.88mmol)和三乙胺(872mg,8.64mmol)的乙腈(30mL)溶液，0℃搅拌2小时。反应液倒入水中，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1～4/1)得标题化合物(120mg,15％)。
LC-MS:m/z[M+H] +＝276.
(3R,11aS)-7-氯-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6',1':2,3]咪唑并[5, 1-C][1,4]恶嗪-9-酮
Figure PCTCN2020127426-appb-000060
((1R,4S)-5-(2,6-二氯嘧啶-4-基)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇(110mg,0.40mmol)和三乙胺(121mg,1.20mmol)加到无水四氢呋喃(3mL)中，冷却到0℃。滴加入甲基磺酰氯(69mg,0.60mmol)，0℃搅拌10分钟。将反应液浓缩并加入碳酸钾(166mg,1.20mmol)和乙腈(2mL)。90℃搅拌5小时。反应液浓缩，制备薄层色谱分离(二氯甲烷/甲醇＝20/1)得标题化合物(50mg,52％)。
LC-MS:m/z[M+H] +＝240.
1H NMR(400MHz,CDCl 3)δ5.60(s,1H),4.78(br.s,1H),4.49(d,J＝12.7Hz,1H),4.07-3.98(m,3H),3.60(d,J＝10.3Hz,1H),3.32(d,J＝9.8Hz,1H),2.10(d,J＝9.8Hz,1H),1.87(d,J＝10.3Hz,1H).
中间体3
(2-(2,6-二氯嘧啶-4-基)-2-氮杂双环[2.1.1]己-1-基)甲醇
Figure PCTCN2020127426-appb-000061
将(2-氮杂双环[2.1.1]己-1-基)甲醇(3.5g,30.98mmol,Journal of Organic Chemistry,2018,83,14350-14361)溶入乙腈(100mL)中，加入碳酸钠(12.6g,93mmol)，反应液冷却至0℃以下，滴加2,4,6-三氯嘧啶(28.3g,154.9mmol)，反应液室温下搅拌过夜，反应液经硅藻土过滤，滤液浓缩，硅胶层析柱分离纯化得到白色固体标题化合物(5.7g,71％)。
LC-MS:m/z[M+H] +＝260.
3-氯-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000062
将(2-(2,6-二氯嘧啶-4-基)-2-氮杂双环[2.1.1]己-1-基)甲醇(5.1g,19.6mmol)溶入二氯甲烷(100mL)中，加入二氯亚砜(7g,58.8mmol)，室温下搅拌1小时，反应液浓缩后，残留物溶入乙腈中(100mL)，加入碳酸钾(8.11g,58.8mmol)，85℃搅拌过夜，反应液硅藻土过滤，滤液浓缩，层析柱分离纯化得到标题化合物(3.9g,89％)。
LC-MS:m/z[M+H] +＝224.
1H NMR(400MHz,DMSO-d 6)δ5.93(s,1H),3.92(s,2H),3.40(s,2H),2.93(br.s,1H),2.06(br.s,2H),1.66-1.61(m,2H).
中间体4
(7-(2,6-二氯嘧啶-4-基)-7-氮杂双环[2.2.1]庚-1-基)甲醇
Figure PCTCN2020127426-appb-000063
1-(羟甲基)-7-氮杂双环[2.2.1]庚烷-7-羧酸叔丁酯(4.3g,18.9mmol,Tetrahedron Letters,2010,51,6741–6744)溶解在混合溶剂二氯甲烷(20mL)和甲醇(20mL)中，加入氯化氢乙酸乙酯溶液(4.0M,20mL)，40-50℃搅拌过夜。反应液浓缩。将残留物溶解在二氯甲烷(80mL)中，冷却到0℃，依次加入三乙胺(5.7g,7.8mL,56.7mmol)和2,4,6-三氯嘧啶(6.9g,4.3mL,37.8mmol)，室温搅拌4小时。饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，有机相浓缩，硅胶柱层析纯化得到标题化合物(1.13g,21％)。
LC-MS:m/z[M+H] +＝274.
3-氯-7,8-二氢-1H,6H,9H-6,8a-乙桥吡咯并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000064
(7-(2,6-二氯嘧啶-4-基)-7-氮杂双环[2.2.1]庚-1-基)甲醇(360mg,1.3mmol)溶解在二氯甲烷(30mL)中，冷却到0℃。滴加氯化亚砜(4.56g,38.35mmol)，室温搅拌1小时。反应液浓缩，将残留物、碳酸钾(3.18g,23.01mmol)加入到乙腈(30mL)中，80℃搅拌过夜。将反应液用硅藻土过滤，滤饼经乙酸乙酯洗涤数次，合并滤液浓缩得标题化合物(0.76g,94％)。
LC-MS:m/z[M+H] +＝238.
1H NMR(400MHz,CDCl 3)δ5.68(s,1H),4.19(t,J＝4.6Hz,1H),4.03(s,2H),2.10(dd,J＝4.6,10.5Hz,2H),1.87-1.76(m,6H)..
中间体5
(2-(2,6-二氯嘧啶-4-基)-2-氮杂双环[2.2.2]辛-1-基)甲醇
Figure PCTCN2020127426-appb-000065
2,4,6-三氯嘧啶(584mg,3.19mmol)加到乙腈(5mL)中，冷却到0℃。滴加(2-氮杂双环[2.2.2]辛-1-基)甲醇(300mg,2.12mmol,J.Org.Chem.,2007,72,3112-3115)和三乙胺(429mg,4.25mmol)的乙腈(5mL)溶液，0℃搅拌2小时。反应液倒入水中，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1～4/1)得标题化合物(198mg,32％)。
LC-MS:m/z[M+H] +＝288.
3-氯-6,7,8,9-四氢-1H,10H-7,9a-乙桥吡啶并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000066
(2-(2,6-二氯嘧啶-4-基)-2-氮杂双环[2.2.2]辛-1-基)甲醇(198mg,0.69mmol)加入二氯甲烷(5mL)中，冷却到0℃。滴加氯化亚砜(409mg,3.44mmol)，室温搅拌30分钟。将反应液浓缩并加入碳酸钾(379mg,2.75mmol)和乙腈(5mL)。90℃搅拌过夜。反应液浓缩，制备薄层色谱分离(二氯甲烷/甲醇＝20/1)得标题化合物(170mg,98％)。
LC-MS:m/z[M+H] +＝252.
中间体6
苄基脯氨酸甲酯
Figure PCTCN2020127426-appb-000067
将1-Boc-2-吡咯烷甲酸甲酯(25g,109.04mmol)加入氯化氢乙酸乙酯溶液(4.0M,100mL)中，室温搅拌4小时。反应液浓缩，将残留物、溴化苄(22.38g,130.85mmol)、无水碳酸钾(30.1g,218.08mmol)加入到乙腈(100mL)中，升温至回流搅 拌过夜。反应液倒入水中，乙酸乙酯萃取，合并有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝200/1～80/1)得到标题化合物(18g,75％)。
LC-MS:m/z[M+H] +＝220.
1-苄基-2-甲基吡咯烷-2-羧酸甲酯
Figure PCTCN2020127426-appb-000068
苄基脯氨酸甲酯(8g,36.48mmol)加到四氢呋喃(100mL)中，氩气保护下冷却到-20℃。将碘甲烷(15.5g,109.44mmol)加入反应液，降温至-50℃，控温-50℃～-40℃滴加二异丙基氨基锂的四氢呋喃溶液(2.0M,63.84mL,127.68mmol)，滴加结束，控温-50℃～-40℃搅拌3小时。向反应液中加入甲醇(50mL)淬灭后，将反应液倒入水中，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝200/1～100/1)得到标题化合物(5g,59％)。
LC-MS:m/z[M+H] +＝234.
(1-苄基-2-甲基吡咯烷-2-基)甲醇
Figure PCTCN2020127426-appb-000069
氢化铝锂(1.63g,42.90mmol)加入无水四氢呋喃(25mL)中，氩气保护下降温至0℃。滴加1-苄基-2-甲基吡咯烷-2-羧酸甲酯(5g,21.45mmol)的无水四氢呋喃(25mL)溶液，室温搅拌过夜。向反应液中加入十水合硫酸钠(20g)淬灭反应，室温搅拌30分钟。反应液过滤，滤液浓缩得标题化合物粗品(3.8g,86％)。
LC-MS:m/z[M+H] +＝206.
(2-甲基吡咯烷-2-基)甲醇
Figure PCTCN2020127426-appb-000070
(1-苄基-2-甲基吡咯烷-2-基)甲醇(3.8g,18.52mmol)和Pd/C(10％,400mg)加入甲醇(40mL)中。50℃常压氢化过夜。反应液过滤，滤液浓缩得标题化合物粗品(2.16g,101％)。
LC-MS:m/z[M+H] +＝116.
(1-(2,6-二氯嘧啶-4-基)-2-甲基吡咯烷-2-基)甲醇
Figure PCTCN2020127426-appb-000071
2,4,6-三氯嘧啶(5.16g,28.15mmol)和三乙胺(3.8g,37.54mmol)加到乙腈(80mL)中。将反应液降温至0℃后加入(2-甲基吡咯烷-2-基)甲醇(2.16g,18.77mmol)，0℃搅拌2小时。反应液倒入水中，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1～2/1)得标题化合物(2g,41％)。
LC-MS:m/z[M+H] +＝262.
3-氯-8a-甲基-7,8,8a,9-四氢-1H,6H-吡咯并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000072
(1-(2,6-二氯嘧啶-4-基)-2-甲基吡咯烷-2-基)甲醇(2g,7.67mmol)加到二氯甲烷(30mL)中，冷却到0℃。滴加氯化亚砜(4.56g,38.35mmol)，室温搅拌30分钟。反应液浓缩，将浓缩后的残留物、碳酸钾(3.18g,23.01mmol)加到乙腈(30mL)中。90℃搅拌过夜。反应液倒入水(100mL)中，分别用乙酸乙酯、二氯甲烷萃取，合并有机相浓缩得标题化合物(1.5g,88％)。
1H NMR(400MHz,DMSO-d 6)δ5.96(s,1H),4.06(d,J＝12.2Hz,1H),3.79(d,J＝12.2Hz,1H),3.48-3.35(m,2H),2.10-1.89(m,2H),1.87-1.68(m,2H),1.32(s,3H).
中间体7
1-苄基-2-乙基吡咯烷-2-羧酸甲酯
Figure PCTCN2020127426-appb-000073
苄基脯氨酸甲酯(8g,36.48mmol)加入到四氢呋喃(100mL)中，氩气保护下冷却到-20℃。将碘乙烷(17.1g,109.45mmol)加入反应液，冷却到-50℃，控温-50℃～-40℃滴加二异丙基氨基锂的四氢呋喃溶液(2.0M,63.84mL,127.68mmol)，滴加结束，控温-50℃～-40℃搅拌3小时。向反应液中加入甲醇淬灭后，反应液倒入水中，用乙酸乙酯萃取，合并有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝200/1～100/1)得到标题化合物(4.9g,54％)。
LC-MS:m/z[M+H] +＝248.
(1-苄基-2-乙基吡咯烷-2-基)甲醇
Figure PCTCN2020127426-appb-000074
将氢化铝锂(1.51g,39.66mmol)加入无水四氢呋喃(25mL)中，氩气保护下冷却到0℃。滴加1-苄基-2-乙基吡咯烷-2-羧酸甲酯(4.9g,19.83mmol)的无水四氢呋喃(25mL)溶液。室温搅拌过夜。向反应液中加入十水合硫酸钠(5g)淬灭反应，室温搅拌30分钟。反应液过滤，滤液浓缩得标题化合物粗品(3.5g,81％)。
LC-MS:m/z[M+H] +＝220.
(2-乙基吡咯烷-2-基)甲醇
Figure PCTCN2020127426-appb-000075
(1-苄基-2-乙基吡咯烷-2-基)甲醇(3.5g,15.97mmol)、Pd/C(10％,350mg)加入甲醇(50mL)中。50℃常压氢化过夜。反应液过滤，滤液浓缩得标题化合物粗品(2.1g,100％)。
LC-MS:m/z[M+H] +＝130.
(1-(2,6-二氯嘧啶-4-基)-2-乙基吡咯烷-2-基)甲醇
Figure PCTCN2020127426-appb-000076
2,4,6-三氯嘧啶(3.5g,19.16mmol)、三乙胺(3.23g,31.94mmol)加入到乙腈(80mL)中，冷却到0℃。将(2-乙基吡咯烷-2-基)甲醇(2.1g,15.97mmol)加入反应液，0℃搅拌2小时。反应液倒入水中，用乙酸乙酯萃取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝5/1～2/1)得标题化合物(1.5g,28％)。
LC-MS:m/z[M+H] +＝276.
3-氯-8a-乙基-7,8,8a,9-四氢-1H,6H-吡咯并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000077
(1-(2,6-二氯嘧啶-4-基)-2-乙基吡咯烷-2-基)甲醇(1.5g,5.45mmol)加入到二氯甲烷(30mL)中，冷却到0℃。滴加氯化亚砜(3.24g,27.27mmol)，室温搅拌30分钟。反应液浓缩，将浓缩后的残留物、碳酸钾(2.26g,16.35mmol)加到乙腈(30mL)中，90℃搅拌过夜。反应液倒入水(30mL)中，分别用乙酸乙酯、二氯甲烷萃取，合并有机相浓缩，制备薄层色谱分离(二氯甲烷/甲醇＝20/1)得标题化合物(260mg,20％)。
LC-MS:m/z[M+H] +＝240.
中间体8
N-Boc-2-甲基哌啶-2-甲酸甲酯
Figure PCTCN2020127426-appb-000078
N-BOC-哌啶-2-甲酸甲酯(10.0g,41.15mmol)和碘甲烷(16.2g,123.4mmol)加到四氢呋喃(60mL)中，冷却到0℃，滴加入二异丙基氨基锂的四氢呋喃溶液(61.7mL,2.0M,123.4mmol)。搅拌3小时后，将反应液倒入饱和氯化铵溶液中，乙酸 乙酯萃取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝20/1)得标题化合物(10.0g,95％)。
LC-MS:m/z[M+H-Boc] +＝158.
(2-甲基哌啶-2-基)甲醇
Figure PCTCN2020127426-appb-000079
N-Boc-2-甲基哌啶-2-甲酸甲酯(5.0g,19.45mmol)溶于二氯甲烷(15mL)中，加入氯化氢乙酸乙酯溶液(30mL)，20分钟后浓缩反应液。加入二氯甲烷(20mL)及碳酸钠固体调节pH到7-8。过滤、滤液浓缩得到2-甲基哌啶-2-甲酸甲酯的粗品，将其溶于四氢呋喃(20mL)中。该溶液0℃滴加到氢化铝锂的四氢呋喃溶液(30mL,23.3mmol)中，0℃搅拌2小时后，十水硫酸钠淬灭反应，室温搅拌30分钟后过滤，滤液浓缩得到标题化合物(1.8g,72％)。
LC-MS:m/z[M+H] +＝130.
(1-(2,6-二氯嘧啶-4-基)-2-甲基哌啶-2-基)甲醇
Figure PCTCN2020127426-appb-000080
2,4,6-三氯嘧啶(3.8g,20.93mmol)加到乙腈(60mL)中，冷却到0℃。加入碳酸钠(2.95g,27.90mmol)搅拌10分钟后，滴加(2-甲基哌啶-2-基)甲醇(1.8g,13.95mmol)的乙腈溶液(20mL)，室温搅拌过夜。过滤，滤液浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1～5/1)得到标题化合物(1.8g,47％)。
LC-MS:m/z[M+H] +＝276.
3-氯-9a-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
Figure PCTCN2020127426-appb-000081
(1-(2,6-二氯嘧啶-4-基)-2-甲基哌啶-2-基)甲醇(1.8g,6.54mmol)加入到二氯甲烷(20mL)中，室温下滴加氯化亚砜(1.56g,13.0mmol)，室温搅拌10分钟后，将反应液浓缩并加入碳酸钾(2.7g,19.62mmol)和乙腈(40mL)。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)得标题化合物(1.2g,77％)。
LC-MS:m/z[M+H] +＝240.
1H NMR(400MHz,CDCl 3)δ5.47(s,1H),3.91-3.78(m,2H),3.40(dd,J＝3.2,13.5Hz,1H),3.25-3.07(m,1H),1.98-1.56(m,7H),1.51(dd,J＝4.2,9.0Hz,2H).
中间体9
N-Boc-2-乙基哌啶-2-甲酸甲酯
Figure PCTCN2020127426-appb-000082
N-BOC-哌啶-2-甲酸甲酯(5.1g,20.98mmol)和碘乙烷(3.2mL,41.0mmol)加入到四氢呋喃(60mL)中，冷却到0℃，加入二异丙基氨基锂的四氢呋喃溶液(21.0mL,2.0M,42.0mmol)。0℃搅拌0.5小时后，将反应液倒入饱和氯化铵溶液(100mL)，乙酸乙酯萃取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝20/1～10/1)得到标题化合物粗品(4.0g,70％)。
LC-MS:m/z[M+H-Boc] +＝172.
2-乙基-2-羟甲基哌啶-1-甲酸叔丁酯
Figure PCTCN2020127426-appb-000083
N-Boc-2-乙基哌啶-2-甲酸甲酯(3.0g,11.0mmol)溶于四氢呋喃(30mL)中，0℃下分批加入氢化铝锂(970mg,25.5mmol)，该温度下搅拌15分钟后，加入十水硫酸钠淬灭反应，混合物室温搅拌30分钟后，过滤，滤液浓缩，柱层析纯化(石油醚/乙酸乙酯＝10/1)得到标题化合物(300mg,11％)。
LC-MS:m/z[M+H-Boc] +＝144.
(1-(2,6-二氯嘧啶-4-基)-2-乙基哌啶-2-基)甲醇
Figure PCTCN2020127426-appb-000084
2-乙基-2-羟甲基哌啶-1-甲酸叔丁酯(400mg,1.65mmol)加到二氯甲烷(3mL)中，氯化氢乙酸乙酯溶液加入(4.0M,6mL)中，室温搅拌10分钟后，浓缩得到(2-乙基哌啶-2-基)甲醇(320mg)。依次将(2-乙基哌啶-2-基)甲醇(320mg,1.10mmol)和2,4,6-三氯嘧啶(600mg,3.33mmol)加到乙腈(16mL)中，冷却到0℃。分别加入碳酸钠(530mg,5.01mmol)和上述所得的(2-乙基哌啶-2-基)甲醇，反应混合物室温搅拌过夜。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(200mg,41％)。
LC-MS:m/z[M+H] +＝290.
3-氯-9a-乙基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
Figure PCTCN2020127426-appb-000085
(1-(2,6-二氯嘧啶-4-基)-2-乙基哌啶-2-基)甲醇(50mg,0.17mmol)加入到二氯甲烷(6mL)中，室温下滴加入氯化亚砜(40mg,0.34mmol)，加毕反应液室温搅拌5分钟。反应液浓缩并加入碳酸钾(70mg,0.51mmol)和乙腈(6mL)，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＝10/1)得到标题化合物(30mg,77％)。
LC-MS:m/z[M+H] +＝254.
1H NMR(400MHz,CDCl 3):δ5.49(s,1H),3.95(d,J＝12.2Hz,1H),3.75(d,J＝12.2Hz,1H),3.41(d,J＝13.7Hz,1H),3.13(t,J＝13.0Hz,1H),1.70-2.05(m,6H),1.52(d,J＝12.7Hz,2H),0.89(t,J＝7.3Hz,3H)；
中间体10
N-Boc-吗啉-3-甲酸甲酯
Figure PCTCN2020127426-appb-000086
将N-Boc-吗啉-3-甲酸(10g,43.3mmol)溶入二氯甲烷(200mL)和甲醇(20mL)中，分批加入三甲基硅重氮甲烷(43mL,2.0M正己烷溶液,86.7mmol)，加完后室温搅拌1小时，将反应液直接浓缩得到标题化合物粗品(11.4g)。
LC-MS:m/z[M+H-Boc] +＝146.
N-Boc-3-甲基吗啉-3-甲酸甲酯
Figure PCTCN2020127426-appb-000087
N-Boc-吗啉-3-甲酸甲酯(11g,44.9mmol)溶在四氢呋喃(120mL)中，氩气保护条件下，加入碘甲烷(10.5g,67.3mmol)，将反应液温度冷却至0℃以下，滴加双(三甲基硅基)氨基钠的四氢呋喃溶液(2.0M,45mL,89.8mmol)，加完后室温搅拌3小时，向反应液滴入甲醇淬灭，将反应液倒入水中，乙酸乙酯萃取合并有机相，干燥，过滤，滤液浓缩，层析柱分离得到标题化合物(8.6g,74％)。
LC-MS:m/z[M+H-Boc] +＝160.
3-羟甲基-3-甲基吗啉-4-羧酸叔丁酯
Figure PCTCN2020127426-appb-000088
将N-Boc-3-甲基吗啉-3-甲酸甲酯(1g,3.86mmol)溶入四氢呋喃(10mL)中，反应液冷却至0℃以下，分批加入氢化锂铝(220mg,5.8mmol)，室温下搅拌30分钟。反应液用十水硫酸钠淬灭，室温搅拌0.5小时，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(550mg,61％)。
LC-MS:m/z[M+H-Boc] +＝132.
(3-甲基吗啉-3-基)甲醇盐酸盐
Figure PCTCN2020127426-appb-000089
将3-羟甲基-3-甲基吗啉-4-羧酸叔丁酯(3.2g,13.85mmol)溶入二氯甲烷(50mL)中，氩气保护，加入氯化氢乙酸乙酯溶液(4.0M,50mL)，室温搅拌1小时，反应液浓缩得到标题化合物粗品(1.7g)。
LC-MS:m/z[M+H] +＝132.
(4-(2,6-二氯嘧啶-4-基)-3-甲基吗啉-3-基)甲醇
Figure PCTCN2020127426-appb-000090
将(3-甲基吗啉-3-基)甲醇盐酸盐(1.5g,11.45mmol)溶在乙腈(50mL)中，加入碳酸钠(3.64g,34.35mmol)，反应液冷却至0℃以下，滴加2,4,6-三氯嘧啶(10.5g,57.25mmol)，50℃搅拌过夜，经硅藻土过滤，滤液浓缩，柱层析纯化得到标题化合物(2.1g,66％)。
LC-MS:m/z[M+H] +＝278.
7-氯-11a-甲基-3,4,11,11a-四氢-1H,9H-嘧啶并[6',1':2,3]咪唑并[5,1-c][1,4]恶 嗪-9-酮
Figure PCTCN2020127426-appb-000091
将(4-(2,6-二氯嘧啶-4-基)-3-甲基吗啉-3-基)甲醇(1.6g,5.76mmol)溶入二氯甲烷(50mL)中，加入二氯亚砜(2.05g,17.3mmol)，室温下搅拌1小时，反应液浓缩缩，将浓缩后的残留物溶入乙腈(50mL)中，加入碳酸钾(2.1g,15.2mmol)，85℃搅拌过夜，反应液经硅藻土过滤，滤液浓缩，硅胶柱层析纯化得到标题化合物(1.2g,98％)。
LC-MS:m/z[M+H] +＝242.
1H NMR(400MHz,DMSO-d 6)δ5.99(s,1H),3.79(d,J＝7.3Hz,1H),3.73(s,2H),3.66-3.58(m,2H),3.57-3.50(m,1H),3.47-3.39(m,2H),1.47(s,3H)；
中间体11
((1S,4R)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲烷-d2-醇
Figure PCTCN2020127426-appb-000092
(1S,4S)-5-叔丁氧基羰基-2-氧杂-5-氮杂双环[2.2.1]庚烷-4-羧酸甲酯(470mg,1.83mmol,Chemistry Letters,2017,566-568)加入氯化氢乙酸乙酯溶液(4.0M,10mL)中，反应混合物室温搅拌5小时。反应液浓缩后加入乙腈(20mL)和碳酸钠(1g)，室温搅拌1小时。反应液过滤，浓缩。向残留物中加入无水四氢呋喃(15mL)和氘代氢化铝锂(138.9mg,3.66mmol)，室温搅拌过夜。反应液加入十水硫酸钠淬灭，过滤，将滤液浓缩得到标题化合物粗品(200mg)。
LC-MS:m/z[M+H] +＝132.
(((1S,4R)-5-(2,6-二氯嘧啶-4-基)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲烷-d2-醇
Figure PCTCN2020127426-appb-000093
三乙胺(307mg,3.04mmol)和2,4,6-三氯嘧啶(335.6mg,1.83mmol)加入乙腈(20mL)中，冷却到0℃。((1S,4R)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲烷-d2-醇(200mg,1.52mmol)缓慢加入反应体系，反应液室温搅拌过夜。反应液浓缩，硅胶柱层析纯化得到标题化合物(130mg,31％)。
LC-MS:m/z[M+H] +＝278.
(3S,11aR)-7-氯-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6',1'：2,3]咪唑[5,1-c] [1,4]恶嗪-9-酮-11,11-d2
Figure PCTCN2020127426-appb-000094
((1S,4R)-5-(2,6-二氯嘧啶-4-基)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲烷-d2-醇(130mg,0.47mmol)加入到二氯甲烷(10mL)中，冷却到0℃。滴加入二氯亚砜(279.6mg,2.35mmol)，0℃搅拌30分钟。将反应液浓缩并加入碳酸钾(194.6mg,1.41mmol)和乙腈(15mL)，回流搅拌过夜。反应液用水稀释，二氯甲烷萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩。残留物用制备薄层色谱分离(二氯甲烷/甲醇＝20/1)得标题化合物(63mg,74％)。
LC-MS:m/z[M+H] +＝242.
中间体12
((1S,4R)-5-(2,6-二氯-5-氟嘧啶-4-基)-2-氧杂-5-氮杂双环[2.2.1]庚基-4-基)甲醇
Figure PCTCN2020127426-appb-000095
2,4,6-三氯-5-氟嘧啶(872mg,4.4mmol)和三乙胺(795mg,7.9mmol)加入到四氢呋喃(10mL)中，冷却到0℃。将((1S,4R)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇(650mg,4.0mmol)加入反应液，0℃搅拌2小时。反应液浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1～2/1)得到标题化合物(700mg,60％)。
LC-MS:m/z[M+H] +＝294.
(3S,11aR)-7-氯-6-氟-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6',1':2,3]咪唑[5, 1-c][1,4]恶嗪-9-酮
Figure PCTCN2020127426-appb-000096
((1S,4R)-5-(2,6-二氯-5-氟嘧啶-4-基)-2-氧杂-5-氮杂双环[2.2.1]庚基-4-基)甲醇(700mg,2.4mmol)加入到氯化亚砜(10mL)中，室温搅拌30分钟。将反应液浓缩 并加入碳酸钾(660mg,4.8mmol)和乙腈(20mL)。80℃搅拌过夜。反应液浓缩，制备薄层色谱分离得标题化合物(560mg,91％)。
LC-MS:m/z[M+H] +＝258.
1H NMR(400MHz,CDCl 3)δ4.80(br.s,1H),4.53(d,J＝12.7Hz,1H),4.15-4.06(m,1H),4.05-3.95(m,2H),3.80(d,J＝10.3Hz,1H),3.67(d,J＝10.8Hz,1H),2.22-2.13(m,1H),2.12-2.05(m,1H).
中间体13
((1S,4R)-5-(2,5,6-三氯嘧啶-4-基)-2-氧杂-5-氮杂双环[2.2.1]庚基-4-基)甲醇
Figure PCTCN2020127426-appb-000097
全氯嘧啶(333mg,1.71mmol)溶解在乙腈(16mL)中，依次加入碳酸钠固体(362mg,3.42mmol)和((1S,4R)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇盐酸盐(200mg,1.14mmol)，室温搅拌过夜。过滤，滤液浓缩，制备薄层色谱纯化(石油醚/乙酸乙酯＝4/1)得到标题化合物(280mg)。
LC-MS:m/z[M+H] +＝310.
(3S,11aR)-6,7-二氯-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6',1':2,3]咪唑并 [5,1-c][1,4]恶嗪-9-酮
Figure PCTCN2020127426-appb-000098
((1S,4R)-5-(2,5,6-三氯嘧啶-4-基)-2-氧杂-5-氮杂双环[2.2.1]庚基-4-基)甲醇(280mg,0.9mmol)和氯化亚砜(650mg,4.5mmol)加入到二氯甲烷(8mL)中，搅拌30分钟。反应液浓缩并加入碳酸钾(620mg,4.8mmol)和乙腈(16mL)，90℃搅拌过夜。反应液过滤，滤液浓缩，制备薄层色谱分离纯化(二氯甲烷/甲醇＝25/1)得到标题化合物(160mg,65％)。
LC-MS:m/z[M+H] +＝274.
1H NMR(400MHz,CDCl 3)δ4.78(br.s,1H),4.51(d,J＝13.2Hz,1H),4.08(d,J＝7.3Hz,1H),3.95-4.04(m,2H),3.89(s,2H),1.96-2.29(m,2H).
中间体14
((1S,4R)-5-(2,6-二氯-5-甲基嘧啶)-4-基-2-氧杂-5-氮杂双环[2.2.1]庚基-4-基)甲醇
Figure PCTCN2020127426-appb-000099
2,4,6-三氯-5-甲基嘧啶(113mg,0.4mmol)溶解在乙腈(8mL)中，分别加入碳酸钠固体(130mg,1.2mmol)和((1S,4R)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇盐酸盐(70mg,0.6mmol)，室温搅拌过夜。过滤，滤液浓缩，制备薄层色谱(石油醚/乙酸乙酯＝4/1)纯化得到标题化合物(80mg)。
LC-MS:m/z[M+H] +＝290.
(3S,11aR)-7-氯-6-甲基-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6',1':2,3]咪唑 并[5,1-c][1,4]恶嗪-9-酮
Figure PCTCN2020127426-appb-000100
((1S,4R)-5-(2,6-二氯-5-甲基嘧啶)-4-基-2-氧杂-5-氮杂双环[2.2.1]庚基-4-基)甲醇(80mg,0.27mmol)和氯化亚砜(160mg,1.35mmol)加入到二氯甲烷(3mL)中，搅拌30分钟。将反应液浓缩并加入碳酸钾(112mg,0.81mmol)和乙腈(12mL)，90℃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＝25/1)得到标题化合物(20mg,29％)。
LC-MS:m/z[M+H] +＝254.
中间体15
5-甲酰基-2-(3-(三氟甲基)苯氧基)苄腈
Figure PCTCN2020127426-appb-000101
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N,N-二甲基甲酰胺(100.0mL)中，在105℃反应8小时，反应液倒入水中，用二氯甲烷萃取，有机相浓缩，浓缩残留物乙醇打浆得标题化合物(22.1g,75.5％)。
1H NMR(400MHz,DMSO-d 6)δ9.96(s,1H),8.49(s,1H),8.14(br.s,1H),7.88(br.s,2H),7.47(br.s,2H),7.19(br.s,1H).
5-(羟甲基)-2-(3-(三氟甲基)苯氧基)苄腈
Figure PCTCN2020127426-appb-000102
将5-甲酰基-2-(3-(三氟甲基)苯氧基)苄腈(24.3g,83.44mmol)加到甲醇(250.0mL)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(s,1H),5.41(s,1H),4.51(s,2H).
参考下表，除了采用“原料”一栏所述原料替代相应的原料以外，参照中间体15的制备方法制备以下中间体。
Figure PCTCN2020127426-appb-000103
Figure PCTCN2020127426-appb-000104
Figure PCTCN2020127426-appb-000105
Figure PCTCN2020127426-appb-000106
中间体34
4-(苄氧基)-2-(三氟甲氧基)吡啶
Figure PCTCN2020127426-appb-000107
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)加入到硝基甲烷(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％)。
LC-MS:m/z[M+H] +＝270.
2-(三氟甲氧基)吡啶-4-醇
Figure PCTCN2020127426-appb-000108
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℃，3.0bar压力的氢气氛下搅拌过夜。反应液过滤，滤液浓缩得到粗品标题化合物(330mg,94％)。
LC-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
Figure PCTCN2020127426-appb-000109
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N,N-二甲基甲酰胺(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，将该粗品加入到乙醇(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％)。
LC-MS:m/z[M+H] +＝322.
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).
中间体35
4-((2-(三氟甲基)吡啶-4-基)氧基)苯甲醛
Figure PCTCN2020127426-appb-000110
将2-(三氟甲基)吡啶-4-醇(1.0g,5.6mmol)，4-氟苯甲醛(0.7g,5.5mmol)和碳酸钾(1.7g,12.0mmol)加到N,N-二甲基甲酰胺(10.0mL)中，120℃搅拌14h，反应液倒入水中，用乙酸乙酯萃取，有机相浓缩，硅胶柱纯化得到标题化合物(0.8g,54％)。
LC-MS:m/z[M+H] +＝268.
2-(三氟甲基)-4-(4-乙烯基苯氧基)吡啶
Figure PCTCN2020127426-appb-000111
将4-((2-(三氟甲基)吡啶-4-基)氧基)苯甲醛(0.8g,2.9mmol)，甲基三苯基溴化磷(1.28g,3.6mmol)加入到四氢呋喃(20mL)中，体系中加入氢化钠(173mg,7.2 mmol,60％)，氩气保护下搅拌16h。反应液倒入冰水中，用二氯甲烷萃取，有机相浓缩，柱层析纯化得到标题化合物(0.2g,26％)。
LC-MS:m/z[M+H] +＝266.
2-(4-((2-(三氟甲基)吡啶-4-基)氧基)苯基)乙-1-醇
Figure PCTCN2020127426-appb-000112
0℃下，2-(三氟甲基)-4-(4-乙烯基苯氧基)吡啶(0.2g,0.75mmol)溶解到四氢呋喃(2mL)中，加入9-硼双环[3.3.1]壬烷的四氢呋喃溶液(0.5M，15mL,7.5mmol)，自然升温至室温搅拌16h。反应液中加入水(1mL)，双氧水(30％,5mL)，氢氧化钠水溶液(3.0M,10mL)，50℃反应2h。反应液加水稀释，二氯甲烷萃取，合并有机相浓缩，制备薄层色谱分离得到标题化合物(116mg,55％)。
LC-MS:m/z[M+H] +＝284.
1H NMR(400MHz,DMSO-d 6)δ8.61(d,J＝5.4Hz,1H),7.38(br.s,2H),7.35(br.s,1H),7.16(d,J＝8.3Hz,2H),7.12(d,J＝3.4Hz,1H),4.67(t,J＝4.9Hz,1H),3.71-3.55(m,2H),2.77(t,J＝6.6Hz,2H).
参考下表，除了采用“原料”一栏所述原料替代相应的原料以外，参照中间体35的制备方法制备以下中间体。
Figure PCTCN2020127426-appb-000113
Figure PCTCN2020127426-appb-000114
参考下表，除了采用“原料”一栏所述原料替代相应的原料以外，参照中间体13的制备方法制备以下中间体。
Figure PCTCN2020127426-appb-000115
参考下表，除了采用“原料”一栏所述原料替代相应的原料以外，参照中间体15的制备方法制备以下中间体。
Figure PCTCN2020127426-appb-000116
Figure PCTCN2020127426-appb-000117
Figure PCTCN2020127426-appb-000118
参考下表，除了采用“原料”一栏所述原料替代相应的原料以外，参照中间体34的制备方法制备以下中间体。
Figure PCTCN2020127426-appb-000119
参考下表，除了采用“原料”一栏所述原料替代相应的原料以外，参照中间体35的制备方法制备以下中间体。
Figure PCTCN2020127426-appb-000120
中间体63
2,4-二氯-6-((1S,4R)-4-((羟甲基)-2-氧杂-5-氮杂双环[2.2.1]庚基-5-基)嘧啶-5-腈
Figure PCTCN2020127426-appb-000121
2,4,6-三氯嘧啶-5-腈(400mg,1.94mmol)溶解在乙腈(12mL)中，依次加入碳酸钠固体(318mg,3.0mmol)和((1S,4R)-2-氧杂-5-氮杂双环[2.2.1]庚-4-基)甲醇盐酸盐(166mg,1.0mmol)，室温搅拌过夜。过滤，滤液浓缩，制备薄层色谱(石油醚/乙酸乙酯＝4/1)纯化得到标题化合物(40mg,13％)。
LC-MS:m/z[M+H] +＝301.
(3S,11aR)-7-氯-9-氧代-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶[6',1'：2,3]咪唑[5, 1-c][1,4]恶嗪-6-腈
Figure PCTCN2020127426-appb-000122
2,4-二氯-6-((1S,4R)-4-((羟甲基)-2-氧杂-5-氮杂双环[2.2.1]庚基-5-基)嘧啶-5-腈(40mg,0.12mmol)和氯化亚砜(0.2mL)加入到二氯甲烷(3mL)中，室温搅拌20分钟。将反应液浓缩并加入碳酸钠(40mg,0.37mmol)和乙腈(6mL)，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＝25/1)得到标题化合物(30mg,91％)。
LC-MS:m/z[M+H] +＝265.
参考下表，除了采用“原料”一栏所述原料替代相应的原料以外，参照中间体63的制备方法制备以下中间体。
Figure PCTCN2020127426-appb-000123
中间体65
(2-(2,6-二氯-5-甲氧基嘧啶-4-基)-2-氮杂双环[2.1.1]己-1-基)甲醇
Figure PCTCN2020127426-appb-000124
(2-氮杂双环[2.1.1]己-1-基)甲醇(500mg,4.42mmol,Journal of Organic Chemistry,2018,83,14350-14361)溶解在乙腈(10mL)中，加入碳酸钠(3.64g,34.35mmol)，反应液冷却至0℃，加入2,4,6-三氯-5-甲氧基嘧啶(1.4g,6.46mmol)，反应液室温下反应过夜，将反应液垫硅藻土过滤，滤液浓缩，硅胶层析柱分离纯化得到白色固体标题化合物(1.1g,72％)。
LC-MS:m/z[M+H] +＝290.
3-氯-4-甲氧基-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2':3,4]咪唑并[1,2-c]嘧 啶-1-酮
Figure PCTCN2020127426-appb-000125
(2-(2,6-二氯-5-甲氧基嘧啶-4-基)-2-氮杂双环[2.1.1]己-1-基)甲醇(1.1g,3.79mmol)溶入二氯甲烷(10mL)中，加入二氯亚砜(1.35g,11.38mmol)，室温下反应4小时，反应液浓缩后溶于乙腈(10mL)中，加入碳酸钾(1.5g,10.9mmol)，85℃下搅拌过夜，将反应液冷却至室温，垫硅藻土过滤，将滤液浓缩层析柱分离纯化得到固体标题化合物(230mg,25％)。
LC-MS:m/z[M+H] +＝254.
1H NMR(400MHz,CDCl 3)δ4.03(s,2H),3.74(s,3H),3.67(s,2H),3.07(br.s,1H),2.13(br.s,2H),1.75(d,J＝4.4Hz,2H).
中间体66
(3-氧杂-8-氮杂双环[3.2.1]辛烷-1-基)甲醇盐酸盐
Figure PCTCN2020127426-appb-000126
将1-(羟甲基)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(200mg,0.82mmol,Tetrahedron Letters,2016,57,599–602)溶入二氯甲烷(5mL)中，氩气保护下，加入氯化氢的乙酸乙酯溶液(4.0M,50mL)，室温搅拌3小时。反应液浓缩得到标题化合物粗品(140mg)。
LC-MS:m/z[M+H] +＝144.
(8-(2,6-二氯嘧啶-4-基)-3-氧杂-8-氮杂双环[3.2.1]辛-1-基)甲醇
Figure PCTCN2020127426-appb-000127
将(3-氧杂-8-氮杂双环[3.2.1]辛烷-1-基)甲醇盐酸盐(140mg,0.98mmol)溶在乙腈(10mL)中，搅拌下加入碳酸钠(311mg,2.94mmol)。将反应液冷却至0℃以下，滴加2,4,6-三氯嘧啶(537mg,2.94mmol)，50℃搅拌过夜。将反应液冷却至室温后经硅藻土过滤，滤液浓缩，硅胶柱层析纯化得到标题化合物(190mg,67％)。LC-MS:m/z[M+H] +＝290.
7-氯-3,4-二氢-1H,9H,11H-4,11a-乙桥嘧啶并[6',1':2,3]咪唑并[5,1-c][1,4]恶 嗪-9-酮
Figure PCTCN2020127426-appb-000128
将(8-(2,6-二氯嘧啶-4-基)-3-氧杂-8-氮杂双环[3.2.1]辛-1-基)甲醇(110mg,0.59mmol)溶入二氯甲烷(2mL)中，搅拌下滴入二氯亚砜(209mg,1.76mmol)，室温搅拌3小时。反应液浓缩，向残留物中依次加入乙腈(10mL)、碳酸钾(243mg,1.76mmol)，85℃搅拌过夜。将反应液冷却至室温后经硅藻土过滤，滤液浓缩，硅胶层析柱纯化得到标题化合物(85mg,57％)。
LC-MS:m/z[M+H] +＝254.
1H NMR(400MHz,CDCl 3)δ5.69(s,1H),4.27(d,J＝12.2Hz,1H),4.05(d,J＝6.4Hz,1H),3.95(d,J＝10.3Hz,1H),3.75(br.s,4H),2.41-2.26(m,1H),2.20-2.05(m,1H),1.94(td,J＝6.2,12.0Hz,1H),1.82-1.68(m,1H).
中间体67
(1R,4S)-1-(羟甲基)-2-氮杂双环[2.2.1]庚烷-2-羧酸苄酯
Figure PCTCN2020127426-appb-000129
2-苄基-1-甲基(1R,4S)-2-氮杂双环[2.2.1]庚烷-1,2-二羧酸酯(300mg,1.04mmol,Tetrahedron,2009,1433–1436)加入到无水四氢呋喃(10mL)和甲醇(1mL)的混合溶剂中，缓慢加入硼氢化钠(117.8mg,3.11mmol)，室温搅拌2小时后。加入硼氢化锂(67.74mg,3.11mmol)，室温搅拌过夜。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯萃取。有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝7/1～1/1)得到标题化合物(230mg,85％)。
LC-MS:m/z[M+H] +＝262.
((1R,4S)-2-氮杂双环[2.2.1]庚基-1-基)甲醇
Figure PCTCN2020127426-appb-000130
将(1R,4S)-1-(羟甲基)-2-氮杂双环[2.2.1]庚烷-2-羧酸苄酯(230mg,0.88mmol)和Pd/C(10％,25mg)加入甲醇(1mL)中，室温下常压氢化2小时。反应液过滤，滤液浓缩得到标题化合物粗品(230mg)。
LC-MS:m/z[M+H] +＝128.
((1R,4S)-2-(2,6-二氯嘧啶-4-基)-2-氮杂双环[2.2.1]庚基-1-基)甲醇
Figure PCTCN2020127426-appb-000131
将((1R,4S)-2-氮杂双环[2.2.1]庚基-1-基)甲醇(125mg,粗品)加入乙腈(10mL)中。搅拌下冷却至0℃，依次将三乙胺(197.96mg,1.96mmol)和2,4,6-三氯嘧啶(215.7mg,1.18mmol)加入反应液，室温搅拌过夜。反应液浓缩，制备薄层分离(石油醚/乙酸乙酯＝2/1)得到标题化合物(140mg,两步收率58％)。
LC-MS:m/z[M+H] +＝274.
(7S,9aR)-3-氯-6,7,8,9-四氢-1H,10H-7,9a-甲桥吡啶并[1',2':3,4]咪唑并[1,2-c] 嘧啶-1-酮
Figure PCTCN2020127426-appb-000132
((1R,4S)-2-(2,6-二氯嘧啶-4-基)-2-氮杂双环[2.2.1]庚基-1-基)甲醇(140mg,0.51mmol)加入到二氯甲烷(5mL)中，冷却到0℃。滴加二氯亚砜(303.77mg,0.19mL,2.0mmol)，0℃搅拌1小时。反应液浓缩，依次向残留物中加入碳酸钾(422.28mg,3.06mmol)和乙腈(10mL)，回流搅拌过夜。反应液加水淬灭，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＝25/1)得标题化合物(110mg,91％)。
LC-MS:m/z[M+H] +＝238.
1H NMR(400MHz,CDCl 3)δ5.54(s,1H),4.37(d,J＝12.7Hz,1H),3.92(d,J＝12.7Hz,1H),3.21(s,2H),2.77(br.s,1H),2.04-1.86(m,3H),1.69-1.54(m,3H).
中间体68
(2-苄基-4-氟-2-氮杂双环[2.1.1]己-1-基)甲醇
Figure PCTCN2020127426-appb-000133
将2-苯甲酰基-4-氟-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(880mg,3.35mmol,Journal of Organic Chemistry,2017,8831-8841)溶入四氢呋喃(10mL)中，冷却至0℃，分批加入氢化锂铝(381mg,10.04mmol)，加料结束，50℃搅拌3小时。向反应液中加入十水硫酸钠淬灭。过滤，滤液浓缩，硅胶层析柱纯化得到标题化合物(370mg,50％)。
LC-MS:m/z[M+H] +＝222.
(4-氟-2-氮杂双环[2.1.1]己-1-基)甲醇
Figure PCTCN2020127426-appb-000134
将(2-苄基-4-氟-2-氮杂双环[2.1.1]己-1-基)甲醇(370mg,1.67mmol)溶在甲醇(100mL)中，加入Pd/C(10％,74mg)，50℃常压氢化过夜。反应液过滤，滤液浓缩得到粗品标题化合物(220mg,100％)。
LC-MS:m/z[M+H] +＝132.
(2-(2,6-二氯嘧啶-4-基)-4-氟-2-氮杂双环[2.1.1]己-1-基)甲醇
Figure PCTCN2020127426-appb-000135
将(4-氟-2-氮杂双环[2.1.1]己-1-基)甲醇(210mg,1.59mmol)、4,6-二氯-2-甲氧基嘧啶(427mg,2.39mmol)和碳酸钠固体(674mg,6.36mmol)加入异丙醇(10mL)中，85℃搅拌3天。反应液过滤，滤液浓缩，硅胶层析柱纯化得到标题化合物(432mg,99％)。
LC-MS:m/z[M+H] +＝275.
3-氯-7-氟-7,8-二氢-1H,6H,9H-7,8a-甲基吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶 -1-酮
Figure PCTCN2020127426-appb-000136
将(2-(2,6-二氯嘧啶-4-基)-4-氟-2-氮杂双环[2.1.1]己-1-基)甲醇(332mg,1.21mmol)加入二氯甲烷(5mL)中，搅拌下滴入二氯亚砜(288mg,2.42mmol)，室温搅拌1小时。反应液浓缩，将残留物加入水中，搅拌下用15％氢氧化钠水溶液调节pH＝14，室温搅拌10分钟。二氯甲烷萃取，有机相浓缩，硅胶层析柱纯化得到标题化合物(213mg,73％)。
LC-MS:m/z[M+H] +＝242.
中间体69
(5-氯甲基-2-氧代-3-氧杂双环[3.1.1]庚-1-基)氨基甲酸叔丁酯
Figure PCTCN2020127426-appb-000137
将5-氯甲基-2-氧代-3-氧杂双环[3.1.1]庚烷-1-羧酸(4.0g,19.5mmol,Tetrahedron Letters,2014,466–468)加入甲苯(60mL)中，搅拌下依次加入三乙胺(3.9g,39.0mmol)和叠氮磷酸二苯酯(8.0g,29.2mmol)，室温搅拌2小时。反应液浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)得到黄色油状物(3.8g)。将油状物加入叔丁醇(80mL)中，搅拌下加入二碳酸二叔丁酯(21.9g,97.5mmol)，90℃搅拌过夜。浓缩反应液，柱层析纯化(石油醚/乙酸乙酯＝10/1)得到标题化合物(2.8g,52％)。LC-MS:m/z[M+H-Boc] +＝176.
2-(叔丁氧羰基)-4-羟甲基-2-氮杂双环[2.1.1]己烷-1-羧酸
Figure PCTCN2020127426-appb-000138
将(5-氯甲基-2-氧代-3-氧杂双环[3.1.1]庚-1-基)氨基甲酸叔丁酯(4.5g,16.3mmol)加入二氯甲烷(20mL)中，搅拌下加入氯化氢的乙酸乙酯溶液(4.0M,40mL)，室 温搅拌1.5小时。反应液浓缩，向残留物中加入氢氧化钠水溶液(0.6M,140mL)，95℃搅拌0.5小时。将反应液冷却至室温后用盐酸(6.0M)调节pH＝7。反应液浓缩，向残留物中加入四氢呋喃(40mL)和氢氧化钠水溶液(5％,35mL)，搅拌下加入二碳酸二叔丁酯(10.6g,48.9mmol)，室温搅拌过夜。反应液浓缩，残留物倒入水中，用浓盐酸将反应液pH调节至2，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(二氯甲烷/甲醇＝50/1～10/1)得到标题化合物(1.6g,38％)。
LC-MS:m/z[M+H-Boc] +＝158.
2-叔丁氧羰基-4-羟甲基-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯
Figure PCTCN2020127426-appb-000139
将2-(叔丁氧羰基)-4-羟甲基-2-氮杂双环[2.1.1]己烷-1-羧酸(1.6g,6.22mmol)和碳酸钾固体(2.57g,18.66mmol)加入N,N-二甲基甲酰胺(30mL)中，氩气保护下室温搅搅拌15分钟。将碘甲烷(2.65g,18.66mmol)加入反应液中，室温搅拌过夜。反应液倒入水中，乙酸乙酯提取，有机相浓缩，硅胶柱层析纯化(二氯甲烷/甲醇＝50/1～10/1)得到标题化合物(1.1g,65％)。
LC-MS:m/z[M+H-Boc] +＝172.
2-叔丁氧羰基-4-甲氧甲基-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯
Figure PCTCN2020127426-appb-000140
将 2-叔丁氧羰基-4-羟甲基-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(400mg,1.47mmol)加入N,N-二甲基甲酰胺(16mL)中，室温搅拌下加入氢化钠(60％,177mg,4.43mmol)，室温搅拌15分钟后加入碘甲烷(630mg,4.43mmol)，室温搅拌3小时。反应液倒入水中，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1～3/1)得到标题化合物(290mg,69％)。
LC-MS:m/z[M+H-Boc] +＝186.
(4-(甲氧基甲基)-2-氮杂双环[2.1.1]己-1-基)甲醇
Figure PCTCN2020127426-appb-000141
将 2-叔丁氧羰基-4-甲氧甲基-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(290mg,1.02mmol)加入二氯甲烷(2mL)中，搅拌下加入氯化氢的乙酸乙酯溶液(4.0M,6mL)，室温搅拌0.5小时。反应液浓缩，向残留物中加入四氢呋喃(6mL)和氢化铝锂(76mg,2.0mmol)，室温搅拌1小时。向反应液中加入十水硫酸钠淬灭，室温搅拌0.5小时，过滤，滤液浓缩得到标题化合物(155mg,97％)。
LC-MS:m/z[M+H] +＝158.
(2-(6-氯-2-甲氧基嘧啶-4-基)-4-(甲氧基甲基)-2-氮杂双环[2.1.1]己-1-基)甲醇
Figure PCTCN2020127426-appb-000142
将(4-(甲氧基甲基)-2-氮杂双环[2.1.1]己-1-基)甲醇(155mg,1.0mmol)、4,6-二氯-2-甲氧基嘧啶(267mg,1.5mmol)和碳酸钠固体(318mg,3.0mmol)加入异丙醇(10mL)中，回流搅拌过夜。反应液冷却至室温，过滤，滤液浓缩。制备薄层色谱分离(二氯甲烷/甲醇＝50/1)得到标题化合物(260mg,87％)。
LC-MS:m/z[M+H] +＝300.
3-氯-7-(甲氧基甲基)-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2'：3,4]咪唑并[1, 2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000143
将(2-(6-氯-2-甲氧基嘧啶-4-基)-4-(甲氧基甲基)-2-氮杂双环[2.1.1]己-1-基)甲醇 (260mg,0.87mmol)加入二氯甲烷(4mL)中，搅拌下滴入氯化亚砜(154mg,1.3mmol)，室温搅拌0.5小时。反应液浓缩，向残留物中依次加入水(4mL)和氢氧化钠水溶液(1.0M,4mL)，室温搅拌0.5小时。二氯甲烷萃取，合并有机相，有机相浓缩得到标题化合物(180mg,78％)。
LC-MS:m/z[M+H] +＝268.
中间体70
2-叔丁氧羰基-4-甲酰基-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯
Figure PCTCN2020127426-appb-000144
将2-叔丁氧羰基-4-(羟甲基)-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(400mg,1.47mmol)加入二氯甲烷(20mL)中，搅拌下加入戴斯-马丁试剂(1.23g,2.94mmol)，室温搅拌过夜。过滤，将滤液倒入饱和碳酸氢钠溶液中，二氯甲烷萃取，有机相浓缩，硅胶柱层析纯化(二氯甲烷/甲醇＝50/1)得到标题化合物(250mg,63％)。LC-MS:m/z[M+H-Boc] +＝170.
2-叔丁氧羰基-4-(二氟甲基)-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯
Figure PCTCN2020127426-appb-000145
将2-(叔丁氧羰基)-4-甲酰基-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(250mg,0.86mmol)加入二氯甲烷(12mL)中，冷却至0℃，加入二乙胺基三氟化硫(741mg,4.6mmol)，0℃搅拌2小时，室温搅拌过夜。反应液倒入饱和碳酸氢钠溶液中，二氯甲烷萃取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)得到标题化合物(150mg,56％)。
LC-MS:m/z[M+H-Boc] +＝192.
(4-(二氟甲基)-2-氮杂双环[2.1.1]己-1-基)甲醇
Figure PCTCN2020127426-appb-000146
将2-(叔丁氧羰基)-4-(二氟甲基)-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(150mg,0.51mmol)加入二氯甲烷(4mL)中，搅拌下加入氯化氢的乙酸乙酯溶液(4.0M,6mL)，室温搅拌0.5小时。反应液浓缩，向残留物中依次加入四氢呋喃(6mL)和氢化铝锂(286mg,0.75mmol)，室温搅拌1小时。反应液加入十水硫酸钠淬灭，室温搅拌0.5小时。过滤，浓缩滤液得到标题化合物粗品(100mg)。
LC-MS:m/z[M+H] +＝164.
2-(6-氯-2-甲氧基嘧啶-4-基)-1-(二氟甲基)-4-(甲氧基甲基)-2-氮杂双环[2.1.1]己烷
Figure PCTCN2020127426-appb-000147
将(4-(二氟甲基)-2-氮杂双环[2.1.1]己-1-基)甲醇(100mg,0.61mmol)、4,6-二氯-2-甲氧基嘧啶(163mg,0.92mmol)和碳酸钠固体(190mg,1.83mmol)加入异丙醇(10mL)中，回流搅拌过夜。反应液冷却至室温，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(60mg，两步收率:38％)。
LC-MS:m/z[M+H] +＝306.
3-氯-7-(二氟甲基)-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2'：3,4]咪唑并[1, 2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000148
将2-(6-氯-2-甲氧基嘧啶-4-基)-1-(二氟甲基)-4-(甲氧基甲基)-2-氮杂双环[2.1.1]己烷(60mg,0.20mmol)加入二氯甲烷(4mL)中，搅拌下滴入氯化亚砜(47mg,0.40 mmol)，室温搅拌0.5小时。反应液浓缩，向残留物中依次加入水(2mL)和氢氧化钠水溶液(1.0M,0.5mL)，室温搅拌0.5小时。反应液用二氯甲烷萃取，有机相浓缩得到标题化合物(45mg,82％)。
LC-MS:m/z[M+H] +＝274.
中间体71
2-(叔丁氧羰基)-4-(((甲磺酰基)氧基)甲基)-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯
Figure PCTCN2020127426-appb-000149
将2-(叔丁氧羰基)-4-(羟甲基)-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(270mg,1.0mmol)和三乙胺(300mg,3.0mmol)加入二氯甲烷(10mL)中，冷却至0℃，滴入甲基磺酰氯(3434mg,3.0mmol)，室温搅拌过夜。反应液倒入饱和碳酸氢钠溶液中，二氯甲烷萃取，有机相浓缩，制备薄层色谱纯化(二氯甲烷/甲醇＝20/1)得到标题化合物(180mg,52％)。
LC-MS:m/z[M+H-Boc] +＝250
2-(叔丁氧羰基)-4-(吗啉代甲基)-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯
Figure PCTCN2020127426-appb-000150
将2-(叔丁氧羰基)-4-(((甲磺酰基)氧基)甲基)-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(180mg,0.52mmol)、吗啉(226mg,2.6mmol)、碳酸钾固体(215mg,1.56mmol)、碘化钾(17mg,0.1mmol)加入乙腈(12mL)中，85℃搅拌过夜。反应液冷却至室温，过滤，滤液浓缩，薄层制备色谱纯化(二氯甲烷/甲醇＝20/1)得到标题化合物(140mg,80％)。
LC-MS:m/z[M+H] +＝341
(4-(吗啉代甲基)-2-氮杂双环[2.1.1]己-1-基)甲醇
Figure PCTCN2020127426-appb-000151
将2-(叔丁氧羰基)-4-(吗啉代甲基)-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(140mg,0.41mmol)加入二氯甲烷(3mL)中，搅拌下加入氯化氢的乙酸乙酯(4.0M,3mL)，室温搅拌0.5小时。反应液浓缩，向残留物中依次加入四氢呋喃(6mL)和氢化铝锂(31mg,0.82mmol)，室温搅拌0.5小时。向反应液中加入十水硫酸钠固体淬灭，室温搅拌0.5小时。过滤，滤液浓缩得到标题化合物粗品(80mg)。
LC-MS:m/z[M+H] +＝213.
(2-(6-氯-2-甲氧基嘧啶-4-基)-4-(吗啉代甲基)-2-氮杂双环[2.1.1]己-1-基)甲醇
Figure PCTCN2020127426-appb-000152
将(4-(吗啉代甲基)-2-氮杂双环[2.1.1]己-1-基)甲醇(80mg,0.38mmol)、4,6-二氯-2-甲氧基嘧啶(135mg,0.76mmol)和碳酸钠固体(120mg,1.14mmol)加入异丙醇(12mL)中，回流搅拌过夜。反应液冷却至室温，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(80mg，两步收率：55％)。
LC-MS:m/z[M+H] +＝355.
3-氯-7-(吗啉代甲基)-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2'：3,4]咪唑并[1, 2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000153
将(2-(6-氯-2-甲氧基嘧啶-4-基)-4-(吗啉代甲基)-2-氮杂双环[2.1.1]己-1-基)甲醇(80mg,0.23mmol)加入二氯甲烷(3mL)中，搅拌下滴入氯化亚砜(81mg,0.69mmol)，室温搅拌0.5小时。反应液浓缩，向残留物中依次加入水(3mL)和氢氧化钠水溶液(1.0M,3mL)，室温搅拌0.5小时。二氯甲烷萃取，有机相浓缩得到标题化合物(45mg,61％)。
LC-MS:m/z[M+H] +＝323.
中间体72
2-(叔丁氧羰基)-4-((((叔丁基二甲基甲硅烷基)氧基)甲基)-2-氮杂双环[2.1.1]己烷 -1-羧酸甲酯
Figure PCTCN2020127426-appb-000154
将2-(叔丁氧羰基)-4-(羟甲基)-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(1.0g,3.69mmol)加入二氯甲烷(10mL)中，搅拌下依次加入咪唑(0.5g,7.35mmol)和叔丁基二甲基氯硅烷(0.66g,4.37mmol)，室温搅拌2小时。反应液中倒入饱和氯化铵水溶液中，乙酸乙酯提取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)得到标题化合物(1.2g,84％)。
LC-MS:m/z[M+H-Boc] +＝286.
4-((((叔丁基二甲基甲硅烷基)氧基)甲基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧 酸叔丁酯
Figure PCTCN2020127426-appb-000155
将2-(叔丁氧羰基)-4-((((叔丁基二甲基甲硅烷基)氧基)甲基)-2-氮杂双环[2.1.1]己烷-1-羧酸甲酯(1.2g,3.11mmol)加入甲醇(15mL)中，反应液升温至65℃，分批次加入硼氢化钠(1.18g,31.16mmol)，65℃搅拌0.5小时。反应液冷却至室温，反应液用饱和氯化铵水溶液淬灭，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)得到标题化合物(1g,90％)。
LC-MS:m/z[M+H-Boc] +＝258.
1-((苄氧基)甲基)-4-((((叔丁基二甲基甲硅烷基)氧基)甲基)-2-氮杂双环[2.1.1]己 烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000156
将4-((((叔丁基二甲基甲硅烷基)氧基)甲基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯(1.0g,2.80mmol)加入N,N-二甲基甲酰胺(16mL)中，氩气保护下降温至0℃，搅拌下加入氢化钠(60％,224mg,5.60mmol)，室温搅拌10分钟后加入溴化苄(718mg,4.20mmol)，室温搅拌过夜。反应液倒入水中，乙酸乙酯萃取，有机相浓缩得到标题化合物(1.2g,96％)。
LC-MS:m/z[M+H-Boc] +＝348.
1-((苄氧基)甲基)-4-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000157
将1-((苄氧基)甲基)-4-((((叔丁基二甲基甲硅烷基)氧基)甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯(1.2g,2.68mmol)加入四氢呋喃(10mL)中，搅拌下加入四丁基氟化铵的四氢呋喃溶液(1.0M,4mL)，室温搅拌2小时。反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(二氯甲烷/甲醇＝20/1) 得到标题化合物(600mg,67％)。
LC-MS:m/z[M+H-Boc] +＝234.
1-((苄氧基)甲基)-2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-羧酸
Figure PCTCN2020127426-appb-000158
室温下将1-((苄氧基)甲基)-4-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯(600mg,1.80mmol)溶于丙酮(6mL)中，缓慢滴入琼斯试剂(2.0M,2mL)中，室温搅拌0.5小时。向反应液中加入异丙醇(6mL)，室温搅拌10分钟，过滤，滤液浓缩。将残留物溶于水中，用饱和碳酸氢钠溶液调节pH为弱碱性，再用盐酸(6.0M)调节pH＝2，乙酸乙酯萃取，有机相浓缩，制备薄层色谱纯化得到标题化合物粗品(400mg,64％)。
LC-MS:m/z[M+H-Boc] +＝248.
2-(叔丁氧羰基)-1-((苄氧基)甲基)-2-氮杂双环[2.1.1]己烷-4-羧酸甲酯
Figure PCTCN2020127426-appb-000159
将1-((苄氧基)甲基)-2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-羧酸(400mg,1.15mmol)和碳酸钾固体(476mg,3.45mmol)加入N,N-二甲基甲酰胺(5mL)中，室温搅拌10分钟后加入碘甲烷(326mg,2.30mmol)，室温搅拌过夜。反应液倒入水中，乙酸乙酯萃取，有机相浓缩。薄层制备色谱纯化(石油醚/乙酸乙酯＝5/1)得到标题化合物(230mg,56％)。
LC-MS:m/z[M+H-Boc] +＝262.
2-(叔丁氧羰基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-4-羧酸甲酯
Figure PCTCN2020127426-appb-000160
将2-(叔丁氧羰基)-1-((苄氧基)甲基)-2-氮杂双环[2.1.1]己烷-4-羧酸甲酯(230mg,0.64mmol)和Pd/C(10％,25mg)加入甲醇(10mL)中，室温常压氢化过夜。过滤，滤液浓缩得到标题化合物(150mg,96％)。
LC-MS:m/z[M+H-Boc] +＝172.
2-(2,6-二氯嘧啶-4-基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-4-羧酸甲酯
Figure PCTCN2020127426-appb-000161
将2-(叔丁氧羰基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-4-羧酸甲酯(80mg,0.29mmol)加入氯化氢的二氧六环溶液(4.0M,6mL)中，50℃搅拌30分钟。反应液浓缩，向残留物中依次加入4,6-二氯-2-甲氧基嘧啶(103mg,0.58mmol)、碳酸钠固体(92mg,0.87mmol)和乙腈(6mL)，85℃搅拌过夜。反应液冷却至室温，过滤。滤液浓缩，制备薄层色谱纯化(二氯甲烷/甲醇＝30/1)得到标题化合物(60mg,66％)。
LC-MS:m/z[M+H] +＝314.
3-氯-1-氧代-1H,6H,9H-7,8a-甲桥吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶-7(8H)- 羧酸甲酯
Figure PCTCN2020127426-appb-000162
将2-(2,6-二氯嘧啶-4-基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-4-羧酸甲酯(60mg,0.87mmol)加入二氯甲烷(3mL)中，随后滴入氯化亚砜(154mg,1.3mmol)，室温 搅拌0.5小时。反应液浓缩。向残留物中依次加入水(4mL)和氢氧化钠水溶液(1.0M,2mL)，室温搅拌0.5小时。二氯甲烷萃取，有机相浓缩得到标题化合物(30mg,56％)。
LC-MS:m/z[M+H] +＝282.
3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-1-氧代-1H,6H,9H-7,8a-甲 桥吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶-7(8H)-羧酸甲酯
Figure PCTCN2020127426-appb-000163
将3-氯-1-氧代-1H,6H,9H-7,8a-甲桥吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶-7(8H)-羧酸甲酯(30mg,0.106mmol)、(3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苯基)甲醇(45mg,0.156mmol)和碳酸铯(103mg,0.318mmol)加入甲苯(6mL)中，130℃搅拌4小时。反应液冷却至室温，过滤，滤液浓缩。制备薄层色谱纯化(二氯甲烷/甲醇＝20/1)得到标题化合物(20mg,35％)。
LC-MS:m/z[M+H] +＝533.
3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-1-氧代-1H,6H,9H-7,8a-甲 基吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶-7(8H)-羧酸
Figure PCTCN2020127426-appb-000164
将3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-1-氧代-1H,6H,9H-7,8a-甲桥吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶-7(8H)-羧酸甲酯(1.1g,2.07mmol)加入乙腈(10mL)和氢氧化钠水溶液(1.0M,20mL)中，室温搅拌1小时。用盐酸水溶液(1.0M)调节反应液pH＝3-4。二氯甲烷提取，有机相浓缩得到标题化合物(1.07g,100％)。
LC-MS:m/z[M+H] +＝519.
(3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-1-氧代-1H,6H,9H-7,8a-甲 基吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶-7(8H)-基)氨基甲酸叔丁酯
Figure PCTCN2020127426-appb-000165
将3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-1-氧代-1H,6H,9H-7,8a-甲基吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶-7(8H)-羧酸(1.07g,2.07mmol)和三乙胺(418mg,4.14mmol)加入二氯甲烷(20mL)中，冷却至0℃加入叠氮磷酸二苯酯(628mg,2.28mmol)，室温搅拌4小时。反应液浓缩，向残留物中依次加入二碳酸二叔丁酯(1.35g,6.21mmol)和叔丁醇(20mL)，90℃搅拌过夜。反应液浓缩，柱层析纯化(二氯甲烷/甲醇＝200/1～50/1)得到标题化合物(350mg,29％)。
LC-MS:m/z[M+H] +＝590.
中间体73
4-氨基甲酰基-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000166
将4-甲氧羰基-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯(200mg,0.74mmol)加入甲醇(3mL)和氨水(6mL)中，室温搅拌3小时。反应液浓缩得到标题化合物(120mg,63％)。
LC-MS:m/z[M+H-Boc] +＝157.
4-氰基-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000167
将4-氨基甲酰基-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯(220mg,0.86mmol)加入二氯甲烷(16mL)中，搅拌下依次加入三乙胺(434mg,4.30mmol)和三氟乙酸酐(722mg,3.44mmol)，室温搅拌1小时。反应液倒入乙酸乙酯中，有机相依次用饱和氯化铵溶液和饱和碳酸钠溶液洗涤，有机相浓缩，制备薄层色谱纯化(石油醚/乙酸乙酯＝5/1)得到标题化合物(100mg,49％)。
LC-MS:m/z[M+H-Boc] +＝139.
2-(6-氯-2-甲氧基嘧啶-4-基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-4-腈
Figure PCTCN2020127426-appb-000168
将4-氰基-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯(100mg,0.42mmol)加入二氯甲烷(4mL)中，搅拌下加入盐酸/二氧六环(4.0M,3mL)，50℃搅拌30分钟。反应液浓缩，向残留物中依次加入4,6-二氯-2-甲氧基嘧啶(146mg,0.82mmol)、碳酸钠固体(133mg,1.26mmol)和乙腈(8mL)，90℃搅拌过夜。反应液冷却至室温，过滤，滤液浓缩，制备薄层色谱纯化(石油醚/乙酸乙酯＝4/1)得到标题化合物(20mg,17％)。
LC-MS:m/z[M+H] +＝281.
3-氯-1-氧代-1H,6H,9H-7,8a-甲桥吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶-7(8H)- 腈
Figure PCTCN2020127426-appb-000169
将2-(6-氯-2-甲氧基嘧啶-4-基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-4-腈(20mg,0.07mmol)加入二氯甲烷(2mL)中，搅拌下加入氯化亚砜(42mg,0.35mmol)，室温搅拌0.5小时。反应液浓缩，将残留物中加入水中，用碳酸钾固体调节pH＝10，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(12mg, 69％)。
LC-MS:m/z[M+H] +＝249.
中间体74
4-(苄基氨基甲酰基)-1-((苄氧基)甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000170
将1-((苄氧基)甲基)-2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-羧酸(750mg,2.16mol)、苄胺(347.4mg,3.24mmol)、HATU(1.64g,4.32mmol)和三乙胺(873mg,8.64mmol)加入二氯甲烷(20mL)中，室温搅拌2小时。反应液浓缩，柱层析纯化(二氯甲烷/甲醇＝20/1)得到标题化合物(800mg,85％)。
LC-MS:m/z[M+H] +＝437.
4-(苄基氨基甲酰基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000171
4-(苄基氨基甲酰基)-1-((苄氧基)甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯(800mg,1.83mmol)和Pd/C(10％,80mg)加入到甲醇(10mL)中，反应液60℃常压氢化过夜。反应液过滤，滤液浓缩标题化合物粗品(480mg)。
LC-MS:m/z[M+H-tBu] +＝291.
N-苄基-2-(2,6-二氯嘧啶-4-基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-4-羧酰胺
Figure PCTCN2020127426-appb-000172
将4-(苄基氨基甲酰基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-2-羧酸叔丁酯(480mg,1.39mmol)加入盐酸/二氧六环(4.0M,5mL)中，室温搅拌1小时。反应液浓缩， 向残留物中依次加入2,4,6-三氯嘧啶(254.5mg,1.39mmol)、碳酸钠固体(294.7mg,2.78mmol)和乙腈(10mL)，室温搅拌2小时。反应液倒入水中，乙酸乙酯萃取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝1/1)得到标题化合物(150mg,两步收率:27％)。
LC-MS:m/z[M+H] +＝393.
N-苄基-3-氯-1-氧代-1H,6H,9H-7,8a-甲基吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶 -7(8H)-羧酰胺
Figure PCTCN2020127426-appb-000173
将N-苄基-2-(2,6-二氯嘧啶-4-基)-1-(羟甲基)-2-氮杂双环[2.1.1]己烷-4-羧酰胺(150mg,0.38mmol)加入二氯甲烷(6mL)中，搅拌下滴入二氯亚砜(2mL)，室温搅拌30分钟。反应液浓缩，向残留物依次加入碳酸钾(263.4mg,1.91mmol)和乙腈(15mL)，回流搅拌过夜。反应液倒入水中，二氯甲烷萃取，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(25mg,18％)。
LC-MS:m/z[M+H] +＝357.
中间体75
1-(叔丁氧羰基)-(4R)-4-((三甲基甲硅烷基)氧基)吡咯烷-2-羧酸甲酯
Figure PCTCN2020127426-appb-000174
1-(叔丁氧羰基)-(4R)-4-羟基吡咯烷-2-二羧酸甲酯(5g,20.39mmol)和三乙胺(2.88g,28.55mmol)加到二氯甲烷(50mL)中。氩气保护下降温至0℃，滴加三甲基氯硅烷(2.88g,26.51mmol)，室温搅拌过夜。反应液倒入二氯甲烷中，有机相依次用水、饱和碳酸氢钠溶液洗涤。有机相浓缩得到标题化合物(6.34g,98％)。
LC-MS:m/z[M+H-tBu] +＝262.
1-(叔丁氧羰基)-(4R)-2-((苄氧基)甲基)-4-((三甲基甲硅烷基)氧基)吡咯烷-2-羧酸 甲酯
Figure PCTCN2020127426-appb-000175
1-(叔丁氧羰基)-(4R)-4-((三甲基甲硅烷基)氧基)吡咯烷-2-羧酸甲酯(6.5g,20.5mmol)和苄基氯甲基醚(6.4g,41mmol)溶入四氢呋喃(100mL)中。氩气保护下降温至0℃滴加二异丙基氨基锂的四氢呋喃溶液(2.0M,20mL,40mmol)。室温搅拌3小时。反应液用甲醇淬灭后倒入水中，乙酸乙酯萃取。有机相浓缩，硅胶柱层析纯化得到标题化合物(3.6g,40％)。
LC-MS:m/z[M+H] +＝438.
1-(叔丁氧羰基)-(4R)-2-((苄氧基)甲基)-4-羟基吡咯烷-2-羧酸甲酯
Figure PCTCN2020127426-appb-000176
将1-(叔丁氧羰基)-(4R)-2-((苄氧基)甲基)-4-((三甲基甲硅烷基)氧基)吡咯烷-2-羧酸甲酯(3g,6.86mmol)加入的柠檬酸甲醇溶液(10％,10mL)中，室温搅拌3小时。反应液过滤，滤液浓缩得到标题化合物(2.3g,89％)。
LC-MS:m/z[M+H] +＝366.
1-(叔丁氧羰基)-(4R)-2-((苄氧基)甲基)-4-((甲基磺酰基)氧基)吡咯烷-2-羧酸甲酯
Figure PCTCN2020127426-appb-000177
依次将1-(叔丁氧羰基)-(4R)-2-((苄氧基)甲基)-4-羟基吡咯烷-2-羧酸甲酯(2.3g,6.3mmol)和三乙胺(1.28g,12.6mmol)加入二氯甲烷(15mL)中。反应液降温至0℃，将甲磺酸酐(2.2g,10.1mmol)溶于二氯甲烷(15mL)中滴入反应液，室温搅拌过夜。将反应液倒入饱和碳酸氢钠溶液中，二氯甲烷萃取。有机相浓缩得到标题化合物(2.6g,100％)。
LC-MS:m/z[M+H] +＝444.
1-(叔丁氧羰基)-(4S)-4-(苄氨基)-2-((苄氧基)甲基)吡咯烷-2-羧酸甲酯
Figure PCTCN2020127426-appb-000178
1-(叔丁氧羰基)-(4R)-2-((苄氧基)甲基)-4-((甲基磺酰基)氧基)吡咯烷-2-羧酸甲酯(2.6g,5.87mmol)溶于苄胺(5mL)中，85℃搅拌过夜。硅胶柱层析纯化得到标题化合物(2.32g,87％)。
LC-MS:m/z[M+H-Boc] +＝355.
(1R,4S)-5-苄基-1-((苄氧基)甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁 酯
Figure PCTCN2020127426-appb-000179
将1-(叔丁氧羰基)-(4S)-4-(苄氨基)-2-((苄氧基)甲基)吡咯烷-2-羧酸甲酯(519mg,114mmol)和氢氧化锂(54.8mg,2.28mmol)加入水(2mL)和甲醇(10mL)中，30℃搅拌2天。反应液浓缩，向残留物中依次加入HATU(865mg,2.28mmol)、三乙胺(460mg,4.56mmol)和N,N-二甲基甲酰胺(35mL)，室温搅拌过夜。反应液倒入乙酸乙酯中，依次用水、饱和食盐水洗涤，无水硫酸钠干燥。有机相浓缩。硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1)，得到标题化合物(150mg,31％)。
LC-MS:m/z[M+H-Boc] +＝323.
(1S,4R)-2-苄基-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚三-3-酮
Figure PCTCN2020127426-appb-000180
将(1R,4S)-5-苄基-1-((苄氧基)甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(150mg,0.36mmol)和Pd/C(10％,20mg)加入甲醇(10mL)中，40℃常压氢化过夜。反应液过滤并浓缩。向残留物加入氯化氢二氧六环溶液(4.0M,5mL)，室温搅拌2小时。反应液浓缩得到标题化合物粗品直接用于下一步。
LC-MS:m/z[M+H] +＝233.
(1S,4R)-2-苄基-5-(2,6-二氯嘧啶-4-基)-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚-3-酮
Figure PCTCN2020127426-appb-000181
将(1S,4R)-2-苄基-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚三-3-酮(粗品)溶解在乙腈(10mL)中，冷却到0℃。依次加入三乙胺(71mg,0.71mmol)和2,4,6-三氯嘧啶(98mg,0.53mmol)，室温搅拌过夜。反应液浓缩，制备薄层分离(石油醚/乙酸乙酯＝2/1)得到标题化合物(40mg，两步收率30％)。
LC-MS:m/z[M+H] +＝379.
(3S,11aR)-2-苄基-7-氯-3,4-二氢-9H,11H-3,11a-甲基吡嗪并[1',2'：3,4]咪唑并[1, 2-c]嘧啶-1,9(2H)-二酮
Figure PCTCN2020127426-appb-000182
将(1S,4R)-2-苄基-5-(2,6-二氯嘧啶-4-基)-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚-3-酮(40mg,0.11mmol)加入二氯甲烷(5mL)中。冷却到0℃后滴加二氯亚砜(0.5mL)，0℃搅拌0.5小时。将反应液浓缩并加入碳酸钾(45.54mg,0.33mmol)和乙腈(5mL)，回流搅拌过夜。反应液倒入水中，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＝25/1)得标题化合物(15mg,40％)。
LC-MS:m/z[M+H] +＝343.
中间体76
1-(叔丁氧羰基)-(4S)-2-((苄氧基)甲基)-4-((3,5-二甲氧基苄基)氨基)吡咯烷-2-羧 酸甲酯
Figure PCTCN2020127426-appb-000183
将1-(叔丁氧羰基)-(4R)-2-((苄氧基)甲基)-4-((甲基磺酰基)氧基)吡咯烷-2-羧酸甲酯(100g,0.23mol)加入2,4-二甲氧基苄胺(200mL)中，90℃搅拌过夜。将反应液直接经柱层析纯化得到标题化合物(75.8g,64％)。
LC-MS:m/z[M+H] +＝515.
(1R,4S)-1-((苄氧基)甲基)-5-(3,5-二甲氧基苄基)-6-氧代-2,5-二氮杂双环[2.2.1] 庚烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000184
1-(叔丁氧羰基)-(4S)-2-((苄氧基)甲基)-4-((3,5-二甲氧基苄基)氨基)吡咯烷-2-羧酸甲酯(75.8g,0.148mol)和氢氧化钠(17.76g,0.444mol)加入到水(28mL)和甲醇(280mL)的混合溶剂中，40℃搅拌过夜。反应液浓缩至干，向残留物中依次加入HATU(112.26g,0.296mol)、三乙胺(59.8g,0.592mol)和N,N-二甲基甲酰胺(90mL)，室温搅拌过夜。反应液倒入水中，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)得到标题化合物(23g,32％)。
LC-MS:m/z[M+H-Boc] +＝383.
(1R,4S)-1-((苄氧基)甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000185
将(1R,4S)-1-((苄氧基)甲基)-5-(3,5-二甲氧基苄基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(21g,0.044mol)和DDQ(29.63g,0.13mol)加入二氯甲烷(100mL)和水(5mL)中，室温搅拌过夜。反应液倒入水中，二氯甲烷萃取。有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到标题化合物(5.6g,38％)。
LC-MS:m/z[M+H-Boc] +＝233.
(1R,4S)-1-((苄氧基)甲基)-5-甲基-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁 酯
Figure PCTCN2020127426-appb-000186
(1R,4S)-1-((苄氧基)甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(1.8g,5.42mmol)加入四氢呋喃(20mL)中，氩气保护下冷却到0℃。搅拌下将钠氢(325mg,8.12mmol)加入反应液，0℃搅拌30分钟。将碘甲烷(1.15g,8.12mmol)滴入反应液，室温搅拌过夜。反应液倒入水中，乙酸乙酯萃取。有机相浓缩，硅胶柱层析纯化(二氯甲烷/甲醇＝15/1)得到标题化合物(800mg,43％)。
LC-MS:m/z[M+H] +＝247.
(1R,4S)-1-(羟甲基)-5-甲基-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000187
(1R,4S)-1-((苄氧基)甲基)-5-甲基-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(800mg,2.3mmol)和Pd/C(10％,80mg)加入到甲醇(8mL)中，反应液60℃常压氢化过夜。反应液过滤，滤液浓缩标题化合物粗品(700mg)。
LC-MS:m/z[M+H] +＝257.
(1S,4R)-5-(6-氯-2-甲氧基嘧啶-4-基)-4-(羟甲基)-2-甲基-2,5-二氮杂双环[2.2.1]庚 -3-酮
Figure PCTCN2020127426-appb-000188
(1R,4S)-1-(羟甲基)-5-甲基-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(700mg,2.7mmol)加入三氟乙酸(5mL)和二氯甲烷(5mL)中，室温搅拌2小时。反应液浓缩，向残留物中依次加入4,6-二氯-2-甲氧基嘧啶(489.4mg,2.7mmol)、碳酸钠固体(1.43g,13.5mmol)和乙腈(15mL)，回流搅拌3天。反应液倒入水中，乙酸乙酯萃取，有机相浓缩。硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化得到标题化合物(520mg，两步收率75％)。
LC-MS:m/z[M+H] +＝299.
(3R,10aR)-6-氯-2-甲基-2,3,4,4a-四氢-10H-3,10a-甲氧基吡啶并[4',3'：3,4]吡咯 并[1,2-c]嘧啶-1,8-二酮
Figure PCTCN2020127426-appb-000189
(1S,4R)-5-(6-氯-2-甲氧基嘧啶-4-基)-4-(羟甲基)-2-甲基-2,5-二氮杂双环[2.2.1]庚-3-酮(420mg,1.4mmol)加入二氯甲烷(7mL)中，将二氯亚砜(836mg,7.0mmol)缓慢滴入体系中。室温搅拌1小时。反应液浓缩，将残留物加入饱和碳酸氢钠水溶液中，二氯甲烷萃取，有机相浓缩得标题化合物(220mg,59％)。
LC-MS:m/z[M+H] +＝267.
中间体77
(1R,4S)-1-((苄氧基)甲基)-5-((1-甲基-1H-吡唑-3-基)甲基)-6-氧代-2,5-二氮杂双 环[2.2.1]庚烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000190
将(1R,4S)-1-((苄氧基)甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(1g,3mmol)和3-(氯甲基)-1-甲基-1H-吡唑(600mg,4.5mmol)加入四氢呋喃(20mL)中。搅拌下将钠氢(200mg,4.5mmol)加入反应液，50℃搅拌3天。反应液倒入水中，乙酸乙酯萃取，有机相浓缩，柱层析纯化(石油醚/乙酸乙酯＝1/1)得到标题化合物(800mg,62％)。
LC-MS:m/z[M+H-Boc] +＝327.
(1R,4S)-1-(羟甲基)-5-((1-甲基-1H-吡唑-3-基)甲基)-6-氧代-2,5-二氮杂双环[2.2.1] 庚烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000191
将(1R,4S)-1-((苄氧基)甲基)-5-((1-甲基-1H-吡唑-3-基)甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(800mg,1.88mmol)和Pd/C(10％,180mg)加入到甲醇(15mL)中，反应液60℃常压氢化过夜。反应液过滤，滤液浓缩得到标题化合物粗品(600mg)。
LC-MS:m/z[M+H-Boc] +＝237.
(1S,4R)-5-(6-氯-2-甲氧基嘧啶-4-基)-4-(羟甲基)-2-((1-甲基-1H-吡唑-3-基)甲基)-2, 5-二氮杂双环[2.2.1]庚-3-酮
Figure PCTCN2020127426-appb-000192
将(1R,4S)-1-(羟甲基)-5-((1-甲基-1H-吡唑-3-基)甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(300mg,1.88mmol)加入盐酸/乙酸乙酯(4.0M,6mL)和乙酸乙酯(5mL)中，室温搅拌3小时。反应液浓缩，向残留物中依次加入4,6-二氯-2-甲氧基嘧啶(159.3mg,0.89mmol)、碳酸钠固体(471.7mg,4.45mmol)和乙腈(15mL)，回流搅拌3天。反应液倒入水中，乙酸乙酯萃取，有机相浓缩。柱层析(石油醚/乙酸乙酯＝1/1)纯化得到标题化合物(220mg,两步收率:65％)。
LC-MS:m/z[M+H] +＝379.
(3R,10aR)-6-氯-2-((1-甲基-1H-吡唑-4-基)甲基)-2,3,4,4a-四氢-10H-3,10a-甲氨 基吡啶[4',3'：3,4]吡咯并[1,2-c]嘧啶-1,8-二酮
Figure PCTCN2020127426-appb-000193
(1S,4R)-5-(6-氯-2-甲氧基嘧啶-4-基)-4-(羟甲基)-2-((1-甲基-1H-吡唑-3-基)甲基)-2,5-二氮杂双环[2.2.1]庚-3-酮(220mg,1.4mmol)加入二氯甲烷(10mL)中，将甲磺酰氯(99.65mg,0.87mmol)缓慢滴入体系中。室温搅拌2小时。反应液浓缩，将残留物加入饱和碳酸氢钠水溶液中，二氯甲烷萃取，有机相浓缩得标题化合物(120mg,60％)。
LC-MS:m/z[M+H] +＝347.
中间体78
(1R,4S)-1-((苄氧基)甲基)-5-(双环[1.1.1]戊-1-基甲基)-6-氧代-2,5-二氮杂双环 [2.2.1]庚烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000194
将(1R,4S)-1-((苄氧基)甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(1g,3mmol)和1-(氯甲基)双环[1.1.1]戊烷(1.05g,9.0mmol)加入四氢呋喃(20mL)中。搅拌下将钠氢(600mg,15mmol)加入反应液，闷罐中50℃搅拌3天。反应液倒入水中，乙酸乙酯萃取。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(780mg,63％)。
LC-MS:m/z[M+H-Boc] +＝313.
(1R,4S)-5-(双环[1.1.1]戊-1-基甲基)-1-(羟甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚 烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000195
将(1R,4S)-1-((苄氧基)甲基)-5-(双环[1.1.1]戊-1-基甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(780mg,1.9mmol)和Pd/C(10％,200mg)加入到甲醇 (20mL)中，反应液氢化(70℃,0.5MPa)过夜。反应液过滤，滤液浓缩得到标题化合物粗品(430mg)。
LC-MS:m/z[M+H-tBu] +＝267.
(1S,4R)-2-(双环[1.1.1]戊基-1-基甲基)-5-(2,6-二氯嘧啶-4-基)-4-(羟甲基)-2,5-二 氮杂双环[2.2.1]庚烷-3-酮
Figure PCTCN2020127426-appb-000196
将(1R,4S)-5-(双环[1.1.1]戊-1-基甲基)-1-(羟甲基)-6-氧代-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(480mg,1.88mmol)加入盐酸/二氧六环(4.0M,5mL)和二氯甲烷(5mL)中，室温搅拌30分钟。反应液浓缩，向残留物中依次加入2,4,6-三氯嘧啶(372.2mg,1.44mmol)、碳酸钠固体(458mg,4.32mmol)和乙腈(15mL)，室温搅拌过夜。反应液过滤，滤液浓缩，柱层析纯化(石油醚/乙酸乙酯＝1/1)得到标题化合物(175mg,两步收率:33％)。
LC-MS:m/z[M+H] +＝369.
(3S,11aR)-2-(双环[1.1.1]戊基-1-基甲基)-7-氯-3,4-二氢-9H,11H-3,11a-甲基吡嗪 并[1',2'：3,4]咪唑并[1,2-c]嘧啶-1,9(2H)-二酮
Figure PCTCN2020127426-appb-000197
将(1S,4R)-2-(双环[1.1.1]戊基-1-基甲基)-5-(2,6-二氯嘧啶-4-基)-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚烷-3-酮(50mg,1.4mmol)加入二氯甲烷(6mL)中，搅拌下滴入二氯亚砜(2mL)，室温搅拌30分钟。反应液浓缩，向残留物依次加入碳酸钠(43.2mg,0.41mmol)和乙腈(10ml)，回流搅拌过夜。反应液倒入水中，二氯甲烷萃取，有机相浓缩，柱层析纯化(二氯甲烷/甲醇＝20/1)得标题化合物(42mg，93％)。
LC-MS:m/z[M+H] +＝333.
中间体79
(1S,4S)-2-苄基-5-(叔丁氧羰基)-2,5-二氮杂双环[2.2.1]庚烷-1-羧酸
Figure PCTCN2020127426-appb-000198
将(1S,4S)-5-苄基-4-氰基-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(6.3g,20mmol,Synthesis,2015,1123-1130)、氢氧化钠水溶液(1.0M,50mL)和固体氢氧化钠(8.3g,207mmol)加入甲醇(150mL)中，100℃搅拌过夜。反应液浓缩除去甲醇，将残留物用盐酸水溶液(1.0M)调节pH＝3.8～4.4。二氯甲烷提取，有机相浓缩得标题化合物(5.4g,81％)。
LC-MS:m/z[M+H] +＝333.
(1S,4S)-5-苄基-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000199
将(1S,4S)-2-苄基-5-(叔丁氧羰基)-2,5-二氮杂双环[2.2.1]庚烷-1-羧酸(3.0g,9mmol)和硼烷二甲硫醚的四氢呋喃溶液(2.0M,9mL,18mmol)加入四氢呋喃(30mL)中，80℃搅拌过夜。反应液经甲醇淬灭后浓缩，硅胶柱层析纯化得标题化合物(2.0g,70％)。
LC-MS:m/z[M+H] +＝319.
(1S,4S)-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯
Figure PCTCN2020127426-appb-000200
将(1S,4S)-5-苄基-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(1.7g 5.3mmol)和Pd/C(10％,100mg)加入甲醇(17mL)中，室温常压氢化过夜。反应液经硅藻土过滤，滤液浓缩得标题化合物粗品(1.4g,115％)，粗品不经进一步纯化直 接用于下一步。
(1S,4S)-5-(2,6-二氯嘧啶-4-基)-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔 丁酯
Figure PCTCN2020127426-appb-000201
将(1S,4S)-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(1.4g,6.1mmol)、碳酸钠固体(1.3g,12mmol)和2,4,6-三氯嘧啶(1.5g,8.0mmol)加入乙腈(14mL)中，室温搅拌过夜。反应液过滤，滤液浓缩，硅胶柱层析纯化得标题化合物(1.3g,56％)。
LC-MS:m/z[M+H] +＝374.
(3S,11aR)-7-氯-9-氧代-3,4-二氢-9H,11H-3,11氨基吡嗪并[1',2'：3,4]咪唑并[1, 2-c]嘧啶-2(1H)-羧酸叔丁酯
Figure PCTCN2020127426-appb-000202
将(1S,4S)-5-(2,6-二氯嘧啶-4-基)-4-(羟甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(1.3g,3.5mmol)和三乙胺(700mg,7.0mmol)加入二氯甲烷(13mL)中，冷却至0℃加入甲基磺酸酐(900mg,5.2mmol)，室温搅拌1小时。反应液浓缩，将残留物和碳酸钾固体(970mg,7.0mmol)加入乙腈(13mL)中，80℃搅拌过夜。反应液倒入水中，二氯甲烷提取，浓缩得标题化合物(1.1g,97％)。
LC-MS:m/z[M+H] +＝339.
1H NMR(400MHz,CDCl 3)δ5.59(br.s,1H),4.45(d,J＝12.7Hz,1H),3.99(br.s,1H),3.65-3.54(m,3H),3.32(d,J＝8.8Hz,1H),3.17-3.06(m,1H),2.09-1.98(m,1H),1.86(d,J＝9.3Hz,1H),1.49(br.s,9H).
(3S,11aR)-7-(((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-9-氧代-3,4-二 氢-9H,11H-3,11a-甲基吡嗪并[1',2'：3,4]咪唑并[1,2-c]嘧啶-2(1H)-羧酸叔丁酯
Figure PCTCN2020127426-appb-000203
将(3S,11aR)-7-氯-9-氧代-3,4-二氢-9H,11H-3,11氨基吡嗪并[1',2'：3,4]咪唑并[1,2-c]嘧啶-2(1H)-羧酸叔丁酯(1.1g,3.4mmol)、(3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苯基)甲醇(1.2g,4.4mmol)和碳酸铯固体(3.3g,10mmol)加入甲苯(11mL)中，120℃搅拌过夜。反应液过滤，滤液浓缩，硅胶柱层析纯化得标题化合物(1.3g,65％)。
LC-MS:m/z[M+H] +＝590.
1H NMR(400MHz,CDCl 3)δ8.58(d,J＝5.4Hz,1H),7.33(d,J＝11.2Hz,1H),7.27-7.16(m,3H),6.96(d,J＝4.9Hz,1H),5.44(d,J＝4.9Hz,2H),5.15-5.06(m,1H),4.43(d,J＝12.7Hz,1H),4.02-3.90(m,1H),3.66-3.47(m,4H),3.23(d,J＝9.8Hz,1H),1.96(d,J＝10.3Hz,1H),1.71(d,J＝9.8Hz,1H),1.49(br.s,9H).
中间体80
2-氟-4-(2-羟乙基)苯酚
Figure PCTCN2020127426-appb-000204
将2-(3-氟-4-羟基苯基)乙酸(2g,11.6mmol)加入四氢呋喃(10mL)中，搅拌下加入硼烷二甲硫醚(3.5mL,34.8mmol)，室温搅拌3小时，反应液浓缩加水稀释，乙酸乙酯萃取，有机相浓缩得到标题化合物粗品(2.2g,120％)。
LCMS:m/z[M+H] +＝157.
2-(3-氟-4-(((2-(三氟甲基)吡啶-4-基)氧基)苯基)乙-1-醇
Figure PCTCN2020127426-appb-000205
将2-氟-4-(2-羟乙基)苯酚(2.1g,13.29mmol)、4-氯-2-(三氟甲基)吡啶(2.35g,13.29mmol)和碳酸钾(3.67g,26.58mmol)加入到N,N-二甲基甲酰胺(20mL)中，120℃搅拌3小时。反应液倒入水中，乙酸乙酯萃取，有机相浓缩，硅胶层析柱分离得到标题化合物(1.63g,40.6％)。
LCMS:m/z[M+H] +＝302.
中间体81
4-溴-2-(二氟甲基)吡啶
Figure PCTCN2020127426-appb-000206
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，二氯甲烷萃取，有机相浓缩得到标题化合物粗品直接用于下一步反应。
LC-MS:m/z[M+H] +＝208.
2-(二氟甲基)-4-甲氧基吡啶
Figure PCTCN2020127426-appb-000207
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。
LC-MS:m/z[M+H] +＝160.
2-(二氟甲基)吡啶-4-醇
Figure PCTCN2020127426-appb-000208
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％)。
LC-MS:m/z[M+H] +＝146.
4-((2-(二氟甲基)吡啶-4-基)氧基)苯甲醛
Figure PCTCN2020127426-appb-000209
将4-氟苯甲醛(200mg,1.6mmol)、2-(二氟甲基)碳酸-4-醇(289mg,1.8mmol)和碳酸钾固体(441mg,3.2mmol)加入到N,N-二甲基甲酰胺(5mL)中，100℃搅拌过夜。制备薄层色谱分离得到标题化合物(180mg,45％)。
LC-MS:m/z[M+H] +＝250.
(4-((2-(二氟甲基)吡啶-4-基)氧基)苯基)甲醇
Figure PCTCN2020127426-appb-000210
将4-((2-(二氟甲基)吡啶-4-基)氧基)苯甲醛(180mg,0.7mmol)加入无水乙醇(5mL)中，搅拌下加入硼氢化钠(41mg,1mmol)，室温搅拌2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(100mg,62％)。
LC-MS:m/z[M+H] +＝252.
参考下表，除了采用“原料”一栏所述原料替代相应的原料以外，参照中间体81的制备方法制备以下中间体。
Figure PCTCN2020127426-appb-000211
Figure PCTCN2020127426-appb-000212
中间体84：
4-(4-溴苯氧基)-2-(三氟甲基)吡啶
Figure PCTCN2020127426-appb-000213
将4-溴酚(9.4g,54.53mmol)、4-氯-2-(三氟甲基)吡啶(9g,49.58mmol)和碳酸钾(13.7g,99.16mmol)加入N,N-二甲基甲酰胺(100mL)中，在120℃搅拌2小时，反应液倒入水中，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)得标题化合物(4.3g,25％).
LCMS:m/z[M+H] +＝318.
2-(三氟甲基)-4-(4-((三甲基甲硅烷基)乙炔基)苯氧基)吡啶
Figure PCTCN2020127426-appb-000214
将4-(4-溴苯氧基)-2-(三氟甲基)吡啶(4.3g,13.52mmol)、乙炔基三甲基硅烷(3.32g,33.8mmol)、四三苯基磷钯(1.56g,1.352mmol)和碘化亚铜(275mg,1.352mmol)加入二异丙基乙胺(15mL)和甲苯(30mL)的混合溶剂中，反应在80℃闷罐下过夜。反应液过滤，滤液倒入水中，乙酸乙酯萃取，有机相浓缩，硅胶柱层析纯化(石油醚/乙酸乙酯＝100/1～20/1)得到标题化合物(1.5g,33％).
LCMS:m/z[M+H] +＝336.
4-(4-乙炔基苯氧基)-2-(三氟甲基)吡啶
Figure PCTCN2020127426-appb-000215
将2-(三氟甲基)-4-(4-((三甲基甲硅烷基)乙炔基)苯氧基)吡啶(1g,2.98mmol)和碳酸钾(822.9mg,5.96mmol)加到甲醇(10mL)中，室温搅拌过夜。反应液加水淬灭， 乙酸乙酯萃取，有机相浓缩得到标题化合物(750mg,96％).
LCMS:m/z[M+H] +＝264.
中间体85：
(3,4-二氟苄基)氨基甲酸叔丁酯
Figure PCTCN2020127426-appb-000216
将(3,4-二氟苯基)甲胺(1.0g,6.99mmol)、二碳酸二叔丁酯(2.3g,10.5mmol)和三乙胺(1.4g,14.0mmol)加入二氯甲烷(10mL)中，室温搅拌过夜。反应液浓缩，硅胶柱层析纯化得标题化合物(1.6g,94％)。
LCMS:m/z[M+H-Boc] +＝144.
1-(3,4-二氟苯基)-N-甲基甲胺
Figure PCTCN2020127426-appb-000217
将(3,4-二氟苄基)氨基甲酸叔丁酯(300mg,1.2mmol)、四氢铝锂(47mg,1.2mmol)，加入四氢呋喃(3mL)中，升温至回流搅拌1小时。反应液加十水硫酸钠淬灭，过滤，滤液浓缩得标题化合物(170mg,88％)。
1H NMR(400MHz,DMSO-d 6)δ7.63(t,J＝9.5Hz,1H),7.56-7.45(m,1H),7.37(br.s,1H),4.15(br.s,1H),3.88(s,2H),2.52(s,3H).
实施例
实施例1
方法A
(3S,11aR)-7-((3,5-二氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-3,5-二氟苄 基)氧基)-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6'-,1':2,3]咪唑并[5,1-c][1, 4]恶嗪-9-酮
Figure PCTCN2020127426-appb-000218
将(3,5-二氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苯基)甲醇(51mg,0.167mmol)溶解在无水四氢呋喃(4mL)中，室温下加入六甲基二硅基胺基锂(0.167mL,1.0M四氢呋喃溶液,0.167mmol)，混合物搅拌15分钟。加入(3S,11aR)-7-氯-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6',1':2,3]咪唑并[5,1-C][1,4]恶嗪-9-酮(20mg,0.083mmol)，反应混合物120℃搅拌16小时。反应用甲醇淬灭，制备薄层色谱分离得到标题化合物(10.7mg,25％)。
LC-MS:m/z[M+H] +＝509.
1H NMR(400MHz,DMSO-d 6)δ8.68(d,J＝4.4Hz,1H),7.65(br.s,1H),7.45(d,J＝8.8Hz,2H),7.30(br.s,1H),5.34(br.s,2H),5.31(br.s,1H),4.68(br.s,1H),4.29(d,J＝11.7Hz,1H),3.99-3.76(m,3H),3.32-3.22(m,2H),1.90(d,J＝9.3Hz,1H),1.79(d,J＝9.8Hz,1H).
实施例2
方法B
5-(((1-氧代-7,8-二氢-1H,6H,9H-6,8a-乙桥吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶 -3-基)氧基)甲基)-2-(3-(三氟甲基)苯氧基)苄腈
Figure PCTCN2020127426-appb-000219
将5-(羟甲基)-2-(3-(三氟甲基)苯氧基)苄腈(233mg,0.80mmol)溶于乙腈中(12mL)，降温至0℃，加入氢化钠(42mg,1.06mmol,60％)和3-氯-7,8-二氢-1H,6H,9H-6,8a-乙桥吡咯并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮(125mg,0.53mmol)，搅拌0.5小时。反应用饱和氯化铵溶液淬灭，乙酸乙酯萃取。有机相用饱和食盐水洗 涤，无水硫酸钠干燥。有机相浓缩，薄层制备色谱分离(二氯甲烷/甲醇＝25/1)得到标题化合物(128mg,49％)。
LC-MS:m/z[M+H] +＝495.
1H NMR(400MHz,DMSO-d 6)δ7.98(s,1H),7.79-7.40(m,5H),7.10(d,J＝8.8Hz,1H),5.44(s,1H),5.27(s,2H),4.27(br.s,1H),3.88(s,2H),1.92(d,J＝7.8Hz,2H),1.81-1.55(m,6H).
下表所列的实施例4-168通过类似于实施例1-2所述的步骤制备，起始于相应的中间体：
Figure PCTCN2020127426-appb-000220
Figure PCTCN2020127426-appb-000221
Figure PCTCN2020127426-appb-000222
Figure PCTCN2020127426-appb-000223
Figure PCTCN2020127426-appb-000224
Figure PCTCN2020127426-appb-000225
Figure PCTCN2020127426-appb-000226
Figure PCTCN2020127426-appb-000227
Figure PCTCN2020127426-appb-000228
Figure PCTCN2020127426-appb-000229
Figure PCTCN2020127426-appb-000230
Figure PCTCN2020127426-appb-000231
Figure PCTCN2020127426-appb-000232
Figure PCTCN2020127426-appb-000233
Figure PCTCN2020127426-appb-000234
Figure PCTCN2020127426-appb-000235
Figure PCTCN2020127426-appb-000236
Figure PCTCN2020127426-appb-000237
Figure PCTCN2020127426-appb-000238
Figure PCTCN2020127426-appb-000239
Figure PCTCN2020127426-appb-000240
Figure PCTCN2020127426-appb-000241
Figure PCTCN2020127426-appb-000242
Figure PCTCN2020127426-appb-000243
Figure PCTCN2020127426-appb-000244
Figure PCTCN2020127426-appb-000245
Figure PCTCN2020127426-appb-000246
Figure PCTCN2020127426-appb-000247
Figure PCTCN2020127426-appb-000248
Figure PCTCN2020127426-appb-000249
Figure PCTCN2020127426-appb-000250
Figure PCTCN2020127426-appb-000251
Figure PCTCN2020127426-appb-000252
Figure PCTCN2020127426-appb-000253
Figure PCTCN2020127426-appb-000254
实施例169
方法C
3-(3,5-二氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苯乙氧基)-7,8-二氢-1H,6H,9H-7, 8a-甲氨基吡咯[1',2'：3,4]咪唑并[1,2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000255
将3-氯-7,8-二氢-1H,6H,9H-7,8a-甲基吡咯并[1',2'：3,4]咪唑[1,2-c]嘧啶-1-酮(80mg,0.359mmol)，2-(3,5-二氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苯基)乙-1-醇(137mg,0.43mmol)和碳酸铯(233mg,0.718mmol)加入甲苯(10mL)中，120℃搅拌16小时。反应液浓缩，薄层色谱纯化得到标题化合物(68mg,37％)。
LC-MS:m/z[M+H] +＝507.
1H NMR(400MHz,CDCl 3)δ8.58(d,J＝5.4Hz,1H),7.24(br.s.,1H),6.96(d,J＝8.3Hz,3H),5.04(s,1H),4.57(t,J＝5.9Hz,2H),3.96(s,2H),3.31(s,2H),3.03(t,J＝6.4Hz,3H),2.04(br.s.,2H),1.81(br.s.,2H).
实施例170
方法D
(3S,11aR)-6-甲氧基-7-((4-((2-(三氟甲基)吡啶-4-基)氧基)苯基)乙炔基)-3,4-二氢 -1H,9H,11H-3,11a-甲桥嘧啶并[6',1':2,3]咪唑[5,1-c][1,4]恶嗪-9-酮
Figure PCTCN2020127426-appb-000256
将4-(4-乙炔基苯氧基)-2-(三氟甲基)吡啶(195.66mg,0.74mmol)溶于无水四氢呋喃(10mL)中，氩气保护下降温至-50℃，滴入正丁基锂的四氢呋喃溶液(2M,0.74mL,1.44mmol)，反应液搅拌15分钟后升温至0℃加入氯化锌(150.96mg,1.11 mmol)，反应液搅拌30分钟后，加入(3S,11aR)-7-氯-6-甲氧基-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6',1'：2,3]咪唑[5,1-c][1,4]恶嗪-9-酮(200mg,0.742mmol)、Pd 2(dba) 3(67.76mg,0.074mmol)和2-二环己基磷-2,4,6-三异丙基联苯(70.6mg,0.148mmol)，反应液升温到120℃搅拌2小时。反应液加水稀释，用乙酸乙酯萃取。有机相浓缩。制备薄层色谱纯化(二氯甲烷/甲醇＝20/1)得到标题化合物(25mg,7％)。
LCMS:m/z[M+H] +＝497.
(3S,11aR)-6-甲氧基-7-(4-((2-(三氟甲基)吡啶-4-基)氧基)苯乙基)-3,4-二氢-1H, 9H,11H-3,11a-甲桥嘧啶并[6',1':2,3]咪唑[5,1-c][1,4]恶嗪-9-酮
Figure PCTCN2020127426-appb-000257
将(3S,11aR)-6-甲氧基-7-((4-((2-(三氟甲基)吡啶-4-基)氧基)苯基)乙炔基)-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6',1':2,3]咪唑[5,1-c][1,4]恶嗪-9-酮(25mg,0.05mmol)和Pd/C(10％,5mg)加入到甲醇(5mL)中，室温常压氢化1小时。反应液过滤，滤液浓缩。制备薄层色谱纯化(二氯甲烷/甲醇＝20/1)得到标题化合物(8mg,32％)。
LCMS:m/z[M+H] +＝501.
1H NMR(400MHz,CDCl 3)δ8.55(d,J＝5.4Hz,1H),7.34(d,J＝7.8Hz,2H),7.19(s,1H),7.02(d,J＝8.3Hz,2H),6.96(d,J＝3.9Hz,1H),4.74(br.s.,1H),4.52(d,J＝12.7Hz,1H),4.09-3.96(m,3H),3.72(s,2H),3.57(s,3H),3.18-3.03(m,2H),2.98-2.84(m,2H),2.09(d,J＝9.8Hz,1H),1.86(d,J＝9.8Hz,1H).
实施例171
方法E
(3S,11aS)-7-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-2-甲基-1,2,3,4- 四氢-9H,11H-3,11a-甲吡嗪[1',2'：3,4]咪唑[1,2-c]嘧啶-9-酮
Figure PCTCN2020127426-appb-000258
将(3S,11aR)-7-(((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-9-氧代-3,4-二氢-9H,11H-3,11a-甲基吡嗪并[1',2'：3,4]咪唑并[1,2-c]嘧啶-2(1H)-羧酸叔丁酯(36mg,0.06mmol)和三氟乙酸(8.4mg,0.07mmol)加入二氯甲烷(1mL)中，室温搅拌1小时。反应液浓缩，向残留物中加入甲醛水溶液(37％,5mg,0.06mmol)、氰基硼氢化钠(12mg,0.18mmol)和甲醇(1mL)，室温搅拌1小时。反应液浓缩，制备薄层色谱纯化得(13mg,41％)。
LCMS:m/z[M+H] +＝504.
1H NMR(400MHz,CDCl 3)δ8.59(br.s.,1H),7.27(br.s.,4H),6.97(br.s.,1H),5.45(br.s.,2H),5.11(br.s.,1H),4.37(br.s.,1H),3.84(br.s.,1H),3.75-3.57(m,2H),3.19(d,J＝1.5Hz,1H),2.73(br.s.,1H),2.50(br.s.,3H),2.00(br.s.,1H),0.87(br.s.,2H).
实施例172
方法F
(3S,11aS)-7-(((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-2-(氧杂环丁-3- 基)-1,2,3,4-四氢-9H,11H-3,11a-甲基吡嗪并[1',2'：3,4]咪唑并[1,2-c]嘧啶-9- 酮
Figure PCTCN2020127426-appb-000259
将(3S,11aR)-7-(((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-9-氧代-3,4-二氢-9H,11H-3,11a-甲基吡嗪并[1',2'：3,4]咪唑并[1,2-c]嘧啶-2(1H)-羧酸叔丁酯(80mg,0.14mmol)加入氯化氢乙酸乙酯溶液(4.0M,1mL)和二氯甲烷(11mL)中，室温搅拌1小时。反应液浓缩，向残留物中加入氧杂环丁酮(20mg,0.28mmol)、 氰基硼氢化钠(17mg,0.28mmol)和甲醇(1mL)，室温搅拌1小时。反应液浓缩，制备薄层色谱纯化得(60mg,81％)。
LCMS:m/z[M+H] +＝546.
1H NMR(400MHz,CDCl 3)δ8.57(d,J＝5.4Hz,1H),7.32(d,J＝10.8Hz,1H),7.27-7.16(m,3H),6.96(d,J＝4.4Hz,1H),5.49-5.38(m,2H),5.09(s,1H),4.75(t,J＝6.4Hz,2H),4.62(t,J＝5.6Hz,1H),4.56(t,J＝5.9Hz,1H),4.40(d,J＝12.2Hz,1H),4.04(t,J＝5.9Hz,1H),3.89(d,J＝12.2Hz,1H),3.62(br.s.,1H),3.43(d,J＝9.8Hz,1H),3.16(d,J＝9.3Hz,1H),3.10(d,J＝9.8Hz,1H),3.00(d,J＝9.3Hz,1H),1.97(d,J＝9.8Hz,1H),1.62(d,J＝9.8Hz,1H).
实施例173
方法G
(3S,11aS)-7-(((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-2-(2,2,2-三氟乙 基)-1,2,3,4-四氢-9H,11H-3,11a-甲基吡嗪并[1',2'：3,4]咪唑并[1,2-c]嘧啶-9- 酮
Figure PCTCN2020127426-appb-000260
将(3S,11aR)-7-(((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-9-氧代-3,4-二氢-9H,11H-3,11a-甲基吡嗪并[1',2'：3,4]咪唑并[1,2-c]嘧啶-2(1H)-羧酸叔丁酯(80mg,0.14mmol)加入氯化氢乙酸乙酯溶液(4.0M,1mL)和二氯甲烷(1mL)中，室温搅拌1小时。反应液浓缩，向残留物中加入2,2,2-三氟乙基三氟甲磺酸盐(49mg,0.21mmol)、三乙胺(140mg,1.4mmol)和甲苯(1mL)，80℃搅拌过夜。反应液倒入饱和氯化铵溶液中，二氯甲烷萃取，有机相浓缩，制备薄层色谱纯化得(25mg,32％)。
LCMS:m/z[M+H] +＝572.
1H NMR(400MHz,CDCl 3)δ8.58(d,J＝5.4Hz,1H),7.33(d,J＝10.8Hz,1H),7.25-7.16(m,3H),6.96(br.s.,1H),5.49-5.41(m,2H),5.11(s,1H),4.40(d,J＝ 12.2Hz,1H),3.88(d,J＝12.7Hz,1H),3.78(br.s.,1H),3.61(d,J＝10.3Hz,1H),3.44(d,J＝9.3Hz,1H),3.26-3.13(m,3H),2.90(d,J＝9.3Hz,1H),2.04(d,J＝9.3Hz,1H),1.67(d,J＝9.8Hz,1H).
实施例174
方法H
(3S,11aS)-2-苯甲酰基-7-(((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-1,2, 3,4-四氢-9H,11H-3,11a-甲基吡嗪并[1',2'：3,4]咪唑[1,2-c]嘧啶-9-酮
Figure PCTCN2020127426-appb-000261
将(3S,11aR)-7-(((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-9-氧代-3,4-二氢-9H,11H-3,11a-甲基吡嗪并[1',2'：3,4]咪唑并[1,2-c]嘧啶-2(1H)-羧酸叔丁酯(80mg,0.14mmol)加入氯化氢乙酸乙酯溶液(4.0M,1mL)和二氯甲烷(1mL)中，室温搅拌1小时。反应液浓缩，向残留物中加三乙胺(42mg,0.42mmol)、苯甲酰氯(29.4mg,0.21mmol)和二氯甲烷(1mL)，室温搅拌过夜。反应液倒入饱和氯化铵溶液中，二氯甲烷萃取，有机相浓缩，制备薄层色谱纯化得(52mg,65％)。
LCMS:m/z[M+H] +＝594.
1H NMR(400MHz,CDCl 3)δ8.57(d,J＝5.4Hz,1H),8.08(d,J＝7.3Hz,1H),7.55(d,J＝5.4Hz,2H),7.50-7.44(m,1H),7.32(d,J＝10.8Hz,1H),7.27-7.14(m,4H),6.95(d,J＝3.9Hz,1H),5.46-5.38(m,2H),5.14(d,J＝7.3Hz,1H),4.61(br.s.,1H),4.51-4.42(m,1H),4.08(d,J＝12.2Hz,1H),3.96(d,J＝10.8Hz,1H),3.82(d,J＝9.3Hz,1H),3.69-3.58(m,1H),3.32(d,J＝10.3Hz,1H),2.12-2.03(m,1H),1.86-1.75(m,1H).
实施例175
方法I
(3S,11aR)-7-((3,4-二氟苄基)氨基)-6-甲氧基-3,4-二氢-1H,9H,11H-3,11a-甲氨 基嘧啶[6',1'：2,3]咪唑[5,1-c][1,4]恶嗪-9-酮
Figure PCTCN2020127426-appb-000262
将(3S,11aR)-7-氯-6-甲氧基-3,4-二氢-1H,9H,11H-3,11a-甲氨基嘧啶[6',1'：2,3]咪唑[5,1-c][1,4]恶嗪-9-酮(100mg,0.37mmol)、(3,4-二氟苯基)甲胺(110mg,0.74mmol)和二异丙基乙胺(480mg,3.7mmol)加入1,4-二氧六环(1mL)中，120℃搅拌过夜。反应液倒入二氯甲烷中，饱和氯化铵水溶液洗涤，有机相浓缩，制备薄层色谱纯化得标题化合物(120mg,86％)。
LCMS:m/z[M+H] +＝377.
1H NMR(400MHz,CDCl 3)δ7.20-7.03(m,3H),5.52(br.s.,1H),4.79-4.68(m,2H),4.66-4.57(m,1H),4.42(d,J＝12.2Hz,1H),4.04-3.95(m,2H),3.86(d,J＝12.2Hz,1H),3.70-3.65(m,1H),3.64-3.59(m,4H),2.02(d,J＝9.8Hz,1H),1.82(d,J＝10.3Hz,1H).
下表所列的实施例176-200通过类似于实施例169-175所述的步骤制备，起始于相应的中间体：
Figure PCTCN2020127426-appb-000263
Figure PCTCN2020127426-appb-000264
Figure PCTCN2020127426-appb-000265
Figure PCTCN2020127426-appb-000266
Figure PCTCN2020127426-appb-000267
Figure PCTCN2020127426-appb-000268
Figure PCTCN2020127426-appb-000269
实施例201
3-((3-氟-4-((2-三氟甲基吡啶-4-基)氧基)苄基)氧基)-7-(2-羟丙-2-基)-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000270
将3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-1-氧代-1H,6H,9H-7,8a-甲桥吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶-7(8H)-羧酸甲酯(20mg,0.038mmol)加入四氢呋喃(4mL)中。氩气保护下降温至0℃，加入甲基氯化镁的四氢呋喃溶液(3.0M,0.13mL)。室温搅拌2小时。反应液用饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相浓缩。制备薄层色谱纯化(二氯甲烷/甲醇＝10/1)得到标题化合物(1mg,5％)。
LC-MS:m/z[M+H] +＝533.
1H NMR(400MHz,CDCl 3)δ8.58(d,J＝5.4Hz,1H),7.34(d,J＝10.8Hz,1H),7.30-7.28(m,1H),7.24(br.s.,1H),7.22-7.15(m,1H),6.96(d,J＝5.4Hz,1H),5.45(s,2H),5.17(br.s.,1H),4.03(s,2H),3.82-3.74(m,1H),3.35(d,J＝3.9Hz,2H),2.07-1.99(m,2H),1.76(br.s.,2H),1.44(s,3H),1.31(s,3H).
实施例202
7-氨基-3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2'：3,4]咪唑[1,2-c]嘧啶-1-酮
Figure PCTCN2020127426-appb-000271
将(3-((3-氟-4-((2-(三氟甲基)吡啶-4-基)氧基)苄基)氧基)-1-氧代-1H,6H,9H-7,8a-甲基吡咯并[1',2'：3,4]咪唑并[1,2-c]嘧啶-7(8H)-基)氨基甲酸叔丁酯(90mg,0.15 mmol)加入乙酸乙酯(4mL)中。搅拌下加入氯化氢的乙酸乙酯溶液(4.0M,2mL)。室温搅拌10分钟。用碳酸钠固体调节反应液pH＝8，过滤，滤液浓缩。制备薄层色谱纯化(二氯甲烷/甲醇＝10/1)得到标题化合物(6mg,7％)。
LC-MS:m/z[M+H] +＝490.
1H NMR(400MHz,CDCl 3)δ8.58(d,J＝5.9Hz,1H),7.34(d,J＝11.2Hz,2H),7.25-7.15(m,2H),6.96(d,J＝3.4Hz,1H),5.44(s,2H),5.15(s,1H),4.04(s,2H),3.25(s,2H),1.97(s,4H).
生物测试和数据
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。
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。
脂蛋白-相关磷脂酶A2(Lp-PLA 2)人血浆测定。
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。
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。
实施例测定活性
Figure PCTCN2020127426-appb-000272
Figure PCTCN2020127426-appb-000273
Figure PCTCN2020127426-appb-000274
活性数据对比(一)
Figure PCTCN2020127426-appb-000275
由对比数据可知，本专利中化合物相比于现有技术中化合物能够具有显著更高的活性。

Claims (31)

  1. 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，
    Figure PCTCN2020127426-appb-100001
    其中
    n为0，1或2；且当n为0时，R 2为甲基或乙基；当n为1或2时，R 2不存在；
    R 1为H，卤素，氰基，C 1-6烷基，C 1-6烷氧基，C 3-8环烷基或3-8元杂环基，R 1可以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6-10元杂芳基；
    R a独立的为H或D；
    m为1或2；
    R x为H，卤素，羟基，羧基，氰基，氨基，C 1-6烷基，C 1-6烷氧基，C 3-8环烷基，3-8元杂环基，6-10元芳基，6-10元杂芳基，-C(O)NR bR c或-S(O) 2NR bR c，R x可以任选被一个或多个以下取代基取代：卤素，羟基，C 1-6烷氧基，氰基，C 3-8环烷基，3-8元杂环基，6-10元芳基或6-10元杂芳基；
    Q为-O-，-S-，-CH 2-或-NR b-；
    X为-O-，-CH 2-,-NR c-，-OCH 2-或不存在；
    R b为H，C 1-6烷基或C 3-8环烷基或3-8元杂环基；
    R c为L，L-C(O)-，L-CH 2-或L-S(O) 2-，其中L为H、C 1-6烷基、C 3-6环烷基、3-8元杂环基，6-10元芳基或6-10元杂芳基，L可以任选被一个或多个下基团取代：卤素，羟基，C 1-6烷氧基，氰基，C 3-8环烷基，3-8元杂环基，6-10元芳基或6-10元杂芳基；
    Y为-CH 2-，-CH 2CH 2-或者不存在；
    U为-CH 2-，-C(O)-或者不存在；
    X与U不同时为不存在；
    Y和U可以任选被一个或多个以下取代基取代：卤素，羟基，C 1-6烷基，C 1- 6烷氧基，氰基，C 3-8环烷基，3-8元杂环基，6-10元芳基或6-10元杂芳基；
    A为
    Figure PCTCN2020127426-appb-100002
    Z为N或CR 3；
    Z’为N或CR 4；
    R 3,R 4,R 5,R 6各自独立的为H、氰基、卤素或C 1-3卤代烷基；
    V为N或CR 9，其中R 9为H、氰基、卤素、C 1-3烷基、C 1-3卤代烷基或-O-W；
    W为苯基或5或6元杂芳基，其可以任选被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。
  2. 如权利要求1所述的化合物，所述化合物具有式I’
    Figure PCTCN2020127426-appb-100003
    其中
    R 1为H，氰基,卤素，C 1-6烷基,C 1-3烷氧基或C 1-3卤代烷基；
    X为-O-，-CH 2-,-NRc-或不存在；
    R c为L或L-C(O)-，其中L为H、C 1-3烷基、C 3-6环烷基，C 3-6杂环烷基，C1-3卤代烷基、或苄基；
    Y为-CH 2-或者不存在；
    n，R 2，R a，A和m如在权利要求1中所定义。
  3. 如权利要求2所述的化合物，其中
    n为0，R 2为甲基或乙基；
    R 1为H；
    R a为H；
    m为1；
    X为-O-或-CH 2-。
  4. 如权利要求1所述的化合物，其中
    n为0；
    R 1为H、氰基、卤素、C 1-6烷基，C 1-6烷氧基或C 1-3卤代烷基；
    R a为H；
    Rx为H，氰基，氟，二氟甲基，氨基，
    Figure PCTCN2020127426-appb-100004
    R 2为甲基或乙基；
    Q为-O-；
    X为-O-，-CH 2或者不存在-；
    Y为-CH 2-；
    U为-CH 2-，或者不存在；
    X与U不同时为不存在。
  5. 如权利要求l所述的化合物，其中n＝1或2；且R 2不存在。
  6. 如权利要求4所述的化合物，其中R x为H。
  7. 如权利要求6所述的化合物，其中X为-O-或-CH 2-。
  8. 如权利要求5所述的化合物，其中n为1；R x为H；R 1为H，氰基，氨基，卤素，C 1-3烷基，C 1-3卤代烷基或C 1-6烷氧基。
  9. 如权利要求8所述的化合物，其中U为-CH 2-；X为-CH 2-或-O-；且Q为-O-。
  10. 如权利要求8所述的化合物，其中U为-CH 2-；X为-NR c-；R c为甲基，氧杂环丁基，三氟乙基，苯甲酰基，环丁基，苄基，
    Figure PCTCN2020127426-appb-100005
  11. 如权利要求8所述的化合物，其中U为-C(O)-；R 1和R x均为H；Y为-CH 2-；X为-NR c-；R c为L或L-C(O)-，其中L为甲基，三氟乙基,苯甲酰基，氧杂环丁烷，环丁烷，苄基，
    Figure PCTCN2020127426-appb-100006
  12. 如权利要求5所述的化合物，其中n为1；X为-CH 2-；U不存在；R x为H，羟基，卤素，氰基，氨基，C 1-3烷氧基，C 1-3卤代烷基或3-8元杂环基，R x可以任选被一个或多个以下取代基取代：卤素，羟基，C 1-6烷氧基，氰基，3-8元杂环基，6-10元芳基或6-10元杂芳基。
  13. 如权利要求12所述的化合物，其中Y为-CH 2-；R 1为H，氰基，卤素，C 1-3烷基，C 1-3卤代烷基或C 1-6烷氧基；且Q为-O-。
  14. 如权利要求13所述的化合物，其中R x为H，卤素，氰基，氨基，二氟甲基，
    Figure PCTCN2020127426-appb-100007
  15. 如权利要求12所述的化合物，其中Y为-CH 2CH 2-；R x为H，卤素，氰基，氨基，二氟甲基，
    Figure PCTCN2020127426-appb-100008
    R 1为H，氰基，卤素，C 1-3烷基，C 1-3卤代烷基或C 1-6烷氧基且Q为-O-。
  16. 如权利要求5所述的化合物，其中n为2；U为-CH 2-；X为-CH 2-或-O-；Y为-CH 2-或不存在；R x为H，卤素，氰基，氨基，二氟甲基，
    Figure PCTCN2020127426-appb-100009
    Figure PCTCN2020127426-appb-100010
    R 1为H，氰基，卤素，C 1-3烷基，C 1-3卤代烷基或C 1-6烷氧基；且Q为-O-。
  17. 如权利要求1-2、4-10、12-16中任一项所述的化合物，其中m＝2；R 1为H，氰基或C 1-3卤代烷基；且R x为H。
  18. 如权利要求1-2、4-10、12-16中任一项所述的化合物，其中m＝1；R 1为H，氰基，卤素，C 1-3烷基，C 1-3卤代烷基或C 1-6烷氧基；R x为H。
  19. 如权利要求l至18中任一项所述的化合物，其中A为
    Figure PCTCN2020127426-appb-100011
    且R 5,R 6,R 7,R 8,R 9各自独立的为H，F或氰基。
  20. 如权利要求l至18中任一项所述的化合物或其药学上可接受的盐或其前体药物，其中A为
    Figure PCTCN2020127426-appb-100012
    R 5,R 6,R 7和R 8各自独立的为H，F或氰基；R 9为-O-W；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、氰基卤素和C 1-6烷基。
  21. 如权利要求l至18中任一项所述的化合物，其中A为
    Figure PCTCN2020127426-appb-100013
    R 7和R 8各自独立的为H，F或氰基；R 9为-O-W；且W为吡啶基、 嘧啶基、吡唑基或苯基，其可以任选被一个或多个独立选自以下的取代基取代：卤素、氰基、CF 3、-OCF 3、CHF 2和CH 3。
  22. 如权利要求1至21中任一项所述的化合物，所述化合物是下述化合物
    Figure PCTCN2020127426-appb-100014
    其中，R 1为H，卤素，氰基，C 1-6烷基，C 1-3卤代烷基或C 1-6烷氧基；R c为C 1- 6烷基，3-8元杂环基，C 1-3卤代烷基，苯甲酰基，C 3-8环烷基，苄基或
    Figure PCTCN2020127426-appb-100015
    R x为H，氰基，卤素，C 1-3卤代烷基，氨基，
    Figure PCTCN2020127426-appb-100016
    Figure PCTCN2020127426-appb-100017
  23. 如权利要求22所述的化合物，其中R 1为H，氟，氯、氰基,甲基,乙基，异丙基，三氟甲基或甲氧基；R2为甲基或乙基；R c为甲基，氧杂环丁基，三氟乙基，苯甲酰基，环丁基，苄基或
    Figure PCTCN2020127426-appb-100018
    R x为H，氰基，氟，二氟甲基，氨基，
    Figure PCTCN2020127426-appb-100019
  24. 如权利要求l至18以及22至23中任一项所述的化合物，其中A选自下述基团：
    Figure PCTCN2020127426-appb-100020
  25. 如权利要求1至24任一项所述的化合物，所述化合物是下述化合物：
    Figure PCTCN2020127426-appb-100021
    Figure PCTCN2020127426-appb-100022
    Figure PCTCN2020127426-appb-100023
    Figure PCTCN2020127426-appb-100024
    Figure PCTCN2020127426-appb-100025
    Figure PCTCN2020127426-appb-100026
    Figure PCTCN2020127426-appb-100027
    Figure PCTCN2020127426-appb-100028
    Figure PCTCN2020127426-appb-100029
    Figure PCTCN2020127426-appb-100030
    Figure PCTCN2020127426-appb-100031
    Figure PCTCN2020127426-appb-100032
    Figure PCTCN2020127426-appb-100033
  26. 组合物，其特征在于包含如权利要求1至25中任一项所述的、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和药学上可接受的赋形剂。
  27. 如权利要求1至25中任一项所述的化合物或权利要求26所述的组合物在制备用于治疗或预防与Lp-PLA 2相关的疾病的药物中的用途。
  28. 如权利要求1至25中任一项所述的化合物或权利要求26所述的组合物在制备治疗或预防下列疾病的药物中的用途：糖尿病并发症、阿兹海默症或动脉粥样硬化。
  29. 一种治疗或预防糖尿病并发症、神经炎症相关疾病或动脉粥样硬化的方法， 其特征在于向患者施用有效剂量的如权利要求1至25中任一项所述的化合物或权利要求26所述的组合物。
  30. 如权利要求29所述的方法，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糖尿病足。
  31. 如权利要求29所述的方法，其特征在于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帕金森病。
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WO2025002454A1 (zh) * 2023-06-29 2025-01-02 上海赛默罗生物科技有限公司 一种化合物在制备预防、缓解、辅助治疗或治疗肺损伤的药物中的用途

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