CN111072675A

CN111072675A - Nitrogen-containing fused tricyclic derivatives and uses thereof

Info

Publication number: CN111072675A
Application number: CN201911274207.7A
Authority: CN
Inventors: 金传飞; 钟文和; 邓康
Original assignee: Shenzhen Dongyangguang Pharmaceutical Co Ltd; Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2019-12-12
Filing date: 2019-12-12
Publication date: 2020-04-28

Abstract

The invention discloses nitrogen-containing fused tricyclic derivatives and application thereof, and particularly relates to novel nitrogen-containing fused tricyclic derivatives and a pharmaceutical composition containing the same, which can be used as selective adenosine A_2AA receptor antagonist. The invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in therapy with adenosine A_2AThe use in the preparation of medicaments for the treatment of receptor-related diseases, in particular Parkinson's disease.

Description

Nitrogen-containing fused tricyclic derivatives and uses thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to novel nitrogen-containing fused tricyclic derivatives, a pharmaceutical composition containing the compounds, and a using method and application of the novel nitrogen-containing fused tricyclic derivatives. In particular, the novel nitrogen-containing fused tricyclic derivatives of the present invention are useful as selective adenosine A_2AReceptor antagonists for the prevention, treatment or alleviation of adenosine A_2AA receptor-associated disease, in particular parkinson's disease.

Background

Parkinson's Disease (PD) is a common chronic degenerative disease of the nervous system, also called parkinsonism, and is common in the elderly, with the average age of about 60 years and the onset of juvenile Parkinson's disease below 40 years being rare. The prevalence rate of PD in people over 65 years old in China is about 1.7%. Most parkinson's disease patients are sporadic cases, with less than 10% of patients having a family history. Parkinson's disease begins with an insidious course and progresses slowly. The first symptoms are often tremors or awkward movements in one limb and further involvement in the contralateral limb. Clinically, the symptoms are static tremor, bradykinesia, muscular rigidity and gait disorder. In recent years, people pay more attention to non-motor symptoms such as depression, constipation and sleep disorder, which are also common complaints of Parkinson patients, and the influence of the non-motor symptoms on the life quality of the patients even exceeds the motor symptoms. PD seriously affects the daily life and social activities of patients, has become a disease that afflicts people and affects the quality of life of millions of people worldwide.

The most prominent pathological change of parkinson's disease is the degenerative death of mesocerebral Dopaminergic (DA) neurons, which causes a marked reduction in striatal DA content and causes disease. The exact etiology of this pathological change is still unclear, and genetic factors, environmental factors, aging, oxidative stress, etc. may all be involved in the degenerative death process of PD dopaminergic neurons.

Current treatments for PD mainly include surgical and pharmaceutical treatments. Surgical treatment can cause severe adverse effects and a high rate of postoperative recurrence, which all limit the broad application of surgical treatment (Kelly PJ, Gillingham FJ. the Long-term results of stereotaxic supply and L-dopa therapy in patients with Parkinson's disease. A10-year follow-up study [ J ]. J neurosuring, 1980,53(3): 332-7.). While the pharmacotherapy of PD is mainly divided into two main categories: anticholinergic agents and agents that affect dopaminergic activity. Anticholinergic agents can only ameliorate symptoms, as an adjuvant. Dopaminergic treatment against PD is primarily intended to reverse striatal dopamine deficiency caused by nigrostriatal lesions (Obeso JA, Olilow CW, Nutt JG. Levodopa motor compatibility sin Parkinson's disease [ J ]. Trends Neurosci,2000,23(10): 2-7.). Levodopa and other dopamine agonist drugs are effective in controlling the symptoms of PD, especially in the early stages of the disease. However, dopamine agonist drugs have acute side effects such as hypotension, nausea, vomiting, and other syndromes that increase with disease severity, including loss of drug effectiveness, psychiatric symptoms, and movement disorders. It follows that current treatments are symptomatic and do not significantly improve the disease process, so there is an urgent need to develop alternative methods of treating PD. New methods of PD therapy should be effective throughout the course of the disease, not only to reduce the side effects of existing therapeutic drugs, but also to have neuroprotective effects, thereby slowing or arresting the progression of the disease.

Many of the drugs currently under investigation for PD are primarily directed to the non-dopaminergic system of the basal ganglia, all of which have strong anti-PD activity and do not produce side effects.

The basal ganglia are important subcortical centers that regulate movement and mainly comprise two pathways: direct pathway (striatum-nigro-reticulum/globus pallidus-thalamus-cortex loop), indirect pathway (striatum-globus pallidus-subthalamic nucleus-nigro-reticulum/globus pallidus-thalamus-cortex loop). Efferent neurons acting on the direct pathway by the striatum contain predominantly dopamine D₁Receptors, efferent neurons acting on indirect pathways, contain predominantly dopamine D₂A receptor. Activation of the direct pathway can facilitate thalamocortical neuron activity, while activation of the indirect pathway inhibits thalamocortical neuron activity. Dopamine pair D₁The receptor has an excitatory effect fromAnd activate the direct path, pair D₂The receptor has an inhibitory effect to inhibit the indirect pathway, keeping the direct pathway and indirect pathway in balance. After injury to DA neurons in the substantia nigra pars compacta of Parkinson's disease patients, activation of direct and inhibition of indirect pathways are reduced, resulting in imbalance between direct and indirect pathways, and increased inhibition of thalamocortical neurons, with symptoms of stiffness, tremor, bradykinesia, hypokinesia, etc. (Lang AE. Lozano AM. Parkinson's disease. second of two parts.New England Journal of Medicine,1998,339(16): 1130-1143.).

Adenosine A_2AReceptor (adenosine A)_2Areceptor) is selectively expressed in basal ganglia and is associated with motor behavior, mainly through the regulation of indirect pathways: (1) adenosine A of GABAergic neurons within the striatum_2AThe receptor is activated to improve the excitability of GABAergic neurons of striatum, so that the excitability of GABAergic neurons outside globus pallidus is inhibited; (2) adenosine A activating striatal GABAergic neuron axon terminals_2AThe receptor can promote GABA release and inhibit excitability of GABAergic neurons outside the globus pallidus (Shindou T, Richardson PJ, Mori Aet. Adenosine modulated structural GABAergic inputs to the globus pallidus via adenosine A)_2Areceptors in rats.Neuroscience Letters,2003,352(3):167-170.)。

Epidemiological and laboratory studies have shown that adenosine A blockade_2AThe receptor can reduce degenerative changes in dopaminergic neurons. Adenosine A_2AReceptor antagonists (adenosine A)_2Areceptor antagonist) improves PD symptoms while slowing disease progression. Thus, adenosine A_2AReceptor antagonists as non-dopamine targets in the basal ganglia may be developed as a novel strategy for the treatment of PD (Pinna A, Wardas J, Simola N, et al. New therapeutics for the treatment of the disease of Parkinson's disease: Adenosine A_2Areceptor antagonists[J]Life Sci,2005,77(26): 3259-67.). A number of basic and clinical studies have shown adenosine A_2AReceptor antagonists are likely to be a new class of drugs for the treatment of Parkinson's disease. How to look for some adenosine A_2AHigh receptor affinity and in vivoCan exert curative effect well and is a medicine with little adverse reaction, namely adenosine A_2AAn important topic for the study of receptor antagonists.

Adenosine receptors (adenosine receptors) represent a subclass of purine nucleotide and nucleoside G protein-coupled receptors (called purine receptors), with four major pharmacologically distinct adenosine receptor subtypes, a₁、A_2A、A_2BAnd A₃. The major adenosine receptor subtype in the brain is A₁And A_2A. However, adenosine A was found₁Receptors are distributed in high density throughout the brain, adenosine A_2AThe distribution of receptors is more limited. Adenosine A_2AReceptors are present in high density in the striatum (olfactory tubercle, nucleus accumbens, lateral caudate putamen) and in dopamine D on striatal output neurons₂Receptor co-localization. Adenosine A_2AReceptor Primary and dopamine D₂Receptors are co-expressed in striatum-globus pallidus intermediate spiny neurons (MSNs), but not with dopamine D₁Receptor co-expression (Fink JS, Weaver DR, Rivkees SAet al, mOLECULAR Cloning of the rat A)₂adenosine receptor:Selective co-expression with D₂BRAIN Res Mol BRAIN rES,1992,14:186-_2AReceptor Primary and dopamine D₂Receptors are also co-expressed in the olfactory tubercle and core and shell regions of the nucleus accumbens (Svenningsson P, LeMoine C, Kull B et al_2Areceptor messenger RNAi n the rate central nerve system with specific reference to dopamiiner and area nerve, nerve reference 1997,80: 1171-1185), and also in the peripheral parts of immune cells (Sitkovsky MV, Lukashev D, Apasov S et al, physiological control of immune response and immune tissue infection dam by hypoxia-index genes A_2Areceptors, annual Review of Immunology,2004,22: 657-. Adenosine A_2ADiscrete localization of receptors in the striatum and functional antagonism thereof D₂The ability of the receptor to act has led to adenosine A_2AReceptor antagonists are potential therapies for the symptoms of Parkinson's disease.

Study (Fuxe K, Ferre S, Canals M et al. Adenosine A)_2Aand dopamine D₂The term of molecular neuroscience,2005,26(2-3):209-220.) indicates adenosine A_2AReceptor and dopamine D₂The receptor is capable of forming heterodimers (heterodimers) and/or heterooligomers (heterooligomers), wherein the heterodimers are capable of reducing dopamine D₂Activity of the receptor: by adenosine A_2ACarboxyl terminal of the acceptor (the carboxyl terminal of the A)_2Areceiver) and dopamine D₂Interaction of the 5,6 transmembrane regions of the receptor, altering dopamine D₂Epitopes of the receptor, reduction of dopamine D₂Affinity of the receptor for its ligand, via adenosine A_2ACarboxyl terminal of the acceptor (the carboxyl terminal of the A)_2Areceptor) and intracellular dopamine D₂The nitrogen terminal portion of the receptor I3 (N-terminal Part of I3 of the D)₂receptor) (arginine-rich epitope) interaction, reduces dopamine D₂Receptor coupling to G protein to reduce dopamine D₂Promotion of K following receptor activation⁺The effects of outflow and calcium influx inhibition, thereby reducing dopamine D₂The activity of the receptor. Adenosine A_2AReceptor agonists promote heterodimer formation, and adenosine A_2AThe receptor antagonist is capable of inhibiting heterodimer formation.

Naturally occurring xanthines are the first generation compounds of adenosine receptor antagonists, for example, caffeine (1,3, 7-caffeine) and theophylline (1, 3-dimethylxanthine, Daly et al, cell. These xanthines have long been known to reverse motor deficits in various PD models. Furthermore, epidemiological investigations suggest that caffeine and theophylline reduce the incidence of parkinson's disease. However, studies (Fredholm BB. connection between coffee and coffee receptors and dopamine. coffee derivatives of the salt of Parkinson's disease, Lakartidengen, 2004,101(34):2552, 2555.) found that coffee is a non-selective adenosine A_2AReceptor antagonists acting to block adenosine A_2AA receptor. Since they are nonselective and potentEtc. to thereby promote further development of selective adenosine A_2AA receptor antagonist.

Various synthetic substitutions on the xanthine moiety were further found to introduce a styryl group at the 8-position of xanthine to give adenosine A with selectivity_2AOf the compounds whose receptor antagonistic properties are of critical importance (Ongini et al, trends Pharmacol. Sci.,1996,17, 364; Shimada et al, J.Med.Chem.,1992,36, 2343; Muller et al, Curr.Pharm.Des.,1996,2, 501; Baraldi et al, Curr.Med.Chem.,1995,2, 707). This work found that the structurally related compound KF17837((E) -1, 3-dipropyl-8- (3, 4-dimethoxystyryl) -7-methylxanthine) and its analogue KW6002(istradefylline, (E) -1, 3-diethyl-8- (3, 4-dimethoxystyryl) -7-methylxanthine), the pharmacological properties of which have been extensively studied. Despite having similar in vitro potency, these two structurally similar xanthines appear to have significant differences in vivo potency, as measured by attenuation of the mice's catalepsy, with KW6002 being significantly more potent. This difference in vivo activity may be due to differences in pharmacokinetics, pharmacodynamics, metabolism and/or bioavailability (Kiec-konowicz et al, Pure and apppl. chem.,2001,73, 1411).

Adenosine A_2AThe receptor antagonist is used as a new medicine for treating PD, has definite effect, safety and better tolerance and has wide application prospect.

Disclosure of Invention

The invention provides a class of adenosine A as selective adenosine_2ANovel nitrogen-containing fused tricyclic derivatives of receptor antagonists useful in therapy with adenosine A_2AA receptor-associated disease, in particular for the treatment of parkinson's disease. Experiments show that the nitrogen-containing fused tricyclic derivative has stable property, good safety, good pharmacodynamics and pharmacokinetic properties, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability and the like. Therefore, the method has good clinical application prospect.

The invention also provides processes for the preparation of such compounds, pharmaceutical compositions containing them and the use of such compounds and pharmaceutical compositions containing them in the manufacture of medicaments.

In one aspect, the invention relates to a compound of formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein:

x is NH, O or S;

y is CH or N;

R¹is C₃-C₆Cycloalkyl, 3-5 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; and

R²and R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₆Alkyl), -C (═ O) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In some embodiments, R¹Is composed of

In other embodiments, R¹Is composed of

In some embodiments, R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₄Alkyl), -C (═ O) - (C)₁-C₄Alkoxy group), C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In other embodiments, R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-CH₃、-C(＝O)-OCH₃Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as disclosed herein.

In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

In another embodiment, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is a monoamine oxidase type B inhibitor, a dopamine agonist, an anticholinergic, a glutamate antagonist, levodopa, or any combination thereof.

In yet another aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein for the preparation of a medicament for the prevention, treatment or alleviation of the interaction with adenosine A_2AA receptor associated disease.

In one embodiment, the peptide is substituted with adenosine A_2AThe receptor-associated disease is parkinson's disease, a tumor, pain, depression, dementia, stroke, myocardial ischemia, asthma, alcohol withdrawal, dyskinetic syndrome, restless legs syndrome, dystonia, catalepsy, a neurodegenerative disorder or osteoporosis.

In a further aspect, the invention relates to the use of the compounds of formula (I) or pharmaceutical compositions thereof disclosed in the invention for the preparation of a medicament for antagonizing adenosine A_2AA receptor.

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).

Biological test results show that the compound can antagonize adenosine A_2AReceptor, and can be used as a better selective adenosine A_2AA receptor antagonist.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and JerryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to one or to more than one (i.e., to at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.

The term "chiral molecule" is a molecule having the property of not overlapping its mirror image; and "achiral molecule" refers to a molecule that can overlap with its mirror image.

The term "enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers, which mixture lacks optical activity.

The term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:APracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization.

"pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.

The term "optionally substituted with … …", is used interchangeably with the term "unsubstituted or substituted with ….," i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to D, F, Cl, Br, I, N₃、-CD₃、-CN、-NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂C (O) - (alkyl), C (O) - (cycloalkyl), C (O) - (heterocyclyl), C (O) - (aryl), C (O) - (heteroaryl), C (O) - (alkoxy), S (O)₂- (alkyl), -S (═ O)₂- (cycloalkyl), -S (═ O)₂- (heterocyclyl), -S (═ O)₂- (aryl), -S (═ O)₂- (heteroaryl), alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a particular substituent. Unless otherwise indicated, a substituent may be substituted at any reasonable position in the group that it may be substituted for. When more than one position in a given formula can be substituted with one or more particular substituents selected from the group, then the substituents may be substituted identically or differently at each of the possible positions in the formula.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₆Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "D" denotes a single deuterium atom.

The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

The term "oxo" refers to the group ═ O, used interchangeably with "carbonyl".

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR ' (like NR ' in N-substituted pyrrolidinyl, R ' being a substituent as described herein).

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) And so on.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) 1-propenyl (i.e., propenyl, -CH ═ CH-CH)₃) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. oneA carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (i.e., propynyl, -C.ident.C-CH)₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) And so on.

The term "alkylthio" means an alkyl group attached to the rest of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1 to 12 carbon atoms. In one embodiment, the alkylthio group contains 1 to 6 carbon atoms; in another embodiment, the alkylthio group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylthio group contains 1 to 3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein.

Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH)₃) Ethylthio (EtS, -SCH)₂CH₃) 1-propylthio (n-PrS, n-propylthio, -SCH)₂CH₂CH₃) 2-propylthio (i-PrS, i-propylthio, -SCH (CH)₃)₂) 1-butylthio (n-BuS, n-butylthio, -SCH)₂CH₂CH₂CH₃) 2-methyl-l-propylthio (i-BuS, i-butylthio, -SCH)₂CH(CH₃)₂) 2-butylthio (s-BuS, s-butylthio, -SCH (CH)₃)CH₂CH₃) 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC (CH)₃)₃) And so on.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like. The alkylamino group is optionally substituted with one or more substituents described herein.

The term "hydroxy-substituted alkyl" denotes an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.

The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CHF₂、-CH₂CF₃、-CHFCH₃、-CH₂CH₂F、-CF₂CH₃、-CH₂CF₂CHF₂And the like. In one embodiment, C₁-C₆The haloalkyl group containing a fluorine-substituted C₁-C₆An alkyl group; in another embodiment, C₁-C₄The haloalkyl group containing a fluorine-substituted C₁-C₄An alkyl group; in yet another embodiment, C₁-C₂The haloalkyl group containing a fluorine-substituted C₁-C₂An alkyl group.

The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, examples of which include, but are not limited to, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CHF₂、-OCH₂CF₃、-OCHFCH₃、-OCH₂CH₂F、-OCF₂CH₃、-OCH₂CF₂CHF₂And the like. In one embodiment, C₁-C₆Haloalkoxy comprises fluorine substituted C₁-C₆An alkoxy group; in another embodiment, C₁-C₄Haloalkoxy comprises fluorine substituted C₁-C₄An alkoxy group; in yet another embodiment, C₁-C₂Haloalkoxy comprises fluorine substituted C₁-C₂An alkoxy group.

The terms "n-member of atoms" or "n-member" are used interchangeably herein, where n is an integer typically describing the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, 5-10 membered heteroaryl means heteroaryl consisting of 5,6, 7,8, 9 or 10 ring atoms. As another example, piperidinyl is heterocyclyl or 6-membered heterocyclyl consisting of 6 ring atoms, and pyridinyl is heteroaryl or 6-membered heteroaryl consisting of 6 ring atoms.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl group is optionally substituted with one or more substituents described herein. Examples of cycloalkyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system can include fused, bridged, and spiro rings. Wherein one or more atoms of the ring are independently replaced by a heteroatom having the meaning as described herein. -CH in said heterocyclyl₂The group is optionally replaced by-C (═ O) -, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N-oxide. In one embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 8 ring atoms (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give compounds like SO, SO₂，PO，PO₂A group of (d); in yet another embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give compounds like SO, SO₂，PO，PO₂A group of (d); in yet another embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 5 ring atoms (2 to 4 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give compounds like SO, SO₂，PO，PO₂A group of (d); in another embodiment, heterocyclyl is a bicyclic heterocyclyl consisting of 7 to 12 ring atoms (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give the same SO, SO₂，PO，PO₂The group of (1). The heterocyclyl group is optionally substituted with one or more substituents described herein.

The ring atoms of the heterocyclic group may be carbon-based or heteroatom-based. Wherein, is cyclic-CH₂The group is optionally replaced by-C (═ O) -, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N-oxide. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, oxazepinyl, and oxazepinyl

Radical, diaza

Radical, S-N-aza

Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH₂Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of the aryl group may include phenyl, indenyl, naphthyl and anthryl. The aryl group is optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

As described in the present invention, the substituent R

The ring system formed by a ring with a bond to the center (as shown in formula f) represents that the substituent R is limited to any substitutable or any reasonable position on the A ring. For example, formula f represents that any possible substituted position on the A ring may be substituted with a substituent R, as shown in formulas f1-f 4:

the term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. For protectionGeneral description of groups can be found in the literature: greene et al, Protective Groups in organic Synthesis, John Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, andorganic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or these salts can be obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C₁-C₈Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that is water.

When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.

The term "treating" any disease or condition, in some embodiments refers to ameliorating the disease or condition (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

The term "prevent" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).

Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are encompassed within the scope of the present invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

The compounds of formula (I) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt need not be a pharmaceutically acceptable salt, and may be an intermediate useful in the preparation and/or purification of a compound of formula (I) and/or in the isolation of an enantiomer of a compound of formula (I).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable salts.

Any formulae given herein are also intended to indicate that the compounds are notIsotopically enriched forms and isotopically enriched forms. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.

Description of the Compounds of the invention

The invention relates to nitrogen-containing fused tricyclic derivatives, pharmaceutically acceptable salts thereof, pharmaceutical preparations and compositions thereof, which can be used for antagonizing adenosine A_2AReceptor, for adenosine A_2AThere is a potential use in the treatment of receptor-related diseases, particularly parkinson's disease. The invention further describes methods for synthesizing the compounds. The compounds of the present invention show good biological activity.

whereinEach R¹、R²、R³X and Y have the meanings given in the description.

In some embodiments, X is NH, O, or S.

In some embodiments, Y is CH or N.

In some embodiments, R¹Is C₃-C₆Cycloalkyl, 3-5 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In some embodiments, R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₆Alkyl), -C (═ O) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In some embodiments, R¹Is composed of

In some embodiments, R¹Is composed of

In some embodiments，R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₄Alkyl), -C (═ O) - (C)₁-C₄Alkoxy group), C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In other embodiments, R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-CH₃、-C(＝O)-OCH₃Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinylPyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound having one of the following structures, but is by no means limited thereto:

In another embodiment, the invention relates to a pharmaceutical composition further comprising an additional therapeutic agent, wherein said additional therapeutic agent is a monoamine oxidase type B inhibitor such as selegiline and rasagiline, a dopamine agonist such as bromocriptine, cabergoline, pergolide, pramipexole, ropinirole and rotigotine (rotigotine), an anticholinergic such as trihexyphenidyl, benztropine, oxypheniramine and propiconazole, a glutamate antagonist such as amantadine, levodopa (optionally in combination with a carboxylase inhibitor such as carbidopa and benserazide, a COMT inhibitor such as tolcapone and entacapone or both a carboxylase inhibitor and COMT inhibitor) or any combination thereof.

In one embodiment, the peptide is substituted with adenosine A_2AThe receptor-related diseases include Parkinson disease, tumor, pain, depression, dementia, apoplexy, myocardial ischemia, asthma, alcohol withdrawal, dyskinesia syndrome, diabetes,restless legs syndrome, dystonia, catalepsy, neurodegenerative disorders or osteoporosis.

In another embodiment, said peptide is substituted with adenosine A_2AThe receptor-associated disease is parkinson's disease.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I) or an individual stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug delivery systems (2004) Lippincott, Williams & Wilkins, philidelphia; gennaro a.r.et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting a compound of the invention from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants (such as talc, magnesium stearate and mineral oil), 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 (such as methyl and propyl hydroxybenzoates), stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation. The compounds of the present invention may be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by methods known in the art.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. sup. 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

Suitable pharmaceutically acceptable carriers depend on the pharmaceutical form and are known to the person skilled in the art.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents and solvent mixtures, coatings, complexing agents, solid carriers, dispersion media, surface active excipients, antibacterial and antifungal agents, isotonic and absorption delaying agents for pharmaceutically active substances, and mixtures thereof, which are also known in the art.

Non-limiting examples for pharmaceutically acceptable carriers include those having a composition selected from the group consisting of: lactose, gelatin, sugar alcohols (e.g. starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, colloidal silicon dioxide, carboxymethylcellulose, microcrystalline cellulose, sodium lauryl sulfate, aqueous buffered solutions, copovidone, polysorbates, ethanol, propylene glycol, polyglycols (preferably polyethylene glycols, such as PEG400),

80 (i.e. PEG (20), sorbitol monooleate), DMSO, a mixture of water and a co-solvent, for example an aqueous solution comprising an alcohol such as ethanol and/or a polyglycol such as polyethylene glycol, an ester of a polyol such as glycerol and/or polyethylene glycol with a fatty acid, a surfactant such as an anionic, cationic, nonionic and amphoteric surfactant, a complexing agent such as a cyclodextrin, for example α -cyclodextrin (α -CD) or hydroxypropyl- β -cyclodextrin (HP- β -CD), a bile acid or lipid, for example a salt of an animal or vegetable phospholipid, a micellizing agent, and an oil such as corn oil, or a mixture of two or more of the aforementioned components.

For the preparation of pharmaceutical compositions using the compounds described herein, the pharmaceutically acceptable carrier can be a solid or liquid carrier. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5% to about 95% of the active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing the various compositions can be found in: gennaro (ed.), Remington's Pharmaceutical Sciences,18^thed.,1990,Mack PublishingCompany Co.,Easton,Pennsylvania。

Non-limiting examples of further suitable pharmaceutically acceptable carriers and suitable additives that may be used in the pharmaceutical compositions of the present invention are mentioned below.

In one embodiment, the present invention relates to a pharmaceutical composition of the present invention, which forms a lipid-based Drug Delivery System (DDS) in an aqueous medium. The pharmaceutical composition comprises at least one surfactant in addition to at least one compound in the compounds shown in the formula (I) or salts thereof. Non-limiting examples of suitable surfactants are as described above. In various embodiments, the lipid-based drug delivery system forms the following structure: (1) liposomes (i.e., dispersed closed bilayer assemblies of lamellar phases in water); (2) nanoparticles of non-lamellar phases (e.g. cubic, hexagonal, sponge); or (3) micelles, emulsions, microemulsions (i.e., simple self-assembled structures of lipids and surfactants).

In some embodiments, lipid-based drug delivery systems that form micelles, emulsions or microemulsions are preferred. Suitable surfactants or surfactant mixtures for forming micelles, emulsions or microemulsions generally have a hydrophilic lipophilic balance (HLB-value) of from about 8 to about 18, from about 10 to about 18, or from about 12 to about 16. The lipid-based drug delivery system forms a self-emulsifying drug delivery system (SEDDS) or a self-microemulsifying drug delivery system (SMEDDS). SEDDS and SMEDDS are mixtures of oil (i.e. lipids, e.g. a compound of formula (I) or a salt thereof), at least one surfactant, optionally at least one co-solvent and optionally at least one co-surfactant, ideally isotropic, which spontaneously emulsify to form an oil-in-water emulsion when introduced into the aqueous phase under mild agitation. Gentle agitation may be provided, for example, by the motility of the stomach.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack publishing company).

Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

The compounds or pharmaceutical compositions of the invention may be administered in a suitable manner, for example, by the buccal, intravenous, subcutaneous, intramuscular or intrathecal routes. Oral, enteral or parenteral administration is preferred. Most preferred is oral administration.

The compounds of the invention may be administered orally, for example, with an inert diluent or with an ingestible food carrier, encapsulated in a capsule, compressed into a tablet, or incorporated directly into a dietary food. For therapeutic administration in the oral cavity, in exemplary embodiments, the active compound is admixed with excipients and used in the form of ingestible tablets, buccal tablets, compressed tablets, capsules, soft gel capsules, pills, powders, dispersions, lozenges, suspensions, syrups, elixirs, solutions, liquids, and the like. Such pharmaceutical compositions and formulations comprise a therapeutically effective amount of the active ingredient, which is typically present at a level of at least 1% by weight of the administered composition. In various embodiments, the pharmaceutical composition comprises about 5-80% by weight of the active compound.

In various embodiments, the tablets, capsules, pills, lozenges, and the like comprise one or more of the following: excipients such as dicalcium phosphate; lubricants such as magnesium stearate; binding agents such as acacia, tragacanth, corn starch or gelatin; disintegrating agents such as alginic acid, corn starch, potato starch and the like; flavoring agent such as wintergreen oil and peppermint; sweetening agents such as saccharin, sucrose or lactose; and (4) cherry essence. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.

Various other materials may be present in the form of coatings or otherwise modify the actual form of the dosage unit. For example, the tablets, capsules, or pills may be coated with sugar, shellac, or both. A syrup or elixir may contain a compound of formula (I), a dye, a preservative such as methylparaben or propylparaben, a sweetening agent such as sucrose and a flavoring such as cherry or orange flavor.

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

In one embodiment of the invention, the compound of formula (I) is contained in a capsule. The capsule may be a hard capsule or a soft capsule. The capsules can be made from any suitable film-forming material, including, for example, cellulose derivatives, polyvinyl alcohol, gelatin, pectin, pullulan or other dextrans, modified starches such as starch ethers and oxidized starches, especially hydroxyethylated starch (HES) or hydroxypropylated starch (HPS), alone or in mixtures. Cellulose derivatives useful for making capsules include, but are not limited to, methylcellulose, ethylcellulose, cellulose acetate, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, cellulose acetate trimellitate, cellulose acetate phthalate, hydroxypropylmethylcellulose succinate, and mixtures thereof. Preferred cellulose derivatives are methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension or solution composition. In one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound of the disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, andmono-, di-and polysaccharides. Fine powders may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns₅₀Values (e.g., measured by laser diffraction).

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.

The compounds of the invention may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The compounds provided by the present invention may also be administered parenterally or intraperitoneally. Dispersions can also be prepared in liquid polyethylene glycols, glycerol and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form is preferably sterile and fluid to the extent that injectability is readily available, must be stable under the conditions of manufacture and storage, and must be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the maintenance of the required particle size (in the case of dispersions), by the use of a coating such as lecithin, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, phenol, chlorobutanol, thimerosal, sorbic acid, paraben, and the like. In many cases, it will be preferable to include isotonic agents, for example, sodium chloride or sugars. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, gelatin and aluminum monostearate.

Sterile injectable solutions are prepared by incorporating the compound of formula (I) in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various bactericidal active ingredients into a sterile vehicle which contains a base dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are freeze-drying and vacuum-drying techniques.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

The pharmaceutical compositions provided herein can be administered by rectal suppository by mixing the drug with a suitable non-irritating excipient (e.g., cocoa butter, glycerol esters synthesized with polyethylene glycol), which is solid at ordinary temperatures, and then liquefying or dissolving in the rectal cavity to release the drug. Because of individual variation, the severity of symptoms can vary widely, and each drug has its unique therapeutic properties, the precise mode of administration, dosage form and treatment regimen for each individual should be determined by the practitioner.

The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms. For example, a sustained release dosage form may contemplate the incorporation of the compound therein to an ion exchange resin, which optionally may be coated with a diffusion barrier coating to modify the release properties of the resin.

The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. Example (b)E.g., an amount sufficient to treat, cure or alleviate symptoms of the disease administered or allowed to equilibrate in vivo. The effective amount required for a particular treatment regimen will depend on a variety of factors including the condition being treated, the severity of the condition, the activity of the particular drug employed, the mode of administration, the clearance rate of the particular drug, the duration of the treatment, the drug combination, the age, body weight, sex, diet and patient health, etc. Other factors that may be considered in The art for a "therapeutically effective amount" are described in Gilman et al, eds., Goodman And Gilman's: The pharmaceutical Bases of Therapeutics,8^thed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17^thed.,MackPublishing Company,Easton,Pa.,1990。

For convenient and effective administration, the compounds are compounded in an effective amount with suitable pharmaceutically acceptable carriers and optionally other suitable additives and excipients in dosage unit form as described above. The dosage of the compound of formula (I) depends on the route of administration, the age and weight of the patient, the nature and severity of the disease to be treated, and other factors. In various embodiments, the daily dose is typically from 2 to 2000mg/d, such as from 50 to 500 mg/d. Within these ranges, in various embodiments, sub-ranges are selected having a lower limit of 2,5, 10, 20, 25, 50, 100, 200, 250, or 400mg/d and an upper limit of 50, 100, 200, 250, 500, 600, 750, 1000, 1500, and 2000 mg/d. The lower and upper values may be combined to give suitable dosage ranges, which will depend on various factors such as those described above. The daily dose may be administered in one single dosage unit per day or in two or more dosage units per day.

It is particularly advantageous to formulate the pharmaceutical compositions of the present invention in dosage unit form to facilitate administration and uniformity of dosage. Dosage unit form as used herein refers to a completely discrete unit suitable as a single dose for the mammal to be treated. Each unit containing a predetermined amount of a compound of formula (I) designed to produce the desired therapeutic effect in conjunction with the required pharmaceutical carrier. The details of the novel dosage unit forms of the invention are specified by and directly dependent on (a) and (b) below: (a) the unique characteristics of the compounds of formula (I) and the particular therapeutic effect to be obtained, and (b) limitations inherent in the art of compounding compounds of formula (I) for the treatment of disease in patients with disease conditions that compromise physical health.

The term "administering" refers to providing a therapeutically effective amount of a drug to an individual by means including oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. The administration forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pellets, troches, injections, sterile or non-aqueous solutions, suspensions, emulsions, patches and the like. The active ingredient is compounded with non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, pulvis Talci, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

The preferred route of administration will vary with clinical characteristics, the dosage will necessarily vary depending upon the condition of the patient being treated, and the physician will determine the appropriate dosage for the individual patient. The therapeutically effective amount per unit dose depends on body weight, physiology and the selected vaccination regimen. The weight of the compound per unit dose, excluding the weight of the carrier (vehicle included in the drug), refers to the weight of the compound per administration.

Any suitable route of administration may be employed to provide an effective dose of a compound of the invention to a mammal, especially a human. For example, oral administration, rectal administration, parenteral administration, topical administration, ocular administration, nasal administration, pulmonary administration, and the like can be employed. Dosage forms include tablets, troches, capsules, creams, ointments, suspensions, dispersions, solutions, aerosols, and the like. Preferably, the compound of formula (I) is administered orally.

The effective dosage of the active ingredient employed will vary with the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages are readily determined by one skilled in the art.

The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.

The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

In one embodiment, the treatment methods of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present invention encompass the treatment of the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.

In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered orally. In another embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered by inhalation. In yet another embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered intranasally.

In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the compounds of the invention or pharmaceutical compositions comprising the compounds of the invention depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, the appropriate dosage regimen, including the duration of the regimen, of the compound of the invention or of the pharmaceutical composition containing the compound of the invention depends on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

The compounds of the present invention may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition. This is selected by the person skilled in the art according to the physical circumstances of the patient, such as health, age, weight, etc. If formulated as a fixed dose, such combination products employ the compounds of the present invention (within the dosage ranges described herein) and the other pharmaceutically active agents (within their dosage ranges).

Accordingly, in one aspect, the present invention includes a combination comprising an amount of at least one compound of the present invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more of the additional therapeutic agents described above.

The compounds of formula (I) may be used in combination with other drugs useful in the prevention, treatment or alleviation of the diseases or conditions for which the compounds of formula (I) are indicated. These other drugs may be administered by their usual routes and amounts, simultaneously or sequentially with the compound of formula (I). When the compound of formula (I) is used contemporaneously with one or more other drugs, a pharmaceutical unit dosage form containing such other drugs as well as the compound of formula (I) is preferred.

In various embodiments, the compounds described in the present invention are combined with other drugs to provide a combination therapy for parkinson's disease or other conditions. The pharmaceutical compositions of the invention include a selective adenosine A as described in the invention_2AAt least one of a receptor antagonist and an additional therapeutic agent, examples of which include, but are not limited to:

(1) monoamine oxidase type B inhibitors such as selegiline and rasagiline;

(2) dopamine agonists such as bromocriptine, cabergoline, pergolide, pramipexole, ropinirole and rotigotine (rotigotine);

(3) anticholinergics such as trihexyphenidyl (trihexyphenidyl), benztropine, oxyphennadine and propiconazole;

(4) glutamate antagonists such as amantadine;

(5) levodopa (optionally in combination with carboxylase inhibitors such as carbidopa and benserazide, COMT inhibitors such as tolcapone and entacapone or both carboxylase and COMT inhibitors).

In all cases, the additional therapeutic agent may be selected from a free base or a neutral compound, or a pharmaceutically acceptable salt. In various embodiments, the selective adenosine a described herein_2AThe receptor antagonist is combined with additional therapeutic agent(s) into a single dosage form. In other embodiments, selective adenosine A_2AThe receptor antagonist and additional therapeutic agent are combined in a kit (kit) or otherwise provided together for administration.

Methods for treating Parkinson's disease or other indications as described above comprise administering a selective adenosine A as described in the present invention in combination therapy_2AReceptor antagonists and one or more of monoamine oxidase type B inhibitors, dopamine agonists, anticholinergics, glutamate antagonists and levodopa, wherein non-limiting examples of adjunctive therapeutic agents are listed above. Selective adenosine A_2AReceptor antagonismThe anti-agent and the additional therapeutic agent are administered together in a single dosage form comprising both active ingredients, or separately in separate dosage forms, as the case may be. In non-limiting examples, one of the agents is administered in a pill or tablet or other solid dosage form, while the other agent is administered in a pill or tablet or other solid dosage form, in a transdermal patch, or in an injectable form.

In one embodiment, the compounds of the invention and the additional therapeutic agents described above are used in the manufacture of a medicament for the prevention, treatment or alleviation of the interaction with adenosine A_2AA medicament for a receptor-associated disease.

In addition, the compounds of the present invention may be administered in the form of a prodrug. In the present invention, a "prodrug" of a compound of the present invention is a functional derivative that, when administered to a patient, is ultimately released in vivo from the compound of the present invention. When administering the compounds of the present invention in prodrug form, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (c) altering the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

Use of the Compounds and pharmaceutical compositions of the invention

The compound and the pharmaceutical composition provided by the invention can be used for preparing antagonistic adenosine A_2AThe pharmaceutical product of the receptor can also be used for preparing a medicament for preventing, treating or alleviating the symptoms of adenosine A_2AA pharmaceutical product for a receptor-related disease, in particular parkinson's disease.

In particular, the amount of the compound or compounds in the pharmaceutical compositions of the present invention is effective to detectably and selectively antagonize adenosine A_2AA receptor.

The compounds of the invention mayFor use in, but in no way limited to, preventing, treating or reducing the effects of adenosine A by administering to a patient an effective amount of a compound or pharmaceutical composition of the present invention_2AA receptor associated disease. The compound with adenosine A_2AA receptor-associated disease further including, but not limited to, parkinson's disease, tumors, pain, depression, dementia, stroke, myocardial ischemia, asthma, alcohol withdrawal, dyskinetic syndrome, restless legs syndrome, dystonia, catalepsy, neurodegenerative disorders or osteoporosis. Preferably, the compounds of the present invention are used for the prevention, treatment or alleviation of parkinson's disease and/or dyskinesia.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

¹H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.¹H NMR Spectrum in CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton, singlet), d (doublet ), t (triplet, triplet), q (quatet, quartet), m (multiplet ), br (broadpede, broad), brs (broadpedsingleton, broad singlet), dd (doublet of doublets), ddd (doublet of doublets), ddl of doublets, ddt (doublet of doublets, doublets), dt (doublet of triplets, doublets), dq (doublet of doublets), doublets of doublets, and so onts, doublet of doublets), td (triplet of doublets), tt (triplet of triplets), qd (quatet of doublets, quadruplicate). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-MS (column model: Zorbax SB-C18,2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following acronyms are used throughout the invention:

CDC1₃deuterated chloroform mg

DMSO dimethyl sulfoxide g

DMSO-d₆Kg of deuterated dimethyl sulfoxide

CH₃OH, MeOH/methanol mL, mL mL

H₂mu.L, mu.l microliter of O water

HCOONH₄Nanoliter of nL and nL ammonium formate

FA formic acid s sec

nM, nmol/L nanomole per liter min

Mu M, mu mol/L micromoles per liter h hours

mM, mmol/L millimole per liter EDTA-K2 dipotassium ethylenediaminetetraacetate

M, mol/L mol cAMP Cyclic adenosine monophosphate per liter

mmol of PEG400 polyethylene glycol 400

ng nanogram DMA N, N-dimethylaniline

Mu g microgram Saline physiological Saline

Ts p-toluenesulfonyl group

PBS phosphate buffer saline, phosphate buffered saline

HBSS Hank's Balanced Salt Solution, Hank's Balanced Salt Solution

NECA (2S,3S,4R,5S)-5-(6-amino-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-car boxamide、C₁₂H₁₆N₆O₄Adenosine receptor agonists, 5- (N-ethylcarboxamido) -adenosine

The following intermediate preparation schemes and synthetic schemes describe the steps for preparing the presently disclosed compounds, wherein R is, unless otherwise indicated¹Having the definitions set out in the present invention.

Intermediate preparation scheme 1

Formula (A), (B) and7) The compound shown can be prepared by the following steps: formula (A), (B) and1) The compound shown in the formula (I) reacts with paratoluensulfonyl chloride to obtain a compound shown in the formula (I)2) A compound shown in the specification; formula (A), (B) and2) A compound of the formula3) The compound shown in the formula (I) is reacted to obtain4) A compound shown in the specification; formula (A), (B) and4) A compound of the formula5) The compound shown in the formula (I) is reacted to obtain6) A compound shown in the specification; then formula (A), (B), (C), (6) The Boc protecting group of the compound is removed to obtain a compound of the formula (7) Intermediate compounds are shown.

Intermediate preparation scheme 2

Formula (A), (B) and15) The compound shown can be prepared by the following steps: formula (A), (B) and8) Reacting the compound with phosphorus oxychloride to obtain a compound of the formula (A)9) A compound shown in the specification; formula (A), (B) and9) A compound of the formula10) The compound shown in the formula (I) is reacted to obtain11) A compound shown in the specification; formula (A), (B) and11) Reacting the compound with hydrazine hydrate to obtain a compound of the formula (A)12) A compound shown in the specification; then formula (A), (B), (C), (12) The ring closing reaction of the shown compound is carried out to obtain a compound of the formula (A)13) A compound shown in the specification; formula (A), (B) and13) A compound of the formula14) The compound shown in the formula (I) is reacted to obtain15) Intermediate compounds are shown.

Synthesis scheme 1

Formula (A), (B) and16) The compound shown can be prepared by the following steps: formula (A), (B) and15) A compound of the formula7) The compound shown in the formula (I) is reacted to obtain16) The target product shown.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

Synthesis of intermediate 11- (4- (oxetan-3-yloxy) phenyl) piperazine

Step 1) Synthesis of Oxetanyl-3-yl 4-methylbenzenesulfonate

Oxetan-3-ol (2.0mL,31.5mmol), p-toluenesulfonyl chloride (7.1g,37.2mmol), and dichloromethane (40mL) were added to a 100mL single neck round bottom flask at 25 deg.C, followed by triethylamine (8.8mL,62.7mmol), and the reaction was allowed to continue stirring for 12 hours; the reaction was stopped, saturated sodium bicarbonate solution (30mL) was added, the organic phase was separated, the organic phase was collected, spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (5.78g, 80.4%).

MS(ESI,pos.ion)m/z:229.2[M+H]⁺；

Step 2) synthesis of 3- (4-bromophenoxy) oxetane

P-bromophenol (4.8g,27.7mmol), oxetan-3-yl 4-methylbenzenesulfonate (5.3g,23.1mmol) and N, N-dimethylformamide (30mL) were charged into a 100mL single-neck round-bottom flask, potassium carbonate (6.4g,46.4mmol) was added, and the reaction was carried out at 100 ℃ for 12 hours. The reaction was stopped, water (60mL) was added, followed by extraction with dichloromethane (60mL), liquid separation, organic phase collection, spin-drying under reduced pressure, and purification by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) gave the title compound as a white solid (5.04g, 95%).

Step 3) Synthesis of t-butyl 4- (4- (oxetan-3-yloxy) phenyl) piperazine-1-carboxylate

3- (4-bromophenoxy) oxetane (5.04g,22.0mmol), 1-Boc-piperazine (8.2g,44mmol), cesium carbonate (10.8g,33.1mmol), palladium acetate (1.04g,4.4mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (5.65g,8.8mmol), and toluene (80mL) were added to a 250mL one-neck flask, and the reaction was continued at 110 ℃ for 18 hours under nitrogen; the reaction was stopped, water (50mL) was added, extraction was performed with dichloromethane (40mL × 2), the organic phase was collected, dried with anhydrous sodium sulfate (2.0g), filtered, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a brown solid (3.26g, 44.3%).

MS(ESI,pos.ion)m/z:335.2[M+H]⁺；

Step 4) Synthesis of 1- (4- (oxetan-3-yloxy) phenyl) piperazine

Tert-butyl 4- (4- (oxetan-3-yloxy) phenyl) piperazine-1-carboxylate (3.2g,9.6mmol) and trifluoroacetic acid (15mL) were added to a 100mL single-neck flask at 25 ℃ and reacted with stirring for 25 hours; the reaction was stopped, the majority of the trifluoroacetic acid was removed by spin-drying under reduced pressure, saturated sodium bicarbonate solution (50mL) was added, followed by extraction with dichloromethane (60mL), liquid separation, collection of the organic phase, and purification by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to afford the title compound as a pale yellow solid (1.02g, 45%).

MS(ESI,pos.ion)m/z:235.2[M+H]⁺；

Synthesis of intermediate 2(R) -1- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazine

Step 1 Synthesis of (S) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate

(S) -tetrahydrofuran-3-ol (2.0mL,25mmol), p-toluenesulfonyl chloride (5.7g,29.9mmol), and dichloromethane (30mL) were added to a 100mL single neck round bottom flask at 25 deg.C, followed by triethylamine (7.0mL,50.4mmol) and the reaction was allowed to stir for an additional 16 hours; the reaction was stopped, saturated sodium bicarbonate solution (30mL) was added, the organic phase was separated, the organic phase was collected, spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (4.1g, 67.2%).

Step 2) Synthesis of (R) -3- (4-bromophenoxy) tetrahydrofuran

P-bromophenol (3.5g,20.2mmol), (S) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate (4.1g,16.9mmol) and N, N-dimethylformamide (20mL) were charged into a 100mL single-neck round-bottom flask, potassium carbonate (4.7g,34.1mmol) was added, and the reaction was carried out at 100 ℃ for 16 hours. The reaction was stopped, cooled to room temperature, and then extracted with water (60mL) followed by dichloromethane (60mL), separated, the organic phase collected, dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a white solid (4.0g, 97.6%).

MS(ESI,pos.ion)m/z:243.1[M+H]⁺；

Step 3 Synthesis of (R) -tert-butyl 4- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazine-1-carboxylate

Adding (R) -3- (4-bromophenoxy) tetrahydrofuran (5.7g,23.5mmol), 1-Boc-piperazine (6.6g,35.4mmol), cesium carbonate (11g,33.8mmol), palladium acetate (0.55g,2.33mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (3.0g,4.67mmol), and toluene (60mL) to a 250mL single-neck flask, and continuing the reaction at 100 ℃ for 12 hours under nitrogen; the reaction was stopped, cooled to room temperature, and then water (50mL) was added, followed by extraction with dichloromethane (40mL × 2), the organic phase was collected, dried over anhydrous sodium sulfate (2.0g), filtered, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (1.09g, 13.3%).

MS(ESI,pos.ion)m/z:349.3[M+H]⁺；

Step 4 Synthesis of (R) -1- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazine

(R) -tert-butyl 4- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazine-1-carboxylate (1.09g,3.13mmol) and trifluoroacetic acid (8mL) were added to a 100mL single-neck flask at 25 ℃ and reacted with stirring for 12 hours; the reaction was stopped, the majority of the trifluoroacetic acid was removed by spin-drying under reduced pressure, saturated sodium bicarbonate solution (50mL) was added, followed by extraction with dichloromethane (60mL), liquid separation, collection of the organic phase, and purification by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to afford the title compound as a pale yellow solid (0.264g, 34%).

MS(ESI,pos.ion)m/z:249.2[M+H]⁺；

Synthesis of intermediate 3(S) -1- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazine

Step 1 Synthesis of (R) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate

(R) -tetrahydrofuran-3-ol (10.0g,113.5mmol), p-toluenesulfonyl chloride (26.0g,136.4mmol) and dichloromethane (60mL) were added to a 250mL single neck round bottom flask at 25 deg.C followed by triethylamine (23mL,165.6mmol) and the reaction was allowed to continue stirring for 3 hours; the reaction was stopped, saturated sodium bicarbonate solution (50mL) was added, the organic phase was separated, the organic phase was collected, spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a pale yellow viscous substance (16.48g, 59.9%).

Step 2) Synthesis of (S) -3- (4-bromophenoxy) tetrahydrofuran

P-bromophenol (6.2g,35.8mmol), (R) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate (8.0g,33.0mmol) and N, N-dimethylformamide (30mL) were charged into a 250mL single-neck round-bottom flask, potassium carbonate (9.1g,66.0mmol) was added, and the reaction was carried out at 100 ℃ for 10 hours. The reaction was stopped, cooled to room temperature, and then extracted with water (100mL) followed by dichloromethane (60mL), separated, the organic phase collected, dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give the title compound as a pale yellow sticky substance (7.23g, 90.1%). MS (ESI, pos.ion) M/z 243.1[ M + H ]]⁺；

Step 3) Synthesis of (S) -tert-butyl 4- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazine-1-carboxylate

(S) -3- (4-bromophenoxy) tetrahydrofuran (7.23g,29.7mmol), 1-Boc-piperazine (11.1g,59.6mmol), potassium tert-butoxide (5.72g,59.5mmol), palladium acetate (0.35g,1.5mmol), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (1.46g,2.97mmol), and toluene (60mL) were charged in a 250mL single-neck flask, and the reaction was continued at 110 ℃ for 7 hours under nitrogen; the reaction was stopped, cooled to room temperature, and then water (50mL) was added, followed by extraction with dichloromethane (60mL), the organic phase was collected, dried over anhydrous sodium sulfate (2.0g), filtered, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (4.5g, 43%).

MS(ESI,pos.ion)m/z:349.2[M+H]⁺；

Step 4 Synthesis of (S) -1- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazine

(S) -tert-butyl 4- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazine-1-carboxylate (4.5g,12.9mmol) and ethyl acetate (24mL) were added to a 100mL single-neck flask at 25 ℃, sulfuric acid (4mL) was added dropwise, and the reaction was stirred for 1 hour; the reaction was stopped, saturated sodium bicarbonate solution (50mL) was added, followed by extraction with ethyl acetate (60mL), liquid separation, collection of the organic phase, spin-drying under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) ═ 10/1) gave the title compound as a pale yellow solid (2.9g, 90.6%).

MS(ESI,pos.ion)m/z:249.2[M+H]⁺.

Example Synthesis of 12- (furan-2-yl) -7- (2- (4- (4- (oxetan-3-yloxy) phenyl) piperazin-1-yl) ethyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-5-amine

Step 1) Synthesis of 2-amino-4, 6-dichloropyrimidine-5-carbaldehyde

Phosphorus oxychloride (58.7mL,630mmol) was added to a 500mL single neck round bottom flask, N-dimethylformamide (12.1mL,157mmol) was added dropwise in a low temperature bath at 5 ℃, then transferred to 25 ℃, 2-amino-4, 6-dihydroxypyrimidine (10g,78.7mmol) was added in portions, and the temperature was raised to 100 ℃ for reaction for 5 hours. The reaction was stopped, the majority of the phosphorus oxychloride was removed by rotary evaporation under reduced pressure, water (900mL) was added, the mixture was stirred at 25 ℃ for 32 hours, filtered, the resulting solid was added to ethyl acetate (50mL), stirred for 30 minutes, filtered, and the filter cake was dried to give the title compound as a yellow solid (12.2g, 80.8%).

MS(ESI,pos.ion)m/z:192.1[M+H]⁺；

Step 2) Synthesis of N' - (2-amino-6-chloro-5-formylpyrimidin-4-yl) furan-2-carbonyl hydrazide

2-amino-4, 6-dichloropyrimidine-5-carbaldehyde (2.0g,10.5mmol) and tetrahydrofuran (300mL) were charged into a 500mL single-neck round-bottom flask, N-diisopropylethylamine (5.2mL,31mmol) was added, then 2-furohydrazide (1.4g,11mmol) was added, and the reaction was carried out at 70 ℃ for 2 hours; the reaction was stopped, most of the solvent was removed by rotary evaporation under reduced pressure, ethyl acetate (25mL) and a saturated sodium bicarbonate solution (15mL) were added, and the mixture was stirred for 15 minutes; filtration and addition of the resulting solid to acetonitrile (10mL), stirring for 10 minutes, filtration and drying of the filter cake afforded the title compound as a pale yellow solid (9.9g, 99%).

MS(ESI,pos.ion)m/z:282.2[M+H]⁺；

Step 3) N' - (6-amino-1H-pyrazolo [3, 4-d)]Synthesis of pyrimidin-4-yl) furan-2-carbonyl hydrazide

N' - (2-amino-6-chloro-5-formylpyrimidin-4-yl) furan-2-carbonyl hydrazide (2.9g,10.3mmol) and acetonitrile (30mL) were added to a 100mL single-neck round bottom flask, hydrazine hydrate (5.6mL,92mmol) was added after stirring at 78 ℃ for half an hour, and the reaction was continued for 1 hour with stirring; the reaction was stopped, cooled and filtered and the filter cake dried to give the title compound as a grey solid (2.5g, 94%).

MS(ESI,neg.ion)m/z:258.0[M-H]^-；

Step 4)2- (furan-2-yl) -7H-pyrazolo [4,3-e][1,2,4]Triazole [1,5-c ]]Synthesis of pyrimidin-5-amines

N' - (6-amino-1H-pyrazolo [3,4-d ] pyrimidin-4-yl) furan-2-carbonyl hydrazide (6.2g,23.9mmol) and N, O-bistrimethylsilyl acetamide (40mL) were added to a 100mL single-neck round-bottom flask and reacted at 130 ℃ for 16 hours; the reaction was stopped, most of the solvent was removed by rotary evaporation under reduced pressure, water (150mL) was added, stirring was carried out at 70 ℃ for 15 minutes, filtration was carried out, the resulting solid was added to an aqueous acetic acid solution (10mL, 80%) and slurried for 15 minutes, filtered and dried to give the title compound as a pale yellow solid (2.68g, 46%).

MS(ESI,pos.ion)m/z:242.2[M+H]⁺；

Step 5)2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4,3-e][1,2,4]Triazole [1,5-c ]]Pyrimidine-7- Synthesis of Yl) Ethyl 4-methylbenzenesulfonate

2- (furan-2-yl) -7H-pyrazole [4,3-e][1,2,4]Triazole [1,5-c ]]Pyrimidin-5-amine (2.14g,8.87mmol) and N, N-dimethylformamide (40mL) were charged into a 100mL single neck round bottom flask, after stirring for 10 minutes at 5 deg.C, sodium hydride (461mg,11.53mmol) was added in portions, and after stirring for 30 minutes, ethane-1, 2-bisBis (4-methylbenzenesulfonate) (3.94g,10.6mmol), transferred to 25 ℃ for 20 hours; the reaction was stopped, water (150mL) was added, stirred, filtered, and the filter cake was dried to give the title compound as a pale yellow solid (1.92g, 49.3%). MS (ESI, pos.ion) M/z 440.2[ M + H ]]⁺；

Step 6) 2- (furan-2-yl) -7- (2- (4- (4- (oxetan-3-yloxy) phenyl) piperazin-1-yl) ethyl Yl) -7H-pyrazolo [4,3-e][1,2,4]Triazole [1,5-c ]]Synthesis of pyrimidin-5-amines

2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-7-yl) ethyl 4-methylbenzenesulfonate (0.45g,1.02mmol) and 1- (4- (oxetan-3-yloxy) phenyl) piperazine (0.36g,1.54mmol) were charged to a 100mL single-neck round-bottomed flask, N-diisopropylethylamine (0.34mL,2.06mmol) and N, N-dimethylformamide (12mL) were added and reacted at 82 ℃ for 36 hours. The reaction was stopped, cooled to room temperature, and then water (40mL) and dichloromethane (40mL) were added, followed by liquid separation, and the organic phase was collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (60mg, 11.7%).

MS(ESI,pos.ion)m/z:502.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.16(s,1H),8.06(s,2H),7.93(s,1H),7.23(d,J＝3.2Hz,1H),6.83(d,J＝8.9Hz,2H),6.77–6.70(m,1H),6.64(d,J＝8.9Hz,2H),5.14(dd,J＝10.8,5.6Hz,1H),4.86(t,J＝6.6Hz,2H),4.53–4.46(m,2H),4.42(t,J＝6.2Hz,2H),2.94(brs,4H),2.84(brs,2H),2.60(brs,4H).

Example 2 Synthesis of (R) -2- (furan-2-yl) -7- (2- (4- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazin-1-yl) ethyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-5-amine

The title compound was prepared as described in example 1, step 6 by reacting 2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-7-yl) ethyl 4-methylbenzenesulfonate (0.708g,1.61mmol), (R) -1- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazine (0.68g,2.74mmol) and N, N-diisopropylethylamine (0.8mL,4.85mmol) in N, N-dimethylformamide (20mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (mg, 45.5%).

MS(ESI,pos.ion)m/z:516.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.16(s,1H),8.05(s,2H),7.93(s,1H),7.23(d,J＝3.1Hz,1H),6.84(d,J＝9.1Hz,2H),6.77(d,J＝9.1Hz,2H),6.73(dd,J＝3.3,1.7Hz,1H),4.88(brs,1H),4.42(t,J＝6.5Hz,2H),3.85–3.76(m,2H),3.75–3.68(m,2H),2.94(brs,4H),2.83(t,J＝6.5Hz,2H),2.59(brs,4H),2.13(td,J＝14.3,8.2Hz,1H),1.95–1.86(m,1H).

Example 3 Synthesis of (S) -2- (furan-2-yl) -7- (2- (4- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazin-1-yl) ethyl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-5-amine

The title compound was prepared as described in example 1, step 6 by reacting 2- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-7-yl) ethyl 4-methylbenzenesulfonate (0.5g,1.14mmol), (S) -1- (4- ((tetrahydrofuran-3-yl) oxy) phenyl) piperazine (0.424g,1.71mmol) and N, N-diisopropylethylamine (0.38mL,2.3mmol) in N, N-dimethylformamide (15mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (154mg, 26.2%).

MS(ESI,pos.ion)m/z:516.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.17(s,1H),8.07(s,2H),7.94(s,1H),7.23(d,J＝3.3Hz,1H),6.84(d,J＝9.1Hz,2H),6.78(d,J＝9.0Hz,2H),6.75–6.71(m,1H),4.89(brs,1H),4.42(t,J＝6.6Hz,2H),3.82(dt,J＝16.0,6.3Hz,2H),3.72(dd,J＝10.7,5.7Hz,2H),2.96(brs,4H),2.84(t,J＝6.5Hz,2H),2.60(brs,4H),2.14(td,J＝14.3,8.2Hz,1H),1.96–1.87(m,1H).

Biological assay

Example A: evaluation of the Compounds of the invention on human adenosine A_2AAntagonism of receptors

Experimental methods

The experimental system adopts human recombinant adenosine A_2AThe receptor, stably expressed in the HEK-293 cell line. HEK-293 was inoculated into plates at a density of 1.25X 10⁵cell/ml. The medium was changed to Modified HBSS solution at pH 7.4, test compounds and solvents (PBS containing 0.1% DMSO) were added at different concentrations, and incubation was carried out at 37 ℃ for 10min, with the test compounds at the respective concentrations: 10. mu.M, 1. mu.M, 0.1. mu.M, 10nM, 1nM, 0.1 nM. The concentration of cAMP (cyclic adenosine monophosphate) in the medium was detected by TR-FRET method. This experiment used NECA as a positive control, (1) the test compound alone stimulated cells to produce a certain amount of cAMP, and then NECA alone (0.1. mu.M) stimulated cells to also produce a certain amount of cAMP. A test compound is considered to have adenosine A if the amount of cAMP production stimulated by the test compound alone is higher than 50% of the amount of cAMP production stimulated by the NECA alone (0.1. mu.M)_2AReceptor agonistic activity. (2) All cells were incubated with test compound and then cells were stimulated with NECA (3nM), and further with NECA alone (3nM) to produce an amount of cAMP that is less than 50% of the amount of cAMP produced by NECA alone (3nM), i.e., the test compound inhibited cAMP production by NECA (3nM) by greater than or equal to 50%, indicating that the test compound has adenosine A_2AAntagonism of the receptor. IC (integrated circuit)₅₀By using MathIQ^TM(ID Business Solutions Ltd., UK) was calculated by analysis of a nonlinear, least squares regression equation. The results are shown in Table A.

Table a compounds of the invention are directed to human adenosine a_2AResults of receptor antagonism experiments

Example No. 2	IC₅₀(μM)
		Example 1	0.0672
Example 2	0.0808
		Example 3	0.0916

The experimental result shows that the compound has stronger adenosine A_2AAntagonism of the receptor.

Example B: pharmacokinetic evaluation of rats after intravenous injection or gavage of a quantitative Compound of the invention

(1) Test animal

The test animals are rats, and the specific conditions are shown in table 1:

TABLE 1

Germling	Grade	Sex	Body weight	The week of the year	Origin of origin
						SD rat	Cleaning stage	Male sex	180～220g	8 weeks	Changzhou Kavens

(2) Analytical method

The LC-MS/MS system for analysis comprises an Agilent 1200 series vacuum degasser, a quaternary pump, an orifice plate automatic sampler, a constant temperature column incubator and an API4000Qtrap triple quadrupole mass spectrometer with an electric spray ionization source (ESI). The quantitative analysis was performed in MRM mode, where the source parameters of the MRM transitions are shown in table 2:

TABLE 2

Air curtain air/CUR:	30psi
		atomizing gas/GS 1:	55psi
auxiliary heating gas/GS 2:	60psi
		ion transmission voltage/IS:	5000V
atomization temperature/TEM:	500℃

analysis A Waters ACQUITY UPLC CSH C18,2.1X 50mm, 1.7 μm column was used to inject 0.8 μ L of sample. Analysis conditions were as follows: the mobile phase is H₂O+2mM HCOONH₄(ammonium formate) + 0.1% FA (formic acid) (mobile phase A) and MeOH (methanol) +2mM HCOONH₄(ammonium formate) + 0.1% FA (formic acid) (mobile phase B). The flow rate was 0.7 mL/min. The column temperature was 40 ℃ and the mobile phase gradient is shown in table 3:

TABLE 3

(3) Experimental methods

The compound of the invention is evaluated by pharmacokinetics in rats, and the specific steps are as follows:

the experiments were divided into two groups: one group was administered by intravenous injection and one group was administered by intragastric gavage. The compounds of the invention were administered to the test animals (12 h overnight fast) as a 10% DMA (heated) + 60% PEG400+ 30% Saline solution. For the group administered by intravenous injection, the dose was 1mg/kg, then blood was taken intravenously (0.3mL) at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h after administration, the anticoagulant EDTA-K2 was added to the blood, and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃. For the gavage administration group, the administration dose was 5mg/kg, then blood (0.3mL) was taken intravenously at time points of 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24h after administration, the anticoagulant EDTA-K2 was added to the blood, and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃.

Add 120. mu.L IS working solution to 20. mu.L plasma and vortex for 2 min. The mixed solution was then centrifuged at 12,000rpm for 2 min. Adding 100 μ L of supernatant110μL MeOH/H₂O (v/v-1/1), vortex for 2min, and then sample 5. mu.L into an LC-MS/MS system. And (3) detecting the concentration of the target compound by adopting an LC-MS/MS method, and calculating pharmacokinetic parameters by adopting a non-compartmental model. Analysis results show that the compound has better pharmacokinetic properties in rats.

Example C: pharmacokinetic evaluation of mice/dogs after intravenous or intragastric dosing of the Compounds of the invention

(1) The test animals were: the tested animals are mice and/or dogs, and the specific conditions are shown in table 4:

TABLE 4

Germling	Grade	Sex	Body weight	The week of the year	Origin of origin
						ICR mice	Cleaning stage	Male sex	18-22g	8 weeks	Changzhou Kavens
Beagle dog	Common stage	Male sex	6-8kg	6-8 months	Beijing Mas Biotech Ltd

(2) The analysis method comprises the following steps:

the LC/MS system for analysis included an Agilent 1200 series vacuum degasser, a quaternary pump, an orifice plate autosampler, a thermostatted column oven, an API4000Qtrap triple quadrupole mass spectrometer with an electrospray ionization source (ESI). The quantitative analysis was performed in MRM mode, where the source parameters of the MRM transitions are shown in table 5:

TABLE 5

Air curtain air/CUR	20psi
		Atomising gas/GSl	6Opsi
Auxiliary heating gas/GS 2	7Opsi
		Ion transport voltage/IS	4500V
Atomization temperature/TEM	550℃

Assay 0.5. mu.L of sample was injected using waters xbridge C18 UPLC, 2.1X 50mm, 3.5. mu.M column. Analysis conditions were as follows: the mobile phase is H₂O+2mM HCOONH₄(ammonium formate) + 0.1% FA (formic acid) (mobile phase A) and MeOH (methanol) +2mM MHCOONH₄(ammonium formate) + 0.1% FA (formic acid) (mobile phase B). The flow rate was 0.7 mL/min. The mobile phase gradients are shown in table 6:

TABLE 6

(3) Test method

1) The compound of the invention is subjected to pharmacokinetic evaluation in mice, and the specific steps are as follows:

the experiments were divided into two groups: one group was administered by intravenous injection and one group was administered by intragastric gavage. The compounds of the invention were administered to the test animals as a 10% DMA + 60% PEG400+ 30% Saline solution. For the group administered by intravenous injection, the dose was 2mg/kg, and then blood was taken intravenously (0.3mL) at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours after administration and centrifuged at 3,000 or 4,000rpm for 10 minutes, and a plasma solution (anticoagulant is EDTA-K2) was collected and stored at-20 ℃ or-70 ℃. For the gavage group, the dose was 5mg/kg, and then blood (0.3mL) was taken intravenously at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours after administration and centrifuged at 3,000 or 4,000rpm for 10 minutes, and a plasma solution (anticoagulant EDTA-K2) was collected and stored at-20 ℃ or-70 ℃.

Add 130. mu.L IS working solution to 10. mu.L plasma and vortex for 5 min. The mixed solution was then centrifuged at 4000rpm for 5 min. 100 μ L of the supernatant was added to 150 μ L H₂And O, swirling for 2min, and taking 2.5 mu L of sample injection LC-MS/MS system. And (3) detecting the concentration of the target compound by adopting an LC-MS/MS method, and calculating pharmacokinetic parameters by adopting a non-compartmental model. Analysis results show that the compound has better pharmacokinetic properties in mice.

2) The pharmacokinetic evaluation of the compounds of the invention in beagle dogs was carried out by the following specific steps:

the experiments were divided into two groups: one group was administered by intravenous injection and one group was administered by intragastric gavage. The compounds of the invention were administered to the test animals as a 10% DMA + 60% PEG400+ 30% Saline solution. For the group administered by intravenous injection, the dose was 1mg/kg, then blood was taken intravenously (0.3mL) at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration and centrifuged at 3,000 or 4,000rpm for 10 minutes, and a plasma solution (anticoagulant was EDTA-K2) was collected and stored at-20 ℃ or-70 ℃. For the gavage group, the dose was 5mg/kg, followed by intravenous blood (0.3mL) at time points of 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours after administration and centrifugation at 3,000 or 4,000rpm for 10 minutes, and the plasma solution (anticoagulant was EDTA-K2) was collected and stored at-20 ℃ or-70 ℃.

Add 120. mu.L IS working solution to 10. mu.L plasma and vortex for 2 min. The mixed solution was then centrifuged at 12000rpm for 2 min. 80 μ L of the supernatant was added with 140 μ L MeOH/H₂O (v/v-1/1), vortex for 2min, and then sample 1.0. mu.L into an LC-MS/MS system. And (3) detecting the concentration of the target compound by adopting an LC-MS/MS method, and calculating pharmacokinetic parameters by adopting a non-compartmental model. Analysis results show that the compound has better pharmacokinetic properties in beagle dogs.

In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A compound which is a compound represented by formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein:

x is NH, O or S;

y is CH or N;

2. According to claim1 wherein R is¹Is composed of

3. The compound of claim 1 or 2, wherein R¹Is composed of

4. The compound of claim 1, wherein R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₄Alkyl), -C (═ O) - (C)₁-C₄Alkoxy group), C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

5. The compound of claim 1 or 4, wherein R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-CH₃、-C(＝O)-OCH₃Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

6. The compound of claim 1, which is a compound having one of the following structures or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof of a compound having one of the following structures:

7. a pharmaceutical composition comprising a compound of any one of claims 1-6; and

the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

8. The pharmaceutical composition of claim 7, further comprising an additional therapeutic agent, wherein the additional therapeutic agent is a monoamine oxidase type B inhibitor, a dopamine agonist, an anticholinergic, a glutamate antagonist, levodopa, or any combination thereof.

9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 8 in the manufacture of a medicament for the prevention, treatment or alleviation of the interaction with adenosine a_2AA receptor associated disease.

10. The use according to claim 9, wherein said administration is with adenosine a_2AThe receptor-associated disease is parkinson's disease, a tumor, pain, depression, dementia, stroke, myocardial ischemia, asthma, alcohol withdrawal, dyskinetic syndrome, restless legs syndrome, dystonia, catalepsy, a neurodegenerative disorder or osteoporosis.