CN112996783B

CN112996783B - 2-aminopyrimidine derivatives, preparation method and application thereof in medicines

Info

Publication number: CN112996783B
Application number: CN202080005991.6A
Authority: CN
Inventors: 陆标; 王胜蓝; 桂斌; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Shandong Shengdi Pharmaceutical Co ltd; Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2019-02-02
Filing date: 2020-01-31
Publication date: 2022-11-18
Anticipated expiration: 2040-01-31
Also published as: CN112996783A; TW202045493A; WO2020156505A1

Abstract

The disclosure relates to 2-aminopyrimidine derivatives, preparation methods thereof and applications thereof in medicine. In particular to aminopyrimidine derivatives shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives and a therapeutic agent thereof, especially A _2a Receptor and/or A _2b Use of receptor antagonists and preparation of pharmaceutical compositions for treating A _2a Receptor and/or A _2b Use in the manufacture of a medicament for a condition or disorder ameliorated by the inhibition of a receptor, wherein each substituent of formula (I) is as defined in the specification.

Description

2-aminopyrimidine derivatives, preparation method and application thereof in medicines

Technical Field

The disclosure belongs to the field of medicine, and relates to aminopyrimidine derivatives shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives and application of the derivatives as a therapeutic agent, in particular to aminopyrimidine derivatives A _2a Receptor and/or A _2b Use of receptor dual antagonists and preparation of pharmaceutical compositions for treating A _2a Receptor and/or A _2b The use in medicine of a condition or disorder ameliorated by inhibition of a receptor.

Background

Adenosine is a naturally occurring purine nucleoside, an endogenous regulator of many physiological functions. Plays an important role in the functional regulation of the cardiovascular system, central nervous system, respiratory system, kidney, fat and platelets.

Adenosine is found in tumor research as an important molecule in tumor-immune interaction, and targeting adenosine pathways can effectively inhibit tumor progression and metastasis through multiple mechanisms. Hypoxic tumor microenvironments provide a strong selective pressure on tumor cells, thereby increasing their invasiveness. The lack of oxygen supply results in a lack of nutrition, forcing tumor cells and immune cells to compete for essential nutrients. In this process, tumor cells may inhibit the proliferation and effector functions of lymphocytes, thereby evading immune surveillance, continue to survive, and may spread to other organs.

The effects of adenosine are mediated by a family of G protein-coupled receptors, and at least four subtypes of adenosine receptors are currently known, classified as A ₁ 、A _2a 、A _2b And A ₃ . Wherein A is ₁ And A ₃ The receptor inhibits the activity of the enzyme adenylate cyclase, and A _2a And A _2b Receptors stimulate the activity of this enzyme, thereby modulating cyclic AMP levels in cells, through which adenosine regulates a wide range of physiological functions.

A _2a Receptor (A) _2a R) is widely distributed in the organism, is mainly expressed in striatum in the central nervous system, and is also expressed in peripheral tissues, heart, liver, lung, kidney and the like. A. The _2b Receptor (A) _2b R) is also widely expressed in various tissues, but the expression amount is low, and the affinity with adenosine is far lower than that of A _2a Receptors, therefore the first people were on A _2b The receptor is less studied.

Recent studies have shown that adenosine a is involved in many pathological processes such as ischemic hypoxia, inflammation, trauma, transplantation, etc _2a Activation of the receptor may play an important immunomodulatory role, possibly in conjunction with A _2a The receptor is related to high expression level on various immune cells such as T cells, B cells, mononuclear macrophages, neutrophils and the like. Furthermore, A _2a The activation of the receptor can promote the organism to generate immune tolerance, and is closely involved in the formation of 'immune escape' or 'immune suppression' of tumor cells, thereby creating favorable conditions for the occurrence and development of tumors. Lokshin and co-workers (Cancer Res.2006Aug1;66 (15): 7758-65) demonstrated A on natural killer cells _2a R activation can inhibit the killing of natural killer cells on tumor cells by raising cAMP and activating PKA. It has also been shown that activation A _2a The receptor can promote proliferation of tumor cells such as melanoma A375 cells, fibroblast NIH3T3 cells and pheochromocytoma PC12 cells, and its effect may be related to A on T cells _2a The activation of the receptor can inhibit the activation and proliferation of T cells, and is related to the adhesion of tumor cells and the generation of cytotoxicity on the tumor cells; and A is _2a Receptor gene knockout miceThen CD8 may be enhanced ⁺ The T cell has the anti-tumor immunity function, and the proliferation of the tumor is obviously inhibited. Thus, A _2a The receptor antagonists are useful in the treatment of tumors. In addition, deepak Mittal et al found that A _2b Receptors are overexpressed in a variety of tumors and are associated with poor prognosis in triple negative breast cancer, multiple myeloma, and acute myeloid leukemia; a. The _2b Overexpression of the receptor promotes proliferation and migration of tumor cells; a. The _2b The combination of a receptor inhibitor and a chemotherapeutic drug or an immune checkpoint inhibitor can significantly reduce tumor metastasis in a mouse triple negative breast cancer model; knock-out of A in mice or in human colon cancer cell lines _2b The receptor significantly reduces colon cancer metastasis and cell tumorigenicity. These results all show that inhibition of A _2b The receptor inhibits tumor metastasis, therefore A _2b The receptor is also expected to be an ideal target for treating tumors (Cancer Res.2016 Aug1 (15): 4372-82).

A _2a Receptor and A _2b The receptor has the function of suppressing immunity, so the mutual regulation mechanism between the two needs to be studied intensively, for example, when A is inhibited _2a Whether or not the receptor is capable of increasing adenosine pair A _2b Sensitivity of the receptor. Study A _2a Receptor and A _2b Receptor dual inhibitors have also become a worthy direction to be explored.

Although compounds with significant biological activity at a variety of adenosine receptor subtypes can have therapeutic effects, they can cause unwanted side effects. For example adenosine A ₁ Receptors in tissue ischemia/hypoxia, in the central, circulatory, digestive and skeletal muscles, when cells are subjected to hypoxic and hypoxic stress, extracellular accumulated adenosine activates a on the cell membrane ₁ The receptor initiates the corresponding protective mechanisms, thereby increasing the tolerance of the cell to hypoxic hypoxia. A on immune cells ₁ Receptors can promote cellular immune responses in hypoxic environments. In addition, A ₁ The receptor also lowers free fatty acids and triglycerides and is involved in regulating blood glucose. Thus, A ₁ Continuous blockade of receptors may cause various adverse reactions in body tissues (Chinese pharmaceutical Bull)etin,2008, 24 (5), 573-576). Blocking A in animal models, as reported in the literature ₁ The receptor will cause the adverse reactions of anxiety, arousal and the like (Basic)&Clinical Pharmacology&Toxicology,2011, 109 (3), 203-7). During myocardial ischemia, adenosine A ₃ Receptors (as described in Gessi S et al, pharmacol. Ther.117 (1), 2008, 123-140) can play a role in cardioprotection, A ₃ Continued blockade of the receptor may increase the likelihood of complications arising from any pre-existing or developing ischemic heart disease, such as angina or heart failure.

At present, although many compounds have been developed as A _2a Antagonists of the receptors are useful in the treatment of a number of diseases, as described in WO2007116106, WO2009080197, WO2011159302, WO2011095625, WO2014101373, WO 2015031221.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by the general formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring a and ring B are the same or different and are each independently aryl or heteroaryl;

ring C is a 7-14 membered polycyclic heterocyclic group;

l is selected from the group consisting of a bond, an alkylene group, an O atom, an S atom and NR ⁵ ；

R ¹ The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ² selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl,Aryl and heteroaryl;

R ³ the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁴ the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁵ selected from the group consisting of hydrogen atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

m is 0, 1,2,3 or 4;

n is 0, 1,2 or 3; and is

s is 0, 1,2,3, 4,5 or 6.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring a and ring B are the same or different and are each independently phenyl or pyridyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring C, L, R ¹ ～R ⁴ M, n and s are as defined for the compounds of formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring C is selected from 7-14 membered spiro heterocyclic group, 7-14 membered fused ring heterocyclic group and 7-14 membered bridged ring heterocyclic group; preferably a 7-9 membered spiro heterocyclic group or a 7-9 membered fused ring heterocyclic group.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

ring C is

G is selected from C (R) ⁴ ) ₂ An O atom and an N atom;

p, q, r and t are the same or different and are each independently 1 or 2;

R ⁴ as defined for the compounds of general formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (III), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

g is selected from C (R) ⁴ ) ₂ An O atom or an N atom;

p, q, r and t are the same or different and are each independently 1 or 2;

s is 0, 1,2,3 or 4;

L、R ¹ ～R ⁴ m and n are as defined in formula (I). In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond or-CH ₂ -。

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IIIaa):

wherein:

g is selected from C (R) ⁴ ) ₂ An O atom or an N atom;

p, q, r and t are the same or different and are each independently 1 or 2;

s is 0, 1,2,3 or 4;

R ¹ ～R ⁴ m and n are as defined for the compounds of the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by formula (III) or (IIIaa), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is an O atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring C is selected from

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ¹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group and a cyano group; m is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: r ² Selected from hydrogen atoms, halogens and alkyl groups; preferably a hydrogen atom; r ³ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, and an alkyl group; n is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁴ Is a hydrogen atom.

Typical compounds of the present disclosure include, but are not limited to:

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a compound of formula (IA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

w is an amino protecting group; preferably tert-butoxycarbonyl;

ring A, ring B, ring C, L, R ¹ ～R ⁴ M, n and s are as defined for the compounds of formula (I). Which is an intermediate for the preparation of the compounds of general formula (I).

Another aspect of the present disclosure relates to a compound of formula (IIA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

w is an amino protecting group; preferably tert-butoxycarbonyl;

ring C, L, R ¹ ～R ⁴ M, n and s are as defined for the compounds of the general formula (II). Which is an intermediate for the preparation of compounds of general formula (II).

Another aspect of the present disclosure relates to a compound of formula (IIIA), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

w is an amino protecting group; preferably tert-butoxycarbonyl;

G、L、R ¹ ～R ⁴ m, n, s, p, q, r and t are as defined for the compounds of the general formula (III). Which is an intermediate for the preparation of the compound of formula (III).

wherein:

w is an amino protecting group; preferably tert-butoxycarbonyl;

G、R ¹ ～R ⁴ m, n, s, p, q, r and t are as defined for the compound of formula (IIIaa). Which is an intermediate for the preparation of the compound of general formula (IIIaa).

Typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a process for preparing a compound of formula (IA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (IB) and the compound of the general formula (ID) are subjected to a Click reaction to obtain the compound of the general formula (IA),

wherein:

ring A, ring B, ring C, L, W, R ¹ ～R ⁴ M, n and s are as defined for the compounds of general formula (IA).

Another aspect of the present disclosure relates to a process for preparing a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (IA) removes the amino protecting group to obtain the compound of the general formula (I),

wherein:

w is an amino protecting group; preferably tert-butoxycarbonyl;

ring A, ring B, ring C, L, R ¹ ～R ⁴ M, n and s are as defined for the compounds of formula (I).

the compound of the general formula (IB) and the compound of the general formula (IC) are subjected to Click reaction to obtain the compound of the general formula (I),

wherein:

Another aspect of the present disclosure relates to a process for preparing a compound of formula (IIA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(ii) subjecting the compound of the general formula (IIB) and the compound of the general formula (IID) to Click reaction to obtain a compound of the general formula (IIA),

wherein:

ring C, L, W, R ¹ ～R ⁴ M, n and s are as defined for the compounds of formula (IIA).

Another aspect of the present disclosure relates to a process for preparing a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

removing amino protecting group from the compound of the general formula (IIA) to obtain a compound of a general formula (II),

wherein:

w is an amino protecting group; preferably tert-butoxycarbonyl;

ring C, L, R ¹ ～R ⁴ M, n and s are as defined for the compound of formula (II).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (IB) and the compound of the general formula (IIC) are subjected to Click reaction to obtain a compound of the general formula (II),

wherein:

ring C, L, R ¹ ～R ⁴ M, n and s are as defined for the compounds of the general formula (II).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (IIIA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (IIIB) and the compound of the general formula (IID) are subjected to Click reaction to obtain a compound of the general formula (IIIA),

wherein:

G、L、W、R ¹ ～R ⁴ m, n, s, p, q, r and t are as defined for the compounds of formula (IIIA).

Another aspect of the present disclosure relates to a process for preparing a compound of formula (III), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

removing the amino protecting group from the compound of the general formula (IIIA) to obtain a compound of a general formula (III),

wherein:

w is an amino protecting group; preferably tert-butoxycarbonyl;

G、L、R ¹ ～R ⁴ m, n, s, p, q, r and t are as defined for the compounds of the general formula (III).

the compound of the general formula (IIIB) and the compound of the general formula (IIC) are subjected to Click reaction to obtain a compound of the general formula (III),

wherein:

Another aspect of the present disclosure relates to a process for preparing a compound of formula (IIIa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (IIIb) and the compound of the general formula (IID) are subjected to Click reaction to obtain the compound of the general formula (IIIa),

wherein:

G、W、R ¹ ～R ⁴ m, n, s, p, q, r and t are as defined for the compounds of formula (IIIa).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (IIIaa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

removing the amino protecting group from the compound of formula (IIIa) to obtain a compound of formula (IIIaa),

wherein:

w is an amino protecting group; preferably tert-butoxycarbonyl;

G、R ¹ ～R ⁴ m, n, s, p, q, r and t are as defined for the compound of formula (IIIaa).

the compound of formula (IIIb) and the compound of formula (IIC) are subjected to a Click reaction to give a compound of formula (IIIaa),

wherein:

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) of the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The present disclosure also relates to a method for preparing the above pharmaceutical composition, which comprises mixing the compounds represented by each formula or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, with a pharmaceutically acceptable carrier, diluent, or excipient.

The disclosure further relates to a compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound in preparation of a medicament for inhibiting A _2a Receptor and/or A _2b Use in the manufacture of a medicament for a subject.

The present disclosure further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for the treatment of a disease or disorder mediated by therapy of a _2a Receptor and/or A _2b Use of a medicament for a disease or condition ameliorated by receptor inhibition.

The present disclosure further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment of cancer, depression, cognitive function disorders, neurodegenerative disorders (parkinson's disease, huntington's disease, alzheimer's disease, amyotrophic lateral sclerosis or the like), attention-related disorders, extra-pyramidal disorders, dyskinesia, cirrhosis, liver fibrosis, fatty liver, dermal fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behaviors, preferably for the preparation of a medicament for the treatment of cancer.

The present disclosure further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumor; preferably lung cancer.

The disclosure further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for inhibiting A _2a Receptor and/or A _2b Use in the manufacture of a medicament for a subject.

The disclosure also relates to a method of inhibiting A _2a Receptor and/or A _2b A method of receptor comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate thereofThe pharmaceutical composition may be in the form of a mixture of enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.

The present disclosure also relates to a therapeutic agent comprising the compound of formula (I) _2a Receptor and/or A _2b A method of treating a disease or condition ameliorated by receptor inhibition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

The present disclosure relates to a method for treating cancer, depression, cognitive function disorders, neurodegenerative disorders (parkinson's disease, huntington's disease, alzheimer's disease, amyotrophic lateral sclerosis, etc.), attention-related disorders, extrapyramidal disorders, abnormal movement disorders, liver cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behaviors, preferably cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method for treating cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer, gall bladder cancer, bile duct cancer, choriocarcinoma, and pediatric tumor; preferably lung cancer.

The present disclosure further relates to a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for use as a medicament.

The disclosure also relates to compounds of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a _2a Receptor and/or A _2b A receptor antagonist.

The present disclosure also relates to compounds of formula (I) or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in therapy by administering to a _2a Receptor and/or A _2b Diseases or conditions ameliorated by receptor inhibition.

The present disclosure also relates to compounds of general formula (I) or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment of cancer, depression, cognitive function disorders, neurodegenerative disorders (parkinson's disease, huntington's disease, alzheimer's disease or amyotrophic lateral sclerosis, etc.), attention-related disorders, extra-pyramidal disorders, abnormal movement disorders, liver cirrhosis, liver fibrosis, fatty liver, dermal fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behaviors, preferably cancer.

In the present disclosure, by pair A _2a Receptor and/or A _2b Diseases or disorders ameliorated by receptor inhibition are selected from the group consisting of cancer, depression, cognitive function disorders, neurodegenerative disorders (Parkinson's disease, huntington's disease, alzheimer's disease, amyotrophic lateral sclerosis, or the like), attention-related disorders, extrapyramidal disorders, dyskinesias, cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation, and addictive behaviors;preferably a cancer, the cancer is a cancer, the cancer is selected from melanoma, brain tumor (glioma with malignant astrocyte and oligodendroglioma components, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, primary or metastatic squamous cancer, etc.), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (cervical cancer, endometrial cancer, etc.), head and neck tumor (maxillocarcinoma, laryngeal cancer, pharyngeal cancer, tongue cancer, oral cancer, etc.), multiple myeloma, malignant lymphoma (reticuloma, lymphosarcoma, hodgkin lymphoma, etc.), polycythemia vera, leukemia (acute granulocytic leukemia, chronic granulocytic leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumor, ureteral tumor, bladder tumor, gall bladder cancer, ductal carcinoma, cancer, epithelioma and neoplasms of the liver (retinoblastoma, hemangioblastoma, angiosarcoma, angioblastoma, hemangioblastoma, angiosarcoma, angioblastoma, etc.; more preferably lung cancer.

The dosage of the compound or composition used in the methods of treatment described in the present invention will generally vary with the severity of the disease, the weight of the patient and the relative efficacy of the compound. However, as a general guide, a suitable unit dose may be 0.1 to 1000mg.

The pharmaceutical compositions of the invention may contain, in addition to the active compound, one or more adjuvants selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding to a mixture of water and glycerol. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bulk injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2-methylbutyl, and the like 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-ethylhexyl, 3-ethylpentyl, 2 zxft 3838-dimethylhexyl, 5749 zxft, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having 2 residues derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, which is a straight chain containing from 1 to 20 carbon atomsOr a branched group, preferably an alkylene group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ -), 1,1-ethylene (-CH (CH) ₃ ) -), 1,2-ethylene (-CH) ₂ CH ₂ -), 1,1-propylene (-CH (CH) ₂ CH ₃ ) -), 1,2-propylene (-CH) ₂ CH(CH ₃ ) -), 1,3-propylene (-CH) ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ -) and 1,5-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. The alkylene groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent group is preferably one or more groups substituted with one or more substituents independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 6 (e.g., 3,4,5 or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 14, most preferably 7 to 9. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:

the term "fused ring alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 14, most preferably 7 to 9. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 14, most preferably 7 to 9. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, according to the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

said cycloalkyl ring includes fused to an aryl, heteroaryl or heterocycloalkyl ring of the above-described cycloalkyl groups (e.g., monocyclic, fused, spiro and bridged cycloalkyl groups), wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like; preferably phenyl and cyclopentyl, tetrahydronaphthyl.

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, heterocyclyloxy, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _g (wherein g is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 14 ring atoms, of which 1 to 4 are heteroatoms; more preferably 7 to 14 ring atoms, wherein 1-4 is a heteroatom; more preferably from 7 to 9 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spirocyclic heterocyclyl" refers to 5 to 20 membered polycyclic heterocyclic group sharing one atom (referred to as spiro) between monocyclic rings, wherein one or more ring atoms are selected fromNitrogen, oxygen or S (O) _g (wherein g is an integer from 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 7 to 14, more preferably 7 to 9 (e.g.7, 8 or 9). The spiro heterocyclic group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi spiro heterocyclic group according to the number of spiro atoms shared between rings, and preferably the single spiro heterocyclic group and the double spiro heterocyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:

the term "fused ring heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _g (wherein g is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably a 7 to 14 membered fused ring heterocyclyl group, more preferably 7 to 9 membered (e.g. 7, 8 or 9). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _g (wherein g is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 14, most preferablyIs 7 to 9 membered (e.g. 7, 8 or 9). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

such heterocyclyl rings include those wherein the above-described heterocyclyl (e.g., monocyclic, fused, spiro and bridged heterocyclyl) is fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

the heterocyclyl group may be substituted or unsubstituted and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered, all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl group described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, heterocyclyloxy, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tetrazolyl and the like. Such heteroaryl rings include those wherein the heteroaryl group described above is fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include t-butyl, t-butyloxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably tert-butyl or tert-butoxycarbonyl.

The term "oxo" means = O.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein alkyl and heterocyclyl groups are as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "hydroxy" refers to-OH.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The compounds of the present disclosure also include various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like. "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, and more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents, each substituent having independent options (i.e., the substituents may be the same or different). It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

The compounds of the present disclosure may also comprise isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only by the presence of one or more isotopically enriched atoms. For example, having the structure of the present disclosure except that "deuterium" or "tritium" is substituted for hydrogen, or ¹⁸ F-fluorine labeling: ( ¹⁸ Isotope of F) instead of fluorine, or with ¹¹ C-， ¹³ C-, or ¹⁴ C-enriched carbon (C) ¹¹ C-， ¹³ C-, or ¹⁴ C-carbon labeling; ¹¹ C-， ¹³ c-, or ¹⁴ C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a drug or agent that is non-toxic but achieves the desired effectSufficient amount of the medicament. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The present disclosure thus provides a novel structure of adenosine A with strong inhibitory activity _2b Receptor antagonists, compounds having such a structure simultaneously, and adenosine A _2a The receptor also has good inhibitory effect on adenosine A ₁ Receptor and adenosine A ₃ The receptor has weak inhibiting effect and is selective adenosine A with a novel structure _2a Receptor and A _2b A receptor bis-inhibitor.

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

scheme one

The preparation method of the compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof comprises the following steps:

carrying out a Click reaction on the compound of the general formula (IB) and the compound of the general formula (ID) in the presence of a catalyst to obtain a compound of the general formula (IA); removing amino protecting group from the compound of the general formula (IA) under acidic condition to obtain a compound of the general formula (I);

wherein:

w is an amino protecting group, preferably tert-butyloxycarbonyl;

ring A, ring B, ring C, L, R ¹ ～R ⁴ M, n and s are as defined in formula (I).

The catalyst includes but is not limited to CuSO ₄ 、CuSO ₄ ·5H ₂ O, cuI, and the like.

Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and sulfuric acid, preferably trifluoroacetic acid.

The above reaction is preferably carried out in a solvent including, but not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, t-butanol, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N, N-dimethylformamide, and mixtures thereof.

Scheme two

carrying out Click reaction on the compound of the general formula (IB) and the compound of the general formula (IC) in the presence of a catalyst to obtain a compound of the general formula (I);

wherein:

The above reaction is preferably carried out in a solvent including, but not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N, N-dimethylformamide, and mixtures thereof.

Scheme three

The preparation method of the compound shown in the general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture of the isomers or a pharmaceutically acceptable salt thereof comprises the following steps:

carrying out Click reaction on a compound of a general formula (IIB) and a compound of a general formula (IID) in the presence of a catalyst to obtain a compound of a general formula (IIA); removing amino protecting groups from the compound of the general formula (IIA) under an acidic condition to obtain a compound of a general formula (II);

wherein:

w is an amino protecting group, preferably t-butoxycarbonyl;

ring C, L, R ¹ ～R ⁴ M, n and s are as defined in formula (II).

Scheme four

The preparation method of the compound shown in the general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof comprises the following steps:

carrying out Click reaction on a compound of a general formula (IIB) and a compound of a general formula (IIC) in the presence of a catalyst to obtain a compound of a general formula (II);

wherein:

ring C, L, R ¹ ～R ⁴ M, n and s are as defined in formula (II).

Scheme five

The preparation method of the compound shown in the general formula (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof comprises the following steps:

carrying out Click reaction on the compound of the general formula (IIIB) and the compound of the general formula (IID) in the presence of a catalyst to obtain a compound of a general formula (IIIA); removing the amino protecting group of the compound of the general formula (IIIA) under an acidic condition to obtain a compound of a general formula (III);

wherein:

w is an amino protecting group, preferably tert-butyloxycarbonyl;

G、L、R ¹ ～R ⁴ m, n, s, p, q, r and t are as defined in formula (III).

Scheme six

carrying out a Click reaction on the compound of the general formula (IIIB) and the compound of the general formula (IIC) in the presence of a catalyst to obtain a compound of a general formula (III);

wherein:

G、L、R ¹ ～R ⁴ m, n, s, p, q, r and t are as defined in formula (III).

Scheme seven

The preparation method of the compound shown in the general formula (IIIaa) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof comprises the following steps:

carrying out a Click reaction on the compound of the general formula (IIIb) and the compound of the general formula (IID) in the presence of a catalyst to obtain a compound of a general formula (IIIa); removing the amino protecting group from the compound of the general formula (IIIa) under an acidic condition to obtain a compound of the general formula (IIIaa);

wherein:

w is an amino protecting group, preferably tert-butyloxycarbonyl;

G、R ¹ ～R ⁴ m, n, s, p, q, r and t are as defined in formula (IIIaa).

Scheme eight

A process for the preparation of a compound of formula (IIIaa) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

the compound of the general formula (IIIb) and the compound of the general formula (IIC) are subjected to Click reaction in the presence of a catalyst to obtain the compound of the general formula (IIIaa),

wherein:

G、R ¹ ～R ⁴ m, n, s, p, q, r and t are as defined in formula (IIIaa).

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: thermo, model: finnigan LCQ advantage MAX).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260 DAD HPLC.

High performance liquid chromatography preparative chromatographs were used, including Waters 2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson-281.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Litsea crassirhizomes as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: acetone, E: dichloromethane/acetone system, F: ethyl acetate/dichloromethane system, G: ethyl acetate/dichloromethane/n-hexane, H: ethyl acetate/dichloromethane/acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

3- (6- (1- ((6- (2-oxa-6-azaspiro [ 3.3))]Heptane-6-yl) pyridin-2-yl) methyl) -1H-1,2,3-triazol-4-yl) -2-aminopyrimidin-4-yl) -2-methylbenzonitrile 1

First step of

6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyridine-2-carboxylic acid methyl ester 1b

Methyl 6-bromopicolinate 1a (5.000g, 23.145mmol, prepared by a known method "Journal of Medicinal Chemistry,2017, 60 (2), 722-748"), 2-oxa-6-azaspiro [3.3] heptane hemioxalate (7.340g, 25.460mmol, nanjing pharma technologies, ltd.), and sodium bicarbonate (19.444g, 231.458mmol) were dissolved in 120mL of acetonitrile in this order, heated to 70 ℃ and reacted with stirring for 17 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1B (1.118 g, yield: 20.62%).

MS m/z(ESI)：235.2[M+1]。

Second step of

(6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyridin-2-yl) methanol 1c

Compound 1b (100mg, 0.427mmol) was dissolved in 5mL of tetrahydrofuran, cooled to 0 deg.C, added with lithium aluminum hydride (100mg, 0.427mmol), warmed to room temperature, and stirred for 0.5 hours. To the reaction mixture was added 0.1mL of water, 50mL of ethyl acetate was added, the mixture was stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1c (88 mg, yield: 100%).

MS m/z(ESI)：207.1[M+1]。

The third step

6- (6- (azidomethyl) pyridin-2-yl) -2-oxa-6-azaspiro [3.3] heptane 1d

Compound 1c (88mg, 0.427mmol) was dissolved in 5mL of toluene under argon, cooled to 0 ℃ and added diphenyl azide phosphate (141mg, 0.512mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (78mg, 0.512mmol), warmed to room temperature and stirred for reaction for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1d (62 mg, yield: 62.83%).

MS m/z(ESI)：232.1[M+1]。

The fourth step

3- (6- (1- ((6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyridin-2-yl) methyl) -1H-1,2,3-triazol-4-yl) -2-aminopyrimidin-4-yl) -2-methylbenzonitrile 1

3- (2-amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile 1e (150mg, 0.64mmol, prepared as disclosed in example 1 of the specification at page 76 of the patent application "WO 2018136700"), compound 1d (193mg, 0.835mmol), copper sulfate pentahydrate (1695g, 0.064mmol), and L (+) -Su Tangxing-2,3,4,5,6-pentahydroxy-2-hexenoic acid-4-lactone sodium (64mg, 0.323mmol) were dissolved in a mixed solvent of 15mL of t-butanol and water (V/V = 2/1) in this order, warmed to 60 ℃, and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1 (122.1 mg, yield: 40.96%).

MS m/z(ESI)：466.1[M+1]。

¹ H NMR(400MHz，DMSO-d ₆ )：δ8.61(s，1H)，7.90-7.88(m，1H)，7.76-7.75(m，1H)，7.53-7.49(m，2H)，7.27(s，1H)，6.89(brs，2H)，6.49-6.47(m，1H)，6.35-6.33(m，1H)，5.61(s，2H)，4.69(s，4H)，4.06(s，4H)，2.55(s，3H)。

Example 2

3- (6- (1- ((6- (2-oxa-7-azaspiro [3.5] nonan-7-yl) pyridin-2-yl) methyl) -1H-1,2,3-triazol-4-yl) -2-aminopyrimidin-4-yl) -2-methylbenzonitrile 2

First step of

6- (2-oxa-7-azaspiro [3.5] nonan-7-yl) pyridine-2-carboxylic acid methyl ester 2a

Compound 1a (141mg, 0.653mmol), 2-oxa-7-azaspiro [3.5] nonane hemioxalate (124mg, 0.360mmol) and potassium carbonate (452mg, 3.271mmol) were dissolved in this order in 1mL of N, N-dimethylformamide, warmed to 90 ℃ and reacted with stirring for 65 hours. To the reaction mixture was added 50mL of water, extracted with ethyl acetate (30 mL. Times.4), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2a (75 mg, yield: 43.80%).

MS m/z(ESI)：263.2[M+1]。

Second step of

(6- (2-oxa-7-azaspiro [3.5] nonan-7-yl) pyridin-2-yl) methanol 2b

Compound 2a (75mg, 0.286 mmol) was dissolved in 10mL of tetrahydrofuran, cooled to 0 ℃, added with lithium aluminum hydride (15mg, 0.442mmol), warmed to room temperature, and reacted with stirring for 1 hour. The reaction mixture was quenched with 30mL of water, extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 2b (65 mg, yield: 97.03%).

MS m/z(ESI)：235.2[M+1]。

The third step

7- (6- (azidomethyl) pyridin-2-yl) -2-oxa-7-azaspiro [3.5] nonane 2c

Compound 2b (65mg, 0.277mmol) was dissolved in 10mL of toluene under argon, cooled to 0 ℃ and added to diphenyl azide phosphate (87mg, 0.336 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (51mg, 0.050mmol, shanghai Shao reagent Ltd.), warmed to room temperature and stirred for reaction for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2c (20 mg, yield: 27.80%).

MS m/z(ESI)：260.1[M+1]。

The fourth step

2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile 2e

3-bromo-2-methylbenzonitrile 2d (42.5 g,216.788mmol, which was prepared by a known method "Bioorganic and Medicinal Chemistry Letters,2011, 21 (2), 644-651"), 4,4,4',4',5,5,5',5' -octamethyl-2,2 '-bis (1,3,2-dioxacyclopentane) (69.0 g,271.720mmol, shanghai Shao reagent Limited), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (8.0 g, 10.933mmol) and potassium acetate (64.0 g, 652.114mmol) were dissolved in 500mL 1, 4-dioxane in this order under argon atmosphere, heated to 90 ℃ and reacted for 4 hours with stirring. Filtration and concentration of the filtrate under reduced pressure were carried out, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2e (38.0 g, yield: 72.10%).

The fifth step

3- (2-bis (tert-butoxycarbonyl) amino-6-chloropyrimidin-4-yl) -2-methylbenzonitrile 2g

2-bis (tert-butoxycarbonyl) amino-4,6-dichloropyrimidine 2f (80.0g, 219.645mmol, prepared by a known method "Chemistry-A European Journal,2005, 11 (2), 662-668"), compound 2e (28.0g, 115.175mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (4.0g, 5.467mmol), and potassium carbonate (24.0g, 173.4651 mmol) were dissolved in this order in a mixed solvent of m600L1, 4-dioxane and water (V/V = 5/1) under argon atmosphere, and the reaction was stirred for 4 hours. The liquid was separated, the aqueous phase was extracted with ethyl acetate (200 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate for 15 minutes, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain 2g (39.6 g, yield: 77.28%) of the title compound.

The sixth step

3- (2-bis (tert-butoxycarbonyl) amino-6- ((triisopropylsilyl) ethynyl) pyrimidin-4-yl) -2-methylbenzonitrile 2h

In an argon atmosphere, 2g (5.0g, 11.238mmol) of the compound, triisopropylsilylacetylene (3.075g, 16.861mmol), palladium (158mg, 0.225mmol) of triphenylphosphine dichloride, cuprous iodide (86mg, 0.452mmol) and triethylamine (3.412g, 33.719mmol) were dissolved in this order in 220mL of tetrahydrofuran, and the reaction was stirred at reflux for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2h (6.476 g, yield: 97.53%).

MS m/z(ESI)：591.2[M+1]。

Seventh step

3- (2-bis (tert-butoxycarbonyl) amino-6-ethynylpyrimidin-4-yl) -2-methylbenzonitrile 2i

Compound 2h (6.476 g, 10.961mmol) was dissolved in 125mL of tetrahydrofuran, cooled to 0 ℃ and tetrabutylammonium fluoride (3.440g, 13.157mmol) was added and the reaction stirred for 30 minutes. To the reaction mixture was added 150mL of saturated ammonium chloride solution, extracted with ethyl acetate (150 mL. Times.3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 2i (3.021 g, yield: 63.43%).

MS m/z(ESI)：435.2[M+1]。

Eighth step

3- (6- (1- ((6- (2-oxa-7-azaspiro [3.5] nonan-7-yl) pyridin-2-yl) methyl) -1H-1,2,3-triazol-4-yl) -2-bis (tert-butoxycarbonyl) aminopyrimidin-4-yl) -2-methylbenzonitrile 2j

Compound 2i (33mg, 0.076mmol), compound 2c (20mg, 0.077mmol), copper sulfate pentahydrate (2mg, 0.008mmol) and L (+) -Su Tangxing-2,3,4,5,6-pentahydroxy-2-hexenoic acid-4-lactone sodium (8mg, 0.040mmol) were dissolved in 9mL of a mixed solvent of t-butanol and water (V/V = 2/1) in this order, and the temperature was raised to 60 ℃ and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2j (52 mg, yield: 98.68%).

MS m/z(ESI)：694.1[M+1]。

The ninth step

Compound 2j (52mg, 0.075mmol) was dissolved in 9mL of a mixed solvent of dichloromethane and trifluoroacetic acid (V/V = 2/1), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, 50mL of saturated sodium bicarbonate solution was added to adjust the pH to more than 7, ethyl acetate was extracted (30 mL. Times.3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 2 (19.7 mg, yield: 53.25%).

MS m/z(ESI)：494.2[M+1]。

¹ H NMR(400MHz，DMSO-d ₆ )：δ8.64(s，1H)，7.90-7.88(m，1H)，7.76-7.74(m，1H)，7.53-7.49(m，2H)，7.26(s，1H)，6.89(brs，2H)，6.80-6.78(m，1H)，6.48-6.46(m，1H)，5.61(s，2H)，4.33-4.28(m，4H)，3.44-3.40(m，4H)，2.55(s，3H)，1.76-1.70(m，4H)。

Example 3

3- (6- (1- ((6- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) pyridin-2-yl) methyl) -1H-1,2,3-triazol-4-yl) -2-aminopyrimidin-4-yl) -2-methylbenzonitrile 3

First step of

6- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) pyridine-2-carboxylic acid ethyl ester 3b

Ethyl 6- (bromomethyl) picolinate 3a (2.179g, 8.927mmol, prepared by the well-known method "Journal of organic Biochemistry,2012, 112, 49-58"), 2-oxa-6-azaspiro [3.3] heptane hemioxalate (2.831g, 9.820mmol) and sodium bicarbonate (7.5g, 89.279mmol) were dissolved in this order in 120mL acetonitrile, heated to 70 ℃ and reacted for 17 hours with stirring. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 3B (685 mg, yield: 29.25%).

MS m/z(ESI)：263.2[M+1]。

Second step of

(6- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) pyridin-2-yl) methanol 3c

Compound 3b (100mg, 0.381mmol) was dissolved in 10mL of tetrahydrofuran, cooled to 0 ℃, added with lithium aluminum hydride (20mg, 0.590mmol), warmed to room temperature, and stirred for 1 hour. To the reaction mixture were added 0.5mL of water, 50mL of ethyl acetate was added, the mixture was stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 3c (76 mg, yield: 90.5%).

MS m/z(ESI)：221.2[M+1]。

The third step

6- ((6- (azidomethyl) pyridin-2-yl) methyl) -2-oxa-6-azaspiro [3.3] heptane 3d

Compound 3c (76mg, 0.345mmol) was dissolved in 10mL of toluene under argon, cooled to 0 ℃, added with diphenyl azide phosphate (108mg, 0.417mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (64mg, 0.420mmol), warmed to room temperature, and stirred for reaction for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 3d (82 mg, yield: 96.89%).

MS m/z(ESI)：246.2[M+1]。

The fourth step

Compound 1e (79mg, 0.337mmol), compound 3d (82mg, 0.334mmol), copper sulfate pentahydrate (9mg, 0.036mmol) and L (+) -Su Tangxing-2,3,4,5,6-pentahydroxy-2-hexenoic acid-4-lactone sodium (34mg, 0.172mmol) were dissolved in this order in a mixed solvent of 12mL t-butanol and water (V/V = 2/1), warmed to 60 ℃ and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 3 (25.3 mg, yield: 15.78%).

MS m/z(ESI)：480.2[M+1]。

¹ H NMR(400MHz，DMSO-d ₆ )：δ8.70(s，1H)，7.90-7.88(m，1H)，7.81-7.74(m，2H)，7.53-7.49(m，1H)，7.29-7.28(m，2H)，7.21-7.19(m，1H)，6.89(brs，2H)，5.81(s，2H)，4.55(s，4H)，3.64(s，2H)，3.39(s，4H)，2.54(s，3H)。

Example 4

3- (2-amino-6- (1- ((6- (tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) pyridin-2-yl) methyl) -1H-1,2,3-triazol-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile 4

First step of

N- [4- [1- [ (6-bromo-2-pyridinyl) methyl ] triazol-4-yl ] -6- (3-cyano-2-methyl-phenyl) pyrimidin-2-yl ] -N-tert-butoxycarbonyl-carbamic acid tert-butyl ester 4b

2- (azidomethyl) -6-bromopyridine 4a (1.272g, 5.970mmol, prepared by the method disclosed in "example 8 on page 47 of the specification in WO 2010011375"), compound 2i (2.45g, 5.638mmol), copper sulfate pentahydrate (20mg, 80.10. Mu. Mol), L (+) -Su Tangxing-2,3,4,5,6-pentahydroxy-2-hexenoic acid-4-lactone sodium salt (80mg, 403.8. Mu. Mol) were added to a mixed solvent of 40mL of water and 80mL of tert-butyl alcohol, and reacted at 60 ℃ for 16 hours. The reaction was cooled to room temperature, concentrated under pressure, the residue was extracted three times with dichloromethane (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified with Combiflash flash Rapid prep with eluent System B to give the title compound 4B (3 g, yield: 82.16%).

Second step of

N- [4- [1- [ [6- (1, 3a,4,6 a-hexahydrofuro [3,4-c ] pyrrol-5-yl) -2-pyridinyl ] methyl ] triazol-4-yl ] -6- (3-cyano-2-methyl-phenyl) pyrimidin-2-yl ] -N-tert-butoxycarbonyl-carbamic acid tert-butyl ester 4d

hexahydro-1H-furo [3,4-c ] pyrrole hydrochloride 4c (160mg, 1.069mmol, prepared by a known method "Synthesis,2017, 49 (14), 3112-3117") and sodium tert-butoxide (174mg, 1.810mmol) were added to 20mL of 1, 4-dioxane, and the mixture was heated to 90 ℃ for 30 minutes. The reaction mixture was cooled to room temperature, and then compound 4b (300mg, 463.3. Mu. Mol), tris (dibenzylideneacetone) dipalladium (55mg, 60.06. Mu. Mol), 4,5-bis-diphenylphosphine-9,9-dimethylxanthene (70mg, 120.9. Mu. Mol) were added under an argon atmosphere, and the mixture was heated to 100 ℃ to react overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 4d (360 mg, yield: 114.3%). The product was used in the next reaction without purification.

The third step

The crude compound 4d (360mg, 529.5. Mu. Mol) was dissolved in 10mL of dichloromethane, 2.5mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 30mL of dichloromethane, a saturated aqueous solution of sodium bicarbonate was added to adjust the pH to more than 7, the mixture was separated, the aqueous phase was extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified with a preparative plate using eluent system A to give the title compound 4 (20 mg, yield: 7.87%).

MS m/z(ESI)：480.1[M+1]。

¹ H NMR(400MHz，CDCl ₃ )：δ8.38(s，1H)，7.71-7.73(m，1H)，7.67-7.71(m，1H)，7.57(s，1H)，7.41-7.47(m，2H)，6.53(d，1H)，6.37(d，1H)，5.56(s，2H)，5.14(s，2H)，3.99-4.02(m，2H)，3.71-3.75(m，2H)，3.65-3.67(m，2H)，3.43-3.47(m，2H)，3.09-3.10(m，2H)，2.65(s，3H)。

Example 5

3- (6- (1- ((6- (7-oxa-2-azaspiro [3.5] nonan-2-yl) pyridin-2-yl) methyl) -1H-1,2,3-triazol-4-yl) -2-aminopyrimidin-4-yl) -2-methylbenzonitrile 5

First step of

6- (7-oxa-2-azaspiro [3.5] nonan-2-yl) pyridine-2-carboxylic acid ethyl ester 5b

Ethyl 6-bromopicolinate 5a (1.0 g,4.347mmol, prepared by the well-known method "Tetrahedron,2012, 68 (24), 4701-4709"), 7-oxa-2-azaspiro [3.5] nonane hemioxalate (1.497g, 4.347mmol) and potassium carbonate (3.004g, 21.736 mmol) were dissolved in 40mLN, N-dimethylformamide sequentially, heated to 90 ℃ and reacted with stirring for 65 hours. To the reaction mixture was added 100mL of water, extracted with ethyl acetate (100 mL. Times.3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 5B (605 mg, yield: 50.37%).

MS m/z(ESI)：277.2[M+1]。

Second step of

(6- (7-oxa-2-azaspiro [3.5] nonan-2-yl) pyridin-2-yl) methanol 5c

Compound 5b (605mg, 2.189mmol) was dissolved in 40mL tetrahydrofuran, cooled to 0 ℃, lithium aluminum hydride (112mg, 3.302mmol) was added, the temperature was raised to room temperature, and the reaction was stirred for 1 hour. To the reaction mixture was added 100mL of water, extracted with ethyl acetate (100 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 5c (510 mg, yield: 99.42%).

MS m/z(ESI)：235.1[M+1]。

The third step

2- (6- (azidomethyl) pyridin-2-yl) -7-oxa-2-azaspiro [3.5] nonane 5d

Compound 5c (210mg, 0.896 mmol) was dissolved in 30mL of a mixed solvent of tetrahydrofuran and toluene (V/V = 1/1) under argon, cooled to 0 ℃, added with diphenyl azide phosphate (279mg, 1.076 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (164mg, 1.077 mmol), warmed to room temperature, and stirred for reaction for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 5d (64 mg, yield: 27.11%).

MS m/z(ESI)：260.2[M+1]。

The fourth step

Compound 1e (34mg, 0.145mmol), compound 5d (64mg, 0.247mmol), copper sulfate pentahydrate (4mg, 0.016mmol) and L (+) -Su Tangxing-2,3,4,5,6-pentahydroxy-2-hexenoic acid-4-lactone sodium (15mg, 0.076mmol) were dissolved in this order in a mixed solvent of 12mL of t-butanol and water (V/V = 2/1), heated to 60 ℃ and stirred for 2 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 5 (37.2 mg, yield: 51.93%).

MS m/z(ESI)：494.2[M+1]。

¹ H NMR(400MHz，DMSO-d ₆ )：δ8.62(s，1H)，7.91-7.89(m，1H)，7.76-7.74(m，1H)，7.53-7.48(m，2H)，7.26(s，1H)，6.91(brs，2H)，6.44-6.42(m，1H)，6.34-6.32(m，1H)，5.60(s，2H)，3.67(s，4H)，3.54-3.51(m，4H)，2.55(s，3H)，1.72-1.69(m，4H)。

Example 6

4- (6- ((4- (2-amino-6- (3-cyano-2-methylphenyl) pyrimidin-4-yl) -1H-1,2,3-triazol-1-yl) methyl) pyridin-2-yl) morpholine-3-carboxylic acid 6

First step of

4- [6- [ [4- [2- [ bis (tert-butoxycarbonyl) amino ] -6- (3-cyano-2-methyl-phenyl) pyrimidin-4-yl ] triazol-1-yl ] methyl ] -2-pyridinyl ] morpholine-3-carboxylic acid methyl ester 6a

Morpholine-3-carboxylic acid methyl ester (440mg, 3.031mmol), compound 4b (900mg, 1.389mmol), cesium carbonate (1.97g, 6.046 mmol), 4,5-bis diphenylphosphine-9,9-dimethylxanthene (233mg, 402.6. Mu. Mol), tris (dibenzylideneacetone) dipalladium (184mg, 200.9. Mu. Mol) were added to 40mL of 1, 4-dioxane under an argon atmosphere, and heated to 90 ℃ for 16 hours. The reaction was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified using CombiFlash flash prep with eluent system a to give the title compound 6a (413 mg, yield: 41.74%).

Second step of

4- [6- [ [4- [ 2-amino-6- (3-cyano-2-methyl-phenyl) pyrimidin-4-yl ] triazol-1-yl ] methyl ] -2-pyridinyl ] morpholine-3-carboxylic acid methyl ester 6b

Compound 6a (413mg, 580.2. Mu. Mol) was dissolved in 20mL of methylene chloride, 4mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution was added to the residue to adjust the pH to more than 7, the aqueous phase was extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified with a Combiflash flash Rapid preparation apparatus using eluent system A to give the title compound 6b (330 mg, yield: 111.1%).

The third step

Compound 6b (250mg, 488.7 μmol) was added to 20mL of water and methanol (V/V = 1/1), lithium hydroxide (41mg, 977.0 μmol) was further added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and 1N hydrochloric acid was added to adjust pH to 7. The aqueous phase was extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified using the preparative plate with eluent system A to give the title compound 6 (50 mg, yield: 20.56%).

MS m/z(ESI)：489.2[M+1]。

¹ H NMR(400MHz，DMSO-d ₆ )：δ12.97(brs，1H)，8.58(s，1H)，7.86(d，1H)，7.43(d，1H)，7.46-7.50(m，2H)，7.24(s，1H)，6.84(s，2H)，6.68(s，1H)，6.47(s，1H)，5.57(s，2H)，4.77(s，1H)，4.23-4.26(m，1H)，3.80-3.89(m，2H)，3.61-3.63(s，1H)，3.44-3.46(m，1H)，3.19-3.20(m，1H)，2.52(s，3H)。

Test example:

biological evaluation

Test examples 1,The compounds of the present disclosure are adenosine A _2a Receptor (adenosine A) _2a receptor，A _2a R) cAMP signalling pathway, adenosine A _2b Receptor (adenosine A) _2b receptor，A _2b R) cAMP signalling pathway, adenosine A ₁ Receptor (adenosine A) ₁ receptor，A ₁ R) cAMP signalling pathway and adenosine A ₃ Receptor (adenosine A) ₃ receptor，A ₃ R) measurement of cAMP Signaling pathway inhibitory Activity.

The following method was used to determine the adenosine A of the compounds of the present disclosure _2a Receptor (adenosine A) _2a receptor，A _2a R) cAMP signalling pathway, adenosine A _2b Receptor cAMP signalling pathway, adenosine A ₁ Receptor cAMP signaling pathway and adenosine A ₃ Inhibitory activity of the receptor cAMP signaling pathway.

The experimental method is briefly described as follows:

1. experimental materials and instruments

1.CHO-K1/A _2a R cells (NM _ 000675.5) or CHO-K1/A _2b R cells (NM _ 000676.2) or CHO-K1/A ₁ R cells (NM _ 000674.2) or CHO-K1/A ₃ R cells (NM _ 000677.3)

2. Fetal bovine serum (Gibco, 10099-141)

3. Bleomycin (Thermo, R25001) or G418 (ENZO, ALX-380-013-G005) or puromycin (Thermo, 10687-010)

DMEM/F12 medium (GE, SH 30023.01)

5. Cell separation buffer (Thermo Fisher, 13151014)

6.HEPES(Gibco，42360-099)

7. Bovine serum albumin (MP Biomedicals, 219989725)

8. Rolipram (sigma, R6520-10 MG)

9. Adenosine deaminase (sigma, 10102105001)

10. Forskolin (sigma, F6886)

11. 2Cl-IB-MECA(Tocrics，1104/10)

N6-cyclopentyladenosine (Tocris, 1702/50)

13. Balanced salt buffer (Thermo, 14025-092)

cAMP dynamics 2 kit (cAMP dynamic 2 kit) (Cisbio, 62AM4 PEB)

15.384 orifice plates (Corning, 4514) or (Nunc, 267462 #)

16. Ethyl carbazole (Torcis, 1691/10)

PHERAstar multifunctional enzyme-labeling instrument (Cisbio, 62AM4 PEB)

2. Experimental procedure

2.1 adenosine A _2a Receptors

CHO-K1/A _2a R cells were cultured in DMEM/F12 medium containing 10% fetal bovine serum and 800. Mu.g/ml bleomycin. In the experiment, cells were digested with a cell isolation buffer, resuspended and counted in a balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 10 ⁶ Each/ml. Mu.l of cell suspension, 2.5. Mu.l of test compound at 4X concentration in balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54. Mu.M rolipram and 2.7U/ml adenosine deaminase were added to each well of 384-well plates and incubated at room temperature for 30 minutes. Mu.l of ethyl carbazole at 4X concentration in a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54. Mu.M rolipram and 2.7U/ml adenosine deaminase was added to each well and incubated at room temperature for 30 minutes. The final compound concentrations were: 10000. 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512, 0.001024nM, and the final concentration of ethyl carbazole is 20nM. Intracellular cAMP concentration was detected using cAMP kinetic 2 kit. cAMP-d2 and Anti-cAMP-Eu-Cryptate (Anti-cAMP-Eu-Cryptate) were diluted with cAMP lysis buffer at a ratio of 1: 4, respectively. Mu.l of diluted cAMP-d2 was added to each well, 5. Mu.l of diluted anti-cAMP-Eu-cryptate was added thereto, and incubation was performed at room temperature for 1 hour in the absence of light. And reading the HTRF signal value by using a PHERAStar multifunctional microplate reader. IC of compound inhibitory activity was calculated using Graphpad Prism software ₅₀ Values, see table 1.

2.2 adenosine A _2b Receptors

CHO-K1/A _2b R was cultured in DMEM/F12 medium containing 10% fetal bovine serum and 1mg/ml G418. In the experiment, cells were digested with cell isolation buffer and treated with 20mM HEPES and 0.1% bovine serum albuminThe cells were resuspended and counted in balanced salt buffer, and the cell density was adjusted to 10 ⁶ One per ml. Mu.l of cell suspension, 2.5. Mu.l of test compound at 4X concentration in balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54. Mu.M rolipram and 2.7U/ml adenosine deaminase were added to each well of 384-well plates and incubated at room temperature for 30 minutes. Mu.l of ethyl carbazole (Torcis, 1691/10) at 4X concentration in a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54. Mu.M rolipram and 2.7U/ml adenosine deaminase was added to each well and incubated at room temperature for 30 minutes. The final compound concentrations were: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0nM, and the final concentration of ethyl carbazole is 1 μ M. Intracellular cAMP concentration was detected using cAMP kinetic 2 kit. cAMP-d2 and anti-cAMP-Eu cryptate were diluted with cAMP lysis buffer at a ratio of 1: 4, respectively. Mu.l of diluted cAMP-d2 was added to each well, 5. Mu.l of diluted anti-cAMP-Eu-cryptate was added thereto, and incubation was performed at room temperature for 1 hour in the absence of light. And reading the HTRF signal value by using a PHERAStar multifunctional microplate reader. IC of compound inhibitory activity was calculated using Graphpad Prism software ₅₀ Values, see table 2.

2.3 adenosine A ₁ Receptors

CHO-K1/A ₁ R was cultured in DMEM/F12 medium containing 10% fetal bovine serum and 1mg/ml G418. In the experiment, cells were digested with a cell isolation buffer, then resuspended and counted in a balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5X 10 ⁵ One per ml. To each well of the 384-well plate, 12.5. Mu.l of the cell suspension, 6.25. Mu.l of the test compound at 4X concentration in a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54. Mu.M rolipram and 2.7U/ml adenosine deaminase were added and incubated at room temperature for 30 minutes. Mu.l of forskolin and N6-cyclopentyladenosine at 4X concentration in balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54. Mu.M rolipram and 2.7U/ml adenosine deaminase were added to each well and incubated at room temperature for 30 minutes. The final compound concentrations were: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0nM, forskolin final concentration 10. Mu.M, CPA final concentration 10nM. Intracellular cAMP concentration Using cAMP dynamic 2 kitAnd (6) measuring. cAMP-d2 and anti-cAMP-Eu-cryptate were diluted with cAMP lysis buffer at a ratio of 1: 4, respectively. Mu.l of diluted cAMP-d2 was added to each well, and 12.5. Mu.l of diluted anti-cAMP-Eu-cryptate was added thereto, followed by incubation for 1 hour at room temperature in the absence of light. And reading the HTRF signal value by using a PHERAStar multifunctional microplate reader. IC of compound inhibitory activity was calculated using Graphpad Prism software ₅₀ Values, see table 1 or table 2.

2.4 adenosine A ₃ Receptors

CHO-K1/A ₃ R was cultured in DMEM/F12 medium containing 10% fetal bovine serum and 10. Mu.g/ml puromycin. In the experiment, cells were digested with a cell separation buffer, resuspended and counted in a balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5X 10 ⁵ And/ml. Mu.l of cell suspension, 6.25. Mu.l of test compound at 4X concentration in balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54. Mu.M rolipram and 2.7U/ml adenosine deaminase, were added to each well of 384-well plates and incubated at room temperature for 30 minutes. Mu.l of forskolin and 2Cl-IB-MECA at 4 Xconcentration in balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54. Mu.M rolipram and 2.7U/ml adenosine deaminase were added to each well and incubated at room temperature for 30 minutes. The final compound concentrations were: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0nM, forskolin final concentration of 10. Mu.M, 2Cl-IB-MECA final concentration of 5nM. Intracellular cAMP concentration was detected using cAMP kinetic 2 kit. cAMP-d2 and anti-cAMP-Eu-cryptate were diluted with cAMP lysis buffer at a ratio of 1: 4, respectively. Mu.l of diluted cAMP-d2 was added to each well, and 12.5. Mu.l of diluted anti-cAMP-Eu-cryptate was added thereto, followed by incubation for 1 hour at room temperature in the absence of light. And reading the HTRF signal value by using a PHERAStar multifunctional microplate reader. IC of compound inhibitory activity was calculated using Graphpad Prism software ₅₀ Values, see table 1 or table 2.

TABLE 1 Compounds of the present disclosure para adenosine A _2a Receptor (adenosine A) _2a receptor，A _2a R) IC for cAMP Signaling pathway inhibition Activity ₅₀ Value of

-: was not tested.

TABLE 2 Compounds of the present disclosure para adenosine A _2b Receptor (adenosine A) _2b receptor，A _2b R) IC for cAMP Signaling pathway inhibitory Activity ₅₀ Value of

-: was not tested.

And (4) conclusion: as can be seen from the data in tables 1 and 2, the compounds of the present disclosure are adenosine A when ring C is a 7-14 membered polycyclic heterocyclic group _2a Receptor and adenosine A _2b The receptors all have good inhibitory activity on adenosine A ₁ Receptor and adenosine A ₃ Receptor inhibitory activity was weak, while negative control example 6 was adenosine A ₁ The receptor has good inhibitory activity and poor selectivity.

It can also be seen from Table 2 that the compounds of the present disclosure, when ring C is a 7-14 membered polycyclic heterocyclic group, are comparable to negative control example 6 for A _2b The difference of the receptor inhibitory activity is 10-20 times.

Claims

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

wherein:

ring a and ring B are the same or different and are each independently phenyl or pyridyl;

ring C is

G is an O atom;

p, q, r and t are the same or different and are each independently 1 or 2;

l is a bond or C _1-6 An alkylene group;

each R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Deuterated alkyl, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino and nitro;

R ² selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Deuterated alkyl, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino and nitro;

each R is ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Deuterated alkyl, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino and nitro;

each R is ⁴ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Deuterated alkyl, hydroxy, C _1-6 Hydroxyalkyl, cyano, amino and nitro;

m is 0, 1,2,3 or 4;

n is 0, 1,2 or 3; and is provided with

s is 0, 1,2,3, 4,5 or 6.

2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, which is a compound of formula (II), or a pharmaceutically acceptable salt thereof:

wherein:

ring C, L, R ¹ To R ⁴ M, n and s are as defined in claim 1.

3. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, which is a compound of formula (III), or a pharmaceutically acceptable salt thereof:

wherein:

g is an O atom;

p, q, r and t are the same or different and are each independently 1 or 2;

s is 0, 1,2,3 or 4;

L、R ¹ to R ⁴ M and n are as defined in claim 1.

4. The compound of the general formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1,

wherein:

ring C is selected from

5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein: l is a bond or-CH ₂ -。

6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein: r ¹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and cyano; m is 0, 1 or 2.

7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein: r is ² Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; r ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; n is 0, 1 or 2.

8. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R ⁴ Is a hydrogen atom.

9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is selected from:

10. a compound of formula (IA), or a pharmaceutically acceptable salt thereof:

wherein:

w is an amino protecting group;

ring A, ring B, ring C, L, R ¹ To R ⁴ M, n and s are as defined in claim 1.

11. The compound of formula (IA) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein W is t-butoxycarbonyl.

12. A compound of formula (IA), or a pharmaceutically acceptable salt thereof, according to claim 10, wherein the compound is selected from:

13. a process for the preparation of a compound of formula (IA), or a pharmaceutically acceptable salt thereof, according to claim 10, which process comprises the steps of:

wherein:

ring A, ring B, ring C, L, W, R ¹ To R ⁴ M, n and s are as defined in claim 10.

14. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, which comprises the steps of:

wherein:

w is an amino protecting group;

ring A, ring B, ring C, L, R ¹ To R ⁴ M, n and s are as defined in claim 1.

15. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, which comprises the steps of:

wherein:

ring A, ring B, ring C, L, R ¹ To R ⁴ M, n and s are as defined in claim 1.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of a compound of general formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 for the preparation of a medicament for the treatment of a _2a Receptor and/or A _2b Use of a medicament for a disease or condition ameliorated by receptor inhibition.

18. The use according to claim 17, wherein the disease or disorder is selected from the group consisting of cancer, depression, cognitive function disorders, neurodegenerative disorders, attention-related disorders, extrapyramidal disorders, dyskinesia, cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, polycythemia vera, neuroinflammation and addictive behaviors.

19. The use according to claim 17, wherein the disease or condition is selected from the group consisting of cancer.

20. The use according to claim 19, wherein the cancer is selected from melanoma, brain tumors, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, and pediatric tumor.

21. The use of claim 20, wherein the sarcoma is osteosarcoma and the osteoma is osteochondrosis.

22. The use of claim 19, wherein the cancer is lung cancer.

23. Use of a compound of general formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 for the preparation of a medicament for inhibiting a _2a Receptor and/or A _2b Use in the manufacture of a medicament for a subject.