CN111205244A

CN111205244A - Thiazolocyclic compound, preparation method, intermediate and application thereof

Info

Publication number: CN111205244A
Application number: CN201911152880.3A
Authority: CN
Inventors: 程建军; 闫文仲
Original assignee: ShanghaiTech University
Current assignee: ShanghaiTech University
Priority date: 2018-11-22
Filing date: 2019-11-22
Publication date: 2020-05-29
Anticipated expiration: 2039-11-22
Also published as: CN111205244B; WO2020103930A1

Abstract

The invention discloses a thiazolo-cyclic compound, and a preparation method, an intermediate and application thereof. The structure of the thiazolocyclic compound is shown in a formula I, and the thiazolocyclic compound can be used as an adenosine A2A receptor antagonist and/or a histone deacetylase HDAC inhibitor. Further, the thiazolocyclic compound of the present invention may have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity. The thiazolocyclic compounds of the present invention may be used in the treatment and/or prevention of diseases associated with the adenosine A2A receptor and/or histone deacetylase HDAC, such as tumours and central nervous system diseases.

Description

Thiazolocyclic compound, preparation method, intermediate and application thereof

Technical Field

The invention relates to a thiazolo ring compound, a preparation method, an intermediate and application thereof.

Background

Adenosine is an endogenous purine nucleoside substance that exerts its physiological regulation function mainly by binding to Adenosine Receptors (ARs) on cell membranes. Adenosine receptors belong to the G protein-coupled receptors (GPCRs, or seven transmembrane receptors, 7TMR) and are divided into 4 subtypes, a1, A2A, A2B and A3, with A2A receptor being widely distributed in both the central nervous system and the periphery. The A2A receptor is distributed in high density in the central nervous system and has close relation with the pathogenesis of various degenerative central nervous system diseases such as Parkinson's disease, Alzheimer's disease, Huntington's chorea and the like (Gomes et al, Biochimica et Biophysica Acta,2011,1808, 1380-. Therefore, the A2A receptor antagonist can enhance the downstream signal of the D2 receptor and is used as a medicine for treating Parkinson's disease. The A2A receptor antagonist can also alleviate the side effects of levodopa (L-DOPA) -induced dyskinesia as a therapeutic agent for Parkinson's disease. A number of small molecule antagonists of the A2A receptor have entered clinical studies as drugs for the treatment of parkinson's disease (Aren van Waarde et al, Medicinal Research Reviews,2018,38,5-56), in which istradefylline (KW-6002) was approved in japan for the market in 2013 as a drug for the treatment of parkinson's disease. The compounds tozadenant (SYN-115), vipadenant (BIIB-014) and the like have also been clinically studied. Although most A2A receptor antagonists have been shown to be ineffective in clinical trials for the treatment of Parkinson's disease as a monotherapy, the potential of A2A receptor antagonists for the treatment of related degenerative central nervous system disorders has been preliminarily demonstrated.

In 2006, the Sitkovsky research group reported that adenosine was able to inhibit T cell attack on tumor cells in the tumor microenvironment by agonizing the A2A receptor (Ohta et al, PNAS,2006,103, 13132-13137). In recent years, the A2A receptor has received increasing attention as a target for tumor immunotherapy. Although current tumor immunotherapy has achieved very good results for the treatment of specific cancer types, and several drugs such as PD-1, PD-L1 antibody Keytruda, Opdivo and Teentriq, CTLA4 antibody Yervoy, etc. have been approved in the United states (Hoos, Nature Reviews drug discovery 2016,15,235-247), the effectiveness of these drugs is still low due to the presence of several immunosuppressive mechanisms in the tumor microenvironment, and the development of new tumor immunopharmaceuticals is still in the forefront. The purinergic signaling pathway plays an important role in multiple immunosuppressive mechanisms of tumors (Vijayan et al, Nature Reviews Cancer,2017,17,709-724), and inhibition of the immune function of the body by adenosine in the tumor microenvironment makes intervention of this signaling pathway a new approach to tumor immunotherapy. In the mechanism of action, the tumor hypoxic microenvironment limits energy utilization and induces the accumulation of extracellular ATP, which is hydrolytically converted to adenosine by the nucleotidases CD39 and CD73, resulting in significantly increased adenosine levels in the tumor periphery. Adenosine binding to adenosine a1, A2A, A2B and A3 receptors activates the receptors and thus performs different regulatory functions. Among them, the A2A receptor plays a major role in the immunosuppression process of tumors, and adenosine binding to A2A receptor on the surface of immune cells inhibits the immune function of these cells. Therefore, the inhibition of the A2A receptor can obviously enhance the function of immune cells and promote the infiltration of the immune cells to tumor tissues, and is favorable for the killing effect of the immune cells on tumors. Known A2A receptor antagonists such as vipadenant, CPI-444, PBF-509, AZD4635 and the like have been clinically studied as agents for tumor immunotherapy. Most of these drugs are used in combination with other tumor immune drugs or antitumor drugs.

On the other hand, Histone Deacetylases (HDACs) are another drug target closely related to tumors and degenerative central nervous system diseases. HDACs and Histone Acetyltransferases (HATs) are two key epigenetic regulating enzymes that together regulate the acetylation status of chromosomal histones and exert opposite effects in this process. HATs catalyze acetylation of N-terminal lysine residues in histones to leave chromatin in a relatively loosely open state, thereby facilitating access of transcription factors to DNA to promote gene expression; HDACs function to catalyze the removal of acetyl groups from lysine residues of histones, which places chromatin in a compact conformation and blocks DNA transcription and gene expression (Kazantsev and Thompson, Nature reviews drug Discovery,2008,7, 854-868). The human HDACs found at present have 18 subtypes, which can be divided into four subfamilies of ClassI-IV. Class I includes HDACs 1,2, 3, and 8; class II is further divided into class IIa (HDAC 4,5, 7 and 9) and class IIb (HDAC 6 and 10); class IV has only one member HDAC 11. All three subgroups are Zn²⁺Dependent HDACs are also known as classical HDACs. While Class III is also known as sirtuins and includes SIRT 1-7, NAD-dependent⁺Exerts catalytic activity.

Currently, anti-tumor is the most important and widespread use of HDAC inhibitors. The over-expression of HDAC can inhibit the expression of a series of cancer suppressor genes to promote the growth of tumor cells, for example, the abnormal function of HDAC can cause the expression of cell cycle inhibitor p21 to be reduced, so as to block the cell cycle; the transcription of an apoptosis gene can be blocked by blocking the combination of the protein and DNA by regulating the deacetylation of the p53 protein; in addition, HDAC has a relationship with angiogenesis of tumor tissues, regulation of immune cell function, etc. (Falkenberg and Johnstone, Nature Reviews Drug Discovery,2014,13, 673-. In view of the great potential exhibited by HDAC inhibitors in inhibiting tumor proliferation, they have attracted considerable attention as antitumor drugs for Research and application (Zagni et al, Medicinal Research Reviews,2017,37,1373-1428), four HDAC inhibitors (vorinostat/SAHA, romidepsin/FK228, belinostat/PDX-101, and pantonostat/LBH-589) are now approved by the U.S. FDA for the treatment of tumors such as T-cell lymphoma, and some HDAC inhibitors such as abexinostat/PCI024781, givinostat/ITF2375, and entinostat/MS-275 are in different stages of clinical Research.

In addition to their anti-tumor applications, HDAC inhibitors have also received increasing attention in the field of neurological diseases such as Alzheimer's disease, parkinson's disease, huntington's chorea, etc. (Falkenberg and johnstone, Nature Reviews Drug Discovery,2014,13,673-691) for example, various models have demonstrated that HDAC2 can modulate brain function and neurological development and deterioration, overexpression of HDAC2 can negatively modulate synaptic plasticity and number and dendritic spine density, thereby leading to the deterioration of learning cognitive function (Guan et al, Nature,2009,459,55-60) as HDAC6 can modulate the phosphorylation level of tau protein, thereby affecting the development of tau protein driven neurological diseases (Selenica et al, Alzheimer's Research & rapy, huntington, 6,12) and zen 6 can also modulate the aggregation of tau protein and inhibit the accumulation of tau protein in the pathological models of HDAC h 8765, HSP 8757-wo 9, HSP 5855, HSP-9, HSP-9, and so on pathological models (HSP 8755, HSP accumulation of pathological protein accumulation in h-wo), and so on pathological models).

Since the A2A receptor and HDAC are closely related to tumors and various central nervous system diseases, the synergistic effect of the two would be likely to exert stronger therapeutic effect in the treatment of related diseases. Currently, although dual-targeted small molecule drugs based on A2A receptor antagonists and HDAC inhibitors, respectively, have been reported, for example, dual-targeted compounds of A2A receptor and dopamine D2 receptor (

et al, J Med Chem,2015,58,718-738), the dual-target compounds of HDAC and cyclin-dependent kinase 4/9(CDK4/9) (Li et al, J Med Chem,2018,61,3166-3192), the dual-target compounds of HDAC and nicotinamide phosphoribosyltransferase (NAMPT) (Dong et al, JMed Chem,2017,60,7965-7983), but the dual-target small molecule compounds having both HDAC and A2A receptors have not been reported.

Disclosure of Invention

The invention aims to solve the problem of providing a thiazolocyclic compound, a preparation method, an intermediate and an application thereof, wherein the thiazolocyclic compound can be used as an adenosine A2A receptor antagonist or a histone deacetylase HDAC inhibitor. Further, the thiazolocyclic compound of the present invention may have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity. The thiazolocyclic compounds of the present invention may be used in the treatment and/or prevention of diseases associated with the adenosine A2A receptor and/or histone deacetylase HDAC, such as tumours and central nervous system diseases.

The invention provides a compound shown as a formula I, and pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer, solvate, metabolite or prodrug thereof:

wherein the content of the first and second substances,

R¹is hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, -NR⁶R⁷Substituted or unsubstituted C₃-C₁₀Cycloalkyl (e.g., cyclohexyl), substituted or unsubstituted 3-10 membered heterocycloalkyl (e.g.

U is CH or N, R¹⁰、R¹¹And U are joined together to form a 5,6, 7 or 8 membered heterocycloalkyl; in another example

Each U is independently CH or N, each U₁Independently O, S or CH₂P is 1 or 2; for another example

) Substituted or unsubstituted C₆-C₁₂Aryl (e.g., phenyl) or substituted or unsubstituted 5-12 membered heteroaryl (e.g., 6 membered heteroaryl); said substituted C₃-C₁₀Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C₆-C₁₂The substituents in aryl or substituted 5-12 membered heteroaryl are each independently C₁-C₆Alkyl or C₁-C₆Alkoxy, the number of the substituent is one or more, and when the number of the substituent is more than one, the substituent is the same or different;

R²is hydrogen, halogen or C₁-C₆An alkyl group;

R³is hydrogen, C₁-C₆Alkyl (e.g. methyl, ethyl, n-propyl or isopropyl, also e.g. methyl or ethyl), C₃-C₁₀Cycloalkyl or- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups);

R⁴is hydrogen or C₁-C₆An alkyl group;

R⁶and R⁷Each independently is hydrogen or C₁-C₆An alkyl group;

x is N or CR⁵；

R⁵Is hydrogen, halogen or C₁-C₆An alkyl group;

in the compounds of formula I

Is composed of

L is substituted or unsubstituted-M₁-(M₂)_m-(M₃)_n-; said substituted-M₁-(M₂)_m-(M₃)_n-means substituted by one or more R²⁰Substitution; when R is²⁰When there are plural, R²⁰The same or different;

-M₁-(M₂)_m-(M₃)_n-the following conditions (i), (ii), (iii), (iv), (v) or (vi) are satisfied:

(i) m is 0 and n is 0, M₁is-NH-, -O-, -S-, C₁-C₁₀Alkylene (e.g. C)₁-C₇Alkylene radicals, as well as C₄、C₅、C₆Or C₇Alkylene group), C₂-C₁₀Alkenylene (e.g. C)₂-C₇Alkenylene radicals, as another example C₄、C₅、C₆Or C₇Alkenylene), C₂-C₁₀Alkynylene (e.g. C)₂-C₇Alkynylene, as another example C₄、C₅、C₆Or C₇Alkynylene), heteroalkylene groups having 2 to 10 chain atoms (e.g., heteroalkylene groups having 2 to 7 chain atoms, e.g., alkylene groups having 4,5, 6, or 7 chain atomsHeteroalkyl radicals, such as

) Heteroalkenylene having 2 to 10 chain atoms (e.g., heteroalkenylene having 2 to 7 chain atoms, such as 4,5, 6 or 7 chain atoms), heteroalkynylene having 3 to 10 chain atoms (e.g., heteroalkynylene having 3 to 7 chain atoms, such as 4,5, 6 or 7 chain atoms), 3 to 10 membered cycloalkylene (e.g., 3 to 7 membered cycloalkylene, such as 1, 4-cyclohexylene), 3 to 10 membered heterocycloalkylene (e.g., 6 membered heterocycloalkylene, such as 1,4- (6 membered heterocycloalkylene), such as

)、C₆-C₁₂Arylene (e.g., 1, 4-phenylene) or 5-12 membered heteroarylene (e.g., 6 membered heteroarylene, such as 1,4- (6 membered heteroarylene));

(ii) m is 1, and n is 0, M₁is-NH-, -O-, -S-, C₁-C₁₀Alkylene (e.g. C)₁-C₆Alkylene radicals, as well as C₁、C₂、C₃Or C₄Alkylene group), C₂-C₁₀Alkenylene (e.g. C)₂-C₆Alkenylene radicals, as another example C₂、C₃Or C₄Alkenylene), C₂-C₁₀Alkynylene (e.g. C)₂-C₆Alkynylene, as another example C₂、C₃Or C₄Alkynylene), heteroalkylene groups having 2 to 10 chain atoms (e.g., heteroalkylene groups having 2 to 5 chain atoms, such as heteroalkylene groups having 2,3, or 4 chain atoms, and again, for example

And e.g.

) Heteroalkenylene having 2 to 10 chain atoms (for example heteroalkenylene having 2 to 5 chain atoms, in turn for example heteroalkenylene having 2,3 or 4 chain atoms), 3-to 10-membered cycloalkylene (for example cyclobutylene, cyclopentylene, cyclohexylene or spirolene [3,3]Heptyl, another example

) 3-to 10-membered heterocycloalkylene (e.g., 1,3- (4-membered heterocycloalkylene), 1,3- (5-membered heterocycloalkylene), 1,4- (6-membered heterocycloalkylene), or 2,6- (heterospiro [3,3 ]]Heptyl); wherein said 1,3- (4-membered heterocycloalkylene) is, for example

The 1,3- (5-membered heterocycloalkylene) group is, for example

The 1,4- (6-membered heterocycloalkylene) group is, for example

The 2,6- (hetero spiro [3,3 ])]Heptyl) such as

M₂is 3-to 10-membered cycloalkylene (e.g. cyclohexylene, also e.g. 1, 4-cyclohexylene), 3-to 10-membered heterocycloalkylene (e.g. 6-membered heterocycloalkylene, also e.g. 1,4- (6-membered heterocycloalkylene)), C₆-C₁₂Arylene (e.g. 1, 4-phenylene) or 5-12 membered heteroarylene (e.g. 6 membered heteroarylene, again e.g. 1,4- (6 membered heteroarylene); examples of said 1,4- (6 membered heteroarylene)Such as

)；

(iii) M is 1, and n is 0, M₁Is 3-to 10-membered cycloalkylene (e.g. 1, 4-cyclohexylene), 3-to 10-membered heterocycloalkylene (e.g. 1,4- (6-membered heterocycloalkylene), further

)、C₆-C₁₂Arylene (e.g., 1, 4-phenylene) or 5-12 membered heteroarylene (e.g., 5-or 6-membered heteroarylene; said 5-membered heteroarylene e.g., 1,3- (5-membered heteroarylene), said 1,3- (5-membered heteroarylene) e.g.

The 6-membered heteroarylene group such as 1,4- (6-membered heteroarylene));

M₂is C₁-C₁₀Alkylene (e.g. C)₁-C₆Alkylene radicals, as well as C₁、C₂、C₃Or C₄Alkylene group), C₂-C₁₀Alkenylene (e.g. C)₂-C₆Alkenylene radicals, as another example C₂、C₃Or C₄Alkenylene radicals, such as furthermore vinylene radicals, the said vinylene radicals preferably being in the trans configuration), C₂-C₁₀Alkynylene (e.g. C)₂-C₆Alkynylene, as another example C₂、C₃Or C₄Alkynylene), heteroalkylene groups having 2 to 10 chain atoms (e.g., heteroalkylene groups having 2 to 5 chain atoms, e.g., heteroalkylene groups having 2,3, or 4 chain atoms, e.g.

) Or heteroalkenylene having 2 to 10 chain atoms (e.g., heteroalkenylene having 2 to 5 chain atoms, as well as heteroalkenylene having 2,3, or 4 chain atoms);

(iv) m is 1 and n is 1, M₁is-NH-, -O-, -S-, C₁-C₄Alkylene (e.g. methylene or ethylene), C₂-C₄Alkenylene radicals (e.g. ethylene)Alkenyl, said vinylidene preferably being in the trans configuration), C₂-C₄Alkynylene (e.g. ethynylene), heteroalkylene having 2,3 or 4 chain atoms (e.g. heteroalkylene having 2 chain atoms, as well as

) Or heteroalkenylene having 2,3 or 4 chain atoms;

M₂is 3-to 10-membered cycloalkylene (e.g. cyclohexylene, also e.g. 1, 4-cyclohexylene), 3-to 10-membered heterocycloalkylene (e.g. 1,4- (6-membered heterocycloalkylene)), C₆-C₁₂Arylene (e.g., 1, 4-phenylene) or 5-12 membered heteroarylene (e.g., 6 membered heteroarylene, such as 1,4- (6 membered heteroarylene));

M₃is C₁-C₄Alkylene (e.g. methylene or ethylene), C₂-C₄Alkenylene (e.g. ethenylene, said ethenylene preferably being in the trans configuration), C₂-C₄Alkynylene (e.g., ethynylene), heteroalkylene having 2,3, or 4 chain atoms, or heteroalkenylene having 2,3, or 4 chain atoms (e.g., heteroalkenylene having 2 chain atoms, the double bond may be in the trans configuration);

(v) m is 1 and n is 1, M₁Is 3-to 10-membered cycloalkylene (e.g. cyclohexylene, also e.g. 1, 4-cyclohexylene), 3-to 10-membered heterocycloalkylene (e.g. 6-membered heterocycloalkylene, further e.g. 1,4- (6-membered heterocycloalkylene)), C₆-C₁₂Arylene (e.g., 1, 4-phenylene) or 5-12 membered heteroarylene (e.g., 6 membered heteroarylene, such as 1,4- (6 membered heteroarylene));

M₂is-NH-, -O-, -S-, C₁-C₄Alkylene (e.g., methylene) or heteroalkylene having 2,3, or 4 chain atoms;

M₃is 3-to 10-membered cycloalkylene (e.g. 5-, 6-or 7-membered cycloalkylene, further e.g. cyclohexylene, further e.g. 1, 4-cyclohexylene), 3-to 10-membered heterocycloalkylene (e.g. 6-membered heterocycloalkylene, further e.g. 1,4- (6-membered heterocycloalkylene)), C₆-C₁₂Arylene (e.g. 1, 4-phenylene) or 5-12 membered heteroarylene (e.g. 6 membered heteroarylene, further e.g. 1,4- (6 membered heteroarylene)Aryl groups); the 1,4- (6-membered heteroarylene) group is, for example

)；

(vi) M is 1 and n is 1, M₁is-NH-, -O-, -S-, C₁-C₄Alkylene (e.g. methylene), C₂-C₄Alkenylene (e.g. vinylene), C₂-C₄Alkynylene (e.g. ethynylene), heteroalkylene having 2,3 or 4 chain atoms (e.g. heteroalkylene having 2 chain atoms, as well as

) Or heteroalkenylene having 2,3 or 4 chain atoms;

M₂is 3-to 10-membered cycloalkylene (e.g. cyclohexylene, again e.g. 1, 4-cyclohexylene), 3-to 10-membered heterocycloalkylene (e.g. 6-membered heterocycloalkylene, again e.g. 1,4- (6-membered heterocycloalkylene) or

The 1,4- (6-membered heterocycloalkylene) group is, for example

M₃is 3-to 10-membered cycloalkylene (e.g. cyclohexylene, also e.g. 1, 4-cyclohexylene), 3-to 10-membered heterocycloalkylene (e.g. 6-membered heterocycloalkylene, also e.g. 1,4- (6-membered heterocycloalkylene)), C₆-C₁₂Arylene (e.g. 1, 4-phenylene) or 5-12 membered heteroarylene (e.g. 6 membered heteroarylene, again e.g. 1,4- (6 membered heteroarylene); said 1,4- (6 membered heteroarylene) e.g.

)；

The heteroatoms in the heteroalkylene, heteroalkenylene, heteroalkynyl, heterocycloalkylene and heteroarylene are each independently nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1,2, 3 or 4;

each R²⁰Independently oxo, thio, halogen, cyano, hydroxy, amino, nitro, C₁-C₆Alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl), C₂-C₆Alkenyl (e.g.

)、C₁-C₆Haloalkyl, C₁-C₆Heteroalkyl group, C₂-C₆Heteroalkenyl, C₂-C₆Alkynyl, C₃-C₆Heteroalkynyl, C₃-C₁₀Cycloalkyl (e.g. cyclopropyl), 3-10 membered heterocycloalkyl, C₆-C₁₂Aryl, 5-12 membered heteroaryl, - (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl) (e.g. cycloalkyl)

)、-(C₁-C₃Alkylene) - (3-to 10-membered heterocycloalkyl), - (C)₁-C₃Alkylene group) - (C₆-C₁₂Aryl), - (C)₁-C₃Alkylene) - (5-12 membered heteroaryl), -NR⁴¹R⁴²、-OR⁴¹、-SR⁴¹、-C(＝O)O-R⁴¹、-C(＝O)-NR⁴¹R⁴²、-N(R⁴²)-C(＝O)-R⁴¹、-O-C(＝O)-R⁴¹、-S(O)₂-R⁴¹、-O-S(O)₂-R⁴¹、-S(O)₂-OR⁴¹、-S(O)₂-NR⁴¹R⁴²or-N (R)⁴¹)-S(O)₂-R⁴²；

Each R⁴¹Or R⁴²Each independently is hydrogen or C₁-C₆An alkyl group;

ZBG is

Each R⁸(i.e. substituents on the phenyl ring) independentlyOr halogen (e.g. fluorine), C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₃-C₆Cycloalkyl, 3-6 membered heterocycloalkyl, C₆-C₁₂Aryl or 5-12 membered heteroaryl (e.g., thienyl, as well as thiophen-2-yl); y is 0, 1,2, 3 or 4;

R⁹is hydrogen or C₁-C₆Alkyl (e.g., n-propyl);

the heteroatoms in the heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of heteroatoms is each independently 1,2, 3, or 4.

C above₁-C₆Alkyl radical, C₁-C₆C in haloalkyl₁-C₆Alkyl and C₁-C₆C in alkoxy₁-C₆The alkyl groups may each independently be C₁-C₄An alkyl group.

C above₂-C₆Alkenyl groups may each independently be C₂-C₄An alkenyl group.

C above₃-C₁₀Cycloalkyl and- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl) C₃-C₁₀Cycloalkyl groups may each independently be C₃-C₈A cycloalkyl group.

3-to 10-membered heterocycloalkyl group as described above and- (C)₁-C₃The 3-10 membered heterocycloalkyl group in alkylene) - (3-10 membered heterocycloalkyl) may each independently be a3, 4,5, 6, 7 or 8 membered heterocycloalkyl group.

C above₆-C₁₂Aryl and- (C)₁-C₃Alkylene group) - (C₆-C₁₂C in aryl)₆-C₁₂The aryl groups may each independently be phenyl.

The above 5-12 membered heteroaryl group and- (C)₁-C₃The 5-12 membered heteroaryl group in alkylene) - (5-12 membered heteroaryl) may each independently be a 5-, 6-or 7-membered heteroaryl group.

The above-mentioned 3-to 10-membered cycloalkylene group may each independently be a 3-, 4-, 5-, 6-, 7-or 8-membered cycloalkylene group.

The above-mentioned 3-to 10-membered heterocycloalkylene group may be each independently a 3-, 4-, 5-, 6-, 7-or 8-membered heterocycloalkylene group.

C above₆-C₁₂The arylene groups may each independently be phenylene.

The above-mentioned 5-12 membered heteroarylene group may each independently be a 5-, 6-or 7-membered heteroarylene group.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, M₁Is C₁-C₁₀Alkylene, heteroalkylene having 2 to 10 chain atoms, 3-to 10-membered cycloalkylene, 3-to 10-membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, M₁Is C₄、C₅、C₆Or C₇Alkylene, heteroalkylene having 4,5, 6 or 7 chain atoms, 1, 4-cyclohexylene, 1, 4-phenylene, 1,4- (6-membered heteroarylene) or 1,4- (6-membered heterocycloalkylene).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, M₁Is C₄、C₅、C₆Or C₇Alkylene, heteroalkylene having 4,5, 6 or 7 chain atoms, 1, 4-cyclohexylene or 1,4- (6-membered heterocycloalkylene).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, M₁Is C₄、C₅、C₆Or C₇Alkylene or heteroalkane having 4,5, 6 or 7 chain atomsAnd (4) a base.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, M₁Is composed of

W₁is-CH₂-or-NH-.

W₁is-CH₂-or-NH-.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, L is

W₂is-CH (R)²¹) -or-N (R)²²)-，R²¹Is hydrogen or R²⁰，R²²Is hydrogen or R²⁰Each R²⁰Each independently as defined herein.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (ii) is satisfied, M₁is-NH-, -O-, -S-, C₁-C₁₀Alkylene having 2-Heteroalkylene of 10 chain atoms, 3-to 10-membered cycloalkylene, 3-to 10-membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene, M₂Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (ii) is satisfied, M₁is-NH-, -O-, -S-, C₁-C₁₀Alkylene, heteroalkylene having 2 to 10 chain atoms, 3-to 10-membered cycloalkylene or 3-to 10-membered heterocycloalkylene, M₂Is C₆-C₁₂Arylene or 5-12 membered heteroarylene.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (ii) is satisfied, M₁is-NH-, -O-, -S-, C₁Alkylene radical, C₂Alkylene radical, C₃Alkylene radical, C₄Alkylene or heteroalkylene having 2,3 or 4 chain atoms,

1,3- (4-membered heterocycloalkylene), 1,3- (5-membered heterocycloalkylene), 1,4- (6-membered heterocycloalkylene) or 2,6- (heterospiro [3,3 ]]Heptyl), M₂Is 1, 4-phenylene or 1,4- (6-membered heteroarylene).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (ii) is satisfied, M₁is-NH-, -O-, -S-, C₁Alkylene radical, C₂Alkylene radical, C₃Alkylene radical, C₄Alkylene or heteroalkylene having 2,3 or 4 chain atoms, M₂Is 1, 4-phenylene or 1,4- (6-membered heteroarylene).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_n-M when condition (ii) is satisfied₁-M₂-is of

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen case (ii) is satisfied, L is

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (iii) is satisfied, M₁Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene, M₂Is C₁-C₁₀Alkylene radical, C₂-C₁₀Alkenylene, heteroalkylene having 2 to 10 chain atoms or heteroalkenylene having 2 to 10 chain atoms.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (iii) is satisfied, M₁Is 3-10 membered cycloalkylene or 3-10 membered heterocycloalkylene, M₂Is C₃Alkylene or heteroalkylene having 3 chain atoms; or, M₁Is C₆-C₁₂Arylene or 5-12 membered heteroarylene, M₂Vinylidene in the trans configuration.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (iii) is satisfied, M₁Is 1, 4-cyclohexylene or 1,4- (6-membered heteroalkylene), M₂Is C₃Alkylene or heteroalkylene having 3 chain atoms; or, M₁Is 1,3- (5-membered heteroarylene), M₂Vinylidene in the trans configuration.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_n-M when condition (iii) is satisfied₁-M₂-is of

In some aspects of the inventionIn the case of the compounds of formula I as described in any of the preceding embodiments, when-M is₁-(M₂)_m-(M₃)_nWhen case (iii) is satisfied, L is

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (iv) is satisfied, M₁is-NH-, -O-, -S-, C₁-C₄Alkylene radical, C₂-C₄Alkenylene, heteroalkylene having 2,3, or 4 chain atoms, or heteroalkenylene having 2,3, or 4 chain atoms; m₂Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene; m₃Is C₁-C₄Alkylene radical, C₂-C₄Alkenylene, heteroalkylene having 2,3 or 4 chain atoms or heteroalkenylene having 2,3 or 4 chain atoms.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (iv) is satisfied, M₁is-NH-, -O-, -S-, C₁-C₄Alkylene radical, C₂-C₄Alkenylene, heteroalkylene having 2,3, or 4 chain atoms, or heteroalkenylene having 2,3, or 4 chain atoms; m₂Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene; m₃Vinylidene in the trans configuration.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (iv) is satisfied, M₁is-NH-, -O-, -S-, methylene, ethylene or a heteroalkylene having 2 chain atoms; m₂Is 1, 4-phenylene or 1,4- (6-membered heteroarylene); m₃In the trans configurationOf (i.e. vinylidene) or (i.e.

)。

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_n-M when condition (iv) is satisfied₁-M₂-M₃-is of

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (iv) is satisfied, L is

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (v) is satisfied, M₁Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene; m₂is-NH-, -O-, -S-or methylene; m₃Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (v) is satisfied, M₁Is 3-10 membered cycloalkylene or 3-10 membered heterocycloalkylene; m₂is-NH-, -O-, -S-or methylene; m₃Is C₆-C₁₂Arylene or 5-12 membered heteroarylene.

In some aspects of the inventionIn a compound of formula I as described in any of the preceding schemes, when-M is₁-(M₂)_m-(M₃)_nWhen condition (v) is satisfied, M₁Is 1, 4-cyclohexylene or 1,4- (6-membered heterocycloalkylene); m₂is-NH-, -O-, -S-or methylene; m₃Is 1, 4-phenylene or 1,4- (6-membered heteroarylene).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_n-M when condition (v) is satisfied₁-M₂-M₃-is of

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen case (v) is satisfied, L is

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (vi) is satisfied, M₁is-NH-, -O-, -S-or methylene; m₂Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene; m₃Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (vi) is satisfied, M₁is-NH-, -O-, -S-or methylene; m₂Is 3-10 membered cycloalkylene or 3-10 membered heterocycloalkylene; m₃Is C₆-C₁₂Arylene or 5-12 membered heteroarylene.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen condition (vi) is satisfied, M₁is-NH-, -O-, -S-or methylene, M₂Is 1, 4-cyclohexylene, 1,4- (6-membered heterocycloalkylene),

M₃Is 1, 4-phenylene or 1,4- (6-membered heteroarylene).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_n-M when condition (vi) is satisfied₁-M₂-M₃-is of

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nWhen case (vi) is satisfied, L is

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, X is CH or N, preferably CH.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is²Is hydrogen.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is³Is C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl or- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is³Is C₁-C₆Alkyl, such as methyl or ethyl, preferably methyl.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is⁴Is hydrogen.

In some embodiments of the invention, in the compound of formula I as described in any one of the preceding embodiments,

is composed of

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein ZBG is

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is⁸Is halogen, C₆-C₁₂Aryl or 5-12 membered heteroaryl. In some embodiments of the invention, y is 0 or 1.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is⁸Is fluorine or thiophen-2-yl.

Preferably, it is

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is²⁰Is oxo, thio, halogen, hydroxy, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Heteroalkyl group, C₃-C₁₀Cycloalkyl, 3-10 membered heterocycloalkyl or — (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is²⁰Is oxo, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Heteroalkyl group, C₃-C₁₀Cycloalkyl or- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is²⁰Is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₁₀Cycloalkyl or- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, is a compound of formula I, wherein-M is₁-(M₂)_m-(M₃)_nBy one or more R²⁰When substituted, R²⁰The number of (a) may be 1,2, 3, 4,5, 6 or 7, for example 1,2 or 3.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is²⁰Is methyl, ethyl, n-propyl, isopropyl, n-butyl,

Cyclopropyl or

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is¹Is substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted

Substituted or unsubstituted C₆-C₁₂Aryl or substituted or unsubstituted 5-12 membered heteroaryl, U is CH or N, R¹⁰、R¹¹And U are joined together to form a 5,6, 7 or 8 membered heterocycloalkyl; the number of the substituents is one or more, and each substituent is independently C₁-C₆An alkyl group.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is¹Is substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted C₆-C₁₂Aryl or substituted or unsubstituted 5-12 membered heteroaryl, each U is independently CH or N, each U is₁Independently O, S or CH₂P is 1 or 2; the number of the substituents is one or more, and each substituent is independently C₁-C₆An alkyl group.

Or substituted or unsubstituted

U is N, each U₁Independently O, S or CH₂P is 1 or 2; the number of the substituents is one or more, and each substituent is independently C₁-C₆An alkyl group.

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, wherein R is¹Is composed of

Preferably, it is

is composed of

Preferably, it is

In some embodiments of the invention, a compound of formula I as described in any of the preceding embodiments, wherein-M is₁-(M₂)_m-(M₃)_n-satisfying either situation (i) or (ii). In some embodiments, -M₁-(M₂)_m-(M₃)_n-satisfying the condition (i). In some embodiments, -M₁-(M₂)_m-(M₃)_n-satisfying situation (ii).

In some embodiments of the invention, the compound of formula I as described in any of the preceding embodiments, when ZBG is

When is, -M₁-(M₂)_m-(M₃)_n-satisfying either situation (i) or (ii).

wherein the content of the first and second substances,

R¹is substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₂Aryl or substituted or unsubstituted 5-12 membered heteroaryl; said substituted C₃-C₁₀Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C₆-C₁₂The substituents in aryl or substituted 5-12 membered heteroaryl are each independently C₁-C₆Alkyl or C₁-C₆Alkoxy, the number of the substituent is one or more, and when the number of the substituent is more than one, the substituent is the same or different;

R²is hydrogen;

R³is hydrogen, C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl or- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups);

R⁴is hydrogen or C₁-C₆An alkyl group;

R⁶and R⁷Each independently is hydrogen or C₁-C₆An alkyl group;

x is N or CR⁵；

R⁵Is hydrogen, halogen or C₁-C₆An alkyl group;

in the compounds of formula I

Is composed of

(i) m is 0 and n is 0, M₁Is C₄、C₅、C₆Or C₇Alkylene, heteroalkylene having 4,5, 6, or 7 chain atoms, 1, 4-cyclohexylene, 1, 4-phenylene, 1,4- (6-membered heteroarylene), or 1,4- (6-membered heterocycloalkylene);

(ii) m is 1, and n is 0, M₁is-NH-, -O-, -S-, C₁Alkylene radical, C₂Alkylene radical, C₃Alkylene radical, C₄Alkylene or heteroalkylene having 2,3 or 4 chain atoms,

1,3- (4-membered heterocycloalkylene), 1,3- (5-membered heterocycloalkylene), 1,4- (6-membered heterocycloalkylene) or 2,6- (heterospiro [3,3 ]]Heptyl), M₂Is 1, 4-phenylene or 1,4- (6-membered heteroarylene);

(iii) m is 1, and n is 0, M₁Is 1, 4-cyclohexylene or 1,4- (6-membered heteroalkylene), M₂Is C₃Alkylene or heteroalkylene having 3 chain atoms, or, M₁Is 1,3- (5-membered heteroarylene), M₂Vinylidene in the trans configuration;

(iv) m is 1 and n is 1, M₁is-NH-, -O-, -S-, methylene, ethylene or a heteroalkylene having 2 chain atoms; m₂Is 1, 4-phenylene or 1,4- (6-membered heteroarylene); m₃Vinylidene in the trans configuration;

(v) m is 1 and n is 1, M₁Is 1, 4-cyclohexylene or 1,4- (6-membered heterocycloalkylene); m₂is-NH-, -O-, -S-or methylene; m₃Is 1, 4-phenylene or 1,4- (6-membered heteroarylene);

(vi) m is 1 and n is 1, M₁is-NH-, -O-, -S-or methylene, M₂Is 1, 4-cyclohexylene, 1,4- (6-membered heterocycloalkylene),

M₃Is 1, 4-phenylene or 1,4- (6-membered heteroarylene);

each R²⁰Independently is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₁₀Cycloalkyl or- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups);

each R⁴¹Or R⁴²Each independently is hydrogen or C₁-C₆An alkyl group;

ZBG is

Each R⁸Independently of one another, halogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₃-C₆Cycloalkyl, 3-6 membered heterocycloalkyl, C₆-C₁₂Aryl or 5-12 membered heteroaryl;

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

R⁹is hydrogen or C₁-C₆An alkyl group;

In some embodiments of the invention, the compound of formula I is of any of the following structures:

the variables are defined as in any of the preceding schemes.

-M₁-(M₂)_m-(M₃)_n-the following situation (i) or (ii) is satisfied:

(i) m is 0 and n is 0, M₁Is C₄、C₅、C₆Or C₇Alkylene, or heteroalkylene having 4,5, 6, or 7 chain atoms;

(ii) m is 1, and n is 0, M₁is-NH-, -O-, -S-, C₁Alkylene radical, C₂Alkylene radical, C₃Alkylene radical, C₄Alkylene, heteroalkylene having 2,3 or 4 chain atoms,

1,3- (4-membered heterocycloalkylene), 1,3- (5-membered heterocycloalkylene) or 1,4- (6-membered heterocycloalkylene), M₂Is 1, 4-phenylene or 1,4- (6-membered heteroarylene);

the other variables are defined as in any of the preceding schemes.

In some embodiments of the invention, the compound of formula I is of the structure:

-M₁-(M₂)_m-(M₃)_n-the following situation (i) or (ii) is satisfied:

(i) m is 0 and n is 0, M₁Is 1, 4-cyclohexylene, 1, 4-phenylene, 1,4- (6-membered heteroarylene) or 1,4- (6-membered heterocycloalkylene);

the other variables are defined as in any of the preceding schemes.

-M₁-(M₂)_m-(M₃)_n-the following situation (i) or (ii) is satisfied:

(i) m is 0 and n is 0, M₁Is 1, 4-phenylene or 1,4- (6-membered heteroarylene);

(ii) m is 1, and n is 0, M₁is-NH-, -O-, -S-, C₁Alkylene radical, C₂Alkylene radical, C₃Alkylene or heteroalkylene having 2 or 3 chain atoms,

Or 1,4- (6-membered heterocycloalkylene), M₂Is 1, 4-phenylene or 1,4- (6-membered heteroarylene);

the other variables are defined as in any of the preceding schemes.

In some embodiments of the present invention, the compound of formula I is selected from any of the following structures:

the invention also provides a preparation method of the compound shown in the formula I, which is at least one scheme as follows:

scheme one

The first scheme comprises the following steps: in an organic solvent (such as methanol),reacting a compound shown as a formula II with NH₂Carrying out substitution reaction on-OH in the presence of alkali (such as potassium hydroxide) to obtain a compound shown as a formula I; wherein ZBG is

R¹、R²、R³、R⁴、X、

And L is as defined above, R^aIs C₁-C₆Alkyl (such as methyl or ethyl);

scheme two

The second scheme comprises the following steps: reacting a compound shown as a formula IV in an organic solvent (such as dichloromethane and/or 1, 4-dioxane) in the presence of acid (such as hydrogen chloride) to obtain a compound shown as a formula I; wherein ZBG is

R¹、R²、R³、R⁴、X、

And L is as defined above;

scheme three

The third scheme comprises the following steps: reacting a compound represented by formula III with an organic solvent (such as DMF)

Performing condensation reaction in the presence of condensing agent (such as HATU) and alkali (such as DIPEA) to obtain compound shown in formula I; wherein ZBG is

R¹、R²、R³、R⁴、R⁸、X、

y and L are as defined above;

scheme four

The fourth scheme comprises the following steps: reacting a compound represented by formula III with an organic solvent (such as DMF)

R¹、R²、R³、R⁴、R⁹、X、

And L is as defined above;

scheme five

The fifth scheme comprises the following steps: in an organic solvent, carrying out a reduction reaction on a compound shown as a formula V to obtain a compound shown as a formula I; wherein ZBG is

R¹、R²、R³、R⁴、R⁹、X、

And L is as defined above, and R⁹Is not hydrogen.

The preparation method of the compound shown in the formula III can comprise the following steps: in a solvent (such as a mixed solvent of tetrahydrofuran and water), carrying out hydrolysis reaction on a compound shown as a formula II in the presence of alkali (such as lithium hydroxide, sodium hydroxide or potassium hydroxide) to obtain a compound shown as a formula III; wherein R is¹、R²、R³、R⁴、X、

And L is as defined above, R^aIs C₁-C₆Alkyl (such as methyl or ethyl);

the preparation method of the compound shown in the formula IV can be at least one scheme as follows:

scheme one

The first scheme comprises the following steps: reacting a compound represented by formula III with an organic solvent (such as DMF)

Performing condensation reaction in the presence of condensing agent (such as HATU) and alkali (such as DIPEA) to obtain compound shown in formula IV; wherein R is¹、R²、R³、R⁴、X、

And L is as defined above;

scheme two

The second scheme comprises the following steps: in an organic solvent (such as DMF), carrying out condensation reaction on the compound A and the compound K in the presence of a condensing agent (such as HATU) and alkali (such as DIPEA) to obtain a compound shown as a formula IV; wherein R is¹、R²、R³、R⁴X and L are as defined above,

is composed of

The preparation method of the compound shown in the formula II can be at least one scheme as follows:

scheme one

The first scheme comprises the following steps: reacting compound B with compound C in organic solvent (such as dichloromethane or chloroform) in the presence of alkali (such as DIPEA) to obtain compound shown in formula II; or reacting the compound A with the compound D in an organic solvent (such as dichloromethane or trichloromethane) in the presence of alkali (such as DIPEA) to obtain a compound shown as a formula II; wherein R is¹、R²、R³、R⁴X and L are as defined above, and L is

The attached atom is N, O or S,

is composed of

R^aIs C₁-C₆Alkyl (e.g. methyl or ethyl), R^bIs hydrogen or nitro. Compound D canBy reacting compound B with

The preparation method comprises the following steps of. Compound C can be prepared by reacting compound A with

The preparation method comprises the following steps of.

Scheme two

The second scheme comprises the following steps: in an organic solvent (such as DMF), carrying out condensation reaction on the compound A and the compound F in the presence of a condensing agent (such as HATU) and alkali (such as DIPEA) to obtain a compound shown as a formula II; or, in an organic solvent (such as dichloromethane), carrying out condensation reaction on the compound A and the compound G in the presence of alkali (such as triethylamine or DIPEA) to obtain a compound shown as a formula II; wherein R is¹、R²、R³、R⁴X and L are as defined above, and L is

The atoms to which they are attached are C,

is composed of

R^aIs C₁-C₆Alkyl (such as methyl or ethyl).

Scheme three

When L is-M₁-M₂-，M₂Is arylene or heteroarylene, and M₁Through which hetero atom (N, O or S, e.g. N) is bound to M₂When connected, L'is-M₁-H, L "is Hal-M₂-; or, when L is-M₁-M₂-M₃-，M₃Is arylene or heteroarylene, and M₂Through which hetero atom (N, O or S, e.g. N) is bound to M₃When attached, L' is-M₁-M₂-H, L "is Hal-M₃-; scheme III may be employed which involves reacting compound K with

Carrying out substitution reaction or coupling reaction to prepare a compound shown as a formula II; wherein R is¹、R²、R³、R⁴X and L are as defined above,

is composed of

R^aIs C₁-C₆Alkyl (e.g. methyl or ethyl), Hal is halogen (e.g. chlorine, bromine or iodine). When L' is equal to

When the atom to which it is attached is N, O or S, the method of preparation of compound K is as described above in scheme one for the preparation of the compound of formula II; when L' is equal to

When the atom to which it is bonded is C, the process for preparing compound K is as described above in scheme two for preparing the compound represented by formula II.

The invention also provides a compound which is of any one of the following structures:

wherein R is¹、R²、R³、R⁴X, L and

as defined above, R^aIs C₁-C₆Alkyl (such as methyl or ethyl).

The invention also provides a pharmaceutical composition, which comprises the compound shown as the formula I, pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer, solvate, metabolite or prodrug thereof, and at least one pharmaceutical adjuvant.

The invention also provides application of the compound shown as the formula I, pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer, solvate, metabolite or prodrug thereof, or the pharmaceutical composition in preparation of adenosine A2A receptor antagonist and/or histone deacetylase HDAC inhibitor.

The invention also provides application of the compound shown as the formula I, pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer, solvate, metabolite or prodrug thereof, or the pharmaceutical composition in preparing medicines for treating and/or preventing diseases related to adenosine A2A receptor and/or histone deacetylase HDAC.

The dosage of the compound shown in formula I, its pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer, solvate, metabolite or prodrug can be therapeutically effective amount.

The present invention also provides a method of treating and/or preventing a "disease associated with the adenosine A2A receptor and/or histone deacetylase HDAC", which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I or I', a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof.

The present invention also provides a method of treating and/or preventing cancer or a central nervous system disorder, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I or I', a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof.

The "disease associated with adenosine A2A receptor and/or histone deacetylase HDAC" as described above may be cancer or a central nervous system disease.

The cancer as described above may be a cancer of the head and neck (e.g. thyroid cancer, nasopharyngeal cancer, meningeal cancer or intracranial metastases), a cancer of the respiratory system (e.g. small cell lung cancer or non-small cell lung cancer), a cancer of the digestive system (e.g. liver cancer, stomach cancer, esophageal cancer, rectal cancer, colon cancer or pancreatic cancer), a cancer of the urinary system (e.g. kidney cancer, bladder cancer, prostate cancer or testicular cancer), a bone cancer, a gynaecological cancer (e.g. breast cancer, cervical cancer or ovarian cancer), a cancer of the hematological system (e.g. leukemia, lymphoma or myeloma or other types of cancer (e.g. melanoma, glioma or skin cancer).

The central nervous system disease as described above may be Parkinson's disease, Alzheimer's disease or Huntington's chorea.

The compounds of formula I, pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites or prodrugs thereof, as described above, or the pharmaceutical compositions thereof, may also be used in any disease process characterized by abnormal cellular proliferation, such as benign prostatic hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, inflammatory bowel disease, transplant rejection, endotoxic shock and fungal infections.

The invention also provides application of the compound shown as the formula I, pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer, solvate, metabolite or prodrug thereof, or the pharmaceutical composition in preparation of a product for regulating the activity of adenosine A2A receptor and/or histone deacetylase HDAC.

The choice of the pharmaceutical excipients depends on the administration route and the action characteristics, and can be generally fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents and the like which are conventional in the art.

The pharmaceutical compositions may be administered by oral, injectable (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, urethral, vaginal, nasal, inhalation or topical routes, the preferred route being oral.

In the present invention, unless otherwise indicated, the following terms appearing in the specification and claims of the invention have the following meanings:

in the present invention, the term "substituted" or "substituent" means that one or more hydrogen atoms are replaced by the specified group. When the position of substitution is not indicated, the substitution may be at any position, but formation of a stable or chemically feasible chemical is permissible.

In the present invention, the term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis that they are chemically realizable.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

In the present invention, the term "alkyl" refers to a saturated straight chain having the specified number of carbon atomsMonovalent hydrocarbon radicals of chain or branched chain, e.g. C₁-C₁₀Alkyl refers to alkyl groups having 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).

In the present invention, the term "haloalkyl" means an alkyl group (as defined herein) in which one or more hydrogen atoms are replaced by halogen (as defined herein), the number of which may be one or more; when the number of the halogen is plural, the halogen may be the same or different. Examples of haloalkyl include, but are not limited to, trifluoromethyl and difluoromethyl.

In the present invention, the term "alkoxy" refers to an alkyl group (as defined herein) attached to the rest of the molecule through an oxygen bridge.

In the present invention, the term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical having the specified number of carbon atoms and at least one carbon-carbon double bond, which may be located anywhere within the alkenyl radical, such as C₂-C₆Alkenyl means alkenyl having 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl.

In the present invention, the term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical having the specified number of carbon atoms and at least one carbon-carbon triple bond, where the carbon-carbon triple bond may be located anywhere within the alkynyl radical, e.g., C₂-C₆Alkynyl means alkynyl having 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl and propynyl.

In the present invention, the term "alkylene" refers to a saturated, straight-chain, divalent hydrocarbon group having the specified number of carbon atoms. Thus, C₁Alkylene (i.e. methylene) means-CH₂-，C₂Alkylene (i.e. ethylene) means-CH₂-CH₂-，C₃Alkylene means-CH₂-CH₂-CH₂-。

In the present inventionThe term "alkenylene" refers to a straight chain divalent hydrocarbon radical having the specified number of carbon atoms and at least one carbon-carbon double bond, which may be located anywhere within the alkenylene radical. Thus, C₂Alkenylene (i.e. ethenylene) means-CH ═ CH-, C₃Alkenylene means-CH₂-CH ═ CH-and-CH₂＝CH-CH₂-，C₄Alkenylene means-CH₂-CH＝CH-CH₂-、-CH₂＝CH-CH₂-CH₂-and-CH₂-CH-CH₂＝CH₂-。

In the present invention, the term "alkynylene" refers to a straight chain divalent hydrocarbon radical having the specified number of carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond may be located anywhere within the alkynylene radical. Thus, C₂Alkynylene (ethynylene) means

C₃Alkynylene means

In the present invention, the term "heteroalkyl" refers to a saturated, straight or branched chain, monovalent hydrocarbon radical having the indicated number of carbon atoms and at least one heteroatom selected from N, O and S. Heteroalkyl groups may be attached to other moieties in the molecule through heteroatoms or carbon atoms therein. The heteroatom may be located at any internal position of the heteroalkyl group (including the position at which the heteroalkyl group is attached to the rest of the molecule), i.e., the heteroalkyl group does not include a hydroxyalkyl group (e.g., -CH₂OH、-CH(CH₃) OH), aminoalkyl (e.g., -CH)₂NH₂、-CH(CH₃)NH₂) And the like. Examples of heteroalkyl groups include, but are not limited to, -O-CH₃、-CH₂-NH-CH₃、-NH-CH(CH₃)-CH₃、-CH₂-O-CH₃and-CH₂-S-CH₃。

In the present invention, the term "heteroalkenyl" refers to a straight or branched chain monovalent hydrocarbon radical having the specified number of carbon atoms, at least one heteroatom selected from N, O and S, and at least one double bond. The heteroalkenyl group may beThrough heteroatoms or carbon atoms thereof to other parts of the molecule. Heteroalkenyl groups may be attached to other parts of the molecule through atoms within the molecule that are single or double bonds. Examples of heteroalkenyl include, but are not limited to, -N ═ CH₂、-N＝CH-CH₃、-CH₂-CH₂＝N-CH₃and-O-CH (CH)₃)-CH₂＝N-CH₃。

In the present invention, the term "heteroalkynyl" refers to a straight or branched chain monovalent hydrocarbon radical having the specified number of carbon atoms, at least one heteroatom selected from N, O and S, and at least one triple bond. Heteroalkynyl groups may be attached to other moieties in the molecule through heteroatoms or carbon atoms therein. Heteroalkynyl groups may be attached to other moieties in the molecule through single or triple bonds therein. Examples of heteroalkynyl groups include, but are not limited to

In the present invention, the term "heteroalkylene" refers to a saturated, straight chain, divalent hydrocarbon radical having the indicated number of chain atoms, wherein at least one of the chain atoms is a heteroatom selected from N, O and S, and the remaining chain atoms are carbon. Heteroalkylene groups can be attached to other moieties in the molecule through heteroatoms or carbon atoms therein. Heteroalkylidene having 2 chain atoms, e.g. -O-CH₂-、-NH-CH₂-etc., heteroalkylene having 3 chain atoms such as-CH₂-NH-CH₂-、-O-CH₂-CH₂-、-CH₂-O-CH₂-etc., heteroalkylene having 4 chain atoms such as-O-CH₂-CH₂-NH-。

In the present invention, the term "heteroalkenylene" refers to a straight chain divalent hydrocarbon radical having the indicated number of chain atoms and at least one double bond, wherein at least one of the chain atoms is a heteroatom selected from N, O and S. Heteroalkenylene groups may be attached to other moieties in the molecule through heteroatoms or carbon atoms therein. Heteroalkenylene having 2 chain atoms, e.g. -N ═ CH₂-and the like, heteroalkenylene having 3 chain atoms such as-N ═ CH-CH₂-、-CH＝N-CH₂-and so on, a hetero atom having 4 chain atomsAlkenyl radicals such as-CH₂＝CH-CH₂-O-、-CH₂＝CH-CH₂NH-, etc., heteroalkenylene having 5 chain atoms such as-CH₂-CH＝CH-CH₂-NH-, etc.

In the present invention, the term "heteroalkynylene" refers to a straight chain divalent hydrocarbon radical having the indicated number of chain atoms and at least one triple bond, wherein at least one of the chain atoms is a heteroatom selected from N, O and S. Heteroalkynylene groups may be attached to other moieties in the molecule through heteroatoms or carbon atoms therein. Examples of heteroalkenylene include, but are not limited to

In the present invention, the term "cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated, monovalent cyclic hydrocarbon group having the specified number of ring carbon atoms, and the cycloalkyl group may be monocyclic or polycyclic (e.g., bicyclic and tricyclic), and may be a bicyclic, spirocyclic, and bridged ring structure. Cycloalkyl groups optionally contain one or more double or triple bonds therein. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Cycloalkyl also includes polycyclic cycloalkyl structures, wherein the polycyclic structure optionally includes a saturated or partially unsaturated cycloalkyl fused to a saturated or partially unsaturated cycloalkyl or heterocyclyl or aryl or heteroaryl ring. Bicyclic carbocycles having 7 to 12 atoms may be arranged, for example, as bicyclo [ 4.5 ], [5,5], [5,6] or [6,6] systems or as bridged ring systems, for example, bis [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane.

In the present invention, the term "heterocycloalkyl" refers to a non-aromatic, saturated or partially unsaturated, monovalent cyclic hydrocarbon radical formed by replacing at least one ring carbon atom in a cycloalkyl group (as defined herein) with a heteroatom selected from N, O and S. Heterocycloalkyl radicals may be attached to other radicals in the molecule via heteroatoms or carbon atoms thereinAnd (4) partial. Examples of heterocycloalkyl include, but are not limited to, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl. Heterocycloalkyl radicals of bridged rings, e.g.

In the present invention, the term "cycloalkylene" refers to a non-aromatic, saturated or partially unsaturated, divalent cyclic hydrocarbon group having the specified number of ring carbon atoms, and the cycloalkylene group may be monocyclic or polycyclic, and may be a fused ring, spiro ring, and bridged ring structure. Examples of cycloalkylene groups include, but are not limited to

(i.e., 1, 3-cyclobutylidene),

(i.e., 1, 3-cyclopentylene),

(i.e., 1, 4-cyclohexylene) or

In the present invention, the term "heterocycloalkylene" refers to a non-aromatic, saturated or partially unsaturated, divalent cyclic hydrocarbon radical formed by replacing at least one ring carbon atom in a cycloalkylene radical (as defined herein) with a heteroatom selected from N, O and S. Heterocycloalkylene groups may be attached to other moieties in the molecule through heteroatoms or carbon atoms in the heterocycloalkylene group. Examples of fused heterocycloalkylene groups include, but are not limited to

Heterocycloalkylene radicals of bridged rings include, but are not limited to

Spirocyclic heterocycloalkylene groups include, but are not limited to

In the present invention, the 6-membered heterocycloalkylene group in the 1,4- (6-membered heterocycloalkylene) has a monocyclic structure, 1 and 4 do not refer to the original number of ring atoms in the 6-membered heterocycloalkylene group, but refer to the relative positions of two linking sites of the 6-membered heterocycloalkylene group as para positions, and examples of the 1,4- (6-membered heterocycloalkylene) include, but are not limited to

Etc.; 1,3- (4-membered heterocycloalkylene) and 1,3- (5-membered heterocycloalkylene) are the same as 1,4- (6-membered heterocycloalkylene), and examples of 1,3- (5-membered heterocycloalkylene) include, but are not limited to

However, 2,6- (hetero-spiro [3,3 ]]Heptyl) 2 and 6 refer to the original numbering of the ring atoms of the spiro ring, 2,6- (hetero spiro [3,3 ]]Heptyl) include, but are not limited to

In the present invention, the term "aryl" refers to any stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocycle of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthryl, or acenaphthenyl (acenaphthyl). It will be understood that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through an aromatic ring.

In the present invention, the term "arylene" refers to a divalent aromatic group. 1, 4-phenylene radicals being

In the present invention, the term "heteroaryl" refers to a stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocycle of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains at least one heteroatom selected from O, N and S. Heteroaryl groups may be attached to other parts of the molecule through heteroatoms or carbon atoms therein. Examples of heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl (e.g., pyrrol-1-yl, i.e., pyrrol-1-yl)

Pyrrol-2-yl radicals i.e.

) And tetrahydroquinolyl. It is understood that where the heteroaryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through the aromatic ring.

In the present invention, the term "heteroarylene" refers to a divalent heteroaryl group. The 6-membered heteroarylene group of 1,4- (6-membered heteroarylene) is monocyclic, wherein 1 and 4 do not refer to the original numbering of the ring atoms in the 6-membered heteroarylene group, but rather to the relative positions of the two attachment sites of the 6-membered heteroarylene group being para, and examples of 1,4- (6-membered heteroarylene) include, but are not limited to

Examples of 1,3- (5-membered heteroarylene) as above, and 1,3- (5-membered heteroarylene) include, but are not limited to

When the number of one linking group is 0, e.g. - (CRR)₀-, represents that the linking group is a single bond. When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, for example, where L represents a single bond in A-L-Z means that the structure is actually A-Z. In particular, in the present invention, at-M₁-(M₂)_m-(M₃)_nIn (a), when M is 0 and n is 0, -M₁-(M₂)_m-(M₃)_n-is in fact-M₁-; when M is 1, n is 0, -M₁-(M₂)_m-(M₃)_n-is in fact-M₁-M₂-。

Where the linking group is recited herein without reference to its direction of attachment, it is attached in the same direction as the reading from left to right, as exemplified below,

middle connecting group L₁is-C-D-in this case-C-D-is formed by connecting ring A and ring B in the same direction as the reading sequence from left to right

Without constituting

In particular to the present invention, it is,

in the case that L is-M₁-M₂-M₃When the structure formed is

Instead of

When L is enumerated

When formed, the structure is

Instead of

Combinations of the linking groups, substituents, and/or variants thereof are permissible only if such combinations result in stable compounds.

In the present invention, the term "halogen" means F, Cl, Br, I unless otherwise specified.

In the present invention, the term "oxo" means ═ O or

For example-CH₂-oxo to form-C (═ O) -, -S-oxo to form-S (O) -or-S (O)₂-，

Is formed by oxo-substitution of the nitrogen atom in (A)

In the present invention, the term "thio" means ═ S. For example-CH₂-is thio to form-C (═ S) -.

In the present invention, the term "pharmaceutically acceptable salt" denotes a salt formed from a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base and a compound of formula I, which retains the biological activity of the compound of formula I. The organic acid may be any of various organic acids capable of forming a salt, which are conventional in the art, and is preferably one or more of methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid, and salicylic acid. The inorganic acid may be any of various inorganic acids capable of forming a salt, which are conventional in the art, and preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The organic base can be various organic bases which are conventional in the field and can form salts, and one or more of pyridine, imidazole, pyrazine, indole, purine, tertiary amine and aniline is/are preferable. The tertiary amine organic base is preferably triethylamine and/or N, N-diisopropylethylamine. The aniline organic base is preferably N, N-dimethylaniline. The pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylamino pyridine and 2-methyl-5-ethyl pyridine. The inorganic base may be any of various inorganic bases capable of forming a salt, which are conventional in the art, and preferably one or more of alkali metal hydride, alkali metal hydroxide, alkali metal alkoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. The alkali metal hydride is preferably sodium hydride and/or potassium hydride. The alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. The alkoxide of the alkali metal is preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide. In some embodiments of the invention, the pharmaceutically acceptable salt is a hydrochloride salt.

The term "solvate" refers to a substance formed by a compound of formula I with a suitable solvent. The solvent is preferably water or an organic solvent.

The compounds of the invention and their structures are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric and conformational isomeric) forms, which may be defined as (R) -/(S) -or (D) -/(L) -or (R, R) -/(R, S) -/(S, S) -, according to the absolute stereochemical definition for an amino acid. The present invention includes all of these possible isomers, as well as their racemic, enantiomerically enriched, and optionally pure forms. Optically active (+) and (-), (R) -and (S) -and (R, R) -/(R, S) -/(S, S) -or (D) -and (L) -isomers can be prepared using chiral synthesis, chiral resolution, or can be resolved using conventional techniques such as, but not limited to, High Performance Liquid Chromatography (HPLC) using a chiral column. When the compounds described herein contain an alkenyl double bond or other geometrically asymmetric center, the compounds include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are also included.

In the present invention, the term "stereoisomer" refers to a compound composed of the same atoms bonded with the same chemical bond but having a different three-dimensional structure, which are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof and includes "enantiomers" which refer to two stereoisomers whose molecules are nonsuperimposable mirror images of each other, and "diastereomers"; diastereoisomers refer to stereoisomers in which the molecules have two or more chiral centers and are in a non-mirror relationship between the molecules.

In the present invention, the term "tautomer" refers to a proton that moves from one atom of a molecule from an original position to another position on the same molecule. The invention includes tautomers of any of the compounds.

In the present invention, the term "prodrug" refers to a derivative of a compound that comprises a bioreactive functional group such that under biological conditions (in vitro or in vivo) the bioreactive functional group can be cleaved or otherwise reacted from the compound to provide the compound. Typically, prodrugs are inactive, or at least less active than the compound itself, such that the compound does not exert its activity until cleaved from a biologically reactive functional group. The bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound. For example, the prodrug may comprise a biohydrolyzable group. Examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable ureides.

In the present invention, the term "isotopic derivative" refers to a compound which differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the invention except that "deuterium" or "tritium" is used in place of hydrogen, or¹⁸F-fluorine labeling: (¹⁸Isotope of F) instead of fluorine, or with¹¹C-，¹³C-, or¹⁴C-enriched carbon (C¹¹C-，¹³C-, or¹⁴C-carbon labeling;¹¹C-，¹³c-, or¹⁴C-isotopes) instead of carbon atoms are within the scope of the invention. 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. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements). Therefore, in the present invention, the isotopic derivative is preferably a deuteron. The number of deuterium atoms in the deuteron may be 1,2, 3, 4 or 5.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, a "therapeutically effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. 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.

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the invention provides a thiazolocyclic compound, a preparation method, an intermediate and an application thereof, and the thiazolocyclic compound can be used as an adenosine A2A receptor antagonist or a histone deacetylase HDAC inhibitor. Further, the thiazolocyclic compound of the present invention may have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity. The thiazolocyclic compounds of the present invention may be used in the treatment and/or prevention of diseases associated with the adenosine A2A receptor and/or histone deacetylase HDAC, such as tumours and central nervous system diseases.

Detailed Description

The invention will be further illustrated in the following examples. These examples are intended to illustrate the invention only and do not limit the scope of protection of the invention in any way. All parameters in the examples and the remaining specifications, unless otherwise stated, are in units of mass (grams).

Example 1: preparation of N-hydroxy-6- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) ureido) hexanamide (Compound I-1)

Step 1: preparation of methyl 6- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) ureido) hexanoate (intermediate Int-1)

With 4-methoxy-7-morpholinylbenzo [ d ]]Thiazole-2-ammonia (see US 20040138465 for preparation) as starting material, which is converted into N- (4-methoxy-7-morpholinobenzo [ d ] according to the method described in US20050261289]Thiazol-2-yl) carbamic acid phenyl ester. Reacting N- (4-methoxy-7-morpholinylbenzo [ d ]]Phenyl thiazol-2-yl) carbamate (0.385g, 1.0mmol) was dissolved in chloroform (5mL), DIPEA (0.388g, 1.0mmol) and methyl 6-aminocaproate (0.145g, 1.0mmol) were added, the mixture was rapidly heated to reflux and stirred for 3 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the remaining solid was purified by silica gel column chromatography to obtain Int-1(0.27g, yield 62%) as a white solid intermediate.¹H NMR(800MHz,chloroform-d)δ6.88(d,J＝8.3Hz,1H),6.81(d,J＝8.1Hz,1H),3.96(s,3H),3.91–3.86(m,4H),3.64(s,3H),3.26(q,J＝6.4Hz,2H),3.16–3.09(m,4H),2.19(t,J＝7.0Hz,2H),1.58–1.52(m,2H),1.50–1.45(m,2H),1.24–1.18(m,2H).HRMS(ESI)C₂₄H₂₉N₄O₅S⁺[M+H]⁺Calculated value 437.1859, found value 437.1871.

Step 2: preparation of 6- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) ureido) hexanoic acid (intermediate Int-2)

Intermediate Int-1(0.218g, 0.50mmol) obtained in step 1 was dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (2.5mL), and lithium hydroxide (0.060g, 2.5mmol) was added thereto, followed by stirring at room temperature overnight. Neutralizing the reaction solution with 1, 4-dioxane solution (4M) of hydrogen chloride to pH7.4, and evaporating the solvent under reduced pressure to obtain the corresponding carboxylic acid intermediate Int-2 crude product, which is directly used in the next reaction. HRMS (ESI) C₂₃H₂₇N₄O₅S⁺[M+H]⁺Calculated value 423.1702, found value 423.1711.

And step 3: preparation of 6- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) ureido) -N- ((tetrahydro-2H-pyran-2-yl) oxy) hexanamide (intermediate Int-3)

All of the crude intermediate Int-2 from step 2 was dissolved in anhydrous DMF (5mL), HATU (0.38g, 1.0mmol) was added and stirred at room temperature for 20 min, then O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.117g, 1.0mmol) and DIPEA (0.387g, 3.0mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, the solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to give intermediate Int-3(0.104g, yield 40%).¹H NMR(500MHz,methanol-d₄)δ6.94–6.86(m,2H),4.88–4.85(m,1H),4.01–3.95(m,1H),3.94(s,3H),3.89–3.82(m,4H),3.60–3.52(m,1H),3.30–3.24(m,2H),3.10–3.03(m,4H),2.15(t,J＝7.2Hz,2H),1.84–1.73(m,2H),1.73–1.56(m,6H),1.55–1.47(m,2H),1.47–1.37(m,2H).HRMS(ESI)C₂₄H₃₆N₅O₆S⁺[M+H]⁺Calculated value 522.2386, found value 522.2389.

And 4, step 4: preparation of N-hydroxy-6- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) ureido) hexanamide (Compound I-1)

Compound Int-3(0.10g, 0.19mmol) obtained in step 3 was dissolved in methylene chloride (5mL), and a 4M hydrogen chloride/1, 4-dioxane solution (0.6mL) was added, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure, and the solid residue was washed with ethyl acetate to give compound (I-1) hydrochloride (63mg, yield 75%).¹H NMR(800MHz,DMSO-d₆)δ10.66(s,1H),10.33(s,1H),6.87(d,J＝8.5Hz,1H),6.80(d,J＝8.5Hz,1H),6.72(s,1H),3.84(s,3H),3.78–3.75(m,4H),3.13(q,J＝6.7Hz,2H),3.00–2.97(m,4H),1.95(t,J＝7.4Hz,2H),1.54–1.49(m,2H),1.48–1.42(m,2H),1.27–1.24(m,2H).HRMS(ESI)C₁₉H₂₈N₅O₅S⁺[M+H]⁺Calculated value 438.1806, found value 438.1814.

Example 2: preparation of N-hydroxy-5- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) ureido) pentanamide (Compound I-2)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 5-aminopentanoate", and the other required raw materials, reagents and preparation methods were the same as in example 1 to obtain a white solid compound (I-2) hydrochloride.¹H NMR(800MHz,DMSO-d₆)δ10.38(s,1H),6.94(d,J＝7.6Hz,1H),6.87(d,J＝8.5Hz,1H),6.82(d,J＝8.5Hz,1H),3.84(s,3H),3.77(t,J＝4.5Hz,4H),3.13(q,J＝6.5Hz,2H),3.00(t,J＝4.5Hz,4H),1.97(t,J＝7.3Hz,2H),1.47(dt,J＝66.1,7.3Hz,4H).HRMS(ESI)C₁₈H₂₆N₅O₅S⁺[M+H]⁺Calculated value 424.1649, found value 424.1660.

Example 3: preparation of N-hydroxy-7- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) ureido) heptanamide (Compound I-3)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 7-aminoheptanoate", and the other required raw materials, reagents and preparation methods were the same as in example 1 to obtain a white solid compound (I-3) hydrochloride.¹H NMR(500MHz,DMSO-d₆)δ10.68(s,1H),10.35(s,1H),8.68(s,1H),6.84(dd,J＝34.7,8.5Hz,2H),6.74(s,1H),3.84(s,3H),3.79–3.72(m,4H),3.13(dd,J＝12.8,6.6Hz,2H),3.03–2.93(m,4H),1.94(t,J＝7.4Hz,2H),1.52–1.42(m,4H),1.31–1.22(m,4H).HRMS(ESI)C₂₀H₃₀N₅O₅S⁺[M+H]⁺Calculated values: 452.1968, respectively; found 452.1963.

Example 4: preparation of N-hydroxy-5- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1-methylureido) pentanamide (Compound I-4)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 5-methylaminovalerate", and the other required raw materials, reagents and preparation methods were the same as in example 1 to obtain a white solid compound (I-4) hydrochloride.¹H NMR(800MHz,DMSO-d₆)δ11.10(s,1H),10.35(s,1H),6.88(d,J＝8.5Hz,1H),6.80(d,J＝8.5Hz,1H),3.85(s,3H),3.78–3.75(m,4H),3.40–3.31(m,2H),3.06–2.89(m,7H),2.00–1.56(m,2H),1.54–1.43(m,4H).HRMS(ESI)C₁₉H₂₈N₅O₅S⁺([M+H]⁺) Calculated value 438.1806, found value 438.1810.

Example 5: preparation of N-hydroxy-6- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1-methylureido) hexanamide (Compound I-5)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 6-methylaminohexanoate", and the other required raw materials, reagents and preparation methods were the same as in example 1, to obtain a white solid compound (I-5) hydrochloride.¹H NMR(800MHz,DMSO-d₆)δ10.33(s,1H),6.88(d,J＝8.5Hz,1H),6.81(d,J＝8.5Hz,1H),3.84(s,3H),3.79–3.74(m,4H),3.38–3.29(m,2H),3.03–2.92(m,7H),1.95(t,J＝7.4Hz,2H),1.51–1.46(m,4H),1.24–1.21(m,2H).HRMS(ESI)C₂₀H₃₀N₅O₅S⁺([M+H]⁺) Calculated value 452.1962, found value 452.1970.

Example 6: preparation of N-hydroxy-7- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1-methylureido) heptanamide (Compound I-6)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 7-methylaminoheptanoate", and the other required raw materials, reagents and preparation methods were the same as in example 1, to obtain a white solid compound (I-6) hydrochloride.¹H NMR(800MHz,DMSO-d₆)δ10.32(s,1H),6.88(d,J＝8.5Hz,1H),6.80(d,J＝8.5Hz,1H),3.84(s,3H),3.79–3.75(m,4H),3.39–3.29(m,2H),3.04–2.91(m,7H),1.94(t,J＝7.4Hz,2H),1.54–1.44(m,4H),1.29–1.22(m,4H).HRMS(ESI)C₂₁H₃₂N₅O₅S⁺([M+H]⁺) Calculated value 466.2119, found value 466.2126.

The compounds listed in examples 7-8 can be prepared in the same manner by changing the corresponding starting materials according to the procedures given in examples 1-6 and detailed in Table 1.

TABLE 1

Example 9: preparation of N-hydroxy-4- ((3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) ureido) methyl) benzamide (Compound I-9)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 4-aminomethylbenzoate", and the other required raw materials, reagents and preparation methods were the same as in example 1, to obtain a white solid compound (I-9) hydrochloride.¹H NMR(800MHz,DMSO-d₆)δ11.17(s,1H),7.73(d,J＝8.2Hz,2H),7.51(s,1H),7.38(d,J＝8.1Hz,2H),6.88(d,J＝8.5Hz,1H),6.83(d,J＝8.5Hz,1H),4.39(d,J＝5.7Hz,2H),3.85(s,3H),3.79–3.72(m,4H),3.04–2.96(m,4H)；HRMS(ESI)C₂₁H₂₄N₅O₅S⁺([M+H]⁺) Calculated value 458.1498, found value 458.1491.

Example 10: preparation of N-hydroxy-4- ((3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1-methylureido) methyl) benzamide (Compound I-10)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 4-methylaminomethylbenzoate" (see WO 2004064721 for preparation), and the other required starting materials, reagents and preparation were the same as in example 1, to give the hydrochloride of compound (I-10) as a white solid.¹H NMR(800MHz,DMSO-d₆)δ11.32(s,1H),11.18(s,1H),9.00(s,1H),7.73(d,J＝8.2Hz,2H),7.32(d,J＝8.0Hz,2H),6.89(d,J＝8.5Hz,1H),6.82(d,J＝8.5Hz,1H),4.66(s,2H),3.85(s,3H),3.81–3.73(m,4H),3.07–2.92(m,7H).HRMS(ESI)C₂₂H₂₆N₅O₅S⁺([M+H]⁺) Calculated value 472.1655, found value 472.1660.

Example 11: preparation of N-hydroxy-4- ((3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1-ethylureido) methyl) benzamide (Compound I-11)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 4-ethylaminomethylbenzoate" (see WO 2015025164 for preparation), and the other required starting materials, reagents and preparation were the same as in example 1 to give the hydrochloride of compound (I-11) as a white solid.¹H NMR(800MHz,DMSO-d₆)δ11.31(s,1H),11.17(s,1H),8.99(s,1H),7.73(d,J＝8.0Hz,2H),7.33(d,J＝7.5Hz,2H),6.88(d,J＝7.9Hz,1H),6.82(d,J＝7.8Hz,1H),4.68(s,2H),3.84(s,3H),3.79–3.72(m,4H),3.50–3.38(m,2H),3.03–2.96(m,4H),1.08(t,J＝6.8Hz,3H).HRMS(ESI)C₂₃H₂₇N₅O₅S⁺([M+H]⁺) Calculated value 486.1806, found value 486.1828.

Example 12: preparation of N-hydroxy-4- ((3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1-N-propylureido) methyl) benzamide (Compound I-12)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 4- ((n-propyl) amino) methylbenzoate" (see ChemMedChem,2017,12,646-651), and the remaining required starting materials, reagents and preparation methods were the same as those of example 1, to obtain a white solid compound (I-12) hydrochloride.¹H NMR(800MHz,DMSO-d₆)δ11.32(s,1H),11.17(s,1H),8.99(s,1H),7.72(d,J＝8.1Hz,2H),7.32(d,J＝7.4Hz,2H),6.89(d,J＝8.4Hz,1H),6.81(d,J＝8.3Hz,1H),4.68(s,2H),3.84(s,3H),3.80–3.73(m,4H),3.40–3.32(m,2H),3.05–2.94(m,4H),1.59–1.45(m,2H),0.84(t,J＝7.3Hz,3H).HRMS(ESI)C₂₄H₃₀N₅O₅S⁺([M+H]⁺) Calculated value 500.1968, found value 500.1966.

Example 13: preparation of N-hydroxy-4- ((3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1-N-butylureido) methyl) benzamide (Compound I-13)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 4- ((n-butyl) amino) methylbenzoate" (see WO 2015017546 for preparation), and the remaining required starting materials, reagents and preparation were the same as in example 1 to give a white solid, compound (I-13) hydrochloride.¹H NMR(800MHz,DMSO-d₆)δ11.32(s,1H),11.17(s,1H),9.00(s,1H),7.73(d,J＝7.8Hz,2H),7.32(d,J＝7.3Hz,2H),6.89(d,J＝7.7Hz,1H),6.82(d,J＝7.9Hz,1H),4.69(s,2H),3.84(s,3H),3.80–3.71(m,4H),3.47–3.35(m,2H),3.07–2.91(m,4H),1.50(qui,J＝7.7Hz,2H),1.30–1.23(m,2H),0.88(t,J＝7.4Hz,3H).HRMS(ESI)C₂₅H₃₂N₅O₅S⁺([M+H]⁺) Calculated value 514.2119, found value 514.2129.

Example 14: preparation of N-hydroxy-4- ((3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1- (cyclopropylmethyl) ureido) methyl) benzamide (Compound I-14)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 4- ((cyclopropylmethyl) amino) methylbenzoate" (see WO 2015017546 for preparation), and the remaining required starting materials, reagents and preparation were the same as in example 1 to give the hydrochloride of compound (I-14) as a white solid.¹H NMR(800MHz,DMSO-d₆)δ11.30(s,1H),11.16(s,1H),8.80(s,1H),7.72(d,J＝8.1Hz,2H),7.32(d,J＝7.9Hz,2H),6.89(d,J＝8.4Hz,1H),6.81(d,J＝8.4Hz,1H),4.79(s,2H),3.84(s,3H),3.79–3.73(m,4H),3.40–3.28(m,2H),3.06–2.92(m,4H),1.05–0.99(m,1H),0.46–0.36(m,2H),0.29–0.17(m,2H).HRMS(ESI)C₂₅H₃₀N₅O₅S⁺([M+H]⁺) MeterCalculated value is 512.1968, found value is 512.1962.

The compounds listed in examples 15-21 can be prepared in the same manner by changing the corresponding starting materials according to the procedures listed in examples 9-14 and as detailed in Table 2.

TABLE 2

Example 22: preparation of N-hydroxy-4- (2- (3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1-methylureido) ethyl) benzamide (Compound I-22)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl 4- (2- (methylamino) ethyl) benzoate" (see WO 2008156820 for preparation), and the remaining required starting materials, reagents and preparation were the same as in example 1, to give the hydrochloride of compound (I-22) as a white solid.¹H NMR(800MHz,DMSO-d₆)δ11.16(s,1H),7.69(d,J＝8.2Hz,2H),7.39–7.32(m,2H),6.91–6.79(m,2H),3.85(s,3H),3.79–3.75(m,4H),3.68–3.56(m,,2H),3.05–2.93(m,7H),2.90–2.85(m,2H).HRMS(ESI)C₂₃H₂₈N₅O₅S⁺([M+H]⁺) Calculated value 486.1806, found value 486.1815.

Example 23: n is a radical of⁴-hydroxy-N¹- (4-methoxy-7-N-morpholinobenzo [ d ]]Preparation of thiazol-2-yl) piperidine-1, 4-dicarboxamide (Compound I-23)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with "methyl piperidine-4-carboxylate", and the remaining required starting materials,the reagents and preparation method were the same as in example 1, to obtain the hydrochloride of compound (I-23) as a white solid.¹H NMR(500MHz,DMSO-d₆)δ10.51(s,1H),6.86(dd,J＝34.4,8.5Hz,2H),4.24(d,J＝12.4Hz,2H),3.85(s,3H),3.80–3.70(m,4H),3.07–2.94(m,4H),2.87(t,J＝11.9Hz,2H),2.29–2.21(m,1H),1.69–1.56(m,2H),1.56–1.44(m,2H).HRMS(ESI)C₁₉H₂₆N₅O₅S⁺([M+H]⁺) Calculated values: 436.1655, respectively; measured value: 436.1660.

example 24: preparation of 4- (4- (hydroxycarbamoyl) phenyl-N- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) piperazine-1-carboxamide (Compound I-24)

The "methyl 6-aminocaproate" in step 1 of example 1 was replaced with ethyl "(4-piperazin-1-yl) benzoate", and the remaining required starting materials, reagents and preparation were the same as in example 1 to give the hydrochloride of compound (I-24) as a white solid.¹H NMR(800MHz,DMSO-d₆)δ10.97(s,1H),7.66(d,J＝8.8Hz,2H),7.01(d,J＝8.8Hz,1H),6.90(d,J＝8.5Hz,1H),6.84(d,J＝8.4Hz,1H),3.86(s,3H),3.81–3.75(m,4H),3.75–3.66(m,4H),3.35–3.28(m,4H),3.05–2.97(m,4H).HRMS(ESI)C₂₄H₂₉N₆O₅S⁺([M+H]⁺) Calculated values: 513.1920, respectively; measured value: 513.1915.

example 25: preparation of N-hydroxy-2- (4- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) piperazin-1-yl) pyrimidine-5-carboxamide (Compound I-25)

Step 1: preparation of ethyl 2- (4-tert-Butoxycarbonylpiperazin-1-yl) pyrimidine-5-carboxylate (intermediate Int-4)

1-tert-Butoxycarbonylpiperazine (1.86g,10mmol), ethyl 2-chloropyrimidine-5-carboxylate (1.86g,10mmol) and triethylamine (1.01g,10mmol) were dissolved in DMF (10mL) and stirred at room temperatureAnd (4) at night. The solvent was distilled off under reduced pressure, and the solid residue was subjected to silica gel column chromatography to give intermediate Int-4(2.98g, yield 89%). MS ([ M + H)]⁺):337.19.

Step 2: preparation of ethyl 2- (piperazin-1-yl) pyrimidine-5-carboxylate (intermediate Int-5)

Compound Int-4(1.68g, 5mmol) obtained in step 1 was dissolved in dichloromethane (5mL), and 4M hydrogen chloride/1, 4-dioxane solution (10mL) was added and stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the solid residue was washed with ethyl acetate to give intermediate Int-5(1.18g, yield 100%). MS ([ M + H)]⁺):237.14.

And step 3: preparation of N-hydroxy-2- (4- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) piperazin-1-yl) pyrimidine-5-carboxamide (Compound I-25)

The methyl 6-aminocaproate in step 1 of example 1 was replaced with Int-5, and the remaining required starting materials, reagents and preparation were the same as in example 1 to give compound (I-25) hydrochloride as a white solid.¹H NMR(500MHz,DMSO-d₆)δ11.44(s,1H),11.12(s,1H),9.04(s,1H),8.71(s,2H),6.90(d,J＝8.5Hz,1H),6.82(d,J＝8.4Hz,1H),3.86(s,7H),3.79–3.73(m,4H),3.66(s,4H),3.00(s,4H).HRMS(ESI)C₂₂H₂₇N₈O₅S⁺([M+H]⁺) Calculated values: 515.1825, respectively; measured value: 515.1824.

the compounds listed in examples 26-31 can be prepared in the same manner by changing the corresponding starting materials according to the procedures set forth in examples 24-25 and as detailed in Table 3.

TABLE 3

Example 32: n is a radical of¹-hydroxy-N⁶- (4-methoxy-7-N-morpholinobenzo [ d ]]Preparation of Thiazol-2-yl) adipamide (Compound I-32)

Step 1: preparation of methyl 6- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -6-oxohexanoate (intermediate Int-6)

Monomethyl adipate (0.080g,0.50mmol) was dissolved in anhydrous DMF (5mL), HATU (0.38g, 1.0mmol) was added, the mixture was stirred at room temperature for 20 minutes, and 4-methoxy-7-N-morpholinobenzo [ d ] was added]Thiazol-2-amine (0.132g, 0.50mmol) and DIPEA (0.387g, 3.0mmol) were stirred at room temperature overnight. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, the solvent was evaporated under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to give intermediate Int-6(0.092g, yield 45%).¹H NMR(800MHz,DMSO-d₆)δ12.44(s,1H),6.95–6.87(m,2H),3.87(s,3H),3.80–3.75(m,4H),3.58(s,3H),3.03–2.98(m,4H),2.47(t,J＝7.2Hz,2H),2.34(t,J＝7.4Hz,2H),1.65–1.53(m,4H).HRMS(ESI)C₁₉H₂₆N₃O₅S⁺([M+H]⁺) Calculated value 408.1588, found value 408.1594.

Step 2: n is a radical of¹-hydroxy-N⁶- (4-methoxy-7-N-morpholinobenzo [ d ]]Preparation of Thiazol-2-yl) adipamide (Compound I-32)

An anhydrous methanol solution (3.22mL) of potassium hydroxide (1.29g,23mmol) was added dropwise to an anhydrous methanol solution (5.52mL) of hydroxylamine hydrochloride (1.07g,15.4mmol) at 0 ℃ while slowly warming to room temperature and stirring for 0.5 hour, and the solid was removed by filtration to obtain a methanol solution of hydroxylamine. Reacting 6- ((4-methoxy-7-N-morpholinobenzo [ d ]]Thiazol-2-yl) amino) -6-oxoMethyl hexanoate (intermediate Int-6) (0.080g, 0.20mmol) was dissolved in a solution of hydroxylamine in methanol and stirred at room temperature for 1 hour. The reaction solution was neutralized with 1, 4-dioxane solution of hydrogen chloride (4M) to pH7.4, the solvent was evaporated under reduced pressure, water was added to the solid residue, and the mixture was stirred at room temperature for 1 hour and filtered under suction to give white solid (I-32) (0.056g, yield 70%). H NMR (800MHz, DMSO-d)₆)δ12.43(s,1H),10.35(s,1H),6.95–6.88(m,2H),3.87(s,3H),3.79–3.76(m,4H),3.02–2.99(m,4H),2.46(t,J＝7.3Hz,2H),1.97(t,J＝7.3Hz,2H),1.61–1.49(m,4H).HRMS(ESI)C₁₈H₂₅N₄O₅S⁺([M+H]⁺) Calculated value 409.1540, found value 409.1545.

Example 33: n is a radical of¹-hydroxy-N⁷- (4-methoxy-7-N-morpholinobenzo [ d ]]Preparation of Thiazol-2-yl) pimelinamide (Compound I-33)

The monomethyl adipate in step 1 of example 32 was replaced with the monomethyl pimelate, and the other required starting materials, reagents and preparation were the same as in example 32 to give compound (I-33) as a white solid.¹H NMR(800MHz,DMSO-d₆)δ12.43(s,1H),10.32(s,1H),8.65(s,1H),6.93(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),3.87(s,3H),3.80–3.74(m,4H),3.04–2.97(m,4H),2.45(t,J＝7.3Hz,2H),1.94(t,J＝7.4Hz,2H),1.64–1.57(m,2H),1.53–1.47(m,2H),1.29–1.25(m,2H).HRMS(ESI)C₁₉H₂₇N₄O₅S⁺([M+H]⁺) Calculated value 423.1697, found value 423.1708.

Example 34: n is a radical of¹-hydroxy-N⁸- (4-methoxy-7-N-morpholinobenzo [ d ]]Preparation of thiazol-2-yl) octanediamide (Compound I-34)

The monomethyl adipate obtained in step 1 of example 32 was replaced by monomethyl suberate, the remaining required starting materials, reagents and preparation methodIn the same manner as in example 32, Compound (I-34) was obtained as a white solid.¹H NMR(800MHz,DMSO-d₆)δ12.42(s,1H),10.32(s,1H),8.64(s,1H),6.93(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),3.87(s,3H),3.79–3.75(m,4H),3.03–2.99(m,4H),2.45(t,J＝7.4Hz,2H),1.93(t,J＝7.4Hz,2H),1.62–1.57(m,2H),1.50–1.46(m,2H),1.31–1.22(m,4H).HRMS(ESI)C₂₀H₂₉N₄O₅S⁺([M+H]⁺) Calculated value 437.1853, found value 437.1564.

Example 35: n is a radical of¹-hydroxy-N⁹- (4-methoxy-7-N-morpholinobenzo [ d ]]Preparation of Thiazol-2-yl) Noonamide (Compound I-35)

The monomethyl adipate obtained in step 1 of example 32 was replaced with monomethyl azelate, and the other required starting materials, reagents and preparation were the same as in example 32 to give compound (I-35) as a white solid.¹H NMR(800MHz,DMSO-d₆)δ12.42(s,1H),10.31(s,1H),8.63(s,1H),6.93(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),3.87(s,3H),3.79–3.75(m,4H),3.04–2.98(m,4H),2.45(t,J＝7.4Hz,2H),1.93(t,J＝7.4Hz,2H),1.62–1.57(m,2H),1.50–1.43(m,2H),1.31–1.25(m,4H),1.25–1.20(m,2H).HRMS(ESI)C₂₁H₃₁N₄O₅S⁺([M+H]⁺) Calculated value 451.2010, found value 451.2024.

Example 36: n is a radical of¹-hydroxy-N⁸- (7-methoxy-4-morpholinylpyrido [5, 4-c)]Preparation of Thiazol-2-yl) octanediamide (Compound I-36)

Step 1: preparation of methyl 8- ((7-methoxy-4-morpholinopyrido [5,4-c ] thiazol-2-yl) amino) -6-oxooctanoate (intermediate Int-7)

Monomethyl suberate (0.095g,0.51mmol) was dissolved in toluene (5mL), thionyl chloride (5mL) was added and stirred under reflux for 2 hours, the solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane and added dropwise to a solution of 7-methoxy-4-morpholinopyrido [5,4-c ] thiazol-2-amine (0.09g,0.34mmol, for preparation see U.S. Pat. No.5, 20050065151) and triethylamine (0.068g,0.68mmol) in dichloromethane (5mL) and stirred at room temperature for 2 hours. The reaction solution was extracted three times with ethyl acetate/water, the organic phases were combined, the solvent was evaporated under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to give intermediate Int-7(0.080g, yield 54%).

¹H NMR(600MHz,CDCl₃)δ9.49(s,1H),7.86(s,1H),4.01(s,3H),3.93–3.86(m,4H),3.67(s,3H),3.53–3.41(m,4H),2.52(t,J＝7.5Hz,2H),2.31(t,J＝7.4Hz,2H),1.80–1.72(m,2H),1.66–1.61(m,2H),1.43–1.31(m,4H).HRMS(ESI)C₂₀H₂₉N₄O₅S⁺([M+H]⁺) Calculated values: 437.1859, found 437.1856.

Step 2: n is a radical of¹-hydroxy-N⁸- (7-methoxy-4-morpholinylpyrido [5, 4-c)]Preparation of Thiazol-2-yl) octanediamide (Compound I-36)

Reacting the' 6- ((4-methoxy-7-N-morpholinylbenzo [ d ] in the step 1]Thiazol-2-yl) amino) -6-oxohexanoic acid methyl ester "instead of" 8- ((7-methoxy-4-morpholinylpyrido [5,4-c]Thiazol-2-yl) amino) -6-oxooctanoic acid methyl ester ", the other required raw materials, reagents and preparation method were the same as in example 32, step 2, to obtain compound (I-36) as a white solid.¹H NMR(800MHz,DMSO)δ12.74(s,1H),10.32(s,1H),8.64(d,J＝1.5Hz,1H),7.89(s,1H),3.92(s,3H),3.79–3.75(m,4H),3.34–3.32(m,4H),2.50–2.48(m,2H),1.93(t,J＝7.4Hz,2H),1.63–1.58(m,2H),1.50–1.46(m,2H),1.30–1.23(m,4H).HRMS(ESI)C₁₉H₂₈N₅O₅S⁺([M+H]⁺) Calculated values: 438.1811, found 438.1815.

Example 37: preparation of N-hydroxy-4- (2- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -2-oxoethyl) benzamide (Compound I-37)

The "monomethyl adipate" in step 1 of example 32 was replaced with "4- (methoxycarbonyl) phenylacetic acid", and the other required raw materials, reagents and preparation methods were the same as in example 32 to obtain a white solid compound (I-37).¹H NMR(800MHz,DMSO-d₆)δ12.76(s,1H),11.19(s,1H),7.72(d,J＝8.2Hz,2H),7.41(d,J＝8.2Hz,2H),6.96–6.88(m,2H),3.89–3.85(m,5H),3.77–3.72(m,4H),3.01–2.97(m,4H).HRMS(ESI)C₂₁H₂₃N₄O₅S⁺([M+H]⁺) Calculated value 443.1384, found value 443.1390.

Example 38: preparation of N-hydroxy-4- (3- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -3-oxopropyl) benzamide (Compound I-38)

The "monomethyl adipate" in step 1 of example 32 was replaced with "3- (4-methoxycarbonylphenyl) propionic acid", and the other required raw materials, reagents and preparation methods were the same as in example 32 to give a white solid compound (I-38).¹H NMR(800MHz,DMSO-d₆)δ12.49(s,1H),11.13(s,1H),8.96(s,1H),7.69–7.65(m,2H),7.32(d,J＝8.2Hz,2H),6.95–6.87(m,2H),3.86(s,3H),3.80–3.76(m,4H),3.03–2.96(m,6H),2.81(t,J＝7.6Hz,2H).HRMS(ESI)C₂₂H₂₄N₄O₅S⁺([M+H]⁺) Calculated value 457.1540, found value 457.1547.

Example 39: preparation of N-hydroxy-4- (4- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -4-oxobutyl) benzamide (Compound I-39)

"monomethyl adipate" in step 1, example 32 was replaced by "4- (4-methoxycarbonylphenyl) butanoic acid "(see WO 2015134973 for preparation), the remaining required starting materials, reagents and preparation method were the same as in example 32 to give compound (I-39) as a white solid.¹H NMR(800MHz,DMSO-d₆)δ12.44(s,1H),11.14(s,1H),7.68(d,J＝8.2Hz,2H),7.29(d,J＝8.2Hz,2H),6.95–6.87(m,2H),3.87(s,3H),3.80–3.75(m,4H),3.03–2.97(m,4H),2.70–2.64(m,2H),2.52–2.51(m,2H),1.93(p,J＝7.4Hz,2H).HRMS(ESI)C₂₃H₂₇N₄O₅S⁺([M+H]⁺) Calculated value 471.1697, found value 471.1701.

Example 40: preparation of N-hydroxy-4- (3- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -3-oxopropoxy) benzamide (Compound I-40)

The "monomethyl adipate" in step 1 of example 32 was replaced with "3- (4- (methoxycarbonyl) phenoxy) propionic acid", and the other required raw materials, reagents and preparation methods were the same as in example 32 to obtain a white solid compound (I-40).¹H NMR(800MHz,DMSO-d₆)δ12.62(s,1H),11.07(s,1H),7.72(d,J＝8.7Hz,2H),6.99(d,J＝8.8Hz,2H),6.94(d,J＝8.5Hz,1H),6.90(d,J＝8.5Hz,1H),4.36(t,J＝5.9Hz,2H),3.88(s,3H),3.78–3.75(m,4H),3.02–2.96(m,6H).HRMS(ESI)C₂₂H₂₅N₄O₆S⁺([M+H]⁺) Calculated value 473.1489, found value 473.1492.

Example 41: (E) preparation of (E) -N-hydroxy-3- (4- (2- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -2-oxoethyl) phenyl) acrylamide (Compound I-41)

The "monomethyl adipate" in step 1 of example 32 was replaced by "(E) -2- (4- (3-methoxy-3-oxoprop-1-en-1 yl) phenyl) acetic acid" (see US20020173421 for preparation), the remaining required starting materials, reagents and preparation methodIn the same manner as in example 32, Compound (I-41) was obtained as a white solid.¹H NMR(800MHz,DMSO-d₆)δ12.75(s,1H),10.74(s,1H),7.53(d,J＝8.1Hz,2H),7.44(d,J＝15.6Hz,1H),7.38(d,J＝8.0Hz,2H),6.94–6.89(m,2H),6.44(d,J＝15.8Hz,1H),3.88(s,3H),3.83(s,2H),3.76–3.74(m,4H),3.00–2.98(m,4H).HRMS(ESI)C₂₃H₂₅N₄O₅S⁺([M+H]⁺) Calculated value 469.1540, found value 469.1545.

The compound listed in example 42 was prepared in the same manner by changing the corresponding starting materials according to the procedure provided in example 32 and is detailed in table 4.

TABLE 4

Example 43: preparation of N-hydroxy-4- ((1- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -2-methyl-1-oxoprop-2-yl) oxy) benzamide (Compound I-43)

Step 1: preparation of 4-hydroxy-N- ((tetrahydro-2H-pyran-2-yl) oxy) benzamide (intermediate Int-8)

Int-2 in step 3 of example 1 is replaced by an intermediate Int-8, and the remaining required raw materials, reagents and preparation methods are the same as those in step 3 of example 1, to obtain an intermediate Int-8. MS ([ M + H)]⁺):238.11。

Step 2: preparation of methyl 2-methyl-2- (4- (((tetrahydro-2H-pyran-2-yl) oxy) carbamoyl) phenoxy) propanoate (intermediate Int-9)

Intermediate Int-8(2.37g,10mmol) obtained in step 1, methyl 2-bromoisobutyrate (2.35g,13mmol) and potassium carbonate (4.14g,30mmol) were dissolved in DMF (20mL) and stirred at 50 ℃ overnight. Distilling off the solvent under reduced pressureThe solid residue was subjected to silica gel column chromatography to give intermediate Int-9(1.35g, yield 40%). MS ([ M + H)]⁺):338.16。

And step 3: preparation of 2-methyl-2- (4- (((tetrahydro-2H-pyran-2-yl) oxy) carbamoyl) phenoxy) propanoic acid (intermediate Int-10)

The intermediate Int-9 was substituted for monomethyl adipate in step 2 of example 1, and the remaining required starting materials, reagents and preparation were the same as in step 2 of example 1 to give intermediate Int-10. MS ([ M + H)]⁺):324.14。

And 4, step 4: preparation of 4- ((1- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -2-methyl-1-oxoprop-2-yl) oxy) -N- ((tetrahydro-2H-pyran-2-yl) oxy) benzamide (intermediate Int-11)

Intermediate Int-11 was obtained by substituting "monomethyl adipate" in step 1 of example 32 for intermediate Int-10 and the remaining required starting materials, reagents and preparation procedures were the same as in step 1 of example 32.¹H NMR(600MHz,DMSO-d₆)δ7.69–7.62(m,2H),6.96–6.84(m,4H),4.95–4.90(m,1H),4.02–3.95(m,1H),3.84(s,3H),3.81–3.75(m,4H),3.59–3.55(m,1H),3.06–2.98(m,4H),1.95–1.39(m,12H).HRMS(ESI)C₂₈H₃₅N₄O₇S⁺([M+H]⁺) Calculated values: 571.2221, found: 571.2230.

and 5: preparation of N-hydroxy-4- ((1- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -2-methyl-1-oxoprop-2-yl) oxy) benzamide (Compound I-43)

Replacement of intermediate Int-3 in step 4 of example 1 with intermediate Int-11, and the remaining required starting materials, reagents and preparation method are the same as in step 4 of example 1 to obtain compound (I-43) as a white solid.¹H NMR(800MHz,DMSO-d₆)δ7.67–7.64(m,2H),6.96–6.90(m,2H),6.88(d,J＝8.8Hz,2H),3.84(s,3H),3.81–3.77(m,4H),3.05–2.99(m,4H),1.64(s,6H).HRMS(ESI)C₂₃H₂₇₉N₄O₆S⁺([M+H]⁺) Calculated value 487.1646, found value 487.1658.

Example 44: (E) preparation of (E) -N-hydroxy-3- (4- ((1- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -2-methyl-1-oxoprop-2-yl) oxy) phenyl) acrylamide (Compound I-44)

The 4-hydroxybenzoic acid in step 1 of example 43 was replaced with 4-hydroxycinnamic acid, and the remaining required starting materials, reagents and preparation were the same as in example 43 to give compound (I-44) as a white solid.¹H NMR(800MHz,DMSO-d₆)δ12.71(s,1H),7.47(d,J＝8.7Hz,2H),7.35(d,J＝15.7Hz,1H),6.96–6.90(m,2H),6.88(d,J＝8.8Hz,2H),6.29(d,J＝15.8Hz,1H),3.84(s,3H),3.80–3.78(m,4H),3.06–2.99(m,4H),1.63(s,6H).HRMS(ESI)C₂₅H₂₉N₄O₆S⁺([M+H]⁺) Calculated value 513.1802, found value 513.1810.

The compounds listed in examples 45-47 can be prepared in the same manner by changing the corresponding starting materials according to the procedure set forth in example 43 and as detailed in Table 5.

TABLE 5

Example 48: preparation of N-hydroxy-2- (3- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) azetidin-1-yl) pyrimidine-5-carboxamide (Compound I-48)

Step 1: preparation of tert-butyl 3- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) azetidine-1-carboxylate (intermediate Int-12)

Hexane 1-N-Boc-3-azetidinecarboxylic acid (0.201g, 1.0mmol) was dissolved in anhydrous DMF (5mL), HATU (0.76g, 2.0mmol) was added, stirring was carried out at room temperature for 20 minutes, and 4-methoxy-7-N-morpholinobenzo [ d ] was added]Thiazol-2-amine (0.265g, 1.0mmol) and DIPEA (0.774g, 6.0mmol) were stirred at room temperature overnight. The reaction solution was diluted with water, extracted with ethyl acetate three times, the organic phases were combined, the solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to give intermediate Int-12(0.193g, yield 43%).¹H NMR(600MHz,CDCl₃)δ6.94–6.90(m,1H),6.89–6.86(m,1H),4.21–4.16(m,2H),4.07–4.00(m,2H),3.95–3.89(m,7H),3.54–3.47(m,1H),3.17–3.12(m,4H),1.43(s,9H).HRMS(ESI)C₂₁H₂₉N₄O₅S⁺([M+H]⁺) Calculated value 449.1859, found value 449.1856.

Step 2: preparation of N- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) azetidine-3-carboxamide (intermediate Int-13)

Compound Int-12(0.19g, 0.42mmol) obtained in step 1 was dissolved in methylene chloride (5mL), and a 4M hydrogen chloride/1, 4-dioxane solution (1mL) was added, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure and the solid residue was washed with ethyl acetate to give intermediate Int-13(0.148g, yield 100%). HRMS (ESI) calculated value C₁₆H₂₁N₄O₃S⁺([M+H]⁺) 349.1334, found: 349.1327.

and step 3: preparation of ethyl 2- (3- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) azetidin-1-yl) pyrimidine-5-carboxylate (intermediate Int-14)

The compound Int-13(0.14g, 0.4mmol) obtained in step 2 was dissolved in DMF, and ethyl 2-chloropyrimidine-5-carboxylate (0.09g, 0.48mmol) and DIPEA (0.104g, 0.8mmol) were added and stirred at room temperature for 3 hours. The reaction solution was diluted with water, extracted with ethyl acetate three times, the organic phases were combined, the solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to give intermediate Int-14(0.148g, yield 74%).¹H NMR(800MHz,CDCl₃)δ8.87(s,2H),7.00(d,J＝8.4Hz,1H),6.93–6.89(m,1H),4.56–4.50(m,2H),4.46(t,J＝9.1Hz,2H),4.36(q,J＝7.1Hz,2H),3.97(s,3H),3.95–3.91(m,4H),3.81–3.77(m,1H),3.19–3.11(m,4H),1.40–1.38(m,3H).HRMS(ESI)C₂₃H₂₇N₆O₅S⁺([M+H]⁺) Calculated value 499.1764, found value 499.1758.

And 4, step 4: preparation of N-hydroxy-2- (3- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) azetidin-1-yl) pyrimidine-5-carboxamide (Compound I-48)

"6- ((4-methoxy-7-N-morpholinobenzo [ d ] in step 2 of example 32]Thiazol-2-yl) amino) -6-oxohexanoic acid methyl ester "instead of" 2- (3- ((4-methoxy-7-N-morpholinobenzo [ d)]Thiazol-2-yl) carbamoyl) azetidin-1-yl) pyrimidine-5-carboxylic acid ethyl ester "(intermediate Int-14), the remaining required starting materials, reagents and preparation were the same as in example 32, step 2 to give compound I-48 as a pink solid.¹H NMR(800MHz,DMSO-d₆)δ12.69(s,1H),11.12(s,1H),9.02(s,1H),8.68(s,2H),6.95(d,J＝8.5Hz,1H),6.91(d,J＝8.4Hz,1H),4.33(t,J＝8.9Hz,2H),4.26–4.20(m,2H),3.88(s,3H),3.86–3.81(m,1H),3.80–3.74(m,4H),3.05–2.97(m,4H).HRMS(ESI)C₂₁H₂₄N₇O₅S⁺([M+H]⁺) Calculated value 486.1560, found value 486.1550.

Example 49: preparation of N-hydroxy-2- (4- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) piperidin-1-yl) pyrimidine-5-carboxamide (Compound I-49)

The procedure of example 48 was repeated except for substituting "1-N-Boc-3-azetidinecarboxylic acid" with "1-N-Boc-4-piperidinecarboxylic acid" in step 1 of example 48 and the other required starting materials, reagents and preparation procedures were the same as those of example 48 to give Compound I-49 as a pink solid.¹H NMR(800MHz,DMSO-d₆)δ12.56(s,1H),11.07(s,1H),8.68(s,2H),6.94(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),4.76–4.69(m,2H),3.87(s,3H),3.77–3.76(m,4H),3.10–3.04(m,2H),3.02–2.97(m,4H),2.90–2.84(m,1H),1.98–1.89(m,2H),1.63–1.55(m,2H).HRMS(ESI)C₂₃H₂₈N₇O₅S⁺([M+H]⁺) Calculated value 514.1873, found value 514.1865.

The compounds listed in examples 50-55 were prepared in the same manner by changing the corresponding starting materials according to the procedure provided in example 48 and are detailed in Table 6.

TABLE 6

Example 56: preparation of N- (2-aminophenyl) -4- (3- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -3-oxopropyl) benzamide (Compound I-56)

Step 1: preparation of 4- (3- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -3-oxopropyl) benzoic acid (intermediate Int-15)

The ester intermediate (0.228g, 0.5mmol) obtained in example 38 was dissolved in a mixed solution of tetrahydrofuran (10mL) and water (2.5mL), and lithium hydroxide (0.060g, 2.5mmol) was added thereto, followed by stirring at room temperature overnight. Neutralizing the reaction solution with 1, 4-dioxane solution (4M) of hydrogen chloride to pH7.4, and evaporating the solvent under reduced pressure to obtain crude product of carboxylic acid intermediate Int-15 for the next reaction. HRMS (ESI) C₂₂H₂₄N₃O₅S⁺([M+H]⁺) Calculated value 442.1437, found value 442.1440.

Step 2: preparation of N- (2-aminophenyl) -4- (3- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -3-oxopropyl) benzamide (Compound I-56)

The mixture of all intermediate Int-15 obtained in step 1 and lithium chloride was dissolved in anhydrous DMF (5mL), HATU (0.38g, 1.0mmol) was added and stirred at room temperature for 20 min, then o-phenylenediamine (0.108g, 1.0mmol) and DIPEA (0.387g, 3.0mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water, extracted with ethyl acetate three times, the organic phases were combined, the solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to give compound I-56(0.106g, yield 40%).¹H NMR(800MHz,DMSO-d₆)δ12.50(s,1H),9.58(s,1H),7.91(d,J＝8.0Hz,2H),7.41–7.37(m,2H),7.15(d,J＝7.6Hz,1H),6.98–6.88(m,3H),6.79–6.75(m,1H),6.61–6.56(m,1H),4.87(s,2H),3.87(s,3H),3.81–3.74(m,4H),3.06–2.98(m,6H),2.85(t,J＝7.6Hz,2H)。HRMS(ESI)C₂₈H₃₀N₅O₄S⁺([M+H]⁺) Calculated value 532.2013, found value 532.2020.

The compounds listed in examples 57-60 can be prepared in the same manner by varying the corresponding starting materials according to the procedure provided in example 56 and as detailed in Table 7.

TABLE 7

Example 61: preparation of N- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -3- (4- (2-propylhydrazine-1-carbonyl) phenyl) propanamide (Compound I-61)

The o-phenylenediamine in step 2 of example 56 was replaced with propylhydrazine, and the remaining required raw materials, reagents and preparation methods were the same as in step 2 of example 56, to give compound I-61.¹H NMR(600MHz,DMSO-d₆)δ12.52(s,1H),7.80(d,J＝8.3Hz,2H),7.42(d,J＝8.3Hz,2H),6.95–6.88(m,2H),3.86(s,3H),3.79–3.77(m,4H),3.07–2.96(m,8H),2.84(t,J＝7.5Hz,2H),1.59(dt,J＝14.9,7.4Hz,2H),0.92(t,J＝7.4Hz,3H).HRMS(ESI)C₂₅H₃₂N₅O₄S⁺([M+H]⁺) Calculated value 498.2170, found value 498.2180.

Example 62: (E) preparation of (E) -3- (3- (hydroxyamino) -3-oxoprop-1-en-1-yl) -N- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1H-pyrrole-1-carboxamide (Compound I-62)

Step 1: (E) preparation of ethyl (1- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) -1H-pyrrol-3-yl) acrylate (intermediate Int-16).

60% NaH (0.41g,1.73mmol) was suspended in tetrahydrofuran (2mL) under N₂Stirring at 0 deg.C under protection. To this solution was slowly added a solution of ethyl (E) -3- (1H-pyrrol-3-yl) acrylate (0.094g, 0.57mmol) in tetrahydrofuran (7mL), and stirred at 0 ℃ for 1 hour. To the reaction mixture was then added a solution of phenyl 4-nitrochloroformate (0.14g, 0.69mmol) in tetrahydrofuran (2mL), followed by stirring at room temperature for 15 hours. Adding acetic acid to the reaction solutionEthyl ester (100mL), washed with water, the ester phase dried and evaporated to dryness under reduced pressure. The residue was dissolved in chloroform (20mL), and N- (4-methoxy-7-morpholinobenzo [ d ] was added]Phenyl thiazol-2-yl) carbamate (0.151g, 0.57mmol) and DIPEA (0.074g, 0.57mmol) were stirred at 100 ℃ until the solvent was evaporated to dryness overnight, and the solid residue was isolated by silica gel column chromatography to give intermediate Int-16(0.114g, yield 43%).¹H NMR(800MHz,CDCl₃)δ7.74(s,1H),7.58(d,J＝15.8Hz,1H),7.56–7.53(m,1H),6.83(d,J＝8.5Hz,1H),6.79(d,J＝8.5Hz,1H),6.47–6.42(m,1H),6.15(d,J＝15.8Hz,1H),4.24(q,J＝7.1Hz,2H),3.92–3.86(m,4H),3.80(s,3H),3.11–3.03(m,4H),1.32(t,J＝7.1Hz,3H)。

Step 2: (E) preparation of (E) -3- (1- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) -1H-pyrrol-3-yl) acrylic acid (intermediate Int-17).

Intermediate Int-16(0.114g, 0.25mmol) obtained in step 1 was dissolved in a mixed solution of tetrahydrofuran (10mL) and water (2.5mL), and sodium hydroxide (0.10g, 2.5mmol) was added thereto, followed by stirring at 50 ℃ for 2 days. Neutralizing the reaction solution with 1, 4-dioxane solution (4M) of hydrogen chloride to pH7.4, and evaporating the solvent under reduced pressure to obtain the corresponding carboxylic acid intermediate Int-17 crude product, which is directly used in the next reaction. HRMS (ESI) C₂₀H₂₁N₄O₅S⁺([M+H]⁺) Calculated value 429.1233, found value 429.1238.

And step 3: (E) preparation of (E) -3- (3- (hydroxyamino) -3-oxoprop-1-en-1-yl) -N- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) -1H-pyrrole-1-carboxamide (Compound I-62)

Int-2 in step 3 of example 1 was replaced with Int-17, and the remaining required starting materials, reagents and preparation were the same as in steps 3 to 4 of example 1 to give compound I-62 as a white solid.¹H NMR(600MHz,DMSO-d₆)δ7.82(s,1H),7.61(s,1H),7.38(d,J＝15.6Hz,1H),7.04(d,J＝8.4Hz,1H),6.96(d,J＝8.6Hz,1H),6.53(s,1H),6.17(d,J＝15.6Hz,1H),3.91(s,3H),3.84–3.74(m,4H),3.06–2.96(m,4H).HRMS(ESI)C₂₀H₂₂N₅O₅S⁺([M+H]⁺) Calculated value 444.1342, found value 444.1339.

Example 63: preparation of (4- (3- (hydroxyamino) -3-oxopropyl) -N- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) cyclohexane-1-carboxamide (Compound I-63)

Step 1: preparation of 4-hydroxy-N- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) cyclohexane-1-carboxamide (intermediate Int-18).

The "monomethyl adipate" in step 1 of example 32 was replaced with "4-hydroxypiperidinecarboxylic acid", and the remaining required starting materials, reagents and preparation were the same as in step 1 of example 32 to give intermediate Int-18.¹H NMR(600MHz,DMSO-d₆)δ12.44–12.35(m,1H),6.95–6.85(m,2H),4.65–4.60(m,1H),3.86(s,3H),3.80–3.73(m,4H),3.04–2.94(m,4H),2.76–2.71(m,1H),2.45–2.37(m,1H),1.97–1.78(m,4H),1.70–1.51(m,2H),1.50–1.41(m,2H)。HRMS(ESI)C₁₉H₂₆N₃O₄S⁺([M+H]⁺) Calculated value 392.1639, found value 392.1641.

Step 2: preparation of 4-hydroxy-N- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) cyclohexane-1-carboxamide (intermediate Int-19).

Intermediate Int-18(3.92g,10mmol) obtained in step 1, ethyl 3-bromopropionate (2.35g,13mmol) and potassium carbonate (4.14g,30mmol) were dissolved in DMF (20mL) and stirred at 50 ℃ overnight. The solvent was distilled off under reduced pressure, and the solid residue was isolated by silica gel column chromatography to give intermediate Int-19(0.34g, yield 10%). MS ([ M + H)]⁺):492.22。

And step 3: preparation of 4-hydroxy-N- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) cyclohexane-1-carboxamide (Compound I-63).

"6- ((4-methoxy-7-N-morpholinobenzo [ d ] in step 2 of example 32]Thiazol-2-yl) amino) -6-oxohexanoic acid methyl ester "was substituted with intermediate Int-19 and the remaining required starting materials, reagents and preparation were the same as in example 32, step 2 to give compound I-63 as a pink solid.¹H NMR(600MHz,DMSO-d₆)δ6.96–6.87(m,2H),3.87(s,3H),3.84–3.81(m,2H),3.79–3.76(m,4H),3.35–3.27(m,1H),3.06–2.95(m,4H),2.78–2.59(m,3H),1.84–1.25(m,8H).HRMS(ESI)C₂₂H₃₁N₄O₆S⁺([M+H]⁺) Calculated value 479.1959, found value 479.1966.

The compound listed in example 64 can be prepared in the same manner by changing the corresponding starting materials according to the procedure outlined in example 63, as detailed in Table 8.

TABLE 8

The compounds listed in examples 65 to 74 can be prepared in the same manner by changing the corresponding starting materials according to examples 9 and 34, as detailed in Table 9.

TABLE 9

Example 75: preparation of N-hydroxy-2- (2- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) 2-oxoethyl) (methyl) amino) pyrimidine-5-carboxamide (Compound I-75)

The procedure of example 48 was repeated except for substituting "1-N-Boc-3-azetidinecarboxylic acid" with "N-Boc-N-methylglycine" in step 1 of example 48 and the other required starting materials, reagents and preparation procedures were the same as those of example 48 to obtain Compound I-75 as a pink solid.¹H NMR(800MHz,DMSO-d₆)δ12.69(s,1H),11.09(s,1H),9.02(s,1H),8.67(d,J＝108.7Hz,2H),6.94(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),4.63(s,2H),3.88(s,3H),3.77–3.70(m,4H),3.26(s,3H),3.01–2.97(m,4H).HRMS(ESI)C₂₀H₂₄N₇O₅S⁺([M+H]⁺) Calculated value 474.1560, found value 474.1554.

Example 76: preparation of N- (2-aminophenyl) -2- (4- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) piperidin-1-yl) pyrimidine-5-carboxamide (Compound I-76)

Step 1: preparation of 2- (4- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) piperidin-1-yl) pyrimidine-5-carboxylic acid (intermediate Int-20)

The ester intermediate (0.263g, 0.5mmol) obtained in example 49 was dissolved in a mixed solution of tetrahydrofuran (10mL) and water (2.5mL), and lithium hydroxide (0.060g, 2.5mmol) was added thereto, followed by stirring at room temperature overnight. Neutralizing the reaction solution with 1, 4-dioxane solution (4M) of hydrogen chloride to pH7.4, and evaporating the solvent under reduced pressure to obtain crude product of carboxylic acid intermediate Int-20, which is directly used in the next reaction. HRMS (ESI) C₂₃H₂₇N₆O₅S⁺([M+H]⁺) Calculated value 499.1764, found value 499.1760.

Step 2: preparation of N- (2-aminophenyl) -2- (4- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) piperidin-1-yl) pyrimidine-5-carboxamide (Compound I-76)

The mixture of all intermediate Int-20 obtained in step 1 and lithium chloride was dissolved in anhydrous DMF (5mL), HATU (0.38g, 1.0mmol) was added and stirred at room temperature for 20 min, then o-phenylenediamine (0.108g, 1.0mmol) and DIPEA (0.387g, 3.0mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water, extracted with ethyl acetate three times, the organic phases were combined, the solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain compound I-76(0.097g, yield 33%).¹H NMR(800MHz,DMSO-d₆)δ12.58(s,1H),9.49(s,1H),8.91(s,2H),7.14(d,J＝7.6Hz,1H),6.98–6.95(m,1H),6.94(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),6.76(dd,J＝8.0,1.3Hz,1H),6.58(td,J＝7.6,1.3Hz,1H),4.94(s,2H),4.78(d,J＝13.3Hz,2H),3.88(s,3H),3.79–3.74(m,4H),3.18–3.07(m,2H),3.04–2.97(m,4H),2.94–2.81(m,1H),2.03–1.92(m,2H),1.67–1.54(m,2H).HRMS(ESI)C₂₉H₃₃N₈O₄S⁺([M+H]⁺) Calculated value 589.2345, found value 589.2340.

Example 77: preparation of N- (2-aminophenyl) -2- (2- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) 2-oxoethyl) (methyl) amino) pyrimidine-5-carboxamide (Compound I-77)

The ester intermediate obtained in example 75 was transformed by the preparation method described in example 76 to obtain compound I-77.¹H NMR(800MHz,DMSO-d₆)δ12.72(s,1H),9.49(s,1H),8.90(d,J＝91.0Hz,2H),7.13(d,J＝7.6Hz,1H),6.98–6.92(m,2H),6.89(d,J＝8.5Hz,1H),6.75(dd,J＝8.0,1.3Hz,1H),6.58–6.54(m,1H),4.94(s,2H),4.66(s,2H),3.88(s,3H),3.78–3.70(m,4H),3.30(s,3H),3.03–2.95(m,4H).HRMS(ESI)C₂₆H₂₉N₈O₄S⁺([M+H]⁺) Calculated value 549.2032, found value 549.2035.

Example 78: preparation of N- (2-aminophenyl) -4- ((3- (4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) ureido) methyl) benzamide (Compound I-78)

The ester intermediate obtained in example 9 was transformed according to the preparation method described in example 56 to obtain compound I-78.¹H NMR(800MHz,DMSO-d₆)δ10.97(s,1H),9.63(s,1H),7.96(d,J＝7.9Hz,2H),7.44(d,J＝8.1Hz,2H),7.32(s,1H),7.16(d,J＝7.6Hz,1H),7.00–6.93(m,1H),6.88(d,J＝8.5Hz,1H),6.81(d,J＝8.5Hz,1H),6.79–6.76(m,1H),6.59(t,J＝7.4Hz,1H),4.88(s,2H),4.43(d,J＝5.7Hz,2H),3.85(s,3H),3.79–3.72(m,4H),3.04–2.94(m,4H).HRMS(ESI)C₂₇H₂₉N₆O₄S⁺([M+H]⁺) Calculated value 533.1971, found value 533.1968.

Example 79: preparation of N- (2-aminophenyl) -4- (2- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -2-oxoethyl) benzamide (Compound I-79)

The ester intermediate obtained in example 37 was transformed by the preparation method described in example 56 to obtain compound I-79.¹H NMR(800MHz,DMSO-d₆)δ12.79(s,1H),9.63(s,1H),7.96(d,J＝8.1Hz,2H),7.48(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),6.98–6.95(m,1H),6.94(d,J＝8.5Hz,1H),6.90(d,J＝8.5Hz,1H),6.79–6.75(m,1H),6.59(t,J＝7.3Hz,1H),4.89(s,2H),3.91(s,2H),3.88(s,3H),3.77–3.73(m,4H),3.02–2.97(m,4H).HRMS(ESI)C₂₇H₂₈N₅O₄S⁺([M+H]⁺) Calculated value 518.1862, found value 518.1873.

Example 80: preparation of N- (2-aminophenyl) -4- (4- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) amino) -4-oxobutyl) benzamide (Compound I-80)

The ester intermediate obtained in example 39 was transformed by the preparation method described in example 56 to obtain compound I-80.¹H NMR(800MHz,DMSO-d₆)δ12.46(s,1H),9.60(s,1H),7.92(d,J＝8.0Hz,2H),7.36(d,J＝8.1Hz,2H),7.16(d,J＝7.7Hz,1H),6.98–6.95(m,1H),6.93(d,J＝8.5Hz,1H),6.90(d,J＝8.4Hz,1H),6.79–6.76(m,1H),6.59(t,J＝7.0Hz,1H),4.88(s,2H),3.87(s,3H),3.79–3.77(m,4H),3.03–3.00(m,4H),2.73–2.69(m,2H),2.53–2.51(m,2H),1.99–1.94(m,2H).HRMS(ESI)C₂₉H₃₂N₅O₄S⁺([M+H]⁺) Calculated value 546.2175, found value 546.2162.

Example 81: n is a radical of¹- (2-aminophenyl) -N⁴- (4-methoxy-7-N-morpholinobenzo [ d ]]Preparation of Thiazol-2-yl) terephthalamide (Compound I-81)

Step 1: preparation of methyl 4- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) benzoate (intermediate Int-21)

4- (methoxycarbonyl) benzoic acid (0.090g,0.50mmol) was dissolved in anhydrous DMF (5mL), HATU (0.38g, 1.0mmol) was added, and the mixture was stirred at room temperature for 20 minutes, and then 4-methoxy-7-N-morpholinobenzo [ d ] was added]Thiazol-2-amine (0.132g, 0.50mmol) and DIPEA (0.387g, 3.0mmol) were stirred at room temperature overnight. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, the solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to give intermediate Int-21(0.10g, yield 30%).¹H NMR(800MHz,DMSO-d₆)δ13.24(s,1H),8.27(d,J＝8.4Hz,2H),8.13–8.10(m,2H),6.99(d,J＝8.5Hz,1H),6.96(d,J＝8.4Hz,1H),3.92–3.90(m,6H),3.83–3.79(m,4H),3.08–3.03(m,4H).HRMS(ESI)C₂₁H₂₂N₃O₅S⁺([M+H]⁺) Calculated value 428.1280, found value 428.1271.

Step 2: preparation of 4- ((4-methoxy-7-N-morpholinobenzo [ d ] thiazol-2-yl) carbamoyl) benzoic acid (intermediate Int-22)

Intermediate Int-21(0.10g, 0.23mmol) obtained in step 1 of this example was dissolved in a mixed solution of tetrahydrofuran (10mL) and water (2.5mL), and lithium hydroxide (0.028g, 1.17mmol) was added and stirred at room temperature overnight. Neutralizing the reaction solution with 1, 4-dioxane solution (4M) of hydrogen chloride to pH7.4, and evaporating the solvent under reduced pressure to obtain carboxylic acid intermediate Int-

20, and directly using the crude product in the next reaction. HRMS (ESI) C₂₀H₂₀N₃O₅S⁺([M+H]⁺) Calculated value 414.1124, found value 414.1125.

And step 3: n is a radical of¹- (2-aminophenyl) -N⁴- (4-methoxy-7-N-morpholinobenzo [ d ]]Preparation of Thiazol-2-yl) terephthalamide (Compound I-81)

The mixture of all intermediate Int-22 from step 2 and lithium chloride was dissolved in anhydrous DMF (5mL), HATU (0.178g, 0.46mmol) was added and stirred at room temperature for 20 min, then o-phenylenediamine (0.051g, 0.46mmol) and DIPEA (0.09g, 0.69mmol) were added and stirred at room temperature overnight. The reaction solution was diluted with water, extracted with ethyl acetate three times, the organic phases were combined, the solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to give compound I-81(0.047g, yield 40%).¹H NMR(800MHz,DMSO-d₆)δ13.19(s,1H),9.82(s,1H),8.27(d,J＝8.2Hz,2H),8.14(d,J＝8.2Hz,2H),7.19(d,J＝7.3Hz,1H),7.01–6.97(m,2H),6.95(d,J＝8.4Hz,1H),6.79(dd,J＝8.0,1.1Hz,1H),6.61(t,J＝7.1Hz,1H),4.96(s,2H),3.91(s,3H),3.86–3.77(m,4H),3.07–3.03(m,4H).HRMS(ESI)C₂₆H₂₆N₅O₄S⁺([M+H]⁺) The calculated value is 504.1706, found value: 504.1692.

Example 82: determination of histone deacetylase HDAC inhibitory activity of compounds. The specific operation method comprises the following steps:

(1) buffer for assay (50mM Tris pH, 0.01% Tween-20,50mM NaCl);

(2) preparing a compound to be tested into a DMSO solution with a corresponding concentration of 10mM, then diluting the DMSO solution to 1mM, and then diluting the DMSO solution by 3-fold gradient to obtain 10 concentration points;

(3) test compounds of different concentrations were transferred to 384-well plates (Perkin Elmer, cat. No.6007279) with Echo at 250nL per well (final DMSO content 1%);

(4) preparing a solution of histone deacetylase with the buffer of step (1) to give a final concentration of HDAC1 (bpsbeiioscience, cat.no.50051) of 4nM and HDAC6(BPS bioscience, cat.no.50056) of 5 nM;

(5) preparing a mixed solution of the substrate (lgk (ac) -AMC, Trypsin) with the buffer in step (1), and determining HDAC1 activity: LGK (Ac) -AMC (Gill Biochemical) concentration 8 μ M and Trypsin concentration 0.05 μ M, for HDAC6 activity assay: LGK (Ac) -AMC at a final concentration of 11. mu.M and Trypsin at a final concentration of 0.01. mu.M;

(6) adding 15. mu.L of the enzyme solution prepared in step (4) to each well of the test 384-well plate, adding 15. mu.L of the buffer solution in step (1) for the low control group, centrifuging at 1000rmp for 1 minute, and then incubating at room temperature for 15 minutes;

(7) adding 10. mu.L of the enzyme solution prepared in step (5) to each well of the test 384-well plate, centrifuging at 1000rmp for 1 minute, and then incubating at room temperature for 60 minutes;

(8) reading the values with Synergy MX (maximum excitation light: 355nm, maximum emission light 460 nm);

(9) data were processed with GraphPad Prism5 to calculate IC₅₀The results are shown in Table 10.

Table 10 inhibitory activity of compounds against HDAC1 and HDAC 6.

Table 10 shows that compounds 56, 76-81 have better selectivity for HDAC 1. It can also be analyzed that ZBG is

Can make the compound have better HDAC1 selectivity.

Example 83: determination of the binding activity of the compounds of the invention to the A2A receptor. Testing of the binding activity of compounds to the human A2A receptor was performed using a radioisotope-based ligand competition binding assay. The specific operation method comprises the following steps:

(1) test compounds were prepared as solutions in DMSO at the corresponding concentrations of 10 mM. Then diluting to 10 mu M by using a buffer solution, and then diluting by using the buffer solution in a 3-fold gradient manner to obtain 10 concentration points;

(2) transferring the compounds to be tested with different concentrations to 384-well plates with 50nL per well by using Echo;

(3) a suspension of human A2a receptor cell membranes (RBHA2AM400 UA; Perkin Elmer) and wheat germ agglutinin coated yttrium silicate SPA beads (RPNQ 0023; Perkin Elmer) was prepared: (0.0334mg/mL A2a cell membranes, 3.33mg/mL SPA beads, 0.02mg/mL ADA, assay buffer containing 1 XDPBS, 10mM MgCl₂1% DMSO), incubated at room temperature for 20 minutes;

(4) add 20. mu.L to each well³A solution of H SCH58261(ART 2128; ARC) (15nM SCH58261, assay buffer containing 1 XDDPBS, 10mM MgCl₂1% DMSO), 1000rmp for 1 minute;

(5) add 30. mu. L A2a cell membrane/SPA bead suspension to each well, centrifuge at 1000rmp for 1 min, seal the plate and incubate at room temperature with shaking for 60 min;

(6) reading CPM values with Microbeta 2(Perkin Elmer);

(7) data were processed with GraphPad Prism5 to calculate IC₅₀The results are shown in Table 11.

TABLE 11 results of competitive binding strength of the compounds of the examples to the radioisotopic ligand of the A2A receptor

Example 84: assay of inhibitory Activity of Compounds of the present invention on A2A receptor function. The inhibitory activity of compounds on the human A2A receptor function was determined using HTRF-based cAMP assay (Perkin Elmer). The specific operation method comprises the following steps:

(1) cell culture: HEK293/A2A cell line, medium: 150mL DMEM,17mL 10% FBS,1.4mLG418, 5% CO at 37 ℃₂；

(2) Removing the cells from the T75 culture flask, washing the cells with 8mL of buffer (Biosera, Lot.No.11169), removing the buffer, and then adding 2mL of trypsin (Gibca, REF 25200-072, Lot.No.1732496) to digest the cells;

(3) adding 8mL of solution (DMEM + 10% FBS + G418) to stop digestion, beating and mixing uniformly, and centrifuging for 4 minutes at 1000 rmp;

(4) cells were resuspended in stimulation buffer (5mM HEPES,0.05mM IBMX, 0.1% BSA) and cell-count adjusted to a cell density of 5X 10⁵cell/mL;

(5) preparing a compound to be tested into a DMSO solution with a corresponding concentration of 10mM, then diluting the DMSO solution to 10 mu M, performing 3-fold gradient dilution on the DMSO solution to obtain 10 concentration points, and performing 3-fold gradient dilution on a positive control CGS15943 by taking 10 mu M as an initial concentration to obtain 10 concentration points; agonist NECA was formulated at 150. mu.M;

(6) transferring test compounds with different concentrations to a 384-well plate (Optiplate-384) by using Echo, wherein each well is 100nL, and transferring an agonist to all the test wells, wherein each well is 10 nL;

(7) adding 10 μ L of cell sap per well into a 384-well test plate, wherein the number of cells per well is 5000, centrifuging at 1000rmp for 1 minute, and incubating at room temperature for 60 minutes;

(8) add 5. mu.L of 4 × Eu-cAMP trap (TRF,0264) solution and 5. mu.L of 4 × ULightTM-anti-cAMP solution to each well, centrifuge at 600rmp for 3 minutes and incubate at room temperature for 60 minutes;

(9) read cAMP levels with EnVision (Perkin Elmer) (maximum excitation light: 320nm, maximum emission light 615/665 nm);

(10) data were processed with GraphPad Prism to calculate IC₅₀The results are shown in Table 12.

Table 12 results of cAMP experiments with compounds antagonizing the A2A receptor.

Example 85: the compound of the invention can be used for testing the tumor cell proliferation inhibition activity. The activity of the compound on the proliferation inhibition of tumor cells is measured by selecting three cells of HCT-116, HL-60 and B16F 10.

(1) Cell plating

a. Preparing complete culture medium, and mixing completely.

b. Cell lines with good growth status were selected.

c. The cell culture flask was removed from the incubator and checked for the cell name, culture medium type and cell generation number marked on the flask.

Removing the culture medium of HCT-116 and B16F10 cells, digesting with pancreatin, neutralizing with a culture medium containing serum after digestion, and blowing the cells to make the cells shed. The cell suspension was pipetted into the centrifuge tube and centrifuged at 800-. HL-60 cells were pipetted into the cell suspension and centrifuged at 800-.

e. And (4) sucking and removing the cell supernatant in the centrifuge tube, adding a proper volume of culture medium into the centrifuge tube, and gently blowing and beating the centrifuge tube to ensure that the cells are evenly resuspended.

f. The Cell suspension was adjusted to the appropriate concentration using a Vi-Cell XR cytometer for counting.

g. The cell suspension was added to a bottom transmural white 384 well plate at 36. mu.L/well. Marking the detailed information of cell name, plate density, date, etc., and placing the culture plate in CO₂The incubator was overnight.

(2) Cell experiments:

a. test compounds were formulated with DMSO at 200 x and diluted 3-fold with DMSO to give compounds at 10 concentration gradients.

b. After 24 hours of plating, 1. mu.L of the compound was added to 19. mu.L of the medium to prepare a 10 Xintermediate plate, and then 4. mu.L of the 10 Xcorresponding compound was added to each well, followed by incubation in an incubator at 37 ℃ for 72 hours.

c. The cell morphology was observed under an inverted microscope.

d. The cell culture plates were allowed to equilibrate at room temperature for 30 minutes, 25. mu.L of CTG was added to each well, and then mixed on a plate shaker for 10 minutes to induce cell lysis.

e. The 384 well plate was left at room temperature for 10 minutes to stabilize the luminescence signal, and then a white bottom membrane was attached to the bottom of the plate, and the plate was read using Flexstation 3 (relative settings: luminescence, integration time 500 ms).

f. The results of the analysis are recorded and shown in Table 13.

Results of experiments with compounds of table 13 inhibiting tumor cell proliferation.

。

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite, or prodrug thereof;

wherein the content of the first and second substances,

R¹is hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, -NR⁶R⁷Substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₂Aryl or substituted or unsubstituted 5-12 membered heteroaryl; said substituted C₃-C₁₀Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C₆-C₁₂The substituents in aryl or substituted 5-12 membered heteroaryl are each independently C₁-C₆Alkyl or C₁-C₆Alkoxy, the number of the substituent is one or more, and when the number of the substituent is more than one, the substituent is the same or different;

R²is hydrogen, halogen or C₁-C₆An alkyl group;

R⁴is hydrogen or C₁-C₆An alkyl group;

R⁶and R⁷Each independently is hydrogen or C₁-C₆An alkyl group;

x is N or CR⁵；

R⁵Is hydrogen, halogen or C₁-C₆An alkyl group;

in the compounds of formula I

Is composed of

L is substituted or unsubstituted-M₁-(M₂)_m-(M₃)_n-; said substituted-M₁-(M₂)_m-(M₃)_n-means substituted by one or more R²⁰Substitution; when R is²⁰Is given byWhen plural is, R²⁰The same or different;

(i) m is 0 and n is 0, M₁is-NH-, -O-, -S-, C₁-C₁₀Alkylene radical, C₂-C₁₀Alkenylene radical, C₂-C₁₀Alkynylene, heteroalkylene having 2 to 10 chain atoms, heteroalkenylene having 2 to 10 chain atoms, heteroalkynylene having 3 to 10 chain atoms, 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene;

(ii) m is 1, and n is 0, M₁is-NH-, -O-, -S-, C₁-C₁₀Alkylene radical, C₂-C₁₀Alkenylene radical, C₂-C₁₀Alkynylene, heteroalkylene having 2 to 10 chain atoms, heteroalkenylene having 2 to 10 chain atoms, 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene or C₆-C₁₂An arylene group;

M₂is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene;

(iii) m is 1, and n is 0, M₁Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene;

M₂is C₁-C₁₀Alkylene radical, C₂-C₁₀Alkenylene radical, C₂-C₁₀Alkynylene, heteroalkylene having 2 to 10 chain atoms, or heteroalkenylene having 2 to 10 chain atoms;

(iv) m is 1 and n is 1, M₁is-NH-, -O-, -S-, C₁-C₄Alkylene radical, C₂-C₄Alkenylene radical, C₂-C₄Alkynylene, heteroalkylene having 2,3, or 4 chain atoms, or heteroalkenylene having 2,3, or 4 chain atoms;

M₂is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene (I)Or 5-12 membered heteroarylene;

M₃is C₁-C₄Alkylene radical, C₂-C₄Alkenylene radical, C₂-C₄Alkynylene, heteroalkylene having 2,3, or 4 chain atoms, or heteroalkenylene having 2,3, or 4 chain atoms;

(v) m is 1 and n is 1, M₁Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene;

M₂is-NH-, -O-, -S-, C₁-C₄Alkylene or heteroalkylene having 2,3, or 4 chain atoms;

M₃is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene;

(vi) m is 1 and n is 1, M₁is-NH-, -O-, -S-, C₁-C₄Alkylene radical, C₂-C₄Alkenylene radical, C₂-C₄Alkynylene, heteroalkylene having 2,3, or 4 chain atoms, or heteroalkenylene having 2,3, or 4 chain atoms;

each R²⁰Independently oxo, thio, halogen, cyano, hydroxy, amino, nitro, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Haloalkyl, C₁-C₆Heteroalkyl group, C₂-C₆Heteroalkenyl, C₂-C₆Alkynyl, C₃-C₆Heteroalkynyl, C₃-C₁₀Cycloalkyl, 3-10 membered heterocycloalkyl, C₆-C₁₂Aryl, 5-12 membered heteroaryl, - (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl), - (C)₁-C₃Alkylene) - (3-to 10-membered heterocycloalkyl), - (C)₁-C₃Alkylene group) - (C₆-C₁₂Aryl), - (C)₁-C₃Alkylene) - (5-12 membered heteroaryl), -NR⁴¹R⁴²、-OR⁴¹、-SR⁴¹、-C(＝O)O-R⁴¹、-C(＝O)-NR⁴¹R⁴²、-N(R⁴²)-C(＝O)-R⁴¹、-O-C(＝O)-R⁴¹、-S(O)₂-R⁴¹、-O-S(O)₂-R⁴¹、-S(O)₂-OR⁴¹、-S(O)₂-NR⁴¹R⁴²or-N (R)⁴¹)-S(O)₂-R⁴²；

Each R⁴¹Or R⁴²Each independently is hydrogen or C₁-C₆An alkyl group;

ZBG is

Each R⁸Independently of one another, halogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₃-C₆Cycloalkyl, 3-6 membered heterocycloalkyl, C₆-C₁₂Aryl or 5-12 membered heteroaryl; y is 0, 1,2, 3 or 4;

R⁹is hydrogen or C₁-C₆An alkyl group;

2. A compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite, or prodrug thereof, according to claim 1, wherein: said C₁-C₆Alkyl radical, C₁-C₆C in haloalkyl₁-C₆Alkyl and C₁-C₆C in alkoxy₁-C₆Each alkyl group is independently C₁-C₄An alkyl group;

and/or, said C₂-C₆Each alkenyl group is independently C₂-C₄An alkenyl group;

and/or, said C₃-C₁₀Cycloalkyl and- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl) C₃-C₁₀Cycloalkyl is each independently C₃-C₈A cycloalkyl group;

and/or said 3-10 membered heterocycloalkyl and — (C)₁-C₃3-10 membered heterocycloalkyl in alkylene) - (3-10 membered heterocycloalkyl) is each independently 3, 4,5, 6, 7 or 8 membered heterocycloalkyl;

and/or, said C₆-C₁₂Aryl and- (C)₁-C₃Alkylene group) - (C₆-C₁₂C in aryl)₆-C₁₂Each aryl group is independently phenyl;

and/or said 5-12 membered heteroaryl and- (C)₁-C₃5-12 membered heteroaryl in alkylene) - (5-12 membered heteroaryl) is each independently 5,6 or 7 membered heteroaryl;

and/or, said 3-10 membered cycloalkylene is each independently 3, 4,5, 6, 7 or 8 membered cycloalkylene;

and/or, said 3-10 membered heterocycloalkylene is each independently 3, 4,5, 6, 7 or 8 membered heterocycloalkylene;

and/or, said C₆-C₁₂Each arylene is independently phenylene;

and/or, the 5-12 membered heteroarylene is each independently a 5-, 6-, or 7 membered heteroarylene.

3. A compound of formula I according to claim 1 or 2, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer thereofA solvate, metabolite or prodrug thereof, characterized in that: when R is¹Is substituted or unsubstituted C₃-C₁₀When there is a cycloalkyl group, said C₃-C₁₀Cycloalkyl is cyclohexyl;

and/or when R¹When the substituted or unsubstituted 3-to 10-membered heterocycloalkyl group is used, the 3-to 10-membered heterocycloalkyl group is

U is CH or N, R¹⁰、R¹¹And U are joined together to form a 5,6, 7 or 8 membered heterocycloalkyl;

and/or when R¹Is substituted or unsubstituted C₆-C₁₂When aryl, said C₆-C₁₂Aryl is phenyl;

and/or when R¹When the substituted or unsubstituted 5-12 membered heteroaryl is used, the 5-12 membered heteroaryl is a 6 membered heteroaryl;

and/or when R³Is C₁-C₆When alkyl, said C₁-C₆Alkyl is methyl, ethyl, n-propyl or isopropyl;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁Is C₁-C₁₀When it is alkylene, said C₁-C₁₀Alkylene being C₁-C₇An alkylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁Is C₂-C₁₀When alkenylene, said C₂-C₁₀Alkenylene radical being C₂-C₇An alkenylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁Is C₂-C₁₀When alkynylene is mentioned, C₂-C₁₀Alkynylene is C₂-C₇An alkynylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁When the alkyl group is a heteroalkylene group having 2 to 10 chain atoms, the "heteroalkylene group having 2 to 10 chain atoms" is a heteroalkylene group having 2 to 7 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁When the heteroalkenylene group has 2 to 10 chain atoms, the heteroalkenylene group having 2 to 10 chain atoms is the heteroalkenylene group having 2 to 7 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁When the heteroalkynylene group has 3 to 10 chain atoms, the heteroalkynylene group with 3 to 10 chain atoms is the heteroalkynylene group with 3 to 7 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is 3-7 membered cycloalkylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁When the heterocyclic group is 3-to 10-membered heterocycloalkylene, the 3-to 10-membered heterocycloalkylene is 6-membered heterocycloalkylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁Is C₆-C₁₂In the case of arylene, said C₆-C₁₂Arylene is 1, 4-phenylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is a 6 membered heteroarylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁Is C₁-C₁₀When it is alkylene, said C₁-C₁₀Alkylene being C₁-C₆An alkylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁Is C₂-C₁₀When alkenylene, said C₂-C₁₀Alkenylene radical being C₂-C₆An alkenylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁Is C₂-C₁₀When alkynylene is mentioned, C₂-C₁₀Alkynylene is C₂-C₆An alkynylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁When the alkyl group is a heteroalkylene group having 2 to 10 chain atoms, the "heteroalkylene group having 2 to 10 chain atoms" is a heteroalkylene group having 2 to 5 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁When the heteroalkenylene group has 2 to 10 chain atoms, the heteroalkenylene group having 2 to 10 chain atoms is the heteroalkenylene group having 2 to 5 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁When the compound is a 3-to 10-membered cycloalkylene group, the 3-to 10-membered cycloalkylene group is a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a spiro [3,3 ]]A heptyl group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁When it is 3-to 10-membered heterocycloalkylene, the 3-to 10-membered heterocycloalkylene is 1,3- (4-membered heterocycloalkylene), 1,3- (5-membered heterocycloalkylene), 1,4- (6-membered heterocycloalkylene) or 2,6- (heterospiro [3,3 ]]Heptyl);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁Is C₆-C₁₂In the case of arylene, said C₆-C₁₂Arylene is 1, 4-phenylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is a 6 membered heteroarylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₂When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₂When the heterocyclic group is 3-to 10-membered heterocycloalkylene, the 3-to 10-membered heterocycloalkylene is 6-membered heterocycloalkylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₂Is C₆-C₁₂In the case of arylene, said C₆-C₁₂Arylene is 1, 4-phenylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₂In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is a 6 membered heteroarylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₁When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is 1, 4-cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₁When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is 1,4- (6-membered heterocycloalkylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₁Is C₆-C₁₂In the case of arylene, said C₆-C₁₂Arylene is 1, 4-phenylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₁In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene groupAryl is 5 or 6 membered heteroarylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂Is C₁-C₁₀When it is alkylene, said C₁-C₁₀Alkylene being C₁-C₆An alkylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂Is C₂-C₁₀When alkenylene, said C₂-C₁₀Alkenylene radical being C₂-C₆An alkenylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂Is C₂-C₁₀When alkynylene is mentioned, C₂-C₁₀Alkynylene is C₂-C₆An alkynylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂When the alkyl group is a heteroalkylene group having 2 to 10 chain atoms, the "heteroalkylene group having 2 to 10 chain atoms" is a heteroalkylene group having 2 to 5 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂When the heteroalkenylene group has 2 to 10 chain atoms, the heteroalkenylene group having 2 to 10 chain atoms is the heteroalkenylene group having 2 to 5 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₁Is C₁-C₄When it is alkylene, said C₁-C₄Alkylene is methylene or ethylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₁Is C₂-C₄When alkenylene, said C₂-C₄Alkenylene is vinylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₁Is C₂-C₄When alkynylene is mentioned, C₂-C₄The alkynylene group is ethynylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₁In the case of a heteroalkylene group having 2,3, or 4 chain atoms, the "heteroalkylene group having 2,3, or 4 chain atoms" is a heteroalkylene group having 2 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₂When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₂When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is 1,4- (6-membered heterocycloalkylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₂Is C₆-C₁₂In the case of arylene, said C₆-C₁₂Arylene is 1, 4-phenylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₂In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is a 6 membered heteroarylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₃Is C₁-C₄When it is alkylene, said C₁-C₄Alkylene is methylene or ethylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₃Is C₂-C₄When alkenylene, said C₂-C₄Alkenylene is vinylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₃Is C₂-C₄When alkynylene is mentioned, C₂-C₄The alkynylene group is ethynylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₃When the heteroalkenylene group has 2,3 or 4 chain atoms, the heteroalkenylene group having 2,3 or 4 chain atoms is the heteroalkenylene group having 2 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₁When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₁When the heterocyclic group is 3-to 10-membered heterocycloalkylene, the 3-to 10-membered heterocycloalkylene is 6-membered heterocycloalkylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₁Is C₆-C₁₂In the case of arylene, said C₆-C₁₂Arylene is 1, 4-phenylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₁In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is a 6 membered heteroarylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₂Is C₁-C₄When it is alkylene, said C₁-C₄Alkylene is methylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₃When it is a 3-to 10-membered cycloalkylene group, said 3-to 10-membered cycloalkylene group is a 5-, 6-or 7-membered cycloalkylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the following conditionsCase (v), M₃When the heterocyclic group is 3-to 10-membered heterocycloalkylene, the 3-to 10-membered heterocycloalkylene is 6-membered heterocycloalkylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₃Is C₆-C₁₂In the case of arylene, said C₆-C₁₂Arylene is 1, 4-phenylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₃In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is a 6 membered heteroarylene group;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₁Is C₁-C₄When it is alkylene, said C₁-C₄Alkylene is methylene;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₁Is C₂-C₄When alkenylene, said C₂-C₄Alkenylene is vinylene;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₁Is C₂-C₄When alkynylene is mentioned, C₂-C₄The alkynylene group is ethynylene;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₁In the case of a heteroalkylene group having 2,3, or 4 chain atoms, the "heteroalkylene group having 2,3, or 4 chain atoms" is a heteroalkylene group having 2 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₂When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₂Is 3-1When the heterocyclic ring is a 0-membered heterocyclic ring, the 3-to 10-membered heterocyclic ring is a 6-membered heterocyclic ring;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₂Is C₆-C₁₂In the case of arylene, said C₆-C₁₂Arylene is 1, 4-phenylene;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₂In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is a 6 membered heteroarylene group;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₃When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₃When the heterocyclic group is 3-to 10-membered heterocycloalkylene, the 3-to 10-membered heterocycloalkylene is 6-membered heterocycloalkylene;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₃Is C₆-C₁₂In the case of arylene, said C₆-C₁₂Arylene is 1, 4-phenylene;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₃In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is a 6 membered heteroarylene group;

and/or when R²⁰Is C₁-C₆When alkyl, said C₁-C₆Alkyl is methyl, ethyl, n-propyl, isopropyl or n-butyl;

and/or when R²⁰Is C₂-C₆When alkenyl, said C₂-C₆Alkenyl is

And/or when R²⁰Is C₃-C₁₀When there is a cycloalkyl group, said C₃-C₁₀Cycloalkyl is cyclopropyl;

and/or when R²⁰Is- (C)₁-C₃Alkylene) - (3-to 10-membered heterocycloalkyl), said- (C)₁-C₃Alkylene) - (3-to 10-membered heterocycloalkyl) is

And/or when R⁸When independently halogen, said halogen is fluorine;

and/or when R⁸When independently a 5-12 membered heteroaryl, said 5-12 membered heteroaryl is thienyl;

and/or when R⁹Is C₁-C₆When alkyl, said C₁-C₆Alkyl is n-propyl.

4. A compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, according to any one of claims 1 to 3, wherein: when R is¹When the substituted or unsubstituted 3-to 10-membered heterocycloalkyl group is used, the 3-to 10-membered heterocycloalkyl group is

Each U is independently CH or N, each U₁Independently O, S or CH₂P is 1 or 2;

and/or when R³Is C₁-C₆When alkyl, said C₁-C₆Alkyl is methyl or ethyl;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁Is C₁-C₁₀When it is alkylene, said C₁-C₁₀Alkylene being C₄、C₅、C₆Or C₇An alkylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁Is C₂-C₁₀When alkenylene, said C₂-C₁₀Alkenylene radical being C₄、C₅、C₆Or C₇An alkenylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁Is C₂-C₁₀When alkynylene is mentioned, C₂-C₁₀Alkynylene is C₄、C₅、C₆Or C₇An alkynylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁In the case of a heteroalkylene group having 2 to 10 chain atoms, the term "heteroalkylene group having 2 to 10 chain atoms" is intended to mean a heteroalkylene group having 4,5, 6, or 7 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁(ii) when heteroalkenylene having 2 to 10 chain atoms, said heteroalkenylene having 2 to 10 chain atoms is heteroalkenylene having 4,5, 6, or 7 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁(ii) when heteroalkynylene having 3 to 10 chain atoms is said heteroalkynylene having 3 to 10 chain atoms is heteroalkynylene having 4,5, 6, or 7 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is 1, 4-cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁Is 1,4- (6-membered heterocycloalkylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁In the case of a 5-12 membered heteroarylene, the 5-12 membered heteroarylene is 1,4- (6 membered heteroarylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁Is C₁-C₁₀When it is alkylene, said C₁-C₁₀Alkylene being C₁、C₂、C₃Or C₄An alkylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁Is C₂-C₁₀When alkenylene, said C₂-C₁₀Alkenylene radical being C₂、C₃Or C₄An alkenylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁Is C₂-C₁₀When alkynylene is mentioned, C₂-C₁₀Alkynylene is C₂、C₃Or C₄An alkynylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁When it is a heteroalkylene group having 2 to 10 chain atoms, the "heteroalkylene group having 2 to 10 chain atoms" is a heteroalkylene group having 2,3, or 4 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁When the heteroalkenylene group has 2 to 10 chain atoms, the heteroalkenylene group having 2 to 10 chain atoms is the heteroalkenylene group having 2,3 or 4 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁In the case of 3-to 10-membered cycloalkylene group, the above3-to 10-membered cycloalkylene is

And/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is

And/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₁In the case of a 5-12 membered heteroarylene, the 5-12 membered heteroarylene is 1,4- (6 membered heteroarylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₂When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is 1, 4-cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₂When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is 1,4- (6-membered heterocycloalkylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₂In the case of a 5-12 membered heteroarylene, the 5-12 membered heteroarylene is 1,4- (6 membered heteroarylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₁When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is

And/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₁In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is 1,3- (5 membered heteroarylene) or 1,4- (6 membered heteroarylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂Is C₁-C₁₀When it is alkylene, said C₁-C₁₀Alkylene being C₁、C₂、C₃Or C₄An alkylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂Is C₂-C₁₀When alkenylene, said C₂-C₁₀Alkenylene radical being C₂、C₃Or C₄An alkenylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂Is C₂-C₁₀When alkynylene is mentioned, C₂-C₁₀Alkynylene is C₂、C₃Or C₄An alkynylene group;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂When it is a heteroalkylene group having 2 to 10 chain atoms, the "heteroalkylene group having 2 to 10 chain atoms" is a heteroalkylene group having 2,3, or 4 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂When the heteroalkenylene group has 2 to 10 chain atoms, the heteroalkenylene group having 2 to 10 chain atoms is the heteroalkenylene group having 2,3 or 4 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₁Is C₂-C₄When alkenylene, said C₂-C₄Alkenylene is ethenylene in the trans configuration;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₁In the case of a heteroalkylene group having 2,3 or 4 chain atoms, the term "heteroalkylene group having 2,3 or 4 chain atoms" is intended to mean

And/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₂When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is 1, 4-cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₂In the case of a 5-12 membered heteroarylene, the 5-12 membered heteroarylene is 1,4- (6 membered heteroarylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₃Is C₂-C₄When alkenylene, said C₂-C₄Alkenylene is ethenylene in the trans configuration;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the conditions (iv), M₃In the case of a heteroalkenylene group having 2,3 or 4 chain atoms, the term "heteroalkenylene group having 2,3 or 4 chain atoms" is a heteroalkenylene group having 2 chain atoms in which the double bond is in the trans configuration;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₁When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is 1, 4-cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₁When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is 1,4- (6-membered heterocycloalkylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₁In the case of a 5-12 membered heteroarylene group, theThe 5-12 membered heteroarylene of (a) is 1,4- (6 membered heteroarylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₃When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₃When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is 1,4- (6-membered heterocycloalkylene);

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₃In the case of a 5-12 membered heteroarylene, the 5-12 membered heteroarylene is 1,4- (6 membered heteroarylene);

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₁In the case of "heteroalkylene having 2,3 or 4 chain atoms", said heteroalkylene having 2,3 or 4 chain atoms is

And/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₂When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is 1, 4-cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₂When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is 1,4- (6-membered heterocycloalkylene) or

And/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₂In the case of a 5-12 membered heteroarylene, the 5-12 membered heteroarylene is 1,4- (6 membered heteroarylene);

and/or the presence of a gas in the gas,when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₃When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is 1, 4-cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₃When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is 1,4- (6-membered heterocycloalkylene);

and/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₃In the case of a 5-12 membered heteroarylene, the 5-12 membered heteroarylene is 1,4- (6 membered heteroarylene);

and/or when R⁸When independently a 5-12 membered heteroaryl, said 5-12 membered heteroaryl is thiophen-2-yl.

5. A compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, according to any one of claims 1 to 4, wherein: when R is¹When the substituted or unsubstituted 3-to 10-membered heterocycloalkyl group is used, the 3-to 10-membered heterocycloalkyl group is

And/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁In the case of a heteroalkylene group having 2 to 10 chain atoms, the term "heteroalkylene group having 2 to 10 chain atoms" is intended to mean

And/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (i), M₁When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is

And/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₂In the case of a heteroalkylene group having 2 to 10 chain atoms, the term "heteroalkylene group having 2 to 10 chain atoms" is intended to mean

And/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (ii), M₂In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is

And/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₁In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is

And/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂Is C₂-C₁₀When alkenylene, said C₂-C₁₀Alkenylene is vinylene, preferably in the trans configuration;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfies the condition (iii), M₂In the case of a heteroalkylene group having 2 to 10 chain atoms, the term "heteroalkylene group having 2 to 10 chain atoms" is intended to mean

And/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₃When the compound is 3-10 membered cycloalkylene, the 3-10 membered cycloalkylene is 1, 4-cyclohexylene;

and/or when-M₁-(M₂)_m-(M₃)_n-satisfying the condition (v), M₃In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is

And/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₂When it is 3-to 10-membered heterocycloalkylene, said 3-to 10-membered heterocycloalkylene is

And/or when-M₁-(M₂)_m-(M₃)_nSatisfy case (vi), M₃In the case of a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is

6. A compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, according to any one of claims 1 to 5, wherein: when-M₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, M₁Is C₁-C₁₀Alkylene, heteroalkylene having 2 to 10 chain atoms, 3-to 10-membered cycloalkylene, 3-to 10-membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (ii) is satisfied, M₁is-NH-, -O-, -S-, C₁-C₁₀Alkylene, heteroalkylene having 2 to 10 chain atoms, 3-to 10-membered cycloalkylene, 3-to 10-membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene, M₂Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (iii) is satisfied, M₁Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene, M₂Is C₁-C₁₀Alkylene radical, C₂-C₁₀Alkenylene, heteroalkylene having 2 to 10 chain atoms, or heteroalkenylene having 2 to 10 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (iv) is satisfied, M₁is-NH-, -O-, -S-, C₁-C₄Alkylene radical, C₂-C₄Alkenylene, heteroalkylene having 2,3, or 4 chain atoms, or heteroalkenylene having 2,3, or 4 chain atoms; m₂Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene; m₃Is C₁-C₄Alkylene radical, C₂-C₄Alkenylene, heteroalkylene having 2,3, or 4 chain atoms, or heteroalkenylene having 2,3, or 4 chain atoms;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (v) is satisfied, M₁Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene; m₂is-NH-, -O-, -S-or methylene; m₃Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene;

and/or the presence of a gas in the gas,when-M₁-(M₂)_m-(M₃)_nWhen condition (vi) is satisfied, M₁is-NH-, -O-, -S-or methylene; m₂Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene; m₃Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene;

and/or, R¹Is substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted

Substituted or unsubstituted C₆-C₁₂Aryl or substituted or unsubstituted 5-12 membered heteroaryl, U is CH or N, R¹⁰、R¹¹And U are joined together to form a 5,6, 7 or 8 membered heterocycloalkyl; the number of the substituents is one or more, and each substituent is independently C₁-C₆An alkyl group;

and/or, R²⁰Is oxo, thio, halogen, hydroxy, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Heteroalkyl group, C₃-C₁₀Cycloalkyl, 3-10 membered heterocycloalkyl or — (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups).

7. A compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, according to any one of claims 1 to 6, wherein: when-M₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, M₁Is C₄、C₅、C₆Or C₇Alkylene, heteroalkylene having 4,5, 6, or 7 chain atoms, 1, 4-cyclohexylene, 1, 4-phenylene, 1,4- (6-membered heteroarylene), or 1,4- (6-membered heterocycloalkylene);

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (ii) is satisfied, M₁is-NH-, -O-, -S-, C₁-C₁₀Alkylene, heteroalkylene having 2 to 10 chain atoms, 3-to 10-membered cycloalkylene or 3-to 10-membered heterocycloalkylene, M₂Is C₆-C₁₂Arylene or 5-12 membered heteroarylene;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (iii) is satisfied, M₁Is 3-10 membered cycloalkylene or 3-10 membered heterocycloalkylene, M₂Is C₃Alkylene or heteroalkylene having 3 chain atoms; or, M₁Is C₆-C₁₂Arylene or 5-12 membered heteroarylene, M₂Vinylidene in the trans configuration;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (iv) is satisfied, M₁is-NH-, -O-, -S-, C₁-C₄Alkylene radical, C₂-C₄Alkenylene, heteroalkylene having 2,3, or 4 chain atoms, or heteroalkenylene having 2,3, or 4 chain atoms; m₂Is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C₆-C₁₂Arylene or 5-12 membered heteroarylene; m₃Vinylidene in the trans configuration;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (v) is satisfied, M₁Is 3-10 membered cycloalkylene or 3-10 membered heterocycloalkylene; m₂is-NH-, -O-, -S-or methylene; m₃Is C₆-C₁₂Arylene or 5-12 membered heteroarylene;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (vi) is satisfied, M₁is-NH-, -O-, -S-or methylene; m₂Is 3-10 membered cycloalkylene or 3-10 membered heterocycloalkylene; m₃Is C₆-C₁₂Arylene or 5-12 membered heteroarylene;

and/or, R¹Is substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted C₆-C₁₂Aryl or substituted or unsubstituted 5-12 membered heteroaryl, each U is independently CH or N, each U is₁Independently O, S or CH₂P is 1 or 2; the number of the substituents is one or more, and each substituent is independently C₁-C₆An alkyl group;

and/or, each R⁸Independently of one another, halogen, C₆-C₁₂Aryl or 5-12 membered heteroaryl;

and/or, R³Is C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl or- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups);

and/or, R²⁰Is oxo, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Heteroalkyl group, C₃-C₁₀Cycloalkyl or- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups).

8. A compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, according to any one of claims 1 to 7, wherein: when-M₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, M₁Is composed of

W₁is-CH₂-or-NH-;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (ii) is satisfied, M₁is-NH-, -O-, -S-, C₁Alkylene radical, C₂Alkylene radical, C₃Alkylene radical, C₄Alkylene or heteroalkylene having 2,3 or 4 chain atoms,

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (iii) is satisfied, M₁Is 1, 4-cyclohexylene or 1,4- (6-membered heteroalkylene), M₂Is C₃Alkylene or heteroalkylene having 3 chain atoms, or, M₁Is 1,3- (5-membered heteroarylene), M₂Vinylidene in the trans configuration;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (iv) is satisfied, M₁is-NH-, -O-, -S-, methylene, ethylene or a heteroalkylene having 2 chain atoms; m₂Is 1, 4-phenylene or 1,4- (6-membered heteroarylene); m₃Vinylidene in the trans configuration;

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (v) is satisfied, M₁Is 1, 4-cyclohexylene or 1,4- (6-membered heterocycloalkylene); m₂is-NH-, -O-, -S-or methylene; m₃Is 1, 4-phenylene or 1,4- (6-membered heteroarylene);

and/or when-M₁-(M₂)_m-(M₃)_nWhen condition (vi) is satisfied, M₁is-NH-, -O-, -S-or methylene, M₂Is 1, 4-cyclohexylene, 1,4- (6-membered heterocycloalkylene),

M₃Is 1, 4-phenylene or 1,4- (6-membered heteroarylene);

and/or, R¹Is substituted or unsubstituted

Or substituted or unsubstituted

U is N, each U₁Independently O, S or CH₂P is 1 or 2; the number of the substituents is one or more, and each substituent is independently C₁-C₆An alkyl group;

and/or, each R⁸Independently fluorine or thiophen-2-yl;

and/or, R³Is C₁-C₆An alkyl group;

and/or when-M₁-(M₂)_m-(M₃)_n-is meant by one or more R²⁰When substituted, R²⁰The number of (a) is 1,2, 3, 4,5, 6 or 7;

and/or, R²⁰Is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₁₀Cycloalkyl or- (C)₁-C₃Alkylene group) - (C₃-C₁₀Cycloalkyl groups).

9. A compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, according to any one of claims 1 to 8, wherein: when-M₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, M₁Is composed of

And/or when-M₁-(M₂)_m-(M₃)_n-M when condition (ii) is satisfied₁-M₂-is of

And/or when-M₁-(M₂)_m-(M₃)_n-M when condition (iii) is satisfied₁-M₂-is of

And/or when-M₁-(M₂)_m-(M₃)_n-M when condition (iv) is satisfied₁-M₂-M₃-is of

And/or when-M₁-(M₂)_m-(M₃)_n-M when condition (v) is satisfied₁-M₂-M₃-is of

And/or when-M₁-(M₂)_m-(M₃)_n-M when condition (vi) is satisfied₁-M₂-M₃-is of

And/or, R¹Is composed of

And/or ZBG is

And/or, X is CH or N;

and/or, R³Is methyl or ethyl;

and/or when-M₁-(M₂)_m-(M₃)_nBy one or more R²⁰When substituted, R²⁰The number of (a) is 1,2 or 3;

and/or, R²⁰Is methyl, ethyl, n-propyl, isopropyl, n-butyl,

Cyclopropyl or

10. A compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, according to any one of claims 1 to 9, wherein: when-M₁-(M₂)_m-(M₃)_nWhen condition (i) is satisfied, L is

And/or when-M₁-(M₂)_m-(M₃)_nWhen case (ii) is satisfied, L is

And/or when-M₁-(M₂)_m-(M₃)_nWhen case (iii) is satisfied, L is

And/or when-M₁-(M₂)_m-(M₃)_nWhen condition (iv) is satisfied, L is

And/or when-M₁-(M₂)_m-(M₃)_nWhen case (v) is satisfied, L is

And/or when-M₁-(M₂)_m-(M₃)_nWhen case (vi) is satisfied, L is

And/or the presence of a gas in the gas,

is composed of

And/or, R¹Is composed of

And/or ZBG is

And/or, X is CH;

and/or, R²Is hydrogen;

and/or, R³Is methyl;

and/or, R⁴Is hydrogen;

and/or, the isotopic derivative is a deuteron.

11. The compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, as claimed in claim 1, wherein the compound of formula I is selected from the following schemes (1) or (2):

scheme (1)

Wherein L is a substituted or unsubstituted-M₁-(M₂)_m-(M₃)_n-; said substituted-M₁-(M₂)_m-(M₃)_n-means substituted by one or more R²⁰Substitution; when R is²⁰When there are plural, R²⁰The same or different;

-M₁-(M₂)_m-(M₃)_n-the following situation (i) or (ii) is satisfied:

R¹、R²、R³、R⁴、R²⁰and X is as defined in any one of claims 1 to 10;

scheme (2)

-M₁-(M₂)_m-(M₃)_n-the following situation (i) or (ii) is satisfied:

R¹、R²、R³、R⁴、R²⁰and X is as defined in any one of claims 1 to 10.

12. The compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, according to claim 1, wherein the compound of formula I is selected from any one of the following structures:

13. a method for preparing a compound of formula I according to claim 1, which is at least one of the following schemes:

scheme one

The first scheme comprises the following steps: in an organic solvent, a compound shown as a formula II and NH₂Carrying out a substitution reaction on-OH in the presence of alkali to obtain a compound shown as a formula I; wherein ZBG is

R¹、R²、R³、R⁴、X、

And L is as defined in any one of claims 1 to 12, R^aIs C₁-C₆An alkyl group;

scheme two

The second scheme comprises the following steps: reacting a compound shown as a formula IV in an organic solvent in the presence of acid to obtain a compound shown as a formula I; wherein ZBG is

R¹、R²、R³、R⁴、X、

And L is as defined in any one of claims 1 to 12;

scheme three

The third scheme comprises the following steps: in an organic solvent, reacting a compound shown as a formula III with

Carrying out condensation reaction in the presence of a condensing agent and alkali to obtain a compound shown as a formula I; wherein ZBG is

R¹、R²、R³、R⁴、R⁸、X、

y and L are as defined in any one of claims 1 to 12;

scheme four

The fourth scheme comprises the following steps: in an organic solvent, reacting a compound shown as a formula III with

R¹、R²、R³、R⁴、R⁹、X、

And L is as defined in any one of claims 1 to 12;

scheme five

R¹、R²、R³、R⁴、R⁹、X、

And L is as defined in any one of claims 1 to 12, and R⁹Is not hydrogen.

14. A compound of any one of the following structures:

wherein R is¹、R²、R³、R⁴X, L and

as defined in any one of claims 1 to 12, R^aIs C₁-C₆An alkyl group.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, as defined in any one of claims 1 to 12, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, and at least one pharmaceutically acceptable adjuvant.

16. Use of a compound of formula I, a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite or prodrug thereof, according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the treatment and/or prevention of a disease associated with the adenosine A2A receptor and/or histone deacetylase HDAC.

17. The use of claim 16, wherein: the "diseases related to adenosine A2A receptor and/or histone deacetylase HDAC" are cancer or central nervous system diseases.