CN114057740A

CN114057740A - Spirocyclic pyrimidone derivatives, preparation method, pharmaceutical composition and application thereof

Info

Publication number: CN114057740A
Application number: CN202111528169.0A
Authority: CN
Inventors: 金赟; 彭军; 吴金华
Original assignee: Shanghai Semerode Biotechnology Co ltd; Shanghai Simr Biotechnology Co ltd
Current assignee: Shanghai Semerode Biotechnology Co ltd; Shanghai Simr Biotechnology Co ltd
Priority date: 2021-12-15
Filing date: 2021-12-15
Publication date: 2022-02-18
Anticipated expiration: 2041-12-15
Also published as: WO2023109471A1; CN114057740B

Abstract

The invention provides a compound shown as a general formula (I), a cis-trans isomer, an enantiomer, a diastereoisomer, a racemate, a solvate, a hydrate or a pharmaceutically acceptable salt or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the compound and Lp-PLA (low-melting polylactic acid) prepared from the compound₂Use of an inhibitor, wherein R₁，R₂，R_x，R_yQ, m, n, p, u and a are as defined herein.

Description

Spirocyclic pyrimidone derivatives, preparation method, pharmaceutical composition and application thereof

Technical Field

The present invention relates to novel pyrimidinone compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy consisting of Lp-PLA₂Use in mediated diseases.

Background

Lipoprotein-associated phospholipase A₂(Lp-PLA₂) Is a phospholipase A involved in the hydrolysis of lipoprotein lipids or phospholipids₂The enzyme is also known as platelet activating factor acetylhydrolase (PAF-AH). Lp-PLA₂Moves with Low Density Lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules resulting from oxidation of LDL. Lp-PLA₂Hydrolysis of the sn-2 ester of oxidized phosphatidylcholine gives the lipid mediator lysophosphatidylcholine (lysoPC) and oxidized non-esterified fatty acids (NEFA). LysoPC and NEFA are reported in the literature to elicit inflammatory responses and thus Lp-PLA₂Mediates oxidative inflammatory responses in vivo. (Zalewski A et al, Arterioscler, Thromb, Vasc.biol., 25, 5, 923-31 (2005)).

Documents (WO 96/13484, WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO97/41098, WO97/41099, WO99/2442, WO00/10980, WO00/66566, WO00/66567, WO 00/00, WO 00/6060805, WO 00/30904, WO 00/30911, WO 00/00, US2008/00, WO 00/00, W005/3606, W006/006, W/0063811. W006/063813, WO2008/141176, WO2013013503A1, WO2013014185A1, WO2014114248A1, WO2014114694A1, WO2016011930A1, JP200188847 US2008/0279846A1, US 2010/0239565A1, US 2008/0280829A 1) describe a number of Lp-PLA₂Inhibitors and/or uses thereof, for the treatment of diseases involving or associated with vascular endothelial dysfunction, involving Lp-PLA₂Diseases associated with activity (e.g. associated with formation of lysophosphatidylcholine and oxidised free fatty acids) lipid oxidation and diseases involving or associated with increased involvement of activated monocytes, macrophages or lymphocytes. Examples of specific diseases include neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia), neuropsychiatric diseases such as schizophrenia and autism, peripheral and cerebral atherosclerosis, stroke, metabolic bone diseases (e.g., bone marrow disorders), dyslipidemia, Paget's disease, type II diabetes, hypertension, angina pectoris, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance and hyperparathyroidism, diabetic complications (e.g., macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcer and diabetic nephropathy), diabetic peripheral neuropathic pain, inflammatory pain, neuropathic pain, various types of cancer (e.g., prostate cancer, colon cancer, breast cancer, kidney cancer, lung cancer and ovarian cancer, etc.), macular edema, wound healing, diabetic neuropathy, diabetic retinopathy, diabetic neuropathy, and the like, Male erectile dysfunction, rheumatoid arthritis, Chronic Obstructive Pulmonary Disease (COPD), sepsis, acute and chronic inflammation, psoriasis and multiple sclerosis.

Scientific research results further prove that Lp-PLA₂The inhibitor can be used for treating atherosclerosis. Wilensky et al demonstrated Lp-PLA in a diabetic and hypercholesterolemic pig model of accelerated coronary atherosclerosis₂The effect of inhibitors on atherosclerotic plaque components (Wilensky et al, Nature Medicine,10, 1015-. The clinical research also finds that Lp-PLA₂The inhibitor can stabilize atherosclerotic plaque of patients with atherosclerotic plaque, and prevent plaque from further development and rupture (Serrouys et al, Circulation 118: 1172-1182 (2008)).

Studies have shown high Lp-PLA₂Activity is associated with a high risk of dementia, including Alzheimer's Disease (AD) and mixed dementia (Van Oijen et al, Annals of Neurology,59,139 (2006); Fitzpatrick et al, Atheroclerosis 235: 384-391 (2014)). Higher levels of oxidized LDL were observed in AD patients (Kassner et al, Current Alzheimer Research, 5, 358-.

Furthermore, US2008/0279846 describes Lp-PLA₂The inhibitors reduce blood-brain barrier leakage and cerebral amyloid (Abeta) loading and may be useful in the treatment of diseases associated with blood-brain barrier leakage, such as alzheimer's disease and vascular dementia. In clinical studies, Lp-PLA₂The inhibitors have a significant effect on Alzheimer's patients in preventing further deterioration of cognitive function (Maher-Edwards et al, Alzheimer's)& Dementia：Translational Research & Clinical Interventions 1，131-140（2015））。

Neuroinflammation, including the release of multiple cytotoxic cytokines, is a common feature of all neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, parkinson's disease, alzheimer's disease, etc. (Perry, Acta Neuropathol,120,277-286 (2010)). Lp-PLA₂Inhibitors reduce the release of various cytokines by inhibiting the production of lysoPC (Shi et al, Atherosclerosis 191,54-62 (2007)). Thus, inhibition of Lp-PLA₂Is a potential treatment method for neurodegenerative diseases (including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and the like).

LysoPC is also involved in leukocyte activation, induction of apoptosis and mediation of vascular endothelial cell dysfunction (Wilensky et al, Current Opinion in lipopology, 20, 415-420, (2009)). Thus, it is considered that Lp-PLA₂The inhibitors may be used to treat tissue damage associated with diabetes by reducing the production of lysoPC. High Lp-PLA₂Activity ofHas relevance to the risk of developing diabetic retinopathy (Siddiqui et al, Diabetologia, 61, 1344-1353 (2018)). Lp-PLA₂Inhibitors can inhibit the main pathological changes of retinopathy in the diabetic rat model (Canning et al, P.N.A.S. 113, 7213-₂Inhibitors may improve retinal macular edema symptoms and vision in diabetic retinopathy patients (Staurenghi et al, Ophthalmology 122, 990-₂The inhibitor can be used for treating diabetic retinopathy.

The study shows that Lp-PLA in the body of the diabetic patient₂The activity is higher than that of normal people (Serban et al J. cell. mol. Med. 6:643-647, (2002); Garg et al Indian J. Med. Res. 141:107-114, (2015)). And Lp-PLA as described above₂Mediates the oxidative inflammatory response, presumably inhibiting Lp-PLA₂The activity can be used for treating various complications of diabetic patients caused by in vivo oxidative inflammatory reaction, such as diabetic nephropathy, diabetic peripheral neuropathy, diabetic skin ulceration, etc.

Glaucoma and age-related macular degeneration (AMD) are retinal neurodegenerative diseases. Inflammation plays an important role in the pathogenesis of glaucoma and AMD (Buschini et al, Progress in Neurobiology, 95, 14-25 (2011); Tezel, Progress in Brain Research, vol.173, ISSN 0079-6123, chapter 28). Thus, Lp-PLA₂Inhibitors may provide potential therapeutic applications for glaucoma and AMD.

In men with erectile dysfunction, Lp-PLA in vivo₂Is significantly higher than that of normal persons, and is considered to be high in Lp-PLA₂Activity can predict early male erectile dysfunction (Otuncatemur et al, Andrologica 47: 706-710 (2015)), suggesting that inhibitors may be useful in the treatment of male erectile dysfunction.

Lp-PLA in prostate cancer tissue₂High expression, reduced Lp-PLA₂Can reduce the canceration of prostate cancer cells and promote the apoptosis of the prostate cancer cells in vitro experiments (Vainio et al, Oncotarget, 2: 1176-1190 (2011)), suggesting that Lp-PLA₂The inhibitor can be used for treating prostate cancer.

Thus, Lp-PLA₂The inhibitor can be used for treating or preventing Lp-PLA₂Inhibiting activity and various related diseases. The invention discovers a novel Lp-PLA₂And (3) an inhibitor.

Disclosure of Invention

An object of the present invention is to provide a compound represented by the general formula (I), a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate thereof, or a pharmaceutically acceptable salt or ester thereof, or a prodrug thereof.

Another object of the present invention is to provide a process for producing the compound represented by the general formula (I).

Another object of the present invention is to provide a compound represented by the general formula (I) as Lp-PLA₂Use of an inhibitor for the manufacture of a medicament for the prevention, treatment or amelioration of a disease associated with Lp-PLA2 inhibition, such as diabetic complications, neuroinflammation-related diseases, such as diabetic retinopathy/diabetic macular edema, diabetic nephropathy, diabetic neuropathy, diabetic peripheral neuropathy degenerative pain or/and diabetic foot, or atherosclerosis, or/and for the treatment, prevention, treatment or amelioration of a disease associated with Lp-PLA2 inhibition, such as alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or/and parkinson's disease.

Another object of the present invention is to provide a pharmaceutical composition, which comprises one or more compounds represented by the general formula (I), its cis-trans isomers, enantiomers, diastereomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts or esters thereof, or prodrugs thereof, in a therapeutically effective amount, and a pharmaceutically acceptable carrier and/or adjuvant.

Another object of the present invention is to provide a method for preventing, treating or ameliorating diseases associated with the inhibition of Lp-PLA2, which comprises administering a compound represented by the general formula (I), its cis-trans isomer, enantiomer, diastereomer, racemate, solvate, hydrate, or a pharmaceutically acceptable salt or ester thereof, or a prodrug thereof, or a composition of the present invention.

In a first aspect, a compound of formula I, a cis-trans isomer thereof, an enantiomer thereof, a diastereoisomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof or a prodrug thereof,

wherein

m is 1 or 2; preferably, m is 1;

n and u are 0,1 or 2; preferably, n, u is 0 or 1;

q is-O-, -S-or-NR_a-, preferably Q is-O-;

R_ais H, C_1-6Alkyl radical, C_1-3Haloalkyl, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

R₁is H, halogen, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl, R₁May be substituted with one or more of the following substituents: halogen, cyano, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl;

(R₂)_prepresenting the hydrogen on the ring by p R₂Substituted, each R₂The same or different;

p is 2, 3,4, 5 or 6;

R₂，R_x，R_yindependently selected from the following substituents: h, halogen, hydroxy, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl, 3-8 membered heteroaryl, -C (O) NR_bR_c，-S(O)₂NR_bR_cAnd may be substituted with one or more of the following substituents: halogen, cyano, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl;

R_x，R_ytogether with the carbon atom to which they are attached, can form a 3-6 membered saturated ring, which is a homocyclic ring or a heterocyclic ring containing one or more atoms selected from N, O and S, and may be substituted by one or more R_mSubstitution;

at p times independently of R₂On the substituted ring, at least two R₂Are attached to the same carbon atom and together with the carbon atom to which they are commonly attached form a 3-6 membered saturated ring, which is a fully carbocyclic ring or a heterocyclic ring containing one or more atoms selected from N, O and S, and may be substituted by one or more R_mSubstitution;

R_mis C_1-6Alkyl radical, C_1-3Haloalkyl, halogen, cyano, -OR_c，-NR_bR_c，C_3-6Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl or 3-8 membered heteroaryl;

R_bis H, C_1-6Alkyl radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

R_cis L, L-C (O) -, L-CH₂-or L-S (O)₂-，

Wherein L is H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl or 3-8 membered heteroaryl, L may be substituted by one or more of the following groups: halogen, hydroxy, C_1-6Alkoxy, cyano, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl or 3-8 membered heteroaryl;

a is

Z is N or CR₃(ii) a Preferably, Z is CR₃；

Z' is N or CR₄(ii) a Preferably Z' is CR₄；

R₃, R₄, R₅, R₆Independently of one another is H, CN, halogen, C_1-3Alkyl or C_1-3A haloalkyl group;

v is N or CR₉Preferably, V is CR₉Wherein R is₉Is H, CN, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl or-O-W;

w is a 5 or 6 membered heteroaryl or phenyl group, preferably a pyridyl, pyrimidinyl, pyrazolyl or phenyl group, which may be optionally substituted by one or more of the following substituents: halogen, cyano, C_1-6Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl and C_1-3A haloalkoxy group.

Detailed Description

In a preferred embodiment, the compound of formula (I) has one of the following 12 structures:

wherein

m is 1 or 2; preferably, m is 1;

q is-O-, -S-or-NR_a-; preferably Q is-O-;

R_x，R_yindependently selected from the following substituents: h, halogen, hydroxy, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl, 3-8 membered heteroaryl, -C (O) NR_bR_c，-S(O)₂NR_bR_cAnd may be substituted with one or more of the following substituents: halogen, cyano, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl;

R_x，R_ytogether with the carbon atoms to which they are attached, can form a 3-6 membered saturated ring, which is a fully carbocyclic ring or a heterocyclic ring containing one or more atoms selected from N, O and S, and which may be substituted with one or more of the following substituents: c_1-6Alkyl radical, C_1-3Haloalkyl, halogen, cyano, oxo (= O), -OR_c，-NR_bR_c，C_3-6Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl or 3-8 membered heteroaryl;

u is 0 or 1, preferably u is 0, and R_x，R_yAre all H;

R₁is H, halogen, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl, R₁Optionally substituted with one or more of the following substituents: halogen, cyano, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl; preferably, R₁Is H, halogen, cyano, C_1-6Alkyl or C_1-6An alkoxy group; preferably, R₁Is H, halogen, cyano, C_1-3Alkyl or C_1-3An alkoxy group; more preferably, R₁Is H, fluoro, chloro, cyano, methyl, ethyl or methoxy; most preferably, R₁Is H or methoxy;

R_mis C_1-6Alkyl radical, C_1-3Haloalkyl, halogen, cyano, oxo (= O), -OR_c，-NR_bR_c，C_3-6Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl or 3-8 membered heteroaryl;

R_bis H, C_1-6Alkyl radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

R_cis L, L-C (O) -, L-CH₂-or L-S (O)₂-，

Wherein L is H, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl or 3-8 membered heteroaryl, L is optionally substituted with one or more of the following: halogen, hydroxy, C_1-6Alkoxy, cyano, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-10Aryl or 3-8 membered heteroaryl;

a is

Z is N or CR_3；Preferably, Z is CR₃；

Z' is N or CR₄(ii) a Preferably Z' is CR₄；

R₃, R₄, R₅, R₆Independently is H, CN, halogen or C_1-3A haloalkyl group;

w is a 5 or 6 membered heteroaryl or phenyl group, preferably a pyridyl, pyrimidinyl, pyrazolyl or phenyl group, which may be optionally substituted by one or more of the following substituents: halogen, cyano, C_1-6Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl and C_1-3A haloalkoxy group;

in formula (I) and the 12 formulae above, preferably, A is

R₅, R_6,R₇, R₈, R₉Independently H, F or CN;

or A is

R₅, R_6,R₇, R₈Independently H, F or CN;

R₉is-O-W;

w is a 5-or 6-membered heteroaryl or phenyl group, preferably a pyridyl, pyrimidinyl, pyrazolyl or phenyl group, which may be optionally substituted by one or more substituents C_1-3Haloalkyl, C_{1- 3}Haloalkoxy, CN, halogen and C_1-6An alkyl group.

More preferably, A is

R₇, R₈Independently H, F or CN;

R₉is-O-W;

w is pyridyl, pyrimidinyl, pyrazolyl or phenyl, which may be optionally substituted with one or more substituents independently selected from: halogen, CN, CF₃、-OCF₃、CHF₂And CH₃；

Most preferably, a is selected from the following groups:

。

in one embodiment, the compound is any one of the following compounds:

the compounds of the above formula, salts thereof (e.g., pharmaceutically acceptable salts), can exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms). Both the individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the invention.

The invention also includes various deuterated forms of the compounds of the above formula, salts thereof (e.g., pharmaceutically acceptable salts). Each available hydrogen atom attached to a carbon atom may be independently substituted with a deuterium atom. One of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of the above formula, salts thereof (e.g., pharmaceutically acceptable salts). Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds of the above formula, salts thereof (e.g., pharmaceutically acceptable salts), or these compounds can be synthesized using conventional techniques employing deuterated reagents, such as lithium aluminum deuteride.

In addition to the free base or free acid forms of the compounds described herein, salt forms of the compounds are also within the scope of the invention. Salts or pharmaceutically acceptable salts of the compounds of the invention may 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. For reviews of suitable Pharmaceutical salts see Berge et al, J. Pharm, Sci.,66,1-19,1977, P L Gould, International Journal of pharmaceuticals, 33 (1986), 201-217, and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.

The compounds, salts (e.g., pharmaceutically acceptable salts), deuterated forms, solvates, or hydrates thereof described herein can exist in one or more polymorphic forms. Thus, in another aspect, the invention provides a polymorph of a compound as defined herein, a salt (e.g., a pharmaceutically acceptable salt) thereof, or a solvate or hydrate of a compound described herein or a salt (e.g., a pharmaceutically acceptable salt) thereof.

The invention also includes isotopically-labeled compounds and salts, which are identical to those recited in the above formula, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most often found in nature, or salts thereof. Examples of isotopes which can be incorporated into compounds of the above formula or salts thereof are isotopes of hydrogen, carbon, nitrogen, deuterium, such as³H、¹¹C、¹⁴C and¹⁸these isotopically labeled compounds of the above formula or salts thereof are useful in drug and/or substrate tissue distribution assays. For example,¹¹c and¹⁸the F isotope can be used for PET (positron emission tomography). PET can be used for brain imaging. In one embodiment, the compound of the above formula or a salt thereof is non-isotopically labeled.

Accordingly, the compounds of the present invention include compounds of the above formula, or salts thereof, such as pharmaceutically acceptable salts thereof. Representative compounds of the invention include the specific compounds described.

The invention also relates to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient.

The invention also relates to the treatment or prevention of Lp-PLA₂Comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein. The disease may be associated with: involvement of monocytes, macrophages or lymphocytes in increasing the formation of lysophosphatidylcholine and oxidized free fatty acids with Lp-PLA₂Activity-associated lipid oxidation or endothelial dysfunction.

The invention also provides for inhibition of Lp-PLA₂Active methods for treating or preventing diseases. Exemplary diseases include, but are not limited to: neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia), neuropsychiatric diseases such as schizophrenia and autism, peripheral and cerebral atherosclerosis, stroke, metabolic bone diseases (e.g., bone marrow abnormalities), dyslipidemia, Paget's disease, type II diabetes, hypertension, angina pectoris, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance and hyperparathyroidism, diabetic complications (e.g., macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcer and diabetic nephropathy), diabetic peripheral neuropathic pain, inflammatory pain, neuropathic pain, cancers of all types (e.g., prostate, colon, breast, kidney, lung and ovarian cancers, etc.), macular edema, wound healing, male erectile dysfunction, peripheral neuropathic pain, diabetic neuropathy, and the like, and inflammatory pain, Rheumatoid arthritis, Chronic Obstructive Pulmonary Disease (COPD), sepsis, acute and chronic inflammation, psoriasis and multiple sclerosis. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. The present invention is not intended to be limited to any particular stage of the disease (e.g., early or late stage).

The invention also provides methods of treating or preventing alzheimer's disease. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.

The invention also provides methods of treating or preventing atherosclerosis. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.

The invention also provides methods of treating or preventing ocular diseases by administering the compounds of the invention. In some embodiments, the present invention provides a method of treating macular edema comprising administering to a subject a therapeutically effective amount of a compound of the present invention. In some embodiments, the macular edema is associated with a diabetic eye disease (e.g., diabetic macular edema or diabetic retinopathy). In one embodiment, the macular edema is associated with posterior uveitis.

The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disease as described herein.

The invention also provides a compound of the invention for use in the treatment or prevention described herein.

As used herein, "and/or" is intended to include any and all possible combinations of one or more of the associated listed items. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and biology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event that there are multiple definitions of a term used in this application, the definition in this section controls, unless otherwise specified.

Definition of

As used herein, unless otherwise indicated, the term "disease" refers to any change in the state of a body or some organ that interrupts or interferes with the performance of function and/or causes symptoms (such as discomfort, dysfunction, adverse stress or even death) in a person suffering from or in contact with the disease.

As used herein, unless otherwise indicated, "diabetic retinopathy" refers to the result of chronic progressive retinal microvascular leakage and obstruction resulting from diabetes. "diabetic macular edema" refers to the thickening or hard exudative deposition of the retina due to the accumulation of extracellular fluid within one disc diameter of the fovea of the macula caused by diabetes.

As used herein, unless otherwise indicated, "neurodegenerative disease" refers to different kinds of central nervous system disorders characterized by gradual, progressive loss of neural tissue and/or neural tissue function. Neurodegenerative diseases are a class of neurological diseases in which the neurological disease is characterized by a gradual, progressive loss of neural tissue and/or altered neural function, usually a decrease in neural function due to a gradual, progressive loss of neural tissue. In some embodiments, the neurodegenerative diseases described herein include neurodegenerative diseases in which a defective blood brain barrier (e.g., a permeable blood brain barrier) is present. Examples of neurodegenerative diseases in which a defective blood brain barrier exists include, but are not limited to, alzheimer's disease, huntington's disease, parkinson's disease, vascular dementia, and the like.

As used herein, unless otherwise indicated, "vascular dementia" is also referred to as "multi-infarct dementia," which refers to a group of syndromes that arise from different mechanisms, all of which result in vascular damage in the brain. For example, the major subtypes of vascular dementia are vascular mild cognitive dysfunction, multi-infarct dementia, vascular dementia due to major single infarcts (affecting the thalamus, anterior cerebral artery, parietal lobe or cingulate gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (including, for example, vascular dementia due to lacunar lesions and Binswanger disease), and mixed-type dementia.

As used herein, unless otherwise indicated, "neuropathic pain" is pain that is provoked or caused by primary damage and dysfunction of the nervous system.

As used herein, unless otherwise indicated, "inflammatory pain" is pain caused by local acute inflammation or by chronic inflammatory-stimulated nerves.

As used herein, unless otherwise indicated, "diabetic peripheral neuropathic pain" refers to pain resulting from nerve damage that is complicated by diabetes, which is caused at least in part by reduced blood flow and hyperglycemia.

As used herein, unless otherwise indicated, "blood brain barrier" or "BBB" are used interchangeably herein to refer to a permeable barrier present in a blood vessel that passes through brain tissue, which severely limits and closely regulates the exchange of substances between blood and brain tissue. The blood brain barrier components include endothelial cells that form the innermost lining of all blood vessels, tight junctions between adjacent endothelial cells that are structural associates of the BBB, the basement membrane of endothelial cells, and enlarged foot processes that cover the proximal astrocytes of the outer surface of almost all exposed blood vessels.

As used herein, unless otherwise indicated, "metabolic bone disease" refers to a different class of bone disease characterized by gradual and progressive loss of bone tissue. Metabolic bone diseases as described herein are bone metabolic diseases in which there is a condition of decreased diffuse bone density and/or decreased bone strength. Such diseases are characterized by histological appearance. Exemplary metabolic bone diseases include, but are not limited to, osteoporosis characterized by a reduction in minerals and bone matrix and osteomalacia characterized by a reduction in minerals but with intact bone matrix.

As used herein, unless otherwise indicated, "osteopenic disease" or "osteopenia" may be used interchangeably herein, and refer to a condition having reduced calcification and/or bone density, as descriptive terms used to refer to all skeletal systems in which a reduction in calcification and/or bone density is observed. Osteopenia also refers to osteopenia due to inadequate synthesis of osteoid (osteopoid).

As used herein, unless otherwise indicated, "osteoporosis" refers to a condition in which minerals and/or bone matrix are reduced and/or bone matrix is reduced.

As used herein, unless otherwise indicated, "alkyl" is a monovalent, saturated, catenary chain having the specified number of carbon atoms. E.g. C_1-3Alkyl refers to alkyl groups having 1 to 3 carbon atoms. C_1-6Alkyl refers to alkyl groups having 1 to 6 carbon atoms. The alkyl group may be linear or branched. In some embodiments, a branched alkyl group may have one, two, or three branches. Exemplary alkyl groups include, but are not limited to, methyl, methylethyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl).

As used herein, unless otherwise indicated, an "alkoxy" substituent is a group of the formula "R-O-", wherein R is alkyl as defined above. E.g. C_1-3Alkoxy 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-hexoxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy, and neopentoxy.

As used herein, unless otherwise indicated, "cycloalkyl" means a monovalent saturated cyclic hydrocarbon group including bridged and spiro rings, preferably having from 3 to 7 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or [1.1.1] squalane, as well as those groups specifically exemplified below.

As used herein, unless otherwise indicated, "aryl" refers to a hydrocarbon group containing one or more aromatic rings, such as phenyl or naphthyl, and the like.

As used herein, unless otherwise indicated, "heteroaryl" means a stable monocyclic, bicyclic, or tricyclic ring of up to 8 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H, 3H-1-oxoisoindolyl, benzotriazolyl, furanyl, thienyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl, benzothienyl, benzofuranyl, benzodioxan, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, thiazolyl, isothiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 5-triazinyl, 1, 2,4, 5-tetrazinyl, tetrazolyl, xanthenyl, phenazinyl, phenothiazinyl, phenoxazinyl, azepinyl, oxazel and thiazel. Particular heteroaryl groups have a 5 or 6 membered ring, for example furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl.

As used herein, unless otherwise indicated, "heterocycle" or "heterocyclyl" refers to a cyclic hydrocarbon in which 1 to 4 carbon atoms have been replaced by a heteroatom independently selected from N, N (R), S, S (O), s (O), and O. The heterocyclic ring may be saturated or unsaturated, but is not aromatic. Heterocyclyl groups may also contain 1, 2 or 3 rings, including bridged and spiro structures. Examples of suitable heterocyclic groups include, but are not limited to: azetidine, oxetane, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrrolinyl, pyranyl, dioxolanyl, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiolyl, oxathiolanyl, dioxanyl, dioxinyl, dioxanyl, dioxazolyl, thiazolyl (oxathizoyl), oxazolonyl, piperazinyl, morpholino, thiomorpholinyl, 3-oxomorpholinyl, dithianyl, trithianyl, and oxazinyl.

The term "bridged ring compound" refers to one or more atoms (i.e., C, O, N or S) connecting two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In bridged rings, ring substituents may also be present on the bridge.

The term "spiro compound" refers to a polycyclic compound in which two single rings share a common carbon atom, which is referred to as a spiro atom.

As used herein, unless otherwise indicated, "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Halo means a halogen group: fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

As used herein, unless otherwise indicated, "haloalkyl" is an alkyl group substituted with one or more halo substituents, which halo substituents may be the same or different. E.g. C_1-3Haloalkyl 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.

As used herein, unless otherwise indicated, when two substituents on a ring are joined together with their interconnecting atoms to form another ring, the ring may be spiro-fused or unilaterally fused. The spiro-fused ring system consists of two rings having only one carbon atom in common. A mono-fused ring system consists of two rings that share only two atoms and one bond.

As used herein, unless otherwise indicated, "optionally substituted" means that a group or ring may be unsubstituted, or that the group or ring may be substituted with one or more substituents as defined herein.

As used herein, unless otherwise indicated, "4-, 5-or 6-membered saturated ring optionally containing a heteroatom selected from N or O" means a 4-, 5-or 6-membered saturated carbocyclic ring and one carbon atom ring member may optionally be replaced by a heteroatom selected from N or O, for example, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl and tetrahydro-2H-pyranyl.

As used herein, reference to "treatment" or "treating" of a disease, unless otherwise indicated, means: (1) alleviating the disease or alleviating one or more biological manifestations of the disease, (2) interfering with (a) one or more points in a biological cascade that causes or contributes to the disease or (b) one or more biological manifestations of the disease, (3) alleviating one or more symptoms or effects associated with the disease, and/or (4) slowing the progression of the disease or one or more biological manifestations of the disease, and/or (5) reducing the likelihood of disease severity or biological manifestations of the disease.

As used herein, unless otherwise indicated, "prevention" refers to the prophylactic administration of a drug to reduce the likelihood of, or delay the onset of, a disease or biological manifestation thereof.

As used herein, unless otherwise indicated, "subject" refers to a mammalian subject (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.), and particularly a human subject.

As used herein, unless otherwise indicated, "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in free acid or free base form with a suitable base or acid, respectively.

As used herein, unless otherwise indicated, the term "therapeutically effective amount" refers to an amount that results in the treatment or prevention of disease as compared to a corresponding subject who has not received that amount, but which is low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A therapeutically effective amount of a compound will vary with the particular compound selected (e.g., 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 being treated; treating the age, size, weight and physical condition of the patient: a medical history of the patient being treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect, etc., will vary, but can still be determined in a routine manner by one skilled in the art.

Synthesis of compounds

It will be appreciated by those skilled in the art that if a substituent described herein is incompatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable under the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to give the desired intermediate or target compound. Suitable protecting groups and methods for protecting and deprotecting various 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 Synthesis (third edition), John Wiley & Sons, NY (1999). In some cases, substituents that are reactive under the reaction conditions used may be specifically selected. In these cases, the reaction conditions convert the selected substituent into another substituent that can be used as an intermediate compound or as a desired substituent in the target compound.

General scheme

General schemes provide general synthetic routes to compounds of formula 1.8, wherein R₁，R₂，R_x，R_yQ, m, n, p, u, A are as defined for formula (I). The route comprises the following steps:

step (i): generating compound (1.2) by removing the Boc protecting group from compound (1.1);

step (ii) of reacting compound (1.2) with compound (1.3) to produce compound (1.5);

step (iv): obtaining a compound (1.7) by ring closure of the compound (1.5);

step (v) reacting Compound (1.7) with HQ- (CH)₂)_m-a reaction to obtain the final product (1.8), i.e. the compound of formula I;

or comprises the following steps:

step (iii): reacting the compound (1.2) with the compound (1.4) to produce a compound (1.6);

step (iv'): obtaining a compound (1.7) by ring closure of the compound (1.6);

wherein R is₁，R₂，R_x，R_yQ, m, n, p, u, a are as defined herein.

In particular, the preparation of the final compound 1.8 can be obtained by the steps of i, ii, iv, v as well as by the steps of i, iii, iv, v. Step (i) may be performed by removing the Boc protecting group from compound 1.1 in a suitable acidic reagent, such as hydrogen chloride/1, 4-dioxane solution, at a suitable temperature, such as room temperature, to yield compound 1.2. Step (ii) or (iii) may be performed as SN_ArReaction of compound 1.2 with 1.3 or compound 1.2 with 1.4 to compound 1.6 using a suitable basic reagent such as triethylamine in a suitable solvent such as acetonitrile at a suitable temperature, e.g. room temperature. Compounds 1.5 or 1.6 can both be obtained by the same procedure of step (iv) to give the same intermediate 1.7, step (iv) can be obtained by reacting compound 1.5 or 1.6 with a suitable reagent, such as triethylamine/methanesulfonyl chloride, or thionyl chloride, at a suitable temperature, such as 0^oC or room temperature, the hydroxy group is converted to mesylate or chloro, and then without further purification, in a basic reagent such as potassium carbonate or sodium carbonate and a suitable solvent such as acetonitrile, heated to react and ring closure to afford compound 1.7. Step (v) reaction of 1.7 with the corresponding alcohol, thiol, amine HQ- (CH)₂)_m-A (Q is-O-, -S-, -NR)_a-) reaction in a suitable solvent such as acetonitrile under conditions of a suitable base such as NaH gave the final product 1.8.

Use of

The compound of the invention is Lp-PLA₂And (3) an inhibitor. Thus, these compounds are useful in therapy, e.g., treatment or prophylaxis, with Lp-PLA₂Comprising the use of a therapeutically effective amount of Lp-PLA₂InhibitorsTreating a subject in need of such treatment. Accordingly, one aspect of the present invention relates to the treatment or prevention of Lp-PLA₂Methods of activity-related disorders. It will be appreciated by those skilled in the art that a particular disease or treatment thereof may involve the interaction with Lp-PLA₂One or more potential mechanisms associated with activity, including one or more of the mechanisms described herein.

In some embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of any of the diseases disclosed in the following published patent applications: WO96/13484, WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805, WO02/30904, WO02/30911, WO03/015786, WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO 086400/086400, US 2008/086400, WO 086400 a, WO 086400/086400 a, WO 086400 a, WO 086400 a and WO 086400 a 086400.

In some embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of an ocular disease. Ocular diseases for which the present invention is applicable may be associated with disruption of the intraretinal barrier (iBRB). Exemplary ocular diseases relate to diabetic ocular diseases including macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion, and the like. Further ocular diseases include, but are not limited to, central retinal vein occlusion, branch retinal vein occlusion, Igat syndrome (post-cataract and post-surgery), retinitis pigmentosa, pars plana, shotgun shell-like retinochoroidal disease, epiretinal membrane, choroidal tumors, cystic macular edema, collateral foveal telangiectasia, tractional maculopathy, vitreous macular traction syndrome, retinal detachment, optic nerve retinitis, idiopathic macular edema, and the like. Use of Lp-PLA₂More detailed description of inhibitor therapy for ocular diseases is providedIn WO2012/080497, this is incorporated by reference into the present application.

Furthermore, some embodiments of the present invention provide the use of a compound of the present invention in the manufacture of a medicament for treating or preventing diabetic macular edema in a subject. In some embodiments, the present invention provides the use of a compound of the present invention for treating diabetic macular edema in a subject.

In certain embodiments, the present invention provides the use of a compound of the invention in the manufacture of a medicament for treating or preventing macular edema in a subject having, or at risk of having, macular edema. In some embodiments, the present invention provides the use of a compound of the invention in the manufacture of a medicament for treating a subject having or at risk of having macular edema. In another embodiment, the macular edema is associated with a diabetic eye disease, such as diabetic macular edema or diabetic retinopathy. In another embodiment, the macular edema is associated with posterior uveitis.

In certain embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of glaucoma or macular degeneration. In some embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of glaucoma or macular degeneration.

In one embodiment, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disease associated with barrier disruption in the blood retina in a subject in need of such treatment. In one embodiment, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease associated with disruption of the intra-retinal barrier in a subject in need of such treatment.

In some embodiments, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of any disease in which endothelial dysfunction is implicated, e.g., atherosclerosis (e.g., peripheral vascular atherosclerosis and cerebrovascular atherosclerosis), diabetes, hypertension, angina pectoris, conditions following ischemia and reperfusion.

In some embodiments, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of any disease involving lipid oxidation associated with enzymatic activity, e.g., other conditions in addition to conditions such as atherosclerosis and diabetes, e.g., rheumatoid arthritis, stroke, inflammatory conditions of the brain (e.g., alzheimer's disease), various neuropsychiatric conditions (e.g., schizophrenia, autism), myocardial infarction, ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.

In some embodiments, the invention provides the use of a compound of the invention in the manufacture of a medicament for reducing the chance of a cardiovascular event (e.g., a heart attack, myocardial infarction, or stroke) in a patient with coronary heart disease.

In some embodiments, the invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prevention of a disease involving activated monocytes, macrophages or lymphocytes, since all these cell types express Lp-PLA₂Including diseases involving activated macrophages (e.g., M1, dendritic and/or other macrophages that produce oxidative stress). Exemplary conditions include, but are not limited to, vitiligo, rheumatoid arthritis, wound healing, Chronic Obstructive Pulmonary Disease (COPD), cirrhosis of the liver, atopic dermatitis, emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, alzheimer's disease, and autoimmune diseases such as lupus.

In other embodiments, the invention provides the use of a compound of the invention in the manufacture of a medicament for the primary or secondary prevention of an acute coronary event (e.g. caused by atherosclerosis); adjuvant treatment to prevent restenosis; or delay the progression of diabetic or hypertensive renal insufficiency. Prevention includes treatment of a subject at risk of such a condition.

In some embodiments, the present invention provides methods of treating or preventing a neurological disorder associated with abnormal Blood Brain Barrier (BBB) function, inflammation, and/or microglia activation in a subject in need of such treatment. In some embodiments, the present invention provides methods of treating or preventing a neurological disorder associated with abnormal Blood Brain Barrier (BBB) function, inflammation, and/or microglia activation in a subject in need of such treatment. The method comprises administering to the subject a therapeutically effective amount of a compound of the invention. In another embodiment, the abnormal BBB is a permeable BBB. In another embodiment, the disease is a neurodegenerative disease. Such neurodegenerative diseases are for example, but are not limited to, vascular dementia, Alzheimer's disease, Parkinson's disease and Huntington's chorea. In one embodiment, the invention provides a method of treating or preventing a disease associated with Blood Brain Barrier (BBB) leakage in a subject. In some embodiments, the present invention provides methods of treating a disease associated with Blood Brain Barrier (BBB) leakage in a subject. Exemplary diseases include, but are not limited to, cerebral hemorrhage, cerebral amyloid angiopathy. In one embodiment, the neurodegenerative disease is alzheimer's disease. In a specific embodiment, the neurodegenerative disease is vascular dementia. In one embodiment, the neurodegenerative disease is Multiple Sclerosis (MS).

In one embodiment, the compounds of the invention are useful for treating or preventing a neurodegenerative disease in a subject. The methods comprise administering a compound of the invention (e.g., in the form of a pharmaceutical composition comprising a compound of the invention) to a subject in need of such treatment. In one embodiment, the compounds of the invention are useful for treating neurodegenerative diseases in a subject. Exemplary neurodegenerative diseases include, but are not limited to, alzheimer's disease, vascular dementia, parkinson's disease, and huntington's disease. In a specific embodiment, the neurodegenerative disease described herein is associated with an abnormal blood brain barrier. In one embodiment, the administration inhibits Lp-PLA₂The subject of the active agent is a human.

In one embodiment, the invention provides a method of treating or preventing vascular dementia in a subject having, or at risk of having, vascular dementia. The methods comprise administering a compound of the invention (e.g., a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention) to a subject. In one embodiment, the invention provides a method of treating a subject suffering from, or at risk of, vascular dementia. In a specific embodiment, the vascular dementia is associated with alzheimer's disease.

In certain embodiments, the invention relates to methods of treating or preventing metabolic bone disease by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention. In some embodiments, the invention relates to methods of treating metabolic bone disease by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention. Exemplary metabolic bone diseases include diseases associated with loss of bone mass and bone density, including but not limited to osteoporosis and osteopenic disease. Exemplary osteoporosis and osteopenic diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Paget's disease, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, and related diseases. In another embodiment, the subject in need of such treatment is a human.

It is believed that methods of preventing osteoporosis and/or osteopenic diseases described herein may be subject to inhibition of Lp-PLA₂Expression and/or inhibition of Lp-PLA₂The effect of protein activity of (a). Thus, some embodiments of the invention provide for inhibition of Lp-PLA by blocking enzyme activity₂The method of (1). In another embodiment, there is provided a method of reducing and/or downregulating Lp-PLA₂Expression of RNA thereby inhibiting Lp-PLA₂The method of (1). In another embodiment, prevention and/or reduction of bone loss and loss of I or bone density results in prevention or reduction of symptoms associated with metabolic bone disease, such as osteoporosis and/or osteopenic disease.

In particular embodiments, the methods further comprise administering to a subject in need of treatment an additional therapeutic agent for treating a metabolic bone disease. For example, when the metabolic bone disease is osteoporosis, other therapeutic agents such as bisphosphonates (e.g., alendronate, ibandronate, risedronate, calcitonin, raloxifene), selective estrogen modulators (SERMs), estrogen therapy, hormone replacement therapy (ET/HRT) and teriparatubu may be used.

In one embodiment, systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic lupus erythematosus, voacanthus altissima-pristina syndrome, lyme disease, behcet's disease, ankylosing spondylitis, chronic granulomatous disease, onset and cessation (enthesitis) may be the underlying cause of posterior uveitis affecting the retina, and which may lead to macular edema. The present invention relates to methods of treating or preventing posterior uveitis or any of these systemic inflammatory diseases by administering a therapeutically effective amount of a compound of the present invention. In one embodiment, the invention provides a method of treating posterior uveitis or any of these systemic inflammatory diseases by administering a therapeutically effective amount of a compound of the invention.

With Lp-PLA₂Treatment and/or prevention of activity-related diseases may be achieved using the compounds of the present invention in monotherapy or in dual or multiple combination therapy. For example, the compounds of the invention may be used in combination with anti-hyperlipidemic agents, anti-atherosclerotic agents, anti-diabetic agents, anti-anginal agents, anti-inflammatory agents or anti-hypertensive agents or agents for lowering lipoproteins (a) (lp (a)) for the treatment or prevention of the diseases described herein. Examples of such agents include, but are not limited to, cholesterol synthesis inhibitors, such as statins: antioxidants, such as probucol; an insulin sensitizer; calcium channel antagonists and anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs). Agents for lowering lp (a) include the amino phosphate acetates described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312. In one embodiment, the compounds of the present invention may be used with one or more statins. Statins are well known cholesterol lowering agents and include atorvastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin and rosuvastatin. In some embodiments, the inventionThe compounds may be used with antidiabetics or insulin sensitizers. In one embodiment, the compounds of the invention may be used with PPAR γ activators, such as GI262570 (GlaxoSmithKline) and glitazone (glitazone) compounds, such as rosiglitazone, troglitazone and pioglitazone. The agent may be administered, for example, in a therapeutically effective amount as known in the art or in an amount that is less than or greater than the amount known in the art to provide effective treatment.

Combination therapy includes administering the therapeutic agents together in separate dosage forms or in a single dosage form. Combination therapy may include simultaneous or separate administration of the therapeutic agents, which may be administered substantially simultaneously or substantially separately. Typically, combination therapy comprises administering each agent such that a therapeutically effective amount of each agent is present in the body of the subject for at least an overlapping period of time.

Application method

A therapeutically effective amount of a compound of the invention will depend on a number of factors including, for example, the age and weight of the intended recipient, the precise condition to be treated and its severity, the nature of the formulation and the route of administration, and will ultimately depend on the judgment of the prescribing physician. However, a therapeutically effective amount of a compound of the invention for use in the treatment of the diseases described herein will generally range from 0.1 to 100 mg/kg of recipient body weight/day, more usually from 1 to 10 mg/kg of body weight/day. Thus, for example, for a 70kg adult mammal, the actual amount per day will typically be 70 to 700 mg, and this amount may be administered daily in a single dose per day or in multiple sub-doses, such as two, three, four, five or six doses. Or administration may be intermittent, such as once every other day, once a week, or once a month. It is contemplated that similar dosages may be applicable for the treatment of the other conditions described above.

The pharmaceutical compositions of the invention may comprise one or more compounds of the invention. In some embodiments, the pharmaceutical composition may comprise more than one compound of the invention. For example, in some embodiments, the pharmaceutical composition may comprise two or more compounds of the present invention. Furthermore, the pharmaceutical composition may optionally also comprise one or more additional pharmaceutically active compounds.

As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, component or carrier that participates in imparting morphology or consistency to the pharmaceutical composition. When mixed, each excipient may be compatible with the other ingredients of the pharmaceutical composition, thereby avoiding interactions that significantly reduce the potency of the compounds of the invention when administered to a subject and interactions that would result in pharmaceutically unacceptable pharmaceutical ingredients.

The compounds of the present invention and one or more pharmaceutically acceptable excipients may be formulated into dosage forms suitable for administration to a subject by a desired route of administration. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration (including buccal or sublingual) such as tablets, capsules, pills, lozenges, powders, syrups, brews, 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, e.g., suppositories; (5) nasal inhalation, such as dry powders, aerosols, suspensions and solutions; and (6) topical administration (including buccal, sublingual, or transdermal), such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association a compound of the formula with a carrier or excipient.

Pharmaceutical compositions suitable for oral administration may be presented as discrete units, such as capsules or tablets; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquid form; edible foams (foams or whips), or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

Suitable pharmaceutically acceptable excipients may vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients may be selected based on the particular function they serve in the composition. For example, some pharmaceutically acceptable excipients may be selected for their ability to facilitate the production of a uniform dosage form. Some pharmaceutically acceptable excipients may be selected for their ability to facilitate the production of stable dosage forms. Some pharmaceutically acceptable excipients may be selected for their ability to facilitate the delivery or transport of one or more compounds of the invention from one organ or portion of the body to another organ or portion of the body when administered to a subject. Some pharmaceutically acceptable excipients may be selected for their ability to increase patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffers. One skilled in the art will appreciate that some pharmaceutically acceptable excipients may provide more than one function, and that other functions may be provided depending on how much of the excipient is present in the formulation and what other ingredients are also present in the formulation.

The skilled person possesses the knowledge and skill in the art to be able to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, the skilled person has access to a number of resources describing pharmaceutically acceptable excipients and available for selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack publishing Co.), The Handbook of Pharmaceutical Additives (The Hand book of Pharmaceutical Additives, Gower publishing Co., Ltd.), and The Handbook of Pharmaceutical Excipients (Handbook of Pharmaceutical Excipients, American society for medicine and Pharmaceutical Press).

The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington pharmaceutical science (Mack press).

In one aspect, the invention relates to a solid oral dosage form, such as a tablet or capsule, comprising a therapeutically effective amount of a compound of the invention and an releasing or filling agent. Suitable diluents and fillers include lactose, cerealose, glucose, mannitol, sorbitol, starches (e.g., corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may also include a binder. Suitable binders include starches (e.g., corn starch, potato starch, and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, xanthan gum, guar gum, povidone, and cellulose and its derivatives (e.g., microcrystalline cellulose). Oral solid dosage forms may also include a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose (croscarmellose), alginic acid and sodium carboxymethylcellulose. The oral solid dosage form may also contain a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

In a specific embodiment, the invention relates to a pharmaceutical composition comprising 0.01mg to 1000mg of one or more compounds of the above formula described herein or a pharmaceutically acceptable salt thereof and 0.01g to 5g of one or more pharmaceutically acceptable excipients.

Examples preparation

Intermediate 1

(S) -2- (((tert-butyloxycarbonyl) amino) -6- (dimethyl (oxo) -lambda⁶-sulfinyl) -5-oxohexanoic acid methyl ester

1- (tert-butyl) 2-methyl (C) at room temperatureS) -5-Oxopyrrolidine-1, 2-dicarboxylic acid ester (49 g, 0.2 mol), potassium tert-butoxide (34 g, 0.3 mol) was added to dimethyl sulfoxide (500 mL) and stirred at room temperature for 1 hour, trimethyl sulfoxide iodide (75 g, 0.34 mol) was added and stirred at room temperature for 3 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to give the title compound (41 g, 61%). MS M/z [ M + H ]]⁺ =336。

1- (tert-butyl) 2-methyl (S) -5-Oxopiperidine-1, 2-dicarboxylic acid ester

At room temperature: (S) -2- (((tert-butyloxycarbonyl) amino) -6- (dimethyl (oxo) -lambda⁶-sulfinyl) -5-oxohexanoic acid methyl ester (4.1 g, 12 mmol) and Ir [ COD]₂Cl (41 mg, 0.6 mmol) was added to 1, 2-dichloroethane (50mL) under argon, 90 deg.f^oC stirring for 2 days. The reaction solution was concentrated and purified by column chromatography to give the title compound (1.3 g, 33%). MS M/z [ M + H ]]⁺ =258。

1- (tert-butyl) 2-methyl (S) -5-Methylenepiperidine-1, 2-dicarboxylic acid ester

1- (tert-butyl) 2-methyl (C) at room temperatureS) Adding 5-oxypiperidine-1, 2-dicarboxylate (500 mg, 1.9 mmol) into anhydrous tetrahydrofuran (50mL), and cooling to 0 under the protection of argon^oC, a n-hexane solution of n-butyllithium (2.5M, 1 mL, 2.5 mmol), 0^oC stirred for 1 hour. Methyltriphenylphosphonium bromide (500 mg, 1.9 mmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to give the compound (250 mg, 50%). MS M/z [ M + H ]]⁺ =256。

1-benzyl 2-methyl (S) -5-Methylenepiperidine-1, 2-dicarboxylic acid ester

1- (tert-butyl) 2-methyl (C) at room temperatureS) -5-Methylenepiperidine-1, 2-dicarboxylate (250 mg, 1.0 mmol) and trifluoroacetic acid (228 mg, 2.0 mmol) were added to dichloromethane (5 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and water (5 mL), potassium carbonate (414 mg, 3.0 mmol) and benzyl chloroformate (170 mg, 1.0 mmol) were successively added to the residue, followed by stirring at room temperature overnight.The reaction mixture was poured into water, extracted with dichloromethane, the organic phase was concentrated, and preparative thin layer chromatography gave the title compound (110 mg, 38%). MS M/z [ M + H ]]⁺ =290。

5-benzyl 6-methyl (S) -5-azaspiro [2.5]Octane-5, 6-dicarboxylic acid esters

At room temperature, a solution of diethyl zinc in n-hexane (1M, 7.6 mL, 7.6 mmol) was added to dichloromethane (7 mL) and the temperature was reduced to 0 under argon^oC, trifluoroacetic acid (560. mu.L, 7.6 mmol) was added to the reaction solution, 0^oC stirred for 1 hour. Diiodomethane (2.0 g, 7.6 mmol) was added to the reaction mixture, 0^oC stirred for 1 hour. 1-benzyl 2-methyl (S) -5-Methylenepiperidine-1, 2-dicarboxylate (1.1 g, 3.8 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and poured into a saturated aqueous sodium bicarbonate solution, and stirred at room temperature for 0.5 hour. Filtration, extraction of the filtrate with dichloromethane, concentration of the organic phase and purification by column chromatography gave the title compound (300 mg, 27%). MS M/z [ M + H ]]⁺ =304。

(S) -5-azaspiro [2.5]Octane-6-carboxylic acid methyl ester

At room temperature, reacting 5-benzyl 6-methyl (S) -5-azaspiro [2.5]Octane-5, 6-dicarboxylate (300 mg, 1.0 mmol) and palladium on carbon (10%, 30 mg) were added to methanol (10mL) and hydrogenated at room temperature under normal pressure overnight. The reaction was filtered and the filtrate was concentrated to give the crude title compound which was used directly in the next reaction. MS M/z [ M + H ]]⁺ =170。

(S) - (5-azaspiro [ 2.5)]Octane-6-yl) methanol

At room temperature, mixingS) -5-azaspiro [2.5]Methyl octane-6-carboxylate (190 mg, 1.1 mmol) was added to anhydrous tetrahydrofuran (2 mL), and lithium aluminum hydride (45 mg, 1.1 mmol) was added with stirring and stirred at room temperature for 2 hours. The reaction solution was quenched with sodium sulfate decahydrate, stirred at room temperature for 30 minutes, filtered, the filter cake was rinsed with tetrahydrofuran, and the filtrate was concentrated to give the title compound (100 mg, 2-step yield: 64%). MS M/z [ M + H ]]⁺ =142。

(S) - (5- (2, 6-dichloropyrimidin-4-yl) -5-azaspiro [2.5]Octane-6-yl) methanol

At room temperature, mixingS) - (5-azaspiro [ 2.5)]Octane-6-yl) methanol (100 mg, 0.7 mmol) and sodium carbonate solid (150 mg, 1.4 mmol) were added to acetonitrile (2 mL) and cooled to 0 under argon^oC, 2,4, 6-trichloropyrimidine (130 mg, 0.7 mmol) was added and stirred at room temperature overnight. The reaction was filtered, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (100 mg, 50%). MS M/z [ M + H ]]⁺ =288。

(S) -3 '-chloro-8', 9', 9a', 10 '-tetrahydro-1'H, 6'HSpiro [ cyclopropane-1, 7' -pyridine [1', 2': 3, 4]]Imidazo [1, 2-c]Pyrimidines]-1' -ketones

At room temperature, mixingS) - (5- (2, 6-dichloropyrimidin-4-yl) -5-azaspiro [2.5]Octane-6-yl) methanol (50 mg, 0.2 mmol) and thionyl chloride (250 mg, 0.2 mmol) were added to dichloromethane (2 mL) and stirred at room temperature overnight. The reaction solution was concentrated, and to the residue were added potassium carbonate solid (50 mg, 0.3 mmol) and acetonitrile (2 mL), 80 in that order^oC stirred overnight. The reaction was filtered, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (20 mg, 45%). MS M/z [ M + H ]]⁺ =252。

Intermediate 2

1-benzyl-5-oxopyrrolidine-2-carboxylic acid methyl ester

At room temperature, 5-oxopyrrolidine-2-carboxylic acid methyl ester (4.0 g, 28.0 mmol) and sodium hydride (60%, 2.24 g, 56.0 mmol) were added to anhydrous tetrahydrofuran (50mL) and the temperature was raised to 60 ℃ under argon^oC, adding benzyl bromide (5.7 g, 33.6 mmol), 60^oC stirred for 2 hours. After the reaction solution was cooled to room temperature, the reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain the title compound (4.2 g, 64%). MS M/z [ M + H ]]⁺ =234。

1-benzyl-5- (hydroxymethyl) pyrrolidin-2-one

1-benzyl-5-oxopyrrolidine-2-carboxylic acid methyl ester (4.2 g, 18.02 mmol) was added to anhydrous tetrahydrofuran (40mL) at room temperature, and lithium borohydride (800 mg, 36.0 mmol) was added with stirring and stirred at room temperature for 1 hour. The reaction solution was quenched with sodium sulfate decahydrate and stirred at room temperature for 30 minutes. Filtration and concentration of the filtrate yielded the crude title compound (3.6 g, 97%). MS M/z [ M + H ]]⁺ =206。

1-benzyl-5- (((tert-butyldimethylsilyl) oxy) methyl) pyrrolidin-2-one

1-benzyl-5- (hydroxymethyl) pyrrolidin-2-one (3.6 g, 14.4 mmol) was dissolved in dichloromethane (50mL) at room temperature, imidazole (2.9 g, 43.2 mmol) and tert-butyldimethylsilyl chloride (3.2 g, 21.6 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the title compound (3.6 g, 78%).MS: m/z [M+H]⁺ =320。

4-benzyl 5- (((tert-butyldimethylsilyl) oxy) methyl) -4-azaspiro [ 2.4 ] heptane

1-benzyl-5- (((tert-butyldimethylsilyl) oxy) methyl) pyrrolidin-2-one (2.0 g, 6.27 mmol) was added to anhydrous tetrahydrofuran (30 mL) at room temperature and cooled to 0 deg.C under argon^oC, tetraisopropyl titanate (4.5 mL, 15.67 mmol) and a solution of ethylmagnesium bromide in tetrahydrofuran (2M, 15 mL, 30 mmol) were added with stirring and left at room temperature overnight. The reaction was quenched with water, the reaction was filtered, the filtrate was concentrated, and column chromatography purification (petroleum ether/ethyl acetate = 20/1) gave the title compound (1.3 g, 63%). MS M/z [ M + H ]]⁺ =332。

(4-benzyl-4-azaspiro [ 2.4 ] heptan-5-yl) methanol

Under the protection of argon, 4-benzyl 5- (((tert-butyldimethylsilyl) oxy) methyl) -4-azaspiro [ 2.4%]Heptane (3.1 g, 9.36 mmol) was added to anhydrous tetrahydrofuran (40mL) and a tetrahydrofuran solution of tetrabutylammonium fluoride (1M, 10.8 mmol, 10.8 mL) and stirred at room temperature for 3 hours. The reaction solution was quenched with a saturated aqueous ammonium chloride solution, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 15/1-10/1) to obtain the title compound (800 mg, 94%). MS M/z [ M + H ]]⁺ =218。

(4-azaspiro [ 2.4 ] heptan-5-yl) methanol

Reacting (4-benzyl-4-azaspiro [ 2.4 ] at room temperature]Heptane-5-yl) methanol (700 mg, 3.22 mmol) and palladium on carbon (10%, 105 mg) were added to methanol (25 mL), 50^oC, hydrogenating for 3 days under normal pressure. The reaction was filtered and the filtrate was concentrated to give the crude title compound (1.2 g, 256%). MS M/z [ M + H ]]⁺ =128。

(4- (2, 6-dichloropyridin-4-yl) -4-azaspiro [ 2.4 ] heptan-5-yl) methanol

2,4, 6-trichloropyrimidine (582 mg, 3.2 mmol) was added to acetonitrile (20 mL) at room temperature and cooled to 0 under argon^oC. Sodium carbonate solid (510 mg, 4.8 mmol) and (4-azaspiro [ 2.4 ] were added sequentially with stirring]Heptan-5-yl) methanol (600 mg, 4.7 mmol) was stirred at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and preparative thin layer chromatography (petroleum ether/ethyl acetate = 5/1) gave the title compound (160 mg, 12%). MS M/z [ M + H ]]⁺ =274。

3 '-chloro-7', 8', 8a', 9 '-tetrahydro-1'HSpiro [ cyclopropane-1, 6' -pyrrolo [1', 2': 3,4]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

Reacting (4- (2, 6-dichloropyridin-4-yl) -4-azaspiro [ 2.4 ] at room temperature]Heptane-5-yl) methanol (120 mg, 0.52 mmol) was added to dichloromethane (8 mL) and thionyl chloride (120 mg, 1.04 mmol) was added dropwise at room temperature and stirred at room temperature for 10 minutes. The reaction solution was concentrated, and potassium carbonate (290 mg, 2.08 mmol) and acetonitrile (12 mL), 85 in that order were added to the residue^oC stirred overnight. The reaction solution was filtered, the filtrate was concentrated, and preparative thin layer chromatography (dichloromethane/methanol = 20/1) gave the title compound (80 mg, 65%). MS M/z [ M + H ]]⁺ =238。

Intermediate 3

1, 1-bis (iodomethyl) cyclopropanes

Triphenylphosphine (26.0 g, 99.0 mmol) and imidazole (6.5 g, 96.0 mmol) were added to dichloromethane (30 mL) at room temperature and the temperature was reduced to 0 deg.C under argon^oC, adding iodine (25.0 g, 99.0 mmol), 0^oC stirred for 1 hour. A solution of 1, 1-cyclopropane-dimethanol (5.0 g, 48.0 mmol) in dichloromethane (20 mL) was added to the reaction solution, and the mixture was stirred at that temperature for 3 hours. The reaction solution was poured into brine (15%), extracted with ethyl acetate, the organic phase was washed with saturated sodium sulfite solution, concentrated, and to the residue were added petroleum ether (200 mL) and ethyl acetate (10mL) in this order, stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated to give the title compound (12 g, 75%).¹H NMR(400 MHz, CDCl₃) d 3.34(br. s., 4 H), 1.02(br. s., 4 H)。

5- (tert-butyl) 6-ethyl 5-azaspiro [ 2.4 ] heptane-5, 6-dicarboxylic acid ester

Sodium hydride (60%, 3.0 g, 75.0 mmol) was added to N, N-dimethylformamide (40mL) at room temperature and the temperature was reduced to 0 deg.C under argon^oC, a solution of 1, 1-bis (iodomethyl) cyclopropane (9.6 g, 28.9 mmol) and ethyl (tert-butoxycarbonyl) glycinate (6.2 g, 30.5 mmol) in N, N-dimethylformamide (40mL) and 0 part of N, N-dimethylformamide were added dropwise with stirring^oC stirred for 1.5 hours. Acetic acid (2.5 mL), 0, was added^oC stirred for 2 hours. The reaction was poured into water, extracted with ethyl acetate and the organic phase was concentrated to give the title compound (4.8 g, 62%). MS M/z [ M + H-Boc]⁺ =170。

(5-Azaspiro [ 2.4 ] Heptan-6-yl) methanolic hydrochloride

Reacting 5- (tert-butyl) 6-ethyl 5-azaspiro [ 2.4 ] at room temperature]Heptane-5, 6-dicarboxylate (540 mg, 2.0 mmol) was added to anhydrous tetrahydrofuran (6 mL), and lithium borohydride (88 mg, 4.0 mmol) was added with stirring and stirred at room temperature overnight. Inverse directionThe reaction solution was quenched with sodium sulfate decahydrate, stirred at room temperature for 0.5 h, filtered, the filtrate was concentrated, and the residue was added to dichloromethane (3 mL) and a solution of hydrogen chloride in ethyl acetate (4M, 6 mL). After stirring at room temperature for 30 minutes, the reaction was concentrated to give the crude title compound (350 mg, 107%). MS M/z [ M + H ]]⁺ =128。

(5- (2, 6-dichloropyrimidin-4-yl) -5-azaspiro [ 2.4 ] heptan-6-yl) methanol

2,4, 6-trichloropyrimidine (760 mg, 4.18 mmol) was added to acetonitrile (12 mL) at room temperature and cooled to 0 under argon^oC, adding sodium carbonate solid (680 mg, 6.42 mmol) and (5-azaspiro [ 2.4 ] in turn under stirring]Heptane-6-yl) methanol hydrochloride (350 mg, 2.14 mmol) was stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was concentrated, and preparative thin layer chromatography (petroleum ether/ethyl acetate = 4/1) gave the title compound (140 mg, 19%). MS M/z [ M + H ]]⁺ =273。

3 '-chloro-8 a', 9 '-dihydro-1'H, 6'H, 8'HSpiro [ cyclopropane-1, 7' -pyrrolo [1', 2': 3,4]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

Reacting (5- (2, 6-dichloropyrimidin-4-yl) -5-azaspiro [ 2.4 ] at room temperature]Heptane-6-yl) methanol (140 mg, 0.51 mmol) was added to methylene chloride (6 mL), and sulfoxide chloride (184 mg, 1.53 mmol) was added dropwise with stirring, and stirred at room temperature for 10 minutes. The reaction solution was concentrated, and to the residue were added solid potassium carbonate (345 mg, 2.5 mmol) and acetonitrile (8 mL), 85 in that order^oC stirred overnight. The reaction solution was filtered, the filtrate was concentrated, and preparative thin layer chromatography (dichloromethane/methanol = 20/1) gave the title compound (80 mg, 66%). MS M/z [ M + H ]]⁺ =238。

Intermediate 4

5-hydroxy-6-oxa-7-azaspiro [ 3.5 ] nonyl-7-ene-8-carboxylic acid ethyl ester

Cyclobutanecarbaldehyde (1 g, 11.9 mmol) and pyrrolidine (1.1 g, 15.5 mmol) were added to anhydrous toluene (12 mL) at room temperature, and 4A molecular sieves (0.1 g) were added with stirring and stirred at room temperature for 2 hours. Anhydrous tetrahydrofuran (12 mL) was added to the reaction solution, followed by addition of ethyl 3-bromo-2- (hydroxyimino) propionate (2.6 g, 12.6 mmol,J. Org. Chem.1982, 47, 2147), stirring at room temperature for 0.5 hour. Triethylamine (1.3 g, 12.7 mmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated and purified by column chromatography (petroleum ether/ethyl acetate = 5/1) and preparative thin layer chromatography (petroleum ether/ethyl acetate = 5/1) to give the title compound (510 mg, 20%).¹H NMR(400 MHz, DMSO-d ₆)d 7.44 - 7.14(m, 1 H), 5.26(br. s., 1 H), 4.21(q, J = 6.8 Hz, 2 H), 2.56(m, 1 H), 2.32(m, 1 H), 2.09 - 1.95(m, 1 H), 1.95 - 1.66(m, 4 H), 1.59(d, J = 10.3 Hz, 1 H), 1.25(t, J = 7.1 Hz, 3 H); MS: m/z [M+H]⁺ =214。

6-Azaspiro [ 3.4 ] octane-7-carboxylic acid ethyl ester

Reacting 5-hydroxy-6-oxa-7-azaspiro [ 3.5 ] at room temperature]Ethyl nonyl-7-ene-8-carboxylate (510 mg, 2.4 mmol) was added to ethanol (30 mL), Raney-Ni catalyst (510 mg) was added under argon, and the mixture was hydrogenated at room temperature under normal pressure overnight. Filtration and concentration of the filtrate yielded the crude title compound (460 mg, 102%).¹H NMR(400 MHz, DMSO-d ₆)d 4.06(d, J = 6.4 Hz, 2 H), 3.63(br. s., 1 H), 2.86(br. s., 1 H), 2.76(br. s., 1 H), 2.04(d, J = 8.3 Hz, 1 H), 1.96 - 1.67(m, 7 H), 1.23 - 1.11(m, 3 H); MS: m/z [M+H]⁺ =184。

(6-azaspiro [ 3.4 ] octyl-7-yl) methanol

Reacting 6-azaspiro [ 3.4 ] at room temperature]The crude octane-7-carboxylic acid ethyl ester (360 mg, 1.97 mmol) was added to anhydrous tetrahydrofuran (10mL) and methanol (1 mL), and lithium borohydride (220 mg, 5.8 mmol), 50, was slowly added^oC stirred for 2 hours. The reaction solution was cooled to 0^oAnd C, quenching the reaction liquid by using sodium sulfate decahydrate. Filtration, rinsing of the filter cake with dichloromethane and concentration of the filtrate yielded the crude title compound (290 mg, 105%). MS M/z [ M + H ]]⁺ =142。

(6- (6-chloro-2-methoxypyrimidin-4-yl) -6-azaspiro [ 3.4 ] octyl-7-yl) methanol

At room temperature, (6-azaspiro [ 3.4 ]]Octyl-7-yl) methanol (290 mg, 2.06 mmol) and 4, 6-dichloro-2-methoxypyrimidine (358 mg, 2 mmol) were dissolved in isopropanol (20 mL), and sodium carbonate (848 mg, 8mmol), 80, was added with stirring^oC stirred for 3 hours. The reaction solution was cooled to room temperature, the reaction mixture was diluted with dichloromethane, filtered through celite, the filtrate was concentrated, and preparative thin layer chromatography (petroleum ether/ethyl acetate = 2/1) gave the title compound (160 mg, 24%).¹H NMR(400 MHz, CDCl₃)d 6.05(br. s., 1 H), 5.55(br. s., 1 H), 4.29(br. s., 1 H), 3.93(s, 3 H), 3.78 - 3.60(m, 2 H), 3.53 - 3.42(m, 1 H), 3.39(br. s., 1 H), 2.17 - 2.10(m, 1 H), 2.10 - 1.85(m, 7 H)； MS: m/z [M+H]⁺ =284。

3 '-chloro-8 a', 9 '-dihydro-1'H, 6'H, 8'HSpiro [ cyclobutane-1, 7' -pyrrolo [1', 2': 3,4]Imidazo [1, 2-c]Pyrimidines]-1' -ketones

Reacting (6- (6-chloro-2-methoxypyrimidin-4-yl) -6-azaspiro [ 3.4 ] at room temperature]Octyl radical-7-yl) methanol (140 mg, 0.49 mmol) and thionyl chloride (176 mg, 1.48 mmol) were added to dichloromethane (3 mL) and stirred at room temperature overnight. The reaction mixture was concentrated and dissolved in water (2 mL), 0^oSodium hydroxide solid (78 mg, 1.96 mmol), 0 was added under C^oC stirred for 0.5 hour. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and preparative thin layer chromatography (dichloromethane/methanol = 40/1) gave the title compound (47 mg, 38%) as a white solid.¹H NMR(400 MHz, CDCl₃)d 5.60(s, 1 H), 4.22(d, J = 7.8 Hz, 2 H), 4.09 - 3.97(m, 1 H), 3.47(d, J = 10.8 Hz, 1 H), 3.23(d, J = 10.8 Hz, 1 H), 2.37 - 2.27(m, 1 H), 2.18 - 1.88(m, 7 H); MS: m/z [M+H]⁺ =252。

Intermediate 5

2- (((tert-butyldimethylsilyl) oxy) methyl) -3-Methenylpiperidine-1-carboxylic acid tert-butyl ester

At room temperature, methyl triphenyl phosphonium bromide (407 mg, 1.14 mmol) is added into anhydrous tetrahydrofuran (10mL), and the temperature is reduced to 0 degree under the protection of argon^oC, a solution of n-butyllithium in n-hexane (2.5M, 0.456 mL, 1.14 mmL), 0.5M was added dropwise^oC stirred for 0.5 hour. Tert-butyl 2- (((tert-butyldimethylsilyl) oxy) methyl) -3-oxopiperidine-1-carboxylate (300 mg, 0.87 mmol,Bioorganic and Medicinal Chemistry Letters2017, 27, 2210-2215) was slowly dropped into the reaction solution at room temperature overnight. The reaction solution was cooled to 0^oC, quench with saturated ammonium chloride solution, extract with ethyl acetate, concentrate the organic phase and preparative thin layer chromatography (dichloromethane/methanol = 100/1) afforded the title compound (92 mg, 29%). MS M/z [ M + H-Boc]⁺ =242。

(5-Azaspiro [2.5 ] octyl-4-yl) methanolic hydrochloride

Tert-butyl 2- (((tert-butyldimethylsilyl) oxy) methyl) -3-alkenylpiperidine-1-carboxylate (82 mg, 0.24 mmol) and a solution of diethyl zinc in n-hexane (1M, 2.4 mL, 2.4 mmL) were added to dichloromethane (20 mL) at room temperature and cooled to 0 under argon^oC, diiodomethane (1.3 g, 4.8 mmol) was added dropwise and stirred at room temperature overnight after the addition. The reaction solution was cooled to 0^oAnd C, quenching the reaction liquid by using sodium sulfate decahydrate, filtering, leaching a filter cake by using dichloromethane, concentrating the filtrate, sequentially adding methanol (2 mL) and an ethyl acetate solution (4M, 1 mL) of hydrogen chloride into the residue, and stirring at room temperature for 5 hours. The reaction was concentrated to give the crude title compound (90 mg, 211%). MS M/z [ M + H ]]⁺ =142。

(5- (6-chloro-2-methoxypyrimidin-4-yl) -5-azaspiro [2.5 ] octyl-4-yl) methanol

At room temperature, (5-azaspiro [2.5 ]]Octyl-4-yl) methanolate crude (90 mg, 0.51 mmol), 4, 6-dichloro-2-methoxypyrimidine (90 mg, 0.39 mmol) and sodium carbonate solid (127 mg, 1.2 mmol) were added to isopropanol (5 mL), 80^oC stirring for 2 days. The reaction solution was cooled to room temperature, poured into water, extracted with dichloromethane, the organic phase was concentrated, and preparative thin layer chromatography (petroleum ether/ethyl acetate = 2/1) gave the title compound (20 mg, 14%).¹H NMR(400 MHz, CDCl₃)d 6.24(s, 1 H), 4.79 - 4.50(m, 2 H), 4.01(br. s., 1 H), 3.88(s, 3 H), 3.81(d, J = 7.3 Hz, 1 H), 3.14(d, J = 7.3 Hz, 1 H), 2.19 - 1.93(m, 2 H), 1.74(br. s., 1 H), 1.71 - 1.59(m, 1 H), 0.88 - 0.76(m, 1 H), 0.68 - 0.49(m, 1 H), 0.47 - 0.36(m, 1 H), 0.21(br. s., 1 H); MS: m/z [M+H]⁺ =284。

3 '-chloro-7', 8', 9a', 10 '-tetrahydro-1'H, 6'HSpiro [1, 9' -pyrido [1', 2': 3, 4)]Imidazo [1, 2-c]Pyrimidines]-1' -ketones

Reacting (5- (6-chloro-2-methoxypyrimidin-4-yl) -5-azaspiro [2.5 ] at room temperature]Octyl-4-yl) methanol (20 mg, 0.07 mmol) and thionyl chloride (26 mg, 0.22 mmol) were added to dichloromethane (3 mL) and stirred at room temperature overnight. The reaction mixture was concentrated, and water (2 mL) was added to the residue to cool the mixture to 0^oC, add sodium hydroxide solid (11 mg, 0.28 mmol) with stirring. 0^oC stirred for 0.5 hour. The reaction was poured into water, extracted with dichloromethane, and the organic phase was concentrated to give the crude title compound (24 mg, 113%). MS M/z [ M + H ]]⁺ =252。

Intermediate 6

3-azaspiro [ 5.5 ] undecane-3-carboxylic acid tert-butyl ester

Reacting 3-azaspiro [ 5.5 ] at room temperature]Undecane (900 mg, 5.87 mmol), di-tert-butyl dicarbonate (1.92 g, 8.81 mmol) and sodium carbonate (1.87 g, 17.61 mmol) were added in this order to dichloromethane (10mL) and stirred at room temperature for 5 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to give the title compound (1.62 g, 94%). MS M/z [ M + H-tBu]⁺ =198。

2-formyl-3-azaspiro [ 5.5 ] undecane-3-carboxylic acid tert-butyl ester

Under the protection of argon, 3-azaspiro [ 5.5 ]]Adding tert-butyl undecane-3-carboxylate (1 g, 3.95 mmol) and tetramethylethylenediamine (458 mg, 3.95 mmol) into anhydrous tetrahydrofuran (10mL), and cooling to-60 deg.C under the protection of argon^oC, dropwise adding n-hexane solution (1.3M, 3.03 mL, 3.95 mmol) of sec-butyl lithium and-50^oC ~ -20 ^oC stirred for 0.5 hour. The reaction solution is cooled to-60 DEG^oC, N-dimethylformamide (432 mg, 5.9) was added dropwise3 mmol)，-50 ^oC was stirred for 1 hour and at room temperature for 1 hour. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (563 mg, 51%). MS M/z [ M + H-tBu]⁺ =226。

2- (hydroxymethyl) -3-azaspiro [ 5.5 ] undecane-3-carboxylic acid tert-butyl ester

Reacting 2-formyl-3-azaspiro [ 5.5 ] at room temperature]Tert-butyl undecane-3-carboxylate (460 mg, 1.64 mmol) was added to ethanol (5 mL), and sodium borohydride (124 mg, 3.27 mmol) was added with stirring, followed by stirring at room temperature for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (430 mg, 93%). MS M/z [ M + H-tBu]⁺ =228。

(3- (2, 6-dichloropyrimidin-4-yl) -3-azaspiro [ 5.5 ] undecan-2-yl) methanol

Reacting 2- (hydroxymethyl) -3-azaspiro [ 5.5 ] at room temperature]Tert-butyl undecane-3-carboxylate (430 mg, 1.52 mmol) was added to methylene chloride (3 mL), and an ethyl acetate solution of hydrogen chloride (4M, 1.9 mL) was added with stirring and stirred at room temperature for 2 hours. The reaction solution was concentrated, and acetonitrile (5 mL) and sodium carbonate (483 mg, 4.56 mmol), 85 were sequentially added to the residue^oC stirred overnight. The reaction was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (410 mg, 82%). MS M/z [ M + H ]]⁺ =330。

3 '-chloro-6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclohexane-1, 8' -pyrido [1', 2': 3, 4]]Imidazo [1, 2-c]Pyrimidines]-1' -ketones

Reacting (3- (2, 6-dichloropyrimidin-4-yl) -3-azaspiro [ 5.5 ] at room temperature]Undecane-2-yl) methanol (360 mg, 1.09 mmol) was added to methylene chloride (5 mL), and thionyl chloride (389 mg, 3.27 mmol) was added with stirring, and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and acetonitrile (5 mL) and potassium carbonate (451 mg, 3.1 mmol), 85 were added to the residue in this order^oC stirred overnight. The reaction was filtered, the filter cake rinsed with dichloromethane, the filtrate concentrated, and purified by preparative thin layer chromatography to give the title compound (220 mg, 60%). MS M/z [ M + H ]]⁺ =294。

Intermediate 7

1, 1-dichloro-2-oxo-7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

At room temperature, 4-methylenepiperidine-1-carboxylic acid tert-butyl ester (49 g, 248.4 mmol) and zinc copper reagent (49 g) are sequentially added into anhydrous ethylene glycol dimethyl ether (500 mL), and the temperature is controlled at 30 DEG^oC-40 ^oC, trichloroacetyl chloride (49.4 g, 273.2 mmol) was added dropwise and stirred at room temperature for 3 hours. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and column chromatography was performed to purify the title compound (38.6 g, 50%). MS M/z [ M + H-tBu]⁺ =252。

2-oxo-7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Sequentially reacting 1, 1-dichloro-2-oxo-7-azaspiro [ 3.5 ] at room temperature]Adding tert-butyl nonane-7-carboxylate (37 g, 120.1 mmol) into saturated ammonium chloride aqueous solution (200 mL) and methanol (200 mL), and cooling to 0 under the protection of argon^oC, zinc powder (37 g, 565.8 mmol) was added in portions and stirred at room temperature overnight. The reaction was filtered, the filter cake was rinsed with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (24.2 g, 84%). MS M/z [ M + H ]-tBu]⁺ =184。

7-azaspiro [ 3.5 ] nonanes

Reacting 2-oxo-7-azaspiro [ 3.5 ] at room temperature]Nonane-7-carboxylic acid tert-butyl ester (5 g, 20.92 mmol) was added to polyethylene glycol (50mL), and hydrazine hydrate (7.32 g, 146.44 mmol) and potassium hydroxide solid (7.03 g, 125.52 mmol), 200, were added with stirring^oC stirred for 4 hours. The reaction was cooled to room temperature, poured into water, extracted with ether and the organic phase was concentrated to give the title compound (3.32 g, 126%). MS M/z [ M + H ]]⁺ =126。

7-Azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Reacting 7-azaspiro [ 3.5 ] at room temperature]Nonane (2.8 g, 22.4 mmol) was added to dichloromethane (50mL), di-tert-butyl dicarbonate (7.32 g, 33.6 mmol) and potassium carbonate (9.27 g, 67.3 mmol) were added successively with stirring, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to give the title compound (4.5 g, 89%). MS M/z [ M + H-tBu]⁺ =170。

6-formyl-7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Tetramethylethylenediamine (1.03 g, 8.89 mmol) and 7-azaspiro [ 3.5 ] were successively reacted at room temperature]Adding nonane-7-carboxylic acid tert-butyl ester (2 g, 8.89 mmol) into anhydrous tetrahydrofuran (20 mL), and cooling to-60 ℃ under the protection of argon^oC, a solution of sec-butyllithium in n-hexane (1.3M, 6.84 mL, 8.89 mmol) was added dropwise with stirring, after completion of the addition, 20-degree of dropwise addition^oC stirring for 30 minutes. The reaction solution is cooled to-60 DEG^oC, dropwise adding N, N-dimethylformamide(973 mg, 13.3 mmol), and the dropwise addition was completed to-60^oC was stirred for 1 hour and at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (0.83 g, 37%). MS M/z [ M + H-tBu]⁺ =198。

6- (hydroxymethyl) -7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Reacting 6-formyl-7-azaspiro [ 3.5 ] at room temperature]Tert-butyl nonane-7-carboxylate (1.63 g, 6.4 mmol) was added to anhydrous ethanol (10mL), and sodium borohydride (487 mg, 12.8 mmol) was added with stirring, followed by stirring at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (1.43 g, 87%). MS M/z [ M + H-tBu]⁺ =200。

(7- (6-chloro-2-methoxypyrimidin-4-yl) -7-azaspiro [ 3.5 ] nonan-6-yl) methanol

Reacting 6- (hydroxymethyl) -7-azaspiro [ 3.5 ] at room temperature]Tert-butyl nonane-7-carboxylate (1.43 g, 6.4 mmol) was added to methylene chloride (100 mL), and a solution of hydrogen chloride in ethyl acetate (4M, 27.8 mL) was added with stirring and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and acetonitrile (10mL), 4, 6-dichloro-2-methoxypyrimidine (2.29 g, 12.8 mmol), and sodium carbonate (2.32 g, 21.87 mmol), 85 were added to the residue in this order^oC stirred for 16 hours. The reaction solution was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and column chromatography was performed to purify the title compound (0.783 g, 35%). MS M/z [ M + H ]]⁺ =298。

3 '-chloro-6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

Reacting (7- (6-chloro-2-methoxypyrimidin-4-yl) -7-azaspiro [ 3.5 ] at room temperature]Nonan-6-yl) methanol (100 mg, 0.33 mmol) was added to methylene chloride (5 mL), and thionyl chloride (118 mg, 0.99 mmol) was added with stirring and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and acetonitrile (5 mL) and potassium carbonate (182 mg, 1.32 mmol), 85 were added to the residue in this order^oC stirred overnight. The reaction was filtered, the filtrate was concentrated, and purified by preparative thin layer chromatography to give the title compound (38 mg, 43%). MS M/z [ M + H ]]⁺ =266。

Intermediate 8

8-azaspiro [ 4.5 ] decane-8-carboxylic acid tert-butyl ester

Reacting 8-azaspiro [ 4.5 ] at room temperature]Decane hydrochloride (1 g, 7.18 mmol) was added to methylene chloride (10mL), and di-tert-butyl dicarbonate (2.35 g, 10.77 mmol) and potassium carbonate (2.98 g, 21.54 mmol) were successively added with stirring, followed by stirring at room temperature overnight. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (1.41 g, 82%). MS M/z [ M + H-tBu]⁺ =184。

7-formyl-8-azaspiro [ 4.5 ] decane-8-carboxylic acid tert-butyl ester

Tetramethylethylenediamine (0.65 g, 5.56 mmol) and 8-azaspiro [ 4.5 ] are successively reacted at room temperature]Adding tert-butyl decane-8-carboxylate (1.33 g, 5.56 mmol) into anhydrous tetrahydrofuran (10mL), and cooling to-60 deg.C under the protection of argon^oC, a solution of sec-butyllithium in n-hexane (1.3M, 5.56 mL, 7.23 mmol) was added dropwise with stirring, after completion of the addition, 20-degree of dropwise addition^oC stirring for 30 minutes. The reaction solution is cooled to-60 DEG^oC, N-dimethylformamide (610 mg, 8.34 mmol) and 60 percent of N, N-dimethylformamide are added dropwise^oC stirringStir at room temperature for 1 hour and 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (0.132 g, 9%). MS M/z [ M + H-tBu]⁺ =212。

7- (hydroxymethyl) -8-azaspiro [ 4.5 ] decane-8-carboxylic acid tert-butyl ester

At room temperature, 7-formyl-8-azaspiro [ 4.5 ] would]Tert-butyl decane-8-carboxylate (132 mg, 0.49 mmol) was added to anhydrous methanol (10mL), and sodium borohydride (92.68 mg, 2.45 mmol) was added with stirring, followed by stirring at room temperature for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (130 mg, 98%). MS M/z [ M + H-tBu]⁺ =214。

(8- (6-chloro-2-methoxypyrimidin-4-yl) -8-azaspiro [ 4.5 ] decan-7-yl) methanol

Reacting 6- (hydroxymethyl) -7-azaspiro [ 3.5 ] at room temperature]Tert-butyl nonane-7-carboxylate (51 mg, 0.19 mmol) was added to dichloromethane (3 mL), and a solution of hydrogen chloride in ethyl acetate (4M, 0.25 mL) was added with stirring and stirred at room temperature for 3 hours. The reaction mixture was concentrated, and acetonitrile (10mL), 4, 6-dichloro-2-methoxypyrimidine (68 mg, 0.38 mmol), and sodium carbonate (165 mg, 1.56 mmol), 85 mmol) were sequentially added to the residue^oC stirred overnight. The reaction was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (55 mg, 93%). MS M/z [ M + H ]]⁺ =312。

3 '-chloro-6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclopentane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

(8- (6-chloro-2-methoxypyrimidin-4-yl) -8-azaspiro [ 4.5 ] at room temperature]Decan-7-yl) methanol (55 mg, 0.18mmol) was added to methylene chloride (5 mL), and thionyl chloride (64 mg, 0.54 mmol) was added with stirring and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and water (5 mL) and an aqueous solution of sodium hydroxide (15%, 186 mg) were sequentially added to the residue, followed by stirring at room temperature for 0.5 hour. The reaction was extracted with dichloromethane and the organic phase was concentrated to give the title compound (28 mg, 72%). MS M/z [ M + H ]]⁺ =280。

Intermediate 8

2-hydroxy-7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Reacting 2-oxo-7-azaspiro [ 3.5 ] at room temperature]Tert-butyl nonane-7-carboxylate (5 g, 20.89 mmol) was added to methanol (50mL), sodium borohydride (2.37 g, 62.67 mmol) was added with stirring, and the mixture was stirred at room temperature for 5 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (4.93 g, 98%). MS M/z [ M + H-tBu]⁺ =186。

2- ((tert-Butyldimethylsilyl) oxy) -7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Sequentially reacting 2-hydroxy-7-azaspiro [ 3.5 ] at room temperature]Tert-butyl nonane-7-carboxylate (4.83 g, 20.01 mmol) and imidazole (2.72 g, 40.02 mmol) were added to dichloromethane (50mL), tert-butyldimethylchlorosilane (4.52 g, 30.01 mmol) was added with stirring, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to give the title compound (6.8 g, 96%). MS M/z [ M + H-tBu]⁺ =300。

2- ((tert-butyldimethylsilyl) oxy) -6-formyl-7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Tetramethylethylenediamine (0.69 g, 5.91 mmol) and 2- ((tert-butyldimethylsilyl) oxy) -7-azaspiro [ 3.5 ] were successively reacted at room temperature]Adding nonane-7-carboxylic acid tert-butyl ester (2.1 g, 5.91 mmol) into anhydrous tetrahydrofuran (15 mL), and cooling to-60 deg.C under the protection of argon^oC, a solution of sec-butyllithium in n-hexane (1.3M, 4.55 mL, 5.91 mmol) was added dropwise with stirring, after completion of the addition, 20-degree of dropwise addition^oC stirring for 30 minutes. The reaction solution is cooled to-60 DEG^oC, N-dimethylformamide (650 mg, 8.87 mmol) is added dropwise, and-60% is obtained after the addition^oC was stirred for 1 hour and at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (2.2 g, 97%). MS M/z [ M + H-tBu]⁺ =328。

2- (tert-Butyldimethylsilyl) oxy) -6- (hydroxymethyl) -7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Reacting 2- ((tert-butyldimethylsilyl) oxy) -6-formyl-7-azaspiro [ 3.5 ] at room temperature]Tert-butyl nonane-7-carboxylate (310 mg, 0.81 mmol) was added to anhydrous methanol (3 mL), sodium borohydride (91 mg, 2.43 mmol) was added with stirring, the mixture was stirred at room temperature for 3 hours, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (298 mg, 95%). MS M/z [ M + H-tBu]⁺ =330。

(2- ((tert-butyldimethylsilyl) oxy) -7- (6-chloro-2-methoxypyrimidin-4-yl) -7-azaspiro [ 3.5 ] nonan-6-yl) methanol

Reacting 2- (tert-butyldimethylsilyl) oxy) -6- (hydroxymethyl) -7-azaspiro [ 3.5 ] with hydrogen peroxide at room temperature]Tert-butyl nonane-7-carboxylate (296 mg, 0.77 mmol) was added to dichloromethane (10mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. Potassium carbonate (320 mg, 2.31 mmol) was added thereto, and the mixture was stirred at room temperature for 0.5 hour. Filtering the reaction solution, leaching a filter cake by using dichloromethane, and concentrating the filtrate. To the residue were added acetonitrile (5 mL), 4, 6-dichloro-2-methoxypyrimidine (196 mg, 1.06 mmol), and sodium carbonate (169 mg, 1.59 mmol), 85 in that order^oC stirred overnight. The reaction was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (55 mg, 17%). MS M/z [ M + H ]]⁺ =428。

3- ((tert-butyldimethylsilyl) oxy) -3 '-chloro-6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

(2- ((tert-butyldimethylsilyl) oxy) -7- (6-chloro-2-methoxypyrimidin-4-yl) -7-azaspiro [ 3.5 ] ring at room temperature]Nonan-6-yl) methanol (55 mg, 0.13 mmol) and triethylamine (66 mg, 0.26 mmol) were added to dichloromethane (5 mL), and methanesulfonic anhydride (45 mg, 0.26 mmol) was added with stirring and stirred at room temperature for 3 hours. The reaction mixture was poured into water, extracted with dichloromethane, the organic phase was concentrated, and water (5 mL) and an aqueous solution of sodium hydroxide (15%, 123 mg) were sequentially added to the residue, followed by stirring at room temperature for 0.5 hour. The reaction was extracted with dichloromethane and the organic phase was concentrated to give the title compound (18 mg, 41%). MS M/z [ M + H ]]⁺ =396。

3- ((tert-butyldimethylsilyl) oxy) -3'- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

3- ((tert-butyldimethylsilyl) oxy) -3 '-chloro-6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -ketone (17 mg, 0.043 mmol), (3-fluoro-4- (2-trifluoromethyl) pyridin-4-yl) phenyl) methanol (37 mg, 0.13 mmol) and cesium carbonate (42 mg, 0.13 mmol) were added to toluene (5 mL), 110^oC stirred overnight. The reaction was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by preparative thin layer chromatography to give the title compound (23 mg, 83%). MS M/z [ M + H ]]⁺ =647。

Intermediate 9

2-methoxy-7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Reacting 2-oxo-7-azaspiro [ 3.5 ] at room temperature]Tert-butyl nonane-7-carboxylate (5 g, 20.89 mmol) was added to methanol (50mL), sodium borohydride (2.37 g, 62.67 mmol) was added with stirring, and the mixture was stirred at room temperature for 5 hours. The reaction solution was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, acetonitrile (30 mL) and methyl iodide (8.96 g, 62.67 mmol) were sequentially added to the residue, and sodium hydride (60%, 2.51 g, 62.67 mmol) was added with stirring and stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (1.9 g, 36%). MS M/z [ M + H-tBu]⁺ =200。

6-formyl-2-methoxy-7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Tetramethylethylenediamine (1.3 g, 11.16 mmol) and 2-methoxy-7-azaspiro [ 3.5 ] are successively reacted at room temperature]Nonane-7-carboxylic acid tert-butyl ester (1.9 g, 7.44 mmol) was added to anhydrous tetrahydrofuran (20 mL) under argonCooling to-60 deg.C^oC, a solution of sec-butyllithium in n-hexane (1.3M, 8.58 mL, 11.16 mmol) was added dropwise with stirring, after completion of the addition, 20-degree of dropwise addition^oC stirring for 30 minutes. The reaction solution is cooled to-60 DEG^oC, N-dimethylformamide (1.63 g, 22.32 mmol) was added dropwise thereto, and completion of the addition was-60^oC was stirred for 1 hour and at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (0.57 g, 27%). MS M/z [ M + H-tBu]⁺ =228。

6- (hydroxymethyl) -2-methoxy-7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

At room temperature, 6-formyl-2-methoxy-7-azaspiro [ 3.5 ] spiro]Tert-butyl nonane-7-carboxylate (380 mg, 1.34 mmol) was added to anhydrous methanol (5 mL), sodium borohydride (150 mg, 4.02 mmol) was added with stirring, the mixture was stirred at room temperature for 3 hours, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (365 mg, 95%). MS M/z [ M + H-tBu]⁺ =230。

(7- (6-chloro-2-methoxypyrimidin-4-yl) -2-methoxy-7-azaspiro [ 3.5 ] nonan-6-yl) methanol

At room temperature, 6- (hydroxymethyl) -2-methoxy-7-azaspiro [ 3.5 ] spiro]Tert-butyl nonane-7-carboxylate (365 mg, 1.28 mmol) was added to dichloromethane (2 mL), and an ethyl acetate solution of hydrogen chloride (4M, 2 mL) was added with stirring and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and acetonitrile (10mL), 4, 6-dichloro-2-methoxypyrimidine (344 mg, 1.92 mmol), and sodium carbonate (385 mg, 3.63 mmol), 85 mmol) were sequentially added to the residue^oC stirred overnight. The reaction was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (310 mg, 74%). MS m/z [M+H]⁺ =328。

3 '-chloro-3-methoxy-6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

Reacting (7- (6-chloro-2-methoxypyrimidin-4-yl) -2-methoxy-7-azaspiro [ 3.5 ] at room temperature]Nonan-6-yl) methanol (270 mg, 0.82 mmol) was added to methylene chloride (5 mL), and thionyl chloride (118 mg, 0.99 mmol) was added with stirring and stirred at room temperature for 1 hour. The reaction was concentrated, and acetonitrile (5 mL) and potassium carbonate solid (298 mg, 2.16 mmol), 85 were added to the residue in this order^oC stirred overnight. The reaction was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by preparative thin layer chromatography to give the title compound (198 mg, 93%). MS M/z [ M + H ]]⁺ =296。

Intermediate 10

1, 4-dioxa-10-aza-dispiro [ 4.1.5 ]⁷. 1⁵]Tridecane-10-carboxylic acid tert-butyl ester

Reacting 2-oxo-7-azaspiro [ 3.5 ] at room temperature]Nonane-7-carboxylic acid tert-butyl ester (5 g, 20.89 mmol), ethylene glycol (1.94 g, 31.34 mmol) and pyridine 4-methylbenzenesulfonate (1.05 g, 4.18 mmol) were added successively to toluene (50mL) at 120^oC stirred overnight. The reaction solution was concentrated and purified by column chromatography to give the title compound (3.6 g, 61%). MS M/z [ M + H-tBu]⁺ =228。

9-formyl-1, 4-dioxa-10-azadispiro [ 4.1.5 ]⁷. 1⁵]Tridecane-10-carboxylic acid tert-butyl ester

At room temperature, in turnTetramethylethylenediamine (2.15 g, 18.52 mmol) and 1, 4-dioxa-10-azadispiro [ 4.1.5 ]⁷. 1⁵]Tridecane-10-carboxylic acid tert-butyl ester (3.5 g, 12.35 mmol) was added to anhydrous tetrahydrofuran (40mL) and the temperature was reduced to-60 deg.C under argon^oC, a solution of sec-butyllithium in n-hexane (1.3M, 14.25 mL, 18.52 mmol) was added dropwise with stirring, after completion of the addition, 20-degree of dropwise addition^oC stirring for 30 minutes. The reaction solution is cooled to-60 DEG^oC, N-dimethylformamide (2.71 g, 37.05 mmol) was added dropwise thereto, and-60% was added after the end of the addition^oC was stirred for 1 hour and at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (1.23 g, 32%). MS M/z [ M + H-tBu]⁺ =256。

9- (hydroxymethyl) -1, 4-dioxa-10-aza-spiro [ 4.1.5⁷. 1⁵]Tridecane-10-carboxylic acid tert-butyl ester

At room temperature, 9-formyl-1, 4-dioxa-10-aza-dispiro [ 4.1.5 ]⁷. 1⁵]Tridecane-10-carboxylic acid tert-butyl ester

(1.13 g, 3.63 mmol) was added to anhydrous methanol (10mL), sodium borohydride (270 mg, 7.26 mmol) was added with stirring, the mixture was stirred at room temperature for 3 hours, the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with dichloromethane, and the organic phase was concentrated to give the title compound (1.1 g, 97%). MS M/z [ M + H-tBu]⁺ =258。

7- (6-chloro-2-methoxypyrimidin-4-yl) -6- (hydroxymethyl) -7-azaspiro [ 3.5 ] nonan-2-one

At room temperature, 9- (hydroxymethyl) -1, 4-dioxa-10-aza-spiro [ 4.1.5⁷. 1⁵]Tridecyl-10-carboxylic acid tert-butyl ester (1.1 g, 3.51 mmol) is added to dichloromethane (10mL) and a solution of hydrogen chloride in ethyl acetate (4) is added with stirringM, 0.32 mL), stirred at room temperature for 3 hours. The reaction mixture was concentrated, and acetonitrile (10mL), 4, 6-dichloro-2-methoxypyrimidine (942 mg, 5.27 mmol) and sodium carbonate (2.07 g, 19.5 mmol), 85 were added to the residue in this order^oC stirred overnight. The reaction was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (180 mg, 8%). MS M/z [ M + H ]]⁺ =312。

3 '-chloro-6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [1, 8' -pyridine [1', 2': 3, 4)]Imidazole [1, 2-c]Pyrimidines]-1', 3-diketones

At room temperature, 7- (6-chloro-2-methoxypyrimidin-4-yl) -6- (hydroxymethyl) -7-azaspiro [ 3.5%]Nonane-2-one (58 mg, 0.19 mmol) was added to dichloromethane (5 mL), thionyl chloride (67.8 mg, 0.57 mmol) was added with stirring, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and acetonitrile (3 mL) and a solid of potassium carbonate (62 mg, 0.45 mmol), 85 were added to the residue in this order^oC stirred overnight. The reaction was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by preparative thin layer chromatography to give the title compound (37 mg, 88%). MS M/z [ M + H ]]⁺ =280。

3'- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1', 3-diketones

Sequentially reacting 3' -chloro-3-methoxy-6 ', 7', 9a ', 10' -tetrahydro-1 ' at room temperature 'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -keto (33 mg, 0.12 mmol), (3-fluoro-4- (2-trifluoromethyl) pyridin-4-yl) phenyl) methanol (51 mg, 0.18mmol) and cesium carbonate (78 mg, 0.24 mmol) were added to toluene (3 mL), 120^oC stirring overnight. The reaction was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated, and purified by preparative thin layer chromatography to give the title compound (41 mg, 64%). MS M/z [ M + H ]]⁺ =531。

Intermediate 11

2-methoxy-6-vinyl-7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Reacting 6-formyl-2-methoxy-7-azaspiro [ 3.5 ] at room temperature]Adding tert-butyl nonane-7-carboxylate (2.4 g, 8.47 mmol) into anhydrous tetrahydrofuran (80 mL), adding methyl triphenyl phosphonium bromide (3.63 g, 10.16 mmol) under stirring, and cooling to 0 deg.C under the protection of argon^oC, sodium hydride (60%, 1.02 g, 25.41 mmol) was added in portions, and the mixture was stirred at room temperature for 3 hours after the addition. The reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to give the title compound (700 mg, 29%). MS M/z [ M + H-tBu]⁺ =226。

6- (2-hydroxyethyl) -2-methoxy-7-azaspiro [ 3.5 ] nonane-7-carboxylic acid tert-butyl ester

Reacting 2-methoxy-6-vinyl-7-azaspiro [ 3.5 ] at room temperature]Nonane-7-carboxylic acid tert-butyl ester (700 mg, 2.49 mmol) 9-borabicyclo [ 3.3.1]Nonane in tetrahydrofuran (0.5M, 20 mL, 9.96 mmol) was stirred at room temperature overnight. Water (2 mL), an aqueous sodium hydroxide solution (3M, 10mL) and hydrogen peroxide (37%, 10mL) were added to the reaction solution in this order to obtain a reaction solution 50^oC stirred for 2 hours. The reaction solution was cooled to room temperature and then extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain the title compound (750 mg, 100%). MS M/z [ M + H-tBu]⁺=244。

2- (2-methoxy-7-azaspiro [ 3.5 ] nonan-6-yl) ethyl-1-ol hydrochloride

At room temperature, the 6- (2-hydroxyethyl) -2-methoxy-7-azaspiro [ 3.5 ] is reacted]Tert-butyl nonane-7-carboxylate (750 mg, 2.50 mmol) was added to a solution of hydrogen chloride in 1, 4-dioxane (10mL) and stirred at room temperature for 2 hours. The reaction was concentrated to give the crude title compound (590 mg, 100%). MS M/z [ M + H ]]⁺ =200。

2- (7- (2, 6-dichloropyrimidin-4-yl) -2-methoxy-7-azaspiro [ 3.5 ] nonan-6-yl) ethyl-1-ol

Reacting 2- (2-methoxy-7-azaspiro [ 3.5 ] at room temperature]Nonan-6-yl) ethyl-1-ol hydrochloride (570 mg, 2.86 mmol) was added to acetonitrile (10mL), 4, 6-dichloro-2-methoxypyrimidine (512 mg, 2.86 mmol) and sodium carbonate solid (909 mg, 8.58 mmol) were added successively with stirring, and the reaction solution was stirred at room temperature overnight. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (dichloromethane/methanol = 50/1) to obtain the title compound (390 mg, 40%). MS M/z [ M + H ]]⁺ =342。

7- (6-chloro-2-methoxypyrimidin-4-yl) -6- (2-chloroethyl) -2-methoxy-7-azaspiro [ 3.5 ] nonane

Reacting 2- (7- (2, 6-dichloropyrimidin-4-yl) -2-methoxy-7-azaspiro [ 3.5 ] at room temperature]Nonan-6-yl) ethan-1-ol (350 mg, 1.02 mmol) was added to dichloromethane (20 mL) and the temperature was reduced to 0^oC, thionyl chloride (394 mg, 3.06 mmol) was added and stirred under reflux for 2 hours. The reaction was concentrated to give the title compound (350 mg, 95%). MS M/z [ M + H ]]⁺ =360。

2 '-chloro-3-methoxy-6', 7', 7a', 8', 10', 11 '-hexahydro-4'H-spiro [ cyclo-butyl ] sAlkane-1, 9' -pyrido [1, 2-c]Pyrimido [1, 6-a]Pyrimidines]-4' -ketones

Under the protection of argon, 7- (6-chloro-2-methoxypyrimidin-4-yl) -6- (2-chloroethyl) -2-methoxy-7-azaspiro [ 3.5%]Nonane (350 mg, 0.97 mmol) and potassium carbonate (402 mg, 2.91 mmol) were added to acetonitrile (10mL), 85^oC was stirred overnight, the reaction was filtered, the organic phase was concentrated, and column chromatography purification (dichloromethane/methanol = 100/1-50/1) gave the title compound (200 mg, 66%). MS M/z [ M + H ]]⁺ =310。

Intermediate 12

6-Oxopiperidine-2-carboxylic acid

6-oxo-1, 6-dihydropyridine-2-carboxylic acid (10 g, 72 mmol) and palladium on carbon (10%, 1 g) were added to methanol (100 mL) at room temperature and hydrogenated at room temperature under normal pressure overnight. The reaction was filtered, and the filtrate was concentrated to give the title compound (5 g, 50%). LC-MS M/z [ M + H ]]⁺ =144。

6-Oxopiperidinylmethyl-2-carboxylic acid methyl ester

Methanol (10mL) was cooled to 0 under argon^oThionyl chloride (830 mg, 7.7 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 10 minutes. 6-Oxopiperidine-2-carboxylic acid (1 g, 7 mmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and toluene (10mL) and triethylamine (1.4 g, 14 mmol) were sequentially added to the residue, followed by stirring at room temperature for 0.5 hour, the reaction solution was filtered, and the filtrate was concentrated to give the title compound (850 mg, 77%). MS M/z [ M + H ]]⁺ =158。

1-benzyl-6- ((benzyloxy) methyl) piperidin-2-one

Methyl 6-oxopiperidinemethyl-2-carboxylate (850 mg, 5.4 mmol) was added to methanol (10mL) at room temperature, sodium borohydride (307 mg, 8.1 mmol) was slowly added with stirring, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated. The residue was added to dimethyl sulfoxide (20 mL) and cooled to 0 under argon^oSodium hydride (3.6 g, 21 mmol) was added slowly with stirring, and stirred at room temperature for 30 minutes. Benzyl bromide (3.6 g, 21 mmol) was added to the reaction solution and stirred at room temperature overnight. The reaction solution was quenched with water, poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (900 mg, 54%). MS M/z [ M + H ]]⁺=310。

4-benzyl-5- ((benzyloxy) methyl) -4-azaspiro [2.5 ] octane

Under the protection of argon, anhydrous tetrahydrofuran (60 mL) is cooled to-40^oC, a tetrahydrofuran solution of ethylmagnesium bromide (1M, 20 mL, 19.4 mmol) and tetraisopropyl titanate (2 g, 7.2 mmol) were added successively with stirring, and stirred at room temperature for 5 minutes. A solution of 1-benzyl-6- ((benzyloxy) methyl) piperidin-2-one (2.0 g, 6.5 mmol) in anhydrous tetrahydrofuran (1 mL) was added to the reaction solution, and stirred under reflux overnight. The reaction solution was quenched with 10% aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to give the title compound (1.1 g, 53%). MS M/z [ M + H ]]⁺=322。

(4-azaspiro [2.5 ] oct-5-yl) methanolic hydrochloride

At room temperature, 4-benzyl-5- ((benzyloxy) methyl) -4-azaspiro [2.5 ]]Octane (200 mg, 0.6 mmol) and palladium on carbon (10%,30 mg) was added to a solution of hydrogen chloride in ethyl acetate (4M, 5 mL) and methanol (5 mL), 40^oC is hydrogenated under normal pressure overnight. The reaction was filtered and the filtrate was concentrated to give the crude title compound (200 mg, 182%). MS M/z [ M + H ]]⁺ =142。

(4- (2, 6-dichloropyrimidin-4-yl) -4-azaspiro [2.5 ] octyl-5-yl) methanol

At room temperature, (4-azaspiro [2.5 ] is sequentially reacted]Octane-5-yl) methanolate (100 mg, 0.6 mmol), 2,4, 6-trichloropyrimidine (146 mg, 0.8 mmol) and sodium carbonate solid (149 mg, 1.4 mmol) were added to acetonitrile (2 mL) and stirred at room temperature overnight. The reaction was filtered, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (100 mg, 62%). MS M/z [ M + H ]]⁺ =288。

3 '-chloro-8', 9', 9a', 10 '-tetrahydro-1'H, 7'HSpiro [ cyclopropane-1, 6' -pyrido [1', 2': 3,4]Imidazo [1, 2-c]Pyrimidines]-1' -ketones

Reacting (4- (2, 6-dichloropyrimidin-4-yl) -4-azaspiro [2.5 ] at room temperature]Octyl-5-yl) methanol (100 mg, 0.3 mmol) and thionyl chloride (47 mg, 0.4 mmol) were added to dichloromethane (2 mL) and stirred at room temperature overnight. The reaction solution was concentrated, and to the residue were added potassium carbonate solid (83 mg, 0.6 mmol) and acetonitrile (5 mL), 80 in that order^oC stirred overnight. The reaction was cooled to room temperature, filtered, the filtrate was concentrated, and preparative chromatography gave the title compound (80 mg, 100%). MS M/z [ M + H ]]⁺ =252。

Intermediate 13

4-Methylenepiperidine-1-carboxylic acid benzyl ester

At room temperature, methyl triphenyl phosphonium bromide (10 g, 27.8 mmol) is added into anhydrous tetrahydrofuran (30 mL), and the temperature is reduced to 0 degree under the protection of argon^oC, controlling the temperature to be 0^oA tetrahydrofuran solution of n-butyllithium (2.5M, 11 mL, 27.8 mmol), 0, was added dropwise to a volume of up to C^oC stirred for 1 hour. Temperature control 0^oC below, a solution of benzyl 4-oxopiperidine-1-carboxylate (5 g, 21.4 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise to the reaction mixture, 0^oC stirred for 1 hour and then stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (3.8 g, 76%). MS M/z [ M + H ]]⁺ =232。

6-Azaspiro [2.5 ] octane-6-carboxylic acid benzyl ester

Under the protection of argon, dichloromethane (60 mL) is cooled to 0^oC, adding a n-hexane solution (1M, 60 mL, 60 mmol) of diethyl zinc under stirring, and controlling the temperature to be 0^oTrifluoroacetic acid (6.8 g, 60 mmol), 0, was added dropwise to a reaction mixture of C or below^oC stirred for 0.5 hour. Diiodomethane (16 g, 60 mmol) was added to the reaction solution, and stirred at room temperature for 30 minutes. Benzyl 4-methylenepiperidine-1-carboxylate (7 g, 30 mmol) was added to the reaction mixture and reacted at room temperature overnight. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to give the title compound (6.1 g, 82%). MS M/z [ M + H ]]⁺ =246。

6-azaspiro [2.5 ] octane hydrochloride

Reacting 6-azaspiro [2.5 ] at room temperature]Benzyl octane-6-carboxylate (8.3 g, 33.9 mmol) and palladium on carbon (10%, 830 mg) were added to methanol (30 mL) and hydrogenated at room temperature under normal pressure overnight. Filtering the reaction solution, adding 1, 4-dioxane solution (4M, 30 mL) of hydrogen chloride into the filtrate, stirring at room temperature for 30 min, concentrating the reaction solution,tetrahydrofuran (15 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. Filtration and drying of the filter cake afforded the title compound (4.3 g, 86%). MS M/z [ M + H ]]⁺ =112。

6-azaspiro [2.5 ] octane-6-carboxylic acid tert-butyl ester

At room temperature, sequentially reacting 6-azaspiro [2.5 ]]Octane hydrochloride (4.27 g, 29 mmol), triethylamine (6.2 g, 61 mmol) and di-tert-butyl dicarbonate (7 g, 32 mmol) were added to dichloromethane (50mL) and stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography to give the title compound (5.3 g, 87%). MS M/z [ M + H ]]⁺ =212。

5-formyl-6-azaspiro [2.5 ] octane-6-carboxylic acid tert-butyl ester

Reacting 6-azaspiro [2.5 ] at room temperature]Adding octane-6-carboxylic acid tert-butyl ester (400 mg, 1.9 mmol) into anhydrous tetrahydrofuran (5 mL), and cooling to-78 under the protection of argon^oC, controlling the temperature to be-50 DEG^oC, tetramethylethylenediamine (660 mg, 5.7 mmol) and a sec-butyllithium n-hexane solution (1.3M, 2.2 mL, 2.9 mmol) were sequentially added dropwise thereto to prepare a solution, 30 mol^oC stirring for 15 minutes. Cooling to-78 deg.C^oN, N-dimethylformamide (416 mg, 5.7 mmol) was added dropwise thereto, and the mixture was stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography to give the title compound (110 mg, 24%). MS M/z [ M + H ]]⁺=240。

5- (hydroxymethyl) -6-azaspiro [2.5 ] octane-6-carboxylic acid tert-butyl ester

At the room temperature, the reaction kettle is used for heating,reacting 5-formyl-6-azaspiro [2.5 ]]Tert-butyl octane-6-carboxylate (110 mg, 0.46 mmol) was added to anhydrous ethanol (5 mL), and sodium borohydride solid (17 mg, 0.46 mmol) was added with stirring and stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (110 mg, 100%). MS M/z [ M + H ]]⁺ =242。

(6- (2, 6-dichloropyrimidin-4-yl) -6-azaspiro [2.5 ] octyl-5-yl) methanol

Reacting 5- (hydroxymethyl) -6-azaspiro [2.5 ] at room temperature]Tert-butyl octane-6-carboxylate (360 mg, 1.5 mmol) was added to a solution of hydrogen chloride in ethyl acetate (4M, 5 mL) and dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and sodium carbonate solid (318 mg, 3.0 mmol), 2,4, 6-trichloropyrimidine (366 mg, 3.0 mmol) and acetonitrile (5 mL) were sequentially added to the residue, followed by stirring at room temperature overnight. The reaction was filtered, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (260 mg, 60%). MS M/z [ M + H ]]⁺ =288。

3 '-chloro-6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclopropane-1, 8' -pyridinyl [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

At room temperature, (6- (2, 6-dichloropyrimidin-4-yl) -6-azaspiro [ 2.5)]Octyl-5-yl) methanol (160 mg, 0.6 mmol) and thionyl chloride (1 mL) were added to dichloromethane (1 mL) and stirred at room temperature overnight. The reaction was concentrated, and to the residue were added solid potassium carbonate (230 mg, 1.7 mmol) and acetonitrile (5 mL) in this order, followed by stirring at reflux overnight. The reaction was cooled to room temperature, filtered, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (80 mg, 50%). MS M/z [ M + H ]]⁺ =252。

Intermediate 14

8-formyl-3-oxa-9-azaspiro [ 5.5 ] undecane-9-carboxylic acid tert-butyl ester

Reacting 3-oxa-9-azaspiro [ 5.5 ] at room temperature]Tert-butyl undecane-9-carboxylate (750 mg, 2.94 mmol) and tetramethylethylenediamine (0.51 g, 4.41 mmol) were added to tetrahydrofuran (10mL) and the temperature was reduced to-60 deg.C under argon^oC, dropwise adding a n-hexane solution (1.3M, 4.5 mL, 5.88 mmol) of sec-butyllithium and-50^oStirring for 1 hr, adding N, N-dimethylformamide (0.32 g, 4.41 mmol), -50^oC was stirred for 1 hour and at room temperature for 1 hour. The reaction solution was quenched with a saturated aqueous ammonium chloride solution, poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the title compound (340 mg, 41%). MS M/z [ M + H-Boc]⁺ =184。

8- (hydroxymethyl) -3-oxa-9-azaspiro [ 5.5 ] undecane-9-carboxylic acid tert-butyl ester

Reacting 8-formyl-3-oxa-9-azaspiro [ 5.5 ] at room temperature]Tert-butyl undecane-9-carboxylate (340 mg, 1.2 mmol) was added to tetrahydrofuran (10mL), and sodium borohydride (40 mg, 1.2 mmol) was added with stirring, followed by stirring at room temperature for 0.5 hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (340 mg, 99%). MS M/z [ M + H-Boc]⁺ =186。

(9- (6-chloro-2-methoxypyrimidin-4-yl) -3-oxa-9-azaspiro [ 5.5 ] undecan-8-yl) methanol

Reacting 8- (hydroxymethyl) -3-oxa-9-azaspiro [ 5.5 ] with water at room temperature]Undecane-9-carboxylic acid tert-butyl ester (340 mg, 1.2 mmol) was addedInto trifluoroacetic acid (1 mL) and dichloromethane (4 mL), stirred at room temperature for 5 minutes. The pH of the reaction system was adjusted to 8-9 with sodium carbonate solid. The reaction mixture was concentrated, and 4, 6-dichloro-2-methoxypyrimidine (0.32 g, 1.78 mmol), sodium carbonate (0.63 g, 5.95 mmol) and acetonitrile (30 mL) were added to the residue in this order to obtain 85%^oC stirred overnight. The reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (dichloromethane/methanol = 20/1) to obtain the title compound (210 mg, 54%). MS M/z [ M + H ]]⁺ =328。

3 '-chloro-2, 3, 5, 6, 6', 7', 9a', 10 '-octahydro-1'H, 9'HSpiro [ pyran-4, 8' -pyrido [1', 2': 3, 4]]Imidazo [1, 2-c]Pyrimidines]-1' -ketones

Reacting (9- (6-chloro-2-methoxypyrimidin-4-yl) -3-oxa-9-azaspiro [ 5.5 ] at room temperature]Undecane-8-yl) methanol (141 mg, 0.43 mmol) and triethylamine (0.13 g, 1.29 mmol) were added to dichloromethane (12 mL), and methanesulfonyl anhydride (74 mg, 0.65 mmol) was added with stirring and stirred at room temperature for 20 minutes. The pH of the reaction solution was adjusted to 8-9 with sodium carbonate solid. The reaction solution was concentrated, and to the residue were added water (8 mL) and potassium carbonate (0.29 g, 2.1 mmol) in this order. Stirred at room temperature for 30 minutes. Dichloromethane extraction, organic phase concentration, preparative thin layer chromatography (dichloromethane/methanol = 20/1) afforded the title compound (60 mg, 47%). MS M/z [ M + H ]]⁺=296。

Intermediate 15

1- (tert-butyl) 4-ethyl-4-methylpiperidine-1, 4, 4-tricarboxylic acid

At room temperature, 1- (tert-butyl) 4-ethylpiperidine-1, 4-dicarboxylate (45.0 g, 175.1 mmol) was added to anhydrous tetrahydrofuran (180 mL) and the temperature was reduced to-60 ℃ under argon protection^oC, adding lithium diisopropylamide solution in tetrahydrofuran/n-heptane (2M, 131 mL, 262 mmol) under stirring, 60-^oC stirring for 0.5 h, adding methyl chloroformate (18.2 g, 192.6 mmol), -60^oC stirring for 30 minutes, room temperature stirring for two hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the title compound (41 g, 91%). MS M/z [ M + H-Boc]⁺ =216。

4, 4-bis (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester

1- (tert-butyl) 4-ethyl 4-methylpiperidine-1, 4, 4-tricarboxylic acid (10.0 g, 31.7 mmol) was added to tetrahydrofuran (50mL) and methanol (50mL) at room temperature, and the reaction was warmed to 50 deg.C^oC, controlling the temperature by 50^oC-60 ^oC sodium borohydride (6.0 g, 158.5 mmol), 60 portions were added^oC stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution, poured into water, extracted with ethyl acetate and the organic phase concentrated to give the crude title compound (8 g, 103%). MS M/z [ M + H-Boc]⁺ =146。

4, 4-bis (((tert-butyldimethylsilyl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4, 4-bis (hydroxymethyl) piperidine-1-carboxylate (45.0 g, 183 mmol) and imidazole (37.9 g, 549 mmol) were added sequentially to dichloromethane (100 mL) at room temperature, tert-butyldimethylchlorosilane (55.2 g, 366 mmol) was added with stirring, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the title compound (66 g, 77%). MS M/z [ M + H-Boc]⁺ =373。

4, 4-bis (((tert-butyldimethylsilyl) oxy) methyl) -2-formylpiperidine-1-carboxylic acid tert-butyl ester

At room temperature, tert-butyl 4, 4-bis (((tert-butyldimethylsilyl) oxy) methyl) piperidine-1-carboxylate (20.0 g, 42.28 mmol) and tetramethylethylenediamine (7.35 g, 64.42 mmol) were added to anhydrous tetrahydrofuran (120 mL) and the temperature was reduced to-60 ℃ under argon^oC, controlling the temperature to be-50 DEG^oA cyclohexane solution of sec-butyllithium (1.3M, 71.5 mL, 93.0 mmol) was added dropwise to a volume of 50 ℃ C^oStirring for 1 hr, adding N, N-dimethylformamide (4.56 g, 63.42 mmol), -50^oC, stirring for 1h, and stirring for 2h at room temperature. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the title compound (12 g, 57%). MS M/z [ M + H-Boc]⁺=402。

(4, 4-bis (((tert-butyldimethylsilyl) oxy) methyl) piperidin-2-yl) methanol

Tert-butyl 4, 4-bis (((tert-butyldimethylsilyl) oxy) methyl) -2-formylpiperidine-1-carboxylate (4.0 g, 8.0 mmol) was added to a solution of trifluoroacetic acid in dichloromethane (10%, 40mL) at room temperature and stirred for 5 minutes at room temperature. The reaction solution is adjusted to 8-9 by potassium carbonate solid, filtered, and the filtrate is concentrated. The residue was added to methanol (20 mL), and sodium borohydride (907 mg, 24.0 mmol) was added with stirring, followed by stirring at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution, poured into water, extracted with ethyl acetate and the organic phase concentrated to give the crude title compound (4 g, 124%). MS M/z [ M + H ]]⁺ =404。

(4, 4-bis (((tert-butyldimethylsilyl) oxy) methyl) -1- (6-chloro-2-methoxypyrimidin-4-yl) piperidin-2-yl) methanol

Crude (3.0 g, 7.44 mmol) of (4, 4-bis (((tert-butyldimethylsilyl) oxy) methyl) piperidin-2-yl) methanol, 4, 6-dichloro-2-methoxypyrimidine (1.32 g, 7.44 mmol) and sodium carbonate solid (1.58 g, 14.88 mmol) were added to acetonitrile (30 mL) at room temperature, 90^oC stirred overnight. Filtration, concentration of the filtrate, and column chromatography purification (petroleum ether/ethyl acetate = 10/1-5/1) yielded the title compound (1 g, 25%). MS M/z [ M + H ]]⁺ =546。

8, 8-bis (((tert-butyldimethylsilyl) oxy) methyl) -3-chloro-6, 7, 8, 9, 9a, 10-hexahydro-1-ylH-pyrido [1', 2': 3,4]Imidazole [1, 2-c]Pyrimidin-1-ones

(4, 4-bis (((tert-butyldimethylsilyl) oxy) methyl) -1- (6-chloro-2-methoxypyrimidin-4-yl) piperidin-2-yl) methanol (1.0 g, 2.0 mmol) was added to methylene chloride (20 mL) at room temperature, and triethylamine (303 mg, 3.0 mmol) and methanesulfonyl chloride (273 mg, 2.4 mmol) were successively added to the reaction mixture with stirring and stirred at room temperature for 20 minutes. The reaction solution was concentrated, water (16 mL) was added to the residue, and the pH of the system was adjusted to 9-10 with solid potassium carbonate while stirring, and the mixture was stirred at room temperature for 30 minutes. Dichloromethane extraction, concentration of the organic phase and column chromatography purification (dichloromethane/methanol = 20/1) gave the title compound (450 mg, 48%). MS M/z [ M + H ]]⁺ =514。

8, 8-bis (((tert-butyldimethylsilyl) oxy) methyl) -3- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -6, 7, 8, 9, 9a, 10-hexahydro-1-yl)H-pyrido [1', 2': 3,4]Imidazo [1, 2-c]Pyrimidin-1-ones

Sequentially reacting 8, 8-bis (((tert-butyldimethylsilyl) oxy) methyl) -3-chloro-6, 7, 8, 9, 9a, 10-hexahydro-1 at room temperatureH-pyrido [1', 2': 3,4]imidazole [1, 2-c]Pyrimidin-1-one (450 mg, 0.88 mmol), (3-fluoro-4- [ (2- (trifluoromethyl) pyridin-4-yl) oxy)]Phenyl) methanol (0.28 g, 0.97 mmol) and cesium carbonate (0.86 g, 2.64 mmol) were added to toluene (20 mL) at 110^oC stirred overnight. The reaction solution was concentrated and poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (dichloromethane/methanol = 20/1) to obtain the title compound (670 mg, 99%). MS M/z [ M + H ]]⁺ =765。

3- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -8, 8-bis (hydroxymethyl) -6, 7, 8, 9, 9a, 10-hexahydro-1H-pyrido [1', 2': 3,4]Imidazo [1, 2-c]Pyrimidin-1-ones

Reacting 8, 8-bis (((tert-butyldimethylsilyl) oxy) methyl) -3- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -6, 7, 8, 9, 9a, 10-hexahydro-1-yl) oxy at room temperatureH-pyrido [1', 2': 3,4]Imidazo [1, 2-c]Pyrimidin-1-one (670 mg, 0.88 mmol) was added to anhydrous tetrahydrofuran (10mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (1M, 2.2 mL, 2.2 mmol) was added with stirring, followed by stirring at room temperature for 1 hour. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (dichloromethane/methanol = 20/1-10/1) to obtain the title compound (350 mg, 74%). MS M/z [ M + H ]]⁺ =537。

(3- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -8- (hydroxymethyl) -1-oxo-6, 7, 8, 9, 9a, 10-hexahydro-1H-pyrido [1', 2': 3,4]Imidazo [1, 2-c]Pyrimidin-8-yl) methanesulfonic acid methyl ester

Reacting 3- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -8, 8-bis (hydroxymethyl) -6, 7, 8, 9, 9a, 10-hexahydro-1-yl) oxy at room temperatureH-pyrido[1', 2': 3, 4]Imidazo [1, 2-c]Adding pyrimidine-1-ketone (100 mg, 0.19 mmol) into dichloromethane (10mL), and cooling to 0 under the protection of argon^oC, triethylamine (23.07 mg, 0.23 mmol) and a solution of methanesulfonyl chloride (13.06 mg, 0.11 mmol) in dichloromethane (1 mL) were added successively with stirring, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was concentrated, and preparative thin layer chromatography (dichloromethane/methanol = 10/1) gave the title compound (60 mg, 51%). MS M/z [ M + H ]]⁺ =615。

Intermediate 16

5-formyl-2- (3- (trifluoromethyl) phenoxy) benzonitrile

2-fluoro-5-formylbenzonitrile (15.0 g, 0.1 mol), 3- (trifluoromethyl) phenol (16.0 g, 0.1 mol) and potassium carbonate (13.8 g, 0.1 mol) were added to DMF (100 mL) at room temperature, 105^oC was stirred for 8 hours, the reaction was poured into water, extracted with dichloromethane, the organic phase was concentrated, ethanol (50mL) was added to the residue, stirred at room temperature for 30 minutes, filtered, and the filter cake was concentrated to dryness to give the title compound (22.1 g, 76%).¹H NMR(400 MHz, DMSO-d ₆)d 9.96(s, 1 H), 8.49(s, 1 H), 8.14(br.s, 1 H), 7.88(d, 2 H), 7.47(d, 2 H), 7.19(d, 1 H)。

5- (hydroxymethyl) -2- (3- (trifluoromethyl) phenoxy) benzonitrile

5-formyl-2- (3- (trifluoromethyl) phenoxy) benzonitrile (24.3 g, 83.44 mmol) was added to methanol (250 mL) at room temperature, sodium borohydride (4.86 g, 127.9 mmol) was added in portions, and the reaction was carried out at room temperature for 0.5 hour. The reaction was poured into water, extracted with dichloromethane and the organic phase was concentrated to give the title compound (24.2 g, 99%).¹H NMR(400 MHz, DMSO-d ₆)d 7.80(s, 1 H), 7.73 - 7.53(m, 3 H), 7.52 - 7.27(m, 2 H), 7.09(br.s, 1 H), 5.41(s, 1 H), 4.51(s, 2 H)。

Referring to the following table, the following intermediates 17 to 23 were prepared according to the preparation method of intermediate 16 using the compounds described in the column "raw materials" as raw materials.

Intermediate 24

4- (benzyloxy) -2- (trifluoromethoxy) pyridine

4- (benzyloxy) pyridin-2-ol (1.91 g, 9.48 mmol) and 1-trifluoromethyl-1, 2-phenyliodoyl-3 (b)H) -ketone (1 g, 3.16 mmol) was added to nitromethane (25 mL) and stirred at 100 ℃ overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to give the title compound (530 mg, 47%). MS M/z [ M + H ]]⁺ =270。

2- (trifluoromethoxy) pyridin-4-ol

4- (benzyloxy) -2- (trifluoromethoxy) pyridine (530 mg, 1.97 mmol) and Pd/C (10%, 125 mg) were added to methanol (20 mL) and stirred overnight at 60 ℃ under hydrogen at a pressure of 3 bar. The reaction was filtered and the filtrate was concentrated to give the crude title compound (330 mg, 94%). MS M/z [ M + H ]]⁺ =180。

(3, 5-difluoro-4- ((2- (trifluoromethoxy) pyridin-4-yl) oxy) phenyl) methanol

3,4, 5-Trifluorobenzaldehyde (294.4 mg, 1.84 mol), 2- (trifluoromethoxy) pyridin-4-ol (330 mg, 1.84 mol) and potassium carbonate (330.6 mg, 2.39 mol) were added to DMF (10mL), stirred at 120 ℃ for 2 hours, the reaction was poured into water, extracted with ethyl acetate, the organic phase was concentrated to give a crude 3, 5-difluoro-4- ((2- (trifluoromethoxy) pyridin-4-yl) oxy) benzaldehyde, which was added to ethanol (250.0 mL), sodium borohydride (69.61 mg, 1.84 mmol) was added and stirred at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated by drying to give the title compound (400 mg, 68%).¹H NMR(400 MHz，DMSO-d ₆)d 8.30(d，J = 5.9 Hz，1 H)，7.29(d，J = 9.3 Hz，2 H)，7.07(d，J = 3.9 Hz，1 H)，6.95(s，1 H)，5.56(br. s.，1 H)，4.56(d，J = 4.9 Hz，2 H); MS: m/z [M+H]⁺ =322。

Intermediate 25

4- (4-chloro-3- (trifluoromethyl) phenoxy) benzaldehyde

2-chloro-5-hydroxytrifluoromethylene (15 g, 76.53 mmol), 4-fluorobenzaldehyde (9.50 g, 76.53 mmol) and potassium carbonate (21.12 g, 153.06 mmol) were added to DMF (150 mL), stirred at 120 ℃ overnight, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 50/1-5/1) to give the title compound (14.6 g, 64%). MS M/z [ M + H ]]⁺ =301。

1-chloro-2- (trifluoromethyl) -4- (4-vinylphenoxy) benzene

4- (4-chloro-3- (trifluoromethyl) phenoxy) benzaldehyde (14.6 g, 48.67 mmol), methyltriphenylphosphonium bromide (19.12 g, 53.53 mmol) were added to THF (150 mL) and the temperature was reduced to 0 deg.C under argon^oC, slowly stirringSodium hydride (60%, 9.73 g, 243.35 mmol) was added slowly and stirred at room temperature overnight. The reaction was quenched with water, poured into ice water, extracted with dichloromethane, the organic phase was concentrated and purified by column chromatography (petroleum ether/ethyl acetate = 50/1-5/1) to give the title compound (13.6 g, 94%). MS M/z [ M + H ]]⁺ =299。

2- (4- (4-chloro-3- (trifluoromethyl) phenoxy) phenyl) ethyl-1-ol

At room temperature, 1-chloro-2- (trifluoromethyl) -4- (4-vinylphenoxy) benzene (13.6 g, 45.48 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL) and the temperature was reduced to 0^oC adding 9-borabicyclo [ 3.3.1 ]]Nonane in tetrahydrofuran (0.5M, 136 mL, 68.00 mmol) was stirred at room temperature overnight. To the reaction mixture were added water (14 mL), an aqueous sodium hydroxide solution (3M, 70 mL) and hydrogen peroxide (30%, 70 mL) in this order, and the mixture was stirred at 50 ℃ for 2 hours. The reaction solution was quenched with saturated aqueous sodium thiosulfate solution and poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (dichloromethane/methanol = 30/1) to obtain the title compound (10.6 g, 74%). MS M/z [ M + H ]]⁺ =317。

Intermediate 26

4-bromo-2- (difluoromethyl) pyridine

4-Bromopyridinecarboxaldehyde (10 g, 53.76 mmol) was added to dichloromethane (100 mL) and the temperature was reduced to 0^oC. Diethylaminosulfur trifluoride (17.3 g, 107.52 mmol) was added dropwise to the reaction mixture with stirring, and the mixture was stirred at room temperature overnight. The reaction was slowly dropped into water, extracted with dichloromethane and the organic phase was concentrated to give the crude title compound which was used directly in the next reaction. MS M/z [ M + H ]]⁺ =208。

2- (difluoromethyl) -4-methoxypyridine

4-bromo-2- (difluoromethyl) pyridine (11.18 g, 53.76 mmol), sodium methoxide (5.81 g, 107.52 mmol) were added to methanol (100 mL). 90^oC stirred overnight. The reaction mixture was cooled to room temperature and poured into water (300 mL) and extracted with ethyl acetate. The organic phase was concentrated to give the crude title compound which was used directly in the next reaction. MS M/z [ M + H ]]⁺ =160。

2- (difluoromethyl) pyridin-4-ol

2- (difluoromethyl) -4-methoxypyridine (9.54 g, 59.95 mmol) was added to hydrobromic acid (40% aq, 58 mL). 90^oC stirring for 2 days. The reaction solution was concentrated, the residue was diluted with water, and sodium bicarbonate solid was added with stirring until no air bubbles were generated in the system, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-1/1) to obtain the title compound (2.5 g, 26% of three-step total yield). MS M/z [ M + H ]]⁺ =146。

4- ((2- (difluoromethyl) pyridin-4-yl) oxy) -3-fluorobenzaldehyde

3, 4-Difluorobenzaldehyde (350 mg, 2.46 mmol), 2- (difluoromethyl) pyridin-4-ol (357 mg, 2.46 mmol), and solid potassium carbonate (1019 mg, 7.38 mmol) were added to N, N-dimethylformamide (5 mL) and 120^oC stirred for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and preparative thin layer chromatography gave the title compound (510 mg, 78%). MS M/z [ M + H ]]⁺ =268。

(4- ((2- (difluoromethyl) pyridin-4-yl) oxy) -3-fluorophenyl) methanol

4- ((2- (difluoromethyl) pyridin-4-yl) oxy) -3-fluorobenzaldehyde (505 mg, 1.89 mmol) was added to anhydrous ethanol (5 mL) and NaBH was added with stirring₄₍140 mg, 3.78 mmol), stirred at room temperature for 2 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the organic phase was concentrated to give the title compound (381 mg, 75%). MS M/z [ M + H ]]⁺ =271。

Examples

Example 1

Method A

3'- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclopropane-1, 8' -pyrido [1', 2': 3,4]Imidazo [1, 2-c]Pyrimidines]-1' -ketones

Reacting 3' -chloro-6 ', 7', 9a ', 10' -tetrahydro-1 ' at room temperature 'H, 9'HSpiro [ cyclopropane-1, 8' -pyridinyl [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -ketone (30 mg, 0.12 mmol), (3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) phenyl) methanol (50 mg, 0.17 mmol) and sodium hydride (7 mg, 0.18mmol) were added to acetonitrile (5 mL) and stirred at room temperature for 1 hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution, poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by preparative thin layer chromatography to give the title compound (9 mg, 15%).¹H NMR(400 MHz, CDCl₃)d 8.56(d, J = 5.4 Hz, 1 H), 7.32(d, J = 11.2 Hz, 1 H), 7.28 - 7.14(m, 3 H), 6.95(d, J = 3.4 Hz, 1 H), 5.43(s, 2 H), 5.04(s, 1 H), 4.35 - 4.13(m, 1 H), 4.01 - 3.84(m, 1 H), 3.67(dd, J = 7.3, 11.2 Hz, 1 H), 3.53(dd, J = 3.9, 12.7 Hz, 1 H), 3.22 - 3.07(m, 1 H), 2.09 - 1.92(m, 2 H), 1.11(d, J = 12.7 Hz, 1 H), 0.88(d, J = 12.7 Hz, 1 H), 0.53 - 0.38(m, 4 H); MS: m/z [M+H]⁺=503。

Example 2

Method B

3'- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -8', 9', 9a', 10 '-tetrahydro-1'H, 7'HSpiro [ cyclopropane-1, 6' -pyridine [1', 2': 3,4]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

Reacting 3' -chloro-8 ', 9', 9a ', 10' -tetrahydro-1 ' at room temperature 'H, 7'HSpiro [ cyclopropane-1, 6' -pyrido [1', 2': 3,4]Imidazo [1, 2-c]Pyrimidines]-1' -one (80 mg, 0.3 mmol), (3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) phenyl) methanol (86 mg, 0.3 mmol) and cesium carbonate solid (195 mg, 0.6 mmol) were added to toluene (10mL), 100^oC stirred overnight. The reaction was filtered, the filtrate was concentrated, and preparative thin layer chromatography gave the title compound (50 mg, 33%).¹H NMR(400 MHz, CDCl₃)d 8.55(d, J = 5.4 Hz, 1 H), 7.34(d, J = 10.8 Hz, 1 H), 7.27 - 7.25(m, 1 H), 7.23 - 7.12(m, 2 H), 6.95(d, J = 5.4 Hz, 1 H), 5.41(s, 2 H), 5.35(s, 1 H), 3.94 - 3.84(m, 3 H), 2.04(t, J = 12.5 Hz, 1 H), 1.85(br. s., 1 H), 1.79 - 1.71(m, 1 H), 1.53(br. s., 1 H), 1.41 - 1.29(m, 1 H), 1.20 - 1.13(m, 1 H), 0.96 - 0.84(m, 2 H), 0.78 - 0.68(m, 1 H), 0.58 - 0.48(m, 1 H); MS: m/z [M+H]⁺ =503。

Example 3

Method C

3'- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -6', 7', 9a', 10 '-tetrahydro-1'H, 9 'HSpiro [ oxetane-3, 8' -pyrido [1', 2': 3,4]Imidazo [1, 2-c]Pyrimidines]-1' -ketones

(3- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -8- (hydroxymethyl) -1-oxo-6, 7, 8, 9, 9a, 10-hexahydro-1-yl) oxyH-pyrido [1', 2': 3,4]Imidazo [1, 2 ] s-c]Pyrimidin-8-yl) methanesulfonic acid methyl ester (60 mg, 0.098 mmol) was added to anhydrous tetrahydrofuran (20 mL), and sodium hydride (60%, 19.6 mg, 0.49 mmol), 50 mmol) was added^oC stirred for 24 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution, poured into water, extracted with ethyl acetate, the organic phase was concentrated, and preparative thin layer chromatography (dichloromethane/methanol = 10/1) gave the title compound (15 mg, 30%).¹H NMR(400 MHz, CDCl₃)d 8.58(d, J = 5.4 Hz, 1 H), 7.33(d, J = 11.2 Hz, 1 H), 7.24(d, J = 9.3 Hz, 2 H), 7.22 - 7.16(m, 1 H), 6.96(d, J = 5.4 Hz, 1 H), 5.46(s, 2 H), 5.05(s, 1 H), 4.69 - 4.52(m, 2 H), 4.43(s, 2 H), 4.33 - 4.17(m, 1 H), 3.74(d, J = 7.3 Hz, 2 H), 3.62 - 3.49(m, 1 H), 3.15 - 2.93(m, 1 H), 2.44(d, J = 12.2 Hz, 1 H), 2.26(d, J = 12.7 Hz, 1 H), 1.74(br. s., 1 H), 1.64 - 1.56(m, 1 H); MS: m/z [M+H]⁺ =519。

Example 4

Method D

3'- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -3-hydroxy-6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

3- ((tert-butyldimethylsilyl) oxy) -3' - ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -6', 7', 9a ', 10' -tetrahydro-1 ' was reacted at room temperature 'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -Ketone (16 mg, 0.026 mmol) was added to anhydrous tetrahydrofuran (2 mL), tetrabutylammonium fluoride (20.39 mg, 0.078 mmol) was added with stirring, and stirred at room temperature for 5 hours. The reaction was poured into water, extracted with dichloromethane, the organic phase was concentrated, and purified by preparative thin layer chromatography to give the title compound (5.5 mg, 40%).¹H NMR(400 MHz, CDCl₃)d 8.57(d, J = 5.4 Hz, 1 H), 7.32(d, J = 10.8 Hz, 1 H), 7.25 - 7.14(m, 3 H), 6.95(d, J = 4.4 Hz, 1 H), 5.42(s, 2 H), 5.02(s, 1 H), 4.48 - 4.33(m, 1 H), 4.26 - 4.15(m, 1 H), 3.82(br. s., 1 H), 3.72 - 3.63(m, 1 H), 3.42(d, J = 10.3 Hz, 1 H), 3.15 - 2.99(m, 1 H), 2.44(d, J = 5.4 Hz, 1 H), 2.25(d, J = 4.9 Hz, 1 H), 2.04(br. s., 1 H), 1.92(d, J = 13.2 Hz, 1 H), 1.72 - 1.62(m, 4 H); MS: m/z [M+H]⁺ =533。

Example 5

Method E

3-amino-3 '- ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -6', 7', 9a', 10 '-tetrahydro-1'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1' -ketones

3' - ((3-fluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzyl) oxy) -6', 7', 9a ', 10' -tetrahydro-1 ' at room temperature 'H, 9'HSpiro [ cyclobutane-1, 8' -pyridine [1', 2': 3, 4]]Imidazole [1, 2-c]Pyrimidines]-1', 3-dione (33 mg, 0.12 mmol) and methylamine hydrochloride (13 mg, 0.2 mmol) were added to methanol (3 mL), and sodium cyanoborohydride (21 mg, 0.33 mmol) was added with stirring and stirred at room temperature overnight. The reaction was quenched with water, extracted with dichloromethane, the organic phase concentrated and purified by preparative thin layer chromatography to give the title compound (9 mg, 25%).¹H NMR(400 MHz, CDCl₃)d 8.58 (d, J = 5.4 Hz, 1 H), 7.33 (d, J = 10.8 Hz, 1 H), 7.27 - 7.25 (m, 1 H), 7.23 - 7.15 (m, 2 H), 6.97 (br. s., 1 H), 5.42 (br. s., 2 H), 5.05 (s, 1 H), 4.29 - 4.19 (m, 1 H), 3.83 (br. s., 1 H), 3.76 - 3.61 (m, 2 H), 3.51 (d, J = 12.2 Hz, 1 H), 3.16 - 2.97 (m, 1 H), 2.58 (br. s., 3 H), 2.52 - 2.34 (m, 3 H), 2.30 - 2.16 (m, 2 H), 2.12 - 1.97 (m, 2 H), 1.67 - 1.59 (m, 1 H); MS: m/z [M+H]⁺ =546。

Examples 6-34, listed in the table below, were prepared by a procedure similar to that described for examples 1-5, starting from the corresponding intermediates:

biological testing and data

The compound of the invention is Lp-PLA₂Inhibitors useful for the treatment and prevention of Lp-PLA₂A mediated disease. The compounds of the inventionBiological activity of the compounds can be determined using the compounds as Lp-PLA₂Any suitable test for the activity of the inhibitor, as well as tissue and in vivo models.

The biological activity data for each compound is reported as the average of at least one experiment or a plurality of experiments. It is to be understood that the data described herein may vary reasonably depending on the particular conditions and methods used by the person carrying out the experiment.

Lipoprotein-associated phospholipase A2 (Lp-PLA)₂) And (4) human plasma assay.

Human plasma assays utilize thioester analogs of PAF (phosphatidylcholine), where hydrolysis results in the formation of phospholipids containing free sulfhydryl groups. The amount of thiol groups was continuously determined by reaction with CPM (7-diethylamino-3- (4' -maleimidophenyl) -4-methylcoumarin), a maleimide that increases in fluorescence upon Michael addition of thiol groups. The assay can detect Lp-PLA in human plasma₂Such as by Lp-PLA₂Specific inhibition of the inhibitor was determined.

The Thio-PAF assay was performed as a 75 μ L quench assay. Compound source plates were prepared by preparing 1:3 (volume) serial dilutions of each compound in pure DMSO on 96-well microtiter plates. Compounds on the source plate were diluted 20-fold by transferring 3 μ Ι _ of compound on the compound source plate by a Rainin multi-channel pipette into a 96-well microplate to which 57 μ Ι _ of assay buffer was previously added. The test buffer contained a composition of 50mM HEPES, pH 7.4, 150mM NaCl, 1mM CHAPS. Compounds after 20-fold dilution were transferred 1 μ L by a Rainin multichannel pipettor into 96-well Greiner 655076 (black) microtiter plates to which 40 μ L pooled human plasma was added in pre-aliquotted and thawed. The plate was shaken on a microplate shaker for 20 seconds and mixed well. After 30 min pre-incubation at room temperature, 10. mu.L of a substrate solution containing 2.5mM 2-thio-PAF [ from ethanol stock solution ] in assay buffer consisting of 50mM HEPES, pH 7.4, 150mM NaCl, 1mM CHAPS was added to a 96-well Greiner 655076 (black) microplate by a Rainin multichannel pipettor]32 μ M CPM from DMSO stock solution]And 3.2mM NEM (N-ethylmaleimide) [ freshly prepared in DMSO for each experimentPrepare for]. After 2 min, the reaction was quenched with 25 μ L of 5% aqueous trifluoroacetic acid (TFA). Plates were centrifuged at 2000rpm for 1 min. The plate was read ex:380/em:485 using a Biotek Synergy H1(H1MF) plate reader. IC Using GraphPad Prism 6.0 and Excel₅₀Data, curves and QC analysis.

EXAMPLES measurement of Activity

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

wherein

m is 1 or 2;

n, u are independently 0,1 or 2;

q is-O-, -S-or-NR_a-；

R₁is H, halogen, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl, R₁Optionally substituted with one or more of the following substituents: halogen, cyano, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl;

p is 2, 3,4, 5 or 6;

R₂，R_x，R_yindependently selected from the following substituents: h, halogen, hydroxy, carboxy, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-to 8-memberedHeterocyclic radical, C_6-10Aryl, 3-8 membered heteroaryl, -C (O) NR_bR_c，-S(O)₂NR_bR_cAnd optionally substituted with one or more of the following substituents: halogen, cyano, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl or 3-8 membered heteroaryl;

at p independent R₂On the substituted ring, at least two R₂Are attached to the same carbon atom and together with the carbon atom to which they are attached form a 3-6 membered saturated ring, which is a fully carbocyclic ring or a heterocyclic ring containing one or more atoms selected from N, O and S, and optionally substituted by one or more R_mSubstitution;

R_bis H, C_1-6Alkyl radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

R_cis L, L-C (O) -, L-CH₂-or L-S (O)₂-，

a is

Z is N or CR_3；

Z' is N or CR_4；

v is N or CR_9，Wherein R is₉Is H, CN, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl or-O-W;

w is a 5 or 6 membered heteroaryl or phenyl group, which may be optionally substituted with one or more of the following substituents: halogen, cyano, C_1-6Alkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkyl and C_1-3A haloalkoxy group.

2. The compound of claim 1, having the structure:

wherein, the substituent R₁，R_x，R_y，R_mQ, m, u and A are as defined in claim 1.

3. The compound of claim 1, wherein

Q is-O-and p is 2;

two independent R₂Are attached to the same carbon atom and together with the carbon atom to which they are commonly attached form a 3-6 membered saturated ring, which is a fully carbocyclic ring or a heterocyclic ring containing one or more atoms selected from N, O and S, and may be substituted by one or more R_mSubstitution;

R₁is H, halogen, cyano, amino, C_1-6Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylamino radical, C_1-3A haloalkyl group.

4. The compound of claim 1 or 2, wherein u is 0 and R is_x, R_yIs H.

5. A compound according to claim 1 or 2Wherein R is₁Is H, halogen, C_1-6Alkyl or C_1-6An alkoxy group.

6. The compound of claim 1 or 2, wherein m is 1.

7. The compound of claim l or 2, wherein a is

R₅, R_6,R₇, R₈, R₉Independently H, F or CN.

8. A compound according to claim i or 2, or a pharmaceutically acceptable salt thereof, wherein a is

R₅, R_6,R₇, R₈Independently H, F or CN;

R₉is-O-W;

w is a 5 or 6 membered heteroaryl or phenyl group, which may be optionally substituted with one or more substituents C_1-3Haloalkyl, C_{1- 3}Haloalkoxy, CN, halogen and C_1-6An alkyl group.

9. The compound of claim l or 2, wherein a is

R₇, R₈Independently H, F or CN;

R₉is-O-W;

w is pyridyl, pyrimidyl,Pyrazolyl or phenyl, optionally substituted with one or more substituents independently selected from: halogen, CN, CF₃、-OCF₃、CHF₂And CH₃。

10. The compound of claim 1 or 2, wherein R_mIs H, hydroxyl, methoxy or methylamino.

11. The compound of claim l or 2, wherein a is selected from the group consisting of:

。

12. the compound of claim 1 or 2, having one of the following structures:

。

13. a composition comprising a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. Use of a compound according to any one of claims 1 to 12 or a composition according to claim 13 in the manufacture of a medicament.

15. A method as claimed in any one of claims 1 to 12Use of a compound of claim 13 or a composition of claim 13 for the preparation of a medicament for treating, preventing or ameliorating Lp-PLA₂The use in medicaments for inhibiting related diseases.

16. Use of a compound according to any one of claims 1 to 12 or a composition according to claim 13 in the manufacture of a medicament for the treatment, prevention or amelioration of: diabetic complications, neuroinflammation-related diseases or/and atherosclerosis.

17. Use according to claim 16, characterized in that the diabetic complication is diabetic retinopathy/diabetic macular edema, diabetic nephropathy, diabetic neuropathy, diabetic peripheral neuropathic pain or/and diabetic foot, and the neuroinflammation-related disease is alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or/and parkinson's disease.

18. A process for preparing a compound according to any one of claims 1 to 12, comprising the steps of:

step (iv): obtaining a compound (1.7) by ring closure of the compound (1.5);

or comprises the following steps:

step (iv'): obtaining a compound (1.7) by ring closure of the compound (1.6);

wherein R is₁，R₂，R_x，R_yQ, m, n, p, u, a are as defined in any one of claims 1 to 12.