TWI689497B - Heteroaromatic derivatives and parmaceutical applications thereof - Google Patents

Abstract

The present invention discloses aromatic heterocyclic derivatives and their application in medicine. Specifically, the present invention provides an aromatic heterocyclic compound or its stereoisomers, geometric isomers, tautomers, racemates , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and pharmaceutical compositions containing the compounds of the present invention. The invention also discloses the use of the compound of the invention or the pharmaceutical composition thereof in the preparation of a medicament for the treatment of respiratory diseases, especially chronic obstructive pulmonary disease (COPD).

Description

Aromatic heterocyclic derivatives and their application in medicine

The present invention belongs to the technical field of medicine, and specifically relates to an aromatic heterocyclic compound, a pharmaceutical composition containing the compound, and its use as a PDE 4 inhibitor to treat chronic obstructive pulmonary disease (COPD).

Cyclic nucleotide phosphodiesterases (PDEs) are an important family of superenzymes, which can effectively control the concentration of cAMP and cGMP in cells through the hydrolysis of cAMP and cGMP, thereby regulating the second messenger in the body. Biochemistry. PDEs are widely distributed in mammalian tissues, and their diversity results in specific distribution of different PDE enzymes at the cellular and subcellular levels, which can selectively regulate a variety of cell functions, and are good targets for drug design and treatment.

It is known that cyclic adenosine-3',5'-monophosphate (cAMP) exhibits an important intracellular secondary messenger role (Sutherland and Roll, Pharmacol. Rev, 1960 , 12:265). Intracellular hydrolysis of cAMP to adenosine 5'-monophosphate (AMP) causes many inflammatory disorders including (but not limited to) psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress Syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, and ulcerative colitis. Cyclic nucleotide phosphodiesterase (PDE) is a super-family of the biochemical and functional variability of this enzyme, and is an important factor to control the level of cAMP (and cGMP). Eleven different families of phosphodiesterases with more than 25 gene products. Although PDE 1, PDE 2, PDE 3, PDE 4, and PDE 7 all use cAMP as a substrate, only PDE 4 and PDE 7 types are highly selective for cAMP hydrolysis. Therefore, PDE inhibitors, especially PDE 4 inhibitors (such as rolipram or Ro-1724) are considered cAMP enhancers. Immune cells contain PDE 3 and PDE 4, PDE 4 is ubiquitous in human monocytes. Therefore, inhibition of type IV phosphodiesterase is a target of therapeutic intervention that is regulated and used for various disease processes. Studies have shown that administration of PDE 4 inhibitors has the effect of restoring memory loss in animal models (including those of Alzheimer's disease) (Expert Opin Ther. Targets, 2005 , 9(6): 1283-1305; Drug Discovery Today, 2005 , 10(22): 1503-19).

Phosphodiesterase type 4 (PDE 4) has been shown to be a major regulator of cyclic AMP of airway smooth muscle and inflammatory cells. PDE 4 is the main cAMP-metabolizing enzyme found in inflammatory cells and immune cells. PDE4 inhibitors have been shown to have potential as anti-inflammatory drugs, especially in inflammatory lung diseases such as asthma, COPD and rhinitis. They inhibit the release of cytokines and other inflammatory signals and inhibit the production of reactive oxygen species. PDE 4 inhibitors can be used to treat various diseases, including allergic and inflammatory diseases, diabetes, central nervous system diseases, pain, and TNF-producing viruses. PDE 4 is characterized by the selective high-affinity hydrolytic degradation of the second messenger cyclic adenosine-3',5'-monophosphate (cAMP), which has been studied for the treatment of asthma and chronic obstructive pulmonary disease (COPD ).

Quoting from an article in the British Journal of Pharmacology, "Since the 1980s, PDE 4 inhibitors have been under development as new anti-inflammatory therapies, with asthma and chronic obstructive pulmonary disease (COPD) as the main indications. In most cases, due to lack of effectiveness, various structural PDE 4 inhibitors, including cilomilast, cilomilast, filaminast, lirimilast, and piramislast (piclamilast), tofimilast (tofimilast), etc. development has ceased. The first issue is the low therapeutic ratio of these compounds, which severely limits the dose that can be administered. Indeed, for most of these compounds, it is likely to be the largest The tolerated dose is the sub-therapeutic dose or at the bottom of the effective dose response curve. Therefore, the problem is to overcome this limitation." (Giembycz, Brit. J. Pharmacol. 155, 2008 , 288-290).

The compounds of the present invention are PDE 4 inhibitors, and based on target rationale and in vitro efficacy, the compounds are expected to be used to prevent, treat, treat or alleviate diseases related to PDE 4, especially chronic obstructive pulmonary disease ( COPD), chronic bronchitis, emphysema, asthma, chronic pneumonia and other respiratory diseases.

The compounds of the present invention have an inhibitory effect on PDE 4. In particular, the compounds and pharmaceutically acceptable pharmaceutical compositions of the present invention can be effectively used as PDE 4 inhibitors Agent.

其中：R¹為H、氘、烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、烷基-C(=O)-、烷基-S(=O)₂-、R^a-C(=O)-亞烷基、R^a-S(=O)₂-亞烷基、烯基、炔基、環烷基烷基、雜環基烷基、芳基烷基或雜芳基烷基；各R²獨立地為H、氘、F、Cl、Br、I、CN、OH、NO₂、NH₂、COOH、-C(=O)-NH₂、-S(=O)₂-NH₂、烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、烷氧基、鹵代烷氧基或烷胺基；R³為H、氘、烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、烷基-C(=O)-、烷基-S(=O)₂-、烷基-C(=O)-亞烷基、烷基-O-C(=O)-亞烷基、烷基-S(=O)₂-亞烷基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、環烷基-C(=O)-亞烷基或雜環基-C(=O)-亞烷基；R⁴為氘、NH₂、C_2-10烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、R^a-C(=O)-亞烷基、R^a-S(=O)₂-亞烷基、烯基、炔基、烷氧基、烷胺基、-C(=O)-NH₂或-S(=O)₂-NH₂；X為N(R^b)、O或S；Y為O或S；A為含有至少一個氮原子的雜環基； 各R⁵獨立地為H、氘、F、Cl、Br、I、CN、OH、NO₂、NH₂、R⁶-C(=O)-、R⁶-C(=O)-亞烷基、R⁶-C(=O)-亞烯基、R⁶-C(=O)-亞烷基-O-C(=O)-、R⁶-C(=O)-亞烯基-O-C(=O)-、R⁶-C(=O)O-亞烷基-O-C(=O)-、R⁶-C(=O)O-亞烯基-O-C(=O)-、R^cR^bN-C(=O)-、R^cR^bN-C(=O)-O-、R^cR^bN-C(=O)-亞烷基、R^cR^bN-C(=O)-亞烯基、R^cR^bN-C(=O)-亞烷基-O-C(=O)-、R^cR^bN-C(=O)-亞烯基-O-C(=O)-、R⁶-C(=O)-N(R^b)-、R⁶-C(=O)-N(R^b)-亞烷基、R⁶-C(=O)-N(R^b)-亞烯基、R⁶-C(=O)-亞烷基-N(R^b)-、R⁶-C(=O)-亞烯基-N(R^b)-、R^cR^bN-C(=O)-N(R^b)-、R^cR^bN-C(=O)-N(R^b)-亞烷基、R^cR^bN-C(=O)-N(R^b)-亞烯基、R^cR^bN-C(=O)-亞烷基-N(R^b)-、R^cR^bN-C(=O)-亞烯基-N(R^b)-、R⁶-C(=O)-N(R^b)-C(=O)-、R⁶-C(=O)-N(R^b)-C(=O)-亞烷基、R⁶-C(=O)-N(R^b)-C(=O)-亞烯基、R^6a-O-亞烷基、R^6a-O-亞烯基、氧代、烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、羧基取代的烷基、烷氧基烷基、羥基取代的烷氧基烷基、羧基取代的烷氧基烷基、烷胺基烷基、芳氧基取代的烷基、烷氧基、鹵代烷氧基、烷氧基烷氧基、烷胺基、烷胺基烷胺基、烷胺基烷氧基、烷氧基烷胺基、烷硫基、烯基、羧基取代的烯基、炔基、R⁶-S(=O)₂-、R⁶-S(=O)₂-亞烷基、R⁶-S(=O)₂-亞烯基、R⁶-S(=O)₂-N(R^b)-、R⁶-S(=O)₂-N(R^b)-亞烷基、R⁶-S(=O)₂-N(R^b)-亞烯基、R^cR^bN-S(=O)₂-、R^cR^bN-S(=O)₂-亞烷基、R^cR^bN-S(=O)₂-亞烯基、環烷基、環烷基氧基、環烷基胺基、環烷基烷基、環烯基、環烯基氧基、環烯基胺基、環烯基烷基、雜環基、雜環基氧基、雜環基胺基、雜環基烷基、芳基、芳基氧基、芳基胺基、芳基烷基、雜芳基、雜芳基氧基、雜芳基胺基或雜芳基烷基； 各R^a和R⁶獨立地為H、氘、OH、NH₂、烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、烷氧基烷基、烷氧基、鹵代烷氧基、羥基取代的烷氧基、羧基取代的烷氧基、烷氧基烷氧基、環烷基烷氧基、雜環基烷氧基、芳基烷氧基、雜芳基烷氧基、烷胺基、環烷基、環烷基烷基、環烷基氧基、雜環基、雜環基烷基、雜環基氧基、芳基、芳基烷基、芳基氧基、雜芳基、雜芳基氧基或雜芳基烷基； 各R^6a獨立地為H、烷基、鹵代烷基、羥基取代的烷基、羧基取代的烷 基、烷氧基烷基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、環烷基、雜環基、芳基或雜芳基；各R^b和R^c獨立地為H、氘、烷基、鹵代烷基、羥基取代的烷基、羧基取代的烷基、烷氧基烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基；或R^b，R^c和與之相連的氮原子一起形成3-12個原子組成的環；m為0、1、2或3；n為0、1、2、3、4、5、6、7、8、9或10；其中所述的R¹、R²、R³、R⁴、R⁵、R⁶、R^6a、R^a、R^b和R^c中的烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、羧基取代的烷基、烷基-C(=O)-、烷基-S(=O)₂-、烷基-C(=O)-亞烷基、烷基-O-C(=O)-亞烷基、烷基-S(=O)₂-亞烷基、R^a-C(=O)-亞烷基、R^a-S(=O)₂-亞烷基、烯基、羧基取代的烯基、炔基、烷氧基、鹵代烷氧基、羥基取代的烷氧基、羧基取代的烷氧基、烷胺基、環烷基-C(=O)-亞烷基、雜環基-C(=O)-亞烷基、C_2-10烷基、R⁶-C(=O)-、R⁶-C(=O)-亞烷基、R⁶-C(=O)-亞烯基、R⁶-C(=O)-亞烷基-O-C(=O)-、R⁶-C(=O)-亞烯基-O-C(=O)-、R⁶-C(=O)O-亞烷基-O-C(=O)-、R⁶-C(=O)O-亞烯基-O-C(=O)-、R^cR^bN-C(=O)-、R^cR^bN-C(=O)-O-、R^cR^bN-C(=O)-亞烷基、R^cR^bN-C(=O)-亞烯基、R^cR^bN-C(=O)-亞烷基-O-C(=O)-、R^cR^bN-C(=O)-亞烯基-O-C(=O)-、R⁶-C(=O)-N(R^b)-、R⁶-C(=O)-N(R^b)-亞烷基、R⁶-C(=O)-N(R^b)-亞烯基、R⁶-C(=O)-亞烷基-N(R^b)-、R⁶-C(=O)-亞烯基-N(R^b)-、R^cR^bN-C(=O)-N(R^b)-、R^cR^bN-C(=O)-N(R^b)-亞烷基、R^cR^bN-C(=O)-N(R^b)-亞烯基、R^cR^bN-C(=O)-亞烷基-N(R^b)-、R^cR^bN-C(=O)-亞烯基-N(R^b)-、R⁶-C(=O)-N(R^b)-C(=O)-、R⁶-C(=O)-N(R^b)-C(=O)-亞烷基、R⁶-C(=O)-N(R^b)-C(=O)-亞烯基、R^6a-O-亞烷基、R^6a-O-亞烯基、烷氧基烷基、羥基取代的烷氧基烷基、羧基取代的烷氧基烷基、烷胺基烷基、芳氧基取代的烷基、烷氧基烷氧基、烷胺基烷胺基、烷胺基烷氧基、烷氧基烷胺基、烷硫基、R⁶-S(=O)₂-、R⁶-S(=O)₂-亞烷基、R⁶-S(=O)₂-亞烯基、R⁶-S(=O)₂-N(R^b)-、R⁶-S(=O)₂-N(R^b)-亞烷基、R⁶-S(=O)₂-N(R^b)-亞烯基、R^cR^bN-S(=O)₂-、R^cR^bN-S(=O)₂-亞烷基、R^cR^bN-S(=O)₂-亞烯基、環烷基、環 烷基氧基、環烷基胺基、環烷基烷基、環烷基烷氧基、環烯基、環烯基氧基、環烯基胺基、環烯基烷基、雜環基、3-12個原子組成的環、雜環基氧基、雜環基胺基、雜環基烷基、雜環基烷氧基、芳基、芳基氧基、芳基胺基、芳基烷基、芳基烷氧基、雜芳基、雜芳基氧基、雜芳基胺基、雜芳基烷基或雜芳基烷氧基獨立任選地被一個或多個R⁷取代；其中各R⁷獨立地為H、氘、F、Cl、Br、I、CN、NO₂、OH、NH₂、COOH、-C(=O)-NH₂、-S(=O)₂-NH₂、氧代、C_1-6烷基、C_1-6烷氧基、鹵代C_1-6烷基、鹵代C_1-6烷氧基、C_1-6烷基-C(=O)-或C_1-6烷基-O-C(=O)-。 In one aspect, the invention relates to a compound which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide of the compound represented by formula (I) Compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein: R ¹ is H, deuterium, alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkyl-C(=O)-, alkyl-S(=O ^{_{) 2 -, R a -C (}} = O) - ^{alkylene, R a -S (= O)} 2 - alkylene, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, aryl Alkyl or heteroarylalkyl; each R ^{2 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , COOH, -C(=O)-NH ₂ , -S(=O) ₂ -NH ₂ , alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkoxy, haloalkoxy or alkylamino; R ³ is H, deuterium, alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkyl-C(=O)-, alkyl-S(=O) ₂ -, alkyl -C(=O)-alkylene, alkyl-OC(=O)-alkylene, alkyl-S(=O) ₂ -alkylene, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl-C(=O)-alkylene or heterocyclyl -C (= O) - alkylene; R ⁴ is deuterium, NH _2, C _2-10 alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl group, R ^a - C (= O) - ^{alkylene, R a -S (= O)} 2 - alkylene group, an alkenyl group, an alkynyl group, an alkoxy group, an alkoxy group, -C (= O) -NH _2, or -S (=O) ₂ -NH ₂ ; X is N(R ^b ), O or S; Y is O or S; A is a heterocyclic group containing at least one nitrogen atom; each R ^{5 is} independently H, deuterium, F , Cl, Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)-, R ⁶ -C(=O)-alkylene, R ⁶ -C(=O)-Asia Alkenyl, R ⁶ -C(=O)-alkylene-OC(=O)-, R ⁶ -C(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O )O-alkylene-OC(=O)-, R ⁶ -C(=O)O-alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-alkylene, R ^c R ^b NC(=O)-alkenylene, R ^c R ^b NC(=O)-alkylene -OC(=O)-, R ^c R ^b NC(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O)-N(R ^b )-, R ⁶ -C( =O)-N(R ^b )-alkylene, R ⁶ -C(=O)-N(R ^b )-alkenylene, R ⁶ -C(=O)-alkylene-N(R ^b )-, R ⁶ -C(=O)-alkenylene-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-alkylene, R ^c R ^b NC(=O)-N(R ^b )-Asia Alkenyl, R ^c R ^b NC(=O)-alkylene-N(R ^b )-, R ^c R ^b NC(=O)-alkenylene-N(R ^b )-, R ⁶ -C( =O)-N(R ^b )-C(=O)-, R ⁶ -C(=O)-N(R ^b )-C(=O)-alkylene, R ⁶ -C(=O) -N(R ^b )-C(=O)-alkenylene, R ^6a -O-alkylene, R ^6a -O-alkenylene, oxo, alkyl, haloalkyl, aminoalkyl, hydroxyl Substituted alkyl, cyano-substituted alkyl, carboxy-substituted alkyl, alkoxyalkyl, hydroxy-substituted alkoxyalkyl, carboxy-substituted alkoxyalkyl, alkylaminoalkyl, aryloxy Substituted alkyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, alkylaminoalkylamino, alkylaminoalkoxy, alkoxyalkylamino, alkylthio, Alkenyl, carboxy substituted alkenyl, alkynyl, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -alkylene, R ⁶ -S(=O) ₂ -alkenylene , R ⁶ -S(=O) ₂ -N(R ^b )-, R ⁶ -S(=O) ₂ -N(R ^b )-alkylene, R ⁶ -S(=O) ₂ -N( R ^b )-alkenylene, R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -alkylene, R ^c R ^b NS(=O) ₂ -alkenylene, Cycloalkyl, cycloalkyloxy, cycloalkylamine, cycloalkylalkyl, cycloalkenyl, cycloalkenyloxy, cycloalkenylamine, cycloalkenylalkyl, heterocyclic, heterocyclic Aryloxy, heterocyclylamino, heterocyclylalkyl, aryl, aryloxy, arylamino, arylalkyl, heteroaryl, heteroaryloxy, heteroarylamino or Heteroarylalkyl; each R ^a and R ^{6 are} independently H, deuterium, OH, NH ₂ , alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkoxy Alkyl, alkoxy, haloalkoxy, hydroxy-substituted alkoxy, carboxy-substituted alkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkyl Oxygen, heteroarylalkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, aryl Alkyl, aryloxy, heteroaryl, heteroaryloxy or heteroarylalkyl; each R ^{6a is} independently H, alkyl, haloalkyl, hydroxy substituted alkyl, carboxy substituted alkyl , Alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; each R ^b and R ^{c is} independently H, deuterium, alkyl, haloalkyl, hydroxy substituted alkyl, carboxy substituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, Heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; or R ^b , R ^c together with the nitrogen atom to which they are attached form a ring of 3-12 atoms; m is 0, 1, 2, or 3; n is 0, ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , 9, or 10; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ^a , R ^b and R ^c alkyl, haloalkyl, aminoalkyl, hydroxy substituted alkyl, cyano substituted alkyl, carboxy substituted alkyl, alkyl- C(=O)-, alkyl-S(=O) ₂ -, alkyl-C(=O)-alkylene, alkyl-OC(=O)-alkylene, alkyl-S(= O) ₂ - ^{alkylene, R a -C (= O)} - ^{alkylene, R a -S (= O)} 2 - alkylene group, an alkenyl group, a carboxy-substituted alkenyl group, an alkynyl group, an alkoxy group , Haloalkoxy, hydroxy-substituted alkoxy, carboxy-substituted alkoxy, alkylamino, cycloalkyl-C(=O)-alkylene, heterocyclyl-C(=O)-alkylene , C _2-10 alkyl, R ⁶ -C(=O)-, R ⁶ -C(=O)-alkylene, R ⁶ -C(=O)-alkenylene, R ⁶ -C(= O)-alkylene-OC(=O)-, R ⁶ -C(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O)O-alkylene-OC( =O)-, R ⁶ -C(=O)O-alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-alkylene, R ^c R ^b NC(=O)-alkenylene, R ^c R ^b NC(=O)-alkylene-OC(=O)-, R ^c R ^b NC(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O)-N(R ^b )-, R ⁶ -C(=O)-N(R ^b ) -Alkylene, R ⁶ -C(=O)-N(R ^b )-alkenylene, R ⁶ -C(=O)-alkylene-N(R ^b )-, R ⁶ -C(= O)-alkenylene-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-alkylene , R ^c R ^b NC(=O)-N(R ^b )-alkenylene, R ^c R ^b NC(=O)-alkylene-N(R ^b )-, R ^c R ^b NC(=O )-Alkenylene-N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-C(=O)-, R ⁶ -C(=O)-N(R ^b )- C(=O)-alkylene, R ⁶ -C(=O)-N(R ^b )-C(=O)-alkenylene, R ^6a -O-alkylene, R ^6a -O-alkylene Alkenyl, alkoxyalkyl, hydroxy-substituted alkoxyalkyl Group, carboxy substituted alkoxyalkyl, alkylaminoalkyl, aryloxy substituted alkyl, alkoxyalkoxy, alkylaminoalkylamino, alkylaminoalkoxy, alkoxyalkyl Amino, alkylthio, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -alkylene, R ⁶ -S(=O) ₂ -alkenylene, R ⁶ -S (=O) ₂ -N(R ^b )-, R ⁶ -S(=O) ₂ -N(R ^b )-alkylene, R ⁶ -S(=O) ₂ -N(R ^b )-Asia Alkenyl, R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -alkylene, R ^c R ^b NS(=O) ₂ -alkenylene, cycloalkyl, cyclo Alkyloxy, cycloalkylamino, cycloalkylalkyl, cycloalkylalkoxy, cycloalkenyl, cycloalkenyloxy, cycloalkenylamine, cycloalkenylalkyl, heterocyclic, 3-12 atom ring, heterocyclyloxy, heterocyclylamino, heterocyclylalkyl, heterocyclylalkoxy, aryl, aryloxy, arylamino, arylalkane Group, arylalkoxy group, heteroaryl group, heteroaryloxy group, heteroarylamine group, heteroarylalkyl group or heteroarylalkoxy group is independently optionally substituted by one or more R ⁷ ; Each R ^{7 is} independently H, deuterium, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, -C(=O)-NH ₂ , -S(=O) ₂ -NH ₂ , Oxo, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _1-6 alkyl-C (=O) -Or C _1-6 alkyl-OC(=O)-.

Some of the embodiments are that R ¹ is H, deuterium, C _1-4 alkyl, halogenated C _1-4 alkyl, amine C _1-3 alkyl, hydroxy substituted C _1-3 alkyl, cyano Substituted C _1-3 alkyl, C _1-3 alkyl-C(=O)-, C _1-3 alkyl-S(=O) ₂ -, C _2-4 alkenyl or C _2-4 alkyne Radical; each R ^{2 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , COOH, -C(=O)-NH ₂ , -S(=O) _2- NH ₂ , C _1-3 alkyl, halogenated C _1-3 alkyl, amine C _1-3 alkyl, hydroxy substituted C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkoxy or C _1-3 alkylamino; R ⁴ is deuterium, NH ₂ , C _2-4 alkyl, halogenated C _1-4 alkyl, amine C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy , C _1-3 alkylamino, -C(=O)-NH ₂ or -S(=O) ₂ -NH ₂ ; m is 0, 1, 2 or 3. In other embodiments, R ¹ is H, deuterium, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH ₃ , -CH ₂ Cl, -CHCl ₂ ,- CCl ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ Cl, -CH ₂ CHCl ₂ , -CH ₂ CH ₂ F, or -CH ₂ CHF ₂ ; each R ^{2 is} independently H, Deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , COOH, -C(=O)-NH ₂ , -S(=O) ₂ -NH ₂ , methyl or methoxy; R ⁴ is NH ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ NH ₂ , -CH(CH ₃ )NH ₂ , -CH ₂ CH ₂ CH ₂ NH ₂ , -CH(CH ₂ CH ₃ )NH ₂ , -CH ₂ CH(CH ₃ )NH ₂ , -CH(CH(CH ₃ ) ₂ )NH ₂ , -C(=O)-NH ₂ or -S(=O) ₂ -NH ₂ .

Some of the embodiments are that R ³ is H, deuterium, C _1-6 alkyl, halogenated C _1-6 alkyl, amino C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, cyano Substituted C _1-6 alkyl, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O) ₂ -, C _1-6 alkyl-C(=O) -C _1-6 alkylene, C _1-6 alkyl-OC(=O)-C _1-8 alkylene, C _1-6 alkyl-S(=O) ₂ -C _1-6 alkylene Group, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _{3- 8} cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl Group, C _3-8 cycloalkyl-C(=O)-C _1-6 alkylene or C _2-10 heterocyclyl-C(=O)-C _1-8 alkylene.

In some other embodiments, R ³ is C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkyl-C(=O)-C _1-6 alkylene, C _1-3 Alkyl-OC(=O)-C _1-6 alkylene, C _1-3 alkyl-S(=O) ₂ -C _1-6 alkylene, C _3-6 cycloalkyl, C _{2- 6} heterocyclyl, C _6-10 aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl, C _{6 -10} aryl C _1-3 alkyl, C _1-5 heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl-C(=O)-C _1-6 alkylene or C _{2- 6} Heterocyclyl-C(=O)-C _1-6 alkylene.

In other embodiments, R ³ is CH ₃ -OC(=O)-C _1-6 alkylene, CH ₃ CH ₂ -OC(=O)-C _1-6 alkylene, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, pyridyl, pyrazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1- Dioxo-thiomorpholinyl, tetrahydropyranyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, pyrrole Alkylmethyl, tetrahydrofurylmethyl, pyridylmethyl, pyrazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, 1-oxo-thiomorpholinylmethyl, 1 ,1-dioxo-thiomorpholinylmethyl, tetrahydropyranylmethyl, benzyl, phenethyl, cyclohexyl-C(=O)-C _1-6 alkylene, pyridinyl -C(=O)-C _1-6 alkylene, morpholinyl-C(=O)-C _1-6 alkylene, pyrazinyl-C(=O)-C _1-6 alkylene , Thiomorpholinyl-C(=O)-C _1-6 alkylene, 1-oxo-thiomorpholinyl-C(=O)-C _1-6 alkylene or 1,1- Dioxo-thiomorpholinyl-C(=O)-C _1-6 alkylene.

In some of these embodiments, A is a heterocyclic group consisting of 3-12 atoms containing at least one nitrogen atom.

其中：各Z獨立地為CH₂、NH、O、S、S(=O)或S(=O)₂；各Z¹獨立地為NH、O、S、S(=O)或S(=O)₂；各W獨立地為CH₂、NH或O；各V獨立地為CH₂或NH；各E獨立地為CH或N；各G獨立地為O或NH；各p獨立地為0、1、2或3； 各q獨立地為1或2；各r獨立地為0、1、2或3；各s獨立地為1、2或3。 In some other embodiments, A is the following substructure formula:

Where: each Z is independently CH ₂ , NH, O, S, S(=O) or S(=O) ₂ ; each Z ^{1 is} independently NH, O, S, S(=O) or S(= O) ₂ ; each W is independently CH ₂ , NH or O; each V is independently CH ₂ or NH; each E is independently CH or N; each G is independently O or NH; each p is independently 0 , 1, 2, or 3; each q is independently 1 or 2; each r is independently 0, 1, 2, or 3; each s is independently 1, 2, or 3.

In some other embodiments, A is the following substructure formula:

其中：各R⁵和n具有如本發明所述的含義；各Z獨立地為CH₂、NH、O、S、S(=O)或S(=O)₂；t為0、1、2或3。 Some of the embodiments are that the present invention relates to a compound which is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, racemate of the compound represented by formula (II) , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Where: each R ⁵ and n have the meaning as described in the present invention; each Z is independently CH ₂ , NH, O, S, S(=O) or S(=O) ₂ ; t is 0, 1, 2 Or 3.

其中：各R⁵具有如本發明所述的含義。 Some of the embodiments are that the present invention relates to a compound which is a compound represented by formula (IIa) or a stereoisomer, geometric isomer, tautomer, racemate of the compound represented by formula (IIa) , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein: each R ⁵ has the meaning as described in the present invention.

其中：各R⁵具有如本發明所述的含義。 Some of the embodiments are that the present invention relates to a compound which is a compound represented by formula (IIb) or formula (IIc) or a stereoisomer or geometric isomer of a compound represented by formula (IIb) or formula (IIc) , Tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein: each R ⁵ has the meaning as described in the present invention.

Some of the embodiments are that the pharmaceutically acceptable salts are hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumaric acid Salt, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate , Tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate Salt or their combination.

In some embodiments, each R ^{5 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)-, R ⁶ -C(= O)-C _1-6 alkylene, R ⁶ -C(=O)-C _2-6 alkenylene, R ⁶ -C(=O)-C _1-6 alkylene-OC(O)- , R ⁶ -C(=O)-C _2-6 alkenylene-OC(=O)-, R ⁶ -C(=O)OC _1-6 alkylene-OC(=O)-, R ⁶ -C(=O)OC _2-6 alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC (=O)-C _1-6 alkylene, R ^c R ^b NC(=O)-C _2-6 alkenylene, R ^c R ^b NC(=O)-C _1-6 alkylene-OC (=O)-, R ^c R ^b NC(=O)-C _2-6 alkenylene-OC(=O)-, R ⁶ -C(=O)-N(R ^b )-, R ^6- C(=O)-N(R ^b )-C _1-6 alkylene, R ⁶ -C(=O)-N(R ^b )-C _2-6 alkenylene, R ⁶ -C(=O )-C _1-6 alkylene-N(R ^b )-, R ⁶ -C(=O)-C _2-6 alkenylene-N(R ^b )-, R ^c R ^b NC(=O) -N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-C _1-6 alkylene, R ^c R ^b NC(=O)-N(R ^b )-C _{2 -6} alkenylene, R ^c R ^b NC(=O)-C _1-6 alkylene-N(R ^b )-, R ^c R ^b NC(=O)-C _2-6 alkenylene-N (R ^b )-, R ⁶ -C(=O)-N(R ^b )-C(=O)-, R ⁶ -C(=O)-N(R ^b )-C(=O)-C _1-6 alkylene, R ⁶ -C(=O)-N(R ^b )-C(=O)-C _2-6 alkenylene, R ^6a -OC _1-8 alkylene, R ^6a- OC _2-8 alkenylene, oxo, C _1-8 alkyl, halogenated C _1-6 alkyl, amine C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, cyano substituted C _1-6 alkyl, carboxy substituted C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, hydroxy substituted C _1-6 alkoxy C _1-6 alkyl, carboxy substituted C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _6-10 aryloxy substituted C _1-6 alkyl, C _1-6 alkyl Oxygen, halogenated C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylamino C _1-6 alkylamino , C _1-6 alkylamino C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkylamino, C _1-6 alkylthio, C _2-6 alkenyl, carboxy substituted C _{2 -6} alkenyl, C _2-6 alkynyl, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -C _1-6 alkylene, R ⁶ -S(=O) ₂ -C _2-6 alkenylene, R ⁶ -S(=O) ₂ -N(R ^b )-, R ⁶ -S(=O) ₂ -N(R ^b )-C _1-6 alkylene, R ⁶ -S(=O) ₂ -N(R ^b )-C _2-6 alkenylene, R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -C _{1- 6} alkylene, R ^c R ^b NS(=O) ₂ -C _2-6 alkenylene, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, C _3-8 cycloalkylamine Group, C _3-8 cycloalkyl C _1-6 alkyl, C _3-8 cycloalkenyl, C _3-8 cycloalkenyloxy, C _3-8 cycloalkenylamino, C _3-8 cycloalkenyl Group C _1-6 alkyl, C _2-10 heterocyclyl, C _2-10 heterocyclyloxy, C _2-10 heterocyclylamino, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl, C _6-10 aryloxy, C _6-10 arylamino, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl, C _1-9 Heteroaryloxy, C _1-9 heteroarylamino or C _1-9 heteroaryl C _1-6 alkyl; each R ^{6 is} independently H, deuterium, OH, NH ₂ , C _1-8 alkyl Group, halogenated C _1-6 alkyl, amino C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, cyano substituted C _1-6 alkyl, C _1-6 alkoxy C _{1 -6} alkyl, C _1-8 alkoxy, halogenated C _1-6 alkoxy, hydroxy substituted C _1-8 alkoxy, carboxy substituted C _1-6 alkoxy, C _1-6 alkyl Oxygen C _1-6 alkoxy, C _3-8 cycloalkyl C _1-6 alkoxy, C _2-10 heterocyclyl C _1-6 alkoxy, C _6-10 aryl C _1-6 Alkoxy, C _1-9 heteroaryl C _1-6 alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _3-8 cycloalkyloxy, C _2-10 heterocyclyl, C _2-10 heterocyclyl C _1-6 alkyl, C _2-10 heterocyclyloxy, C _6-10 aryl, C _{6 -10} aryl C _1-6 alkyl, C _6-10 aryloxy, C _1-9 heteroaryl, C _1-9 heteroaryloxy or C _1-9 heteroaryl C _1-6 alkyl Each R ^{6a is} independently H, C _1-8 alkyl, halogenated C _1-8 alkyl, hydroxy substituted C _1-8 alkyl, carboxy substituted C _1-8 alkyl, C _1-6 Alkoxy C _1-6 alkyl, C _3-8 cycloalkyl C _1-6 alkyl , C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl; each R ^b and R ^{c is} independently H, deuterium, C _1-8 alkyl, halo C _1-6 alkyl Group, hydroxy substituted C _1-8 alkyl, carboxy substituted C _1-8 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkane Radical C _1-6 alkyl, C _2-10 heterocyclyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl or C _1-9 heteroaryl C _1-6 alkyl; or R ^b , R ^c together with the nitrogen atom to which they are attached form a ring of 3-8 atoms.

In other embodiments, each R ^{5 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)-, R ⁶ -C(= O)-C _1-3 alkylene, R ⁶ -C(=O)-C _2-4 alkenylene, R ⁶ -C(=O)OC _1-4 alkylene-OC(=O)- , R ⁶ -C(=O)OC _2-4 alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-C _1-3 alkylene, R ^c R ^b NC(=O)-C _2-4 alkenylene, R ⁶ -C(=O)-N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-C _1-3 alkylene, R ⁶ -C(=O)-N(R ^b )-C _2-4 alkenylene, R ^c R ^b NC(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-C _1-3 alkylene, R ^c R ^b NC(=O)-N(R ^b ) -C _2-4 alkenylene, R ^6a -OC _1-6 alkylene, R ^6a -OC _2-6 alkenylene, oxo, C _1-6 alkyl, halo C _1-4 alkyl Group, amine C _1-4 alkyl, hydroxy substituted C _1-6 alkyl, cyano substituted C _1-4 alkyl, carboxy substituted C _1-4 alkyl, C _1-6 alkoxy C _1-3 alkyl, hydroxy substituted C _1-6 alkoxy C _1-3 alkyl, carboxy substituted C _1-6 alkoxy C _1-4 alkyl, C _1-3 alkylamino C _{1- 3} alkyl, C _6-10 aryloxy substituted C _1-3 alkyl, C _1-3 alkoxy, C _2-4 alkenyl, carboxy substituted C _2-4 alkenyl, C _2-4 alkyne Group, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -C _1-3 alkylene, R ⁶ -S(=O) ₂ -C _2-4 alkenylene, R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -C _1-3 alkylene, R ^c R ^b NS(=O) ₂ -C _2-4 alkenylene, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _1-3 alkyl, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, C _1-6 heteroaryl or C _1-6 heteroaryl C _1-3 alkyl; each R ^{6 is} independently H, deuterium, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, hydroxy substituted C _1-6 alkoxy, carboxy substituted C _1-6 alkoxy, C _1-3 alkoxy C _1-4 alkoxy Group, C _3-6 cycloalkyl C _1-3 alkoxy, C _2-6 heterocyclyl C _1-3 alkoxy, C _6-10 aryl C _1-3 alkoxy, C _1-5 heteroaryl C _1-3 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-3 alkyl, C _3-8 cycloalkane Yloxy, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _1-3 alkyl, C _2-6 heterocyclyloxy, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, C _6-10 aryloxy, C _1-6 heteroaryl, C _1-5 heteroaryloxy or C _1-6 heteroaryl C _1-3 alkyl; each R ^6a Independently H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, carboxy substituted C _1-6 alkyl, C _1-3 alkoxy C _{1 -4} alkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl, C _6-10 aryl C _1-3 alkyl, C _1-5 Heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _6-10 aryl or C _1-5 heteroaryl; each R ^b and R ^{c are} independently H, deuterium, C _1-6 alkyl, halogenated C _1-3 alkyl, hydroxy substituted C _1-6 alkyl, carboxy substituted C _1-6 alkyl, C _1-3 alkoxy C _{1- 4} alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _1-3 alkyl, C _{6 -10} aryl, C _6-10 aryl C _1-3 alkyl, C _1-5 heteroaryl or C _1-5 heteroaryl C _1-3 alkyl; or R ^b , R ^c and connected thereto The nitrogen atoms together form a ring of 3-6 atoms.

In other embodiments, each R ^{5 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)-, R ⁶ -C(= O)-C _1-3 alkylene, R ⁶ -C(=O)-C _2-4 alkenylene, R ⁶ -C(=O)OC _1-4 alkylene-OC(=O)- , R ⁶ -C(=O)OC _2-4 alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-C _1-3 alkylene, R ^c R ^b NC(=O)-C _2-4 alkenylene, R ⁶ -C(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-, R ^6a -OC _1-6 alkylene, R ^6a -OC _2-6 alkenylene, oxo, methyl, cyano substituted methyl Group, carboxymethyl, ethyl, cyano-substituted ethyl, carboxyethyl, propyl, cyano-substituted propyl, carboxypropyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary Butyl, hydroxy substituted C _1-4 alkyl, phenoxymethyl, phenoxyethyl, C _1-5 alkoxy C _1-3 alkyl, hydroxy substituted C _1-5 alkoxy C _1-3 alkyl, carboxy substituted C _1-4 alkoxy C _1-3 alkyl, methoxy, ethoxy, propoxy, isopropoxy, halogenated C _1-3 alkyl, ethylene Group, carboxy substituted vinyl, propenyl, carboxy substituted propenyl, ethynyl, propynyl, R ⁶ -S(=O) ₂ -, R ^c R ^b NS(=O) ₂ -, cyclopropyl , Cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, pyrrolidinyl, tetrahydrofuranyl, pyridinyl, pyrazinyl, morpholine Group, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydropyranyl, pyrrolidinylmethyl, tetrahydrofuranylmethyl, Pyridinylmethyl, pyrazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, 1-oxo-thiomorpholinylmethyl, 1,1-dioxo-thio? Pynylmethyl, tetrahydropyranylmethyl, phenyl, indenyl, naphthyl, benzyl, phenethyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazole , Oxadiazolyl, thiazolyl, isothiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidine Ethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, or pyridazinylethyl; each R ^{6 is} independently H, deuterium, OH, NH ₂ , methyl, ethyl, propylene Group, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, hydroxy substituted methoxy, carboxy substituted methoxy, ethoxy, hydroxy substituted ethoxy, Carboxyl substituted ethoxy, propoxy, hydroxy substituted propoxy, carboxy substituted propoxy, isopropoxy, hydroxy substituted isopropoxy, carboxy taken Isopropyloxy, butoxy, hydroxy substituted butoxy, carboxy substituted butoxy, isobutoxy, hydroxy substituted isobutoxy, carboxy substituted isobutoxy, methoxymethyl Oxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy, benzyloxy, phenylethoxy, cyclopropyl, cyclobutyl, cyclo Amyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, Cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, pyrrolidinyl, tetrahydrofuranyl, pyridyl, pyrazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydropyranyl, pyrrolidinylmethyl, tetrahydrofuranylmethyl, pyridylmethyl, pyrazine Methyl, morpholinylmethyl, thiomorpholinylmethyl, 1-oxo-thiomorpholinylmethyl, 1,1-dioxo-thiomorpholinylmethyl, tetrahydropyridine Furylmethyl, phenyl, indenyl, naphthyl, benzyl, phenethyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazole Group, isothiazolyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridylmethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl, pyrazinyl Ethyl, pyridazinylmethyl or pyridazinylethyl; each R ^{6a is} independently H, methyl, ethyl, propyl, isopropyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl , Hydroxy-substituted isopropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, carboxymethyl, carboxyethyl, carboxypropyl, 2-carboxy-2-methylethyl, methoxymethyl Group, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropyl Ethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, phenyl, pyridyl, pyrimidinyl, Pyrazinyl or pyridazinyl; each R ^b and R ^{c is} independently H, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hydroxyl Substituted C _1-5 alkyl, carboxy substituted C _1-4 alkyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentyl Ethyl, cyclohexylmethyl, cyclohexylethyl, phenyl, benzyl, phenethyl or phenylpropyl; or R ^b , R ^c together with the nitrogen atom to which they are attached to form azetidine, Pyrrolidine, pyridine, pyrazine, morpholine, thiomorpholine, 1-oxo-thiomorpholine or 1,1-dioxo-thiomorpholine.

One aspect of the present invention relates to a pharmaceutical composition comprising the compound of the present invention, or their stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, Pharmaceutically acceptable salts or their prodrugs.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.

In some of these embodiments, the pharmaceutical composition of the present invention further includes additional therapeutic agents, which are drugs, pharmaceutically active agents, or a combination thereof for treating chronic obstructive pulmonary disease (COPD).

In other embodiments, the additional therapeutic agent of the present invention is sodium pyruvate, doxofylline, Roflumilast, Apremilast, Tetomilast , Tipelukast, Theophylline (Theophylline), Formoterol (Formoterol), Salmeterol (Salmeterol), Flutica Fluticasone propionate, Salmeterol Xinafoate/Fluticasone Propionate, Rolipram, Piclamist, Cilomilast, CDP -840, Indacaterol, olodaterol, QVA149, Midesteine, Zileuton, salbutamol, carmoxiol, budesonide and others Epimers, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, roflunide, ciclesonide, ipratropium bromide, ipratropium Compound of ammonium bromide and salbutamol, oxitropium bromide, tiotropium bromide, glycopyrronium bromide, Umeclidinium bromide, vilanterol, vildirolium bromide/vilante Compound (umeclidinium/vilanterol), aclidinium bromide, aclidinium/formoterol fumarate, LAS40464, LAS100977 (abediterol), AZD-8999, RPL-554, OCID-2987, CHF-6001, CR-3465, HPP-737, fluticasone furoate/vilanterol (FF/VI), Benralizumab, tralokinumab, rivastolate, or a combination thereof.

Another aspect of the present invention relates to the use of a compound of the present invention or a pharmaceutical composition containing the compound of the present invention for the preparation of a medicament for the prevention, treatment, treatment or alleviation of diseases associated with phosphodiesterase type 4 (PDE 4) use.

Some of the embodiments are that the diseases related to phosphodiesterase type 4 (PDE 4) described herein are respiratory diseases, allergies and inflammations, central nervous system (CNS) diseases, pulmonary fibrosis or non-insulin-dependent diabetes.

In other embodiments, the respiratory diseases described in the present invention are: chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, allergic bronchitis, bronchus Dilatation, tuberculosis fibrosis, pulmonary cystic fibrosis, diffuse panbronchiolitis, bronchiolitis obliterans, acute respiratory distress syndrome (ARDS) or inflammation of the respiratory tract.

In other embodiments, the inflammation described in the present invention is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing Spondylitis, rheumatoid arthritis or psoriatic arthritis.

In one aspect, the invention relates to intermediates for the preparation of compounds contained in formula (I), (II), (IIa), (IIb) or (IIc).

Another aspect of the present invention relates to methods for the preparation, isolation, and purification of compounds contained in formula (I), (II), (IIa), (IIb), or (IIc).

The foregoing describes only certain aspects of the present invention, but is not limited to these and other aspects. The content will be described in more detail below.

Definitions and general terms

Some embodiments of the present invention will now be described in detail, examples of which are illustrated by the accompanying structural formula and chemical formula. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included in the scope of the present invention as defined by the scope of the patent application. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is by no means limited to the methods and materials described in the present invention. In the case where one or more of the incorporated documents, patents, and similar materials are different or contradictory to this application (including but not limited to defined terms, terminology, described technology, etc.), The application shall prevail.

It should be further recognized that certain features of the present invention have been described in multiple independent embodiments for clarity, but may also be provided in combination in a single embodiment. Conversely, various features of the invention have been described in a single embodiment for the sake of brevity, but can also be provided individually or in any suitable sub-combination.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated by reference in their entirety.

Unless otherwise stated, the following definitions used in the present invention shall apply. For the purposes of the present invention, chemical elements are consistent with the CAS version of the periodic table of elements, and the Handbook of Chemistry and Physics, 75th edition, 1994 . In addition, the general principles of organic chemistry can refer to "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 , and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 The entire content of the description is incorporated into the present invention by reference.

Unless otherwise stated or there is a clear conflict in the context, the articles "a", "an" and "said" as used herein are intended to include "at least one" or "one or more". Therefore, the articles used herein refer to one or more than one (ie, at least one) object articles. For example, "a component" refers to one or more components, that is, there may be more than one component that is considered to be employed or used in the implementation of the embodiment.

The term "test object" as used in the present invention refers to an animal. Typically the animal is a mammal. The test object, for example, also refers to primates (eg, humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the test object is a primate. In other embodiments, the test object is a human.

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

The term "comprising" is an open-ended expression, that is, it includes the content specified by the present invention, but does not exclude other aspects.

"Stereoisomer" refers to compounds that have the same chemical structure, but the atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

"Chiral" is a molecule that has the property of not overlapping with its mirror image; "Achiral" refers to a molecule that can overlap with its mirror image.

"Enantiomer" refers to two isomers of a compound that cannot overlap but are mirror images of each other.

"Diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Diastereomer mixtures can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.

The stereochemical definitions and rules used in the present invention generally follow SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994 .

Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the first codes D and L or R and S are used to denote the absolute configuration of the molecule about one or more of its chiral centers. The first codes d and l or (+) and (-) are symbols used to specify the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with an initial code (+) or d are right-handed. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (for example, carbon, etc.) of the compounds disclosed in the present invention can exist in racemic or enantiomerically enriched forms, such as ( R )-, ( S )-, or ( R , S )-configuration forms exist. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, at least in the ( R )- or ( S )-configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and methods, the compounds of the invention may be in one of the possible isomers or their mixtures, such as racemates and diastereomer mixtures (this depends on the number of asymmetric carbon atoms) Form exists. Optically active ( R )- or ( S )-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography Method and/or step crystallization method.

The racemates of any resulting end products or intermediates can be resolved into optical enantiomers by methods known to those skilled in the art using known methods, for example, by obtaining the diastereomeric salts obtained Separate. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981 ); Principles of Asymmetric Synthesis ( ^2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012 ); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962 ); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972 ); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007 ).

The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversion through proton migration, such as keto-enol isomerization and imine-enamine isomerization Texturing. Valence tautomers include interconversion through the recombination of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

As described in the present invention, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples A class of compounds. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with specific substituents. Unless otherwise indicated, an optional substituent may be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted with one or more substituents selected from specific groups, the substituents may be substituted at the same positions or differently. The substituents described herein may be, but not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amine, carboxy, alkyl, alkoxy, alkoxyalkyl, Alkoxyalkoxy, alkoxyalkylamino, aryloxy, Heteroaryloxy, heterocyclyloxy, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, cycloalkylalkoxy, alkylamino, alkylaminoalkyl, alkyl Aminoalkylamino, cycloalkylamino, cycloalkylalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxy substituted alkyl, hydroxy substituted alkylamino, cyano substituted alkyl, Cyano-substituted alkoxy, cyano-substituted alkylamino, amine-substituted alkyl, alkyl acetyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, Heterocyclylalkyl, heterocyclylamide, aryl, arylalkyl, arylamino, heteroaryl, heteroarylalkyl, heteroarylamino, amide, sulfonyl, amine Sulfonyl and so on.

In addition, it should be noted that, unless it is clearly indicated in other ways, the descriptions used in the present invention "each...independently" and "...independently each"and"...independently"can be interchanged, both should be For a broad understanding, it can mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols Between each other does not affect each other. Taking R ^b as an example, the structural formula NR ^b R ^c -C(=O)- and the structural formula R ⁶ -C(=O)-N(R ^b )-the specific options of R ^b are different from each other. Influence; within the same structural formula NR ^b R ^c -C(=O)-N(R ^b )-, the specific options of multiple R ^b do not affect each other.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of groups. In particular, the present invention includes each independent sub-combination of each member of these group types and ranges. For example, the term "C ₁ -C ₆ alkyl" or "C _1-6 alkyl" particularly refers to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl base.

In various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents the linked group, respectively An alkylene group or an arylene group.

The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally Are replaced by one or more substituents described in this invention. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, The alkyl group contains 1-4 carbon atoms; also in one embodiment, the alkyl group contains 1-3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl ( n -Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl ( i -Pr, -CH(CH ₃ ) ₂ ), n-butyl ( n -Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl ( i -Bu, -CH ₂ CH (CH ₃ ) ₂ ), sec-butyl ( s -Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl ( t -Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl -2-butyl(-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl(-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, etc.

The term "alkylene" means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in yet another embodiment, the alkylene group The group contains 1-3 carbon atoms; also in one embodiment, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), isopropylidene (-CH (CH ₃ )CH ₂ -) etc.

The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, that is, there is a carbon-carbon sp ² double bond, wherein the alkenyl group The group may be optionally substituted with one or more substituents described in the present invention, which include the positioning of " cis " and " tans ", or the positioning of " E " and " Z ". In one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), propenyl (CH ₃ -CH=CH-) and the like.

The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturated site, that is, there is a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more substituents described in the present invention. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (-C≡C-CH ₃ ), etc. .

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

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy ( n- PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy ( i -PrO, i -propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propoxy ( i -BuO, i -butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butan Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy ( t -BuO, t -butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy Group (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), and so on.

The term "alkoxyalkyl" means that the alkyl group is substituted with one or more alkoxy groups, wherein the alkyl group and the alkoxy group have the meanings as described in the present invention, such examples include , But not limited to methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, etc.

The term "alkoxyalkoxy" means that the alkoxy group is substituted by one or more alkoxy groups, wherein the alkoxy group has the meaning as described in the present invention, such examples include, but It is not limited to methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy and the like.

The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means alkyl, alkenyl or alkoxy group is substituted by one or more halogen atoms, such examples include, but are not limited to, -CF ₃ , -CHF ₂ , -CH ₂ Cl, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -OCF ₃ , -OCHF ₂ , -OCHCl ₂ , -OCH ₂ CHF ₂ , -OCH ₂ CHCl ₂ , -OCH(CH ₃ )CHF ₂ and so on.

The term "cyano-substituted alkyl" means that the alkyl group is substituted with one or more CNs. Examples include, but are not limited to, -CH ₂ CN, -CH ₂ CH ₂ CN, -CH ₂ CH ₂ CH ₂ CN, etc.

The term "hydroxy substituted alkyl" or "hydroxy substituted alkoxy" means that the alkyl group or alkoxy group is substituted by one or more OH, such examples include, but are not limited to, -CH ₂ OH, -CH ₂ CH ₂ OH, -CH(CH ₃ )OH, -C(CH ₃ ) ₂ OH, -CH ₂ C(CH ₃ ) ₂ OH, -CH ₂ CH ₂ CH ₂ OH, -OCH ₂ OH , -OCH ₂ CH ₂ OH, -OCH ₂ C(CH ₃ ) ₂ OH, etc.

The term "carboxy substituted alkyl" or "carboxy substituted alkoxy" means that the alkyl group or alkoxy group is substituted with one or more COOH, such examples include, but are not limited to, -CH ₂ COOH, -CH ₂ CH ₂ COOH, -CH(CH ₃ )COOH, -C(CH ₃ ) ₂ COOH, -CH ₂ CH ₂ CH ₂ COOH, -CH(CH(CH ₃ ) ₂ )COOH, -OC( CH ₃ ) ₂ COOH etc.

The term "aminoalkyl" or "amino-substituted alkyl" includes C _1-10 linear or branched alkyl groups substituted with one or more amine groups. In some embodiments, the aminoalkyl group is a C _1-6 "lower aminoalkyl group" substituted with one or more amino groups. Examples include, but are not limited to, aminomethyl Group, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

The term "alkylamino" or "alkylamino" includes " N -alkylamino" and " N , N -dialkylamino", wherein the amine groups are independently separated by one or two alkyl groups Group substituted. In some of these embodiments, the alkylamino group is a lower alkylamino group having one or two C _1-6 alkyl groups attached to a nitrogen atom. In other embodiments, the alkylamino group is a lower alkylamino group of C _1-3 . Suitable alkylamino groups may be monoalkylamine groups or dialkylamine groups, examples of which include, but are not limited to, N -methylamino, N -ethylamino, N , N -dimethyl Amino group, N , N -diethylamino group, etc.

The term "alkylaminoalkyl" means that the alkyl group is substituted with one or more alkylamino groups, wherein the alkyl group and the alkylamino group have the meaning as described in the present invention, such examples include , But not limited to N -methylaminomethyl, N -ethylaminomethyl, N , N -dimethylaminoethyl, N , N -diethylaminoethyl, etc.

The term "alkylaminoalkylamino group" means that the alkylamino group is substituted with one or more alkylamino groups, wherein the alkylamino group has the meaning as described in the present invention.

The term "alkylaminoalkoxy" means that the alkoxy group is substituted by one or more alkylamino groups, wherein the alkylamino group and the alkoxy group have the meaning as described in the present invention.

The term "alkoxyalkylamino group" means that the alkylamino group is substituted with one or more alkoxy groups, wherein the alkylamino group and the alkoxy group have the meaning as described in the present invention.

The term "alkylthio" refers to a C _1-10 linear or branched alkyl group attached to a divalent sulfur atom, wherein the alkyl group has the meaning as described in the present invention. Such examples include, but are not limited to, methylthio (CH ₃ S-), ethylthio, and the like.

The term "carbocyclic group" or "carbocyclic ring" means a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Carbobicyclic groups include spiro-carbocyclic groups and fused carbocyclic groups. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl Group, cyclononyl group, cyclodecyl group, cycloundecyl group, cyclododecyl group, etc.

The term "cycloalkyl" means a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. In one embodiment, the cycloalkyl group contains 3-12 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3-6 carbon atoms carbon atom. The cycloalkyl group may independently be unsubstituted or substituted with one or more substituents described in the present invention. Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl Alkyl, etc.

The term "cycloalkyloxy" includes an optionally substituted cycloalkyl group, as defined in the present invention, is attached to an oxygen atom and is connected to the rest of the molecule by an oxygen atom, wherein the cycloalkyl group has the present invention Such meanings include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

The term "cycloalkylamino" means that the amine group is substituted with one or two cycloalkyl groups. Examples include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclopentyl Amino group, cyclohexylamino group. In some embodiments, the cycloalkyl group on the cycloalkylamine group may be further substituted with the substituent described in the present invention.

The term "cycloalkylalkyl" means that the alkyl group is substituted with one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group have the meanings as described in the present invention, such examples include , But not limited to cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl , Cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, etc.

The term "cycloalkylalkoxy" means that the alkoxy group is substituted by one or more cycloalkyl groups, wherein the alkoxy group and the cycloalkyl group have the meaning as described in the present invention, such that Examples include, but are not limited to, cyclopropylmethoxy, cyclopropylethoxy, cyclopropylpropoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclobutylpropoxy, cyclopentyl Methoxy, cyclopentylethoxy, cyclopentylpropoxy, cyclohexylmethoxy, cyclohexylethoxy, cyclohexylpropoxy, etc.

The term "cycloalkenyl" means a monovalent or polyvalent partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Examples of cycloalkenyl groups include, but are not limited to 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, 1-cyclohexyl -1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, etc.

The term "cycloalkenyloxy" includes optionally substituted cycloalkenyl groups, as defined in the present invention, attached to an oxygen atom and connected to the rest of the molecule by an oxygen atom, wherein the cycloalkenyl group has the present invention Such meanings include, but are not limited to, cyclopentenyloxy, cyclohexenyloxy, cyclohexadienyloxy, and the like.

The term "cycloalkenylamino" means that the amine group is substituted with one or two cycloalkenyl groups. Examples include, but are not limited to, cyclopentenylamino, cyclohexenylamino, Cyclohexadienylamino. In some embodiments, the cycloalkenyl group on the cycloalkenylamine group may be further substituted with the substituent described in the present invention.

The term "cycloalkenylalkyl" means that the alkyl group is substituted with one or more cycloalkenyl groups, wherein the alkyl group and the cycloalkenyl group have the meaning as described in the present invention, such examples include , But not limited to cyclopentenylmethyl, cyclopentenylethyl, cyclohexenylmethyl, cyclohexenylethyl, cyclohexadienylmethyl, cyclohexadienylethyl, etc.

基，二氮雜

基，硫氮雜

基，吲哚啉基，1,2,3,4-四氫喹啉基，1,2,3,4-四氫異喹啉基，1,3-苯並二噁茂基，2-氧雜-5-氮雜雙環[2.2.1]庚-5-基，苯並吡咯烷基，二氫苯並呋喃基，苯並嗎啉基，3,4-二氫-吡啶[3,2-b][1,4]噁嗪基，1,3-苯並二惡茂烷基，四氫吡啶基，1,4-苯並二惡烷基，吡啶-2(1H)-酮-3-基，吡啶-2(1H)-酮-4-基，吡啶-2(1H)-酮-5-基，吡啶-2(1H)-酮-6-基，吡嗪-2(1H)-酮-3-基，吡嗪-2(1H)-酮-5-基，吡嗪-2(1H)-酮-6-基。雜環基中-CH₂-基團被-C(=O)-取代的實例包括，但不限於：2-氧代吡咯烷基，氧代-1,3-噻唑烷基，2-呱啶酮基，3,5-二氧代呱啶基和嘧啶二酮基。雜環基中硫原子被氧化的實例包括，但不限於：環丁碸基，1,1-二氧代硫代嗎啉基。所述的雜環基基團可以任選地被一個或多個本發明所描述的取代基所取代。當該結構清楚地需要連接基團時，針對該基團所列舉的馬庫什變數應理解為連接基團。例如，如果該結構需要 連接基團並且針對該變數的馬庫什基團定義列舉了“雜環基”，則應該理解，該“雜環基”代表連接的亞雜環基基團。 The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms, wherein at least one ring atom is selected from Atoms of nitrogen, sulfur and oxygen. Unless otherwise specified, the heterocyclic group may be a carbon group or a nitrogen group, and the -CH ₂ -group may be optionally replaced by -C(=O)-, and the sulfur atom of the ring may be optionally oxidized to S-oxidation The nitrogen atom of the ring can be optionally oxidized to an N -oxygen compound. Examples of heterocyclic groups include, but are not limited to: ethylene oxide, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, disulfide Amyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, pyridyl, morpholinyl, thiomorpholinyl, 1-oxo Thio-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, pyrazinyl, dioxanyl, dithioalkyl, thioxanyl, homopyridazinyl, homopyridinyl , Homomorpholinyl, oxepanyl, thiazepanyl, oxazepine

Base, diaza

Base, thiaza

Group, indolinyl group, 1,2,3,4-tetrahydroquinolinyl group, 1,2,3,4-tetrahydroisoquinolinyl group, 1,3-benzodioxolyl group, 2-oxa -5-azabicyclo[2.2.1]hept-5-yl, benzopyrrolidinyl, dihydrobenzofuranyl, benzomorpholinyl, 3,4-dihydro-pyridine[3,2-b ][1,4]oxazinyl, 1,3-benzodioxanyl, tetrahydropyridyl, 1,4-benzodioxanyl, pyridin-2(1H)-one-3-yl , Pyridine-2(1H)-one-4-yl, pyridine-2(1H)-one-5-yl, pyridine-2(1H)-one-6-yl, pyrazin-2(1H)-one- 3-yl, pyrazin-2(1H)-one-5-yl, pyrazin-2(1H)-one-6-yl. Examples of -CH ₂ -groups substituted by -C(=O)- in heterocyclic groups include, but are not limited to: 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-pyridinium Ketone, 3,5-dioxopyridinyl and pyrimidinedione. Examples of oxidized sulfur atoms in the heterocyclic group include, but are not limited to: cyclobutanyl, 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted with one or more substituents described in the present invention. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for the variable enumerates a "heterocyclic group", it should be understood that the "heterocyclic group" represents a linked heterocyclylene group.

基，二氮雜

基，硫氮雜

基。雜環基中-CH₂-基團被-C(=O)-取代的實例包括，但不限於：2-氧代吡咯烷基，氧代-1,3-噻唑烷基，2-呱啶酮基，3,5-二氧代呱啶基和嘧啶二酮基。雜環基中硫原子被氧化的實例包括，但不限於：環丁碸基，1,1-二氧代硫代嗎啉基。所述的4-7個原子組成的雜環基基團可以任選地被一個或多個本發明所描述的取代基所取代。 In one embodiment, the heterocyclic group is a heterocyclic group composed of 4-7 atoms, which means a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms, wherein at least one ring atom is selected from nitrogen and sulfur And oxygen atoms. Unless otherwise specified, a heterocyclic group composed of 4-7 atoms may be a carbon group or a nitrogen group, and the -CH ₂ -group may be optionally replaced by -C(=O)-, and the sulfur atom of the ring may be optionally The nitrogen atoms of the ring can be optionally oxidized to N -oxygen compounds. Examples of heterocyclic groups consisting of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thiacyclobutyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, pyridinyl, morpholinyl, thiomorpholinyl, pyrazine Group, dioxanyl, dithianyl, thioxanyl, homopyridazinyl, homopyridinyl, oxepanyl, thioheptanyl, oxaza

Base, diaza

Base, thiaza

base. Examples of -CH ₂ -groups substituted by -C(=O)- in heterocyclic groups include, but are not limited to: 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-pyridinium Ketone, 3,5-dioxopyridinyl and pyrimidinedione. Examples of oxidized sulfur atoms in the heterocyclic group include, but are not limited to: cyclobutanyl, 1,1-dioxothiomorpholinyl. The heterocyclic group consisting of 4-7 atoms can be optionally substituted with one or more substituents described in the present invention.

In another embodiment, a heterocyclic group is a heterocyclic group consisting of 4 atoms, which means a saturated or partially unsaturated monocyclic ring containing 4 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms Replaced by. Unless otherwise specified, a 4-atom heterocyclic group may be a carbon group or a nitrogen group, and the -CH ₂ -group may be optionally replaced by -C(=O)-, and the sulfur atom of the ring may be optionally substituted Oxidized to an S-oxide, the nitrogen atom of the ring can optionally be oxidized to an N -oxygen compound. Examples of 4-atom heterocyclic groups include, but are not limited to: azetidinyl, oxetanyl, and thietanyl. The 4-atom heterocyclic group may be optionally substituted with one or more substituents described in the present invention.

In another embodiment, the heterocyclic group is a heterocyclic group consisting of 5 atoms, which means a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms . Unless otherwise specified, a 5-atom heterocyclic group may be a carbon group or a nitrogen group, and the -CH ₂ -group may be optionally substituted with -C(=O)-, and the sulfur atom of the ring may be optionally substituted Oxidized to an S-oxide, the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolinyl, imidazolinyl, imidazolinyl, Tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, dithiocyclopentyl. Examples of the -CH ₂ -group substituted by -C(=O)- in the heterocyclic group include, but are not limited to: 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl. Examples of oxidized sulfur atoms in the heterocyclic group include, but are not limited to: cyclobutanyl. The 5-atom heterocyclic group may be optionally substituted with one or more substituents described in the present invention.

In another embodiment, a heterocyclic group is a heterocyclic group consisting of 6 atoms, which means a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms . Unless otherwise specified, a heterocyclic group consisting of 6 atoms may be a carbon group or a nitrogen group, and the -CH ₂ -group may be optionally replaced by -C(=O)-, and the sulfur atom of the ring may be optionally substituted Oxidized to an S-oxide, the nitrogen atom of the ring can optionally be oxidized to an N -oxygen compound. Examples of 6-atom heterocyclic groups include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, pyridinyl, Morpholinyl, thiomorpholinyl, pyrazinyl, dioxanyl, dithianyl, thioxanyl. Examples of the -CH ₂ -group substituted by -C(=O)- in the heterocyclic group include, but are not limited to: 2-pyridinyl, 3,5-dioxopyridinyl and pyrimidindione. Examples of oxidized sulfur atoms in the heterocyclic group include, but are not limited to: 1,1-dioxothiomorpholinyl. The 6-membered heterocyclic group may be optionally substituted with one or more substituents described in the present invention.

In still another embodiment, the heterocyclic group is a heterocyclic group composed of 7-12 atoms, which means a saturated or partially unsaturated spiro bicyclic ring or fused bicyclic ring containing 7-12 ring atoms, at least one of which is a ring atom It is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group composed of 7-12 atoms may be a carbon group or a nitrogen group, and the -CH ₂ -group may be optionally replaced by -C(=O)-, and the sulfur atom of the ring may be optionally The nitrogen atoms of the ring can be optionally oxidized to N -oxygen compounds. Examples of 7-12 atom heterocyclic groups include, but are not limited to: indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinoline Group, 1,3-benzodioxanyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. The heterocyclic group consisting of 7-12 atoms can be optionally substituted with one or more substituents described in the present invention.

The term "heterocyclyloxy" includes an optionally substituted heterocyclyl group, as defined in the present invention, is attached to an oxygen atom and is connected to the rest of the molecule by an oxygen atom, wherein the heterocyclyl group has the present invention Examples of such meanings include, but are not limited to, pyrrolidinyloxy, pyridinyloxy, pyrazinyloxy, morpholinyloxy, thiomorpholinyloxy, 1-oxo -Thiomorpholinyloxy, 1,1-dioxo-thiomorpholinyloxy, tetrahydropyranyloxy, etc.

The term "heterocyclylamino" means that the amine group is substituted with one or two heterocyclyl groups. Examples include, but are not limited to, pyrrolidinylamino, pyridylamino, pyrazinyl Amino group, morpholinyl amino group and so on. In some embodiments, the heterocyclic group on the heterocyclic amino group can be further substituted with the substituent described in the present invention.

The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group; wherein the heterocyclyl group and the alkyl group have the meanings as described in the present invention. Such examples include, but are not limited to thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetane-3-ylmethyl, pyrrolidin-2-ylmethyl, Phenyl-4-ylmethyl and the like.

The term "heterocyclylalkoxy" means that the alkoxy group is substituted by one or more heterocyclic groups, wherein the alkoxy group and the heterocyclic group have the meanings as described in the present invention, such that Examples include, but are not limited to, pyrrolidinylmethoxy, pyrrolidinylethoxy, pyridinylmethoxy, pyridinylethoxy, pyrazinylmethoxy, pyrazinylethoxy, Morpholinyl methoxy, morpholinyl ethoxy, etc.

等。 The term "heterocyclic ring containing at least one nitrogen atom" means that the heterocyclic ring contains no additional heteroatoms other than the nitrogen atom, or the heterocyclic ring contains one, two, three, four, five or six Additional heteroatoms selected from nitrogen, oxygen or sulfur, and -CH ₂ -constituting the ring is optionally replaced by -C(=O)-, and the sulfur atom constituting the ring is optionally substituted Oxidation to S-oxide results in groups like S(=O) or S(=O) ₂ , and the nitrogen atoms that make up the ring are optionally oxidized to N -oxygen compounds. The heterocyclic group containing at least one nitrogen atom may be optionally substituted with one or more substituents described in the present invention. Examples include, but are not limited to

Wait.

In one embodiment, a heterocyclyl group containing at least one nitrogen atom consists of 3-10 atoms.

In one embodiment, a heterocyclyl group containing at least one nitrogen atom consists of 4-10 atoms.

In one embodiment, a heterocyclyl group containing at least one nitrogen atom consists of 3-8 atoms.

In one embodiment, a heterocyclyl group containing at least one nitrogen atom consists of 4-8 atoms.

In one embodiment, a heterocyclyl group containing at least one nitrogen atom consists of 3-7 atoms.

In one embodiment, a heterocyclyl group containing at least one nitrogen atom consists of 4-7 atoms.

In another embodiment, a heterocyclyl group containing at least one nitrogen atom consists of 5-7 atoms.

等。 In yet another embodiment, the heterocyclyl group containing at least one nitrogen atom consists of 5-6 atoms. Examples include, but are not limited to

Wait.

The terms "fused bicyclic" and "fused bicyclic group" are used interchangeably herein to refer to a monovalent or polyvalent saturated or partially unsaturated bridged ring system, which refers to a non-aromatic bicyclic system , Such a system may contain an independent or conjugated unsaturated system, but its core structure does not contain aromatic rings or aromatic heterocycles (but aromatic groups can be used as substituents thereon). The term "bridge ring" means that any two rings share two atoms that are directly or indirectly connected. For example, as described in formulas a and b below, ring A ¹ and ring A ² , ring B ¹ and ring B ² share two C atoms (labeled 1 and 2 in the formula); as shown in formula c and formula d below As described, ring A ³ and ring A ⁴ , ring B ³ and ring B ⁴ share 1 C atom and 1 N atom (marked as 3 and 4 respectively in the formula). Each ring in the fused bicyclic ring is either a carbocyclic or heterocyclic ring. Examples include, but are not limited to, hexahydrofuro[3,2-b]furan, 2,3,3a,4,7, 7a-Hexahydro-1H-indene, 7-azabicyclo[2.2.1]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, 1,2,3, 4,4a,5,8,8a-octahydronaphthalene, these are included in the fused bicyclic system, and the fused bicyclic group may be substituted or unsubstituted.

The term "fused heterobicyclic ring" means a saturated or partially unsaturated fused ring system, and at least one ring system contains one or more heteroatoms, wherein each ring system contains a 3-7 membered ring, that is, contains 1-6 carbons Atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give groups like SO, SO ₂ , PO, PO ₂ Examples of such include, but are not limited to, hexahydrofuro[3,2-b]furan, 7-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.3.0]octane, 3 ,5,8-trioxabicyclo[5,1,0]octane, 1-aza-4,6-dioxabicyclo[3.3.0]octane, etc., and the fused heterobicyclo group may be Replaced or unsubstituted.

The terms "spiro bicyclic group" or "spiro bicyclic group" are used interchangeably herein to refer to a monovalent or polyvalent saturated or partially unsaturated ring system in which one ring originates from a specific ring carbon atom on the other ring. For example, as described in the following formula f, ring D ¹ and ring D ² share a carbon atom in two saturated ring systems, and are called "spiro ring" or "spiro bicyclic ring". Each ring in the spirobicyclic group may be a carbocyclic group or a heterocyclic group, and each ring is optionally substituted with one or more substituents described in the present invention.

The term "spiroheterobicyclyl" means that one ring originates from a special cyclic carbon on the other ring, and at least one ring system contains one or more heteroatoms, where each ring system contains a 3-7 membered ring, that is, contains 1 -6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give, for example, SO, SO ₂ , PO, PO Examples of groups of ₂ include, but are not limited to, 4-azaspiro[2.4]heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[ 2.4] Heptane-5-yl, 7-hydroxy-5-azaspiro[2.4]heptane-5-yl and the like.

The term "heterocycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur or oxygen atoms.

The term "composed of n atoms", where n is an integer, typically describes the number of ring-forming atoms in the molecule, and the number of ring-forming atoms in the molecule is n. For example, pyridinyl is a 6-atom heterocycloalkyl group, and 1,2,3,4-tetrahydronaphthalene is a 10-atom carbocyclic group.

The term "unsaturated" as used in the present invention means that the group contains one or more degrees of unsaturation.

The term "heteroatom" refers to O, S, N, P, and Si, including N, S, and P in any oxidation state; primary, secondary, tertiary amine, and quaternary ammonium salt forms; or heterocyclic nitrogen atoms Hydrogen substituted forms, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "azido" or "N _3" represents an azido structure. Such a group may be linked to other groups, for example, it may be linked to a methyl group to form azide methane (MeN ₃ ), or to a phenyl group to form an azide benzene (PhN ₃ ).

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring of 3-7 atoms, and one or more attachment points are connected to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, indenyl, naphthyl and anthracene. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.

The term "aryloxy" or "aryloxy" includes an optionally substituted aryl group, as defined in the present invention, is attached to an oxygen atom and is connected to the rest of the molecule by an oxygen atom, wherein the aryl group has As the meaning of the present invention, such examples include, but are not limited to phenoxy, p-tolyloxy, p-ethylphenoxy and the like.

The term "arylamino group" or "arylamino group" means that the amine group is substituted with one or two aryl groups, and examples include, but are not limited to, N -anilino groups. In some embodiments, the aromatic ring on the arylamine group may be further substituted.

The term "arylalkyl" or "aralkyl" means that the alkyl group is substituted with one or more aryl groups, wherein the alkyl group and the aryl group have the meaning as described in the present invention, such examples include, But it is not limited to benzyl, phenylethyl, p-tolylethyl, etc.

The term "arylalkoxy" means that the alkoxy group is substituted with one or more aryl groups, wherein the alkoxy group and the aryl group have the meaning as described in the present invention, such examples include, but not Limited to benzyloxy, phenylethoxy, p-tolueneethoxy, etc.

The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, at least one of which is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 5-7 atoms, and one or more attachment points are connected to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one implementation In the case, the heteroaryl group consisting of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg 5-tetrazolyl), triazolyl (eg 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (eg 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also includes the following bicyclic rings, but by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (Eg 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (eg 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole P[[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolyl And [1,5-a]pyridyl, etc.

The term "heteroaryloxy" includes an optionally substituted heteroaryl group, as defined in the present invention, is attached to an oxygen atom and is connected to the rest of the molecule by an oxygen atom, wherein the heteroaryl group has the present invention Examples of such meanings include, but are not limited to, imidazolyloxy, pyrazolyloxy, oxazolyloxy, isoxazolyloxy, pyrrolyloxy, pyridyloxy, pyrimidinyl Oxy, pyridazinyloxy, thiazolyloxy and so on.

The term "heteroarylamino" means that the amine group is substituted with one or two heteroaryl groups. Examples include, but are not limited to, imidazolylamino, pyrazolylamino, thienylamino , Pyridylamino, pyrimidinylamino, pyrazinylamino, pyridazinylamino, etc. In some of these embodiments, the heteroaryl ring on the heteroarylamine group may be further substituted.

The term "heteroarylalkyl" means that the alkyl group is substituted with one or more heteroaryl groups, wherein the alkyl group and the heteroaryl group have the meaning as described in the present invention, such examples include , But not limited to pyridin-2-ylethyl, thiazol-2-ylmethyl, imidazol-2-ylethyl, pyrimidin-2-ylpropyl, etc.

The term "heteroarylalkoxy" means that the alkoxy group is substituted by one or more heteroaryl groups, wherein the alkoxy group and the heteroaryl group have the meaning as described in the present invention, such that Examples include, but are not limited to pyridin-2-ylethoxy, thiazol-2-ylmethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy and the like.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means -CO ₂ H or -COOH; the term "carbonyl", whether used alone or in combination with other terms, such as "amino "Carbonyl", "acyloxy", "alkylacyl", "cycloalkylacyl", "heterocyclic acyl", "arylacyl" or "heteroarylacyl", meaning -( C=O)-.

The term "oxo" refers to =O, which means that oxygen and the atom at the substitution position are connected by a double bond.

The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups and is usually used to block or protect a particular functionality. For example, "amine-protecting group" refers to a substituent connected to an amine group to block or protect the functionality of the amine group in the compound. Suitable amine-protecting groups include acetyl and trifluoroacetyl Group, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorene methoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of the hydroxyl group substituent to block or protect the hydroxyl group. Suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl group used to block or protect the functionality of carboxyl group, general carboxyl protecting group includes -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane Group) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(di Phenylphosphino) ethyl, nitroethyl, etc. For a general description of protecting groups, reference can be made to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 ; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005 .

The term "prodrug" as used in the present invention represents a compound converted into a compound represented by formula (I), formula (II), formula (IIa), formula (IIb) or formula (IIc) in vivo. Such conversion is affected by prodrug hydrolysis in the blood or enzymatic conversion into the parent structure in the blood or tissue. The prodrug compounds of the present invention may be esters. In the existing invention, esters may be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, oxymethyl esters, carbonates, Carbamates and carbamates. For example, a compound in the present invention contains a hydroxyl group, which can be compounded to obtain a prodrug compound. Other prodrug forms include phosphate esters, as these phosphate compounds are obtained by phosphorylation of hydroxyl groups on the parent. For a complete discussion of prodrugs, please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 , J. Rautio et al. , Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery , 2008 , 7,255-270, and SJHecker et al. , Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008 , 51,2328-2345.

"Metabolite" refers to a product obtained by metabolizing a specific compound or its salt in the body. The metabolite of a compound can be identified by techniques well known in the art, and its activity can be characterized by an experimental method as described in the present invention. Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the present invention includes metabolites of the compound, including metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al. , describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977 , 66: 1-19. Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amine groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in books and literature such as ion exchange to obtain these salt. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate , Camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate , Gluconate, hemisulfate, enanthate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate Salt, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, paraben, pectate, persulfate, 3-benzene Propionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by suitable ketenes include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salt formed by any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. The alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C _{1- 8} sulfonate and aromatic sulfonate.

The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

The term "treating" any disease or disorder as used in the present invention, in some of these embodiments, "treating" refers to improving the disease or disorder (ie, slowing or preventing or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating a disease or condition physically (eg, stabilizing perceptible symptoms) or physiologically (eg, stabilizing the parameters of the body) or both. In other embodiments, "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

"Inflammation" as used in the present invention refers to a local protective response caused by tissue damage or destruction, which is used to destroy, dilute, or isolate (isolate) harmful substances and damaged tissue. Inflammation is significantly associated with leukocyte influx and/or neutrophil chemotaxis. Inflammation can result from infection by pathogenic organisms and viruses and non-infectious means, such as trauma or reperfusion after myocardial infarction or stroke, immune response to foreign antigens, and autoimmune response. Therefore, inflammatory diseases that can be treated with the compounds disclosed herein include diseases related to specific defense system responses as well as non-specific defense system responses.

As used in the present invention, "arthritis disease" refers to various diseases attributable to Any disease characterized by academic arthritis. "Dermatitis" as used in the present invention refers to any of a large family of skin diseases characterized by skin inflammation that can be attributed to various etiologies.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate Salt, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconic acid Salt, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, propionate Diacid, mandelate, methanesulfonate, methylsulfate, naphthalate, naphthalenesulfonate, nicotinate, nitrate, octadecate, oleate, oxalate, palmitic acid Salt, paraben, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonic acid Salt and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the periodic table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

Organic bases from which salts can be derived include primary, secondary, and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, pyrazine and tromethamine .

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties using conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by The free base forms of these compounds are prepared by reacting with stoichiometric amounts of suitable acids. This type of reaction is usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile need to be used. In, for example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., 1985 ; and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002 ) can find a list of other suitable salts.

In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of solvents containing them (eg, ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in the present invention can form solvates inherently or by design with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms.

Any structural formula given in the present invention is also intended to represent the forms in which these compounds are not isotopically enriched and in isotopically enriched forms. Isotope-enriched compounds have the structure depicted by the general formula given in this invention, except that one or more atoms are replaced with atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

On the other hand, the compounds described in the present invention include isotopically enriched compounds defined in the present invention, for example, those in which radioactive isotopes such as ³ H, ¹⁴ C, and ¹⁸ F are present, or in which non-radioactive isotopes are present, such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetic studies (using eg ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single-photon emission computed tomography (SPECT) for the determination of the distribution of substrate tissues may be used in patient radiotherapy. ¹⁸ F enriched compounds are particularly ideal for PET or SPECT studies. Isotope-enriched compounds of formula (I), formula (II), formula (IIa), formula (IIb), or formula (IIc) can be prepared by conventional techniques familiar to those skilled in the art or examples and preparations in the present invention The process described was prepared using suitable isotope-labeled reagents instead of the unlabeled reagents originally used.

In addition, the substitution of heavier isotopes, especially deuterium (ie, ² H or D), may provide certain therapeutic advantages that are brought about by higher metabolic stability. For example, an increase in half-life in the body or a decrease in dosage requirements or an improvement in the therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound of formula (I), formula (II), formula (IIa), formula (IIb) or formula (IIc). The isotope enrichment factor can be used to define the concentration of this type of heavier isotope, especially deuterium. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope. If the substituent of the compound of the present invention is designated as deuterium, the compound has at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation) for each designated deuterium atom, At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% of Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). The present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D ₂ O, acetone - d _6, DMSO- d ₆ solvate of those.

Description of the compounds of the invention

The compounds of the present invention and their pharmaceutical compositions have potential use for the treatment of chronic obstructive pulmonary disease (COPD).

其中：R¹為H、氘、烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、烷基-C(=O)-、烷基-S(=O)₂-、R^a-C(=O)-亞烷基、R^a-S(=O)₂-亞烷 基、烯基、炔基、環烷基烷基、雜環基烷基、芳基烷基或雜芳基烷基；各R²獨立地為H、氘、F、Cl、Br、I、CN、OH、NO₂、NH₂、COOH、-C(=O)-NH₂、-S(=O)₂-NH₂、烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、烷氧基、鹵代烷氧基或烷胺基；R³為H、氘、烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、烷基-C(=O)-、烷基-S(=O)₂-、烷基-C(=O)-亞烷基、烷基-O-C(=O)-亞烷基、烷基-S(=O)₂-亞烷基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、環烷基-C(=O)-亞烷基或雜環基-C(=O)-亞烷基；R⁴為氘、NH₂、C_2-10烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、R^a-C(=O)-亞烷基、R^a-S(=O)₂-亞烷基、烯基、炔基、烷氧基、烷胺基、-C(=O)-NH₂或-S(=O)₂-NH₂；X為N(R^b)、O或S；Y為O或S；A為含有至少一個氮原子的雜環基；各R⁵獨立地為H、氘、F、Cl、Br、I、CN、OH、NO₂、NH₂、R⁶-C(=O)-、R⁶-C(=O)-亞烷基、R⁶-C(=O)-亞烯基、R⁶-C(=O)-亞烷基-O-C(=O)-、R⁶-C(=O)-亞烯基-O-C(=O)-、R⁶-C(=O)O-亞烷基-O-C(=O)-、R⁶-C(=O)O-亞烯基-O-C(=O)-、R^cR^bN-C(=O)-、R^cR^bN-C(=O)-O-、R^cR^bN-C(=O)-亞烷基、R^cR^bN-C(=O)-亞烯基、R^cR^bN-C(=O)-亞烷基-O-C(=O)-、R^cR^bN-C(=O)-亞烯基-O-C(=O)-、R⁶-C(=O)-N(R^b)-、R⁶-C(=O)-N(R^b)-亞烷基、R⁶-C(=O)-N(R^b)-亞烯基、R⁶-C(=O)-亞烷基-N(R^b)-、R⁶-C(=O)-亞烯基-N(R^b)-、R^cR^bN-C(=O)-N(R^b)-、R^cR^bN-C(=O)-N(R^b)-亞烷基、R^cR^bN-C(=O)-N(R^b)-亞烯基、R^cR^bN-C(=O)-亞烷基-N(R^b)-、R^cR^bN-C(=O)-亞烯基-N(R^b)-、R⁶-C(=O)-N(R^b)-C(=O)-、R⁶-C(=O)-N(R^b)-C(=O)-亞烷基、R⁶-C(=O)-N(R^b)-C(=O)-亞烯基、R^6a-O-亞烷基、R^6a-O-亞烯基、氧代、烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、羧基取代的烷基、烷氧基烷基、羥基取代的烷氧基烷基、羧基取代的烷氧基烷基、烷胺基烷基、芳氧基取代的烷基、烷氧基、鹵代烷氧基、烷氧基烷氧基、烷胺 基、烷胺基烷胺基、烷胺基烷氧基、烷氧基烷胺基、烷硫基、烯基、羧基取代的烯基、炔基、R⁶-S(=O)₂-、R⁶-S(=O)₂-亞烷基、R⁶-S(=O)₂-亞烯基、R⁶-S(=O)₂-N(R^b)-、R⁶-S(=O)₂-N(R^b)-亞烷基、R⁶-S(=O)₂-N(R^b)-亞烯基、R^cR^bN-S(=O)₂-、R^cR^bN-S(=O)₂-亞烷基、R^cR^bN-S(=O)₂-亞烯基、環烷基、環烷基氧基、環烷基胺基、環烷基烷基、環烯基、環烯基氧基、環烯基胺基、環烯基烷基、雜環基、雜環基氧基、雜環基胺基、雜環基烷基、芳基、芳基氧基、芳基胺基、芳基烷基、雜芳基、雜芳基氧基、雜芳基胺基或雜芳基烷基；各R^a和R⁶獨立地為H、氘、OH、NH₂、烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、烷氧基烷基、烷氧基、鹵代烷氧基、羥基取代的烷氧基、羧基取代的烷氧基、烷氧基烷氧基、環烷基烷氧基、雜環基烷氧基、芳基烷氧基、雜芳基烷氧基、烷胺基、環烷基、環烷基烷基、環烷基氧基、雜環基、雜環基烷基、雜環基氧基、芳基、芳基烷基、芳基氧基、雜芳基、雜芳基氧基或雜芳基烷基；各R^6a獨立地為H、烷基、鹵代烷基、羥基取代的烷基、羧基取代的烷基、烷氧基烷基、環烷基烷基、雜環基烷基、芳基烷基、雜芳基烷基、環烷基、雜環基、芳基或雜芳基；各R^b和R^c獨立地為H、氘、烷基、鹵代烷基、羥基取代的烷基、羧基取代的烷基、烷氧基烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、芳基、芳基烷基、雜芳基或雜芳基烷基；或R^b，R^c和與之相連的氮原子一起形成3-12個原子組成的環；m為0、1、2或3；n為0、1、2、3、4、5、6、7、8、9或10；其中所述的R¹、R²、R³、R⁴、R⁵、R⁶、R^6a、R^a、R^b和R^c中的烷基、鹵代烷基、胺基烷基、羥基取代的烷基、氰基取代的烷基、羧基取代的烷基、烷基-C(=O)-、烷基-S(=O)₂-、烷基-C(=O)-亞烷基、烷基-O-C(=O)-亞烷基、烷基-S(=O)₂-亞烷基、R^a-C(=O)-亞烷基、R^a-S(=O)₂-亞烷基、烯基、羧基取代的烯基、炔基、烷氧基、鹵代烷氧基、羥基取代的烷氧基、羧基取代的烷氧基、烷胺基、環烷基-C(=O)-亞烷基、雜環基-C(=O)-亞烷基、C_2-10 烷基、R⁶-C(=O)-、R⁶-C(=O)-亞烷基、R⁶-C(=O)-亞烯基、R⁶-C(=O)-亞烷基-O-C(=O)-、R⁶-C(=O)-亞烯基-O-C(=O)-、R⁶-C(=O)O-亞烷基-O-C(=O)-、R⁶-C(=O)O-亞烯基-O-C(=O)-、R^cR^bN-C(=O)-、R^cR^bN-C(=O)-O-、R^cR^bN-C(=O)-亞烷基、R^cR^bN-C(=O)-亞烯基、R^cR^bN-C(=O)-亞烷基-O-C(=O)-、R^cR^bN-C(=O)-亞烯基-O-C(=O)-、R⁶-C(=O)-N(R^b)-、R⁶-C(=O)-N(R^b)-亞烷基、R⁶-C(=O)-N(R^b)-亞烯基、R⁶-C(=O)-亞烷基-N(R^b)-、R⁶-C(=O)-亞烯基-N(R^b)-、R^cR^bN-C(=O)-N(R^b)-、R^cR^bN-C(=O)-N(R^b)-亞烷基、R^cR^bN-C(=O)-N(R^b)-亞烯基、R^cR^bN-C(=O)-亞烷基-N(R^b)-、R^cR^bN-C(=O)-亞烯基-N(R^b)-、R⁶-C(=O)-N(R^b)-C(=O)-、R⁶-C(=O)-N(R^b)-C(=O)-亞烷基、R⁶-C(=O)-N(R^b)-C(=O)-亞烯基、R^6a-O-亞烷基、R^6a-O-亞烯基、烷氧基烷基、羥基取代的烷氧基烷基、羧基取代的烷氧基烷基、烷胺基烷基、芳氧基取代的烷基、烷氧基烷氧基、烷胺基烷胺基、烷胺基烷氧基、烷氧基烷胺基、烷硫基、R⁶-S(=O)₂-、R⁶-S(=O)₂-亞烷基、R⁶-S(=O)₂-亞烯基、R⁶-S(=O)₂-N(R^b)-、R⁶-S(=O)₂-N(R^b)-亞烷基、R⁶-S(=O)₂-N(R^b)-亞烯基、R^cR^bN-S(=O)₂-、R^cR^bN-S(=O)₂-亞烷基、R^cR^bN-S(=O)₂-亞烯基、環烷基、環烷基氧基、環烷基胺基、環烷基烷基、環烷基烷氧基、環烯基、環烯基氧基、環烯基胺基、環烯基烷基、雜環基、3-12個原子組成的環、雜環基氧基、雜環基胺基、雜環基烷基、雜環基烷氧基、芳基、芳基氧基、芳基胺基、芳基烷基、芳基烷氧基、雜芳基、雜芳基氧基、雜芳基胺基、雜芳基烷基或雜芳基烷氧基獨立任選地被一個或多個R⁷取代；其中各R⁷獨立地為H、氘、F、Cl、Br、I、CN、NO₂、OH、NH₂、COOH、-C(=O)-NH₂、-S(=O)₂-NH₂、氧代、C_1-6烷基、C_1-6烷氧基、鹵代C_1-6烷基、鹵代C_1-6烷氧基、C_1-6烷基-C(=O)-或C_1-6烷基-O-C(=O)-。 In one aspect, the invention relates to a compound which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide of the compound represented by formula (I) Substances, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein: R ¹ is H, deuterium, alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkyl-C(=O)-, alkyl-S(=O ^{_{) 2 -, R a -C (}} = O) - ^{alkylene, R a -S (= O)} 2 - alkylene, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, aryl Alkyl or heteroarylalkyl; each R ^{2 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , COOH, -C(=O)-NH ₂ , -S(=O) ₂ -NH ₂ , alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkoxy, haloalkoxy or alkylamino; R ³ is H, deuterium, alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkyl-C(=O)-, alkyl-S(=O) ₂ -, alkyl -C(=O)-alkylene, alkyl-OC(=O)-alkylene, alkyl-S(=O) ₂ -alkylene, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl-C(=O)-alkylene or heterocyclyl -C (= O) - alkylene; R ⁴ is deuterium, NH _2, C _2-10 alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl group, R ^a - C (= O) - ^{alkylene, R a -S (= O)} 2 - alkylene group, an alkenyl group, an alkynyl group, an alkoxy group, an alkoxy group, -C (= O) -NH _2, or -S (=O) ₂ -NH ₂ ; X is N(R ^b ), O or S; Y is O or S; A is a heterocyclic group containing at least one nitrogen atom; each R ^{5 is} independently H, deuterium, F , Cl, Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)-, R ⁶ -C(=O)-alkylene, R ⁶ -C(=O)-Asia Alkenyl, R ⁶ -C(=O)-alkylene-OC(=O)-, R ⁶ -C(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O )O-alkylene-OC(=O)-, R ⁶ -C(=O)O-alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-alkylene, R ^c R ^b NC(=O)-alkenylene, R ^c R ^b NC(=O)-alkylene -OC(=O)-, R ^c R ^b NC(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O)-N(R ^b )-, R ⁶ -C( =O)-N(R ^b )-alkylene, R ⁶ -C(=O)-N(R ^b )-alkenylene, R ⁶ -C(=O)-alkylene-N(R ^b )-, R ⁶ -C(=O)-alkenylene-N(R ^b )-, R ^c R ^b N C(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-alkylene, R ^c R ^b NC(=O)-N(R ^b )-Asia Alkenyl, R ^c R ^b NC(=O)-alkylene-N(R ^b )-, R ^c R ^b NC(=O)-alkenylene-N(R ^b )-, R ⁶ -C( =O)-N(R ^b )-C(=O)-, R ⁶ -C(=O)-N(R ^b )-C(=O)-alkylene, R ⁶ -C(=O) -N(R ^b )-C(=O)-alkenylene, R ^6a -O-alkylene, R ^6a -O-alkenylene, oxo, alkyl, haloalkyl, aminoalkyl, hydroxyl Substituted alkyl, cyano-substituted alkyl, carboxy-substituted alkyl, alkoxyalkyl, hydroxy-substituted alkoxyalkyl, carboxy-substituted alkoxyalkyl, alkylaminoalkyl, aryloxy Substituted alkyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, alkylaminoalkylamino, alkylaminoalkoxy, alkoxyalkylamino, alkylthio, Alkenyl, carboxy substituted alkenyl, alkynyl, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -alkylene, R ⁶ -S(=O) ₂ -alkenylene , R ⁶ -S(=O) ₂ -N(R ^b )-, R ⁶ -S(=O) ₂ -N(R ^b )-alkylene, R ⁶ -S(=O) ₂ -N( R ^b )-alkenylene, R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -alkylene, R ^c R ^b NS(=O) ₂ -alkenylene, Cycloalkyl, cycloalkyloxy, cycloalkylamine, cycloalkylalkyl, cycloalkenyl, cycloalkenyloxy, cycloalkenylamine, cycloalkenylalkyl, heterocyclic, heterocyclic Aryloxy, heterocyclylamino, heterocyclylalkyl, aryl, aryloxy, arylamino, arylalkyl, heteroaryl, heteroaryloxy, heteroarylamino or Heteroarylalkyl; each R ^a and R ^{6 are} independently H, deuterium, OH, NH ₂ , alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkoxy Alkyl, alkoxy, haloalkoxy, hydroxy-substituted alkoxy, carboxy-substituted alkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkyl Oxygen, heteroarylalkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, aryl Alkyl, aryloxy, heteroaryl, heteroaryloxy or heteroarylalkyl; each R ^{6a is} independently H, alkyl, haloalkyl, hydroxy substituted alkyl, carboxy substituted alkyl , Alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; each R ^b and R ^{c is} independently H, deuterium, alkyl, haloalkyl, hydroxy substituted alkyl, carboxy substituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl Alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; or R ^b , R ^c together with the nitrogen atom to which they are connected to form a ring of 3-12 atoms; m is 0, 1 , 2 or 3; n is 0, ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , 9 or 10; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ^a , R ^b and R ^c alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, carboxy-substituted alkyl, alkyl-C (= O)-, alkyl-S(=O) ₂ -, alkyl-C(=O)-alkylene, alkyl-OC(=O)-alkylene, alkyl-S(=O) ₂ - alkylene ^{group, R a -C (= O)} - ^{alkylene, R a -S (= O)} 2 - alkylene, alkenylene, carboxyl-substituted alkenyl group, alkynyl group, alkoxy group, haloalkoxy Group, hydroxy-substituted alkoxy group, carboxy-substituted alkoxy group, alkylamino group, cycloalkyl-C(=O)-alkylene group, heterocyclic group-C(=O)-alkylene group, C _{2 -10} alkyl, R ⁶ -C(=O)-, R ⁶ -C(=O)-alkylene, R ⁶ -C(=O)-alkenylene, R ⁶ -C(=O)- Alkylene-OC(=O)-, R ⁶ -C(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O)O-alkylene-OC(=O) -, R ⁶ -C(=O)O-alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-alkylene, R ^c R ^b NC(=O)-alkenylene, R ^c R ^b NC(=O)-alkylene-OC(=O)-, R ^c R ^b NC(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O)-N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-alkylene Group, R ⁶ -C(=O)-N(R ^b )-alkenylene, R ⁶ -C(=O)-alkylene-N(R ^b )-, R ⁶ -C(=O)- Alkenylene-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-alkylene, R ^c R ^b NC(=O)-N(R ^b )-alkenylene, R ^c R ^b NC(=O)-alkylene-N(R ^b )-, R ^c R ^b NC(=O)-ene Alkenyl-N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-C(=O)-, R ⁶ -C(=O)-N(R ^b )-C(= O)-alkylene, R ⁶ -C(=O)-N(R ^b )-C(=O)-alkenylene, R ^6a -O-alkylene, R ^6a -O-alkenylene, Alkoxyalkyl, hydroxy-substituted alkoxyalkyl, carboxyl -Substituted alkoxyalkyl, alkylaminoalkyl, aryloxy-substituted alkyl, alkoxyalkoxy, alkylaminoalkylamino, alkylaminoalkoxy, alkoxyalkylamino , Alkylthio, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -alkylene, R ⁶ -S(=O) ₂ -alkenylene, R ⁶ -S(= O) ₂ -N(R ^b )-, R ⁶ -S(=O) ₂ -N(R ^b )-alkylene, R ⁶ -S(=O) ₂ -N(R ^b )-alkenylene , R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -alkylene, R ^c R ^b NS(=O) ₂ -alkenylene, cycloalkyl, cycloalkyl Oxygen, cycloalkylamino, cycloalkylalkyl, cycloalkylalkoxy, cycloalkenyl, cycloalkenyloxy, cycloalkenylamine, cycloalkenylalkyl, heterocyclyl, 3- 12-atom ring, heterocyclyloxy, heterocyclylamino, heterocyclylalkyl, heterocyclylalkoxy, aryl, aryloxy, arylamino, arylalkyl, Arylalkoxy, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylalkyl or heteroarylalkoxy are independently optionally substituted by one or more R ⁷ ; wherein each R ⁷ Independently for H, deuterium, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, -C(=O)-NH ₂ , -S(=O) ₂ -NH ₂ , oxygen Substituted, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _1-6 alkyl-C(=O)- or C _1-6 alkyl-OC(=O)-.

Some of the embodiments are that R ¹ is H, deuterium, C _1-4 alkyl, halogenated C _1-4 alkyl, amine C _1-3 alkyl, hydroxy substituted C _1-3 alkyl, cyano Substituted C _1-3 alkyl, C _1-3 alkyl-C(=O)-, C _1-3 alkyl-S(=O) ₂ -, C _2-4 alkenyl or C _2-4 alkyne base.

In some embodiments, each R ^{2 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , COOH, -C(=O)-NH ₂ , -S(= O) ₂ -NH ₂ , C _1-3 alkyl, halogenated C _1-3 alkyl, amine C _1-3 alkyl, hydroxy substituted C _1-3 alkyl, cyano substituted C _1-3 Alkyl, C _1-3 alkoxy, halogenated C _1-3 alkoxy or C _1-3 alkylamino.

Some of these embodiments are that R ⁴ is deuterium, NH ₂ , C _2-4 alkyl, halogenated C _1-4 alkyl, amine C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, cyano Substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 alkoxy, C _1-3 alkylamino, -C(=O)-NH ₂ or -S(=O) ₂ -NH ₂ .

In some of these embodiments, m is 0, 1, 2, or 3.

In other embodiments, R ¹ is H, deuterium, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH ₃ , -CH ₂ Cl, -CHCl ₂ ,- CCl ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ Cl, -CH ₂ CHCl ₂ , -CH ₂ CH ₂ F, or -CH ₂ CHF ₂ .

In other embodiments, each R ^{2 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , COOH, -C(=O)-NH ₂ , -S(= O) ₂ -NH ₂ , methyl or methoxy.

In other embodiments, R ⁴ is NH ₂ , —CH ₂ CH ₃ , —CH ₂ CH ₂ NH ₂ , —CH(CH ₃ )NH ₂ , —CH ₂ CH ₂ CH ₂ NH ₂ , —CH(CH ₂ CH ₃ )NH ₂ , -CH ₂ CH(CH ₃ )NH ₂ , -CH(CH(CH ₃ ) ₂ )NH ₂ , -C(=O)-NH ₂ or -S(=O) ₂ -NH ₂ .

Some of the embodiments are that R ³ is H, deuterium, C _1-6 alkyl, halogenated C _1-6 alkyl, amino C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, cyano Substituted C _1-6 alkyl, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O) ₂ -, C _1-6 alkyl-C(=O) -C _1-6 alkylene, C _1-6 alkyl-OC(=O)-C _1-8 alkylene, C _1-6 alkyl-S(=O) ₂ -C _1-6 alkylene Group, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 heteroaryl, C _{3- 8} cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl C _1-6 alkyl Group, C _3-8 cycloalkyl-C(=O)-C _1-6 alkylene or C _2-10 heterocyclyl-C(=O)-C _1-8 alkylene.

In some other embodiments, R ³ is C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkyl-C(=O)-C _1-6 alkylene, C _1-3 Alkyl-OC(=O)-C _1-6 alkylene, C _1-3 alkyl-S(=O) ₂ -C _1-6 alkylene, C _3-6 cycloalkyl, C _{2- 6} heterocyclyl, C _6-10 aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl, C _{6 -10} aryl C _1-3 alkyl, C _1-5 heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl-C(=O)-C _1-6 alkylene or C _{2- 6} Heterocyclyl-C(=O)-C _1-6 alkylene.

In other embodiments, R ³ is CH ₃ -OC(=O)-C _1-6 alkylene, CH ₃ CH ₂ -OC(=O)-C _1-6 alkylene, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, pyridyl, pyrazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1- Dioxo-thiomorpholinyl, tetrahydropyranyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, pyrrole Alkylmethyl, tetrahydrofurylmethyl, pyridylmethyl, pyrazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, 1-oxo-thiomorpholinylmethyl, 1 ,1-dioxo-thiomorpholinylmethyl, tetrahydropyranylmethyl, benzyl, phenethyl, cyclohexyl-C(=O)-C _1-6 alkylene, pyridinyl -C(=O)-C _1-6 alkylene, morpholinyl-C(=O)-C _1-6 alkylene, pyrazinyl-C(=O)-C _1-6 alkylene , Thiomorpholinyl-C(=O)-C _1-6 alkylene, 1-oxo-thiomorpholinyl-C(=O)-C _1-6 alkylene or 1,1- Dioxo-thiomorpholinyl-C(=O)-C _1-6 alkylene.

In some of these embodiments, A is a heterocyclic group consisting of 3-12 atoms containing at least one nitrogen atom.

其中：各Z獨立地為CH₂、NH、O、S、S(=O)或S(=O)₂；各Z¹獨立地為NH、O、S、S(=O)或S(=O)₂；各W獨立地為CH₂、NH或O；各V獨立地為CH₂或NH；各E獨立地為CH或N；各G獨立地為O或NH；各p獨立地為0、1、2或3；各q獨立地為1或2；各r獨立地為0、1、2或3；各s獨立地為1、2或3。 In some other embodiments, A is the following substructure formula:

Where: each Z is independently CH ₂ , NH, O, S, S(=O) or S(=O) ₂ ; each Z ^{1 is} independently NH, O, S, S(=O) or S(= O) ₂ ; each W is independently CH ₂ , NH or O; each V is independently CH ₂ or NH; each E is independently CH or N; each G is independently O or NH; each p is independently 0 , 1, 2, or 3; each q is independently 1 or 2; each r is independently 0, 1, 2, or 3; each s is independently 1, 2, or 3.

In some other embodiments, A is the following substructure formula:

其中：各R⁵和n具有如本發明所述的含義；各Z獨立地為CH₂、NH、O、S、S(=O)或S(=O)₂；t為0、1、2或3。 Some of the embodiments are that the present invention relates to a compound which is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, racemate of the compound represented by formula (II) , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Where: each R ⁵ and n have the meaning as described in the present invention; each Z is independently CH ₂ , NH, O, S, S(=O) or S(=O) ₂ ; t is 0, 1, 2 Or 3.

其中：各R⁵具有如本發明所述的含義。 Some of the embodiments are that the present invention relates to a compound which is a compound represented by formula (IIa) or a stereoisomer, geometric isomer, tautomer, racemate of the compound represented by formula (IIa) , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein: each R ⁵ has the meaning as described in the present invention.

其中：各R⁵具有如本發明所述的含義。 Some of the embodiments are that the present invention relates to a compound which is a compound represented by formula (IIb) or a stereoisomer, geometric isomer, tautomer, racemate of the compound represented by formula (IIb) , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein: each R ⁵ has the meaning as described in the present invention.

其中：各R⁵具有如本發明所述的含義。 Some of the embodiments are that the present invention relates to a compound which is a compound represented by formula (IIc) or a stereoisomer, geometric isomer, tautomer, racemate of the compound represented by formula (IIc) , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein: each R ⁵ has the meaning as described in the present invention.

其中：各R⁵具有如本發明所述的含義。 Some of the embodiments are that the present invention relates to a compound which is a compound represented by formula (IId) or a stereoisomer, geometric isomer, tautomer, racemate of the compound represented by formula (IId) , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein: each R ⁵ has the meaning as described in the present invention.

其中：各R⁵具有如本發明所述的含義。 Some of the embodiments are that the present invention relates to a compound which is a compound represented by formula (IIe) or a stereoisomer, geometric isomer, tautomer, racemate of a compound represented by formula (IIe) , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein: each R ⁵ has the meaning as described in the present invention.

其中：各R⁵具有如本發明所述的含義。 Some of the embodiments are that the present invention relates to a compound which is a compound represented by formula (IIf) or a stereoisomer, geometric isomer, tautomer, racemate of the compound represented by formula (IIf) , Nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

Wherein: each R ⁵ has the meaning as described in the present invention.

Some of the embodiments are that the pharmaceutically acceptable salts are hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumaric acid Salt, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate , Tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate Salt or their combination.

In some embodiments, each R ^{5 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)-, R ⁶ -C(= O)-C _1-6 alkylene, R ⁶ -C(=O)-C _2-6 alkenylene, R ⁶ -C(=O)-C _1-6 alkylene-OC(=O) -, R ⁶ -C(=O)-C _2-6 alkenylene-OC(=O)-, R ⁶ -C(=O)OC _1-6 alkylene-OC(=O)-, R ⁶ -C(=O)OC _2-6 alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-C _1-6 alkylene, R ^c R ^b NC(=O)-C _2-6 alkenylene, R ^c R ^b NC(=O)-C _1-6 alkylene- OC(=O)-, R ^c R ^b NC(=O)-C _2-6 alkenylene-OC(=O)-, R ⁶ -C(=O)-N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-C _1-6 alkylene, R ⁶ -C(=O)-N(R ^b )-C _2-6 alkenylene, R ⁶ -C(= O)-C _1-6 alkylene-N(R ^b )-, R ⁶ -C(=O)-C _2-6 alkenylene-N(R ^b )-, R ^c R ^b NC(=O )-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-C _1-6 alkylene, R ^c R ^b NC(=O)-N(R ^b )-C _2-6 alkenylene, R ^c R ^b NC(=O)-C _1-6 alkylene-N(R ^b )-, R ^c R ^b NC(=O)-C _2-6 alkenylene- N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-C(=O)-, R ⁶ -C(=O)-N(R ^b )-C(=O)- C _1-6 alkylene, R ⁶ -C(=O)-N(R ^b )-C(=O)-C _2-6 alkenylene, R ^6a -OC _1-8 alkylene, R ^6a -OC _2-8 alkenylene, oxo, C _1-8 alkyl, halogenated C _1-6 alkyl, amino C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, cyano substitution C _1-6 alkyl, carboxy substituted C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, hydroxy substituted C _1-6 alkoxy C _1-6 alkyl, carboxy Substituted C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, C _6-10 aryloxy substituted C _1-6 alkyl, C _1-6 Alkoxy, halogenated C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylamino C _1-6 alkylamine base , C _1-6 alkylamino C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkylamino, C _1-6 alkylthio, C _2-6 alkenyl, carboxy substituted C _2-6 alkenyl, C _2-6 alkynyl, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -C _1-6 alkylene, R ⁶ -S(=O) ₂ -C _2-6 alkenylene, R ⁶ -S(=O) ₂ -N(R ^b )-, R ⁶ -S(=O) ₂ -N(R ^b )-C _1-6 alkylene , R ⁶ -S(=O) ₂ -N(R ^b )-C _2-6 alkenylene, R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -C _{1 -6} alkylene, R ^c R ^b NS(=O) ₂ -C _2-6 alkenylene, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, C _3-8 cycloalkyl Amino group, C _3-8 cycloalkyl C _1-6 alkyl group, C _3-8 cycloalkenyl group, C _3-8 cycloalkenyloxy group, C _3-8 cycloalkenylamino group, C _3-8 ring Alkenyl C _1-6 alkyl, C _2-10 heterocyclyl, C _2-10 heterocyclyloxy, C _2-10 heterocyclylamino, C _2-10 heterocyclyl C _1-6 alkyl , C _6-10 aryl, C _6-10 aryloxy, C _6-10 arylamino, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl, C _{1- 9} Heteroaryloxy, C _1-9 heteroarylamino or C _1-9 heteroaryl C _1-6 alkyl; wherein each R ⁶ , R ^6a , R ^b and R ^c have the Meaning.

In some embodiments, each R ^{6 is} independently H, deuterium, OH, NH ₂ , C _1-8 alkyl, halogenated C _1-6 alkyl, amino C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-8 alkoxy, halogenated C _1-6 alkoxy, hydroxy Substituted C _1-8 alkoxy, carboxy substituted C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _3-8 cycloalkyl C _1-6 alkoxy , C _2-10 heterocyclyl C _1-6 alkoxy, C _6-10 aryl C _1-6 alkoxy, C _1-9 heteroaryl C _1-6 alkoxy, C _1-6 alkoxy Amino, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _3-8 cycloalkyloxy, C _2-10 heterocyclyl, C _2-10 heterocyclyl C _1-6 alkyl, C _2-10 heterocyclyloxy, C _6-10 aryl, C _6-10 aryl C _1-6 alkyl, C _6-10 aryloxy, C _1-9 Heteroaryl, C _1-9 heteroaryloxy or C _1-9 heteroaryl C _1-6 alkyl.

In some embodiments, each R ^{6a is} independently H, C _1-8 alkyl, halogenated C _1-8 alkyl, hydroxy substituted C _1-8 alkyl, carboxy substituted C _1-8 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _{1 -6} alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl.

In some embodiments, each R ^b and R ^{c are} independently H, deuterium, C _1-8 alkyl, halogenated C _1-6 alkyl, hydroxy substituted C _1-8 alkyl, carboxy substituted C _{1 -8} alkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl or C _1-9 heteroaryl C _{1 -6} alkyl.

In some of these embodiments, R ^b and R ^c together with the nitrogen atom to which they are attached form a ring of 3-8 atoms.

In other embodiments, each R ^{5 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)-, R ⁶ -C(= O)-C _1-3 alkylene, R ⁶ -C(=O)-C _2-4 alkenylene, R ⁶ -C(=O)OC _1-4 alkylene-OC(=O)- , R ⁶ -C(=O)OC _2-4 alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-C _1-3 alkylene, R ^c R ^b NC(=O)-C _2-4 alkenylene, R ⁶ -C(=O)-N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-C _1-3 alkylene, R ⁶ -C(=O)-N(R ^b )-C _2-4 alkenylene, R ^c R ^b NC(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-C _1-3 alkylene, R ^c R ^b NC(=O)-N(R ^b ) -C _2-4 alkenylene, R ^6a -OC _1-6 alkylene, R ^6a -OC _2-6 alkenylene, oxo, C _1-6 alkyl, halo C _1-4 alkyl Group, amine C _1-4 alkyl, hydroxy substituted C _1-6 alkyl, cyano substituted C _1-4 alkyl, carboxy substituted C _1-4 alkyl, C _1-6 alkoxy C _1-3 alkyl, hydroxy substituted C _1-6 alkoxy C _1-3 alkyl, carboxy substituted C _1-6 alkoxy C _1-4 alkyl, C _1-3 alkylamino C _{1- 3} alkyl, C _6-10 aryloxy substituted C _1-3 alkyl, C _1-3 alkoxy, C _2-4 alkenyl, carboxy substituted C _2-4 alkenyl, C _2-4 alkyne Group, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -C _1-3 alkylene, R ⁶ -S(=O) ₂ -C _2-4 alkenylene, R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -C _1-3 alkylene, R ^c R ^b NS(=O) ₂ -C _2-4 alkenylene, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _1-3 alkyl, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, C _1-6 heteroaryl or C _1-6 heteroaryl C _1-3 alkyl; wherein each R ⁶ , R ^6a , R ^b and R ^c have The meaning of the present invention.

In other embodiments, each R ^{6 is} independently H, deuterium, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, hydroxy substituted C _1-6 alkoxy, carboxy substituted C _1-6 alkoxy, C _1-3 alkoxy C _1-4 alkoxy, C _3-6 cycloalkyl C _1-3 alkoxy, C _2-6 heterocyclyl C _1-3 alkyl Oxy, C _6-10 aryl C _1-3 alkoxy, C _1-5 heteroaryl C _1-3 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _{1- 3} alkyl, C _3-8 cycloalkyloxy, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _1-3 alkyl, C _2-6 heterocyclyloxy, C _6-10 Aryl, C _6-10 aryl C _1-3 alkyl, C _6-10 aryloxy, C _1-6 heteroaryl, C _1-5 heteroaryloxy or C _1-6 heteroaryl C _1-3 alkyl.

In other embodiments, each R ^{6a is} independently H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, carboxy substituted C _1-6 alkyl, C _1-3 alkoxy C _1-4 alkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl, C _6-10 aryl C _{1 -3} alkyl, C _1-5 heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _6-10 aryl or C _1-5 heteroaryl.

In other embodiments, each R ^b and R ^{c are} independently H, deuterium, C _1-6 alkyl, halogenated C _1-3 alkyl, hydroxy substituted C _1-6 alkyl, carboxy substituted C _{1 -6} alkyl, C _1-3 alkoxy C _1-4 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _1-3 alkyl, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, C _1-5 heteroaryl or C _1-5 heteroaryl C _{1 -3} alkyl.

In other embodiments, R ^b and R ^c together with the nitrogen atom to which they are attached form a ring of 3-6 atoms.

In other embodiments, each R ^{5 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)-, R ⁶ -C(= O)-C _1-3 alkylene, R ⁶ -C(=O)-C _2-4 alkenylene, R ⁶ -C(=O)OC _1-4 alkylene-OC(=O)- , R ⁶ -C(=O)OC _2-4 alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-C _1-3 alkylene, R ^c R ^b NC(=O)-C _2-4 alkenylene, R ⁶ -C(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-, R ^6a -OC _1-6 alkylene, R ^6a -OC _2-6 alkenylene, oxo, methyl, cyano substituted methyl Group, carboxymethyl, ethyl, cyano substituted ethyl, carboxyethyl, propyl, cyano substituted propyl, carboxypropyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary Butyl, hydroxy substituted C _1-4 alkyl, phenoxymethyl, phenoxyethyl, C _1-5 alkoxy C _1-3 alkyl, hydroxy substituted C _1-5 alkoxy C _1-3 alkyl, carboxy substituted C _1-4 alkoxy C _1-3 alkyl, methoxy, ethoxy, propoxy, isopropoxy, halogenated C _1-3 alkyl, ethylene Group, carboxy substituted vinyl, propenyl, carboxy substituted propenyl, ethynyl, propynyl, R ⁶ -S(=O) ₂ -, R ^c R ^b NS(=O) ₂ -, cyclopropyl , Cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, pyrrolidinyl, tetrahydrofuranyl, pyridinyl, pyrazinyl, morpholine Group, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydropyranyl, pyrrolidinylmethyl, tetrahydrofuranylmethyl, Pyridinylmethyl, pyrazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, 1-oxo-thiomorpholinylmethyl, 1,1-dioxo-thio? Pynylmethyl, tetrahydropyranylmethyl, phenyl, indenyl, naphthyl, benzyl, phenethyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazole Group, oxadiazolyl, thiazolyl, isothiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidine Ethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl or pyridazinylethyl; wherein each of R ⁶ , R ^6a , R ^b and R ^c has the meaning as described in the present invention.

In other embodiments, each R ^{6 is} independently H, deuterium, OH, NH ₂ , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methyl Oxy, hydroxy substituted methoxy, carboxy substituted methoxy, ethoxy, hydroxy substituted ethoxy, carboxy substituted ethoxy, propoxy, hydroxy substituted propoxy, carboxy substituted propoxy Oxygen, isopropoxy, hydroxy substituted isopropoxy, carboxy substituted isopropoxy, butoxy, hydroxy substituted butoxy, carboxy substituted butoxy, isobutoxy, hydroxy substituted Isobutoxy, carboxy substituted isobutoxy, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy, benzyloxy Group, phenylethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyloxy, Cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, pyrrolidinyl, tetrahydrofuranyl, quat Pyridinyl, pyrazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydropyranyl, pyrrolidine Methyl, tetrahydrofuranylmethyl, pyridylmethyl, pyrazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, 1-oxo-thiomorpholinylmethyl, 1, 1-Dioxo-thiomorpholinylmethyl, tetrahydropyranylmethyl, phenyl, indenyl, naphthyl, benzyl, phenethyl, pyrrolyl, imidazolyl, pyrazolyl, triazole Group, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridylmethyl, pyrimidinyl Methyl, pyrimidinylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl or pyridazinylethyl.

In other embodiments, each R ^{6a is} independently H, methyl, ethyl, propyl, isopropyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy-substituted isopropyl, hydroxy Butyl, 2-hydroxy-2-methylpropyl, carboxymethyl, carboxyethyl, carboxypropyl, 2-carboxy-2-methylethyl, methoxymethyl, methoxyethyl, methyl Oxypropyl, ethoxymethyl, ethoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, Cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

In other embodiments, each R ^b and R ^{c are} independently H, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hydroxy substituted C _1-5 alkyl, carboxy substituted C _1-4 alkyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, cyclopropyl , Cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl Group, cyclohexylmethyl, cyclohexylethyl, phenyl, benzyl, phenethyl or phenylpropyl.

In some other embodiments, ^Rb , ^Rc and the nitrogen atom to which they are attached form azetidine, pyrrolidine, pyridine, pyrazine, morpholine, thiomorpholine, 1-oxo-thioxo Morpholine or 1,1-dioxo-thiomorpholine.

In one aspect, the invention relates to a compound, including but not limited to a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate of the compound having one of the following structures , Solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

The present invention also includes the use of the compounds of the present invention and pharmaceutically acceptable salts thereof for the production of pharmaceutical products for the treatment of respiratory diseases, allergies and inflammations, central nervous system (CNS) diseases, pulmonary fibrosis or non-insulin dependent diabetes, including Those described in this invention.

The compounds of the present invention are also used to produce a medicinal product for reducing, preventing, controlling or treating PDE 4 mediated disorders, especially chronic obstructive pulmonary disease (COPD).

The present invention includes a pharmaceutical composition comprising a compound represented by formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) and at least An effective therapeutic dose required by the combination of a pharmaceutically acceptable carrier, adjuvant or diluent.

Unless otherwise indicated, all stereoisomers of the compounds of the invention Isomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, metabolic precursors, salts and pharmaceutically acceptable prodrugs are all within the scope of the present invention.

Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes substances or compositions that must be chemically or toxicologically related to the other components that make up the formulation and the mammal used for treatment.

The salts of the compounds of the present invention also include intermediates used to prepare or purify compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) Salts of the enantiomers separated by the compound or formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf), but not necessarily It is a pharmaceutically acceptable salt.

If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Or use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, and salicylic acid; pyranoic acid, such as glucuronic acid and galactose Glyoxylic acid; α -hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid and ethanesulfonic acid Sour, etc.

If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic base or an organic base, such as an amine (primary amine, secondary amine, tertiary amine), alkali metal hydroxide or alkaline earth Metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, amines such as primary, secondary and tertiary amines, and cyclic amines such as pyridine, Porphyrin, pyrazine, etc., and inorganic salts are obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Compounds and pharmaceutical compositions, formulations and administration of the present invention

The compounds of the present invention can be produced and formulated as racemic mixtures, enantiomers, diastereomers, rotamers, N -oxides, polymorphs, solvates and pharmaceutically acceptable Accepted salt and active metabolite forms; can also produce compounds containing formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) Its metabolites, enantiomers, diastereomers, N -oxides, polymorphs, solvates or pharmaceutically acceptable salts with pharmaceutically acceptable carriers and optional excipients Pharmaceutical composition.

The pharmaceutical composition of the present invention can be produced and administered in dosage units, each unit containing an amount of at least one compound of the present invention and/or at least one physiologically acceptable addition salt thereof. The dosage can vary within a very wide range because the compound is effective even at low dosage levels and is relatively non-toxic. The compound can be administered in a therapeutically effective low micromolar, and the dose can be increased to the maximum dose that the patient can bear as needed.

When it can be used for treatment, a therapeutically effective amount of the compound represented by formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) and its pharmaceutically acceptable The accepted salt can be administered as an unprocessed chemical or as an active ingredient of a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (II IIf) the compound shown or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

In fact, according to conventional pharmaceutical compounding techniques, the compound of the present invention or a pharmaceutically acceptable salt thereof can be combined as an active ingredient with a pharmaceutical carrier in an intimately mixed manner. The carrier can take a wide variety of forms, depending on the form of the formulation desired to be administered, such as oral or parenteral (including intravenous). Therefore, the pharmaceutical composition may be present as separate units suitable for oral administration, such as capsules, cachets, or tablets, each of which contains a predetermined amount of active ingredient. In addition, the composition may be present in the following forms: powder, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions. In addition to the usual dosage forms shown above, the compounds or pharmaceutically acceptable salts thereof can also be administered by controlled release means and/or delivery devices. The composition can be prepared by any method in the pharmaceutical industry. Generally, such methods include the step of combining the active ingredient with the carrier, which constitutes one or more necessary ingredients. Generally, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or finely divided solid carrier or both. The product can then be conveniently made into the desired form.

The pharmaceutical carrier used may be solid, liquid or gas. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gas carriers include carbon dioxide and nitrogen.

The term "therapeutically effective amount" as used in the present invention refers to the total amount of each active ingredient sufficient to show a meaningful patient benefit. When a single active ingredient is administered alone, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that cause a therapeutic effect regardless of combination, sequential or simultaneous administration. The compound represented by the formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) and the pharmaceutically acceptable salt thereof are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient. According to another aspect of the present disclosure, there is also provided a method for preparing a pharmaceutical formulation, the method comprising formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe ) Or (IIf) or a pharmaceutically acceptable salt thereof is mixed with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used in the present invention refers to such compounds, raw materials, compositions and/or dosage forms, which are suitable for contact with patient tissues without excessive toxicity and irritation within the scope of reasonable medical judgment , Allergies or other problems and complications commensurate with a reasonable benefit/risk ratio, and are effectively used for their intended purpose.

Generally, the compounds of the present invention are administered in a therapeutically effective amount by any conventional mode of administration for substances that exert similar effects. A suitable dosage range is typically 1-500 mg per day, preferably 1-100 mg per day, and most preferably 1-30 mg per day, depending on various factors, such as the severity of the disease being treated, the age and relative health of the object to be applied, and the The efficacy of the compound, the route and form of administration, the indications targeted for administration, and the preferences and experience of the relevant medical practitioner. A person of ordinary skill in the field of treating the disease can determine the therapeutically effective amount of the compound of the present invention for a given disease without undue experimentation relying on personal knowledge and the disclosure of this application.

The administration of the compound of the present invention can be carried out according to the needs of patients, for example, oral administration, nasal administration, parenteral administration (subcutaneous, intravenous, intramuscular, intrasternal and infusion), inhalation administration, administration Rectal administration, transvaginal administration, body surface administration, topical administration, transdermal administration, and transocular administration.

Various solid oral dosage forms can be used for administration of the compound of the present invention, for example, solid dosage forms of tablets, soft capsules, capsules, caplets, granules, lozenges, and bulk powders. The compound of the present invention can be administered alone or with various pharmaceutically acceptable carriers and diluents known in the art (Eg, sucrose, mannitol, lactose, starch) and excipients in combination, including but not limited to suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, coloring agents, flavoring agents, Lubricants, etc. Time-release capsules, tablets and gels are also advantageous for the administration of the compounds of the invention.

Tablets can be prepared by compression or molding, optionally using one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (eg, powder or granules) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. Each tablet preferably contains about 0.1 mg to about 500 mg of active ingredient; and each cachet or capsule preferably contains about 0.1 mg to about 500 mg of active ingredient. Therefore, in the case of taking one or two tablets, capsules, or capsules (once, twice, or three times a day), the tablets, capsules, or capsules conveniently contain 0.1 mg, 1 mg, 5 mg, 25 mg , 50mg, 100mg, 200mg, 300mg, 400mg or 500mg of active ingredient.

The compounds of the invention can also be administered in a variety of liquid oral dosage forms, including aqueous and anhydrous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms may also contain suitable inert diluents known in the art, such as water, and suitable excipients known in the art, such as preservatives, lubricants, sweeteners, flavoring agents. And reagents for emulsifying and/or suspending the compounds of the invention. The compound of the present invention can be administered by injection in the form of an isotonic sterile solution, for example, intravenous injection. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with suitable excipients such as cocoa butter, salicylate and polyethylene glycol.

Formulations for vaginal administration can be in the form of creams, gels, pastes, foams, or sprays, and contain, in addition to the active ingredients, suitable carriers known in the art, for example.

For topical administration, the pharmaceutical composition may be a cream, ointment, liniment, lotion, emulsion, suspension, gel, solution, paste, powder suitable for administration to the skin, eyes, ears, or nose , Sprays and drops. Topical administration may also include transdermal administration by, for example, a transdermal patch.

For the treatment of respiratory diseases, it is preferred that the compounds of the present invention be administered by inhalation medicine. For this purpose, they can be administered directly as powders (preferably in micronized form), or by spray solutions or suspensions containing them.

Inhalable preparations include inhalable powders, propellant-containing metered aerosols or propellant-free inhalable preparations.

A diluent or carrier may be added to the powder compound of the present invention, which is generally non-toxic and chemically inert to the compound of the present invention, such as lactose or any other additives suitable for improving the respirable part.

Inhalation aerosols containing gaseous propellants such as hydrofluoroalkanes may contain the compounds of the invention in solution or in dispersed form. The propellant-driven formulation may also contain other ingredients, such as co-solvents, stabilizers, and optionally other excipients.

Propellant-free inhalable formulations containing the compounds of the present invention may be in the form of solutions or suspensions in aqueous media, alcoholic media or aqueous alcoholic media, and they may be spray nebulizers or ultrasonic mists known in the art gasifier delivery, by a fine mist or nebulizer (soft-mist nebulizers) e.g. Respimat ^® delivery.

The compounds of the present invention can be administered as a separate active agent or in combination with other pharmaceutically active ingredients, including those currently used to treat respiratory disorders, for example, β2-agonists, such as salbutamol , Formoterol, salmeterol and carmoxirol (TA 2005); corticosteroids, such as budesonide and its epimers, beclomethasone dipropionate, triamcinolone, fluticasone propionate, Flunisolide, mometasone furoate, roflunide and ciclesonide; and anticholinergic or antimuscarinic drugs such as ipratropium bromide, oxitropium bromide, tiotropium bromide, Glycopyrronium bromide, rifatropate, or the compounds disclosed in WO 03/053966.

Preferably, the compound represented by formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) is administered alone or in combination with other active ingredients For the prevention and/or treatment of respiratory diseases characterized by airway obstruction, such as asthma, chronic bronchitis or chronic respiratory obstructive pulmonary disease (COPD).

The term "combined use" or "combination" is to be understood as meaning that the ingredients can be administered simultaneously or more or less simultaneously, or sequentially separately. In some of these embodiments, one therapeutic agent/pharmaceutical active ingredient can be administered in the morning and the other is administered at a later time on the same day. In other embodiments, one therapeutic agent/pharmaceutical active ingredient can be administered once a day, while the other Dosing once a week. It is to be understood that if the components are administered directly in succession, the delay in the administration of the second component should not cause the loss of the beneficial effects of the combination.

Simultaneous administration can be performed by any suitable route, and it is preferable to administer the therapeutic agent to the object in need by oral route, intravenous route, intramuscular route or subcutaneous injection, so that the administration The form has a fixed ratio of each therapeutic agent.

The more or less simultaneous or sequential administration of each therapeutic agent can be performed by any suitable route, including but not limited to oral route, intravenous route, intramuscular route, and absorption through mucosal tissue. These therapeutic agents can be administered by the same route or by different routes. For example, both therapeutic agents of the combination can be administered orally.

The compounds of the present invention can be included in pharmaceutical compositions. The pharmaceutical composition comprises the compound described in the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier; and optionally other therapeutic ingredients or adjuvants. Optional additional therapeutic ingredients include, for example, i) leukotriene receptor antagonists, ii) leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) β2 adrenergic receptors Agonists, vi) COX-2 selective inhibitors, vii) inhibin, viii) non-steroidal anti-inflammatory drugs ("NSAID"), and ix) M2/M3 antagonists.

The composition includes compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although in a given case, the most suitable route depends on the specific host, and Instead, the nature and severity of the pathology of the active ingredient is applied. The pharmaceutical composition may conveniently be presented in unit dosage form and prepared by using any method well known in the pharmaceutical art.

Creams, ointments, jellies, solutions or suspensions containing the compounds can be used for topical use. For the purposes of the present invention, oral lotions and mouthwashes are included within the scope of topical use.

Pharmaceutical compositions suitable for parenteral administration can be prepared as solutions or suspensions of the active ingredients in water. A suitable surfactant may be included, such as hydroxypropyl cellulose. It is also possible to prepare dispersions in glycerin, liquid polyethylene glycol and mixtures thereof (in oil). In addition, preservatives may be included to prevent harmful growth of microorganisms.

Those pharmaceutical compositions suitable for injection include sterile aqueous solutions or dispersions body. The composition may be in the form of a sterile powder for the immediate preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid so that it can be easily injected.

The pharmaceutical composition must be stable under the conditions of production and storage; therefore, it should preferably be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium, including, for example, water, ethanol, polyol (for example, glycerin, propylene glycol, and liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical composition may be in a form suitable for topical use, such as aerosol, cream, ointment, lotion, powder, etc. In addition, the composition may be in a form suitable for use in transdermal devices, and these preparations may be prepared by conventional processing methods using compounds or pharmaceutically acceptable salts thereof. As an example, creams and ointments are prepared by mixing a hydrophilic material with water and about 5 wt% to about 10 wt% of the compound to produce a cream or ointment with a desired consistency.

The present invention provides a method of treating a lung disease (eg, COPD, asthma, or fibrocyst) in a patient in need of such treatment, the method comprising co-administering to the patient a therapeutically effective amount of at least one formula (I), (II), ( Compounds represented by IIa), (IIb), (IIc), (IId), (IIe) or (IIf), or pharmaceutically acceptable salts or solvates thereof, and at least one compound selected from the group consisting of steroids ( Such as glucocorticoids), 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists, α-adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists , Mushroom M2 agonist, NK3 antagonist, LTB4 antagonist, cysteamine leukotriene antagonist, bronchodilator, PDE4 inhibitor, PDE inhibitor, elastase inhibitor, MMP inhibitor, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-b agonists, nociceptive peptide agonists, Expectorants, mucolytics, decongestants, mast cell stabilizers, antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecules Inhibitors, growth hormones and other PDE 4 inhibitors.

Non-limiting examples of anti-resistance amines used in combination with compounds represented by formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) include : Astemizole (astemizole), azatadine, azelastine, arivastine, brompheniramine, certirizine, chlorpheniramine ), clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, decarbonyl ethoxy loratadine ( descarboethoxyloratadine), doxylamine (doxylamine), dimethindene (dimethindene), ebastine (epastine), epicastine (epinastine), ethflurazine (efletirizine), fexofenadine (fexofenadine ), hydroxyzine, ketotifen, loratadine, levocbastine, mizolastine, equitazine, mianserin (mianserin), noberastine (noberastine), meclizine (meclizine), norastemizole (norastemizole), picumast (picumast), mepyramine (pyrilamine), promethazine ( promethazine), terfenadine, tripelennamine, temelastine, trimeprazine, and triprolidine.

Non-limiting examples of histamine H3 receptor antagonists include: thioperamide, impromidine, burimamide, clobenpropit, impentamine, mifetidine, S -S-sopromidine, R-sopromidine, SKF-91486, GR-175737, GT-2016, UCL-1199 and clozapine. Other compounds can be evaluated to determine the activity on the H3 receptor using known methods, including the guinea pig meningeal assay and the guinea pig neuroileal contraction assay, both of which are described in US Patent No. 5,352,707. Another useful assay utilizes rat meninges and is described by West et al. in "Identification of Two-H3-Histamine Receptor Subtypes" Molecular Pharmacology, 1990 , Vol. 38, 610-613.

The term "leukotriene inhibitor" includes any agent or compound that inhibits, suppresses, delays, or interacts with the action or activity of leukotrienes. Non-limiting examples of leukotriene inhibitors include: montelukast (montelukast) and its sodium salt; 1-(((R)-(3-(2-(6,7-difluoro-2-quinoline Yl)vinyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropaneacetic acid and its sodium salt, which are described in US Patent No. 5,270,324 ; 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-( E )-vinyl)phenyl )-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid and its sodium salt, which are described in US Patent 5,472,964; Prolen Pranlukast; zafirlukast; and [2-[[2(4-(tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid , Which is described in US Patent No. 5,296,495.

Non-limiting examples of beta-adrenergic receptor agonists include: albuterol (albuterol), bitolterol (bitolterol), isoetharine (isoetharine), mataproterenol, perbuterol, salmeterol (salmeterol), terbutaline (terbutaline), isoproterenol (isoproterenol), ephedrine (ephedrine) and epinephrine (epinephrine). Non-limiting examples of alpha-adrenergic receptor agonists include arylalkylamines (such as phenylpropanolamine and pseudoephedrine), imidazoles (such as naphazoline, oxymetazoline) (oxymetazoline), tetrahydrozoline (tetrahydrozoline) and xylometazoline (xylometazoline)) and cycloalkylamines (such as hexahydrodeoxyephedrine (propylhexedrine)).

A non-limiting example of a mast cell stabilizer is nedocomilsodium. A non-limiting example of phlegm medicine is guaifenesin. Non-limiting examples of decongestants are pseudoephedrine, phenylpropanolamine, and phenylephrine.

Non-limiting examples of NK1, NK2 and NK3 tachykinin receptor antagonists include CP-99, 994 and SR 48968. Non-limiting examples of toadstool antagonists include ipratropium bromide and tiatropium bromide.

Non-limiting examples of GABA _B agonists include baclofen and 3-aminopropyl-phosphonic acid. Dopamine agonists include quinpirole, ropinirole, pramipexole, pergolide and bromociptine.

"5-lipoxygenase inhibitor" includes any agent or compound that can inhibit, stop, delay or interact with the enzymatic action of 5-lipoxygenase. Non-limiting examples of 5-lipoxygenase inhibitors include zileuton, docbenone, and pioprost (Piripost), ICI-D2318 and ABT 761.

The treatment method comprising administration of the compound or the pharmaceutical composition of the present invention further includes administration of other anti-chronic respiratory obstruction drugs (combined therapy) to the patient, wherein the other anti-chronic respiratory obstruction drugs are sodium pyruvate, rolipram ( Rolipram), Piramist (Piclamist), Cilomilast, CDP-840, Indacaterol, Indacaterol, olodaterol, QVA149, Doxofylline, Roflumilast, Apremilast, Tetomilast, Tipelukast, Theophylline, Formoterol, Salmeterol, Fluticasone propionic acid (Fluticasone propionate), Salmeterol Xinafoate/Fluticasone Propionate, Midesteine, Zileuton, Salbutamol, Carmoxiol, Budesonide and Its epimers, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, roflunide, ciclesonide, ipratropium Bromide, isopropyl Combination of atropium bromide and salbutamol, oxitropium bromide, tiotropium bromide, glycopyrronium bromide, Umeclidinium bromide, vilanterol, vildirolium bromide/vilan Tetro compound (umeclidinium/vilanterol), aclidinium bromide, aclidinium bromide/formoterol fumarate compound, LAS40464, LAS100977 (abediterol), AZD-8999, RPL-554, OCID-2987 , CHF-6001, CR-3465, HPP-737, fluticasone furoate/vilanterol (FF/VI), Benralizumab, rivastolate, or a combination thereof.

The dosage of the compound of the present invention depends on various factors, including the specific disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dose interval, the specific compound used, the potency of the compound, the toxicological characteristics and the pharmacokinetics feature.

The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. For example, formulations intended for oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, which is compounded with a suitable and convenient amount of carrier material (which may account for about 5% to about 95% of the total composition) . The unit dosage form will generally contain from about 1 mg to about 1000 mg of active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800mg or 1000mg.

For any particular patient, the specific dosage level will depend on a range of factors, including age, weight, general health, gender, diet, timing of administration, route of administration, excretion rate, drug combination, and severity of the specific disease undergoing treatment .

Advantageously, they are administered in a dose of 0.01-1000 mg/day, preferably 0.1-500 mg/day.

When administered by the inhalation route, the compound of the present invention may be administered at a dose of 0.01-10 mg/day, preferably 0.05-5 mg/day, more preferably 0.1-2 mg/day.

Use of compounds and pharmaceutical compositions of the invention

The characteristics of the pharmaceutical composition of the present invention include compounds represented by formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or listed in the present invention Compounds, as well as pharmaceutically acceptable carriers, adjuvants or excipients.

The amount of compound in the composition of the present invention can effectively and detectably antagonize PDE 4 to treat: pain (eg, acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation, chronic inflammation, Rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, Georgia Lans-negative septicemia, toxic shock syndrome, stroke, ischemic reperfusion injury, renal reperfusion injury, glomerulonephritis, Parkinson's disease, Alzheimer's disease, mild cognitive impairment (MCI ), depression, anxiety, graft response to the host (ie, graft versus host disease), allograft rejection (eg, acute allograft rejection and chronic allograft rejection), acute respiratory distress syndrome, delay Type allergic reaction, atherosclerosis, cerebral ischemia, osteoarthritis, multiple sclerosis, angiogenesis, osteoporosis, gingivitis, respiratory virus, herpes virus, hepatitis virus, HIV, Kaposi's sarcoma-associated virus ( Namely, Kaposi's sarcoma), meningitis, fibrocysts, premature delivery, cough, pruritus, multiple organ dysfunction, psoriatic arthritis, herpes, encephalitis, traumatic brain injury, CNS tumor, interstitial pneumonia , Allergy, crystal-induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, eye inflammation, corneal neovascularization, polymyositis, acne, esophagitis, Glossitis, airflow obstruction, airway hypersensitivity (ie, airway hyperresponsiveness), bronchiectasis, bronchiolitis, obstructive bronchiolitis (I.e. obstructive bronchiolitis syndrome), chronic bronchitis, cystic fibrosis, dyspnea, emphysema, adult respiratory disease, acute respiratory distress syndrome, respiratory virus, hypercapnia, and hyperinflation (hyperinflation), hypoxemia, hyperoxia-induced inflammation, hypoxia, pulmonary fibrosis, pulmonary hypertension, peritonitis (CAPD) associated with continuous emergency peritoneal dialysis (CAPD), granulocyte Ehrlich disease, sarcomatosis, Small airway disease, airway obstruction, disorders of ventilation and blood perfusion, wheezing, cold, gout, alcoholic liver disease, lupus, periodontitis, cancer signs, transplant reperfusion injury, early transplant rejection (eg, acute allograft) Graft rejection), airway hyperresponsiveness, allergic contact dermatitis, allergic rhinitis, non-allergic rhinitis, alopecia areata, autoimmune deafness (including, for example, Meniere's disease), autoimmune hemolytic syndrome Signs, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune pillitis, autoimmune thrombocytopenia, chronic inflammatory demyelinating polyneuropathy, liver cirrhosis, dermatomyositis, diabetes, Drug-induced autoimmunity, endometriosis, fibrotic diseases, gastritis, Goodpasture syndrome, Graves' disease, Gullain-Barre disease, Hashimoto's thyroiditis, hepatitis-related autoimmunity, HIV-related self Immune syndrome and blood diseases, hypophytis, interstitial cystitis, juvenile arthritis, Langerhans cell tissue cell proliferation, lichen planus, metal-induced autoimmunity, myocarditis (including viral Myocarditis), myositis, neuropathy (including, for example, IgA neuropathy, cell membrane neuropathy, and idiopathic neuropathy), nephritis syndrome, optic neuritis, pancreatitis, post-infection autoimmunity, primary cholecystectomy, reactivity Arthritis, ankylosing spondylitis, Wright's syndrome, reperfusion injury, scleritis, scleroderma, autoimmune disease secondary blood disorders (such as anemia), silicone implants Autoimmune diseases, Sjogren’s syndrome, systemic lupus erythematosus, transverse myelitis, tubulointerstitial nephritis, uveitis, and leukoplakia, the method includes administering an effective amount of At least one compound represented by formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or a pharmaceutically acceptable salt or solvate thereof.

"Effective amount" or "effective dose" of a compound of the present invention or a pharmaceutically acceptable composition refers to an effective amount to treat or reduce the severity of one or more of the disorders mentioned in the present invention. According to the method of the present invention, the compounds and compositions can be used in any amount and route of administration to effectively treat or reduce the severity of the disease. The exact amount necessary will vary according to the patient's condition, depending on race, age, general condition of the patient, feeling Severity of infection, special factors, mode of administration, etc. The compound or composition can be administered in combination with one or more other therapeutic agents, as discussed in the present invention.

General synthesis process

In general, the compounds of the present invention can be prepared by the method described in the present invention, unless otherwise specified, wherein the definition of the substituent is as formula (I), (II), (IIa), (IIb), (IIc) , (IId), (IIe) or (IIf). The following reaction schemes and examples are used to further illustrate the content of the present invention.

Those skilled in the art will recognize that the chemical reactions described in the present invention can be used to properly prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to the description of the present invention, or will The reaction conditions should be modified regularly. In addition, the reactions disclosed in the present invention or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

The embodiments described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents are purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by refluxing and drying sodium metal. Anhydrous dichloromethane and chloroform are obtained by refluxing calcium hydride and drying. Ethyl acetate, petroleum ether, n-hexane, N , N -dimethylacetamide and N , N -dimethylformamide were dried in advance using anhydrous sodium sulfate.

The following reaction is generally carried out under a positive pressure of nitrogen or argon or a dry tube on an anhydrous solvent (unless otherwise indicated), the reaction bottles are plugged with a suitable rubber stopper, and the substrate is injected through a syringe. Glassware is dried.

Chromatography column is a silica gel column. Silicone (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The test conditions for NMR hydrogen spectroscopy are: at room temperature, Bruker 400MHz or 600MHz NMR instrument, with CDCl ₃ , d ⁶ -DMSO, CD ₃ OD or d ⁶ -acetone as the solvent (reported in ppm units) ), using TMS (0ppm) or chloroform (7.26ppm) as a reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, Multiple peaks), br (broadened, broad peaks), dd (doublet of doublets, double doublets), dt (doublet of triplets, double triplets). Coupling constant, expressed in Hertz (Hz).

The conditions for the measurement of low-resolution mass spectrometry (MS) data are: Agilent 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30mm, 3.5μm, 6min, flow rate 0.6mL/min, mobile phase: 5%- 95% (proportion of CH ₃ CN with 0.1% formic acid) in (H ₂ O with 0.1% formic acid)), UV detection at 210/254 nm, electrospray ionization mode (ESI).

Compound purity is characterized by: Agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column model: NOVASEP, 50/80mm, DAC), at 210nm /254nm with UV detection.

The following abbreviations are used throughout the present invention:

Synthesis method one :

The target compound (11) can be prepared by the first synthesis method , wherein R ¹ , R ² , R ³ , R ⁵ , A, m and n have the meanings as described in the present invention. Compound (1) is condensed with methyl glycinate hydrochloride (2) to obtain compound (3) ; compound (3) is vulcanized by Lawesson's reagent to obtain compound (4) ; compound (4) in trimethyloxonium tetrafluoro A methylthio group is formed under the condition of boric acid to obtain compound (5) ; compound (5) is reacted with acetyl fluoride compound (6) to obtain compound (7) ; compound (7) is hydrolyzed to obtain compound (8) ; compound (8) and compound ( 9) The compound (10) is formed by the reaction; the compound (10) is deprotected to obtain the target compound (11) .

Synthetic method two :

The target compound (11) can be prepared by the second synthesis method , wherein R ¹ , R ² , R ³ , R ⁵ , A, m and n have the meanings as described in the present invention; R ^5x is R ⁵ -PG, as the case may be , PG is a protecting group for amine groups, or PG does not exist. Compound (8) and compound (9-a) react to form compound (10-a) ; compound (10-a) is deprotected to obtain target compound (11) .

Synthetic method three :

0，v

1，且w+v為1、2、3、4、5、6、7、8、9或10；R^5y為R^6y-C(=O)-、R^6y-C(=O)-亞烷基、R^6y-C(=O)-亞烷基-O-C(=O)-、R^6y-C(=O)-N(R^b)-、R^6y-C(=O)-N(R^b)-亞烷基、R^6y-C(=O)-亞烷基-N(R^b)-、R^6y-C(=O)-N(R^b)-C(=O)-或R^6y-C(=O)-N(R^b)-C(=O)-亞烷基；R^6y為烷氧基、鹵代烷氧基、羥基取代的烷氧基、羧基取代的烷氧基、烷氧基烷氧基、環烷基烷氧基、雜環基烷氧基、芳基烷氧基或雜芳基烷氧基；R^5z為HO-C(=O)-、HO-C(=O)-亞烷基、HO-C(=O)-亞烷基-O-C(=O)-、HO-C(=O)-N(R^b)-、HO-C(=O)-N(R^b)-亞烷基、HO-C(=O)-亞烷基-N(R^b)-、HO-C(=O)-N(R^b)-C(=O)-或HO-C(=O)-N(R^b)-C(=O)-亞烷基。化合物(8)和化合物(9-b)反應生成化合物(10-b)；化合物(10-b)在鹼性條件下經過一步或多步反應得到化合物(10-c)；化合物(10-c)脫保護得到目標化合物(11-a)。 The target compound (11-a) can be prepared by synthetic method three , wherein R ¹ , R ² , R ³ , R ⁵ , R ^b , A and m have the meanings as described in the present invention; w

0, v

1, and w+v is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R ^5y is R ^6y -C(=O)-, R ^6y -C(=O) ^-Asia Alkyl, R ^6y -C(=O)-alkylene-OC(=O)-, R ^6y -C(=O)-N(R ^b )-, R ^6y -C(=O)-N( R ^b )-alkylene, R ^6y -C(=O)-alkylene-N(R ^b )-, R ^6y -C(=O)-N(R ^b )-C(=O)- or R ^6y -C(=O)-N(R ^b )-C(=O)-alkylene; R ^6y is alkoxy, haloalkoxy, hydroxy substituted alkoxy, carboxy substituted alkoxy, Alkoxyalkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkoxy or heteroarylalkoxy; R ^5z is HO-C(=O)-, HO-C( =O)-alkylene, HO-C(=O)-alkylene-OC(=O)-, HO-C(=O)-N(R ^b )-, HO-C(=O)- N(R ^b )-alkylene, HO-C(=O)-alkylene-N(R ^b )-, HO-C(=O)-N(R ^b )-C(=O)- or HO-C(=O)-N(R ^b )-C(=O)-alkylene. Compound (8) and compound (9-b) react to form compound (10-b) ; compound (10-b) undergoes one or more steps under basic conditions to obtain compound (10-c) ; compound (10-c) ) Deprotection yields the target compound (11-a) .

Synthetic method four :

1，v

1，且u+v為2、3、4、5、6、7、8、9或10；R^5x是R⁵-PG，視情況，PG是胺基的保護基團，或PG不存在；R^5y為R^6y-C(=O)-、R^6y-C(=O)-亞烷基、R^6y-C(=O)-亞烷基-O-C(=O)-、R^6y-C(=O)-N(R^b)-、R^6y-C(=O)-N(R^b)-亞烷基、R^6y-C(=O)-亞烷基-N(R^b)-、R^6y-C(=O)-N(R^b)-C(=O)-或R^6y-C(=O)-N(R^b)-C(=O)-亞烷基；R^6y為烷氧基、鹵代烷氧基、羥基取代的烷氧基、羧基取代的烷氧基、烷氧基烷氧基、環烷基烷氧基、雜環基烷氧基、芳基烷氧基或雜芳基烷氧基；R^5z為HO-C(=O)-、HO-C(=O)-亞烷基、HO-C(=O)-亞烷基-O-C(=O)-、HO-C(=O)-N(R^b)-、HO-C(=O)-N(R^b)-亞烷基、HO-C(=O)-亞烷基-N(R^b)-、HO-C(=O)-N(R^b)-C(=O)-或HO-C(=O)-N(R^b)-C(=O)-亞烷基。化合物(8)和化合物(9-c)反應生成化合物(10-d)；化合物(10-d)在鹼性條件下經過一步或多步反應得到化合物(10-e)；化合物(10-e)脫保護得到目標化合物(11-b)。 The target compound (11-b) can be prepared by synthesis method 4 , wherein R ¹ , R ² , R ³ , R ⁵ , R ^b , A and m have the meanings as described in the present invention; u

1, v

1, and u+v is 2, 3, 4, 5, 6, 7, 8, 9 or 10; R ^5x is R ⁵ -PG, as the case may be, PG is a protective group of the amine group, or PG does not exist; R ^5y is R ^6y -C(=O)-, R ^6y -C(=O)-alkylene, R ^6y -C(=O)-alkylene-OC(=O)-, R ^6y -C (=O)-N(R ^b )-, R ^6y -C(=O)-N(R ^b )-alkylene, R ^6y -C(=O)-alkylene-N(R ^b )- , R ^6y -C(=O)-N(R ^b )-C(=O)- or R ^6y -C(=O)-N(R ^b )-C(=O)-alkylene; R ^6y Alkoxy, haloalkoxy, hydroxy substituted alkoxy, carboxy substituted alkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkoxy or Heteroarylalkoxy; R ^5z is HO-C(=O)-, HO-C(=O)-alkylene, HO-C(=O)-alkylene-OC(=O)-, HO-C(=O)-N(R ^b )-, HO-C(=O)-N(R ^b )-alkylene, HO-C(=O)-alkylene-N(R ^b ) -, HO-C(=O)-N(R ^b )-C(=O)- or HO-C(=O)-N(R ^b )-C(=O)-alkylene. Compound (8) and compound (9-c) react to form compound (10-d) ; compound (10-d) undergoes one or more steps under basic conditions to obtain compound (10-e) ; compound (10-e) ) Deprotection yields the target compound (11-b) .

Synthetic method five :

The target compound (12) can be prepared by synthetic method 5 , wherein R ¹ , R ² , R ³ and m have the meanings as described in the present invention; R ¹² is H, alkyl, haloalkyl, hydroxy substituted alkyl, Carboxy substituted alkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, R ^{12 is} optionally substituted with the substituent described in the present invention. The compound N- Boc-cis-4-hydroxy- L -proline methyl ester is reacted with 4-toluenesulfonyl chloride to obtain the compound (2 S ,4 S )-2-methoxycarbonyl-4-p-toluenesulfonamide Tert-Butyl oxypyrrolidine-1-carboxylate; compound (2 S ,4 S )-2-methoxycarbonyl-4-p-toluenesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester reacts with sodium azide To give compound (2 S ,4 R )-2-methoxycarbonyl-4-azidopyrrolidine-1-carboxylic acid tert-butyl ester; compound (2 S ,4 R )-2-methoxycarbonyl-4-azido Catalytic hydrogenation of tert-butyl pyrrolidine-1-carboxylate to give compound (2 S ,4 R )-2-methoxycarbonyl-4-aminopyrrolidine-1-carboxylic acid tert-butyl ester; compound (2 S ,4 R )-2-methoxycarbonyl-4-aminopyrrolidine-1-carboxylic acid tert-butyl ester under basic conditions to give the compound (2 S ,4 R )-2-methoxycarbonyl-4-(( Methoxycarbonyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester; compound (2 S ,4 R )-2-methoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine-1-carboxylic acid tert The butyl ester is hydrolyzed under basic conditions to give the compound (2 S ,4 R )-1-(tert-butoxycarbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid. Compound (2 S ,4 R )-1-(tert-butoxycarbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid reacts with R ¹² OH to give compound (12-1) ; compound (12-1) Deprotection yields compound (12-2) ; Compound (12-2) and compound (8) react to form compound (12-3) ; Compound (12-3) deprotection yields target compound (12) .

Synthetic method six :

The target compound (13) can be prepared by Synthesis Method 6 , wherein R ¹ , R ² , R ³ , R ^b , R ^c and m have the meanings as described in the present invention. Compound (2 S ,4 R )-1-(tert-butoxycarbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid reacts with NHR ^b R ^c to obtain compound (13-1) ; Compound (13-1) is deprotected to obtain compound (13-2) ; compound (13-2) and compound (8) are reacted to form compound (13-3) ; compound (13-3) is deprotected to obtain target compound (13) .

Examples Example 1: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-yl)(4-(cyclopropylcarbonyl)pyrazin-1-yl)methanone hydrochloride

Step 1: Synthesis of compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamide)acetate

Dissolve 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (3g, 11.63mmol), HOAT (2.374g, 17.44mmol) and EDCI (3.331g, 17.44mmol) in DCM (40mL), after stirring at room temperature for 30min, then add methyl glycinate hydrochloride (1.744g, 13.95mmol), slowly add DIPEA (8.1mL, 46.51mmol) dropwise in an ice bath, in the room Stirring was continued overnight at room temperature. After adding water (30 mL), it was extracted with CH ₂ Cl ₂ (25 mL×3). After the organic phases were combined, dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (leaching Washing agent: Petroleum ether/EtOAc (v/v)=2/1), to obtain 3.295 g of white solid, yield: 86.1%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.47(s,1H),7.29(dd, J ₁ =8.3Hz, J ₂ =1.9Hz,1H),7.18(d, J =8.3Hz,1H), 6.68 (t, J _FH = 75.0 Hz, 1H), 4.22 (d, J = 5.0 Hz, 2H), 3.92 (d, J = 7.0 Hz, 2H), 3.80 (s, 3H), 1.25-1.32 (m, 1H), 0.62-0.67 (m, 2H), 0.33-0.37 (m, 2H); MS-ESI: m/z 330.2 [M+H] ⁺ .

Step 2: Synthesis of compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenylthiomethylamide)acetate

Compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamide)acetate (3.295g, 10.02mmol) and Lawson's reagent (4.051g, 10.02mmol) ) Dissolve in THF (30mL), continue the reaction at 75°C for 2h, remove THF, add saturated NaHCO ₃ solution (30mL), and then extract with ethyl acetate (25mL×3), combine the organic phases, use anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 3.3195 g of a yellow solid in a yield of 96%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 8.07(s,1H),7.55(d, J =2.0Hz,1H),7.24(d, J =2.1Hz,1H),7.16(d, J =8.3 Hz, 1H), 6.68 (t, J _FH = 75.0Hz, 1H), 4.56 (d, J = 4.6Hz, 2H), 3.94 (d, J = 7.0Hz, 2H), 3.85 (s, 3H), 1.27 -1.32 (m, 1H), 0.65-0.67 (m, 2H), 0.36-0.38 (m, 2H); MS-ESI: m/z 346.2 [M+H] ⁺ .

Step 3: Synthesis of compound 2-(((3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(methylthio)methylene)amino)acetate

Under the condition of -78°C, the compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenylthiomethylamide) acetate (3.3195g, 9.62mmol) CH ₂ Cl ₂ (10mL) solution was slowly added dropwise to a solution of trimethyloxonium tetrafluoroborate (2.846mg, 19.24mmol) in CH ₂ Cl ₂ (10mL), at 0 ℃, after continuing the reaction for 3h, Saturated NaHCO ₃ solution (25 mL) was added to quench the reaction, and then extracted with DCM (25 mL×3), dried over anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 3.3222 g of yellow oily liquid, yield: 96.1%. MS-ESI: m/z 360.1 [M+H] ⁺ .

Step 4: Compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy ) Synthesis of phenyl)oxazole-4-carboxylic acid methyl ester

Dissolve N -tert-butoxycarbonyl- L -alanine (6.5g, 34.4mmol) and triethylamine (5.27mL, 37.83mmol) in dichloromethane (60mL) at -40°C to this solution was added dropwise cyanuric fluoride (5.62mL, 68.8mmol), the reaction at -10 ℃ 2h, washed, dried ice water (20mL × 5) the organic phase was dried over anhydrous Na ₂ SO _4, the solvent was removed to give 5.84g of white Solid: ( S )-(1-fluoro-1-oxoprop-2-yl)aminocarboxylic acid tert-butyl ester, yield: 89%.

At -78°C, a solution of potassium hexamethyldisilazide (1M, 32.39 mmol) in THF (32.4 mL) was slowly added dropwise to the compound 2-((((3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)(methylthio)methylene)amino)acetic acid methyl ester (3.3222g, 9.25mmol) and compound ( S )-(1-fluoro-1-oxo Propyl-2-yl)carbamic acid tert-butyl ester (2.651 g, 13.88 mmol) in THF (25 mL). After the reaction was continued for 1 h, H ₂ O (25 mL) was added to quench the reaction, followed by ethyl acetate ( 25mL×3) extraction, the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=5/1) to obtain 2.3944 g white solid, yield: 53.7%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.64(s,1H),7.62(d, J =8.4Hz,1H),7.23(d, J =8.3Hz,1H),6.70(t, J _FH = 75.0Hz, 1H), 5.43-5.47 (m, 1H), 3.98 (s, 3H), 3.96 (d, J = 7.0Hz, 2H), 1.54 (d, J = 7.0Hz, 3H), 1.43 (s, 9H), 1.27-1.29 (m, 1H), 0.65-0.68 (m, 2H), 0.36-0.39 (m, 2H); MS-ESI: m/z 483.1 [M+H] ⁺ .

Step 5: Compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy ) Synthesis of phenyl)oxazole-4-carboxylic acid

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene yl) oxazole-4-carboxylate (1.75g, 3.63mmol) was dissolved in THF (20mL) and H ₂ O (10mL) mixed solvent, was added lithium hydroxide monohydrate (762.4mg, 18.15mmol), the reaction at 40 ℃ 4h, removal of THF, and then HCl (1M) and the solution was adjusted to pH around 1, and extracted with ethyl acetate (25mL × 3), the combined organic phases were dried over anhydrous Na2SO _4, the solvent was removed 1.4509g of a yellow solid was obtained, yield: 87.9%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.80 (d, J =1.8 Hz, 1H), 7.66 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.29 (d, J = 8.3Hz, 1H), 6.90 (t, J _FH = 74.8Hz, 1H), 5.51 (m, 1H), 4.03 (d, J = 7.0Hz, 2H), 1.54 (d, J = 7.1Hz, 3H), 1.44 (s, 9H), 1.35-1.38 (m, 1H), 0.67-0.70 (m, 2H), 0.42-0.44 (m, 2H); MS-ESI: m/z 467.3 [MH] ^- .

Step 6: Compound ( S )-(1-(4-(4-(Cyclopropylcarbonyl)pyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of tert-butyl methoxy)phenyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (0.35g, 0.75mmol), compound cyclopropyl-pyrazin-1-yl-methyl ketone hydrochloride (185mg, 0.97mmol), 1-ethyl-3-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (214 mg, 1.12 mmol) and N -hydroxy-7-azabenzotriazole (135 mg, 1.12 mmol) were dissolved in dichloromethane (10 mL), To this solution was added N , N -diisopropylethylamine (0.52mL, 3.0mmol) dropwise at 0°C, stirred at room temperature for 4h, washed with water (10mL×3), and the organic phase was dried over anhydrous Na ₂ SO ₄ After removing the solvent, the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 280 mg of white solid in a yield of 62%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.60 (dd, J ₁ =8.3 Hz, J ₂ = 1.9 Hz, 1H), 7.56 (d, J =1.8 Hz, 1H), 7.26 (d, J =8.3 Hz, 1H), 6.72(t, J _FH = 75.0Hz, 1H), 5.24-5.28(m, 1H), 3.99(d, J =6.9Hz, 2H), 3.77-3.82(m, 6H), 1.57( d, J = 7.0Hz, 3H), 1.44(s, 9H), 1.30-1.37(m, 2H), 1.03-1.07(m, 2H), 0.83-0.85(m, 2H), 0.69-0.73(m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 605.2 [M+H] ⁺ .

Step 7: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4 -Yl)(4-(cyclopropylcarbonyl)pyrazin-1-yl)methanone hydrochloride

To the compound ( S )-(1-(4-(4-(cyclopropylcarbonyl)pyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Ethyl) phenyl) oxazol-5-yl) ethyl) aminocarboxylic acid tert-butyl ester (0.28g, 0.46mmol) in dichloromethane (1mL) was added HCl in ethyl acetate solution (4M, 8mL), After stirring at room temperature for 15 min, the solvent was removed to obtain 250 mg of white solid. Yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.75 (d, J =1.6 Hz, 1H), 7.73 (d, J =8.4 Hz, 1H), 7.33 (d, J =8.3 Hz, 1H), 6.93 (t, J _FH = 74.7Hz, 1H), 5.06-5.11(m, 1H), 4.30-4.20(m, 2H), 4.05(d, J = 6.9Hz, 2H), 3.76-3.95(m, 6H) , 1.80 (d, J = 7.0 Hz, 3H), 1.30-1.37 (m, 2H), 0.86-0.96 (m, 4H), 0.67-0.71 (m, 2H), 0.42-0.46 (m, 2H); MS -ESI: m/z 505.3 [M+H-HCl] ⁺ .

Example 2: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-yl)(4-(pyrimidin-2-yl)pyrazin-1-yl)methanone dihydrochloride

Step 1: Compound ( S )-(1-(2-(3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(pyrimidin-2-yl ) Synthesis of terazin-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (0.33g, 0.70mmol), 1-(3-pyrimidinyl)pyrazine (0.12mL, 0.85mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (202mg, 1.06mmol) and N -hydroxy-7-azabenzotriazole (144mg, 1.06mmol) were dissolved in dichloromethane (10mL), stirred at 0 °C for 30min, then dropped was added N, N - diisopropylethylamine (0.37 mL, 2.11 mmol), stirred for 17H at room temperature, add water (10mL × 3), dried the organic phase with Na ₂ SO _4, the solvent was removed by column chromatography, concentrate Separation (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 260 mg of white solid in a yield of 60%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 8.36 (d, J = 4.7 Hz, 2H), 7.61 (dd, J ₁ = 8.3 Hz, J ₂ = 1.9 Hz, 1 H), 7.57 (d, J = 1.8 Hz, 1H), 7.26 (d, J = 8.3Hz, 1H), 6.72 (t, J _FH = 75.1Hz, 1H), 6.58 (t, J = 4.7Hz, 1H), 5.24-5.32 (m, 1H) , 3.88-4.15 (m, 8H), 3.99 (d, J = 6.9Hz, 2H), 1.58 (d, J = 7.0Hz, 3H), 1.42 (s, 9H), 1.32-1.36 (m, 1H), 0.68-0.73 (m, 2H), 0.41-0.45 (m, 2H).

Step 2: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4 -Yl)(4-(pyrimidin-2-yl)pyrazin-1-yl)methanone dihydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(pyrimidin-2-yl)Xia Aziridine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (0.26g, 0.42mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 8mL) After stirring at room temperature for 30 min, the solvent was removed to obtain 200 mg of white solid. Yield: 86%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.68 (d, J = 5.2 Hz, 2H), 7.78 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.2Hz, 1H), 7.08 (t, J = 5.1Hz, 1H), 6.93 (t, J _FH = 74.8Hz, 1H), 5.11-5.13 (m, 1H), 4.46 (s, 2H), 4.06 (d , J = 6.9Hz, 2H), 4.01-4.14 (m, 6H), 1.82 (d, J = 6.8Hz, 3H), 1.32-1.36 (m, 1H), 0.67-0.70 (m, 2H), 0.43- 0.47 (m, 2H); MS-ESI: m/z 515.3 [M+H-2HCl] ⁺ .

Example 3: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-yl)(4-pyridylmethylpyrazine-1-yl)methanone dihydrochloride

Step 1: Synthesis of compound N- (2'-pyridinecarboxamide)pyrazine hydrochloride

Combine 2-picolinic acid (2g, 16.25mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (4.65g, 24.37mmol) and N -hydroxy-7-nitrogen Heterobenzotriazole (3.31g, 24.37mmol) was dissolved in dichloromethane (30mL), stirred at room temperature for 40min, added N- Bocpyrazine (3.63g, 19.5mmol), stirred at 0°C for 30min, added dropwise N , N -diisopropylethylamine (8.5mL, 48.74mmol), stirred at room temperature for 14h, washed with water (20mL×3) after stopping the reaction, the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated by column chromatography (leaching Washing agent: Petroleum ether/EtOAc (v/v)=1/2), to obtain 3.92 g of a yellow solid: compound N- (2'-pyridinecarboxamide) -N- Bocpyrazine, yield: 83%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.60 (d, J =4.5 Hz, 1H), 7.83 (td, J ₁ =7.7 Hz, J ₂ =1.7 Hz, 1H), 7.69 (d, J =7.8Hz,1H),7.36-7.39(m,1H),3.78-3.79(m,2H),3.56-3.62(m,4H),3.47-3.49(m,2H),1.49(s,9H); MS-ESI: m/z 292.3 [M+H] ⁺ .

To a solution of the compound N- (2'-pyridinecarboxamide) -N- Bocpyrazine (3.9g, 13.4mmol) in dichloromethane (10mL) was added a solution of HCl in ethyl acetate (4M, 15mL) at room temperature After stirring for 2h, the reaction was stopped, and the solvent was removed to obtain 3g of a white solid: compound N- (2'-pyridinecarboxamide)pyrazine hydrochloride, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.27 (d, J = 5.2 Hz, 1H), 6.83 (t, J = 7.9 Hz, 1H), 6.49 (d, J = 7.2 Hz, 1H) , 6.33-6.36 (m, 1H), 2.37-2.49 (m, 4H), 1.80-1.85 (m, 4H); MS-ESI: m/z 192.2 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-pyridinecarboxamide) Synthesis of tert-butyl -1-carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (0.3g, 0.64mmol), compound N- (2'-pyridinecarboxamido)pyrazine hydrochloride (175mg, 0.77mmol), 1-ethyl-3-(3- Dimethylaminopropyl) carbodiimide hydrochloride (183mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (131mg, 0.96mmol) were dissolved in dichloromethane (10mL), 0 ℃ stirred for 30min, added dropwise N, N - diisopropylethylamine (0.45mL, 2.56mmol), stirred for 14H at room temperature, add water (10mL × 3), dried the organic phase with Na ₂ SO _4, the solvent was removed and concentrated The liquid was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/2) to obtain 180 mg of white viscous material, yield: 44%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.66 (br.s, 1H), 7.91 (br.s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.58 (m, 2H), 7.45 (m, 1H), 7.26 (m, 1H), 6.72 (t, J _FH = 75.0Hz, 1H), 5.94 (br.s, 1H), 5.20-5.26 (m, 1H), 3.68- 3.99(m, 8H), 1.57(d, J = 7.0Hz, 3H), 1.44(s, 9H), 1.29-1.30(m, 1H), 0.70-0.71(m, 2H), 0.40-0.43(m, 2H).

Step 3: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4 -Yl)(4-pyridylmethylpyrazine-1-yl)methanone dihydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-pyridylmethylpyrazine-1 -Carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (120mg, 0.20mmol) in dichloromethane (1mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature After 20 min, the solvent was removed to obtain 150 mg of light yellow solid. Yield: 93%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.82 (s, 1H), 8.39 (t, J = 7.5 Hz, 1H), 8.00-8.02 (br.s, 1H), 7.89 (br.s ,1H),7.73-7.76(m,2H),7.32(br.s,1H),6.91(t, J _FH =74.7Hz,1H),5.08-5.10(m,1H),4.30-4.36(m, 2H), 3.67-4.13 (m, 8H), 1.80 (d, J = 7.2Hz, 3H), 1.20-1.28 (m, 1H), 0.67-0.69 (m, 2H), 0.39-0.43 (m, 2H) ; MS-ESI: m/z 542.2 [M+H-2HCl] ⁺ .

Example 4: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of azole-4-carbonyl)- N , N -dimethyl-1-pyrazinesulfonamide hydrochloride

Step 1: Synthesis of compound N , N -dimethyl-1-pyrazinesulfonamide hydrochloride

N- Boc pyrazine (1g, 5.36mmol) was dissolved in dichloromethane (19mL), and at 0°C, dimethylaminosulfonyl chloride (1.15g, 8.05mmol) and triethylamine (1.5 mL, 10.73 mmol), stirred at room temperature for 4 h, washed with water (15 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , and the concentrated liquid was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 3/1) to obtain 1.4 g of white solid: 4-( N , N -dimethylsulfonyl)pyrazine-1-carboxylic acid tert-butyl ester, yield: 89%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 3.50 (t, J =5.1 Hz, 4H), 3.22 (t, J =5.1 Hz, 4H), 2.86 (s, 6H), 1.49 (s, 9H ).

To a solution of the compound 4-( N , N -dimethylsulfonyl)pyrazine-1-carboxylic acid tert-butyl ester (1.3g, 4.4mmol) in dichloromethane (3mL) was added HCl in ethyl acetate (4M , 5mL), stirred at room temperature for 3h, the solvent was removed, to obtain 1g of white solid: compound N , N- dimethyl-1-pyrazinesulfonamide hydrochloride, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 3.50 (t, J = 5.2 Hz, 4H), 3.32-3.34 (m, 4H), 2.88 (s, 6H); MS-ESI: m/z 194.2[M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-( N , N -di Synthesis of methylsulfonyl)pyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (0.3g, 0.64mmol), compound N , N -dimethyl-1-pyrazinesulfonamide hydrochloride (176mg, 0.77mmol), 1-ethyl-3-( 3-Dimethylaminopropyl)carbodiimide hydrochloride (184mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (131mg, 0.96mmol) were dissolved in dichloromethane (10mL) , Stirred at 0°C for 30min, added N , N -diisopropylethylamine (0.45mL, 2.6mmol) dropwise, stirred at room temperature for 14h, washed with water (10mL×3), the organic phase was dried over Na ₂ SO ₄ and the solvent was removed The concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 186 mg of white solid in a yield of 44%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.59 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.55 (d, J =1.7 Hz, 1H), 7.26 (d, J =8.3Hz,1H),6.72(t, J _FH =75.0Hz,1H),5.22-5.25(m,1H),4.06-4.15(m,2H),3.99(d, J =6.9Hz,2H), 3.80-3.90(m, 2H), 3.37-3.38(m, 4H), 2.88(s, 6H), 1.56(d, J = 7.0Hz, 3H), 1.44(s, 9H), 1.33-1.37(m, 1H), 0.69-0.73 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 644.4 [M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole -4-Carbonyl) -N , N -dimethyl-1-pyrazinesulfonamide hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-( N , N -dimethyl Sulfonyl)pyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (186 mg, 0.29 mmol) in dichloromethane (1 mL) was added HCl in ethyl acetate solution ( 4M, 3mL), stirred at room temperature for 20min, the solvent was removed to obtain 150mg white solid, yield: 87%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.75 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.91 (t, J _FH = 74.7Hz, 1H), 5.04-5.09 (m, 1H), 4.23-4.27 (m, 2H), 4.05 (d, J = 6.8Hz, 2H), 3.84-3.87 (m, 2H), 3.37- 3.41 (m, 4H), 2.87 (s, 6H), 1.80 (d, J = 6.8Hz, 3H), 1.32-1.35 (m, 1H), 0.66-0.71 (m, 2H), 0.43-0.45 (m, 2H); MS-ESI: m/z 544.2 [M+H-HCl] ⁺ .

Example 5: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-yl)(4-(cyclopropylsulfonyl)pyrazazin-1-yl)methanone hydrochloride

Step 1: Synthesis of compound 1-(cyclopropylsulfonyl)pyrazine hydrochloride

Combine cyclopropanesulfonic acid (2g, 16.38mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (4.7g, 24.56mmol) and N -hydroxy-7-nitrogen Heterobenzotriazole (3.4g, 24.56mmol) was dissolved in dichloromethane (25mL), stirred at room temperature for 20min, N- Boc pyrazine (3.7g, 19.65mmol) was added, N was added dropwise at 0°C , N -diisopropylethylamine (8.6mL, 49.12mmol), stirred at room temperature for 15h, washed with water (15mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and the concentrated solution was subjected to column chromatography (elution Agent: Petroleum ether/EtOAc (v/v)=2/1), to obtain 4.7g white solid: N- Boc- N -cyclopropylsulfonylpyrazine, yield: 97%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.51 (t, J =5.1 Hz, 4H), 4.24 (t, J =5.0 Hz, 4H), 3.21-3.25 (m, 1H), 2.46 (s, 9H ), 2.14-2.18 (m, 2H), 1.96-2.00 (m, 2H).

To a solution of the compound N- Boc- N -cyclopropylsulfonylpyrazine (4.75g, 16.4mmol) in dichloromethane (5mL) was added an ethyl acetate solution of HCl (4M, 10mL) and stirred at room temperature for 12h, Removal of the solvent gave 3.6 g of white solid, yield: 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 3.29 (t, J = 4.8 Hz, 4H), 2.96 (t, J = 4.9 Hz, 4H), 2.25-2.29 (m, 1H), 1.17-1.19( m, 2H), 0.98-1.01 (m, 2H); MS-ESI: m/z 191.1 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(cyclopropylsulfonamide ))-Pyrazin-1-carbonyl)oxazol-5-yl)ethyl)tert-butylaminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropanylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (0.3g, 0.64mmol), compound 1-(cyclopropylsulfonyl)pyrazine hydrochloride (110mg, 0.64mmol), 1-ethyl-3-(3-di (Methylaminopropyl) carbodiimide hydrochloride (154mg, 0.80mmol) and N -hydroxy-7-azabenzotriazole (110mg, 0.80mmol) were dissolved in dichloromethane (10mL), 0 ℃ stirred for 30min, added dropwise N, N - diisopropylethylamine (0.28 mL, 1.60 mmol), stirred for 14H at room temperature, add water (10mL × 3), dried the organic phase with Na ₂ SO _4, the solvent was removed, concentrate Column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) was performed to obtain 190 mg of white solid in a yield of 56%.

¹ H NMR (600 MHz, CDCl ₃ ): δ (ppm) 7.59 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.55 (d, J =1.7 Hz, 1H), 7.26 (d, J =8.3Hz,1H),6.72(t, J _FH =75.0Hz,1H),5.84(br.s,1H),5.24-5.26(m,1H),4.11-4.15(m,2H),3.98(d , J = 6.9Hz, 2H), 3.41-3.47 (m, 4H), 3.39 (s, 2H), 2.29-2.32 (m, 1H), 1.56 (d, J = 7.1Hz, 3H), 1.43 (s, 9H), 1.33-1.37 (m, 1H), 1.20-1.22 (m, 2H), 1.00-1.05 (m, 2H), 0.69-0.72 (m, 2H), 0.41-0.44 (m, 2H); MS- ESI: m/z 641.2[M+H] ⁺ .

Step 3: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4 -Yl)(4-(cyclopropylsulfonyl)pyrazin-1-yl)methanone hydrochloride

Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(cyclopropylsulfonyl)) To a solution of tert-butyl ester of pyrazin-1-carbonyl)oxazol-5-yl)ethyl)carbamate (155 mg, 0.24 mmol) in dichloromethane (1 mL) was added a solution of HCl in ethyl acetate (4M, 2 mL) After stirring at room temperature for 40 min, the solvent was removed to obtain 130 mg of white solid. Yield: 93%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH =74.6Hz,1H),5.05-5.08(m,1H),4.27(br.s,2H),4.04(d, J =6.9Hz,2H),3.87-3.89(m,2H),3.45-3.47( m, 4H), 2.56-2.57 (m, 1H), 1.79 (d, J = 6.8Hz, 3H), 1.33-1.35 (m, 1H), 1.08-1.10 (m, 4H), 0.67-0.71 (m, 2H), 0.43-0.45 (m, 2H); MS-ESI: m/z 541.9 [M+H-HCl] ⁺ .

Example 6: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-yl)(4-(4-pyridylmethyl)pyrazin-1-yl)methanone trihydrochloride

Step 1: Compound ( S )-(1-(2-(3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(4-pyridylmethyl ) Synthesis of terazin-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (0.25g, 0.53mmol), 1-(4-pyridylmethyl)pyrazine (114mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (153mg, 0.80mmol) and N -hydroxy-7-azabenzotriazole (109mg, 0.80mmol) were dissolved in dichloromethane (10mL), at 0 ℃, to this N , N -diisopropylethylamine (0.28mL, 0.60mmol) was added dropwise to the solution, stirred at room temperature for 5h, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: EtOAc/MeOH (v/v) = 20/1), 220 mg of white solid was obtained, yield: 65%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 8.60 (d, J = 4.2 Hz, 2H), 7.58 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J = 4.2 Hz, 2H), 7.24 (d, J = 8.3Hz, 1H), 6.71 (t, J _FH = 75.0Hz, 1H), 6.00 (br.s, 1H), 5.22-5.26 (m, 1H), 3.97 ( d, J = 6.9Hz, 2H), 4.06-4.01(m, 2H), 3.65(s, 2H), 3.93-3.94(m, 1H), 3.80-3.84(m, 1H), 2.61-2.65(m, 4H), 1.56 (d, J = 7.0Hz, 3H), 1.45 (s, 9H), 1.32-1.37 (m, 1H), 0.69-0.72 (m, 2H), 0.40-0.43 (m, 2H); MS -ESI: m/z 628.3[M+H] ⁺ .

Step 2: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4 -Yl)(4-(4-pyridylmethyl)pyrazin-1-yl)methanone trihydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(4-pyridylmethyl)Xia Aziridine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (0.22g, 0.35mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 3mL) , Stir at room temperature for 0.5h, remove the solvent to obtain 190mg white solid, yield: 96%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.95 (d, J = 3.6 Hz, 2H), 8.33 (d, J = 5.1 Hz, 2H), 7.75 (s, 1H), 7.72 (d, J = 6.4Hz, 1H), 7.33(d, J =8.1Hz, 1H), 6.92(t, J _FH =74.8Hz, 1H), 5.12-5.14(m, 1H), 4.62(s, 2H), 4.08-4.16 (m,1H), 4.04 (d, J = 6.8Hz, 2H), 3.41-3.45 (m, 4H), 1.80 (d, J = 6.8Hz, 3H), 1.32-1.35 (m, 1H), 0.68- 0.70 (m, 2H), 0.43-0.44 (m, 2H); MS-ESI: m/z 528.3 [M+H-3HCl] ⁺ .

Example 7: Compound ( S )-1-(4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carbonyl)pyrazin-1-yl)-2-cyclopropylethanone hydrochloride

Step 1: Synthesis of compound 2-cyclopropyl-1-(1-pyrazinyl)ethanone hydrochloride

Combine N- Boc-pyrazine (1g, 5.37mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.54g, 8.05mmol) and N -hydroxy-7 -Azabenzotriazole (1.09g, 8.05mmol), cyclopropionic acid (0.65g, 6.44mmol) was dissolved in dichloromethane (25mL), stirred at room temperature for 20min, at 0 ℃, N was added dropwise, N -diisopropylethylamine (2.8mL, 16.10mmol), stirred at room temperature for 4h, washed with water (15mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and the concentrated solution was subjected to column chromatography (eluent : Petroleum ether/EtOAc (v/v) = 2/1) to obtain 1.01 g of white solid: 4-(2-cyclopropylacetyl)pyrazine-1-carboxylic acid tert-butyl ester, yield: 70%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 3.61-3.63 (m, 2H), 3.43-3.45 (m, 6H), 2.30 (d, J = 6.8 Hz, 2H), 1.49 (s, 9H), 1.04 -1.07 (m, 1H), 0.58-0.61 (m, 2H), 0.18-0.21 (m, 2H).

To a solution of the compound 4-(2-cyclopropylacetyl)pyrazine-1-carboxylic acid tert-butyl ester (1.01 g, 3.76 mmol) in dichloromethane (10 mL) was added a solution of HCl in ethyl acetate (4M, 6 mL ), stirred at room temperature for 2h, and removed the solvent to obtain 0.77g of colorless viscous material: 2-cyclopropyl-1-(1-呱 Azido) ethyl ketone hydrochloride, yield: 100%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 3.72-3.74 (m, 4H), 3.12-3.16 (m, 4H), 2.28 (d, J = 6.8 Hz, 2H), 0.90-0.91 (m, 1H ), 0.44-0.47 (m, 2H), 0.08-0.10 (m, 2H); MS-ESI: m/z 169.2 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(4-(4-(2-Cyclopropylacetoxy)pyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound 2-cyclopropyl-1-(1-pyrazinyl)ethanone hydrochloride (160 mg, 0.77 mmol), 1-ethyl-3- (3-Dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) and N -hydroxy-7-azabenzotriazole (130 mg, 0.96 mmol) were dissolved in methylene chloride (15 mL) Medium, stirred at room temperature for 30min, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise at 0°C, stirred at room temperature for 5h, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1), 300 mg of colorless viscous material was obtained, yield: 75%.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.59 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.55 (s, 1H), 7.26 (d, J =8.3 Hz, 1H ), 6.72 (t, J _FH = 75.0 Hz, 1H), 5.23-5.27 (m, 1H), 3.98 (d, J = 6.9 Hz, 2H), 3.76-3.95 (m, 6H), 3.55-3.59 (m , 2H), 2.32-2.34 (m, 2H), 1.56 (d, J = 7.0Hz, 3H), 1.43 (s, 9H), 1.32-1.36 (m, 1H), 1.05-1.09 (m, 1H), 0.68-0.73(m, 2H), 0.60-0.62(m, 2H), 0.40-0.44(m, 2H), 0.21-0.22(m, 2H); MS-ESI: m/z 619.3[M+H] ⁺ .

Step 3: Compound ( S )-1-(4-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Synthesis of oxazole-4-carbonyl)pyrazin-1-yl)-2-cyclopropylethanone hydrochloride

To the compound ( S )-(1-(4-(4-(2-cyclopropylethynyl)pyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (290mg, 0.47mmol) in dichloromethane (3mL) was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 2h, the solvent was removed to obtain 260mg white solid, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.75 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 6.92 (t, J _FH =74.7Hz,1H),5.06-5.08(m,1H),4.20-4.25(m,2H),4.04(d, J =6.9Hz,2H),3.73-3.84(m,6H),2.42(d, J = 5.7Hz, 2H), 1.79 (d, J = 6.6Hz, 3H), 0.67-0.71 (m, 2H), 0.57-0.59 (m, 2H), 0.42-0.46 (m, 2H), 0.23-0.24 (m, 2H); MS-ESI: m/z 519.2 [M+H-HCl] ⁺ .

Example 8: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-yl)(4-methylpyrazin-1-yl)methanone dihydrochloride

Step 1: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-methylpyrazine-1 -Synthesis of carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-methylpyrazine (0.09mL, 0.77mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Hydrochloride (184mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (217mg, 1.60mmol) were dissolved in dichloromethane (15mL), and N was added dropwise to this solution at 0°C , N -diisopropylethylamine (0.45mL, 2.56mmol), stirred at room temperature for 20h, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v) = 30/1) , To obtain 275mg colorless oil, yield: 78%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.60 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.56 (d, J =1.9 Hz, 1H), 7.25 (d, J =8.3 Hz, 1H), 6.72 (t, J _FH = 75.1Hz, 1H), 5.21-5.25 (m, 1H), 3.99 (d, J = 6.9Hz, 2H), 3.93-4.02 (m, 2H), 3.78- 3.82 (m, 2H), 2.51-2.53 (m, 2H), 2.47-2.49 (m, 2H), 2.36 (s, 3H), 1.56 (d, J = 7.0Hz, 3H), 1.45 (s, 9H) , 1.33-1.36 (m, 1H), 0.68-0.73 (m, 2H), 0.40-0.44 (m, 2H); MS-ESI: m/z 551.3 [M+H] ⁺ .

Step 2: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4 -Yl)(4-methylpyrazin-1-yl)methanone dihydrochloride

Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-methylpyrazine-1-carbonyl ) Oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (0.26g, 0.47mmol) in dichloromethane (4mL) was added HCl in ethyl acetate solution (4M, 3mL), stirred at room temperature for 50min , Remove the solvent to obtain 233mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.76 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.93 (t, J _FH =74.7Hz,1H),5.39(br.s,1H),5.12-5.14(m,1H),4.80-4.84(m,1H),4.05(d, J =6.9Hz,2H),3.74-3.78( m,1H),3.62-3.66(m,2H),3.36-3.38(m,1H),3.24-3.30(m,1H),3.00(s,3H),1.80(d, J =6.9Hz,3H) , 1.33-1.37 (m, 1H), 0.68-0.71 (m, 2H), 0.43-0.46 (m, 2H); MS-ESI: m/z 451.2 [M+H-2HCl] ⁺ .

Example 9: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-yl)(pentazin-1-yl) ketone dihydrochloride

Step 1: Compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of tert-butyl oxy)phenyl)oxazole-4-carbonyl)pyrazine-1-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (0.3g, 0.64mmol), N- Boc pyrazine (143mg, 0.77mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride Salt (184mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (217mg, 1.60mmol) were dissolved in dichloromethane (15mL), N , N was added dropwise to this solution at 0℃ -Diisopropylethylamine (0.45mL, 2.56mmol), stirred at room temperature for 17h, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 3/1), 397 mg of white solid was obtained, yield: 97%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.59 (dd, J ₁ =8.3 Hz, J ₂ =1.7 Hz, 1H), 7.56 (d, J =1.6 Hz, 1H), 7.26 (d, J =8.3 Hz, 1H), 6.72 (t, J _FH = 75.0Hz, 1H), 5.98 (br.s, 1H), 5.21-5.26 (m, 1H), 3.98 (d, J = 7.0Hz, 2H), 3.94 3.97 (m, 1H), 3.87-3.90 (m, 1H), 3.72-3.78 (m, 2H), 3.54-3.58 (m, 4H), 1.56 (d, J = 7.0Hz, 3H), 1.50 (s, 9H), 1.44 (s, 9H), 1.33-1.35 (m, 1H), 0.69-0.72 (m, 2H), 0.41-0.44 (m, 2H); MS-ESI: m/z 637.3 [M+H] ⁺ .

Step 2: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4 -Yl) (pentazin-1-yl) ketone dihydrochloride

To the compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)pyrazine-1-carboxylic acid tert-butyl ester (0.40g, 0.63mmol) in dichloromethane (6mL) was added HCl in ethyl acetate solution (4M, 5mL), room Stir at a warm temperature for 40 min and remove the solvent to obtain 319 mg of white solid. Yield: 99%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.76(s,1H),7.73(dd, J ₁ =8.4Hz, J ₂ =1.4Hz,1H),7.33(d, J =8.3Hz,1H) ,6.93(t, J _FH =74.7Hz,1H),5.12-5.14(m,1H),4.52-4.55(m,2H),4.05(d, J =6.8Hz,2H),4.05-4.07(m, 2H), 3.41-3.44 (m, 4H), 1.80 (d, J = 6.8Hz, 3H), 1.34-1.36 (m, 1H), 0.67-0.70 (m, 2H), 0.43-0.46 (m, 2H) ; MS-ESI: m/z 437.3 [M+H-2HCl] ⁺ .

Example 10: Compound 1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazole-4-carbonyl)pyrazine-2-carboxylic acid methyl ester dihydrochloride

Step 1: Compound 1-tert-butoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) Synthesis of methyl-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrazine-3-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (0.6g, 1.28mmol), methyl 1-Boc-3-pyrazinecarboxylate (376mg, 1.54mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (368mg, 1.92mmol) and N -hydroxy-7-azabenzotriazole (435mg, 3.20mmol) were dissolved in dichloromethane (20mL), and the solution was added at 0℃ N , N -diisopropylethylamine (0.89mL, 5.12mmol) was added dropwise, stirred at room temperature for 6h, washed with saturated sodium chloride solution (15mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , The solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=4/1) to obtain 714 mg of a white solid in a yield of 80%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (s, 1H), 7.52-7.54 (m, 1H), 7.24-7.27 (m, 1H), 6.72 (t, J _FH = 75.0 Hz, 1H), 5.21-5.28 (m, 1H), 4.60-4.68 (m, 2H), 3.99 (d, J = 6.9Hz, 2H), 3.81 (s, 3H), 3.24-3.29 (m, 1H), 3.00-3.10 ( m,1H),1.52-1.57(m,3H),1.49(s,9H),1.44(s,9H),1.32-1.37(m,1H),0.68-0.73(m,2H),0.42-0.44( m, 2H); MS-ESI: m/z 695.3 [M+H] ⁺ .

Step 2: Compound 1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of methyl-4-carbonyl)pyrazine-2-carboxylate dihydrochloride

To compound 1-tert-butoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrazine-3-carboxylic acid methyl ester (0.21 g, 0.30 mmol) in methylene chloride (4 mL) was added HCl in ethyl acetate ( 4M, 3mL), stirred at room temperature for 40min, the solvent was removed to obtain 170mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.73-7.78 (m, 1H), 7.67-7.72 (m, 1H), 7.34 (t, J = 6.7Hz, 1H), 6.93 (t, J _FH = 74.7Hz, 1H), 5.13-5.18(m, 1H), 4.01-4.12(m, 3H), 3.91(s, 3H), 3.61-3.70(m, 1H), 3.38-3.55(m, 2H), 3.28 -3.33(m,1H),1.80(t, J =6.7Hz,3H),1.32-1.36(m,1H),0.69-0.70(m,2H),0.42-0.45(m,2H); MS-ESI : M/z 495.2 [M+H-2HCl] ⁺ .

Example 11: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazole-4-carbonyl)pyrazine-2-carboxylic acid methyl ester dihydrochloride

Step 1: Compound 1-tert-butoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) Synthesis of methyl-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrazine-2-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (0.25g, 0.53mmol), methyl 1-Boc-2-pyrazinecarboxylate (157mg, 0.64mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (153mg, 0.80mmol) and N -hydroxy-7-azabenzotriazole (181mg, 1.33mmol) were dissolved in dichloromethane (20mL), and the solution was added at 0℃ N , N -diisopropylethylamine (0.37mL, 2.13mmol) was added dropwise, stirred at room temperature for 5h, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 3/1) to obtain 260 mg of colorless viscous material, yield: 70%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.55-7.62 (m, 2H), 7.26 (d, J = 8.4 Hz, 1H), 6.72 (t, J _FH = 75.1 Hz, 1H), 5.25-5.29 ( m, 1H), 3.97-4.01(m, 3H), 3.79(br.s, 1H), 3.58-3.63(m, 2H), 1.50-1.52(m, 3H), 1.48(s, 9H), 1.45( s, 9H), 1.32-1.35 (m, 1H), 0.68-0.73 (m, 2H), 0.42-0.44 (m, 2H); MS-ESI: m/z 695.3 [M+H] ⁺ .

Step 2: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of methyl-4-carbonyl)pyrazine-2-carboxylate dihydrochloride

To compound 1-tert-butoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrazine-2-carboxylic acid methyl ester (0.26g, 0.37mmol) in dichloromethane (6mL) was added HCl in ethyl acetate solution ( 4M, 5mL), stirred at room temperature for 50min, the solvent was removed to obtain 212mg white solid, yield: 99%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.81(s, 1H), 7.72-7.75(m, 1H), 7.32-7.34(m, 1H), 6.93(t, J _FH = 74.7Hz, 1H) ,5.14-5.16(m,1H),4.63-4.69(m,1H),4.05(d, J =6.8Hz, 2H),3.89-3.94(m,3H),3.61-3.64(m,1H),3.40 -3.54(m,1H), 1.80(d, J =6.8Hz,3H),1.37-1.42(m,1H),0.67-0.72(m,2H),0.43-0.46(m,2H); MS-ESI : M/z 495.2 [M+H-2HCl] ⁺ .

Example 12: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazole-4-carbonyl)pyrazine-1,3-dicarboxylic acid methyl ester hydrochloride

Step 1: Synthesis of the compound methylpyrazine-1,3-dicarboxylic acid methyl ester hydrochloride

Under 25 ℃, to N 'N - (6mL) was added dropwise a solution of 1-Boc-2- carboxylic acid methyl piperazine carbonyl diimidazole (205mg, 1.23mmol) and triethylamine (0.26mL, 1.84mmol) in anhydrous DMF Ester (250mg, 1.02mmol) in anhydrous DMF (10mL), react at 60℃ for 30min, add anhydrous methanol (10mL), react at 60℃ for 21h, remove the solvent, add saturated sodium chloride solution (10mL×3) to wash, ethyl acetate The ester (15 mL×2) was extracted, and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=4/1) , To obtain 194mg colorless oil: 1-tert-butoxycarbonyl-pyrazine-2,4-dicarboxylic acid methyl ester, yield: 62%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.59-4.78 (m, 2H), 3.81-4.03 (m, 2H), 3.76 (s, 3H), 3.72 (m, 1H), 2.90-3.17 (m, 3H), 1.49 (s, 9H); MS-ESI: m/z 203.2 [M+H-100] ⁺ .

To a solution of compound 1-tert-butoxycarbonylpyrazine-2,4-dicarboxylic acid methyl ester (0.18 g, 0.61 mmol) in methylene chloride (6 mL) was added HCl in ethyl acetate (4M, 3 mL) at room temperature After stirring for 1 h, the solvent was removed to obtain 146 mg of a white solid: the compound methylpyrazine-1,3-dicarboxylic acid methyl ester hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.30-4.40 (m, 2H), 4.05-4.10 (m, 1H), 3.91 (s, 3H), 3.77 (m, 1H), 3.40-3.54 (m , 3H), 3.18-3.24 (m, 1H).

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of methyloxy)phenyl)oxazole-4-carbonyl)pyrazine-1,3-dicarboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (0.25g, 0.53mmol), compound methylpyrazine-1,3-dicarboxylic acid methyl ester hydrochloride (150mg, 0.64mmol), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (153mg, 0.80mmol) and N -hydroxy-7-azabenzotriazole (181mg, 1.33mmol) were dissolved in dichloromethane (20mL) at 0℃ To this solution, N , N -diisopropylethylamine (0.37mL, 2.13mmol) was added dropwise, stirred at room temperature for 17h, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc ( v/v)=2/1), 260 mg of yellow viscous material was obtained, yield: 74%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.56-7.62(m,1H),7.52-7.54(m,1H),7.24-7.27(m,1H),6.72(t, J _FH =75.0Hz,1H ), 5.25-5.29 (m, 1H), 4.01-4.68 (m, 3H), 3.99 (dd, J ₁ = 6.9Hz, J ₂ = 3.0Hz, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.30-3.35 (m, 3H), 1.53-1.57 (m, 3H), 1.44 (s, 9H), 1.32-1.37 (m, 1H), 0.69-0.73 (m, 2H), 0.42-0.44 ( m, 2H); MS-ESI: m/z 653.2 [M+H] ⁺ .

Step 3: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of methyl-4-carbonyl)pyrazine-1,3-dicarboxylate hydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)methylazine-1,3-dicarboxylate (0.25g, 0.39mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 3mL) , Stir at room temperature for 1.5h, remove the solvent to obtain 211mg white solid, yield: 93%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.72-7.77 (m, 1H), 7.63-7.71 (m, 1H), 7.32-7.34 (m 1H), 6.80-7.05 (m, 1H), 5.05- 5.14 (m, 1H), 4.90-4.95 (m, 1H), 4.61-4.65 (m, 1H), 4.40-4.43, 3.40-3.44 (m, m, 0.5H, 1.5H), 4.06-4.10 (m, 1H), 4.04-4.08 (m, 2H), 3.81-3.82 (m, 3H), 3.74 (s, 3H), 3.17-3.25 (m, 1H), 1.77-1.80 (m, 3H), 1.34-1.37 ( m, 1H), 0.69-0.70 (m, 2H), 0.44-0.45 (m, 2H); MS-ESI: m/z 553.2 [M+H-HCl] ⁺ .

Example 13: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazol-4-carbonyl)-3-aminomethylacetophenazine-1-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of the compound 3-aminomethylacetophenazine-1-carboxylic acid methyl ester

A solution of the compound methylpyrazine-1,3-dicarboxylic acid methyl ester hydrochloride (399 mg, 1.67 mmol) in methanol (7 mL) was added with a solution of amine in methanol (8 mL), and the reaction was performed in a sealed tube at 70° C. for 30 h, and the solvent was removed. Obtained 310 mg of white viscous material: compound 3-aminomethylacetomethylazine-1-carboxylic acid methyl ester, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.16-4.19 (m, 1H), 3.89-3.92 (m, 1H), 3.73 (s, 3H), 3.49-3.52 (m, 1H), 3.06-3.12 (m,3H), 2.80-2.86(m,1H).

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of Methyloxy)phenyl)oxazole-4-carbonyl)-3-aminomethylcarboxamazine-1-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (0.25g, 0.53mmol), compound 3-aminomethylacetophenazine-1-carboxylic acid methyl ester (120mg, 0.64mmol), 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide hydrochloride (153mg, 0.80mmol) and N -hydroxy-7-azabenzotriazole (181mg, 1.33mmol) were dissolved in dichloromethane (20mL), 0 ℃ N , N -diisopropylethylamine (0.37mL, 2.13mmol) was added dropwise to this solution under conditions, stirred at room temperature for 16h, washed with saturated sodium chloride solution (10mL×5), and the organic phase was washed with Na ₂ SO ₄ Dry, remove the solvent, and separate the concentrated solution by column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 20 mg of yellow viscous material, yield: 5%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.54-7.59 (m, 2H), 7.24-7.26 (m, 1H), 6.70 (t, J _FH = 75.0 Hz, 1H), 5.17-5.20 (m, 1H ), 4.88-4.92 (m, 1H), 3.97 (d, J = 6.8Hz, 2H), 3.75 (s, 3H), 3.17-3.25 (m, 3H), 1.37-1.41 (m, 3H), 1.33 ( s, 9H), 1.27-1.29 (m, 1H), 0.67-0.71 (m, 2H), 0.39-0.43 (m, 2H); MS-ESI: m/z 638.2 [M+H] ⁺ .

Step 3: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of methyl-4-carbonyl)-3-aminomethylacetophenazine-1-carboxylate hydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-3-aminomethylacetophenazine-1-carboxylic acid methyl ester (22mg, 0.03mmol) in dichloromethane (3mL) was added HCl in ethyl acetate solution ( 4M, 2mL), stirred at room temperature for 2.5h, the solvent was removed to obtain 19mg of light yellow solid, yield: 95%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.73 (s, 1H), 7.64-7.68 (m, 1H), 7.30-7.34 (m, 1H), 6.91 (t, J _FH = 73.9Hz, 1H) , 5.04-5.10(m, 2H), 4.48-4.58(m, 1H), 4.22-4.23(m, 1H), 4.00-4.04(m, 2H), 3.85-3.98(m, 2H), 3.73(s, 3H), 3.56-3.65 (m, 2H), 1.77 (d, J = 5.0Hz, 3H), 1.42-1.46 (m, 1H), 0.68-0.69 (m, 2H), 0.42-0.44 (m, 2H) ; MS-ESI: m/z 538.1 [M+H-HCl] ⁺ .

Example 14: Compound 1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Synthesis of oxazole-4-carbonyl)-4-(methoxycarbonyl)pyrazine-2-carboxylic acid hydrochloride

Step 1: Compound 1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonyl)pyrazine-2-carboxylic acid

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)pyrazine-1,3-dicarboxylic acid methyl ester (351mg, 0.53mmol) in a mixed solvent of tetrahydrofuran (16mL) and water (8mL) was added sodium hydroxide (108mg, 2.69 mmol), react at 45°C for 3h, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate (10mL×3) for extraction, combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 330mg of white solid. Rate: 96%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.60-7.73 (m, 2H), 7.27-7.30 (m, 1H), 6.89 (t, J _FH = 74.9Hz, 1H), 5.17-5.29 (m, 2H), 4.65-4.68 (m, 1H), 4.30-4.50 (m, 1H), 4.09-4.13 (m, 1H), 4.02-4.04 (m, 2H), 3.74 (s, 3H), 3.37-3.39 ( m,1H),1.49-1.54(m,3H),1.43(s,9H),1.32-1.35(m,1H),0.66-0.71(m,2H),0.42-0.46(m,2H); MS- ESI: m/z 639.2 [M+H] ⁺ .

Step 2: Compound 1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-carbonyl)-4-(methoxycarbonyl)pyrazine-2-carboxylic acid hydrochloride

To compound 1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-4-(methoxycarbonyl)pyrazine-2-carboxylic acid (90mg, 0.14mmol) in dichloromethane (3mL) was added HCl in ethyl acetate (4M, 3mL), stirred at room temperature for 2h, the solvent was removed to obtain 80mg white solid, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.74-7.76 (m, 1H), 7.67-7.72 (m, 1H), 7.32-7.35 (m, 1H), 6.79-7.05 (m, 1H), 5.04 -5.12(m,1H), 4.66-4.69(m,1H), 4.30-4.33(m,1H), 4.08-4.11(m,1H), 4.03-4.06(m,2H),3.75(s,3H) , 3.40-3.50 (m, 2H), 1.76-1.79 (m, 3H), 1.35-1.37 (m, 1H), 0.69-0.70 (m, 2H), 0.44-0.45 (m, 2H); MS-ESI: m/z 539.1 [M+H-HCl] ⁺ .

Example 15: Compound 3-((pivaloyloxy)methoxycarbonyl)-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate hydrochloride

Step 1: Compound 3-((pivaloyloxy)methoxycarbonyl)-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3- Synthesis of (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrazine-1-carboxylic acid methyl ester

To compound 1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-4-(methoxycarbonyl)pyrazine-2-carboxylic acid (234mg, 0.36mmol) in anhydrous ethanol (6mL) was added potassium hydroxide (21mg, 0.36mmol), Reaction at 40℃ for 20min, after removing ethanol, add anhydrous N , N -dimethylformamide (15mL), dropwise add chloromethyl pivalate (0.16mL, 1.10mmol) at 25℃, react at 25℃ for 6h, remove the solvent Ice water (8 mL) was added, ethyl acetate (10 mL×3) was extracted, the organic phases were combined and dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v /v)=2/1) to obtain 228 mg of colorless viscous material, yield: 82%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.54-7.59 (m, 1H), 7.49-7.54 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.70 (t, J _FH = 75.1 Hz, 1H), 5.75-5.83 (m, 2H), 5.22-5.25 (m, 1H), 4.40-4.65 (m, 2H), 3.97 (d, J = 6.9Hz, 2H), 3.72 (s, 3H) , 3.10-3.34 (m, 3H), 1.49-1.55 (m, 3H), 1.42 (s, 9H), 1.32-1.35 (m, 1H), 1.11-1.21 (m, 9H), 0.66-0.71 (m, 2H), 0.41-0.42 (m, 2H); MS-ESI: m/z 753.3 [M+H] ⁺ .

Step 2: Compound 3-((pivaloyloxy)methoxycarbonyl)-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy) Synthesis of methyl-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate hydrochloride

To compound 3-((pivaloyloxy)methoxycarbonyl)-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclo Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate (220 mg, 0.29 mmol) in methylene chloride (3 mL) was added A solution of HCl in ethyl acetate (4M, 3mL) was stirred at room temperature for 1.5h, and the solvent was removed to obtain 200mg of a white solid. Yield: 99%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.72-7.77 (m, 1H), 7.64-7.72 (m, 1H), 7.33 (d, J = 8.2Hz, 1H), 6.92 (t, J _FH = 74.7Hz, 1H), 5.82-5.87(m, 2H), 5.06-5.15(m, 1H), 4.61-4.65(m, 1H), 4.35-4.41(m, 1H), 4.05-4.07(m, 2H) , 4.06-4.09 (m, 1H), 3.75 (s, 3H), 3.42-3.45 (m, 1H), 3.10-3.25 (m, 1H), 1.75-1.81 (m, 3H), 1.39-1.44 (m, 1H), 1.11-1.23 (m, 9H), 0.68-0.70 (m, 2H), 0.45-0.47 (m, 2H); MS-ESI: m/z 653.2 [M+H-HCl] ⁺ .

Example 16: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of azole-4-carbonyl)pyrazine-2-carboxylic acid dihydrochloride

Step 1: Compound 1-tert-butoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) Synthesis of -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrazine-2-carboxylic acid

Compound 1-tert-butoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)methylazine-2-carboxylate (230 mg, 0.33 mmol) and sodium hydroxide (66 mg, 1.65 mmol) are dissolved in tetrahydrofuran (18 mL) and water (9mL) in a mixed solvent, react at 50°C for 4h, add hydrochloric acid (1M) to adjust the pH to 1, add ethyl acetate (10mL×3) for extraction, combine the organic phases and dry with anhydrous Na ₂ SO _{4 to} remove the solvent, 220 mg of white solid was obtained, yield: 97%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.58-7.61 (m, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.78 (t, J _FH =76.0Hz,1H),5.03-5.08(m,1H),4.36-4.40(m,1H),3.91(d, J =6.4Hz,2H),3.80-3.84(m,1H),3.63- 3.65 (m, 1H), 1.89-1.90 (m, 3H), 1.37-1.39 (m, 9H), 1.30-1.32 (m, 9H), 1.19-1.24 (m, 1H), 0.56-0.58 (m, 2H ), 0.31-0.32 (m, 2H); MS-ESI: m/z 681.4 [M+H] ⁺ .

Step 2: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-carbonyl)pyrazine-2-carboxylic acid dihydrochloride

To compound 1-tert-butoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrazine-2-carboxylic acid (0.21 g, 0.31 mmol) in methylene chloride (4 mL) was added HCl in ethyl acetate (4M, 3mL), stirred at room temperature for 2h, the solvent was removed, to obtain 170mg white solid, yield: 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.59-7.65 (m, 1H), 7.57 (d, J = 5.4 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.77 (t, J _FH =74.7Hz,1H), 4.95-4.97(m,1H),4.33-4.45(m,1H),3.85-3.88(m,2H),3.75-3.78(m,1H),3.35-3.43(m , 2H), 3.24-3.30 (m, 1H), 1.63-1.65 (m, 3H), 1.17-1.19 (m, 1H), 0.52-0.53 (m, 2H), 0.27-0.28 (m, 2H); MS -ESI: m/z 481.1 [M+H-2HCl] ⁺ .

Example 17: Compound 1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of azole-4-carbonyl)pyrazine-2-carboxylic acid dihydrochloride

Step 1: Compound 4-tert-butoxycarbonyl-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) Synthesis of -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrazine-2-carboxylic acid

Compound 1-tert-butoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)methylazine-3-carboxylate (250mg, 0.36mmol) and sodium hydroxide (72mg, 1.80mmol) dissolved in tetrahydrofuran (18mL) and water (9mL) in a mixed solvent, react at 50°C for 3h, add hydrochloric acid (1M) to adjust the pH to 1, add ethyl acetate (10mL×3) for extraction, combine the organic phases and dry with anhydrous Na ₂ SO _{4 to} remove the solvent, 243 mg of white solid was obtained, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.69-7.73 (m, 1H), 7.60-7.67 (m, 1H), 7.26-7.30 (m, 1H), 6.90 (t, J _FH = 74.9Hz, 1H), 5.17-5.30 (m, 1H), 4.56-4.68 (m, 1H), 4.31-4.43 (m, 1H), 4.01-4.03 (m, 2H), 3.35-3.45 (m, 1H), 3.01- 3.20 (m, 1H), 1.52-1.54 (m, 3H), 1.49 (s, 9H), 1.42-1.46 (m, 9H), 1.35-1.38 (m, 1H), 0.66-0.70 (m, 2H), 0.43-0.45 (m, 2H); MS-ESI: m/z 681.4 [M+H] ⁺ .

Step 2: Compound 1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-carbonyl)pyrazine-2-carboxylic acid dihydrochloride

To compound 4-tert-butoxycarbonyl-1-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrazine-2-carboxylic acid (0.24g, 0.35mmol) in dichloromethane (6mL) was added HCl in ethyl acetate (4M, 5mL), stirred at room temperature for 2h, the solvent was removed to obtain 195mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75-7.78 (m, 1H), 7.70-7.71 (m, 1H), 7.32-7.35 (m, 1H), 6.93 (t, J _FH = 74.9Hz, 1H), 5.13-5.17 (m, 1H), 4.03-4.05 (m, 2H), 4.01-4.03 (m, 1H), 3.59-3.71 (m, 1H), 3.41-3.52 (m, 2H), 3.28- 3.30 (m, 1H), 1.78-1.81 (m, 3H), 1.34-1.36 (m, 1H), 0.65-0.71 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 481.3[M+H-2HCl] ⁺ .

Example 18: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of azole-4-carbonyl)pyrazin-2-one hydrochloride

Step 1: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(3-oxopyrazine-1 -Synthesis of carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), 2-pyridazinone (77 mg, 0.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (184 mg, 0.96 mmol) and N -hydroxy-7-azabenzotriazole (218 mg, 1.60 mmol) were dissolved in dichloromethane (20 mL), and N , N -was added dropwise to this solution at 0°C diisopropylethylamine (0.45mL, 2.56mmol), stirred for 21H at room temperature, washed with water (15 mL), the organic phase was dried over anhydrous Na ₂ SO _4, the solvent was removed, the concentrate was subjected to column chromatography (eluent: DCM/MeOH (v/v)=30/1), to obtain 285 mg of colorless viscous material, yield: 80%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 7.57-7.59(m,1H),7.51-7.54(m,1H),7.23(d, J =8.3Hz,1H),6.70(t, J _FH =75.0 Hz, 1H), 5.88-5.92 (m, 1H), 5.25-5.26 (m, 1H), 4.68-4.78 (m, 1H), 4.35-4.39 (m, 1H), 4.19-4.25 (m, 1H), 3.96 (d, J = 6.5Hz, 2H), 3.49-3.54 (m, 2H), 1.53 (d, J = 7.0Hz, 3H), 1.41 (s, 9H), 1.30-1.35 (m, 1H), 0.66 -0.70 (m, 2H), 0.39-0.41 (m, 2H); MS-ESI: m/z 551.4 [M+H] ⁺ .

Step 2: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-carbonyl)pyrazin-2-one hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(3-oxopyrazin-1-carbonyl ) Oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (0.27g, 0.50mmol) in dichloromethane (6mL) was added HCl in ethyl acetate solution (4M, 5mL), stirred at room temperature for 1h After removing the solvent, 240 mg of white solid was obtained with a yield of 99%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.72-7.79 (m, 2H), 7.32 (d, J = 8.2Hz, 1H), 6.93 (t, J _FH = 74.7Hz, 1H), 5.08-5.11 (m,1H), 4.38-4.42(m,1H), 4.34(m,1H), 4.04(d, J =6.8Hz, 2H), 3.96-3.99(m,1H), 3.56(m,1H), 3.48 (m, 1H), 1.80 (d, J = 6.3Hz, 3H), 1.32-1.35 (m, 1H), 0.68-0.69 (m, 2H), 0.43-0.45 (m, 2H); MS-ESI: m/z 451.3 [M+H-HCl] ⁺ .

Example 19: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazol-4-carbonyl)-6-methylpyrazine-2-one hydrochloride

Step 1: Compound ((1 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(3-methyl-5- Synthesis of tert-butyl oxo-pyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), 6-methylpyrazine 2-one (88 mg, 0.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Amine hydrochloride (184mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (218mg, 1.60mmol) were dissolved in dichloromethane (20mL) and added dropwise to this solution at 0°C N, N - diisopropylethylamine (0.45mL, 2.56mmol), stirred for 16 h at room temperature, washed with water and dried (15mL) The organic phase was dried over anhydrous Na ₂ SO _4, solvent was separated by column chromatography to remove, concentrate ( Eluent: DCM/MeOH (v/v) = 40/1), to obtain 325mg of colorless viscous material, yield: 89%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 7.56-7.59(m,1H),7.52-7.54(m,1H),7.22-7.25(m,1H),6.70(t, J _FH =75.0Hz,1H ), 5.92 (br.s, 1H), 5.24-5.27 (m, 1H), 4.84-5.02 (m, 1H), 4.62-4.65 (m, 1H), 4.37-4.50 (m, 1H), 3.95-3.97 (m, 2H), 3.78-3.84(m, 1H), 3.17-3.21(m, 1H), 1.53-1.54(m, 3H), 1.41(s, 9H), 1.32-1.34(m, 1H), 1.28 -1.30 (m, 3H), 0.67-0.70 (m, 2H), 0.40 (m, 2H); MS-ESI: m/z 565.2 [M+H] ⁺ .

Step 2: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-carbonyl)-6-methylpyrazine-2-one hydrochloride

To the compound ((1 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(3-methyl-5-oxo To a solution of tert-butyl ester of pyrazin-1-carbonyl)oxazol-5-yl)ethyl)carbamate (0.31 g, 0.55 mmol) in dichloromethane (4 mL) was added a solution of HCl in ethyl acetate (4M, 6 mL) ), stirred at room temperature for 40 min, and removed the solvent to obtain 279 mg of white solid, yield: 99%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.76(d, J =11.6Hz,1H),7.71-7.73(m,1H),7.32-7.34(m,1H),6.92(t, J _FH = 74.7Hz, 1H), 5.07-5.11(m, 1H), 4.62-4.75(m, 1H), 4.17-4.26(m, 1H), 4.04(d, J = 6.7Hz, 2H), 3.96-4.01, 3.47 (m,m,0.5H,0.5H),3.75-3.88(m,1H),1.79(d, J =4.7Hz,3H),1.33-1.35(m,1H),1.29-1.31(m,3H) , 0.68-0.69 (m, 2H), 0.44 (m, 2H); MS-ESI: m/z 465.3 [M+H-HCl] ⁺ .

Example 20: Compound ( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of compound L -proline methyl ester hydrochloride

To a solution of Boc- L -proline (1.50g, 6.97mmol) in methanol (20mL) was added dropwise chlorite (0.51mL, 6.97mmol) under ice bath. The reaction was carried out under ice bath for 30min and at 70℃ for 7h. After removing the solvent, dichloromethane (8 mL) and HCl in ethyl acetate (4M, 6 mL) were added, and the mixture was stirred at room temperature for 5 min. The solvent was removed to obtain 800 mg of a white viscous substance, yield: 88%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 4.47 (t, J = 7.8Hz, 1H), 3.88 (s, 3H), 3.37-3.45 (m, 2H), 2.41-2.50 (m, 1H), 2.07-2.21 (m, 3H).

Step 2: Compound ( S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300mg, 0.64mmol), L -proline methyl ester hydrochloride (127mg, 0.77mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodicarbonate Imine hydrochloride (184 mg, 0.96 mmol) and N -hydroxy-7-azabenzotriazole (218 mg, 1.60 mmol) were dissolved in dichloromethane (20 mL), and the solution was dropped at 0°C was added N, N - diisopropylethylamine (0.45mL, 2.56mmol), stirred for 16 h at room temperature, washed with water and dried (15mL) The organic phase was dried over anhydrous Na ₂ SO _4, solvent was separated by column chromatography to remove, concentrate (Eluent: Petroleum ether/EtOAc (v/v)=3/1), 280 mg of white solid was obtained, yield: 75%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.54-7.61 (m, 1H), 7.50-7.53 (m, 1H), 7.20-7.24 (m, 1H), 6.69 (t, J _FH = 75.1 Hz, 1H ), 5.24-5.35(m, 1H), 4.09-4.21(m, 1H), 3.96-4.00(m, 2H), 3.85-3.91(m, 1H), 3.73-3.79(m, 1H), 3.71(s ,3H),2.22-2.34(m,2H),1.91-2.04(m,2H),1.50-1.52(m,3H),1.43(s,9H),1.30-1.34(m,1H),0.66-0.71 (m, 2H), 0.39-0.43 (m, 2H); MS-ESI: m/z 580.1 [M+H] ⁺ .

Step 3: Compound ( S )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of methyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

To compound ( S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid methyl ester (102mg, 0.17mmol) in dichloromethane (3mL) was added HCl in ethyl acetate (4M, 4mL) , Stir at room temperature for 40min, remove the solvent to obtain 90mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.72 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.92 (t, J _FH =74.7Hz,1H),5.38-5.39(m,1H),5.17-5.20(m,1H),4.04-4.08(m,2H),3.80-3.85(m,1H),3.75-3.78(m,1H ), 3.73(s,3H),2.26-2.46(m,2H),2.01-2.12(m,2H),1.77-1.79(m,3H),1.32-1.37(m,1H),0.67-0.71(m , 2H), 0.45-0.46 (m, 2H); MS-ESI: m/z 480.1 [M+H-HCl] ⁺ .

Example 21: Compound ( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid hydrochloride

Step 1: Compound ( S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid

The compound ( S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid methyl ester (178mg, 0.30mmol) and sodium hydroxide (61mg, 1.53mmol) were dissolved in tetrahydrofuran (10mL) and water (5mL) In the mixed solvent, react at 90℃ for 5h, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate (20mL×3) for extraction, combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 159mg white solid , Yield: 91%.

¹ H NMR(400MHz,CD ₃ OD): δ ppm 7.74(d, J =1.9Hz,1H),7.61(dd, J ₁ =8.3Hz, J ₂ =1.9Hz,1H),7.26(d, J = 8.3Hz, 1H), 6.88(t, J _FH = 75.0Hz, 1H), 5.44-5.50(m, 1H), 5.18-5.21(m, 1H), 4.02(d, J = 6.9Hz, 2H), 3.74 -3.81(m,2H),2.23-2.41(m,2H),2.03-2.07(m,1H),1.96-2.00(m,1H),1.53(d, J =7.1Hz,3H),1.43(s , 9H), 1.31-1.34 (m, 1H), 0.66-0.71 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 566.2 [M+H] ⁺ .

Step 2: Compound ( S )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene ))Oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid hydrochloride

To compound ( S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid (154mg, 0.27mmol) in dichloromethane (3mL) was added HCl in ethyl acetate (4M, 4mL), room Warm stirring for 1.5h, remove the solvent to obtain 135mg white solid, yield: 98%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.78(d, J =1.3Hz,1H),7.67(dd, J ₁ =8.3Hz, J ₂ =1.34Hz,1H),7.30(d, J = 8.3Hz, 1H), 6.92(t, J _FH = 74.8Hz, 1H), 5.39-5.40(m, 1H), 5.09-5.18(m, 1H), 4.23-4.28(m, 1H), 4.02-4.05( m,2H),3.75-3.87(m,1H),2.23-2.33(m,1H), 2.10-2.13(m,1H),1.95-2.05(m,2H),1.77(d, J =6.9Hz, 3H), 1.34-1.38 (m, 1H), 0.68-0.70 (m, 2H), 0.43-0.45 (m, 2H); MS-ESI: m/z 466.1 [M+H-HCl] ⁺ .

Example 22: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazol-4-carbonyl)imidazol-4-one hydrochloride

Step 1: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-oxoimidazolidine-1 -Synthesis of carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (330 mg, 0.70 mmol), 4-imidazolidinone hydrochloride (104 mg, 0.85 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Hydrochloride (203mg, 1.06mmol) and N -hydroxy-7-azabenzotriazole (240mg, 1.76mmol) were dissolved in dichloromethane (20mL), and N was added dropwise to this solution at 0°C , N -diisopropylethylamine (0.49mL, 2.82mmol), stirred at room temperature for 5h, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v) = 40/1) , To obtain 360mg white solid, yield: 95%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.56-7.61 (m, 1H), 7.50-7.53 (m, 1H), 7.24 (d, J = 7.1Hz, 1H), 6.71 (t, J _FH = 74.2 Hz, 1H), 5.52-5.62(m, 1H), 5.33-5.39(m, 1H), 5.10-5.13(m, 1H), 4.62-4.79(m, 1H), 4.22(m, 1H), 3.97( d, J = 6.9Hz, 2H), 1.54 (d, J = 7.0Hz, 3H), 1.42 (s, 9H), 1.31-1.36 (m, 1H), 0.65-0.71 (m, 2H), 0.37-0.44 (m, 2H); MS-ESI: m/z 537.3 [M+H] ⁺ .

Step 2: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-carbonyl)imidazol-4-one hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-oxoimidazolidine-1-carbonyl ) Oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (350mg, 0.65mmol) in dichloromethane (12mL) was added HCl in ethyl acetate solution (4M, 8mL), stirred at room temperature for 2h, Removal of the solvent gave 308 mg of white solid, yield: 99%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.68-7.69 (m, 2H), 7.29 (d, J = 8.2Hz, 1H), 6.80 (t, J _FH = 74.7Hz, 1H), 5.60 (m ,1H),5.11-5.12(m,1H), 5.08(m,1H),4.72(m,2H),4.17(m,1H),4.01(d, J =6.6Hz, 2H),1.78(d, J = 6.4Hz, 3H), 1.31-1.32 (m, 1H), 0.67-0.68 (m, 2H), 0.42-0.43 (m, 2H); MS-ESI: m/z 437.3 [M+H-HCl] ⁺ .

Example 23: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of azole-4-carbonyl)morpholine-2-carboxylic acid methyl ester hydrochloride

Step 1: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of methyloxy)phenyl)oxazole-4-carbonyl)morpholine-2-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), 2-morpholinecarboxylic acid methyl ester hydrochloride (140 mg, 0.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimine hydrochloride (184 mg, 0.96 mmol) and N -hydroxy-7-azabenzotriazole (218 mg, 1.60 mmol) were dissolved in dichloromethane (20 mL) and added to this solution at 0°C N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise, stirred at room temperature for 6h, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 3/1), to obtain 350 mg of colorless viscous material, yield: 91%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.52-7.59 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 6.70 (t, J _FH = 75.0 Hz, 1H), 5.21-5.27 ( m,1H),4.25-4.33(m,1H),3.97(d, J =6.7Hz,2H),3.70-3.82(m,4H),3.50-3.58(m,1H),3.15-3.22(m, 1H), 1.55 (d, J = 7.0Hz, 3H), 1.42 (s, 9H), 1.29-1.34 (m, 1H), 0.66-0.70 (m, 2H), 0.38-0.42 (m, 2H); MS -ESI: m/z 596.1[M+H] ⁺ .

Step 2: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)morpholine-2-carboxylic acid methyl ester hydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)morpholine-2-carboxylic acid methyl ester (135mg, 0.22mmol) in dichloromethane (4mL) was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature After 1h, the solvent was removed to obtain 120mg of white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.74-7.79 (m, 1H), 7.71 (d, J = 8.2Hz, 1H), 7.32-7.35 (m, 1H), 6.93 (t, J _FH = 74.7Hz, 1H), 5.08-5.10(m, 1H), 4.99-5.04(m, 1H), 4.65-4.67, 4.35-4.51(m, m, 0.5H, 1.5H), 4.10-4.18, 3.92-3.93 (m,m,1.5H,0.5H), 4.03-4.06(m,2H),3.74-3.78(m,3H),3.81(m,1H),3.43-3.46(m,1H),1.79-1.80( m, 3H), 1.32-1.36 (m, 1H), 0.68-0.70 (m, 2H), 0.43-0.45 (m, 2H); MS-ESI: m/z 496.3 [M+H-HCl] ⁺ .

Example 24: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Azole-4-carbonyl)morpholine-2-carboxylate hydrochloride

Step 1: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)morpholine-2-carboxylic acid

Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)morpholine-2-carboxylic acid methyl ester (200 mg, 0.33 mmol) and sodium hydroxide (67 mg, 1.68 mmol) are dissolved in a mixed solvent of tetrahydrofuran (16 mL) and water (8 mL) , 50 ℃ reaction 2.5h, add hydrochloric acid (1M) to adjust the pH value to 1, add ethyl acetate (20mL × 3) extraction, the organic phase was combined and dried with Na ₂ SO _{4 to} remove the solvent, to obtain 195mg white solid, yield : 99%.

¹ H NMR(400MHz,CD ₃ OD): δ ppm 7.71(br.s,1H),7.65(dd, J ₁ =8.4Hz, J ₂ =1.8Hz,1H),7.29(d, J =8.3Hz, 1H), 6.89 (t, J _FH = 74.9Hz, 1H), 5.17 (m, 1H), 4.50-4.59, 4.09-4.10 (m, m, 0.5H, 0.5H), 4.20-4.31 (m, 2H) ,4.02(d, J =6.9Hz,2H),3.72-3.80(m,1H),3.60-3.65,3.40-3.45(m,m,0.5H,0.5H),1.55(d, J =7.1Hz, 3H), 1.43 (s, 9H), 1.33-1.36 (m, 1H), 0.66-0.70 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 582.3[M+H] ⁺ .

Step 2: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole -4-carbonyl)morpholine-2-carboxylic acid hydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)morpholine-2-carboxylic acid (194mg, 0.33mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 1.5h After removing the solvent, 170 mg of white solid was obtained with a yield of 98%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.62-7.66 (m, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.20 (d, J = 8.2Hz, 1H), 6.80 (t, J _FH = 74.8Hz, 1H), 4.96-4.98(m, 1H), 4.46-4.62(m, 1H), 4.09-4.26(m, 2H), 3.98-4.00(m, 1H), 3.91(d, J =6.6Hz, 2H), 3.60-3.65(m, 2H), 3.20-3.30(m, 1H), 1.66-1.68(m, 3H), 1.20-1.23(m, 1H), 0.54-0.59(m, 2H ), 0.30-0.34 (m, 2H); MS-ESI: m/z 482.3 [M+H-HCl] ⁺ .

Example 25: Compound ( S )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of compound 2-( S )-methylmethylpyrazine-1-carboxylic acid methyl ester hydrochloride

To N 'N - carbonyldiimidazole (1.00g, 5.99mmol) in anhydrous DMF (8mL) was added dropwise triethylamine (1.25mL, 8.99mmol) and (S) -4- N - tert-butoxycarbonyl-2 -A solution of methylpyrazine (1.00g, 4.99mmol) in anhydrous DMF (10mL), react in a sealed tube at 60°C for 30min, add anhydrous methanol (15mL), react at 65°C for 24h, remove the solvent, add saturated sodium chloride solution (10mL×3) washed, extracted with ethyl acetate (15mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v /v)=5/1), 409 mg of colorless liquid was obtained: methyl 2-( S )-methyl-4-tert-butoxycarbonylpyrazine-1-carboxylate, yield: 31%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 4.27 (m, 1H), 4.07-4.11, 3.72-3.85 (m, 0.5H, 2.5H), 3.70 (s, 3H), 3.06-3.10 (m, 1H ), 3.01 (m, 1H), 2.76-2.86 (m, 1H), 1.45 (s, 9H), 1.14 (d, J = 6.8Hz, 3H); MS-ESI: m/z 159.2 [M+H- 100] ⁺ .

To a solution of compound 2-( S )-methyl-4-tert-butoxycarbonylpyrazine-1-carboxylic acid methyl ester (0.40g, 1.55mmol) in dichloromethane (5mL) was added HCl in ethyl acetate (4M , 6mL), stirred at room temperature for 2h, and removed the solvent to obtain 300mg of white viscous material: compound 2-( S )-methylpyrazine-1-carboxylic acid methyl ester hydrochloride, yield: 99%.

¹ H NMR(400MHz, CD ₃ OD): δ ppm 4.56-4.59(m,1H),4.14-4.17(m,1H),3.75(s,3H),3.34-3.38(m,2H),3.22-3.31 (m, 2H), 3.04-3.11 (m, 1H), 1.35 (d, J = 7.2 Hz, 3H); MS-ESI: m/z 159.2 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (600 mg, 1.28 mmol), 2-( S )-methylpyrazine-1-carboxylic acid methyl ester hydrochloride (300 mg, 1.54 mmol), 1-ethyl-3-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (368 mg, 1.92 mmol) and N -hydroxy-7-azabenzotriazole (434 mg, 3.20 mmol) were dissolved in dichloromethane (20 mL), To this solution, N , N -diisopropylethylamine (0.89mL, 5.12mmol) was added dropwise at 0°C, stirred at room temperature for 16h, water (10mL×2) was added, and the organic phase was dried over anhydrous Na ₂ SO ₄ After removing the solvent, the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 552 mg of white solid in a yield of 71%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.55-7.58 (m, 1H), 7.53 (s, 1H), 7.23 (d, J = 8.3Hz, 1H), 6.69 (t, J _FH = 75.0Hz, 1H), 5.19-5.29 (m, 1H), 4.36-4.66 (m, 3H), 3.91-4.03 (m, 1H), 3.96 (d, J = 6.9Hz, 2H), 3.73 (s, 3H), 3.40 -3.43,3.18-3.24(m,m,0.5H,1.5H),3.02-3.04,2.85-2.95(m,m,0.5H,0.5H),1.54(d, J =7.0Hz,3H),1.40 (s,9H), 1.29-1.34 (m, 1H), 1.23-1.27 (m, 3H), 0.66-0.70 (m, 2H), 0.38-0.42 (m, 2H); MS-ESI: m/z 609.2 [M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of methyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester hydrochloride

To the compound ( S )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester (547 mg, 0.90 mmol) in dichloromethane (6 mL) was added HCl in ethyl acetate (4M, 6mL), stirred at room temperature for 2h, the solvent was removed to obtain 489mg of white solid, yield: 99%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.68(s,1H),7.63-7.66(m,1H),7.25(d, J =8.3Hz,1H),6.85(t, J _FH =74.7Hz ,1H),4.96-5.05(m,1H),4.85-4.90(m,1H),4.36-4.44(m,2H),3.97(d, J =6.7Hz,2H),3.93-3.95(m,1H ), 3.67 (s, 3H), 3.52-3.55, 3.19-3.22 (m, m, 0.5H, 0.5H), 3.28-3.30 (m, 1H), 3.08-3.10, 2.94-2.99 (m, 0.5H, 0.5H), 1.71(d, J =6.1Hz, 3H), 1.25-1.31(m, 1H), 1.15-1.20(m, 3H), 0.59-0.63(m, 2H), 0.36-0.37(m, 2H ); MS-ESI: m/z 509.2 [M+H-HCl] ⁺ .

Example 26: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-yl)(pyrrol-1-yl)methanone hydrochloride

Step 1: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(pyrrole-1- Synthesis of tert-butyl carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300mg, 0.64mmol), tetrahydropyrrole (0.06mL, 0.77mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride ( 184mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (218mg, 1.60mmol) were dissolved in dichloromethane (20mL), N , N -di diisopropylethylamine (0.45mL, 2.56mmol), stirred at rt for 12h, water was added (10mL × 2), the organic phase was dried over anhydrous Na ₂ SO _4, separated by column chromatography (eluent solvent was removed, the concentrate : Petroleum ether/EtOAc (v/v)=4/1), 225 mg of white solid was obtained, yield: 67%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.59 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.53 (d, J =1.9 Hz, 1H), 7.23 (d, J =8.3 Hz, 1H), 6.69 (t, J _FH = 75.1Hz, 1H), 5.24-5.27 (m, 1H), 4.01-4.05 (m, 1H), 3.97 (d, J = 7.0Hz, 2H), 3.93 3.95 (m, 1H), 3.66 (t, J = 6.9Hz, 2H), 1.92-2.01 (m, 4H), 1.53 (d, J = 7.0Hz, 3H), 1.43 (s, 9H), 1.32-1.35 (m, 1H), 0.67-0.70 (m, 2H), 0.39-0.42 (m, 2H); MS-ESI: m/z 522.4 [M+H] ⁺ .

Step 2: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4 -Yl)(pyrrol-1-yl)methanone hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(pyrrole-1-carbonyl)oxazole-5 -Yl)ethyl)tert-butyl carbamate (200mg, 0.38mmol) in dichloromethane (6mL) was added HCl in ethyl acetate (4M, 3mL), stirred at room temperature for 4h, the solvent was removed to give 175mg White solid, yield: 99%.

¹ H NMR(400MHz,CD ₃ OD): δ ppm 7.70(s,1H),7.67(d, J =8.6Hz,1H),7.27(d, J =8.2Hz,1H),6.89(t, J _FH =74.8Hz,1H),5.09-5.10(m,1H),4.08(t, J =5.9Hz,1H),4.00(d, J =6.8Hz,2H),3.62(t, J =6.6Hz,1H ), 2.01-2.04 (m, 2H), 1.92-1.97 (m, 2H), 1.78 (d, J = 6.4Hz, 3H), 1.26-1.33 (m, 1H), 0.64-0.67 (m, 2H), 0.40-0.42 (m, 2H); MS-ESI: m/z 422.1 [M+H-HCl] ⁺ .

Example 27: Compound ( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl) -N , N -dimethylpyrrolidine-2-carboxamide hydrochloride

Step 1: Synthesis of compound ( S ) -N , N -dimethylpyrrolidine-2-carboxamide hydrochloride

The Boc- L -proline acid (500mg, 2.32mmol), dimethylamine hydrochloride (227mg, 2.79mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride ( 668mg, 3.48mmol) and N -hydroxy-7-azabenzotriazole (790mg, 5.81mmol) were dissolved in dichloromethane (20mL), N , N -di diisopropylethylamine (1.6mL, 9.29mmol), stirred at rt for 4h, water was added (10mL × 2), the organic phase was dried over anhydrous Na ₂ SO _4, separated by column chromatography (eluent solvent was removed, the concentrate : DCM/MeOH (v/v) = 50/1), to obtain 540mg colorless oil: ( S ) -N , N -dimethyl- N -tert-butoxycarbonylpyrrolidine-2-carboxamide, the Rate: 95%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.64-4.67, 4.51-4.54 (m, 0.5H, 0.5H), 3.53-3.63 (m, 1H), 3.39-3.50 (m, 1H), 3.06 (d , J =11.6Hz, 3H), 2.94(d, J = 6.8Hz, 3H), 1.98-2.18(m, 2H), 1.78-1.86(m, 2H), 1.38-1.44(m, 9H); MS- ESI: m/z 143.3 [M+H-100] ⁺ .

To a solution of compound ( S ) -N , N -dimethyl- N -tert-butoxycarbonylpyrrolidine-2-carboxamide (520mg, 2.14mmol) in dichloromethane (6mL) was added HCl in ethyl acetate (4M, 6mL), stirred at room temperature for 2h, and removed the solvent to obtain 383mg of white viscous material: compound ( S ) -N , N -dimethylpyrrolidine-2-carboxamide hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.60 (t, J = 7.9 Hz, 1H), 3.33-3.40 (m, 1H), 3.25-3.31 (m, 1H), 3.02 (s, 3H), 2.94(s,3H),2.43-2.52(m,1H),1.98-2.07(m,2H),1.85-1.91(m,1H); MS-ESI: m/z 143.2[M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)-4-(( S )-2-(dimethylaminomethyl acetyl) pyrrole-1-carbonyl) oxazol-5-yl) ethyl) aminocarbamic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300mg, 0.64mmol), ( S ) -N , N -dimethylpyrrolidine-2-carboxamide hydrochloride (140mg, 0.77mmol), 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) and N -hydroxy-7-azabenzotriazole (218 mg, 1.60 mmol) were dissolved in dichloromethane (20 mL ), N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 5h, water (10mL×2) was added, and the organic phase was anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=50/1) to obtain 250 mg of a white solid in a yield of 65%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.58(dd, J ₁ =8.3Hz, J ₂ =1.8Hz,1H),7.44(s,1H),7.21(dd, J ₁ =8.2Hz, J ₂ =2.6Hz,1H),6.69(t, J _FH =75.1Hz,1H),5.20-5.31(m,1H),5.55-5.57,5.01-5.04(m,0.5H,0.5H),4.11-4.21( m,1H),3.94-3.97(m,2H),3.15(d, J =17.4Hz,3H),2.98(d, J =5.0Hz,3H),2.04-2.34(m,2H),1.91-2.01 (m,2H),1.50-1.53(m,3H),1.42(s,9H),1.31-1.34(m,1H),0.65-0.71(m,2H),0.37-0.42(m,2H); MS -ESI: m/z 593.4[M+H] ⁺ .

Step 3: Compound ( S )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carbonyl) -N , N -dimethylpyrrolidine-2-carboxamide hydrochloride

To the compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( S )-2-(dimethylamine A solution of dimethylformyl)pyrrole-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (239 mg, 0.40 mmol) in dichloromethane (3 mL) was added HCl in ethyl acetate (3 mL) 4M, 4mL), stirred at room temperature for 3h, the solvent was removed to obtain 213mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.64-7.68 (m, 1H), 7.55-7.61 (m, 1H), 7.25-7.29 (m, 1H), 6.73-6.98 (m, 1H), 4.99 -5.07(m, 2H), 4.27-4.32, 4.08-4.12(m, 0.5H, 0.5H), 3.97(d, J = 6.8Hz, 2H), 3.70-3.80(m, 1H), 3.17(d, J = 8.6Hz, 3H), 2.94, 2.84 (s, 1.3H, 1.7H), 2.42-2.49, 2.28-2.33 (m, 0.5H, 0.5H), 1.98-2.10 (m, 2H), 1.83-1.90 (m,1H),1.71(d, J =6.9Hz,3H),1.25-1.28(m,1H),0.60-0.63(m,2H),0.34-0.38(m,2H); MS-ESI: m /z 493.1[M+H-HCl] ⁺ .

Example 28: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazole-4-carbonyl)-2-ethylpyrazine-1-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of compound 2-ethylpyrazine-1-carboxylic acid methyl ester hydrochloride

To N 'N - carbonyldiimidazole (468mg, 2.80mmol) in anhydrous DMF (2mL) was added dropwise triethylamine (0.59mL, 4.20mmol) and N - tert-butoxycarbonyl-3-ethyl piperazine (500mg , 2.33mmol) in anhydrous DMF (2mL) solution, in a sealed tube at room temperature for 30min, add anhydrous methanol (12mL), react at 60 ℃ for 24h, remove the solvent, add saturated sodium chloride solution (30mL), ethyl acetate ( 15mL×2) extraction, the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=5/1) to obtain 260 mg Colorless liquid: methyl 4-tert-butoxycarbonyl-2-ethylpyrazine-1-carboxylate, yield: 40%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.88-3.97 (m, 4H), 3.70 (s, 3H), 2.76-3.02 (m, 3H), 1.52-1.61 (m, 2H), 1.45 (s, 9H), 0.89 (t, J = 7.4 Hz, 3H); MS-ESI: m/z 173.1 [M+H-100] ⁺ .

To a solution of compound 4-tert-butoxycarbonyl-2-ethylpyrazine-1-carboxylate (417 mg, 1.53 mmol) in dichloromethane (4 mL) was added a solution of HCl in ethyl acetate (4M, 6 mL). After stirring for 1 hour at a warm temperature, the solvent was removed to obtain 319 mg of a white viscous substance: compound 2-ethylpyrazine-1-carboxylic acid methyl ester hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.33-4.38 (m, 1H), 4.18-4.23 (m, 1H), 3.75 (s, 3H), 3.38, 3.27 (m, m, 0.5H, 0.5 H), 3.31-3.34(m, 3H), 3.20-3.24(m, 1H), 3.07(td, J ₁ =12.3Hz, J ₂ =4.0Hz, 1H), 1.85-1.93(m, 1H), 1.67 -1.75 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); MS-ESI: m/z 173.2 [M+H-HCl] ⁺ .

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of methyloxy)phenyl)oxazole-4-carbonyl)-2-ethylpyrazine-1-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), 2-ethylpyrazine-1-carboxylic acid methyl ester hydrochloride (132 mg, 0.77 mmol), 1-ethyl-3-(3-dimethylamine Propyl)carbodiimide hydrochloride (184mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (218mg, 1.60mmol) were dissolved in dichloromethane (20mL) at 0℃ To this solution, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise, stirred at room temperature for 16h, water (10mL×2) was added, the organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed, The concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 313 mg of a colorless viscous substance, yield: 78%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.56-7.58(m,1H),7.54(s,1H),7.24(d, J =8.3Hz,1H),6.70(t, J _FH =75.0Hz, 1H), 5.18-5.28 (m, 1H), 4.77-4.80, 4.55-4.63 (m, 0.5H, 1.5H), 4.21, 3.35-3.38 (m, m, 0.5H, 0.5H), 4.09-4.10 ( m,1H),3.94-3.97(m,2H),3.73(s,3H),3.13-3.26(m,2H),2.87-2.98(m,1H),1.54(d, J =7.0Hz,3H) ,1.41(s,9H),1.29-1.34(m,1H),0.81-0.95(m,3H),0.66-0.71(m,2H),0.39-0.40(m,2H); MS-ESI: m/ z 623.4[M+H] ⁺ .

Step 3: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of methyl-4-carbonyl)-2-ethylpyrazine-1-carboxylate hydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-2-ethylpyrazine-1-carboxylic acid methyl ester (298mg, 0.48mmol) in methylene chloride (3mL) was added HCl in ethyl acetate (4M, 4mL) ), stirred at room temperature for 1.5h, and removed the solvent to obtain 266mg of white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.68 (s, 1H), 7.64-7.66 (m, 1H), 7.27 (dd, J ₁ =8.3 Hz, J ₂ =3.3 Hz, 1H), 6.85( t, J _FH = 74.7Hz, 1H), 5.00-5.04 (m, 1H), 4.89-4.97 (m, 1H), 4.52-4.54, 4.44-4.46 (m, m, 0.5H, 0.5H), 4.13 4.18(m,1H),4.01-4.03(m,1H),3.96-3.98(m,2H),3.68(s,3H),3.49-3.52, 3.13(m,0.5H,0.5H),3.16-3.24 (m,1H),3.01-3.04,2.91-2.96(m,0.5H,0.5H),1.71(d, J =7.0Hz,3H),1.56-1.67(m,2H),1.26-1.30(m, 1H), 0.85-0.90 (m, 3H), 0.61-0.64 (m, 2H), 0.37-0.39 (m, 2H); MS-ESI: m/z 523.1 [M+H-HCl] ⁺ .

Example 29: Compound ( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid isopropyl ester hydrochloride

Step 1: Synthesis of compound ( S )-pyrrolidine-2-carboxylic acid isopropyl ester hydrochloride

The Boc- L - proline (500mg, 2.32mmol) and N 'N - carbonyldiimidazole (1.16g, 6.97mmol) was dissolved in dry tetrahydrofuran (16 mL), the reaction conditions of 50min at 60 ℃, cooled to room temperature, Isopropanol (0.21mL, 2.79mmol) and DBU (1.06mL, 6.97mmol) were added dropwise to this solution, and the reaction was carried out at 60°C for 10h. Saturated ammonium chloride solution (15mL) was added to wash, ethyl acetate (10mL× 2) Extraction, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=8/1) to obtain 419 mg of colorless liquid: ( S )-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid isopropyl ester, yield: 70%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 4.99-5.06(m,1H),4.16-4.28(m,1H),3.35-3.58(m,2H),2.14-2.25(m,1H),1.82- 1.97 (m, 3H), 1.41 (s, 9H), 1.22-1.25 (m, 6H); MS-ESI: m/z 158.3 [M+H-100] ⁺ .

To a solution of compound ( S )-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid isopropyl ester (410 mg, 1.59 mmol) in dichloromethane (3 mL) was added HCl in ethyl acetate (4 M, 5 mL). Stir at a warm temperature for 1.5h and remove the solvent to obtain 308mg of a colorless oil: Compound ( S )-Pyrrolidine-2-carboxylic acid isopropyl ester hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 5.05-5.11 (m, 1H), 4.33-4.37 (m, 1H), 3.31-3.39 (m, 2H), 2.36-2.43 (m, 1H), 2.00 -2.11 (m, 3H), 1.27 (t, J = 5.6 Hz, 6H); MS-ESI: m/z 158.2 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid isopropyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), ( S )-pyrrolidine-2-carboxylic acid isopropyl ester hydrochloride (149 mg, 0.77 mmol), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (184mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (218mg, 1.60mmol) were dissolved in dichloromethane (20mL) at 0℃ To this solution, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise, stirred at room temperature for 16h, water (10mL×2) was added, and the organic phase was dried over anhydrous Na ₂ SO _{4 to} remove the solvent The concentrated solution was subjected to column separation (eluent: Petroleum ether/EtOAc (v/v)=4/1) to obtain 267 mg of white solid in a yield of 68%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.55(s,1H),7.53-7.54(m,1H),7.20(d, J =8.4Hz,1H),6.69(t, J _FH =75.1Hz, 1H), 5.24-5.37 (m, 1H), 4.93-5.08 (m, 1H), 4.09-4.22 (m, 1H), 3.96-4.00 (m, 2H), 3.71-3.88 (m, 2H), 2.20- 2.37(m, 2H), 1.89-2.04(m, 2H), 1.50-1.58(m, 3H), 1.43(s, 9H), 1.33-1.36(m, 1H), 1.18-1.27(m, 3H), 1.03-1.14 (m, 3H), 0.65-0.70 (m, 2H), 0.39-0.43 (m, 2H); MS-ESI: m/z 608.0 [M+H] ⁺ .

Step 3: Compound ( S )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of propyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid isopropyl ester hydrochloride

To compound ( S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid isopropyl ester (258mg, 0.42mmol) in dichloromethane (3mL) was added HCl in ethyl acetate (4M, 3mL) ), stirred at room temperature for 3h, the solvent was removed to obtain 220mg white solid, yield: 95%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.74-7.76 (m, 1H), 7.66-7.68 (m, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.92 (t, J _FH = 74.7Hz, 1H), 5.39-5.42(m, 1H), 5.16-5.21(m, 1H), 4.95-5.01(m, 1H), 4.04-4.06(m, 2H), 3.75-3.86(m, 2H) ,2.43-2.48(m,1H),2.24-2.28(m,1H),2.01-2.05(m,1H),1.90-1.97(m,1H),1.78-1.80(m,3H),1.34-1.38( m,1H),1.18(t, J =6.1Hz,3H),1.13(t, J =6.6Hz,3H),0.67-0.71(m,2H),0.43-0.46(m,2H); MS-ESI : M/z 508.0 [M+H-HCl] ⁺ .

Example 30: Compound ( S )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)-2-isopropylpyrazine-1-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of compound 2-( S )-isopropylpyrazine-1-carboxylic acid methyl ester hydrochloride

(2mL) was added dropwise a solution of carbonyl diimidazole (1.10g, 6.57mmol) in anhydrous DMF triethylamine (1.10mL, 7.88mmol) and (S) -1-BOC-3- isopropyl-Gua - to N 'N A solution of azine (1.00g, 4.38mmol) in anhydrous DMF (2mL), react in a sealed tube at room temperature for 50min, add anhydrous methanol (12mL), react at 80°C for 48h, remove the solvent, add a saturated sodium chloride solution (10mL×3) ) Wash, extract with ethyl acetate (15mL×2), combine the organic phases, dry with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrate by column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 4/1), 339 mg of colorless liquid was obtained: methyl 4-tert-butoxycarbonyl-2-( S )-isopropylpyrazine-1-carboxylate, yield: 27%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.75-4.16 (m, 4H), 3.70 (s, 3H), 2.77-2.95 (m, 3H), 1.91-2.00 (m, 1H), 1.46 (s, 9H), 1.02 (d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H); MS-ESI: m/z 187.1[M+H-100] ⁺ .

To a solution of the compound 4-tert-butoxycarbonyl-2-( S )-isopropylpyrazine-1-carboxylic acid methyl ester (388mg, 1.35mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M) , 4mL), stirred at room temperature for 1h, the solvent was removed, to obtain 301mg of a white solid: compound 2- ( S )-isopropylpyrazine-1-carboxylic acid methyl ester hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.22-4.26 (m, 1H), 3.98-4.02 (m, 1H), 3.75 (s, 3H), 3.53-3.56 (m, 1H), 3.28-3.30 (m,1H), 3.22-3.26(m,1H), 3.04-3.19(m,2H), 2.22-2.29(m,1H), 1.07(d, J =6.6Hz, 3H), 0.92(d, J = 6.6 Hz, 3H); MS-ESI: m/z 187.2 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)oxazole-4-carbonyl)-2-isopropylpyrazine-1-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), 2-( S )-isopropylpyrazine-1-carboxylic acid methyl ester hydrochloride (143 mg, 0.77 mmol), 1-ethyl-3-( 3-Dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) and N -hydroxy-7-azabenzotriazole (218 mg, 1.60 mmol) were dissolved in dichloromethane (20 mL) At 0℃, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 8h, water (10mL×2) was added, and the organic phase was anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 342 mg of a white solid in a yield of 83%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.53-7.58 (m, 2H), 7.23 (d, J = 8.5Hz, 1H), 6.69 (t, J _FH = 75.0Hz, 1H), 5.17-5.29 ( m,1H), 4.81-4.97(m,1H),4.55-4.58(m,1H),3.93-3.97(m,2H),3.83-3.91(m,1H),3.73(s,3H),3.17- 3.33 (m, 1H), 3.07 (m, 1H), 2.86-2.89 (m, 1H), 2.04-2.07 (m, 1H), 1.53 (d, J = 7.0Hz, 3H), 1.42 (s, 9H) , 1.29-1.34 (m, 1H), 1.11,0.94 (m, m, 1.5H, 1.5H), 0.85 (d, J = 6.6Hz, 3H), 0.66-0.71 (m, 2H), 0.41-0.44 ( m, 2H); MS-ESI: m/z 637.0 [M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of methyl)oxazole-4-carbonyl)-2-isopropylpyrazine-1-carboxylic acid methyl ester hydrochloride

To the compound ( S )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-2-isopropylpyrazine-1-carboxylic acid methyl ester (330 mg, 0.52 mmol) in methylene chloride (3 mL) was added HCl in ethyl acetate The solution (4M, 4 mL) was stirred at room temperature for 1 h, and the solvent was removed to obtain 290 mg of white solid in a yield of 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75 (s, 1H), 7.71-7.73 (m, 1H), 7.33-7.35 (m, 1H), 6.92 (t, J _FH = 74.7 Hz, 1H) ,5.23-5.26,5.10-5.14(m,m,0.5H,0.5H),5.02-5.05(m,1H),4.80-4.83(m,1H),4.14(t, J =14.3Hz,1H), 4.02-4.05(m, 2H), 3.87-3.93(m, 1H), 3.75(s, 3H), 3.55-3.57, 3.29-3.32(m, m, 0.5H, 0.5H), 3.00-3.03(m, 1H), 2.03-2.10 (m, 1H), 1.78 (d, J = 7.0Hz, 3H), 1.30-1.37 (m, 1H), 1.11, 1.05 (d, d, J = 6.5Hz, J = 6.4Hz , 1.5H, 1.5H), 0.88 (d, J = 6.9Hz, 3H), 0.69-0.70 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 537.0 [M+H -HCl] ⁺ .

Example 31: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of azole-4-carbonyl) -N -methyl- N -propylpyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of compound 1- N -methyl- N -propylmethanylpyrazine hydrochloride

Dissolve N , N -carbonyldiimidazole (538mg, 3.22mmol) and N- Boc pyrazine (500mg, 2.68mmol) in anhydrous DMF (6mL), and add triethylamine (1.90) to this solution dropwise at room temperature mL, 13.42mmol), react at 60°C for 30min, add N -methyl n-propylamine (0.96mL, 9.40mmol), react in a sealed tube at 80°C for 29h, remove the solvent, add saturated sodium chloride solution (15mL), Extracted with ethyl acetate (10mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1), 180 mg of a light yellow solid was obtained: 1- N -methyl- N -propylcarboxamide-4-tert-butoxycarbonylpyrazine, yield: 23%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.42 (t, J =5.1 Hz, 4H), 3.16 (t, J =5.2 Hz, 6H), 2.82 (s, 3H), 1.53-1.59 (m, 2H ), 1.46 (s, 9H), 0.87 (t, J = 7.4 Hz, 3H); MS-ESI: 186.3 [M-100+H] ⁺ .

To a solution of compound 1- N -methyl- N -propylmethanyl-4-tert-butoxycarbonylpyrazine (242mg, 0.85mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M) , 4mL), stirred at room temperature for 1.5h, and removed the solvent to obtain 188mg of a pale yellow viscous material: compound 1- N -methyl- N -propylmethanylpyrazine hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.29 (t, J =5.1 Hz, 4H), 3.11 (t, J =5.0 Hz, 4H), 3.06 (t, J =7.3 Hz, 2H), 2.76 (s, 3H), 1.43-1.49 (m, 2H), 0.75 (t, J = 7.4 Hz, 3H); MS-ESI: m/z 186.2 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(methyl(propyl )Synthesis of aminomethylamide)pyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300mg, 0.64mmol), 1- N -methyl- N -propylmethanylpyrazine hydrochloride (184mg, 0.77mmol), 1-ethyl-3-( 3-Dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) and N -hydroxy-7-azabenzotriazole (218 mg, 1.60 mmol) were dissolved in dichloromethane (20 mL) At 0°C, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 15h, washed with water (10mL×2), and the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 245 mg of a colorless viscous substance, yield: 60%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.54 (d, J =1.7 Hz, 1H), 7.23 (d, J =8.3 Hz, 1H), 6.69 (t, J _FH = 75.1Hz, 1H), 5.19-5.23 (m, 1H), 3.96 (d, J = 6.9Hz, 2H), 3.90-3.98 (m, 2H), 3.77 ( m, 2H), 3.30 (m, 4H), 3.16 (t, J = 7.4Hz, 2H), 2.85 (s, 3H), 1.57-1.61 (m, 2H), 1.54 (d, J = 7.0Hz, 3H ), 1.42 (s, 9H), 1.29-1.33 (m, 1H), 0.89 (t, J = 7.4Hz, 3H), 0.66-0.70 (m, 2H), 0.38-0.42 (m, 2H); MS- ESI: m/z 636.1[M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole -4-carbonyl) -N -methyl- N -propylpyrazine-1-carboxamide hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(methyl(propyl)amine Ethyl acetate solution of methylene chloride (3mL) solution of tert-butyl methylcarbamoyl))pyrazine-1-carbonyl)oxazol-5-yl)ethyl)carbamate (240mg, 0.38mmol) (4M, 4mL), stirred at room temperature for 40min, and removed the solvent to obtain 215mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.69 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.86 (t, J _FH = 74.7Hz, 1H), 4.99-5.02(m, 1H), 4.13(m, 2H), 3.98(d, J = 6.8Hz, 2H), 3.75(m, 2H), 3.30(m, 4H), 3.17 (t, J = 7.2Hz, 2H), 2.87 (s, 3H), 1.74 (d, J = 6.8Hz, 3H), 1.54-1.60 (m, 2H), 1.26-1.28 (m, 1H), 0.86 ( t, J = 7.3 Hz, 3H), 0.61-0.64 (m, 2H), 0.37-0.38 (m, 2H); MS-ESI: m/z 536.0 [M+H-HCl] ⁺ .

Example 32: Compound 1-(( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-yl)-2-cyclopropylethanone hydrochloride

Step 1: Synthesis of compound 1-cyclopropylacetyl-2-( R )-methylpyrazine hydrochloride

Compound ( R )-4-Boc-2-methylpyrazine (200mg, 1.00mmol), cyclopropionic acid (120mg, 1.20mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimine hydrochloride (287 mg, 1.50 mmol) and N -hydroxy-7-azabenzotriazole (340 mg, 2.50 mmol) were dissolved in dichloromethane (20 mL) and added to this solution at 0°C N , N -diisopropylethylamine (0.70mL, 4.00mmol) was added dropwise, stirred at room temperature for 16h, washed with water (10mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was carried out Column chromatography separation (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 260 mg of a colorless liquid: 1-cyclopropylacetyl-4-tert-butoxycarbonyl-2-( R ) -Methylpyrazine, yield: 92%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.85-4.14 (m, 3H), 3.31-3.55 (m, 1H), 2.80-2.97 (m, 3H), 2.30-2.33, 2.20-2.23 (m, m , 0.5H, 1.5H), 1.46 (s, 9H), 1.15-1.24 (m, 3H), 1.03-1.07 (m, 1H), 0.55-0.57 (m, 2H), 0.15-0.18 (m, 2H) .

To a solution of the compound 1-cyclopropylacetyl-4-tert-butoxycarbonyl-2-( R )-methylpyrazine (260mg, 0.90mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 1.5h, and the solvent was removed to obtain 201mg of white solid: compound 1-cyclopropylacetyl-2-( R )-methylpyrazine hydrochloride, yield: 99%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 4.86-4.90, 4.30-4.50 (m, m, 0.5H, 0.5H), 3.92-4.01, 3.38-3.52 (m, m, 0.5H, 0.5H) , 3.28-3.31 (m, 1H), 3.22-3.24 (m, 1H), 3.10-3.15 (m, 1H), 2.91-2.97 (m, 1H), 2.31-2.35 (m, 1H), 2.20-2.26 ( m,1H),1.21-1.30(m,3H),0.88-0.94(m,1H),0.44-0.48(m,2H),0.08-0.11(m,2H); MS-ESI: m/z 183.2[ M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(4-(( R )-4-(2-Cyclopropylacetyl)-3-methylpyrazine-1-carbonyl)-2-(3-( Synthesis of cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), 1-cyclopropylacetyl-2-( R )-methylpyrazine hydrochloride (168 mg, 0.77 mmol), 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) and N -hydroxy-7-azabenzotriazole (218 mg, 1.60 mmol) were dissolved in dichloromethane (20 mL ), N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 17h, washed with water (10mL×2), and the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 226 mg of a white solid in a yield of 55%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.57(d, J =8.3Hz,1H),7.53(s,1H),7.24(d, J =8.4Hz,1H),6.70(t, J _FH = 75.0Hz, 1H), 6.09 (br.s, 1H), 5.20-5.28 (m, 1H), 4.50-4.85 (m, 3H), 3.96 (d, J = 6.9Hz, 2H), 3.44-3.68 (m , 2H), 2.92-3.21(m, 2H), 2.21-2.40(m, 2H), 1.54-1.59(m, 3H), 1.41(s, 9H), 1.29-1.32(m, 1H), 1.24-1.27 (m, 3H), 1.08-1.17(m, 1H), 0.66-0.71(m, 2H), 0.58-0.60(m, 2H), 0.40-0.41(m, 2H), 0.18-0.19(m, 2H) ; MS-ESI: m/z 633.1 [M+H] ⁺ .

Step 3: Compound 1-(( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-yl)-2-cyclopropylethanone hydrochloride

To the compound (( S )-1-(4-((R)-4-(2-cyclopropylethynyl)-3-methylpyrazine-1-carbonyl)-2-(3-(cyclopropyl Methoxymethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (219 mg, 0.35 mmol) in methylene chloride (3 mL) was added A solution of HCl in ethyl acetate (4M, 4mL) was stirred at room temperature for 1h, and the solvent was removed to obtain 190mg of a white solid. Yield: 96%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.72-7.77 (m, 2H), 7.33 (d, J = 7.6Hz, 1H), 6.93 (t, J _FH = 74.7Hz, 1H), 5.06-5.09 (m,1H),4.93-5.04(m,1H),4.41-4.58(m,2H),4.05(d, J =6.0Hz,2H),3.93-3.95,3.46-3.61(m,m,0.5H , 1.5H), 2.95-3.16, 2.52-2.54 (m, m, 1.5H, 0.5H), 2.38-2.40 (m, 1H), 2.30-2.35 (m, 1H), 1.79-1.82 (m, 3H) , 1.30-1.35 (m, 3H), 1.23-1.26 (m, 1H), 1.05-1.09 (m, 1H), 0.69-0.70 (m, 2H), 0.55-0.58 (m, 2H), 0.44-0.45 ( m, 2H), 0.22-0.23 (m, 2H); MS-ESI: m/z 533.0 [M+H-HCl] ⁺ .

Example 33: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid (2-methoxy) ethyl ester hydrochloride

Step 1: Synthesis of compound 2-( R )-methylpyrazine-1-carboxylic acid (2-methoxy) ethyl ester hydrochloride

Dissolve N , N -carbonyldiimidazole (501mg, 3.00mmol) and ( R )-4-Boc-2-methylpyrazine (500mg, 2.50mmol) in anhydrous DMF (4mL). Triethylamine (0.63mL, 4.49mmol) was added dropwise to the solution, stirred at room temperature for 50min, ethylene glycol monomethyl ether (10mL) was added, reacted in a sealed tube at 80°C for 47h, the solvent was removed, and ethyl acetate was added, Washed with saturated sodium chloride solution (15mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1 ) To obtain 372 mg of yellow liquid: 4-tert-butoxycarbonyl-2-( R )-methylpyrazine-1-carboxylic acid (2-methoxy) ethyl ester, yield: 49%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 4.26-4.29 (m, 1H), 4.23-4.25 (m, 2H), 4.07-4.08, 3.79-3.80 (m, m, 0.5H, 0.5H), 3.85 -3.89(m, 2H), 3.59(t, J = 4.7Hz, 2H), 3.38(s, 3H), 3.07-3.12(m, 1H), 2.95-3.02(m, 1H), 2.72-2.85(m , 1H), 1.46 (s, 9H), 1.15 (d, J = 6.8Hz, 3H).

To a solution of compound 4-tert-butoxycarbonyl-2-( R )-methylpyrazine-1-carboxylic acid (2-methoxy) ethyl ester (367mg, 1.21mmol) in dichloromethane (4mL) was added HCl Ethyl acetate solution (4M, 4mL), stirred at room temperature for 1h, and removed the solvent to obtain 289mg of yellow oil: Compound 2-( R )-methylpyrazine-1-carboxylic acid (2-methoxy) ethyl salt Acid salt, yield: 99%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 4.58-4.60 (m, 1H), 4.25-4.30 (m, 2H), 4.16-4.19 (m, 1H), 3.64 (t, J = 4.6Hz, 2H) ), 3.39(s, 3H), 3.35-3.38(m, 2H), 3.29-3.31(m, 1H), 3.24-3.27(m, 1H), 3.06-3.11(m, 1H), 1.36(d, J = 7.2 Hz, 3H); MS-ESI: m/z 203.2 [M+H-HCl] ⁺ .

Step 2: Compound ( R )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid (2-methoxy) ethyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), 2-( R )-methylpyrazine-1-carboxylic acid (2-methoxy) ethyl ester hydrochloride (184 mg, 0.77 mmol), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (184mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (218mg, 1.60mmol) were dissolved in N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution in methyl chloride (20mL) at 0℃, stirred at room temperature for 17h, washed with water (10mL×2), organic The phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 241 mg of colorless viscous material, yield: 57% .

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.57(d, J =8.3Hz,1H),7.53(s,1H),7.24(d, J =8.4Hz,1H),6.70(t, J _FH = 75.0Hz, 1H), 5.20-5.30(m, 1H), 4.55-4.70(m, 2H), 4.27(t, J =4.2Hz, 2H), 3.96(d, J =5.6Hz, 2H), 3.61( t, J = 4.6Hz, 2H), 3.39(s, 3H), 3.21-3.25(m, 2H), 2.90-3.06(m, 1H), 2.20-2.31(m, 2H), 1.53-1.56(m, 3H), 1.42 (s, 9H), 1.31-1.35 (m, 1H), 1.24-1.27 (m, 3H), 0.66-0.71 (m, 2H), 0.40-0.41 (m, 2H); MS-ESI: m/z 653.4[M+H] ⁺ .

Step 3: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of hydroxy)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid (2-methoxy) ethyl ester hydrochloride

To the compound ( R )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid (2-methoxy)ethyl ester (235mg, 0.36mmol) in dichloromethane (3mL) A solution of HCl in ethyl acetate (4M, 4mL) was added, and the mixture was stirred at room temperature for 1h. The solvent was removed to obtain 210mg of a white solid. Yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75 (d, J = 8.0 Hz, 1H), 7.71-7.74 (m, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.92 (t, J _FH = 74.7Hz, 1H), 5.07-5.09(m, 1H), 4.96-4.98(m, 1H), 4.44-4.51(m, 2H), 4.24-4.30(m, 2H), 4.03-4.05(m ,1H),4.05(d, J =5.8Hz,2H),3.65(t, J =4.5Hz,2H),3.60-3.62,3.28-3.30(m,m,0.5H,0.5H),3.40(s ,3H),3.36-3.39(m,1H),3.17-3.19,3.03-3.08(m,m,0.5H,0.5H),1.80(d, J =6.5Hz,3H),1.32-1.35(m, 1H), 1.31-1.32, 1.24-1.25 (m, m, 1.5H, 1.5H), 0.67-0.70 (m, 2H), 0.44-0.45 (m, 2H); MS-ESI: m/z 553.1 [M +H-HCl] ⁺ .

Example 34: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) phenyl) oxazole-4-carbonyl) - N - (cyclopropylmethyl) -2-methyl-piperazine -1-carboxylic Amides hydrochloride

Step 1: Compound (R) - carboxylic acid hydrochloride Amides (cyclopropylmethyl) -2-methyl-piperazine -1- - N

Dissolve N , N -carbonyldiimidazole (626mg, 3.74mmol) in anhydrous DMF (4mL), add triethylamine (0.52mL, 3.74mmol) to this solution dropwise at room temperature, and slowly add cyclopropyl dropwise Methylamine (0.32mL, 3.74mmol), react at room temperature for 50min, add ( R )-4-Boc-2-methylpyrazine (300mg, 1.50mmol) in anhydrous DMF (3mL), and seal the tube at 60℃ After reacting for 23 hours, the solvent was removed, washed with saturated sodium chloride solution (15 mL), extracted with ethyl acetate (10 mL × 2), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (leaching Washing agent: Petroleum ether/EtOAc (v/v)=1/1), to obtain 400 mg of white solid: ( R )-4-((cyclopropylmethyl)carbonyl)-3-methylpyrazine-1-carboxylic acid Tert-butyl ester, yield: 89%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.50 (m, 1H), 4.09-4.14 (m, 1H), 3.60-3.83 (m, 1H), 3.07-3.14 (m, 2H), 3.02-3.05( m, 3H), 2.80-2.90 (m, 1H), 1.46 (s, 9H), 1.15 (d, J = 6.5Hz, 3H), 0.96-0.99 (m, 1H), 0.46-0.50 (m, 2H) , 0.14-0.18 (m, 2H).

To a solution of compound ( R )-4-((cyclopropylmethyl)carbonyl)-3-methylpyrazine-1-carboxylic acid tert-butyl ester (684mg, 2.30mmol) in dichloromethane (6mL) was added HCl ethyl acetate solution (4M, 6mL), stirred at room temperature for 3.5 h, the solvent was removed to give 537mg as colorless viscous composition: compound (R) - N - (cyclopropylmethyl) -2-methyl-1-piperazine Acetamide hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.33-4.36 (m, 1H), 3.88-3.92 (m, 1H), 3.20-3.23 (m, 1H), 3.12-3.13 (m, 1H), 3.04 -3.08(m,1H), 2.91(d, J =7.0Hz, 2H), 2.88-2.89(m,2H), 1.18(d, J =7.1Hz, 3H), 0.87-0.88(m,1H), 0.29-0.31 (m, 2H), 0.04-0.06 (m, 2H); MS-ESI: m/z 198.3 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)-4-(( R )-4-((cyclopropylmethoxy)carbonyl)-3-methylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl Ester synthesis

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), ( R )- N -(cyclopropylmethyl)-2-methylpyrazine-1-carboxamide hydrochloride (224 mg, 0.96 mmol) , 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (184mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (218mg, 1.60mmol) Dissolve in dichloromethane (20mL), add N , N -diisopropylethylamine (0.45mL, 2.56mmol) to this solution dropwise at 0℃, stir at room temperature for 15h, add water (10mL×2) After washing, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/2) to obtain 241 mg of a white solid in a yield of: 58%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 7.56-7.58(m,1H),7.53(s,1H),7.23(d, J =8.3Hz,1H),6.69(t, J _FH =75.0Hz, 1H), 5.22-5.28(m,1H),4.65-4.70(m,1H),4.52-4.58(m,2H),4.20-4.25(m,1H),3.95-3.97(m,2H),3.72- 3.85 (m, 1H), 3.52-3.55, 2.97-3.01 (m, m, 0.5H, 0.5H), 3.24-3.32 (m, 1H), 3.10-3.12 (m, 2H), 1.53-1.55 (m, 3H), 1.41 (s, 9H), 1.31-1.33 (m, 1H), 1.24-1.26 (m, 3H), 0.96-0.99 (m, 1H), 0.67-0.70 (m, 2H), 0.49-0.52 ( m, 2H), 0.39-0.41 (m, 2H), 0.18-0.21 (m, 2H); MS-ESI: m/z 648.5 [M+H] ⁺ .

Step 3: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene yl) oxazole-4-carbonyl) - N - (cyclopropylmethyl) -2-methyl-piperazine-1-acyl-amine hydrochloride

To the compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( R )-4-((cyclopropyl Methoxy)carbonyl)-3-methylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)tert-butylaminocarbamate (232mg, 0.36mmol) in dichloromethane (4mL) A solution of HCl in ethyl acetate (4M, 4mL) was added, and the mixture was stirred at room temperature for 30min. The solvent was removed to obtain 208mg of a white solid. Yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75 (d, J = 7.9 Hz, 2H), 7.71-7.72 (m, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.92 (t, J _FH = 74.7Hz, 1H), 5.06-5.08(m, 1H), 4.98-5.00(m, 1H), 4.44-4.53(m, 1H), 4.49-4.41(m, 1H), 4.04(d, J =5.8Hz, 2H), 3.91-3.95(m, 1H), 3.58-3.61, 3.37-3.39(m, m, 0.5H, 0.5H), 3.17-3.25(m, 1H), 3.06-3.10(m, 2H), 3.02-3.04, 3.27-3.30 (m, m, 0.5H, 0.5H), 1.80 (d, J = 6.4Hz, 3H), 1.33-1.35 (m, 1H), 1.29, 1.21 (d, J =6.4Hz, d, J =6.4Hz, 1.5H, 1.5H), 1.04-1.06(m, 1H), 0.68-0.71(m, 2H), 0.47-0.50(m, 2H), 0.44-0.45(m , 2H), 0.22-0.24 (m, 2H); MS-ESI: m/z 548.4 [M+H-HCl] ⁺ .

Example 35: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazole-4-carbonyl)pyridine-4-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of Compound 4-Pyridoxic Acid Methyl Ester Hydrochloride

To a solution of methyl N- Boc-4-pyridinecarboxylate (2.16 g, 8.88 mmol) in dichloromethane (3 mL) was added a solution of HCl in ethyl acetate (4M, 6 mL), stirred at room temperature for 1.5 h, and the solvent was removed, 1.59 g of a white solid was obtained: the compound 4-picolinic acid methyl ester hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.73 (s, 3H), 3.44-3.39 (m, 2H), 3.15-3.09 (m, 2H), 2.82-2.77 (m, 1H), 2.21-2.16 (m,2H), 1.99-1.89(m,2H); MS-ESI: m/z 144.2[M+H-HCl] ⁺ .

Step 2: Compound ( S )-1-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of methyloxy)phenyl)oxazole-4-carbonyl)pyridin-4-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (1.5g, 3.20mmol), methyl 4-pyridinecarboxylate hydrochloride (690mg, 3.84mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimine hydrochloride (921mg, 4.80mmol) and N -hydroxy-7-azabenzotriazole (1.09g, 8.01mmol) were dissolved in dichloromethane (20mL) and added to this solution at 0°C N , N -diisopropylethylamine (2.2 mL, 12.8 mmol) was added dropwise, stirred at room temperature for 12 h, washed with water (10 mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution Column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) was performed to obtain 1.49 g of light yellow oil, yield: 78%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.58 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.54 (d, J =1.9 Hz, 1H), 7.22 (d, J =8.3 Hz, 1H), 6.69 (t, J _FH = 75.1Hz, 1H), 5.22-5.18 (m, 1H), 4.46 (br.s, 2H), 3.96 (d, J = 7.0Hz, 2H), 3.71 ( s, 3H), 2.65-2.60 (m, 1H), 2.03-1.93 (m, 2H), 1.82-1.78 (m, 2H), 1.53 (d, J = 7.1Hz, 3H), 1.42 (s, 9H) , 1.33-1.31 (m, 1H), 0.69-0.66 (m, 2H), 0.41-0.39 (m, 2H); MS-ESI: m/z 594.0 [M+H] ⁺ .

Step 3: Compound ( S )-1-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of methyl-4-carbonyl)pyridin-4-carboxylate hydrochloride

To compound ( S )-1-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)pyridine-4-carboxylic acid methyl ester (210mg, 0.35mmol) in dichloromethane (3mL) was added HCl in ethyl acetate (4M, 3mL), stirred at room temperature After 1.5h, the solvent was removed to obtain 175mg of white solid. Yield: 93%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.74 (d, J =1.8 Hz, 1H), 7.71 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.32 (d, J = 8.3Hz, 1H), 6.92(t, J _FH = 74.7Hz, 1H), 5.04-5.01(m, 1H), 4.77-4.75(m, 1H), 4.49-4.47(m, 1H), 4.04(d, J = 6.9Hz, 2H), 3.72 (s, 3H), 3.48-3.45 (m, 1H), 3.13-3.10 (m, 1H), 2.80-2.76 (m, 1H), 2.07-2.05 (m, 2H) ,1.84-1.80(m,1H),1.79(d, J =7.0Hz,3H),1.76-1.72(m,1H),1.35-1.32(m,1H),0.70-0.67(m,2H),0.45 -0.43 (m, 2H); MS-ESI: m/z 494.0 [M+H-HCl] ⁺ .

Example 36: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazol-4-carbonyl) -N -cyclopropylpyridin-4-carboxamide hydrochloride

Step 1: Compound ( S )-1-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)pyridine-4-carboxylic acid

The compound ( S )-1-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy ) phenyl) oxazole-4-carbonyl) piperidine-4-carboxylate (623mg, 1.05mmol) was dissolved in THF (10mL) and H ₂ O (5mL) mixed solvent, was added lithium hydroxide monohydrate (220mg, 5.25mmol), react at 45°C for 1.5h, add HCl (1M) to adjust the pH of the solution to about 1, extract with ethyl acetate (10mL×3), and combine the organic phases with anhydrous Na ₂ SO _4. Dry and remove the solvent to obtain 592 mg of white solid. Yield: 97%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.58 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.54 (d, J =1.7 Hz, 1H), 7.23 (d, J =8.3 Hz, 1H), 6.69 (t, J _FH = 75.1Hz, 1H), 5.24-5.16 (m, 1H), 4.45 (br.s, 2H), 3.96 (d, J = 6.9Hz, 2H), 3.40- 3.30 (m, 1H), 3.10-3.05 (m, 1H), 2.70-2.65 (m, 1H), 2.04-2.00 (m, 2H), 1.85-1.80 (m, 2H), 1.54 (d, J = 7.0 Hz, 3H), 1.42 (s, 9H), 1.34-1.32 (m, 1H), 0.70-0.65 (m, 2H), 0.42-0.38 (m, 2H); MS-ESI: m/z 580.4[M+ H] ⁺ .

Step 2: Compound ( S )-(1-(4-(4-(Cyclopropylaminomethylcarbonyl)pyridin-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-1-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)pyridine-4-carboxylic acid (220 mg, 0.38 mmol), cyclopropylamine (0.03 mL, 0.45 mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (109mg, 0.57mmol) and N -hydroxy-7-azabenzotriazole (129mg, 0.95mmol) were dissolved in dichloromethane (15mL), and the solution was added at 0℃ N , N -diisopropylethylamine (0.27mL, 1.52mmol) was added dropwise, stirred at room temperature for 20h, washed with water (10mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution Column chromatography (eluent: DCM/MeOH (v/v) = 30/1) was performed to obtain 213 mg of white solid in a yield of 90%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.54 (s, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.69(t, J _FH = 75.1Hz, 1H), 5.20-5.17(m, 1H), 4.56-4.64(m, 2H), 3.96(d, J = 6.9Hz, 2H), 3.20-3.15(m, 1H) ), 2.90-2.85(m, 1H), 2.72-2.70(m, 1H), 2.37-2.30(m, 1H), 1.89-1.84(m, 2H), 1.80-1.74(m, 2H), 1.53(d , J = 7.0Hz, 3H), 1.42 (s, 9H), 1.35-1.32 (m, 1H), 0.81-0.76 (m, 2H), 0.70-0.66 (m, 2H), 0.50-0.47 (m, 2H ), 0.42-0.38 (m, 2H); MS-ESI: m/z 619.3 [M+H] ⁺ .

Step 3: Compound ( S )-1-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-carbonyl) -N -cyclopropylpyridin-4-carboxamide hydrochloride

To the compound ( S )-(1-(4-(4-(cyclopropylaminomethylcarbonyl) pyridine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (200mg, 0.32mmol) in dichloromethane (3mL) was added HCl in ethyl acetate solution (4M, 3mL), stirred at room temperature for 3h, the solvent was removed to obtain 167mg white solid, yield: 93%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.74 (s, 1H), 7.71 (dd, J ₁ =8.4 Hz, J ₂ =1.3 Hz, 1H), 7.32 (d, J =8.3 Hz, 1H) ,6.91(t, J _FH =74.7Hz,1H),5.04-5.01(m,1H),4.93-4.91(m,1H),4.66-4.64(m,1H),4.03(d, J =6.8Hz, 2H), 2.96-2.92 (m, 1H), 2.69-2.66 (m, 1H), 2.56-2.53 (m, 1H), 1.90-1.82 (m, 3H), 1.78 (d, J = 6.8Hz, 3H) ,1.75-1.73(m,1H),1.35-1.32(m,1H),0.76-0.72(m,2H),0.70-0.66(m,2H),0.52-0.50(m,2H),0.45-0.42( m, 2H); MS-ESI: m/z 519.2 [M+H-HCl] ⁺ .

Example 37: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazole-4-carbonyl)pyridin-4-carboxylic acid hydrochloride

To compound ( S )-1-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)pyridine-4-carboxylic acid (150mg, 0.26mmol) in dichloromethane (3mL) was added HCl in ethyl acetate (4M, 3mL), stirred at room temperature for 2h, Removal of the solvent gave 128 mg of white solid, yield: 95%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.74 (s, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.91 (t, J _FH =74.8Hz,1H),5.04-5.01(m,1H),4.77-4.74(m,1H),4.49-4.47(m,1H),4.04(d, J =6.8Hz,2H),3.49-3.45( m,1H),3.14-3.11(m,1H),2.74-2.71(m,1H),2.08-2.05(m,2H),1.79(d, J =6.9Hz,3H),1.35-1.32(m, 1H), 0.70-0.67 (m, 2H), 0.45-0.41 (m, 2H); MS-ESI: m/z 480.0 [M+H-HCl] ⁺ .

Example 38: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid benzyl ester hydrochloride

Step 1: Synthesis of compound 1-benzyloxycarbonyl-2-( R )-methylpyrazine hydrochloride

At room temperature to N 'N - (5mL) was added dropwise a solution of carbonyl diimidazole (1.0g, 5.99mmol) in anhydrous THF triethylamine (0.42mL, 3.00mmol), stirred at room temperature, was slowly added dropwise benzyl alcohol (0.62mL, 5.99mmol), react at room temperature for 20min, add ( R )-4-Boc-2-methylpyrazine (300mg, 1.50mmol) in anhydrous THF (9mL), react at 75°C for 26h, add dilute The hydrochloric acid solution (10 mL×3) was washed until the aqueous phase was acidic, extracted with ethyl acetate (15 mL×2), the organic phase was washed with saturated sodium bicarbonate solution (10 mL×2), and the organic phases were combined and dried over anhydrous Na ₂ SO ₄ , The solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=5/1) to obtain 267 mg of colorless liquid: 1-benzyloxycarbonyl-4-tert-butoxycarbonyl-2 -( R )-methylpyrazine, yield: 53%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.36-7.31 (m, 5H), 5.14 (s, 2H), 4.32 (br.s, 1H), 4.15-3.97 (m, 1H), 3.91-3.83 ( m,2H),3.15-3.07(m,1H),3.01-2.82(m,2H),1.46(s,9H),1.16(d, J =6.8Hz,3H); MS-ESI: m/z 235.3 [M+H-100] ⁺ .

To a solution of compound 1-benzyloxycarbonyl-4-tert-butoxycarbonyl-2-( R )-methylpyrazine (260mg, 0.78mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M, 5mL), stirred at room temperature for 1.5h, and removed the solvent to obtain 210mg of colorless viscous material: compound 1-benzyloxycarbonyl-2-( R )-methylpyrazine hydrochloride, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.39-7.34 (m, 5H), 5.21-5.16 (m, 2H), 4.61-4.59 (m, 1H), 4.20-4.17 (m, 1H), 3.38 -3.36(m,2H),3.30-3.23(m,2H),3.09-3.07(m,1H),1.35(d, J =7.2Hz,3H); MS-ESI: m/z 235.2[M+H -HCl] ⁺ .

Step 2: Compound ( R )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy Of phenyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid benzyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (250 mg, 0.53 mmol), 1-benzyloxycarbonyl-2-( R )-methylpyrazine hydrochloride (173 mg, 0.64 mmol), 1-ethyl-3-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (154 mg, 0.80 mmol) and N -hydroxy-7-azabenzotriazole (182 mg, 1.33 mmol) were dissolved in dichloromethane (15 mL), To this solution was added N , N -diisopropylethylamine (0.37mL, 2.14mmol) dropwise at 0°C, stirred at room temperature for 12h, washed with water (10mL×2), and the organic phase was washed with anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 246 mg of a white solid in a yield of 67%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.37-7.33 (m, 5H), 7.23 (d, J = 8.3 Hz, 1H ), 6.69(t, J _FH = 74.7Hz, 1H), 5.29-5.20(m, 1H), 5.17(s, 2H), 4.70-4.40(m, 3H), 4.06-4.02(m, 1H), 3.96 (d, J = 6.8Hz, 2H), 3.23-3.29 (m, 2H), 3.06-2.93 (m, 1H), 1.55-1.54 (m, 3H), 1.42 (s, 9H), 1.32-1.28 (m , 1H), 1.26-1.21 (m, 3H), 0.71-0.66 (m, 2H), 0.42-0.38 (m, 2H); MS-ESI: m/z 685.7 [M+H] ⁺ .

Step 3: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid benzyl ester hydrochloride

To the compound ( R )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid benzyl ester (246 mg, 0.36 mmol) in methylene chloride (4 mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 3h, the solvent was removed, to obtain 220mg white solid, yield: 98%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.59-7.57 (m, 1H), 7.55 (s, 1H), 7.38-7.32 (m, 5H), 7.20-7.18 (m, 1H), 6.68 (t, J _FH = 74.9Hz, 1H), 5.18-5.13(m, 2H), 5.09-5.00(m, 2H), 4.48-4.46, 4.39-4.37(m, m, 1.5H, 0.5H), 4.03-4.00( m,1H), 3.94 (d, J = 4.3Hz, 2H), 3.48-3.46, 3.24-3.20 (m, m, 0.5H, 0.5H), 3.31-3.29 (m, 1H), 3.06-3.04, 2.92 -2.90(m,m,0.5H,0.5H),1.86-1.84(m,3H),1.31-1.28(m,1H),1.26-1.19(m,3H),0.65-0.63(m,2H), 0.39-0.37 (m, 2H); MS-ESI: m/z 585.8 [M+H-HCl] ⁺ .

Example 39: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazol-4-yl)(1,1-dioxythiomorpholine) ketone hydrochloride

Step 1: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(1,1-dioxythiomorpholine Synthesis of tert-Butyl-4-oxo)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (250 mg, 0.53 mmol), thiomorpholine-1,1-dioxide hydrochloride (110 mg, 0.64 mmol), 1-ethyl-3-(3-dimethylamine Propyl)carbodiimide hydrochloride (153mg, 0.80mmol) and N -hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (15mL) at 0℃ N , N -diisopropylethylamine (0.37mL, 2.14mmol) was added dropwise to this solution, stirred at room temperature for 13h, washed with water (10mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed The concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 186 mg of white solid in a yield of 58%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.52 (d, J =1.6 Hz, 1H), 7.25 (d, J =8.4 Hz, 1H), 6.70(t, J _FH = 75.0Hz, 1H), 5.46(br.s, 1H), 5.28-5.21(m, 1H), 4.48-4.34(m, 4H), 3.96(d, J =6.9Hz, 2H), 3.23-3.12(m, 4H), 1.56(d, J =7.1Hz, 3H), 1.41(s, 9H), 1.34-1.30(m, 1H), 0.71-0.67(m, 2H), 0.42-0.38 (m, 2H); MS-ESI: m/z 586.3 [M+H] ⁺ .

Step 2: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of hydroxy)oxazol-4-yl)(1,1-dithiothiomorpholine) ketone hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(1,1-dioxythiomorpholine-4 -Carbonyl)oxazol-5-yl)ethyl)tert-butylaminocarbamate (183mg, 0.31mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL) and stirred at room temperature 2h, the solvent was removed to obtain 163mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.92 (t, J _FH =74.7Hz,1H),5.13-5.11(m,1H),4.62-4.60(m,2H),4.23-4.20(m,2H),4.04(d, J =6.7Hz,2H),3.40-3.37( m, 2H), 3.30-3.29 (m, 2H), 1.80 (d, J = 6.5Hz, 3H), 1.35-1.32 (m, 1H), 0.69-0.67 (m, 2H), 0.45-0.43 (m, 2H); MS-ESI: m/z 486.9 [M+H-HCl] ⁺ .

Example 40: Compound (5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazol-4-yl)(3-methylpyrazine-1-yl)methanone dihydrochloride

Step 1: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of tert-butyl oxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (250 mg, 0.53 mmol), 1-Boc-2-methylpyrazine (130 mg, 0.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodi Imine hydrochloride (155 mg, 0.80 mmol) and N -hydroxy-7-azabenzotriazole (182 mg, 1.33 mmol) were dissolved in dichloromethane (15 mL), and the solution was dropped at 0°C Add N , N -diisopropylethylamine (0.37mL, 2.14mmol), stir at room temperature for 5h, add water (10mL×2) to wash, dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and concentrate the column Chromatographic separation (eluent: Petroleum ether/EtOAc (v/v) = 2/1) gave 215 mg of colorless viscous material, yield: 60%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.58 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.69 (t, J _FH = 75.0Hz, 1H), 5.27-5.20(m, 1H), 4.64-4.43(m, 3H), 3.96(d, J = 6.7Hz, 2H), 3.92-3.89(m, 1H), 3.25-3.02(m , 3H), 1.54 (d, J = 7.0Hz, 3H), 1.48 (s, 9H), 1.41 (s, 9H), 1.35-1.32 (m, 1H), 1.22-1.14 (m, 3H), 0.71- 0.66 (m, 2H), 0.41-0.40 (m, 2H); MS-ESI: m/z 651.3 [M+H] ⁺ .

Step 2: Compound (5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of yl)oxazol-4-yl)(3-methylpyrazin-1-yl)methanone dihydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid tert-butyl ester (196mg, 0.30mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 1.5h, the solvent was removed to obtain 156mg white solid, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75 (s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH =74.7Hz,1H),5.14-5.10(m,1H),4.69-4.65(m,1H),4.05(d, J =6.9Hz,2H),3.85-3.79(m,1H),3.70-3.62( m,1H),3.55-3.45(m,2H),3.41-3.37(m,1H),3.28-3.15(m,1H),1.79(d, J =7.0Hz,3H),1.46-1.43(m, 3H), 1.36-1.34 (m, 1H), 0.71-0.68 (m, 2H), 0.43-0.41 (m, 2H); MS-ESI: m/z 451.4 [M+H-2HCl] ⁺ .

Example 41: Compound 1-(( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpentazin-1-yl)ethanone hydrochloride

Step 1: Synthesis of compound N -acetyl-2-( R )-methylpyrazine hydrochloride

The compound ( R )-4-Boc-2-methylpyrazine (528 mg, 2.64 mmol), glacial acetic acid (190 mg, 3.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodicarbonate Imine hydrochloride (758mg, 3.95mmol) and N -hydroxy-7-azabenzotriazole (897mg, 6.59mmol) were dissolved in dichloromethane (20mL) and added dropwise to this solution at 0°C Add N , N -diisopropylethylamine (1.8mL, 10.54mmol), stir at room temperature for 12h, add water (10mL×2) to wash, dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and concentrate the column Chromatographic separation (eluent: DCM/MeOH (v/v) = 40/1) to give 580 mg of colorless oil: compound N -acetyl-4-tert-butoxycarbonyl-2-( R )-methyl Gypazine, yield: 90%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 4.75, 4.37-4.34 (m, m, 0.5H, 0.5H), 4.13-4.08 (m, 0.5H), 3.95-3.75 (m, 2H), 3.52- 3.31 (m, 1H), 2.99 (m, 1H), 2.86-2.83 (m, 1.5H), 2.08 (d, J =12.2Hz, 3H), 1.46 (s, 9H), 1.30-1.12 (m, 3H ).

To a solution of the compound N -acetyl-4-tert-butoxycarbonyl-2-( R )-methylpyrazine (580mg, 2.39mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M, 5 mL), stirred at room temperature for 2 h, and removed the solvent to obtain 427 mg of white viscous substance: compound N -acetyl-2-( R )-methylpyrazine hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.59-4.48 (m, 1H), 3.99, 3.67-3.54 (m, m, 0.5H, 0.5H), 3.41-3.37 (m, 2H), 3.19- 3.02 (m, 2H), 2.17 (s, 3H), 1.43-1.31 (m, 3H); MS-ESI: m/z 143.3 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(4-(( R )-4-Acetyl 3-methylxazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (250 mg, 0.53 mmol), N -acetyl-2-( R )-methylpyrazine hydrochloride (114 mg, 0.64 mmol), 1-ethyl-3-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (154 mg, 0.80 mmol) and N -hydroxy-7-azabenzotriazole (182 mg, 1.33 mmol) were dissolved in dichloromethane (15 mL), N , N -diisopropylethylamine (0.37mL, 2.14mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 16h, washed with water (10mL×2), and the organic phase was washed with anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=40/1) to obtain 230 mg of a white solid in a yield of 72%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.57 (d, J = 8.2Hz, 1H), 7.53 (s, 1H), 7.24 (d, J = 8.4Hz, 1H), 6.70 (t, J _FH = 75.0Hz, 1H), 5.25-5.23(m, 1H), 4.82-4.51(m, 3H), 3.96(d, J = 6.9Hz, 2H), 3.48-3.45(m, 1H), 3.21-3.01(m ,3H),2.16-2.08(m,3H),1.55(d, J =6.7Hz,3H),1.41(s,9H),1.29-1.27(m,1H),1.25-1.23(m,3H), 0.71-0.66 (m, 2H), 0.41-0.39 (m, 2H); MS-ESI: m/z 593.3 [M+H] ⁺ .

Step 3: Compound 1-(( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-yl)ethanone hydrochloride

To the compound (( S )-1-(4-(( R )-4-acetoyl-3-methylpyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)tert-butyl carbamate (230 mg, 0.39 mmol) in dichloromethane (4 mL) was added HCl in ethyl acetate (4 mL) 4M, 5mL), stirred at room temperature for 3.5h, the solvent was removed to obtain 205mg white solid, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.75 (s, 1H), 7.73-7.72 (m, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.92 (t, J _FH = 74.7 Hz , 1H), 5.10-5.08 (m, 1H), 5.01-4.94 (m, 1H), 4.53-4.37 (m, 2H), 4.05 (d, J = 6.6Hz, 2H), 3.98-3.83 (m, 1H ), 3.60-3.53, 3.24-3.08 (m, m, 1.5H, 1.5H), 2.21-2.17 (m, 3H), 1.80 (d, J = 6.0Hz, 3H), 1.40-1.39 (m, 1H) , 1.34-1.28 (m, 3H), 0.70-0.68 (m, 2H), 0.45-0.43 (m, 2H); MS-ESI: m/z 493.9 [M+H-HCl] ⁺ .

Example 42: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazol-4-yl)(4-(cyclopentanecarbonyl)pyrazin-1-yl)methanone hydrochloride

Step 1: Synthesis of the compound cyclopentyl(pentazin-1-yl)methanone hydrochloride

Compound 1-tert-butoxycarbonylpyrazine (1.0g, 5.4mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.1g, 11mmol) and N- Hydroxy-7-azabenzotriazole (1.1g, 8.1mmol) was dissolved in dichloromethane (15mL), and cyclopentanoic acid (0.74g, 6.5mmol) was added dropwise to this solution at 0°C. and N, N - diisopropylethylamine (2.8mL, 16mmol), stirred at room temperature 12h, add water (10mL × 3), dried the organic phase over anhydrous Na ₂ SO _4, the solvent was removed by column chromatography, concentrate Separation (eluent: Petroleum ether/EtOAc (v/v)=1/4) to obtain 1.1 g of white solid: 4-(cyclopentanecarbonyl)pyrazine-1-carboxylic acid tert-butyl ester, yield: 73% .

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.58-3.63 (m, 2H), 3.48-3.54 (m, 2H), 3.39-3.54 (m, 4H), 2.85-2.94 (m, 1H), 1.79- 1.87 (m, 4H), 1.71-1.78 (m, 2H), 1.54-1.63 (m, 2H), 1.49 (s, 9H); MS-ESI: m/z 228.10 [M+H-55] ⁺ .

Compound 4-(cyclopentanecarbonyl)pyrazine-1-carboxylic acid tert-butyl ester (1.1 g, 3.9 mmol) was dissolved in dichloromethane (4 mL), and HCl in ethyl acetate solution (4M, 7 mL), stirred at room temperature for 1 h, the solvent was removed, the solid was washed with petroleum ether/ethyl acetate (v/v=4/1) (5 mL×2), and suction filtered to obtain 0.8 g of a white solid: cyclopentyl (pyrazine -1-yl) ketone hydrochloride, yield: 90%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.85-3.90 (m, 4H), 3.20-3.30 (m, 4H), 3.06-3.14 (m, 1H), 1.86-1.94 (m, 2H), 1.62 -1.81 (m, 6H); MS-ESI: m/z 183.15 [M+H] ⁺ .

Step 2: Compound ( S )-(1-(4-(4-(cyclopentanecarbonyl)pyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy Of 4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), cyclopentyl(pentazin-1-yl)methanone hydrochloride (140 mg, 0.64 mmol), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (250mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96mmol) were dissolved in dichloromethane (25mL) at 0℃ Next, N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and removed The solvent and the concentrated liquid were separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/1) to obtain 200 mg of a white solid in a yield of 49%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.59-7.61(m,1H),7.56(s,1H),7.26(d, J =8.3Hz,1H),6.72(t, J _FH =75.1Hz, 1H), 5.92 (br.s, 1H), 5.23-5.28 (m, 1H), 3.99 (d, J = 6.9Hz, 2H), 3.90-4.01 (m, 2H), 3.66-3.81 (m, 6H) , 2.88-2.99 (m, 1H), 1.82-1.91 (m, 4H), 1.74-1.80 (m, 2H), 1.57 (d, J = 7.0Hz, 3H), 1.43 (s, 9H), 1.28-1.38 (m, 3H), 0.69-0.73 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 633.25 [M+H] ⁺ .

Step 3: Compound ( S )-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Synthesis of oxazol-4-yl)(4-(cyclopentanecarbonyl)pyrazin-1-yl)methanone hydrochloride

The compound ( S )-(1-(4-(4-(cyclopentanecarbonyl)pyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Yl)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (200mg, 0.32mmol) was dissolved in dichloromethane (1mL), was added HCl in ethyl acetate solution (4M, 3mL), After stirring at room temperature for 30 min, the solvent was removed, and the solid was washed with petroleum ether (5 mL×3) to obtain 135 mg of a white solid in a yield of 80%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.76 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH =75.0Hz,1H),5.08(q, J =6.9Hz,1H),4.18-4.24(m,2H),4.05(d, J =6.9Hz,2H),3.72-3.85(m,6H),3.13 (s,1H),1.86-1.96(m,2H),1.80(d, J =7.0Hz,3H),1.60-1.81(m,6H),1.31-1.37(m,1H),0.67-0.71(m , 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 533.20 [M+H-HCl] ⁺ .

Example 43: Compound ( S )-1-(4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyrazin-1-yl)ethanone hydrochloride

Step 1: Synthesis of compound 1-(pyrazin-1-yl)ethanone hydrochloride

Compound 1-tert-butoxycarbonylpyrazine (1.0g, 5.4mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.1g, 11mmol) and N- Hydroxy-7-azabenzotriazole (1.1g, 8.1mmol) was dissolved in dichloromethane (15mL), at 0 ℃, to this solution were added dropwise acetic acid (0.64g, 11mmol) and N , N -diisopropylethylamine (2.8 mL, 16 mmol), stirred at room temperature for 12 h, washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (leaching Washing agent: Petroleum ether/EtOAc (v/v) = 1/1), 0.9 g of white solid was obtained: tert-butyl 4-acetoxypyrazine-1-carboxylate, yield: 70%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.59-3.61 (m, 2H), 3.41-3.46 (m, 6H), 2.13 (s, 3H), 1.49 (s, 9H); MS-ESI: m/ z 173.30[M-55] ⁺ .

To a solution of tert-butyl 4-acetophenazine-1-carboxylate (300 mg, 1 mmol) in dichloromethane (1 mL) was added a solution of HCl in ethyl acetate (4M, 2 mL), stirred at room temperature for 1 h, and the solvent was removed, 200 mg of white solid was obtained: 1-(pentazin-1-yl)ethanone hydrochloride, yield: 90%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.83-3.86 (m, 4H), 3.28-3.33 (m, 2H), 3.21-3.25 (m, 2H), 2.17 (s, 3H); MS-ESI : M/z 129.20 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(4-(4-Acetylpyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of tert-butyl fluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound 1-(pentazin-1-yl)ethanone hydrochloride (158 mg, 0.96 mmol), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (250mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96mmol) were dissolved in dichloromethane (25mL) at 0℃ Next, N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and removed The solvent and the concentrated liquid were separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 140 mg of a white solid in a yield of 38%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.58-7.61(m,1H),7.56(d, J =1.8Hz,1H),7.26(d, J =8.3Hz,1H),6.72(t, J _FH = 75.0Hz, 1H), 5.21-5.29 (m, 1H), 3.99 (d, J = 6.9Hz, 2H), 3.70-3.87 (m, 4H), 3.55-3.63 (m, 2H), 2.13-2.19 (s,3H),1.57(d, J =7.1Hz,3H),1.45(s,9H),1.31-1.38(m,1H),0.69-0.74(m,2H),0.41-0.45(m,2H ); MS-ESI: m/z 579.20 [M+H] ⁺ .

Step 3: Compound ( S )-1-(4-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrazin-1-yl)ethanone hydrochloride

Compound ( S )-(1-(4-(4-Acetylpyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (130mg, 0.23mmol) in dichloromethane (1mL) was added HCl in ethyl acetate (4M, 3mL), stirred at room temperature for 30min After removing the solvent, the solid was washed with petroleum ether (5 mL×3) to obtain 110 mg of white solid in a yield of 95%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.71-7.75 (m, 2H), 7.34 (d, J = 8.3Hz, 1H), 6.93 (t, J _FH = 75.0Hz, 1H), 5.04-5.10 (m,1H), 4.20-4.27(m,2H), 4.04(d, J =6.9Hz, 2H), 3.75-3.84(m,2H), 3.69-3.87(m,4H), 2.19(s,3H ), 1.79 (d, J = 7.0 Hz, 3H), 1.33-1.38 (m, 1H), 0.67-0.72 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 479.20[ M+H-HCl] ⁺ .

Example 44: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate hydrochloride

Step 1: Compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of methyloxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound 1-methyl formate, pyrazine (138 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (250mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96mmol) were dissolved in dichloromethane (25mL) and added dropwise to this solution at 0°C N, N - diisopropylethylamine (0.44mL, 2.56mmol), stirred at rT for 5h, add water (10mL × 3), dried the organic phase over anhydrous Na ₂ SO _4, the solvent was removed by column chromatography, concentrate Separation (eluent: Petroleum ether/EtOAc (v/v) = 1/1) to obtain 160 mg of white solid, yield: 44%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.58-7.60 (m, 1H), 7.56 (s, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.73 (t, J _FH = 75.0 Hz, 1H), 5.22-5.27 (m, 1H), 3.99 (d, J = 6.9Hz, 2H), 3.90-3.99 (m, 2H), 3.76 (s, 3H), 3.73-3.81 (m, 2H), 3.55 -3.67(m,4H),1.56(d, J =7.0Hz,3H),1.43(s,9H),1.34-1.37(m,1H),0.69-0.72(m,2H),0.41-0.44(m , 2H); MS-ESI: m/z 595.30 [M+H] ⁺ .

Step 2: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of methyl)oxazole-4-carbonyl)methylazine-1-carboxylate hydrochloride

The compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy ) Phenyl) oxazole-4-carbonyl) methylazine-1-carboxylate (75mg, 0.13mmol) was dissolved in dichloromethane (1mL), added ethyl acetate solution of HCl (4M, 3mL), room temperature After stirring for 30 min, the solvent was removed to obtain 65 mg of white solid. Yield: 97%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.74 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.91 (t, J _FH =75.0Hz,1H),5.02-5.08(m,1H),4.19(s,2H),4.04(d, J =6.8Hz,2H),4.79(s,2H),3.75(s,3H),3.64 (s, 4H), 1.79 (d, J = 6.2Hz, 3H), 1.30-1.37 (m, 1H), 0.67-0.71 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m /z 495.20[M+H-HCl] ⁺ .

Example 45: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of the compound xylazine-1-carboxamide hydrochloride

Compound 1-tert-butoxycarbonylpyrazine (0.6g, 3.2mmol) and triethylamine (4.6mL, 32mmol) were dissolved in anhydrous tetrahydrofuran (10mL), and at room temperature, trimethylamine was added dropwise to this solution Silyl isocyanate (4.2mL, 32mmol), stirred at room temperature for 1.5h, added ice water (10mL), spin out tetrahydrofuran, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phase was dried over anhydrous Na ₂ SO ₄ , The solvent was removed, concentrated, and the solid was ultrasonically washed with ethyl acetate (2 mL) for 1 min and filtered with suction to obtain 0.3 g of white solid: tert-butyl 4-aminomethylpyrazine-1-carboxylate, yield: 40%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.42-3.49 (m, 4H), 3.37-3.42 (m, 4H), 1.49 (s, 9H); MS-ESI: m/z 252.05 [M+Na] ⁺ .

The compound 4-aminomethyl acetophenazine-1-carboxylic acid tert-butyl ester (0.16g, 0.7 mmol) was dissolved in dichloromethane (2mL), HCl in ethyl acetate solution (4M, 2mL) was added, stirred at room temperature for 30min, the solvent was removed to obtain 0.16g white solid: Azozine-1-carboxamide hydrochloride , Yield: 100%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 3.71-3.73 (m, 4H), 3.25-3.27 (m, 4H); MS-ESI: m/z 130.10 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(4-(4-Aminomethylpyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy Of 4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound pyrazin-1-carboxamide hydrochloride (127 mg, 0.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (250mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96mmol) were dissolved in dichloromethane (15mL), at 0 ℃, to this N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to the solution, stirred at room temperature for 5h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution Column chromatography (eluent: DCM/MeOH (v/v) = 40/1) was performed to obtain 250 mg of white solid in a yield of 70%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.59 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.55 (d, J =1.9 Hz, 1H), 7.26 (d, J =8.3 Hz, 1H), 6.73(t, J _FH = 75.0Hz, 1H), 5.93(br.s, 1H), 5.21-5.30(m, 1H), 3.92-4.07(m, 2H), 3.99(d, J =6.9Hz, 2H), 3.82(br.s, 2H), 3.50-3.57(m, 4H), 1.57(d, J =7.0Hz, 3H), 1.45(s, 9H), 1.27-1.37(m, 1H), 0.69-0.73 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 580.20 [M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of hydroxy)oxazole-4-carbonyl)pyrazine-1-carboxamide hydrochloride

The compound ( S )-(1-(4-(4-aminomethylacetophenazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy ) Phenyl) oxazol-5-yl) ethyl) aminocarboxylic acid tert-butyl ester (245mg, 0.42mmol) was dissolved in dichloromethane (2mL), was added HCl in ethyl acetate solution (4M, 3mL), room After stirring for 30 min at a warm temperature, the solvent was removed to obtain 217 mg of white solid. Yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.75 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.92 (t, J _FH =74.8Hz,1H),5.02-5.10(m,1H),4.25(s,2H),4.04(d, J =6.9Hz,2H),3.83(s,2H),3.65(s,4H),1.80 (d, J =5.7Hz,3H),1.31-1.35(m,1H),0.67-0.70(m,2H),0.42-0.46(m,2H); MS-ESI: m/z 480.20[M+H -HCl] ⁺ .

Example 46: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazol-4-yl)(4-(4-fluorobenzyl)pyridazin-1-yl)methanone hydrochloride

Step 1: Synthesis of compound (4-fluorophenyl)(pyrazin-1-yl)methanone hydrochloride

Compound 1-tert-butoxycarbonylpyrazine (1.0g, 5.4mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.5g, 8.1mmol) and N -Hydroxy-7-azabenzotriazole (1.1g, 8.1mmol) was dissolved in dichloromethane (15mL), at 0 ℃, 4-fluorobenzoic acid (0.91g, 6.4 mmol) and N, N - Na ₂ SO dried diisopropylethylamine (2.8mL, 16mmol), stirred at room temperature 12h, add water (10mL × 3) washing the organic phase with anhydrous _4, removing the solvent from the concentrated solution Column chromatography separation (eluent: Petroleum ether/EtOAc (v/v)=1/5) to obtain 0.9 g of white solid: 4-(4-fluorobenzyl)pyrazine-1-carboxylic acid tert-butyl ester , Yield: 50%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.41-7.45 (m, 2H), 7.10-7.14 (m, 2H), 3.47-3.82 (m, 2H), 3.47 (s, 6H), 1.48 (s, 9H); MS-ESI: m/z 331.20 [M+Na] ⁺ .

Compound 4-(4-fluorobenzyl)pyrazine-1-carboxylic acid tert-butyl ester (0.9 g, 2.9 mmol) was dissolved in dichloromethane (3 mL), and a solution of HCl in ethyl acetate (4M, 6 mL) was added ), stirred at room temperature for 50 min, and removed the solvent to obtain 0.8 g of a white solid: (4-fluorophenyl) (pentazin-1-yl) ketone hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.56-7.59 (m, 2H), 7.23-7.27 (m, 2H), 3.88 (br.s, 4H); MS-ESI: m/z 209.00 [M +H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(4- Synthesis of tert-butyl fluorophenyl)pyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound (4-fluorophenyl)(pentazin-1-yl)methanone hydrochloride (188 mg, 0.77 mmol), 1-ethyl-3- (3-Dimethylaminopropyl)carbodiimide hydrochloride (250 mg, 1.3 mmol) and N -hydroxy-7-azabenzotriazole (175 mg, 0.77 mmol) were dissolved in dichloromethane (15 mL) At 0℃, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/2) to obtain 310 mg of a white solid in a yield of 73%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.54-7.59 (m, 2H), 7.46-7.48 (m, 2H), 7.26 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 8.2 Hz ,2H),6.73(t, J _FH =75.0Hz,1H),5.24-5.29(m,1H),3.94-4.10(m,2H),3.98(d, J =6.7Hz,2H),3.69-4.95 (m,4H),3.50-3.74(m,2H),1.57(d, J =7.0Hz,3H),1.45(s,9H),1.33-1.36(m,1H),0.69-0.72(m,2H ), 0.41-0.43 (m, 2H); MS-ESI: m/z 659.30 [M+H] ⁺ .

Step 3: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of yl)oxazol-4-yl)(4-(4-fluorobenzyl)pyrazin-1-yl)methanone hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(4-fluorophenyl)Xia Aziridine-1-carbonyl)oxazol-5-yl)ethyl)tert-butylaminocarbamate (310mg, 0.47mmol) in dichloromethane (2mL), add HCl in ethyl acetate (4M, 4mL) After stirring at room temperature for 30 min, the solvent was removed, and the solid was washed with petroleum ether (5 mL×3) to obtain 275 mg of a white solid. Yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.72-7.74 (m, 2H), 7.56-7.58 (m, 2H), 7.29-7.35 (m, 1H), 7.25 (t, J = 8.4 Hz, 2H) ), 6.92(t, J _FH = 74.8Hz, 1H), 5.05-5.10(m, 1H), 4.18-4.34(m, 2H), 3.99-4.07(m, 2H), 3.78-3.94(m, 4H) , 3.57-3.76 (m, 2H), 1.80 (d, J = 7.0Hz, 3H), 1.30-1.37 (m, 1H), 0.67-0.70 (m, 2H), 0.42-0.44 (m, 2H); MS -ESI: m/z 559.20 [M+H-HCl] ⁺ .

Example 47: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl) -N -(2,4-difluorobenzyl)pyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of compound N- (2,4-difluorobenzyl)pyrazine-1-carboxamide hydrochloride

Dissolve triethylamine (0.56mL, 4.1mmol) and N , N' -carbonyldiimidazole (CDI) (653mg, 4.1mmol) in anhydrous DMF (2mL), add 2,4-difluorobenzylamine (461mg, 3.2 mmol), after stirring at room temperature for 30 min, a solution of compound 1-tert-butoxycarbonylpyrazine (500 mg, 2.7 mmol) in anhydrous DMF (3 mL) was added, the reaction was stopped after 1 h at 60°C, the solvent DMF was removed, and water (5 mL) was added, Extracted with ethyl acetate (10mL×3), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 730mg of white solid: 4-((2,4-Difluorobenzyl)aminomethylacetoyl)pyrazine-1-carboxylic acid tert-butyl ester, yield: 77%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.34-7.40 (m, 1H), 6.77-6.88 (m, 2H), 4.88-4.98 (m, 1H), 4.43 (d, J = 5.6 Hz, 2H) , 3.36-3.44 (m, 8H), 1.47 (s, 9H); MS-ESI: m/z 300.10 [M-55] ⁺ .

To a solution of compound 4-((2,4-difluorobenzyl)aminomethylacetoyl)pyrazine-1-carboxylic acid tert-butyl ester (730 mg, 2.1 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate Ester solution (4M, 4mL), stirred at room temperature for 50min, and removed the solvent to obtain 570mg white solid: N- (2,4-difluorobenzyl)pyrazine-1-carboxamide hydrochloride, yield: 95% .

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.41 (dd, J ₁ =15.0 Hz, J ₂ = 8.2 Hz, 1H), 6.93 (t, J = 8.6 Hz, 2H), 4.40 (s, 2H) , 3.68-3.71 (m, 4H), 3.22-3.25 (m, 4H); MS-ESI: m/z 256.20 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-((2,4- Synthesis of tert-butyl difluorobenzyl)aminocarbamoyl)pyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound N -(2,4-difluorobenzyl)pyrazine-1-carboxamide hydrochloride (224 mg, 0.77 mmol), 1-ethyl -3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (250mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (175mg, 1.3mmol) dissolved in dichloromethane (15mL), at 0℃, add N , N -diisopropylethylamine (0.45mL, 2.56mmol) dropwise to this solution, stir at room temperature for 5h, wash with water (10mL×3), the organic phase is used Anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/3) to obtain 400 mg of a white solid in a yield of 88%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.58-7.60 (m, 1H), 7.55 (s, 1H), 7.39-7.42 (m, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.81 -6.88(m,2H),6.72(t, J _FH =75.0Hz,1H),5.96(br.s,1H),5.22-5.27(m,1H),4.47(d, J =5.7Hz,2H) , 4.03 (br.s, 2H), 3.98 (d, J = 6.9Hz, 2H), 3.80 (br.s, 2H), 3.52 (br.s, 4H), 1.56 (d, J = 7.0Hz, 3H ), 1.43 (s, 9H), 1.30-1.37 (m, 1H), 0.69-0.72 (m, 2H), 0.41-0.44 (m, 2H); MS-ESI: m/z 706.30 [M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-carbonyl) -N -(2,4-difluorobenzyl)pyrazine-1-carboxamide hydrochloride

Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-((2,4-difluoro To a solution of benzyl)aminocarbamoyl)pyrazine-1-carbonyl)oxazol-5-yl)ethyl)tert-butylaminocarbamate (400 mg, 0.57 mmol) in dichloromethane (2 mL) was added HCl Ethyl acetate solution (4M, 3mL), stirred at room temperature for 30min, the solvent was removed, the solid was washed with petroleum ether (5mL x 3) to obtain 360mg white solid, yield: 99%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.74(s,1H),7.71(d, J =8.4Hz,1H),7.41(dd, J ₁ =15.0Hz, J ₂ =8.3Hz,1H) ,7.33(d, J =8.3Hz,1H),6.91-6.94(m,2H),6.92(t, J _FH =75.0Hz,1H),5.04-5.08(m,1H),4.41(s,2H) , 4.20 (br.s, 2H), 4.03 (d, J = 6.8Hz, 2H), 3.80 (br.s, 2H), 3.60 (br.s, 4H), 1.79 (d, J = 6.6Hz, 3H ), 1.31-1.35 (m, 1H), 0.67-0.70 (m, 2H), 0.43-0.45 (m, 2H); MS-ESI: m/z 606.25 [M+H-HCl] ⁺ .

Example 48: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of ethyl-4-carbonyl)pyrazine-1-carboxylate hydrochloride

Step 1: Synthesis of compound ethyl pyrazine-1-carboxylate hydrochloride

Dissolve triethylamine (130mg, 1.3mmol) and N , N' -carbonyldiimidazole (CDI) (209mg, 1.3mmol) in anhydrous DMF (2mL), add 1-tert-butoxycarbonylpyrazine (200mg, 1.1mmol) ), after stirring at room temperature for 30 min, add absolute ethanol (3 mL), stop the reaction after reaction at 60 °C for 1 h, remove the solvent DMF, add water (5 mL), extract with ethyl acetate (10 mL × 3), dry over anhydrous sodium sulfate, remove the solvent, The concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 230 mg of white solid: compound 4-ethoxycarbonylpyrazine-1-carboxylic acid tert-butyl ester, yield : 83%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.17 (q, J =7.1 Hz, 2H), 3.43-3.45 (m, 8H), 1.48 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H ).

The compound 4-ethoxycarbonylpyrazine-1-carboxylic acid tert-butyl ester (220 mg, 0.85 mmol) was dissolved in dichloromethane (2 mL), HCl in ethyl acetate solution (4 M, 2 mL) was added, and stirred at room temperature for 30 min, Removal of the solvent gave 160 mg of a white solid: ethyl pyrazine-1-carboxylate hydrochloride, yield: 96%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.18 (q, J =7.1Hz, 2H), 3.74-3.76(m,4H), 3.23-3.26(m,4H), 1.30(t, J =7.1 Hz, 3H); MS-ESI: m/z 159.15 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy Of ethyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrazine-1-carboxylic acid ethyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound ethyl pyrazine-1-carboxylic acid ethyl ester hydrochloride (149 mg, 0.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (250mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (175mg, 1.3mmol) were dissolved in dichloromethane (25mL), at 0 ℃, to this N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to the solution, stirred at room temperature for 5h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution Column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) was performed to obtain 330 mg of a white solid in a yield of 84%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.58-7.61(m,1H),7.56(s,1H),7.26(d, J =8.3Hz,1H),6.72(t, J _FH =75.0Hz, 1H), 5.21-5.28 (m, 1H), 4.20 (q, J = 7.1Hz, 2H), 3.99 (d, J = 6.9Hz, 2H), 3.94 (br.s, 2H), 3.77 (br.s , 2H), 3.59 (br.s, 4H), 1.57 (d, J = 7.0Hz, 3H), 1.44 (s, 9H), 1.34-1.37 (m, 1H), 1.31 (t, J = 7.1Hz, 3H), 0.69-0.73 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 609.30 [M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of ethyl)oxazole-4-carbonyl)pyrazine-1-carboxylic acid ethyl ester hydrochloride

The compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)pyrazine-1-carboxylic acid ethyl ester (75mg, 0.54mmol) was dissolved in dichloromethane (2mL), added HCl in ethyl acetate solution (4M, 2mL), room temperature After stirring for 30 min, the solvent was removed to obtain 275 mg of white solid. Yield: 93%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75 (s, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.93 (t, J _FH = 75.0Hz, 1H), 5.05-5.09 (m, 1H), 4.17-4.21 (m, 4H), 4.04 (d, J = 6.9Hz, 2H), 3.79 (br.s, 2H), 3.63 (br. s, 4H), 1.80 (d, J = 6.2Hz, 3H), 1.34-1.37 (m, 1H), 1.31 (t, J = 7.1Hz, 3H), 0.67-0.71 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 509.25 [M+H-HCl] ⁺ .

Example 49: Compound 2-methoxycarbonyl-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate hydrochloride

Step 1: Synthesis of compound 2-methoxycarbonylpyrazine-1-carboxylic acid methyl ester hydrochloride

Dissolve triethylamine (201mg, 1.2mmol) and N , N' -carbonyldiimidazole (CDI) (160mg, 0.98mmol) in anhydrous DMF (2mL), add methyl 1-tert-butoxycarbonyl-3-carboxylate Azine (200mg, 0.82mmol), stirred at room temperature for 30min, added anhydrous methanol (5mL), the reaction was stopped after 60 hours at 60 ℃, the solvent was removed DMF, water (5mL) was added, ethyl acetate (10mL × 3) extraction, anhydrous sodium sulfate After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 4/1) to obtain 60 mg of a white solid: 3,4-dimethoxycarbonylpyrazine-1- Tert-butyl formate, yield: 24%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.71-4.77 (m, 0.5H), 4.51-4.60 (m, 1.5H), 3.90-4.09 (m, 1H), 3.80-3.95 (m, 1H), 3.72(s,3H),3.15-3.34(m,1H),3.05-3.07(m,1H),2.72-2.93(m,1H),1.42(s,9H); MS-ESI: m/z 203.10[ M+H-100] ⁺ .

The compound 3,4-dimethoxycarbonylpyrazine-1-carboxylic acid tert-butyl ester (320 mg, 1.1 mmol) was dissolved in dichloromethane (2 mL), and a solution of HCl in ethyl acetate (4M, 2 mL) was added at room temperature After stirring for 30 min, the solvent was removed to obtain 250 mg of a white solid: 2-methoxycarbonylpyrazine-1-carboxylic acid methyl ester hydrochloride, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.19-4.26 (m, 2H), 3.87-3.91 (m, 2H), 3.37-3.41 (m, 3H); MS-ESI: m/z 203.15 [M +H-HCl] ⁺ .

Step 2: Compound 2-methoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound 2-methoxycarbonylpyrazine-1-carboxylic acid methyl ester hydrochloride (153 mg, 0.64 mmol), 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide hydrochloride (250mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.3mmol) were dissolved in dichloromethane (25mL), 0 ℃ Under the conditions, N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL×3), and the organic phase was dried over anhydrous Na ₂ SO ₄ , The solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) to obtain 240 mg of a white solid in a yield of 58%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.54-7.62 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 6.73 (t, J _FH = 75.0 Hz, 1H), 5.38-5.54, 5.06-5.17(m,0.5H,0.5 H),5.25-5.29(m,1H),4.61-4.95(m,2H),3.73-4.07(m,1H),3.96-4.05(m,2H),3.74 -3.82(m,4H),3.59-3.66(m,2H),3.26-3.55(m,2H),3.00-3.19(m,1H),1.50-1.55(m,3H),1.45(s,9H) , 1.31-1.38 (m, 1H), 0.69-0.73 (m, 2H), 0.43-0.45 (m, 2H); MS-ESI: m/z 653.20 [M+H] ⁺ .

Step 3: Compound 2-methoxycarbonyl-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate hydrochloride

Compound 2-methoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate (100 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL), and HCl in ethyl acetate (4M) was added , 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 90mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.58-7.72 (m, 2H), 7.22-7.27 (m, 1 H), 6.83 (t, J _FH = 75.0 Hz, 1H), 5.46-5.60, 4.42 -4.51(m,0.5H,0.5H),4.83-4.93(m,2H),3.91-4.00(m,3 H),3.60-3.71(m,5H),3.49-3.56(m,2H),2.95 -3.03, 3.19-3.23 (m, 0.5H, 0.5H), 3.29-3.36 (m, 1H), 3.11-3.16 (m, 1H), 1.62-1.70 (m, 3H), 1.21-1.29 (m, 1H) ), 0.56-0.62 (m, 2H), 0.32-0.37 (m, 2H); MS-ESI: m/z 553.25 [M+H-HCl] ⁺ .

Example 50: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of methyl 4--4-carbonyl)-2-((2,4-difluorobenzyl)aminomethylacetoyl)pyrazine-1-carboxylate hydrochloride

Step 1: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-1-methoxycarbonylpyrazine-2-carboxylic acid

Compound 2-methoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate (150mg, 0.23mmol) and NaOH (0.4g, 10mmol) were dissolved in tetrahydrofuran (5mL) and water (5mL) In the mixed solvent, react at 40°C for 2h, add hydrochloric acid (1M) to adjust the pH to 1, extract with ethyl acetate (10mL×3), combine the organic phases, dry with Na ₂ SO ₄ and remove the solvent to obtain 145mg of white solid. Yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.58-7.62, 7.75-7.79 (m, 0.5H, 0.5H), 7.64-7.68 (m, 1H), 7.29 (d, J = 8.3 Hz, 1H) ,6.89(t, J _FH =75.0Hz,1H),5.13-5.28(m,1H),4.02(d, J =6.9Hz,2H),3.76(d, J =10.2Hz,2H),1.49-1.55 (m,3H),1.45(s,9H),1.32-1.37(m,1H),0.66-0.71(m,2H),0.42-0.45(m,2H); MS-ESI: m/z 639.30[M +H] ⁺ .

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Oxy)phenyl)oxazole-4-carbonyl)-2-((2,4-difluorobenzyl)aminomethylformyl)pyrazine-1- Synthesis of methyl formate

Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-1-methoxycarbonylpyrazine-2-carboxylic acid (150 mg, 0.23 mmol), 2,4-difluorobenzylamine (41 mg, 0.28 mmol), 1-ethyl- 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (90mg, 0.47mmol) and N -hydroxy-7-azabenzotriazole (64mg, 0.47mmol) were dissolved in dichloromethane ( 10mL), 0, N , N -diisopropylethylamine (0.13mL, 0.94mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL × 3), the organic phase was anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/3) to obtain 70 mg of a white solid in a yield of 39%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.71-7.75 (m, 1H), 7.49-7.58 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 7.67-7.76 (m, 2H) , 6.73(t, J _FH = 75.0Hz, 1H), 5.25-5.31(m, 1H), 4.71-4.91(m, 1H), 4.42-4.48(m, 2H), 4.35-4.40(m, 1H), 4.10-4.11, 4.32-4.34 (m, 0.5H, 0.5H), 4.20-4.27 (m, 1H), 3.97-3.99 (m, 2H), 3.78-3.82 (m, 3H), 3.62-3.64, 3.72 3.74(m,0.5H,0.5H),3.15-3.21,3.36-3.42(m,0.5H,0.5H),3.04-3.09,3.25-3.31(m,0.5H,0.5H),1.52-1.56(m ,3H),1.45(s,9H),1.36-1.39(m,1H),0.69-0.73(m,2H),0.41-0.44(m,2H); MS-ESI: m/z 764.30[M+H ] ⁺ .

Step 3: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-carbonyl)-2-((2,4-difluorobenzyl)aminomethylacetoyl)pyrazine-1-carboxylic acid methyl ester hydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-2-((2,4-difluorobenzyl)aminomethanyl)methylazine-1-carboxylate (60 mg, 0.08 mmol) in dichloromethane ( 1mL) solution was added HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 30min, the solvent was removed, to obtain 55mg white solid, yield: 99%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.68-7.74 (m, 2H), 7.30-7.35 (m, 1H), 7.15-7.26 (m, 1H), 6.92 (t, J _FH = 75.0Hz, 1H), 6.74-6.86 (m, 2H), 4.96-5.04 (m, 1H), 4.41-4.49 (m, 1H), 4.27-4.38 (m, 2H), 3.98-4.08 (m, 3H), 3.72 3.83(m, 3H), 3.40-3.57(m, 2H), 3.16-3.24(m, 1H), 1.76(d, J =4.8Hz, 3H), 1.31-1.38(m, 1H), 0.65-0.70( m, 2H), 0.37-0.44 (m, 2H); MS-ESI: m/z 664.20 [M+H-HCl] ⁺ .

Example 51: Compound (5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-yl) (2-methylpyrazin-1-yl) ketone dihydrochloride

Step 1: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of tert-butyl oxy)phenyl)oxazole-4-carbonyl)-3-methylpyrazine-1-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound N -tert-butoxycarbonyl-3-methylpyrazine (154 mg, 0.77 mmol), 1-ethyl-3-(3-dimethylaminopropane Group) carbodiimide hydrochloride (245mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.3mmol) were dissolved in dichloromethane (25mL) at 0 ℃, N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed, The concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) to obtain 130 mg of a white solid in a yield of 31%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.58(d, J =8.3Hz,1H),7.54(s,1H),7.23(d, J =8.3Hz,1H),6.70(t, J _FH = 75.0Hz, 1H), 5.98 (br.s, 1H), 5.14-5.24 (m, 1H), 3.97 (d, J = 6.9Hz, 2H), 4.77-4.87 (m, 1H), 4.32-4.48 (m , 1H), 3.85-3.98 (m, 1H), 3.47 (s, 3H), 2.97-3.13 (m, 2H), 1.53-1.55 (m, 3H), 1.48 (s, 9H), 1.42 (s, 9H ), 1.33-1.36 (m, 1H), 1.28 (d, J = 7.2Hz, 3H), 0.66-0.71 (m, 2H), 0.39-0.43 (m, 2H); MS-ESI: m/z 651.30[ M+H] ⁺ .

Step 2: Compound (5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of yl)oxazol-4-yl)(2-methylpyrazin-1-yl)methanone dihydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-3-methylpyrazine-1-carboxylic acid tert-butyl ester (120mg, 0.18mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 90mg white solid, yield: 93%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.93 (t, J _FH =75.0Hz,1H),5.40-5.50,5.14-5.26(m,0.5H,0.5H),5.07-5.14(m,1H),4.04(d, J =6.9Hz,2H),3.62-3.81(m , 1H), 3.41-3.51(m, 5H), 1.80(t, J = 6.7Hz, 3H), 1.52-1.67(m, 3H), 1.33-1.37(m, 1H), 0.67-0.71(m, 2H ), 0.43-0.45 (m, 2H); MS-ESI: m/z 451.25 [M+H-2HCl] ⁺ .

Example 52: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of compound 2-methylpyrazine-1-carboxylic acid methyl ester hydrochloride

Dissolve triethylamine (380mg, 3.75mmol) and N , N' -carbonyldiimidazole (CDI) (486mg, 3.0mmol) in anhydrous DMF (2mL), add tert-butyl 3-methylpyrazine-1-carboxylate (500mg, 2.5mmol), after stirring at room temperature for 30min, add anhydrous methanol (10mL), stop the reaction after reaction at 60℃ for 8h, remove the solvent DMF, add water (5mL), extract with ethyl acetate (10mL×3), and dry over anhydrous sodium sulfate , The solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=8/1) to obtain 620 mg of a white solid: 2-methyl-4-tert-butoxycarbonylpyrazine- 1-Methyl formate, yield: 96%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.24-4.34 (m, 1H), 3.93-4.16 (m, 1H), 3.79-3.92 (m, 2H), 3.73 (s, 3H), 3.07-3.14 ( m,1H),2.95-3.09 (m,1H),2.73-2.93(m,1H),1.48(s,9H),1.17(d, J =6.8Hz,3H); MS-ESI: m/z 159.20 [M+H-100] ⁺ .

To a solution of compound 2-methyl-4-tert-butoxycarbonylpyrazine-1-carboxylate (600 mg, 2.3 mmol) in dichloromethane (2 mL) was added a solution of HCl in ethyl acetate (4 M, 4 mL). Stir at a warm temperature for 30 min and remove the solvent to obtain 420 mg of a white solid: methyl 2-methylpyrazine-1-carboxylate hydrochloride, yield: 93%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 4.53-4.61(m, 1H), 4.14-4.18(m, 1H), 3.75(s, 3H), 3.33-3.38(m, 2H), 3.22-3.30 (m, 2H), 3.04-3.11 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H); MS-ESI: m/z 159.15 [M+H-HCl] ⁺ .

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy Of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound 2-methylpyrazine-1-carboxylic acid methyl ester hydrochloride (150 mg, 0.77 mmol), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (246mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (175mg, 1.3mmol) were dissolved in dichloromethane (15mL) at 0℃ Next, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 12h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and removed The solvent and the concentrated solution were separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) to obtain 186 mg of white solid in a yield of 47%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.60 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.72 (t, J _FH = 75.0Hz, 1H), 5.21-5.31(m, 1H), 4.39-4.67(m, 3H), 3.93-4.05(m, 1H), 3.99(d, J = 6.9Hz, 2H), 3.76(s, 3H ), 3.20-3.52 (m, 2H), 2.90-3.07 (m, 1H), 1.57 (d, J = 7.0Hz, 3H), 1.43 (s, 9H), 1.31-1.38 (m, 1H), 1.26 ( m, 3H), 0.69-0.73 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 609.25 [M+H] ⁺ .

Step 3: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester hydrochloride

Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester (180mg, 0.3mmol) was dissolved in dichloromethane (1mL), was added HCl in ethyl acetate solution (4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 125mg white solid, yield: 77%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.70-7.75 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.93 (t, J _FH = 75.0 Hz, 1H), 5.03-5.09 (m,1H), 4.98 (m, 1H), 4.45-4.52 (m, 2H), 4.04 (d, J = 6.9Hz, 2H), 3.99-4.06 (m, 1H), 3.75 (s, 3H), 3.57-3.63 (m, 1H), 3.34-3.40 (m, 1H), 3.21-3.28 (m, 1H), 3.02-3.18 (m, 1H), 1.79 (d, J = 7.0Hz, 3H), 1.33- 1.37(m,1H), 1.22-1.31(m,3H), 0.68-0.71(m,2H), 0.43-0.45(m,2H); MS-ESI: m/z 509.30[M+H-HCl] ⁺ .

Example 53: Compound 1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyrazine-2-carboxamide dihydrochloride

Step 1: Synthesis of the compound tert-butyl 3-aminomethylacetophenazine-1-carboxylate

Methyl N- 1-tert-butoxycarbonyl-3-pyrazinecarboxylate (500mg, 2.04mmol) and amine methanol solution (7M, 10mL) were placed in a 100mL sealed tube and reacted at 60°C. After 12h, the reaction was stopped and spun out Solvent, to obtain 450mg white solid, yield: 95%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.01-4.08 (m, 1H), 3.65-3.88 (m, 1H), 3.31-3.38 (m, 1H), 2.90-3.12 (m, 3H), 2.73 -2.82 (m, 1H), 1.47 (s, 9H); MS-ESI: m/z 130.20 [M+H-100] ⁺ .

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-3-aminomethylamylpyrazine-1-carboxylic acid tert-butyl ester synthesis

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300mg, 0.64mmol), compound 3-amino-methyl carbamoylazine-1-carboxylic acid tert-butyl ester (153mg, 0.64mmol), 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide hydrochloride (250mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.3mmol) were dissolved in dichloromethane (25mL), 0 ℃ Under this condition, N , N -diisopropylethylamine (0.33mL, 1.93mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL×3), and the organic phase was dried over anhydrous Na ₂ SO ₄ , The solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/3) to obtain 220 mg of a white solid in a yield of 50%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.52-7.61 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 6.72 (t, J _FH = 75.0 Hz, 1H), 5.42-5.49 ( m,1H),5.15-5.23(m,1H),4.01(d, J =6.9Hz,2H),3.71-3.79(m,1H),3.17-3.24(m,2H),1.59-1.64(m, 3H), 1.51 (s, 9H), 1.42 (m, 9H), 1.30-1.35 (m, 1H), 0.69-0.73 (m, 2H), 0.42-0.45 (m, 2H); MS-ESI: m/ z 680.30[M+H] ⁺ .

Step 3: Compound 1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrazine-2-carboxamide dihydrochloride

Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-3-aminomethylacetophenazine-1-carboxylic acid tert-butyl ester (225mg, 0.33mmol) in dichloromethane (2mL) was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 180mg of white solid, yield: 99%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.70-7.75 (m, 2H), 7.34 (d, J = 8.3Hz, 1H), 6.93 (t, J _FH = 75.0Hz, 1H), 5.17-5.23 (m,1H), 4.06(d, J =6.6Hz, 2H), 3.87-3.99(m,1H),3.35-3.57(m,3H),1.80-1.84(m,3H),1.32-1.37(m , 1H), 0.67-0.71 (m, 2H), 0.42-0.47 (m, 2H); MS-ESI: m/z 480.30 [M+H-2HCl] ⁺ .

Example 54: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)-1-(methoxycarbonyl)pyrazine-2-carboxylic acid hydrochloride

Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-1-methoxycarbonylpyrazine-2-carboxylic acid (180mg, 0.28mmol) was dissolved in dichloromethane (4mL), and a solution of HCl in ethyl acetate (4M, 4mL) was added ), stirred at room temperature for 30 min, and removed the solvent to obtain 160 mg of white solid, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.71-7.78 (m, 2H), 7.33 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH = 75.0 Hz, 1H), 5.07-5.16 , 5.57-5.64 (m, 0.5H, 0.5H), 4.99-5.07 (m, 1H), 4.57-4.83 (m, 1H), 4.05 (d, J = 6.8Hz, 2H), 3.99-4.09 (m, 1H), 3.77(d, J =10.1Hz, 3H), 3.36-3.47(m, 1H), 3.09-3.29(m, 1H), 1.77(t, J =7.5Hz, 3H), 1.30-1.40(m , 1H), 0.61-0.71 (m, 1H), 0.42-0.46 (m, 1H); MS-ESI: m/z 539.20 [M+H-HCl] ⁺ .

Example 55: Compound 1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazol-4-carbonyl)-4-aminomethylacetophenazine-2-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of the compound 4-aminomethylacetophenazine-2-carboxylic acid methyl ester hydrochloride

Compound N- 1-tert-butoxycarbonyl-2-pyrazinecarboxylic acid methyl ester (0.2g, 0.82mmol) and triethylamine (1.2mL, 8.2mmol) were dissolved in anhydrous tetrahydrofuran (5mL), at room temperature, to To this solution, trimethylsilyl isocyanate (1.1 mL, 8.2 mmol) was added dropwise, stirred at room temperature for 8 h, ice water (10 mL) was added, and tetrahydrofuran was spun out. The aqueous phase was extracted with ethyl acetate (10 mL×3), organic The phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and concentrated to obtain 0.2 g of a white solid: 2-methoxycarbonyl-4-aminomethylamylpyrazine-1-carboxylic acid tert-butyl ester, yield: 90%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.24 (br.s, 2H), 4.30 (d, J =13.3 Hz, 1H), 3.98-4.14 (m, 1H), 3.83-3.94 (m, 1H) , 3.78 (s, 3H), 3.18-3.28 (m, 1H), 3.03-3.12 (m, 1H), 2.79-2.96 (m, 1H), 1.50 (d, J =16.7Hz, 9H); MS-ESI : M/z 232.25[M-55] ⁺ .

Dissolve the compound 2-methoxycarbonyl-4-aminomethylacetophenazine-1-carboxylic acid tert-butyl ester (0.2 g, 0.7 mmol) in dichloromethane (2 mL) and add HCl in ethyl acetate (4M) , 2mL), stirred at room temperature for 30min, the solvent was removed, to obtain 0.15g of white solid: 4-aminomethylacetophenazine-2-carboxylic acid methyl ester hydrochloride, yield: 96%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.24-4.32 (m, 2H), 3.90-3.96 (m, 1H), 3.86 (s, 3H), 3.39-3.49 (m, 2H), 3.32-3.38 (m,1H),3.13-3.21(m,1H).

Step 2: Compound 1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of Methyloxy)phenyl)oxazole-4-carbonyl)-4-aminomethylcarbamoylazine-2-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound 4-aminomethylacetophenazine-2-carboxylic acid methyl ester hydrochloride (172 mg, 0.77 mmol), 1-ethyl-3-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (245 mg, 1.3 mmol) and N -hydroxy-7-azabenzotriazole (174 mg, 1.3 mmol) were dissolved in dichloromethane (15 mL), At 0°C, N , N -diisopropylethylamine (0.33mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=30/1) to obtain 140 mg of a white solid in a yield of 34%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.50-7.60 (m, 2H), 7.22-7.25 (m, 1H), 6.70 (t, J _FH = 75.0 Hz, 1H), 5.23-5.32 (m, 1H ), 4.95 (br.s, 2H), 4.37-4.43 (m, 1H), 4.07-4.14 (m, 1H), 3.96-3.98 (m, 2H), 3.75-3.81 (m, 3H), 3.36-3.57 (m,1.5H),3.02-3.22(m,1.5H),1.54(t, J =8.0Hz,3H),1.42(s,9H),1.31-1.35(m,1H),0.66-0.71(m , 2H), 0.39-0.43 (m, 2H); MS-ESI: m/z 638.20 [M+H] ⁺ .

Step 3: Compound 1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-carbonyl)-4-aminomethylacetophenazine-2-carboxylic acid methyl ester hydrochloride

Compound 1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-4-aminomethylacetophenazine-2-carboxylic acid methyl ester (120 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), and HCl in ethyl acetate was added (4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 100mg white solid, yield: 93%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.64-7.77 (m, 2H), 7.32-7.35 (m, 1H), 6.92 (t, J _FH = 75.0 Hz, 1H), 578-5.82, 5.20- 5.24(m,0.5H,0.5H),5.05-5.14(m,1H),4.52-4.60(m,1H),4.33-4.40(m,1H),4.02-4.06(m,2H),3.94-4.04 (m,1H),4.34-4.37,3.84-3.90(m,0.5H,0.5H),3.82(s,3H),3.46-3.55(m,1H),3.22-3.28(m,1H),1.78( t, J =7.1Hz,3H),1.31-1.36(m,1H),0.67-0.73(m,2H),0.43-0.46(m,2H); MS-ESI: m/z 538.25[M+H- HCl] ⁺ .

Example 56: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazol-4-carbonyl)-2-aminomethylcarboxamazine-1-carboxylic acid methyl ester hydrochloride

Step 1: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of methyl oxy)phenyl)oxazole-4-carbonyl)-2-aminomethylcarboxamazine-1-carboxylate

In a 50 mL sealed tube, add 2-methoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate (150mg, 0.23mmol) and amine methanol solution (7M, 15mL), after 60°C for 72h The reaction was stopped, the solvent was removed, and the residue was subjected to silica gel column separation (eluent: Petroleum ether/EtOAc (v/v)=1/2) to obtain 25 mg of a white solid in a yield of 17%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.54-7.59 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 6.73 (t, J _FH = 75.0 Hz, 1H), 5.24-5.29 ( m,1H), 3.98 (d, J = 6.9Hz, 3H), 3.81 (s, 3H), 1.56 (t, J = 6.4Hz, 3H), 1.45 (d, J = 4.9Hz, 9H), 1.31- 1.36 (m, 1H), 0.68-0.73 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 638.25 [M+H] ⁺ .

Step 2: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of Phenyl)oxazole-4-carbonyl)-2-aminomethylacetophenazine-1-carboxylic acid methyl ester hydrochloride

Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-2-aminomethylacetophenazine-1-carboxylic acid methyl ester (100 mg, 0.16 mmol) was dissolved in dichloromethane (4 mL) and HCl in ethyl acetate was added (4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 85mg white solid, yield: 94%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.71-7.76 (m, 2H), 7.33 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH = 75.0 Hz, 1H), 5.26-5.36 (m,1H), 4.99-5.02(m,1H), 4.69-4.81(m,1H), 4.41-4.49(m,1H), 4.04(d, J =6.9Hz, 3H), 3.75-3.81(m ,4H),3.43-3.57(m,1H),3.13-3.19(m,1H),1.76-1.79(m,3H),1.31-1.37(m,1H),0.68-0.72(m,2H),0.43 -0.46 (m, 2H); MS-ESI: m/z 538.20 [M+H-HCl] ⁺ .

Example 57: Compound 7-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazol-4-carbonyl)tetrahydroimidazo[1,5- a ]pyrazine-1,3-(2 H ,5 H )-dione hydrochloride

Step 1: Compound ((1 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(1,3-dioxo Synthesis of tert-Butyl tetrahydroimidazo[1,5- a ]pyrazine-7-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid

Compound 2-methoxycarbonyl-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate (150mg, 0.23mmol) and amine methanol solution (7M, 10mL) were placed in a 100mL sealed tube and reacted at 60℃ After 12h, the reaction was stopped, the solvent was swirled out, and the residue was separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 1/2) to obtain 50mg of a white solid in a yield of 35%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 8.16 (br.s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.72 (t, J _FH =75.0Hz,1H),5.25-5.30(m,1H),5.07-5.17,5.51-5.63(m,0.5H,0.5H),4.79(d, J =11.0Hz,1H),4.17-4.34( m, 2H), 3.99 (d, J = 6.9Hz, 2H), 3.09-3.25 (m, 2H), 2.75-2.87 (m, 1H), 1.54-1.59 (m, 3H), 1.42 (s, 9H) , 1.30-1.36 (m, 1H), 0.66-0.73 (m, 2H), 0.41-0.43 (m, 2H); MS-ESI: m/z 606.20 [M+H] ⁺ .

Step 2: Compound 7-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene ))Oxazol-4-carbonyl)tetrahydroimidazo[1,5- a ]pyrazine-1,3-(2 H ,5 H )-dione hydrochloride

To the compound ((1 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(1,3-dioxotetrahydro A solution of imidazo[1,5- a ]pyrazine-7-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (150 mg, 0.25 mmol) in dichloromethane (1 mL) was added with HCl Ethyl acetate solution (4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 120mg white solid, yield: 89%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.72-7.81 (m, 2H), 7.33-7.35 (m, 1H), 6.93 (t, J _FH = 75.0 Hz, 1H), 5.12-5.20, 5.45 5.53(m,0.5H,0.5H),5.07-5.13(m,1H),4.68-4.70,4.96-5.00(m,0.5H,0.5H),4.22-4.27,4.44-4.50(m,0.5H, 0.5H), 4.11-4.17 (m, 1H), 4.04 (d, J = 6.9Hz, 2H), 3.13-3.19, 3.29-3.37 (m, 0.5H, 0.5H), 2.95-3.03 (m, 1H) ,1.77-1.82(m,3H),1.31-1.35(m,1H),0.68-0.71(m,2H),0.43-0.46(m,2H); MS-ESI: m/z 506.20[M+H- HCl] ⁺ .

Example 58: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole- Synthesis of 4-yl) (morpholinyl) ketone hydrochloride

Step 1: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(morpholine-4-carbonyl)oxo Synthesis of tert-butyl 5-oxoyl-5-ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300mg, 0.64mmol), morpholine (83mg, 0.96mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (245mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96mmol) were dissolved in dichloromethane (25mL), at 0 ℃, to this solution was added N , N- diiso propyl-ethylamine (0.34mL, 1.92mmol), stirred at rT for 5h, add water (10mL × 3), dried the organic phase over anhydrous Na ₂ SO _4, the solvent was removed, the concentrate was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1), 175 mg of white solid was obtained, yield: 51%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.59 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.55 (d, J =1.9 Hz, 1H), 7.25 (d, J =8.3 Hz, 1H), 6.72 (t, J _FH = 75.1Hz, 1H), 5.21-5.28 (m, 1H), 4.00-4.08 (m, 2 H), 3.99 (d, J = 6.9Hz, 2H), 3.74 -3.81(m,6H),1.57(d, J =7.0Hz,3H),1.45(s,9H),1.33-1.36(m,1H),0.68-0.73(m,2H),0.40-0.44(m , 2H); MS-ESI: m/z 538.20 [M+H] ⁺ .

Step 2: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of hydroxy)oxazol-4yl)(morpholinyl) ketone hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(morpholine-4-carbonyl)oxazole- 5-Methyl) ethyl) tert-butyl carbamate (170mg, 0.13mmol) in dichloromethane (2mL) was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 145mg white solid, yield: 97%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.74(s,1H),7.71(dd, J ₁ =8.3Hz, J ₂ =1.7Hz,1H),7.33(d, J =8.3Hz,1H) ,6.93(t, J _FH =75.1Hz,1H),5.05-5.88(m,1H),4.20(br.s,2H),4.04(d, J =6.9Hz,2H),3.80(s,6H) , 1.79 (d, J = 7.0Hz, 3H), 1.33-1.37 (m, 1H), 0.68-0.71 (m, 2H), 0.43-0.46 (m, 2H); MS-ESI: m/z 438.30 [M +H-HCl] ⁺ .

Example 59: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyrazine-2-carboxamide dihydrochloride

Step 1: Synthesis of the compound 2-aminomethyl acetophenazine-1-carboxylic acid tert-butyl ester

A solution of methyl 1-tert-butoxycarbonyl-2-pyrazinecarboxylate (500 mg, 2.04 mmol) and amine methanol (7M, 10 mL) was placed in a 100 mL sealed tube and reacted at 60°C. After 72 h, the reaction was stopped and the solvent was swirled out. 200 mg of white solid was obtained, yield: 42%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 5.47-5.76, 6.11-6.36 (m, 0.5H, 0.5H), 4.51-4.68 (m, 1H), 3.44-3.57 (m, 1H), 2.89- 3.02 (m, 2H), 2.66-2.80 (m, 2H), 1.47 (m, 9H); MS-ESI: m/z 230.30 [M+H] ⁺ .

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-2-aminomethylamylpyrazine-1-carboxylic acid tert-butyl ester to make

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300mg, 0.64mmol), compound 2-amino-methyl acetoazine-1-carboxylic acid tert-butyl ester (153mg, 0.64mmol), 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide hydrochloride (250mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.3mmol) were dissolved in dichloromethane (25mL), 0 At ℃, N , N -diisopropylethylamine (0.33mL, 1.93mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL×3), and the organic phase was dried over anhydrous Na ₂ SO ₄ After removing the solvent, the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 90 mg of a white solid in a yield of 21%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.54-7.60 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 6.72 (t, J _FH = 75.0 Hz, 1H), 5.43-5.62 ( m,1H),5.21-5.32(m,1H),4.94-5.12(m,1H),4.58-4.84(m,1H),4.33-4.49(m,1H),3.99(d, J =6.9Hz, 2H), 3.57-3.80 (m, 1H), 3.05-3.29 (m, 2H), 1.52-1.57 (m, 3H), 1.52 (s, 9H), 1.45 (d, J = 3.9Hz, 9H), 1.32 -1.38 (m, 1H), 0.68-0.73 (m, 2H), 0.41-0.44 (m, 2H); MS-ESI: m/z 680.40 [M+H] ⁺ .

Step 3: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrazine-2-carboxamide dihydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-2-aminomethylacetophenazine-1-carboxylic acid tert-butyl ester (80mg, 0.33mmol) in dichloromethane (2mL) was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, and removed the solvent to obtain 60mg of white solid, yield: 92%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.73-7.77 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.94 (t, J _FH = 75.0 Hz, 1H), 5.23-5.28 (m,1H),5.14-5.18(m,1H),4.34-4.50(m,1H),4.11-4.28(m,1H),4.05(d, J =6.6Hz, 2H),3.79-3.86(m , 1H), 3.51-3.60 (m, 2H), 3.37-3.46 (m, 1H), 1.78-1.82 (m, 3H), 1.34-1.37 (m, 1H), 0.67-0.71 (m, 2H), 0.43 -0.46 (m, 2H); MS-ESI: m/z 480.15 [M+H-2HCl] ⁺ .

Example 60: Compound (2 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)tetrahydropyrrole-2-carboxylic acid methyl ester hydrochloride Synthesis

Step 1: Synthesis of compound (2 S )-2-methoxycarbonyl-4-methoxycarbonylaminopyrrolidine hydrochloride

Dissolve methyl N -tert-butoxycarbonyl-4-oxo- L -proline (520mg, 2.14mmol) in absolute ethanol (10mL), add sodium borohydride (86mg, 2.14mmol) under ice bath, 0℃ After 20 minutes of reaction, the reaction was stopped, ice water (10 mL) was added, ethanol was swirled out, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and concentrated to obtain 510 mg of colorless liquid: (2 S )-2-Methoxycarbonyl-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, yield: 97%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.32-4.40 (m, 1H), 3.80 (d, J = 6.0 Hz, 3H), 3.50-3.75 (m, 3H), 2.28-3.40 (m, 1H) , 2.07-2.13 (m, 1H), 1.46 (d, J =16.9 Hz, 9H); MS-ESI: m/z 146.25 [M+H-100] ⁺ .

The compound ( 2S )-2-methoxycarbonyl-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (210mg, 0.86mmol), p-toluenesulfonyl chloride (195mg, 1.03mmol), triethylamine ( 200mg, 2.14mmol) and 4-dimethylaminopyridine (12mg, 0.086mmol) were dissolved in dichloromethane (10mL), the reaction was stopped after 6h reaction at room temperature, water (20mL) was added, dichloromethane (10mL × 3) extraction , The organic phases were combined and dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=4/1) to obtain 110 g of colorless liquid: (2 S ) 2-Methoxycarbonyl-4-p-toluenesulfonylpyrrolidine-1-carboxylic acid tert-butyl ester, yield: 32%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.78 (d, J =8.1 Hz, 2H), 7.37 (d, J =7.8 Hz, 2H), 5.07 (d, J =15.1 Hz, 1H), 4.33- 4.43(m, 1H), 3.71(d, J = 3.5Hz, 3H), 3.57-3.74(m, 2H), 2.36-2.49(m, 2H), 2.47(s, 3H), 1.46(s, 9H) .

Compound (2 S )-2-methoxycarbonyl-4-p-toluenesulfonylpyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 1.00 mmol) and sodium azide (325 mg, 5.00 mmol) were dissolved in DMF (10mL), 80 ℃ reaction was stopped after the reaction 2h, spin out of DMF, was added water (20 mL), ethyl acetate (10mL × 3) was extracted, the combined organic phases were dried over anhydrous Na ₂ SO _4, the solvent was removed, concentrate Column chromatography (eluent: Petroleum ether/EtOAc (v/v)=4/1) was performed to obtain 240 mg of colorless liquid: (2 S )-2-methoxycarbonyl-4-azidopyrrolidine-1 -Tert-butyl formate, yield: 88%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 4.34-4.46(m,1H),4.35(t, J =7.6Hz,1H),4.22(dd, J ₁ =9.0Hz, J ₂ =4.8Hz,1H ), 3.77 (m, 3H), 3.72-3.74 (m, 1H), 3.48-3.61 (m, 1H), 2.30-2.39 (m, 1H), 2.17-2.22 (m, 1H), 1.45 (d, J = 30.9 Hz, 9H); MS-ESI: m/z 171.20[M+H-100] ⁺ .

Compound (2 S )-2-methoxycarbonyl-4-azidopyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.85 mmol) and Pd/C (10%, 120 mg) were dissolved in methanol (10 mL) At room temperature, hydrogen is reduced under normal pressure. After 12 hours of reaction, the reaction is stopped, filtered with suction, and the filtrate is concentrated to obtain 440 mg of colorless liquid: (2 S )-2-methoxycarbonyl-4-aminopyrrolidine-1-carboxylic acid tert-butyl Ester, yield: 97%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 4.36-4.46 (m, 1H), 3.67-3.78 (m, 2H), 3.75 (d, J = 3.5Hz, 3H), 3.09-3.23 (m, 1H) , 2.11-2.19 (m, 1H), 1.97-2.08 (m, 1H), 1.45 (d, J = 20.1Hz, 9H); MS-ESI: m/z 145.25 [M+H-100] ⁺ .

Dissolve triethylamine (136mg, 1.35mmol) and N , N' -carbonyldiimidazole (CDI) (175mg, 1.08mmol) in anhydrous DMF (2mL), add compound ( 2S )-2-methoxycarbonyl-4 -Aminopyrrolidine-1-carboxylic acid tert-butyl ester (220mg, 0.90mmol), stirred at room temperature for 30min, then added anhydrous methanol (5mL), the reaction was stopped after 60°C for 24h, the solvent was removed DMF, water (5mL), ethyl acetate was added The ester (10 mL×3) was extracted, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/3) to obtain 260 mg of a white solid: (2 S ) 2-Methoxycarbonyl-4-methoxycarbonylaminopyrrolidine-1-carboxylic acid tert-butyl ester, yield: 95%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.86 (br.s, 1H), 4.29-4.41 (m, 2H), 3.78-3.84 (m, 1H), 3.75 (s, 3H), 3.69 (br. s,3H),3.25-3.41(m,1H),2.14-2.31(m,2H),1.45(d, J =18.2Hz,9H); MS-ESI: m/z 203.20[M+H-100] ⁺ .

To a solution of compound (2 S )-2-methoxycarbonyl-4-methoxycarbonylaminopyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.82 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate The solution (4M, 2mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 190mg of viscous solid: ( 2S )-2-methoxycarbonyl-4-methoxycarbonylaminopyrrolidine hydrochloride, yield: 96% .

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.65 (t, J = 8.6 Hz, 1H), 4.29-4.33 (m, 1H), 3.89 (s, 3H), 3.68 (s, 3H), 3.63 3.66 (m, 1H), 3.38-3.43 (m, 1H), 2.43-2.46 (m, 2H); MS-ESI: m/z 203.20 [M+H] ⁺ .

Step 2: Compound (2 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)tetrahydropyrrole-2-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (400 mg, 0.84 mmol), compound (2 S )-2-methoxycarbonyl-4-methoxycarbonylaminopyrrolidine hydrochloride (200 mg, 0.84 mmol), 1-ethyl -3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (320mg, 1.68mmol) and N -hydroxy-7-azabenzotriazole (230mg, 1.68mmol) dissolved in dichloromethane (25mL), at 0℃, add N , N -diisopropylethylamine (0.59mL, 3.35mmol) dropwise to this solution, stir at room temperature for 10h, wash with water (10mL×3), the organic phase is used Anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/1) to obtain 224 mg of a white solid in a yield of 41%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.52-7.62(m,2H),7.23-7.27(m,1H),6.72(t, J _FH =75.0Hz,1H),5.30-5.38(m,1H ), 5.17-5.29 (m, 1H), 5.04 (m, 1H), 4.33-4.52 (m, 1H), 3.97-4.07 (m, 3H), 3.67-3.80 (m, 6H), 2.23-2.50 (m , 2H), 1.52-1.55 (m, 3H), 1.45 (s, 9H), 1.33-1.39 (m, 1H), 0.69-0.73 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI : M/z 653.20[M+H] ⁺ .

Step 3: Compound (2 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)tetrahydropyrrole-2-carboxylic acid methyl ester hydrochloride

To compound (2 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)tetrahydropyrrole-2-carboxylic acid methyl ester (210 mg, 0.32 mmol) in dichloromethane (2 mL) To the solution was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 30min, and the solvent was removed to obtain 170mg of white solid, yield: 90%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.64-7.77 (m, 2H), 7.34 (d, J = 8.2Hz, 1H), 6.92 (t, J _FH = 75.0Hz, 1H), 5.49-5.52 (m,1H), 5.12-5.18(m,1H), 4.38-4.42,4.75-4.79(m,0.5H,0.5H),4.25-4.35(m,1H),4.03-4.08(m,2H), 3.66-3.73, 3.95-3.99 (m, 0.5H, 0.5H), 3.66-3.79 (m, 6H), 2.44-2.48 (m, 1H), 2.25-2.35 (m, 1H), 1.78 (s, 3H) , 1.32-1.39 (m, 1H), 0.67-0.73 (m, 2H), 0.42-0.47 (m, 2H); MS-ESI: m/z 553.30 [M+H-HCl] ⁺ .

Example 61: Compound (2 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)tetrahydropyrrole-2-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of compound (2 S )-4-cyclopropylcarboxamidopyrrolidine-2-carboxylic acid methyl ester hydrochloride

The compound cyclopropionic acid (116 mg, 1.35 mmol), compound (2 S )-2-methoxycarbonyl-4-aminopyrrolidine-1-carboxylic acid tert-butyl ester (220 mg, 0.90 mmol), 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride (345 mg, 1.80 mmol) and N -hydroxy-7-azabenzotriazole (245 mg, 1.80 mmol) were dissolved in dichloromethane (25 mL ), at 0 ℃, N , N -diisopropylethylamine (0.47mL, 2.70mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL × 3), the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/2) to obtain 225 mg of colorless liquid: (2 S )-2-methoxycarbonyl Tert-Butyl-4-cyclopropylcarboxamidopyrrolidine-1-carboxylate, yield: 80%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 5.80-5.89 (m, 1H), 4.52-4.60 (m, 1H), 4.30-4.44 (m, 1H), 3.77-3.83 (m, 1H), 3.75 ( s, 3H), 3.29-3.45 (m, 1H), 2.19-2.31 (m, 1H), 1.44-1.48 (m, 9H), 1.30-1.37 (m, 1H), 0.96-1.00 (m, 2H), 0.74-0.79 (m, 2H); MS-ESI: m/z 213.10 [M+H-100] ⁺ .

To a solution of the compound (2 S )-2-methoxycarbonyl-4-cyclopropylcarboxamidopyrrolidine-1-carboxylic acid tert-butyl ester (220 mg, 0.71 mmol) in dichloromethane (2 mL) was added HCl in acetic acid Ethyl acetate solution (4M, 2mL), stirred at room temperature for 30min, and removed the solvent to obtain 170mg viscous solid: ( 2S )-4-cyclopropylcarboxamidopyrrolidine-2-carboxylic acid methyl ester hydrochloride. Rate: 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.71 (t, J = 8.6 Hz, 1H), 4.45 (br.s, 1H), 3.89 (s, 3H), 3.65-3.69 (m, 1H), 3.34-3.39(m,1H),2.46-2.49(m,2H),1.62-1.65(m,1H),0.85-0.89(m,2H),0.80-0.83(m,2H); MS-ESI: m /z 213.20[M+H-HCl] ⁺ .

Step 2: Compound (2 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)tetrahydropyrrole-2-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound (2 S )-4-cyclopropylcarboxamidopyrrolidine-2-carboxylic acid methyl ester hydrochloride (160 mg, 0.64 mmol), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (245mg, 1.28mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.28mmol) were dissolved in di In methyl chloride (10mL), at 0℃, add N , N -diisopropylethylamine (0.45mL, 2.56mmol) dropwise to this solution, stir at room temperature for 10h, wash with water (10mL×3), organic The phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 134 mg of a white solid in a yield of 32%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.51-7.61(m,2H),7.23-7.26(m,1H),6.72(t, J _FH =75.0Hz,1H),6.18(br.s,1H ), 5.37-5.44 (m, 1H), 5.20-5.23 (m, 1H), 4.63-4.79 (m, 1H), 4.21-4.33 (m, 1H), 3.97-4.01 (m, 3H), 3.75 (d , J = 32.8Hz, 3H), 2.31-2.52(m, 2H), 1.52-1.56(m, 3H), 1.44(s, 9H), 1.31-1.41(m, 2H), 0.96-1.03(m, 2H) ), 0.73-0.81 (m, 2H), 0.68-0.73 (m, 2H), 0.41-0.46 (m, 2H); MS-ESI: m/z 663.40 [M+H] ⁺ .

Step 3: Compound (2 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)tetrahydropyrrole-2-carboxylic acid methyl ester hydrochloride

To compound (2 S )-1-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)tetrahydropyrrole-2-carboxylic acid methyl ester (130mg, 0.20mmol) in dichloromethane (2mL) To the solution was added HCl ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, and the solvent was removed to obtain 115mg of white solid, yield: 98%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.75-7.76 (m, 2H), 7.34 (d, J = 8.2Hz, 1H), 6.92 (t, J _FH = 75.0Hz, 1H), 5.55 (m ,1H),5.12-5.18(m,1H),4.27-4.32,4.53-4.57(m,0.5H,0.5H),4.40-4.47(m,1H),4.03-4.07(m,2H),3.97- 4.03(m,1H), 3.76(d, J = 32.8Hz, 3H), 3.73-3.76(m, 1H), 2.49(t, J =6.7Hz, 1H), 2.20-2.37(m, 1H), 1.76 -1.79(m, 3H), 1.31-1.41(m, 2H), 0.84-0.90(m, 2H), 0.74-0.82(m, 2H), 0.66-0.73(m, 2H), 0.43-0.47(m, 2H); MS-ESI: m/z 563.35 [M+H-HCl] ⁺ .

Example 62: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazole-4-carbonyl)-3-methylpyrazine-1-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of compound 3-methylpyrazine-1-carboxylic acid methyl ester hydrochloride

Dissolve triethylamine (760mg, 7.5mmol) and N , N' -carbonyldiimidazole (CDI) (970mg, 6.0mmol) in anhydrous DMF (2mL), add N -tert-butoxycarbonyl-2-methylpyrazine (1.0g, 5.0mmol), after stirring at room temperature for 30min, add anhydrous methanol (10mL), stop the reaction after reacting at 60℃ for 8h, remove the solvent, add water (5mL), extract with ethyl acetate (10mL×3), anhydrous sodium sulfate After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) to obtain 710 mg of colorless liquid: 2-methyl-4-methoxycarbonylpyrazine- 1-tert-Butyl formate, yield: 55%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.22-4.30 (m, 1H), 3.91-4.12 (m, 1H), 3.78-3.91 (m, 2H), 3.73 (s, 3H), 3.02-3.09 ( m, 2H), 2.81-2.96 (m, 1H), 1.48 (s, 9H), 1.15 (d, J = 6.8Hz, 3H); MS-ESI: m/z 159.25 [M+H-100] ⁺ .

To a solution of the compound 2-methyl-4-methoxycarbonylpyrazine-1-carboxylic acid tert-butyl ester (700 mg, 2.7 mmol) in dichloromethane (2 mL) was added a solution of HCl in ethyl acetate (4 M, 6 mL). After stirring for 30 min at a warm temperature, the solvent was removed to obtain 520 mg of white viscous solid: methyl 3-methylpyrazine-1-carboxylate hydrochloride, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.18-4.22 (m, 2H), 3.75 (s, 3H), 3.34-3.42 (m, 2H), 3.21-3.34 (m, 1H), 3.11-3.16 (m, 1H), 2.99-3.10 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H); MS-ESI: m/z 159.20 [M+H-HCl] ⁺ .

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of methyloxy)phenyl)oxazole-4-carbonyl)-3-methylpyrazine-1-carboxylate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (500 mg, 1.07 mmol), compound 3-methylpyrazine-1-carboxylic acid methyl ester hydrochloride (250 mg, 1.28 mmol), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (410mg, 2.14mmol) and N -hydroxy-7-azabenzotriazole (290mg, 2.14mmol) were dissolved in dichloromethane (15mL) at 0℃ Next, N , N -diisopropylethylamine (0.75mL, 4.27mmol) was added dropwise to this solution, stirred at room temperature for 12h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and removed The solvent and the concentrated solution were separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/1) to obtain 290 mg of white solid in a yield of 45%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.56-7.60 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 6.72 (t, J _FH = 75.0 Hz, 1H), 5.20-5.26 ( m,1H), 4.80-4.93(m,1H), 4.39-4.51(m,1H), 3.99(d, J =6.9Hz, 2H), 3.89-4.03(m,1H), 3.76(s,3H) , 3.07-3.42m, 3H), 1.55-1.57 (m, 3H), 1.43 (s, 9H), 1.33-1.38 (m, 1H), 1.30-1.34 (m, 3H), 0.68-0.73 (m, 2H ), 0.41-0.45 (m, 2H); MS-ESI: m/z 609.25 [M+H] ⁺ .

Step 3: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of methyl-4-carbonyl)-3-methylpyrazine-1-carboxylate hydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-3-methylpyrazine-1-carboxylic acid methyl ester (290mg, 0.48mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 4mL) ), stirred at room temperature for 30 min, and removed the solvent to obtain 250 mg of white solid, yield: 97%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.71-7.75 (m, 2H), 7.33 (d, J = 8.3Hz, 1H), 6.93 (t, J _FH = 75.0Hz, 1H), 5.03-5.07 (m,1H),4.75-4.85(m,1H),4.48,5.17(br.s,0.5H,0.5H),4.09-4.19(m,1H),4.05(d, J =6.9Hz,3H) ,3.94-4.01(m,1H),3.76(s,3H),3.12-3.13(m,1H),2.99-3.11,3.54-3.62(m,0.5H,0.5H),1.78-1.80(m,3H ), 1.39-1.46(m, 1H), 1.29-1.36(m, 3H), 0.68-0.71(m, 2H), 0.43-0.46(m, 2H); MS-ESI: m/z 509.30[M+H -HCl] ⁺ .

Example 63: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazole-4-carbonyl)-1-methylpyrazine-2-carboxylic acid methyl ester dihydrochloride

Step 1: Synthesis of compound 1-methylpyrazine-2-carboxylic acid methyl ester hydrochloride

Tert-Butyl 3-methoxycarbonylpyrazine-1-carboxylate (500mg, 2.05mmol), iodine Methane (580mg, 4.10mmol) and potassium carbonate (424mg, 3.07mmol) were added to a 50mL sealed tube, acetone (10mL) was added, the reaction was stopped after 6h reaction at 50°C, the solvent was removed, water (20mL), dichloromethane (10mL) was added ×3) Extraction, drying over anhydrous sodium sulfate, removing the solvent, and concentration to obtain 290 mg of light yellow solid: tert-butyl 3-methoxycarbonyl-4-methylpyrazine-1-carboxylate, yield: 54%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.65-4.83 (m, 1H), 4.29-4.33 (m, 1H), 4.18-4.23 (m, 1H), 4.05-4.11 (m, 1H), 3.80- 3.94 (m, 3H), 3.88 (s, 3H), 3.66 (s, 3H), 1.48 (s, 9H); MS-ESI: m/z 259.30 [M+H] ⁺ .

To a solution of the compound 3-methoxycarbonyl-4-methylpyrazine-1-carboxylic acid tert-butyl ester (290 mg, 1.1 mmol) in dichloromethane (2 mL) was added a solution of HCl in ethyl acetate (4M, 4 mL). After stirring for 30 min at a warm temperature, the solvent was removed to obtain 220 mg of a yellow solid: 1-methylpyrazine-2-carboxylic acid methyl ester hydrochloride, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.88 (dd, J ₁ =11.1 Hz, J ₂ = 3.8 Hz, 1H), 3.93-3.99 (m, 2H), 3.87-3.91 (m, 2H), 3.84 (s, 3H), 3.70-3.75 (m, 1H), 3.63-3.68 (m, 1H), 3.5 (s, 3H); MS-ESI: m/z 159.20 [M+H-HCl] ⁺ .

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of methyloxy)phenyl)oxazole-4-carbonyl)-1-methylpyrazine-2-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound 1-methylpyrazine-2-carboxylic acid methyl ester hydrochloride (160 mg, 0.77 mmol), 1-ethyl-3-(3-dimethyl Aminopropyl) carbodiimide hydrochloride (245mg, 1.28mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.28mmol) were dissolved in dichloromethane (10mL) at 0℃ Next, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 12h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and removed The solvent and the concentrated liquid were separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 40 mg of a white solid in a yield of 24%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 7.54-7.63(m,1H),7.26(d, J =8.3Hz,1H),6.73(t, J _FH =75.0Hz,1H),5.24-5.28( m,1H),4.15-4.21,4.48-4.64(m,0.5H,0.5H),4.33-4.48(m,1H),3.98-4.02(m,2H),3.77(d, J = 45.3Hz,3H ), 3.42-3.54 (m, 1H), 3.01-3.21 (m, 2H), 2.41 (s, 3H), 1.56 (d, J = 7.0Hz, 3H), 1.45 (s, 9H), 1.31-1.37 ( m, 1H), 0.69-0.73 (m, 2H), 0.42-0.44 (m, 2H); MS-ESI: m/z 609.40 [M+H] ⁺ .

Step 3: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of methyl-4-carbonyl)-1-methylpyrazine-2-carboxylate dihydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-1-methylpyrazine-2-carboxylic acid methyl ester (30mg, 0.05mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 2mL) ), stirred at room temperature for 30 min, and removed the solvent to obtain 27 mg of white solid, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.66-7.71 (m, 2H), 7.26-7.28 (m, 1H), 6.84 (t, J _FH = 75.0 Hz, 1H), 5.04-5.09 (m, 1H), 4.55-4.61 (m, 1H), 4.38-4.44 (m, 1H), 3.93-3.98 (m, 2H), 3.80-3.86 (m, 3H), 3.65-3.71 (m, 1H), 3.48- 3.58 (m, 1H), 3.35-3.44 (m, 1H), 3.01 (s, 3H), 1.70 (d, J = 7.0Hz, 3H), 1.23-1.30 (m, 1H), 0.59-0.62 (m, 2H), 0.34-0.36 (m, 2H); MS-ESI: m/z 509.10 [M+H-2HCl] ⁺ .

Example 64: Compound (( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

Step 1: Synthesis of compound ( S )-3-methoxycarbonylaminopyrrolidine hydrochloride

Compound ( R ) tert-butyl-3-hydroxypyrrolidine-1-carboxylate (1.0g, 5.3mmol), p-toluenesulfonyl chloride (1.5g, 8.0mmol), triethylamine (1.1g, 11mmol) Dissolve with 4-dimethylaminopyridine (65mg, 0.53mmol) in dichloromethane (10mL), stop the reaction after reacting at room temperature for 10h, add water (20mL), extract with dichloromethane (10mL×3), and combine organic phases It was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 5/1) to obtain 460 mg of colorless liquid: ( R )-3-pair Tert-butyl methyl sulfonyl pyrrolidine-1-carboxylate, yield: 25%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.79 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 7.7 Hz, 2H), 5.04 (s, 1H), 3.38-3.50 (m, 4H ), 2.45 (s, 3H), 1.97-2.15 (m, 2H), 1.43 (m, 9H); MS-ESI: m/z 286.20 [M-55] ⁺ .

Compound ( R )-3-p-toluenesulfonylpyrrolidine-1-carboxylic acid tert-butyl ester (460mg, 1.34mmol) and sodium azide (380mg, 6.74mmol) were dissolved in DMF (5mL), 80 ℃ reaction was stopped after 2h the reaction, spin out of DMF, was added water (20 mL), ethyl acetate (10mL × 3) was extracted, dried over anhydrous Na ₂ SO ₄ the combined organic phases, the solvent was removed by column chromatography, concentrated liquid (wash Removal agent: Petroleum ether/EtOAc (v/v)=4/1), to obtain 250 mg of colorless liquid: ( S )-3-azidopyrrolidine-1-carboxylic acid tert-butyl ester, yield: 87%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.10-4.15 (m, 1H), 3.34-3.49 (m, 4H), 1.95-2.11 (m, 2H), 1.46 (s, 9H); MS-ESI: m/z 157.10[M-55] ⁺ .

Dissolve compound ( S )-3-azidopyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 1.18 mmol) and Pd/C (10%, 50 mg) in methanol (10 mL) at room temperature under normal pressure hydrogen After reduction, the reaction was stopped after 12 hours of reaction, filtered with suction, and the filtrate was concentrated to obtain 210 mg of colorless liquid: ( S )-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester, yield: 96%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 3.42-3.56 (m, 3H), 3.30-3.40 (m, 1H), 2.96-3.07 (m, 1H), 1.99-2.05 (m, 1H), 1.58- 1.67 (m, 1H), 1.44 (s, 9H); MS-ESI: m/z 131.20 [M-55] ⁺ .

Dissolve triethylamine (162mg, 1.61mmol) and N , N' -carbonyldiimidazole (CDI) (208mg, 1.28mmol) in anhydrous DMF (5mL), add compound ( S )-3-aminopyrrolidine-1 -Tert-butyl formate (200mg, 1.07mmol), after stirring at room temperature for 30min, anhydrous methanol (5mL) was added, the reaction was stopped after reaction at 60°C for 24h, the solvent DMF was removed, water (5mL) was added, ethyl acetate (10mL×3) was extracted , Dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) to obtain 230 mg of colorless liquid: ( S )-3-methoxycarbonyl Tert-butyl aminopyrrolidine-1-carboxylate, yield: 87%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 4.77 (br.s, 1H), 4.23 (br.s, 1H), 3.67 (s, 3H), 3.58-3.61 (m, 1H), 3.38-3.41 ( m,2H),3.15-3.21(m,1H), 2.10-2.15(m,1H),1.76-1.88(m,1H),1.45(m,9H); MS-ESI: m/z 145.20[M+ H-Boc] ⁺ .

To a solution of the compound ( S )-3-methoxycarbonylaminopyrrolidine-1-carboxylic acid tert-butyl ester (220mg, 0.90mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M, 2mL), After stirring at room temperature for 30 min, the solvent was removed to obtain 160 mg of a viscous solid: ( S )-3-methoxycarbonylaminopyrrolidine hydrochloride, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.16-4.20 (m, 1H), 3.58 (s, 3H), 3.34-3.41 (m, 2H), 3.26-3.31 (m, 1H), 3.16-3.21 (m, 1H), 2.18-2.24 (m, 1H), 1.95 (m, 1H); MS-ESI: m/z 145.10 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (400mg, 0.854mmol), compound ( S )-3-methoxycarbonylaminopyrrolidine hydrochloride (200mg, 0.854mmol), 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide hydrochloride (327mg, 1.71mmol) and N -hydroxy-7-azabenzotriazole (232mg, 1.71mmol) were dissolved in dichloromethane (25mL), 0 ℃ Under this condition, N , N -diisopropylethylamine (0.60mL, 3.42mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL×3), and the organic phase was dried over anhydrous Na ₂ SO ₄ , The solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 250 mg of a white solid in a yield of 49%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.52-7.59 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.0 Hz, 1H), 5.20-5.30 ( m,1H), 4.27-4.37(m,1H), 4.13-4.22(m,1H), 3.98(d, J =6.9Hz, 2H), 3.89-4.07(m,1H), 3.69-3.82(m, 2H), 3.68(m, 3H), 2.14-2.28(m, 1H), 1.87-2.13(m, 1H), 1.51-1.54(m, 3H), 1.42(s, 9H), 1.27-1.34(m, 1H), 0.65-0.71 (m, 2H), 0.37-0.43 (m, 2H); MS-ESI: m/z 595.30 [M+H] ⁺ .

Step 3: Compound (( S )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

To compound (( S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester (240 mg, 0.40 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 210mg of white solid, yield: 98%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.61-7.64 (m, 2H), 7.24 (d, J = 8.2Hz, 1H), 6.82 (t, J _FH = 75.0Hz, 1H), 5.00-5.03 (m, 1H), 4.21-4.23, 3.98-4.04 (m, 0.5H, 0.5H), 4.09-4.20 (m, 2H), 3.92-3.95 (m, 2H), 3.76-3.79, 3.66-3.71 (m ,0.5H,0.5H),3.60-3.65(m,1H),3.57(d, J =10.0Hz,3H),2.09-2.22(m,1H),1.85-2.00(m,1H),1.69(d , J = 6.9Hz, 3H), 1.21-1.27 (m, 1H), 0.58-0.62 (m, 2H), 0.32-0.37 (m, 2H); MS-ESI: m/z 495.30 [M+H-HCl ] ⁺ .

Example 65: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of azole-4-carbonyl) -N -methylpyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of compound N -methylpyrazine-1-carboxamide hydrochloride

Compound 1-tert-butoxycarbonylpyrazine (0.5g, 2.68mmol), triethylamine (1.2mL, 8.05mmol) and N , N' -carbonyldiimidazole (CDI) (520mg, 3.22mmol) were dissolved in anhydrous DMF (2mL), after stirring at room temperature for 30min, methylamine hydrochloride (720mg, 0.73mmol) was added, the reaction was stopped after 6h reaction at 60°C, the solvent DMF was removed, water (5mL) was added, ethyl acetate (10mL×3) was extracted, anhydrous After drying over sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=60/1) to obtain 550 mg of a white solid: 4-methylaminomethyl methanylazine- 1-tert-Butyl formate, yield: 84%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.50-3.60 (m, 2H), 3.30-3.40 (m, 4H), 2.81 (d, J = 4.6 Hz, 3H), 1.45 (s, 9H); MS -ESI: m/z 144.10[M+H-100] ⁺ .

To a solution of the compound 4-methylaminomethylcarbamoylazine-1-carboxylic acid tert-butyl ester (0.16 g, 0.7 mmol) in dichloromethane (2 mL) was added a solution of HCl in ethyl acetate (4 M, 2 mL). Stir at a warm temperature for 30 min and remove the solvent to obtain 160 mg of a white solid: N -methylpyrazine-1-carboxamide hydrochloride, yield: 100%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.65-3.66 (m, 4H), 3.20-3.24 (m, 4H), 2.75 (s, 3H); MS-ESI: m/z 144.25 [M+H -HCl] ⁺ .

Step 2: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(methylaminomethyl Synthesis of Acyl) Pyrazin-1-carbonyl) Oxazol-5-yl) Ethyl) Aminocarboxylic Acid Tert-Butyl Ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound N -methylpyrazine-1-carboxamide hydrochloride (127 mg, 0.77 mmol), 1-ethyl-3-(3-dimethyl Aminopropyl) carbodiimide hydrochloride (254mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.3mmol) were dissolved in dichloromethane (15mL) at 0℃ Next, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and removed The solvent and the concentrated solution were separated by column chromatography (eluent: DCM/MeOH (v/v)=40/1) to obtain 250 mg of a white solid in a yield of 70%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.55-7.61 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 6.72 (t, J _FH = 75.0 Hz, 1H), 5.21-5.28 ( m,1H), 4.49 (s, 1H), 3.99 (d, J = 6.9Hz, 2H), 3.98 (br.s, 2H), 3.80 (br.s, 2H), 3.51 (br.s, 4H) , 2.87 (d, J = 3.8Hz, 3H), 1.56 (d, J = 7.0Hz, 3H), 1.43 (s, 9H), 1.32-1.36 (m, 1H), 0.68-0.73 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 594.20 [M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl) -N -methylpyrazine-1-carboxamide hydrochloride

To compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(methylaminomethylamide )Pyrazine-1-carbonyl)oxazol-5-yl)ethyl)tert-butylaminocarbamate (110mg, 0.42mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 3mL) ), stirred at room temperature for 30 min, and removed the solvent to obtain 90 mg of white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.60-7.64 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 6.81 (t, J _FH = 75.0 Hz, 1H), 4.93-4.97 (m,1H), 4.08 (br.s, 1H), 3.93 (d, J = 6.9Hz, 2H), 3.68 (br.s, 2H), 3.44 (br.s, 4H), 2.66 (s, 3H ), 1.68 (d, J = 6.8Hz, 3H), 1.22-1.26 (m, 1H), 0.57-0.60 (m, 2H), 0.32-0.35 (m, 2H); MS-ESI: m/z 494.10[ M+H-HCl] ⁺ .

Example 66: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl) -N , N -dimethylpyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of compound N , N -dimethylpyrazine-1-carboxamide hydrochloride

Compound 1-Boc-pyrazine (0.5g, 2.50mmol), triethylamine (1.74mL, 12.48mmol) and N , N' -carbonyldiimidazole (CDI) (485mg, 3.00mmol) were dissolved in anhydrous DMF (2mL ), after stirring at room temperature for 30min, dimethylamine hydrochloride (810mg, 9.99mmol) was added, the reaction was stopped after 6h reaction at 80°C, the solvent DMF was removed, water (5mL) was added, ethyl acetate (10mL×3) was extracted, and anhydrous sulfuric acid was extracted. After drying with sodium, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=100/1) to obtain 650 mg of a white solid: 4-(dimethylaminemethylamide)pyrazine Tert-Butyl-1-carboxylate, yield: 94%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.40-3.44 (m, 4H), 3.16-3.18 (m, 4H), 2.83 (s, 6H), 1.45 (s, 9H); MS-ESI: m/ z 158.30[M+H-100] ⁺ .

To a solution of the compound 4-(dimethylaminemethylamide)pyrazine-1-carboxylic acid tert-butyl ester (0.3 g, 1.17 mmol) in dichloromethane (2 mL) was added a solution of HCl in ethyl acetate (4M, 4 mL) After stirring at room temperature for 30 min, the solvent was removed to obtain 220 mg of a white solid: N , N -dimethylpyrazine-1-carboxamide hydrochloride, yield: 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 3.25-3.29 (m, 4H), 3.05-3.08 (m, 4H), 2.71 (s, 6H); MS-ESI: m/z 158.20 [M+H -HCl] ⁺ .

Step 2: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(dimethyl Synthesis of Tert-Butyl Carboxylamido)Pyrazin-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (400 mg, 0.85 mmol), compound N , N -dimethylpyrazine-1-carboxamide hydrochloride (200 mg, 1.03 mmol), 1-ethyl-3-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (327 mg, 1.71 mmol) and N -hydroxy-7-azabenzotriazole (232 mg, 1.71 mmol) were dissolved in dichloromethane (15 mL), At 0°C, N , N -diisopropylethylamine (0.6mL, 3.42mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/3) to obtain 230 mg of a white solid in a yield of 44%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.53-7.59 (m, 1H), 7.24 (d, J = 8.3Hz, 1H), 6.70 (t, J _FH = 75.0Hz, 1H), 5.18-5.25 ( m,1H), 3.89-4.01 (m, 2H), 3.97 (d, J = 6.9Hz, 2H), 3.77 (br.s, 2H), 3.32 (br.s, 4H), 2.86 (s, 6H) , 1.54 (d, J = 6.9Hz, 3H), 1.42 (s, 9H), 1.28-1.35 (m, 1H), 0.66-0.71 (m, 2H), 0.38-0.42 (m, 2H); MS-ESI : M/z 608.40[M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl) -N , N -dimethylpyrazine-1-carboxamide hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(dimethylformamide) )Pyrazine-1-carbonyl)oxazol-5-yl)ethyl)tert-butylaminocarbamate (230mg, 0.38mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 4mL) ), stirred at room temperature for 30 min, and removed the solvent to obtain 200 mg of white solid, yield: 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.64 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.81 (t, J _FH = 75.0Hz, 1H), 4.94-4.99 (m, 1H), 4.09 (br.s, 2H), 3.94 (d, J = 6.8Hz, 2H), 3.70 (br.s, 2H), 3.27 (br. s, 4H), 2.81 (s, 3H), 1.69 (d, J = 6.7Hz, 3H), 1.21-1.26 (m, 1H), 0.56-0.60 (m, 2H), 0.3-0.34 (m, 2H) ; MS-ESI: m/z 508.35 [M+H-HCl] ⁺ .

Example 67: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid methyl ester hydrochloride Synthesis

Step 1: Synthesis of compound (2 S ,4 R )-2-methoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine hydrochloride

Combine N -tert-butoxycarbonyl-cis-4-hydroxy- L -proline methyl ester (210 mg, 0.86 mmol), p-toluenesulfonyl chloride (195 mg, 1.03 mmol), triethylamine (200 mg, 2.14 mmol) and 4-dimethylaminopyridine (12mg, 0.086mmol) were dissolved in dichloromethane (10mL), the reaction was stopped after 10h at room temperature, water (20mL) was added, dichloromethane (10mL × 3) extraction, combined organic After the phase was dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 4/1) to obtain 110 g of colorless liquid: (2 S , 4 S ) 2-Methoxycarbonyl-4-p-toluenesulfonylpyrrolidine-1-carboxylic acid tert-butyl ester, yield: 32%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.77 (d, J =8.1 Hz, 2H), 7.35 (d, J =7.8 Hz, 2H), 5.06 (d, J =15.1 Hz, 1H), 4.31- 4.34(m, 1H), 3.69(d, J = 3.5Hz, 3H), 3.55-3.66(m, 2H), 2.34-2.46(m, 2H), 2.47(s, 3H), 1.39-1.44(m, 9H).

Compound (2 S ,4 S )-2-methoxycarbonyl-4-p-toluenesulfonylpyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 1.00 mmol) and sodium azide (325 mg, 5.00 mmol) Dissolve in DMF (10mL), stop the reaction after reacting at 80℃ for 2h, spin out DMF, add water (20mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry with anhydrous Na ₂ SO ₄ , remove the solvent and concentrate The liquid was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=4/1) to obtain 240 g of colorless liquid: (2 S ,4 R )-2-methoxycarbonyl-4-azido Pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 88%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 4.30-4.43(m,1H),4.16-4.21(m,1H),4.35(t, J =7.6Hz,1H),3.74(d, J =3.7Hz ,3H),3.68-3.72(m,1H),3.44-3.60(m,1H),2.26-2.38(m,1H),2.13-2.21(m,1H),1.41-1.46(m,9H); MS -ESI: m/z 171.20[M+H-100] ⁺ .

Compound (2 S ,4 R )-2-methoxycarbonyl-4-azidopyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.85 mmol) and Pd/C (10%, 120 mg) were dissolved in methanol ( 10mL), at room temperature, atmospheric pressure hydrogen reduction, the reaction was stopped after 12h reaction, suction filtration, the filtrate was concentrated to obtain 440mg colorless liquid: (2 S , 4 R )-2-methoxycarbonyl-4-aminopyrrolidine- 1-tert-Butyl formate, yield: 97%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.33-4.43 (m, 1H), 3.67-3.78 (m, 2H), 3.74 (s, 3H), 3.06-3.20 (m, 1H), 2.08-2.15( m, 1H), 1.91-2.05 (m, 1H), 1.40-1.45 (m, 9H); MS-ESI: m/z 145.25 [M+H-100] ⁺ .

Dissolve triethylamine (136mg, 1.35mmol) and N , N' -carbonyldiimidazole (CDI) (175mg, 1.08mmol) in anhydrous DMF (2mL), add compound ( 2S , 4R )-2-methoxy Carbonyl-4-aminopyrrolidine-1-carboxylate tert-butyl ester (220mg, 0.90mmol), stirred at room temperature for 30min, added anhydrous methanol (5mL), the reaction was stopped after 60°C reaction for 24h, the solvent DMF was removed, and water (5mL) was added , Ethyl acetate (10mL×3) extracted, dried over anhydrous sodium sulfate, the solvent was removed, the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/3) to obtain 260mg white solid : (2 S ,4 R )-2-methoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 95%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 4.81-4.86(m,1H),4.26-4.38(m,2H),3.74-3.81(m,1H),3.73(s,3H),3.66(s, 3H), 3.25-3.38 (m, 1H), 2.22 (m, 2H), 1.45 (d, J =18.2 Hz, 9H); MS-ESI: m/z 203.20 [M+H-100] ⁺ .

To a solution of the compound (2 S ,4 R )-2-methoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.82 mmol) in dichloromethane (2 mL) Add HCl in ethyl acetate solution (4M, 2mL), stir at room temperature for 30min, remove the solvent to obtain 190mg viscous solid: ( 2S , 4R )-2-methoxycarbonyl-4-((methoxycarbonyl) Amino)pyrrolidine hydrochloride, yield: 96%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.58 (t, J = 8.6 Hz, 1H), 4.20-4.24 (m, 1H), 3.81 (s, 3H), 3.60 (s, 3H), 3.54- 3.60 (m, 1H), 3.30-3.34 (m, 1H), 2.35-2.38 (m, 2H); MS-ESI: m/z 203.20 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethyl Oxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid Synthesis of methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (400 mg, 0.84 mmol), compound (2 S ,4 R )-2-methoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine hydrochloride (200 mg, 0.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (320mg, 1.68mmol) and N -hydroxy-7-azabenzotriazole (230mg, 1.68 mmol) was dissolved in methylene chloride (25mL), N , N -diisopropylethylamine (0.59mL, 3.35mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 10h, and water (10mL× 3) The organic phase was washed with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 224 mg of a white solid. Rate: 41%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.49-7.60 (m, 2H), 7.20-7.24 (m, 1H), 6.69 (t, J _FH = 75.0 Hz, 1H), 5.28-5.36 (m, 1H ), 5.16-5.27 (m, 1H), 4.88-5.09 (m, 1H), 4.29-4.35, 4.70-4.75 (m, 0.5H, 0.5H), 4.35-4.50 (m, 1H), 3.96-4.01 ( m, 2H), 3.67-3.78(m, 6H), 2.23-2.50(m, 2H), 1.49-1.53(m, 3H), 1.42(s, 9H), 1.29-1.36(m, 1H), 0.66- 0.71 (m, 2H), 0.39-0.43 (m, 2H); MS-ESI: m/z 653.20 [M+H] ⁺ .

Step 3: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid methyl ester hydrochloride synthesis

To compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid methyl ester (210 mg, 0.32 mmol) in methylene chloride ( 2mL) solution was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, the solvent was removed, to obtain 170mg white solid, yield: 90%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.64-7.77 (m, 2H), 7.34 (d, J = 8.2Hz, 1H), 6.92 (t, J _FH = 75.0Hz, 1H), 5.10-5.19 (m,1H),4.76-4.78,5.49-5.52(m,0.5H,0.5H),4.22-4.42(m,2H),4.04-4.07(m,2H),3.71-4.74,3.96-3.99(m ,0.5H,0.5H),3.73,3.79(s,2H,1H),3.66(d, J =9.0Hz,3H),2.45-2.48(m,1H),2.24-2.37(m,1H),1.76 -1.78(m,3H),1.34-1.39(m,1H),0.68-0.73(m,2H),0.43-0.47(m,2H); MS-ESI: m/z 553.30[M+H-HCl] ⁺ .

Example 68: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid methyl ester hydrochloride Synthesis

Step 1: Synthesis of compound (2 S ,4 R )-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

Combine cyclopropionic acid (116 mg, 1.35 mmol), compound (2 S ,4 R )-2-methoxycarbonyl-4-aminopyrrolidine-1-carboxylic acid tert-butyl ester (220 mg, 0.90 mmol), 1-ethyl -3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (345mg, 1.80mmol) and N -hydroxy-7-azabenzotriazole (245mg, 1.80mmol) dissolved in dichloromethane (25mL) At 0°C, N , N -diisopropylethylamine (0.47mL, 2.70mmol) was added dropwise to the solution, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was used Anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/2) to obtain 225 mg of colorless liquid: (2 S , 4 R )- 2-Methoxycarbonyl-4-cyclopropylcarboxamidopyrrolidine-1-carboxylic acid tert-butyl ester, yield: 80%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 5.86 (d, J = 42.0 Hz, 1H), 4.54 (br.s, 1H), 4.27-4.44 (m, 1H), 3.73-3.81 (m, 1H) , 3.73(s,3H),3.25-3.45(m,1H),2.13-2.32(m,1H),1.45(d, J =18.2Hz,9H),1.28-1.35(m,1H),0.93-0.98 (m, 2H), 0.71-0.78 (m, 2H); MS-ESI: m/z 213.30 [M+H-100] ⁺ .

To a solution of the compound (2 S ,4 R )-2-methoxycarbonyl-4-cyclopropylcarboxamidopyrrolidine-1-carboxylic acid tert-butyl ester (220 mg, 0.71 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate solution (4M, 2mL), stirred at rt for 30min, the solvent was removed to give a sticky solid 170mg: (2 S, 4 R) -4- ( cyclopropyl carboxylic acyl group) pyrrolidin-2 Methyl formate hydrochloride, yield: 97%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.60 (t, J = 8.6 Hz, 1H), 4.31-4.37 (m, 1H), 3.79 (s, 3H), 3.55-3.60 (m, 1H), 3.22-3.28(m,1H), 2.35-2.39(m,2H),1.49-1.56(m,1H), 0.68-0.80(m,4H); MS-ESI: m/z 213.10[M+H-HCl ] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-methyl Synthesis of methyl acid ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound (2 S ,4 R )-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (160 mg, 0.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (245mg, 1.28mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.28 mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, water (10mL × 3) The organic phase was washed with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 134 mg of a white solid. Rate: 32%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.50-7.59 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 6.70 (t, J _FH = 75.0 Hz, 1H), 5.34-5.40 ( m,1H),5.17-5.22(m,1H),4.61-4.77(m,1H),4.60-4.67,4.24-4.32(m,0.5H,0.5H),4.00(m,2H),3.95-4.00 (m,1H), 3.73 (s, 1H), 3.70 (s, 2H), 2.27-2.49 (m, 2H), 1.51-1.55 (m, 3H), 1.42 (s, 9H), 1.31-1.39 (m , 2H), 0.95-1.01 (m, 2H), 0.72-0.79 (m, 2H), 0.68-0.71 (m, 2H), 0.40-0.43 (m, 2H); MS-ESI: m/z 663.40 [M +H] ⁺ .

Step 3: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

To the compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid methyl ester (130 mg, 0.20 mmol) in methylene chloride To the solution (2mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 30min, and the solvent was removed to obtain 115mg of white solid, yield: 98%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.57-7.68 (m, 2H), 7.26 (d, J = 8.2Hz, 1H), 6.85 (t, J _FH = 75.0Hz, 1H), 5.05-5.11 (m,1H),4.43-4.51,4.18-4.24(m,0.5H,0.5H),4.32-4.41(m,1H),3.95-4.00(m,2H),3.89-3.95(m,1H), 3.64-3.71 (m, 1H), 3.67 (d, J = 27.5Hz, 3H), 2.40-2.43 (m, 1H), 2.18-2.30 (m, 1H), 1.71 (d, J = 6.5Hz, 3H) , 1.23-1.31 (m, 2H), 0.77-0.83 (m, 2H), 0.68-0.74 (m, 2H), 0.59-0.64 (m, 2H), 0.34-0.39 (m, 2H); MS-ESI: m/z 563.35 [M+H-HCl] ⁺ .

Example 69: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of compound ( R )-2-methylpyrazine-1-carboxylic acid tert-butyl ester hydrochloride

Dissolve triethylamine (380mg, 3.75mmol) and N , N' -carbonyldiimidazole (CDI) (486mg, 3.0mmol) in anhydrous DMF (2mL), add N -tert-butoxycarbonyl-( R )-3- Methylpyrazine (500mg, 2.5mmol), after stirring at room temperature for 30min, added anhydrous methanol (10mL), the reaction was stopped after 8 hours at 80 ℃, the solvent was removed DMF, water (5mL), ethyl acetate (10mL × 3) was extracted, After drying over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=8/1) to obtain 620 mg of a white solid: ( R )-1-methoxycarbonyl- 2-Methylpyrazine-1-carboxylic acid tert-butyl ester, yield: 96%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 4.20-4.30 (m, 1H), 3.75-3.96 (m, 3H), 3.70 (s, 3H), 3.05-3.11 (m, 1H), 2.91-3.07 ( m, 1H), 2.71-2.88 (m, 1H), 1.45 (s, 9H), 1.15 (d, J = 6.8Hz, 3H); MS-ESI: m/z 159.25 [M+H-100] ⁺ .

To a solution of compound ( R )-1-methoxycarbonyl-2-methylpyrazine-1-carboxylic acid tert-butyl ester (600mg, 2.3mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 30min, and removed the solvent to obtain 420mg of white solid: ( R )-2-methylpyrazine-1-carboxylic acid tert-butyl ester hydrochloride, yield: 93%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.51-4.54 (m, 1H), 4.06-4.13 (m, 1H), 3.70 (s, 3H), 3.27-3.32 (m, 1H), 3.16-3.28 (m, 3H), 2.98-3.06 (m, 1H), 1.31 (d, J = 7.2 Hz, 3H); MS-ESI: m/z 159.20 [M+H-HCl] ⁺ .

Step 2: Compound ( R )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy Of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound ( R )-2-methylpyrazine-1-carboxylic acid tert-butyl ester hydrochloride (150 mg, 0.77 mmol), 1-ethyl-3- (3-Dimethylaminopropyl)carbodiimide hydrochloride (246 mg, 1.3 mmol) and N -hydroxy-7-azabenzotriazole (175 mg, 1.3 mmol) were dissolved in dichloromethane (15 mL) At 0℃, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 12h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) to obtain 186 mg of a white solid in a yield of 47%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.58(d, J =8.3Hz,1H),7.53(s,1H),7.25(d, J =8.3Hz,1H),6.70(t, J _FH = 75.0Hz, 1H), 6.14 (br.s, 1H), 5.20-5.27 (m, 1H), 4.35-4.68 (m, 3H), 3.91-4.02 (m, 1H), 3.97 (d, J = 6.9Hz , 2H), 3.73 (s, 3H), 3.46-3.50, 3.14-3.20 (m, 0.5H, 0.5H), 3.20-3.31 (m, 1H), 2.89-3.06 (m, 1H), 1.52-1.55 ( m,3H),1.42(d, J =5.1Hz,9H),1.28-1.35(m,1H),1.17-1.25(m,3H),0.66-0.71(m,2H),0.38-0.42(m, 2H); MS-ESI: m/z 609.20 [M+H] ⁺ .

Step 3: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester hydrochloride

To the compound ( R )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester (180 mg, 0.3 mmol) in dichloromethane (1 mL) was added HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 125mg white solid, yield: 77%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.63-7.68 (m, 2H), 7.27 (d, J = 8.3Hz, 1H), 6.85 (t, J _FH = 75.0Hz, 1H), 4.97-5.00 (m,1H), 4.87-4.92(m,1H), 4.37-4.45(m,2H), 3.97(d, J =6.9Hz, 2H), 3.92-3.98(m,1H), 3.68(s,3H ), 3.49-3.52, 3.17-3.22 (m, 0.5H, 0.5H), 3.23-3.32 (m, 1H), 3.07-3.12, 2.92-2.98 (m, 0.5H, 0.5H), 1.72 (d, J =6.6Hz, 3H), 1.22-1.30(m, 1H), 1.15-1.24(m, 3H), 0.60-0.64(m, 2H), 0.35-0.38(m, 2H); MS-ESI: m/z 509.15[M+H-HCl] ⁺ .

Example 70: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of azole-4-carbonyl)- N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of compound N , N , 2-trimethylpyrazine-1-carboxamide hydrochloride

The compound N -tert-butoxycarbonyl-2-methylpyrazine (0.5g, 2.50mmol), triethylamine (1.74mL, 12.48mmol) and N , N' -carbonyldiimidazole (CDI) (485mg, 3.00mmol ) Dissolve in anhydrous DMF (2mL), add dimethylamine hydrochloride (800mg, 9.99mmol) after reacting at 60℃ for 30min, stop the reaction after reacting at 80℃ for 12h, remove the solvent DMF, add water (5mL), ethyl acetate (10mL) ×3) Extraction, drying over anhydrous sodium sulfate, removal of solvent, and separation of the concentrated solution by column chromatography (eluent: DCM/MeOH (v/v)=150/1) to obtain 444 mg of pale yellow liquid: 4-(dimethyl Tert-butyl methylaminomethylcarboxamide)-3-methylpyrazine-1-carboxylate, yield: 65%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.64-4.01 (m, 3H), 3.24-3.32 (m, 1H), 3.01-3.17 (m, 2H), 2.86-2.95 (m, 1H), 2.81 ( s, 6H), 1.45 (s, 9H), 1.17 (d, J = 6.7 Hz, 3H); MS-ESI: m/z 216.10 [M-55] ⁺ .

To a solution of the compound 4-(dimethylaminomethylamide)-3-methylpyrazine-1-carboxylic acid tert-butyl ester (0.44 g, 1.62 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate The solution (4M, 4mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 330mg of a white solid: N , N , 2 -trimethylpyrazine-1-carboxamide hydrochloride, yield: 98%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 3.69-3.76(m, 1H), 3.14-3.26(m, 2H), 3.04-3.11(m, 2H), 2.94-3.03(m, 2H), 2.71 (s, 6H), 1.14 (d, J = 6.7 Hz, 3H); MS-ESI: m/z 172.25 [M+H-HCl] ⁺ .

Step 2: Compound ((1 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(dimethylamine Synthesis of tert-Butyl Carboxymethyl)-3-methylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound N , N , 2 -trimethylpyrazine-1-carboxamide hydrochloride (158 mg, 0.77 mmol), 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (245 mg, 1.3 mmol) and N -hydroxy-7-azabenzotriazole (174 mg, 1.3 mmol) were dissolved in methylene chloride (15 mL) At 0℃, N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/3) to obtain 220 mg of a white solid in a yield of 55%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.51-7.60 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.0 Hz, 1H), 5.19-5.29 ( m,1H),4.34-4.53(m,2H),3.97(m,1H),3.97(d, J =6.9Hz,2H),3.35-3.60(m,2H),3.01-3.28(m,2H) , 2.85 (s, 6H), 1.55 (d, J = 7.0Hz, 3H), 1.41 (s, 9H), 1.28-1.36 (m, 1H), 1.22-1.30 (m, 3H), 0.65-0.71 (m , 2H), 0.37-0.43 (m, 2H); MS-ESI: m/z 622.40 [M+H] ⁺ .

Step 3: Compound 4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)- N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride

To the compound ((1 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(dimethylaminomethyl Acetic acid (HCl) was added to a solution of tert-butyl amidyl)-3-methylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid (220 mg, 0.35 mmol) in dichloromethane (2 mL) Ethyl acetate solution (4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 190mg white solid, yield: 96%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.61-7.66(m,2H),7.24(d, J =8.3Hz,1H),6.83(t, J _FH =75.0Hz,1H),4.94-5.01 (m,1H),4.20-4.23,4.34-4.36(m,0.5H,0.5H),3.96(d, J =6.9Hz,2H),3.89-3.98(m,1H), 3.39-3.45,3.55- 3.60(m,0.5H,0.5H),3.34-3.99(m,1H),3.17-3.25(m,1H),3.01-3.07,3.28-3.34(m,0.5H,0.5H),2.82(s, 6H), 1.70 (d, J = 5.8Hz, 3H), 1.23-1.29 (m, 1H), 1.15-1.23 (m, 3H), 0.58-0.61 (m, 2H), 0.32-0.38 (m, 2H) ; MS-ESI: m/z 522.35 [M+H-HCl] ⁺ .

Example 71: Compound 3-(( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)-1,1-dimethylurea hydrochloride

Step 1: Synthesis of compound ( S )-3-(3,3-dimethylurea)pyrrolidine hydrochloride

Dissolve triethylamine (680mg, 6.7mmol) and N , N' -carbonyldiimidazole (CDI) (261mg, 1.6mmol) in anhydrous DMF (5mL), add compound ( S )-3-aminopyrrolidine-1 -Tert-butyl formate (250mg, 1.34mmol), after stirring at room temperature for 30min, dimethylamine hydrochloride (430mg, 5.4mmol) was added, the reaction was stopped after reaction at 80°C for 24h, the solvent DMF was removed, water (10mL), ethyl acetate was added The ester (10 mL×3) was extracted, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=60/1) to obtain 120 mg of light yellow-brown liquid: ( S ) tert-butyl-3-(3,3-dimethylurea)pyrrolidine-1-carboxylate, yield: 35%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.32-4.39 (m, 2H), 3.59-3.68 (m, 1H), 3.34-3.47 (m, 2H), 3.07-3.20 (m, 1H), 2.89 ( s, 6H), 2.10-2.19 (m, 1H), 1.73-1.88 (m, 1H), 1.45 (m, 9H); MS-ESI: m/z 202.20 [M+H-55] ⁺ .

To a solution of the compound ( S )-3-(3,3-dimethylurea)pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 0.47 mmol) in dichloromethane (2 mL) was added a solution of HCl in ethyl acetate ( 4M, 2mL), stirred at room temperature for 30min, and removed the solvent to obtain 90mg of white solid: ( S )-3-(3,3-dimethylurea)pyrrolidine hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.19-4.25 (m, 1H), 3.31-3.42 (m, 2H), 3.17-3.23 (m, 1H), 3.11-3.16 (m, 1H), 2.79 (s, 6H), 2.14-2.23 (m, 1H), 1.94-2.01 (m, 1H); MS-ESI: m/z 158.20 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)-4-(( S )-3-(3,3-dimethylurea)pyrrolidine-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester Synthesis

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (200 mg, 0.43 mmol), compound ( S )-3-(3,3-dimethylurea)pyrrolidine hydrochloride (100 mg, 0.52 mmol), 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride (165mg, 0.85mmol) and N -hydroxy-7-azabenzotriazole (120mg, 0.85mmol) were dissolved in dichloromethane (15mL ), at 0 ℃, N , N -diisopropylethylamine (0.3mL, 1.71mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL × 3), the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: EtOAc) to obtain 180 mg of a white solid in a yield of 69%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.52-7.59 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.0 Hz, 1H), 5.22-5.29( m,1H),4.44-4.56(m,2H),4.20-4.29,4.00-4.06(m,0.5H,0.5H),3.97(d, J =6.9Hz,2H),3.80-3.93(m,1H ), 3.73-3.79 (m, 1H), 2.89-2.92 (m, 6H), 2.17-2.31 (m, 1H), 1.85-2.04 (m, 1H), 1.54 (d, J = 7.0Hz, 3H), 1.41 (s, 9H), 1.28-1.36 (m, 1H), 0.65-0.70 (m, 2H), 0.39-0.42 (m, 2H); MS-ESI: m/z 608.05 [M+H] ⁺ .

Step 3: Compound 3-(( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)-1,1-dimethylurea hydrochloride

To the compound ( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( S )-3-(3,3- Dimethylurea)pyrrolidine-1-carbonyl)oxazol-5-yl)ethyl)tert-butyl carbamate (180 mg, 0.30 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 160mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.58 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.14-7.16 (m, 1H), 6.75 (t, J _FH = 75.0 Hz ,1H),4.93-4.99(m,1H),4.14-4.29(m,2H),3.97-4.04,3.64-3.70(m,0.5H,0.5H),3.88(d, J =6.9Hz,2H) , 3.75-3.84(m, 1H), 3.49-3.55, 3.68-3.40(m, 0.5H, 0.5H), 2.78(s, 3H), 2.77(s, 3H), 2.04-2.14(m, 1H), 1.86-1.96 (m, 1H), 1.64 (d, J = 6.9Hz, 3H), 1.13-1.20 (m, 1H), 0.49-0.53 (m, 2H), 0.25-0.30 (m, 2H); MS- ESI: m/z 508.00 [M+H-HCl] ⁺ .

Example 72: Compound 3-(( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)-1,1-dimethylurea hydrochloride

Step 1: Synthesis of compound ( R )-3-(3,3-dimethylurea)pyrrolidine hydrochloride

N -tert-butoxycarbonyl-( S )-3-pyrrolidinol (1.5g, 8.0mmol), p-toluenesulfonyl chloride (2.7g, 14.0mmol), triethylamine (1.6g, 16mmol) and 4-Dimethylaminopyridine (980mg, 8.0mmol) was dissolved in dichloromethane (10mL), the reaction was stopped at room temperature for 10h, the reaction was stopped, water (20mL) was added, dichloromethane (10mL × 3) was extracted, the organic phases were combined and used Anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=5/1) to obtain 2.5 g of a white solid: ( S )-3-( Tert-Butyl p-toluenesulfonyloxy)pyrrolidine-1-carboxylate, yield: 91%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.78 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 4.98-5.07 (m, 1H), 3.36-3.48 (m , 4H), 2.45 (s, 3H), 1.90-2.18 (m, 2H), 1.42 (m, 9H); MS-ESI: m/z 286.00 [M-55] ⁺ .

Dissolve compound ( S )-3-(p-toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (460mg, 1.34mmol) and sodium azide (380mg, 6.74mmol) in DMF (5mL), 80 ℃ reaction was stopped after 2h the reaction, spin out of DMF, was added water (20 mL), ethyl acetate (10mL × 3) was extracted, dried over anhydrous Na ₂ SO ₄ the combined organic phases, the solvent was removed by column chromatography, concentrated liquid (wash Removal agent: Petroleum ether/EtOAc (v/v) = 4/1), to obtain 250 mg of colorless liquid: ( R )-3-azidopyrrolidine-1-carboxylic acid tert-butyl ester, yield: 87%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.10-4.13 (m, 1H), 3.34-3.49 (m, 4H), 1.99-2.06 (m, 2H), 1.45 (s, 9H); MS-ESI: m/z 157.20[M-55] ⁺ .

Dissolve compound ( R )-3-azidopyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 1.18 mmol) and Pd/C (10%, 50 mg) in methanol (10 mL) at room temperature under normal pressure hydrogen After reduction, the reaction was stopped after 12 hours of reaction, filtered with suction, and the filtrate was concentrated to obtain 210 mg of colorless liquid: ( R )-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester, yield: %%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 3.39-3.49 (m, 3H), 3.27-3.32 (m, 1H), 2.95-3.03 (m, 1H), 1.98-2.08 (m, 1H), 1.63- 1.70 (m, 1H), 1.41 (s, 9H); MS-ESI: m/z 131.20 [M-55] ⁺ .

Dissolve triethylamine (680mg, 6.7mmol) and N , N' -carbonyldiimidazole (CDI) (261mg, 1.6mmol) in anhydrous DMF (5mL), add compound ( R )-3-aminopyrrolidine-1 -Tert-butyl formate (250mg, 1.34mmol), after stirring at room temperature for 30min, dimethylamine hydrochloride (430mg, 5.4mmol) was added, the reaction was stopped after reaction at 80°C for 24h, the solvent DMF was removed, water (10mL), ethyl acetate was added The ester (10 mL×3) was extracted, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=60/1) to obtain 120 mg of light yellow-brown liquid: ( R )-3-(3,3-dimethylurea)pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 35%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.30-4.40 (m, 2H), 3.57-3.67 (m, 1H), 3.34-3.46 (m, 2H), 3.04-3.20 (m, 1H), 2.88 ( s, 6H), 2.08-2.18 (m, 1H), 1.44 (m, 9H); MS-ESI: m/z 202.15 [M-55] ⁺ .

To a solution of the compound ( R )-3-(3,3-dimethylurea)pyrrolidine-1-carboxylic acid tert-butyl ester (120mg, 0.47mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate ( 4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 90mg white solid: ( R )-3-(3,3-dimethylurea)pyrrolidine hydrochloride, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.20-4.24 (m, 1H), 3.30-3.41 (m, 2H), 3.18-3.23 (m, 1H), 3.12-3.15 (m, 1H), 2.80 (s, 3H), 2.16-2.22 (m, 1H), 1.95-2.03 (m, 1H); MS-ESI: m/z 158.30 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)-4-((R)-3-(3,3-dimethylurea)pyrrolidine-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester Synthesis

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (200 mg, 0.43 mmol), compound ( R )-3-(3,3-dimethylurea)pyrrolidine hydrochloride (100 mg, 0.52 mmol), 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride (165mg, 0.85mmol) and N -hydroxy-7-azabenzotriazole (120mg, 0.85mmol) were dissolved in dichloromethane (15mL ), at 0 ℃, N , N -diisopropylethylamine (0.3mL, 1.71mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL × 3), the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: EtOAc) to obtain 180 mg of a white solid in a yield of 69%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.59 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.0Hz, 1H), 5.23-5.30(m, 1H), 4.45-4.53(m, 2H), 4.21-4.26, 4.01-4.11(m, 0.5H, 0.5H), 3.97(d, J = 6.9Hz, 2H), 3.85-3.94(m, 1H), 3.73-3.78(m, 1H), 2.91(s, 6H), 2.22-2.32(m, 1H), 1.84-2.03(m, 1H), 1.51-1.55( m,3H),1.42(s,9H),1.28-1.35(m,1H),0.66-0.71(m,2H),0.37-0.42(m,2H); MS-ESI: m/z 608.04[M+ H] ⁺ .

Step 3: Compound 3-(( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)-1,1-dimethylurea hydrochloride

To the compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( R )-3-(3,3 -Dimethylurea)pyrrolidine-1-carbonyl)oxazol-5-yl)ethyl)tert-butylaminocarbamate (180 mg, 0.30 mmol) in methylene chloride (2 mL) was added HCl in ethyl acetate The solution (4M, 4mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 160mg of white solid, yield: 99%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.66(s,1H),7.64(d, J =8.3Hz,1H),7.22-7.24(m,1H),6.82(t, J _FH =75.0Hz , 1H), 4.99-5.05 (m, 1H), 4.25-4.35 (m, 2H), 4.03-4.09, 3.71-3.77 (m, 0.5H, 0.5H), 3.96 (d, J = 6.9Hz, 2H) , 3.82-3.90 (m, 1H), 3.57-3.64, 3.42-3.47 (m, 0.5H, 0.5H), 2.84 (d, J = 6.4Hz, 6H), 2.10-2.23 (m, 1H), 1.98- 2.06 (m, 1H), 1.70 (d, J = 6.4Hz, 3H), 1.19-1.28 (m, 1H), 0.56-0.61 (m, 2H), 0.32-0.36 (m, 2H); MS-ESI: m/z 508.00[M+H-HCl] ⁺ .

Example 73: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)- N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of compound ( R )- N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride

Compound ( R )-3-methylpyrazine-1-carboxylic acid tert-butyl ester (0.5g, 2.50mmol), triethylamine (1.74mL, 12.48mmol) and N , N' -carbonyldiimidazole (CDI) ( 485mg, 3.00mmol) was dissolved in anhydrous DMF (2mL), after stirring at room temperature for 30min, dimethylamine hydrochloride (800mg, 9.99mmol) was added, the reaction was stopped after 12h reaction at 80°C, the solvent DMF was removed, water (5mL) was added, Extracted with ethyl acetate (10mL×3), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=150/1) to obtain 444mg of pale yellow liquid: ( R )-4-(Dimethylaminomethylamide)-3-methylpyrazine-1-carboxylic acid tert-butyl ester, yield: 65%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.63-4.02 (m, 3H), 3.25-3.32 (m, 1H), 3.02-3.19 (m, 2H), 2.87-2.98 (m, 1H), 2.81 ( s, 6H), 1.45 (s, 9H), 1.17 (d, J = 6.7 Hz, 3H); MS-ESI: m/z 216.20 [M-55] ⁺ .

To a solution of the compound ( R )-4-(dimethylaminomethylamide)-3-methylpentazine-1-carboxylic acid tert-butyl ester (0.44 g, 1.62 mmol) in dichloromethane (2 mL) was added HCl Ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, the solvent was removed, to obtain 330mg white solid: ( R ) -N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride, the Rate: 98%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 3.74-3.81 (m, 1H), 3.22-3.32 (m, 2H), 3.09-3.17 (m, 2H), 2.99-3.02 (m, 2H), 2.77 (s, 6H), 1.20 (d, J = 6.9 Hz, 3H); MS-ESI: m/z 172.15 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)-4-(( R )-4-(dimethylaminomethylamide)-3-methylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)amino Synthesis of tert-butyl formate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound ( R )- N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride (158 mg, 0.77 mmol), 1-B 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (245mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.3mmol) dissolved in dichloromethane In methane (15mL), at 0℃, add N , N -diisopropylethylamine (0.45mL, 2.56mmol) dropwise to this solution, stir at room temperature for 5h, wash with water (10mL×3), organic phase It was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/3) to obtain 220 mg of a white solid in a yield of 55%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.52-7.59 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.0 Hz, 1H), 6.16 (br. s,1H),5.19-5.26(m,1H),4.34-4.56(m,2H),3.97(m,1H),3.97(d, J =6.9Hz,2H),3.34-3.60(m,2H) , 3.00-3.32 (m, 2H), 2.85 (s, 6H), 1.55 (d, J = 7.0Hz, 3H), 1.41 (s, 9H), 1.28-1.36 (m, 1H), 1.19-1.28 (m , 3H), 0.65-0.71 (m, 2H), 0.37-0.43 (m, 2H); MS-ESI: m/z 622.00 [M+H] ⁺ .

Step 3: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)- N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride

To the compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( R )-4-(dimethyl A solution of tert-butyl aminocarbamateyl)-3-methylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamate (220 mg, 0.35 mmol) in methylene chloride (2 mL) was added HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 190mg white solid, yield: 96%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.63-7.69 (m, 2H), 7.27 (d, J = 8.3 Hz, 1H), 6.85 (t, J _FH = 75.0 Hz, 1H), 4.96-5.02 (m,1H),4.23-4.25,4.37-3.39(m,0.5H,0.5H),3.98(d, J =6.9Hz,2H),3.93-3.98(m,1H),3.43-3.49,3.58- 3.60(m,0.5H,0.5H),3.36-3.44(m,1H),3.21-3.28(m,2H),3.04-3.10,3.30-3.35(m,0.5H,0.5H),2.85(s, 6H), 1.73 (d, J = 6.7Hz, 3H), 1.25-1.32 (m, 1H), 1.18-1.26 (m, 3H), 0.60-0.65 (m, 2H), 0.35-0.39 (m, 2H) ; MS-ESI: m/z 522.00 [M+H-HCl] ⁺ .

Example 74: Compound ( S )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Oxygen)phenyl)oxazole-4-carbonyl)- N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of compound ( S )- N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride

Compound ( S )-3-methylpyrazine-1-carboxylic acid tert-butyl ester (0.5g, 2.50mmol), triethylamine (1.74mL, 12.48mmol) and N , N' -carbonyldiimidazole (CDI) ( 485mg, 3.00mmol) was dissolved in anhydrous DMF (2mL), after stirring at room temperature for 30min, dimethylamine hydrochloride (800mg, 9.99mmol) was added, the reaction was stopped after 12h reaction at 80°C, the solvent DMF was removed, water (5mL) was added, Extracted with ethyl acetate (10mL×3), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=150/1) to obtain 443mg of pale yellow liquid: ( S )-4-(Dimethylaminomethylamide)-3-methylpentazine-1-carboxylic acid tert-butyl ester, yield: 65%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.64-4.00 (m, 3H), 3.24-3.33 (m, 1H), 3.01-3.18 (m, 2H), 2.86-2.98 (m, 1H), 2.80 ( s, 6H), 1.45 (s, 9H), 1.17 (d, J = 6.7 Hz, 3H); MS-ESI: m/z 216.20 [M-55] ⁺ .

HCl was added to a solution of the compound ( S )-4-(dimethylaminomethylamide)-3-methylpyrazine-1-carboxylic acid tert-butyl ester (0.44g, 1.62mmol) in dichloromethane (2mL) Ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 330mg white solid: ( S ) -N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride, the Rate: 98%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 3.70-3.75(m, 1H), 3.14-3.26(m, 2H), 3.04-3.11(m, 2H), 2.94-3.03(m, 2H), 2.71 (s, 6H), 1.15 (d, J = 6.9 Hz, 3H); MS-ESI: m/z 172.15 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)-4-(( S )-4-(dimethylaminocarbamoyl)-3-methylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)amino Synthesis of tert-butyl formate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound ( S )- N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride (158 mg, 0.77 mmol), 1-B 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (245mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.3mmol) dissolved in dichloromethane In methane (15mL), at 0℃, add N , N -diisopropylethylamine (0.45mL, 2.56mmol) dropwise to this solution, stir at room temperature for 5h, wash with water (10mL×3), organic phase It was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/3) to obtain 220 mg of a white solid in a yield of 55%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.53-7.59 (m, 2H), 7.24 (d, J = 8.3Hz, 1H), 6.69 (t, J _FH = 75.0Hz, 1H), 5.17-5.29 ( m,1H),4.34-4.55(m,2H),3.92-4.00(m,1H),3.97(d, J =6.9Hz,2H),3.36-3.54(m,2H),3.20-3.31(m, 1H), 3.00-3.19 (m, 1H), 2.85 (s, 6H), 1.55 (d, J = 7.0Hz, 3H), 1.41 (s, 9H), 1.27-1.35 (m, 1H), 1.21-1.30 (m, 3H), 0.65-0.71 (m, 2H), 0.37-0.43 (m, 2H); MS-ESI: m/z 622.05 [M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carbonyl)- N , N ,2-trimethylpyrazine-1-carboxamide hydrochloride

To the compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( S )-4-(dimethyl A solution of tert-butyl aminocarbamateyl)-3-methylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamate (220 mg, 0.35 mmol) in methylene chloride (2 mL) was added HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 190mg white solid, yield: 96%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.62-7.67(m,2H),7.26(d, J =8.3Hz,1H),6.84(t, J _FH =75.0Hz,1H),4.96-5.01 (m,1H),4.70-4.76(m,1H),4.22-4.24,4.35-3.37(m,0.5H,0.5H),3.97(d, J =6.9Hz,2H),3.90-3.98(m, 1H), 3.40-3.44, 3.60-3.62(m,0.5H,0.5H),3.35-3.41(m,1H),3.18-3.26(m,1H),3.04-3.09,3.29-3.36(m,0.5H , 0.5H), 2.83 (s, 6H), 1.70 (d, J = 5.6Hz, 3H), 1.23-1.29 (m, 1H), 1.16-1.22 (m, 3H), 0.58-0.62 (m, 2H) , 0.34-0.39 (m, 2H); MS-ESI: m/z 522.35 [M+H-HCl] ⁺ .

Example 75: Compound (5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazol-4-yl)(( R )-4-(cyclopropylcarbonyl)-3-methylpyrazine-1-yl)methanone hydrochloride

Step 1: Synthesis of compound ( R )-cyclopropyl(2-methylpyrazin-1-yl)methanone hydrochloride

Compound ( R )-3-methylpyrazine-1-carboxylic acid tert-butyl ester (250mg, 1.25mmol), cyclopropylcarboxylic acid (130mg, 1.50mmol), 1-ethyl-3-(3-dimethylamine Propyl)carbodiimide hydrochloride (480mg, 2.50mmol) and N -hydroxy-7-azabenzotriazole (254mg, 1.87mmol) were dissolved in dichloromethane (10mL) at 0℃ , N , N -diisopropylethylamine (0.65mL, 3.74mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed , The concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 310 mg of colorless liquid: ( R )-4-(cyclopropylcarbonyl)-3-methyl Tert-Butyl carbazine-1-carboxylate, yield: 93%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.24-4.50 (m, 1H), 3.78-4.07 (m, 2H), 2.90-3.41 (m, 3H), 2.81 (s, 6H), 1.50 (s, 9H), 1.12-1.36 (m, 4H), 0.96-1.05 (m, 2H), 0.74-0.82 (m, 2H); MS-ESI: m/z 213.10 [M-55] ⁺ .

To a solution of the compound ( R )-4-(cyclopropylcarbonyl)-3-methylpyrazine-1-carboxylic acid tert-butyl ester (310mg, 1.16mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 50min, and removed the solvent to obtain 220mg of white viscous solid: ( R )-cyclopropyl(2-methylpyrazin-1-yl)methanone hydrochloride, yield: 93 %.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.74-4.78 (m, 1H), 4.30-4.38 (m, 1H), 3.28 (d, J =12.4 Hz, 1H), 3.20-3.22 (m, 1H) ), 3.07-3.17 (m, 1H), 2.88-2.99 (m, 1H), 1.82-1.86 (m, 1H), 1.18-1.32 (m, 3H), 0.71-0.80 (m, 4H); MS-ESI : M/z 169.15 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(4-(( R )-4-(cyclopropylcarbonyl)-3-methylpyrazine-1-carbonyl)-2-(3-(ring Synthesis of propylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound ( R )-cyclopropyl(2-methylpyrazin-1-yl)methanone hydrochloride (130 mg, 0.64 mmol), 1-ethyl 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (245mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.3mmol) dissolved in dichloromethane In methane (10mL), at 0℃, add N , N -diisopropylethylamine (0.45mL, 2.56mmol) dropwise to this solution, stir at room temperature for 6h, wash with water (10mL×3), organic phase It was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 300 mg of a white solid in a yield of 76%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.58 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.24 (d, J = 8.7 Hz, 1H), 6.70 (t, J _FH = 75.0Hz, 1H), 5.19-5.30(m, 1H), 4.65-4.77(m, 1H), 4.56-4.64, 4.36-4.47(m, 0.5H, 0.5H), 4.48-4.55(m, 1H), 3.97 (d, J = 6.9Hz, 2H), 3.42-3.66 (m, 1H), 2.94-3.04, 3.20-3.36 (m, 0.5H, 0.5H), 3.04-3.20 (m, 1H), 2.51-2.68 (m, 1H), 1.69-1.79(m, 1H), 1.53-1.57(m, 3H), 1.42(s, 9H), 1.28-1.36(m, 4H), 0.97-1.07(m, 2H), 0.76 -0.84 (m, 2H), 0.65-0.72 (m, 2H), 0.38-0.43 (m, 2H); MS-ESI: m/z 619.00 [M+H] ⁺ .

Step 3: Compound (5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of (yl)oxazol-4-yl)(( R )-4-(cyclopropylcarbonyl)-3-methylpyrazine-1-yl)methanone hydrochloride

To the compound (( S )-1-(4-(( R )-4-(cyclopropylcarbonyl)-3-methylpyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)tert-butylaminocarbamate (300mg, 0.35mmol) in dichloromethane (2mL) was added HCl in ethyl acetate The ester solution (4M, 2mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 260mg of a white solid in a yield of 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.71-7.76 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH = 75.0 Hz, 1H), 5.04-5.11 (m,1H),4.44-4.56(m,1H),4.26-4.42(m,1H),4.05(d, J =6.6Hz,2H),3.57-3.75(m,1H),3.32-3.50(m , 1H), 3.05-3.29 (m, 2H), 1.80 (d, J = 6.4Hz, 3H), 1.97-2.06 (m, 1H), 1.39-1.48 (m, 1H), 1.24-1.43 (m, 3H ), 0.83-0.97 (m, 4H), 0.64-0.75 (m, 2H), 0.39-0.48 (m, 2H); MS-ESI: m/z 519.35 [M+H-HCl] ⁺ .

Example 76: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl) -N -cyclopropyl-2-methylpyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of compound ( R ) -N -cyclopropyl-2-methylpyrazine-1-carboxamide hydrochloride

Dissolve triethylamine (0.52mL, 3.74mmol) and N , N' -carbonyldiimidazole (CDI) (607mg, 3.74mmol) in anhydrous DMF (5mL), add cyclopropylamine (213mg, 3.74mmol) at room temperature, react After 20 min, compound ( R )-3-methylpyrazine-1-carboxylic acid tert-butyl ester (300mg, 1.49mmol) was added. After reaction at 80°C for 10h, the reaction was stopped, the solvent DMF was removed, water (5mL), ethyl acetate (10mL) was added ×3) Extraction, dry with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by column chromatography (eluent: DCM/MeOH(v/v)=100/1) to obtain 370 mg of light yellow liquid: ( R )-4 -(Cyclopropylaminomethylcarboxamide)-3-methylpyrazine-1-carboxylic acid tert-butyl ester, yield: 87%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 4.68 (s, 1H), 4.00-4.15 (m, 1H), 3.72-3.96 (m, 2H), 2.98-3.10 (m, 2H), 2.76-2.94 ( m,1H), 2.64 (s, 1H), 1.45 (s, 9H), 1.08-1.17 (m, 3H), 0.68-0.74 (m, 2H), 0.43-0.49 (m, 2H); MS-ESI: m/z 228.30[M-55] ⁺ .

To a solution of the compound ( R )-4-(cyclopropylaminomethylcarbonyl)-3-methylpyrazine-1-carboxylic acid tert-butyl ester (180 mg, 0.64 mmol) in dichloromethane (2 mL) was added HCl Ethyl acetate solution (4M, 2mL), stirred at room temperature for 30min, and removed the solvent to obtain 140mg white viscous solid: ( R ) -N -cyclopropyl-2-methylpyrazine-1-carboxamide hydrochloride , Yield: 97%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.24-4.31 (m, 1H), 3.76-3.84 (m, 1H), 3.06-3.17 (m, 2H), 2.96-3.02 (m, 1H), 2.77 -2.84(m,1H), 2.31-2.39(m,1H), 1.10(d, J =7.1Hz, 3H), 0.46-0.51(m,2H), 0.27-0.30(m,2H); MS-ESI : M/z 184.20[M+H] ⁺ .

Step 2: Compound (( S )-1-(4-(( R )-4-(cyclopropylaminomethylformyl)-3-methylpyrazine-1-carbonyl Yl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl Ester synthesis

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300mg, 0.64mmol), compound ( R ) -N -cyclopropyl-2-methylpyrazine-1-carboxamide hydrochloride (140mg, 0.64mmol), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (245mg, 1.3mmol) and N -hydroxy-7-azabenzotriazole (174mg, 1.3mmol) were dissolved in In methyl chloride (10mL), at 0℃, add N , N -diisopropylethylamine (0.45mL, 2.56mmol) dropwise, stir at room temperature for 6h, add water (10mL×3) to wash, organic The phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/2) to obtain 240 mg of a white solid in a yield of 59%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 7.56-7.58(m,1H),7.53(s,1H),7.24(d, J =8.3Hz,1H),6.70(t, J _FH =75.0Hz, 1H), 6.12 (br.s, 1H), 5.21-5.23 (m, 1H), 4.71 (d, J =12.3Hz, 1H), 4.43-4.46, 4.53-4.55 (m, 0.5H, 0.5H), 4.13-4.21 (m, 1H), 3.97-4.00 (m, 2H), 3.81-3.84, 3.67-3.69 (m, 0.5H, 0.5H), 3.49-3.53, 2.93-2.99 (m, 0.5H, 0.5H ), 3.20-3.31 (m, 1H), 3.05-3.18 (m, 1H), 2.64-2.70 (m, 1H), 1.53-1.55 (m, 3H), 1.41 (s, 9H), 1.29-1.35 (m ,1H),1.15-1.25(m,3H),0.72-0.77(m,2H),0.66-0.71(m,2H),0.45-0.50(m,2H),0.38-0.42(m,2H); MS -ESI: m/z 634.40[M+H] ⁺ .

Step 3: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl) -N -cyclopropyl-2-methylpyrazine-1-carboxamide hydrochloride

To the compound (( S )-1-(4-(( R )-4-(cyclopropylaminomethylamide)-3-methylpyrazine-1-carbonyl)-2-(3-(cyclopropyl Methoxymethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamic acid tert-butyl ester (230 mg, 0.36 mmol) in methylene chloride (2 mL) was added A solution of HCl in ethyl acetate (4M, 4mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 190mg of white solid, yield: 92%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.68-7.73 (m, 2H), 7.32 (d, J = 8.3Hz, 1H), 6.90 (t, J _FH = 75.0Hz, 1H), 4.99-5.07 (m,1H), 4.87-4.95(m,1H), 4.40-4.48(m,1H), 4.30-4.38(m,1H), 4.03(d, J =5.4Hz, 2H), 3.82-3.89(m , 1H), 2.95-3.04(m, 0.5H, 0.5H), 3.21-3.36(m, 1H), 3.11-3.21(m, 1H), 2.53-2.59(m, 1H), 1.78(d, J = 5.9Hz, 3H), 1.28-1.36(m, 1H), 1.14-1.25(m, 3H), 0.64-0.71(m, 4H), 0.45-0.50(m, 2H), 0.39-0.45(m, 2H) ; MS-ESI: m/z 534.05 [M+H-HCl] ⁺ .

Example 77: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid isopropyl ester salt Synthesis of acid salt

Step 1: Synthesis of compound (2 S ,4 R )-2-isopropoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine hydrochloride

The compound (2 S ,4 R )-2-methoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (360 mg, 1.85 mmol) and LiOH. H ₂ O (250 mg, 5.95 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL), reacted at 40° C. for 30 min, adjusted to pH 1 with hydrochloric acid (1M), and extracted with ethyl acetate (10 mL×3) The organic phases were combined and dried with Na ₂ SO ₄ , and the solvent was removed to obtain 280 mg of a white solid: (2 S ,4 R )-1-tert-butoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine-2 -Formic acid, yield: 82%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.29-4.36 (m, 1H), 4.20-4.27 (m, 1H), 3.68-3.74 (m, 1H), 3.65 (s, 3H), 3.27-3.33 (m,1H),2.22-2.2(m,2H),1.46(d, J =14.2Hz,9H); MS-ESI: m/z 189.20[M+H-100] ⁺ .

The compound (2 S ,4 R )-1-tert-butoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (300 mg, 1.04 mmol) and N , N′ -carbonyldiimidazole ( CDI) (506mg, 3.12mmol) was dissolved in anhydrous THF (10mL), reacted at 60℃ for 1h, then cooled, DBU (0.5mL, 3.12mmol) and isopropanol (0.12mL, 1.56mmol) were added, the reaction was stopped at 60℃ for 4h The reaction was washed with saturated aqueous ammonium chloride solution (10 mL), spin-off THF, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (Eluent: Petroleum ether/EtOAc (v/v)=6/1) to obtain 230 mg of colorless liquid: (2 S ,4 R )-2-isopropoxycarbonyl-4-((methoxycarbonyl)amino ) Pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 67%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 5.71-5.77(m,1H), 5.06-5.10(m,1H),4.35-4.39(m,1H),4.23-4.32(m,1H),3.66( s,3H),3.46-3.57(m,1H),2.43-2.52(m,1H),1.94-1.99(m,1H),1.46(d, J =14.2Hz,9H),1.25-1.32(m, 6H); MS-ESI: m/z 231.10 [M+H-100] ⁺ .

Compound (2 S ,4 R )-2-isopropoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.61 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate (4M, 2mL), stirred at rt for 30min, the solvent was removed to give a sticky white solid 153mg: (2 S, 4 R) -2- isopropoxycarbonyl-4 - ((a Oxycarbonyl)amino)pyrrolidine hydrochloride, yield: 95%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 5.13-5.19 (m, 1H), 4.60 (t, J = 8.6 Hz, 1H), 4.28-4.33 (m, 1H), 3.68 (s, 3H), 3.63-3.67(m,1H), 3.78-3.42(m,1H), 2.40-2.45(m,2H),1.33-1.36(m,6H); MS-ESI: m/z 231.20[M+H-HCl ] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethyl Oxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-methyl Synthesis of isopropyl acid

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (200 mg, 0.43 mmol), compound (2 S ,4 R )-2-isopropoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine hydrochloride (110 mg, 0.43mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (165mg, 0.85mmol) and N -hydroxy-7-azabenzotriazole (116mg, 0.85mmol) was dissolved in dichloromethane (10mL), at 0 ℃, N , N -diisopropylethylamine (0.3mL, 1.71mmol) was added dropwise to this solution, stirred at room temperature for 10h, water (10mL) was added ×3) Washing, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) to obtain 110 mg of white solid, Yield: 38%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.54-7.62 (m, 2H), 7.22-7.26 (m, 1H), 6.72 (t, J _FH = 75.0 Hz, 1H), 5.31-5.41 (m, 1H ), 5.21-5.30 (m, 1H), 4.96-5.13 (m, 2H), 4.66-4.71, 4.29-4.34 (m, 0.5H, 0.5H), 4.36-4.51 (m, 1H), 3.98-4.01 ( m, 2H), 3.70(s, 3H), 2.35-2.47(m, 2H), 1.52-1.56(m, 3H), 1.45(s, 9H), 1.35-1.39(m, 1H), 1.25-1.29( m,2H),1.20(d, J =6.3Hz,2H),1.10(d, J =6.2Hz,2H),0.66-0.71(m,2H),0.39-0.43(m,2H); MS-ESI : M/z 681.00[M+H] ⁺ .

Step 3: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid isopropyl ester hydrochloric acid Salt Synthesis

To compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid isopropyl ester (110 mg, 0.16 mmol) in dichloro To the methane (2mL) solution was added HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 30min, and the solvent was removed to obtain 95mg of white solid, yield: 95%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.68-7.79 (m, 2H), 7.33-7.36 (m, 1H), 6.94 (t, J _FH = 75.0 Hz, 1H), 5.06-5.15 (m, 1H), 4.72-4.75, 3.97-4.01 (m, 0.5H, 0.5H), 4.37-4.43 (m, 1H), 4.24-4.33 (m, 1H), 4.05-4.10 (m, 2H), 3.73-3.76 (m,1H), 3.68 (d, J =9.1Hz, 3H), 2.43-2.53 (m, 1H), 2.22-2.28, 2.34-2.39 (m, 0.5H, 0.5H), 1.78-1.80 (m, 3H), 1.36-1.41 (m, 1H), 1.32 (dd, J ₁ = 22.3Hz, J ₂ = 6.2Hz, 3H), 1.16 (dd, J ₁ = 22.0Hz, J ₂ = 6.2Hz, 3H), 0.69-0.73 (m, 2H), 0.44-0.48 (m, 2H); MS-ESI: m/z 581.00 [M+H-HCl] ⁺ .

Example 78: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of compound ( R )-2-methylpyrazine-1-carboxamide hydrochloride

The compound ( R )-4-tert-butoxycarbonyl-2-methylpyrazine (0.5g, 2.5mmol) and triethylamine (1.1mL, 7.5mmol) were dissolved in anhydrous tetrahydrofuran (10mL) at room temperature To this solution, trimethylsilyl isocyanate (1.0 mL, 7.5 mmol) was added dropwise, stirred at room temperature for 1.5 h, ice water (10 mL) was added, and tetrahydrofuran was swirled out, and the aqueous phase was extracted with ethyl acetate (30 mL×3) The organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=40/1) to obtain 500 mg of white solid: ( R )-4 -Tert-butyl aminomethylamido-3-methylpyrazine-1-carboxylate, yield: 82%.

¹ H NMR(400MHz,CD ₃ OD): δ ppm 4.58(s,1H),4.16-4.22(m,1H),4.00(d, J =12.2Hz,1H),3.85(d, J =13.4Hz, 1H), 3.74 (d, J =13.1Hz, 1H), 3.09 (td, J =12.7, 3.5Hz, 2H), 1.49 (s, 9H), 1.16 (d, J = 6.7Hz, 3H); MS- ESI: m/z 188.20 [M+H-100] ⁺ .

To a solution of the compound ( R )-4-aminocarbamoyl-3-methylpyrazine-1-carboxylic acid tert-butyl ester (0.5g, 2.1mmol) in methylene chloride (4mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 30min, and removed the solvent to obtain 370mg of white solid: ( R )-2-methylpyrazine-1-carboxamide hydrochloride, yield: 99%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 4.51-4.54 (m, 1H), 4.07-4.11 (m, 1H), 3.35-3.43 (m, 3H), 3.25-3.30 (m, 1H), 3.05 -3.14 (m, 1H), 1.39 (d, J = 6.7 Hz, 3H); MS-ESI: m/z 144.20 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(4-(( R )-4-Aminomethylamido-3-methylpyrazine-1-carbonyl)-2-(3-(cyclopropyl Of methoxymethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound ( R )-2-methylpyrazine-1-carboxamide hydrochloride (122 mg, 0.64 mmol), 1-ethyl-3-( 3-Dimethylaminopropyl) carbodiimide hydrochloride (250 mg, 1.3 mmol) and N -hydroxy-7-azabenzotriazole (130 mg, 0.96 mmol) were dissolved in dichloromethane (15 mL) At 0℃, N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 5h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ Dry, remove the solvent, and separate the concentrated solution by column chromatography (eluent: DCM/MeOH (v/v)=40/1) to obtain 290 mg of white solid, yield: 76%.

¹ H NMR(400MHz,CD ₃ OD): δ ppm 7.59(d, J =8.2Hz,1H), 7.55(s,1H),7.26(d, J =8.3Hz,1H),6.72(t, J _FH =75.0Hz,1H),5.11(br.s,1H),5.23-5.32(m,1H),4.64-4.73(m,1H),4.47-4.63(m,1H),4.20-4.26(m,1H ), 3.99 (d, J = 6.9Hz, 2H), 3.76-3.87 (m, 1H), 3.20-3.33 (m, 2H), 2.99-3.15 (m, 1H), 1.57 (d, J = 6.9Hz, 3H), 1.43 (s, 9H), 1.33-1.37 (m, 1H), 1.22-1.27 (m, 3H), 0.68-0.73 (m, 2H), 0.40-0.44 (m, 2H); MS-ESI: m/z 594.30[M+H] ⁺ .

Step 3: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxamide hydrochloride

The compound (( S )-1-(4-(( R )-4-aminomethylamide-3-methylpentazin-1-carbonyl)-2-(3-(cyclopropylmethoxy) 4-(Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (280 mg, 0.47 mmol) was dissolved in a solution of dichloromethane (4 mL), and HCl was added in acetic acid Ethyl acetate solution (4M, 6mL), stirred at room temperature for 30min, the solvent was removed to obtain 235mg white solid, yield: 94%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.67-7.72 (m, 2H), 7.30 (d, J = 8.3Hz, 1H), 6.88 (t, J _FH = 74.8Hz, 1H), 5.02-5.06 (m,1H), 4.95-5.01(m,1H), 4.42-4.49(m,1H), 4.33-4.38(m,1H), 4.01(d, J =6.8Hz, 2H), 3.90-3.94(m ,1H),3.58-3.61,3.26-3.30(m,0.5H,0.5H),3.33-3.40(m,1H),3.16-3.20,3.03-3.10(m,0.5H,0.5H),1.76(d , J =6.9Hz,3H),1.28-1.33(m,1H),1.26(dd, J ₁ =45.0Hz, J ₂ =6.6Hz,3H),0.64-0.67(m,2H),0.39-0.42( m, 2H); MS-ESI: m/z 494.20 [M+H-HCl] ⁺ .

Example 79: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyridin-4-carboxamide hydrochloride

Step 1: Synthesis of compound pyridine-4-carboxamide hydrochloride

The compound N -tert-butoxycarbonyl-4-pyridinecarboxylic acid methyl ester (1.0 g, 4.1 mmol) and lithium hydroxide monohydrate (860 mg, 21 mmol) were dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL), The reaction was carried out at 45°C for 1 h, hydrochloric acid (1M) was added to adjust the pH to 1, and ethyl acetate (20 mL×3) was added for extraction. The combined organic phases were dried over Na ₂ SO ₄ and the solvent was removed to obtain 860 mg of a white solid: 1-(tert-butyl Oxycarbonyl) pyridine-4-carboxylic acid, yield: 91%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 3.97-4.02 (m, 2H), 2.88-2.95 (m, 2H), 2.48-2.55 (m, 1H), 1.88-1.92 (m, 2H), 1.54 -1.61(m,2H), 1.47(s,9H); MS-ESI: m/z 174.20[M-55] ⁺ .

Compound 1-(tert-butoxycarbonyl)pyridin-4-carboxylic acid (220 mg, 0.96 mmol), ammonium chloride (154 mg, 2.88 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimine hydrochloride (367mg, 1.92mmol) and N -hydroxy-7-azabenzotriazole (195mg, 1.44mmol) were dissolved in dichloromethane (10mL), at 0 ℃, to this solution N , N -diisopropylethylamine (1.0 mL, 5.77 mmol) was added dropwise, stirred at room temperature for 10 h, washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was carried out Column chromatography (eluent: EtOAc) gave 160 mg of a white solid: tert-butyl 4-aminomethylamidopyridine-1-carboxylate, yield: 73%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.11 (d, J =13.4 Hz, 2H), 2.76-2.86 (m, 2H), 2.38-2.45 (m, 1H), 1.79 (d, J =11.2 Hz, 2H), 1.52-1.62 (m, 2H), 1.47 (s, 9H); MS-ESI: m/z 173.20 [M-55] ⁺ .

Dissolve the compound 4-aminomethyl acetyl pyridine-1-carboxylic acid tert-butyl ester (160 mg, 0.7 mmol) in dichloromethane (2 mL), add HCl in ethyl acetate (4 M, 2 mL), and stir at room temperature After 30 minutes, the solvent was removed to obtain 112 mg of a white solid: pyridine-4-carboxamide hydrochloride, yield: 97%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.33-3.39 (m, 2H), 2.95-3.24 (m, 2H), 2.50-2.58 (m, 1H), 1.95-1.99 (m, 2H), 1.76 -1.87 (m, 2H); MS-ESI: m/z 129.20 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(4-(4-Aminomethylpyridine-1-carbonyl)-2-(cyclopropylmethoxy Of 4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound pyridine-4-carboxamide hydrochloride (125 mg, 0.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (245mg, 1.28mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96mmol) were dissolved in dichloromethane (10mL), at 0 ℃, to this N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to the solution, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution Column chromatography (eluent: EtOAc) was performed to obtain 240 mg of a white solid in a yield of 64%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.54-7.59 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.1 Hz, 1H), 5.16-5.21 ( m,1H),4.52-4.65(m,2H),3.95(d, J =6.9Hz,2H),3.13-3.30(m,1H),2.84-2.98(m,1H),2.45-2.52(m, 1H), 1.75-1.98 (m, 4H), 1.54 (d, J = 7.0Hz, 3H), 1.42 (s, 9H), 1.28-1.35 (m, 1H), 0.65-0.70 (m, 2H), 0.37 -0.42(m,2H).

Step 3: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-carbonyl)pyrimidine-4-carboxamide hydrochloride

The compound ( S )-(1-(4-(4-aminomethylpyridine-1-carbonyl)-2-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Oxazol-5-yl) ethyl) aminocarboxylic acid tert-butyl ester (200mg, 0.35mmol) was dissolved in dichloromethane (4mL), added HCl in ethyl acetate solution (4M, 6mL), stirred at room temperature for 50min, Removal of solvent gave 130 mg of white solid, yield: 73%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.74 (s, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.91 (t, J _FH = 74.8Hz, 1H), 4.99-5.04(m, 1H), 4.87-4.94(m, 1H), 4.62-4.67(m, 1H), 4.04(d, J = 6.9Hz, 2H), 3.32-3.37( m,1H),2.95-3.00(m,1H),2.62-2.67(m,1H),1.90-1.99(m,2H),1.73-1.84(m,2H),1.79(d, J =6.5Hz, 3H), 1.30-1.35 (m, 1H), 0.66-0.70 (m, 2H), 0.42-0.45 (m, 2H); MS-ESI: m/z 479.10 [M+H-HCl] ⁺ .

Example 80: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Yl) phenyl) oxazole-4-carbonyl) - N - Synthesis of (cyclopropanemethyl) piperidine-4-acyl-amine hydrochloride

Step 1: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-((cyclopropanemethyl ) Carbonyl) pyridine-1-carbonyl) oxazol-5-yl) ethyl) tert-butyl aminocarbamate

The compound ( S )-1-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)pyridine-4-carboxylic acid (170 mg, 0.29 mmol), compound cyclopropylmethylamine (25 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylamine Propyl)carbodiimide hydrochloride (115mg, 0.58mmol) and N -hydroxy-7-azabenzotriazole (60mg, 0.44mmol) were dissolved in dichloromethane (10mL) at 0℃ , N , N -diisopropylethylamine (0.15mL, 0.88mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed The concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/2) to obtain 150 mg of white solid in a yield of 75%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.58(dd, J ₁ =8.3Hz, J ₂ =11.8Hz,1H),7.54(s,1H),7.23(d, J =8.3Hz,1H), 6.69(t, J _FH =75.1Hz,1H),5.15-5.23(m,1H),4.60-4.66(m,2H),3.97(d, J =6.9Hz,2H),3.14-3.26(m,1H ), 3.14 (t, J = 5.9Hz, 2H), 2.85-2.95 (m, 1H), 2.38-2.44 (m, 1H), 1.78-1.95 (m, 4H), 1.53 (d, J = 7.0Hz, 3H), 1.42 (s, 9H), 1.29-1.35 (m, 1H), 0.91-0.97 (m, 1H), 0.65-0.70 (m, 2H), 0.49-0.53 (m, 2H), 0.38-0.42 ( m, 2H), 0.18-0.22 (m, 2H); MS-ESI: m/z 633.35 [M+H] ⁺ .

Step 2: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl) oxazole-4-carbonyl) - N - (cyclopropane meth) Synthesis of 4-piperidine hydrochloride Amides

The compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-((cyclopropanemethyl)carbonyl ) Pyridin-1-carbonyl) oxazol-5-yl) ethyl) tert-butyl aminocarbamate (140mg, 0.23mmol) was dissolved in dichloromethane (4mL), was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 125mg white solid, yield: 94%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.76(s,1H),7.58(dd, J ₁ =8.3Hz, J ₂ =11.8Hz,1H),7.35(d, J =8.3Hz,1H) ,6.94(t, J _FH =74.8Hz,1H),5.04-5.06(m,1H),4.90-4.97(m,1H),4.68-4.70(m,1H),4.06(d, J =6.9Hz, 2H), 3.30-3.39 (m, 1H), 3.10 (d, J = 6.9Hz, 2H), 2.96-3.02 (m, 1H), 2.62-2.67 (m, 1H), 1.78-1.97 (m, 4H) , 1.78-1.82 (m, 3H), 1.32-1.37 (m, 1H), 0.90-0.99 (m, 1H), 0.68-0.73 (m, 2H), 0.52-0.55 (m, 2H), 0.43-0.47 ( m, 2H), 0.24-0.27 (m, 2H); MS-ESI: m/z 533.30 [M+H-HCl] ⁺ .

Example 81: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid ethyl ester hydrochloride

Step 1: Synthesis of compound ( R )-2-methylpyrazine-1-carboxylic acid ethyl ester hydrochloride

Anhydrous THF (5mL) was added to N , N' -carbonyldiimidazole (CDI) (1.21g, 7.49mmol), triethylamine (760mg, 7.49mmol) and absolute ethanol (344mg, 7.49mmol) were added, room temperature After stirring for 15 min, tert-butyl 3-( R )-methylpyrazine-1-carboxylate (500 mg, 2.5 mmol) was added, the reaction was stopped after 24 hours at 70°C, the solvent was removed, water (5 mL), ethyl acetate (10 mL× 3) Extraction, drying over anhydrous sodium sulfate, removal of the solvent, and separation of the concentrated solution by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=8/1) to obtain 140 mg of colorless liquid: ( R )-1- Ethoxycarbonyl-2-methylpyrazine-4-carboxylic acid tert-butyl ester, yield: 21%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 4.25-4.32 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.75-3.89 (m, 2H), 3.70 (s, 3H), 2.98 -3.11(m,2H),2.74-2.89(m,1H),1.92-1.99(m,1H),1.47(s,9H),1.44(t, J =7.2Hz,3H),1.15(d, J = 6.8Hz, 3H); MS-ESI: m/z 173.20[M+H-100] ⁺ .

To a solution of the compound ( R )-1-ethoxycarbonyl-2-methylpyrazine-4-carboxylic acid tert-butyl ester (140mg, 0.51mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 30min, and removed the solvent to obtain 101mg of white liquid: ( R )-2-methylpyrazine-1-carboxylic acid ethyl ester hydrochloride, yield: 99%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 4.54-4.61 (m, 1H), 3.63 (q, J = 7.0Hz, 2H), 3.35-3.39 (m, 1H), 3.22-3.28 (m, 3H ), 3.02-3.10 (m, 2H), 1.30-1.36 (m, 3H), 1.20 (d, J = 7.1 Hz, 3H); MS-ESI: m/z 173.10 [M+H-HCl] ⁺ .

Step 2: Compound ( R )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy Of ethyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid ethyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl) oxazole-4-carboxylic acid (250 mg, 0.53 mmol), compound ( R )-2-methylpyrazine-1-carboxylic acid ethyl ester hydrochloride (130 mg, 0.64 mmol), 1-ethyl-3-( 3-Dimethylaminopropyl) carbodiimide hydrochloride (204 mg, 1.07 mmol) and N -hydroxy-7-azabenzotriazole (110 mg, 0.8 mmol) were dissolved in dichloromethane (15 mL) At 0°C, N , N -diisopropylethylamine (0.36mL, 2.14mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ Dry, remove the solvent, and separate the concentrated solution by column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 4/1) to obtain 105 mg of a white solid in a yield of 32%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.57(d, J =8.3Hz,1H),7.53(s,1H),7.24(d, J =8.3Hz,1H),6.70(t, J _FH = 75.0Hz, 1H), 6.15 (br.s, 1H), 5.20-5.29 (m, 1H), 4.36-4.67 (m, 3H), 4.17 (q, J = 7.1Hz, 2H), 3.96-4.03 (m , 1H), 3.96 (d, J = 6.9Hz, 2H), 3.46-3.50, 3.14-3.20 (m, 0.5H, 0.5H), 3.20-3.30 (m, 1H), 2.89-3.06 (m, 1H) ,1.52-1.55(m,3H),1.42(d, J =5.1Hz,9H),1.28-1.35(m,1H),1.20(d, J =7.1Hz,3H),1.17-1.25(m,3H ), 0.66-0.71 (m, 2H), 0.38-0.42 (m, 2H); MS-ESI: m/z 623.80 [M+H] ⁺ .

Step 3: Compound ( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of ethyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid ethyl ester hydrochloride

To the compound ( R )-4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid ethyl ester (95 mg, 0.15 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate (4M, 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 79mg white solid, yield: 93%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.73-7.78 (m, 2H), 7.35 (d, J = 8.3 Hz, 1H), 6.94 (t, J _FH = 75.0 Hz, 1H), 5.07-5.13 (m,1H), 4.97-5.03(m,1H), 4.47-4.54(m,2H), 4.20(q, J =7.1Hz, 2H), 4.08(d, J =6.9Hz, 2H), 4.03- 4.07(m,1H), 3.37-3.42(m,1H), 3.26-3.32(m,1H), 3.18-3.21,3.04-3.09(m,0.5H,0.5H),1.82(d, J =6.6Hz ,3H),1.33-1.39(m,1H),1.32(d, J =7.1Hz,3H),1.25-1.30(m,3H),0.70-0.73(m,2H),0.45-0.48(m,2H ); MS-ESI: m/z 523.30 [M+H-HCl] ⁺ .

Example 82: Compound (5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazol-4-yl)(( R )-3-methyl4-(methylsulfonyl)pyrazin-1-yl)methanone hydrochloride

Step 1: Synthesis of compound ( R )-2-methyl-1-(methylsulfonyl)pyrazine hydrochloride

Dissolve compound ( R )-3-methylpyrazine-1-carboxylic acid tert-butyl ester (500 mg, 2.5 mmol) and triethylamine (700 mg, 6.3 mmol) in dichloromethane (10 mL) at 0°C, To this solution was added mesyl chloride (0.39 mL, 4.99 mmol) dropwise, stirred at room temperature for 8 h, washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography Separated (eluent: Petroleum ether/EtOAc (v/v)=2/1) to obtain 444 mg of white solid: ( R )-3-methyl-4-(methylsulfonyl)pyrazine-1-carboxylic acid tert Butyl ester, yield: 63%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 4.04-4.24(m,2H), 3.82-3.98(m,1H), 3.54(d, J =12.7Hz,1H),3.14-3.21(m,1H) , 3.04-3.18 (m, 1H), 2.87-3.00 (m, 1H), 2.88 (s, 3H), 1.48 (s, 9H), 1.26 (d, J = 6.8Hz, 3H); MS-ESI: m /z 223.15[M-55] ⁺ .

The compound ( R )-3-methyl-4-(methylsulfonyl)pyrazine-1-carboxylic acid tert-butyl ester (200mg, 0.72mmol) was dissolved in dichloromethane (4mL) and HCl in ethyl acetate was added (4M, 6mL), stirred at room temperature for 50min, and removed the solvent to obtain 147mg of a white solid: ( R )-2-methyl-1-(methylsulfonyl)pyrazine hydrochloride, yield: 95%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.32-4.40 (m, 1H), 3.80-3.86 (m, 1H), 3.47-3.55 (m, 1H), 3.37-3.40 (m, 1H), 3.30 -3.34(m,2H), 3.13-3.20(m,1H), 3.05(s,3H), 1.47(d, J =6.8Hz, 3H); MS-ESI: m/z 179.20[M+H-HCl ] ⁺ .

Step 2: Compound (( S )-1-(2-(3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( R )-3- Synthesis of tert-butyl methyl-4-(methylsulfonyl)pyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound ( R )-2-methyl-1-(methylsulfonyl)pyrazine hydrochloride (164 mg, 0.77 mmol), 1-ethyl- 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (245mg, 1.28mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96mmol) were dissolved in dichloromethane ( 15mL), at 0 ℃, N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL × 3), the organic phase was anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 296 mg of a white solid in a yield of 73%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (d, J = 7.9 Hz, 1H), 7.51 (s, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.70 (t, J _FH = 75.1Hz, 1H), 5.20-5.31 (m, 1H), 4.57-4.78 (m, 2H), 4.17-4.26 (m, 1H), 3.97 (d, J = 6.9Hz, 2H), 3.54-3.71 (m , 1.5H), 3.27-3.39 (m, 1.5H), 2.98-3.15 (m, 1H), 2.89 (s, 3H), 1.55 (d, J = 6.7Hz, 3H), 1.34 (s, 9H), 1.31-1.36(m,1H), 1.24-1.34(m,3H), 0.67-0.71(m,2H), 0.39-0.43(m,2H); MS-ESI: m/z 629.70[M+H] ⁺ .

Step 3: Compound (5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4 -Yl)(( R )-3-methyl-4-(methylsulfonyl)pyrazin-1-yl)methanone hydrochloride

To the compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( R )-3-methyl-4 -(Methsulfonyl)pyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (290 mg, 0.46 mmol) in methylene chloride (4 mL) was added HCl in ethyl acetate The ester solution (4M, 4 mL) was stirred at room temperature for 50 min, and the solvent was removed to obtain 254 mg of a white solid in a yield of 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.71-7.76 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH = 75.0 Hz, 1H), 5.00-5.10 (m,2H), 4.48-4.58(m,1H), 4.21-4.30(m,1H), 4.05(d, J =5.0Hz, 2H), 3.69-3.76(m,1H),3.35-3.46(m ,1H),3.09-3.25(m,2H),3.00(s,3H),1.79(d, J =6.3Hz,3H),1.32-1.36(m,1H),1.31-1.41(m,3H), 0.67-0.71 (m, 2H), 0.43-0.46 (m, 2H); MS-ESI: m/z 529.80 [M+H-HCl] ⁺ .

Example 83: Compound 1-(( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazin-1-yl)-2-methylpropane-1-one hydrochloride to make

Step 1: Synthesis of compound ( R )-2-methyl-1-(2-methylpyrazin-1-yl)propane-1-one hydrochloride

The compound ( R )-3-methylpyrazine-1-carboxylic acid tert-butyl ester (500 mg, 2.5 mmol), isobutyric acid (263 mg, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl Group) carbodiimide hydrochloride (957mg, 5.0mmol) and N -hydroxy-7-azabenzotriazole (507mg, 3.7mmol) were dissolved in dichloromethane (10mL) at 0 ℃, N , N -diisopropylethylamine (1.3 mL, 7.49 mmol) was added dropwise to this solution, stirred at room temperature for 10 h, washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , and the solvent was removed, The concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/1) to obtain 670 mg of a white solid: ( R )-4-isobutyryl-3-methylpyrazine-1- Tert-butyl formate, yield: 99%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 4.70-4.80, 4.30-4.42 (m, 0.5H, 0.5H), 3.76-4.02 (m, 2H), 3.54-3.68, 3.32-3.34 (m, 0.5H , 0.5H), 2.70-2.97 (m, 4H), 1.48 (s, 9H), 1.12 (d, J = 6.8Hz, 9H); MS-ESI: m/z 261.10 [M-55] ⁺ .

The compound ( R )-4-isobutylamide-3-methylpyrazine-1-carboxylic acid tert-butyl ester (670mg, 2.48mmol) was dissolved in dichloromethane (4mL), and a solution of HCl in ethyl acetate (4M, 6mL) was added ), stirred at room temperature for 50 min, and removed the solvent to obtain 520 mg of pale yellow liquid: ( R )-2-methyl-1-(2-methylpyrazin-1-yl)propane-1-one hydrochloride, yield : 100%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.43-3.46 (m, 1H), 3.45-3.39 (m, 2H), 3.20-3.28 (m, 3H), 3.02-3.10 (m, 2H), 1.30 -1.36 (m, 3H), 1.20 (d, J = 7.1 Hz, 6H); MS-ESI: m/z 171.10 [M+H-HC] ⁺ .

Step 2: Compound (( S )-1-(2-(3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( R )-4- Synthesis of tert-butyl isobutylamide-3-methylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300mg, 0.64mmol), compound ( R )-2-methyl-1-(2-methylpyrazin-1-yl)propane-1-one hydrochloride (158mg, 0.77mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (245mg, 1.28mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96mmol) was dissolved in dichloromethane (15mL), N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, water (10mL) was added ×3) Washing, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/2) to obtain 290 mg of white solid, Yield: 73%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.60 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.72 (t, J _FH = 75.1Hz, 1H), 6.11 (br.s, 1H), 5.23-5.31 (m, 1H), 4.60-4.66, 4.87-4.99 (m, 0.5H, 0.5H), 4.68-4.80 (m, 1H), 4.50-4.56 (m, 1H), 3.99 (d, J = 6.9Hz, 2H), 3.66-3.87 (m, 1H), 3.36-3.55 (m, 1H), 3.16-3.33 (m, 1H), 2.99- 3.10 (m, 1H), 2.76-2.83 (m, 1H), 1.57 (d, J = 5.1Hz, 3H), 1.44 (s, 9H), 1.31-1.36 (m, 1H), 1.18 (d, J = 6.6 Hz, 9H), 0.68-0.73 (m, 2H), 0.40-0.44 (m, 2H); MS-ESI: m/z 621.80 [M+H] ⁺ .

Step 3: Compound 1-(( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazin-1-yl)-2-methylpropane-1-one hydrochloride

To the compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( R )-4-isobutylamide-3 -Methylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)tert-butyl carbamate (270mg, 0.44mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M , 4mL), stirred at room temperature for 50min, the solvent was removed to obtain 230mg white solid, yield: 92%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75-7.80 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 6.96 (t, J _FH = 75.0 Hz, 1H), 5.07-5.13 (m, 2H), 4.95-5.01 (m, 1H), 4.47-4.61 (m, 2H), 4.08 (d, J = 6.9Hz, 2H), 3.57-3.66 (m, 1H), 3.11-3.26 (m , 1H), 2.97-3.08 (m, 1H), 1.84 (d, J = 6.6Hz, 3H), 1.31-1.39 (m, 3H), 1.15-1.27 (m, 7H), 0.70-0.75 (m, 2H ), 0.45-0.50 (m, 2H); MS-ESI: m/z 521.30 [M+H-HCl] ⁺ .

Example 84: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)-1,4-homopyrazine-1-carboxylic acid methyl ester hydrochloride

Step 1: Synthesis of Compound 1,4-Homopyrazine-1-carboxylic acid methyl ester hydrochloride

Anhydrous THF (5mL) was added to N , N' -carbonyldiimidazole (CDI) (1.21g, 7.49mmol), triethylamine (760mg, 7.49mmol) and absolute ethanol (344mg, 7.49mmol) were added, room temperature After stirring for 15 min, tert-butyl 1,4-homopyrazine-1-carboxylate (500 mg, 2.5 mmol) was added, the reaction was stopped after 24 hours at 70°C, the solvent was removed, water (5 mL) was added, and ethyl acetate (10 mL×3) was extracted. , Dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=8/1) to obtain 140 mg of colorless liquid: 4-methoxycarbonyl-1,4 -Tert-Butyl homopyrazine-1-carboxylate, yield: 21%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.70 (s, 3H), 3.36-3.46 (m, 8H), 1.83-1.86 (m, 2H), 1.46 (s, 9H); MS-ESI: m/ z 173.20[M+H-100] ⁺ .

The compound 4-methoxycarbonyl-1,4-homopyrazine-1-carboxylic acid tert-butyl ester (140 mg, 0.51 mmol) was dissolved in dichloromethane (2 mL), and a solution of HCl in ethyl acetate (4M, 2 mL) was added After stirring at room temperature for 30 min, the solvent was removed to obtain 101 mg of a colorless liquid: methyl 1,4-homoxazine-1-carboxylate hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.78-3.79 (m, 4H), 3.78 (s, 3H), 3.63 (d, J = 6.2 Hz, 3H), 2.07-2.13 (m, 3H); MS-ESI: m/z 173.10 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy Of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-1,4-homoxazine-1-carboxylic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (250 mg, 0.53 mmol), compound 1,4-homoxazine-1-carboxylic acid methyl ester hydrochloride (130 mg, 0.64 mmol), 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide hydrochloride (204mg, 1.07mmol) and N -hydroxy-7-azabenzotriazole (110mg, 0.8mmol) were dissolved in dichloromethane (15mL), 0 ℃ Under the conditions, N , N -diisopropylethylamine (0.36mL, 2.14mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL×3), and the organic phase was dried over anhydrous Na ₂ SO ₄ , The solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=4/1) to obtain 105 mg of a white solid in a yield of 32%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.53-7.58 (m, 2H), 7.24 (d, J = 8.3Hz, 1H), 6.69 (t, J _FH = 75.0Hz, 1H), 6.05 (br. s,1H),5.18-5.25(m,1H),3.97(d, J =6.9Hz,2H),3.87-3.97(m,2H),3.72(s,3H),3.42-3.77(m,6H) , 1.93-2.10(m, 2H), 1.53(d, J = 7.0Hz, 3H), 1.42(s, 9H), 1.28-1.35(m, 1H), 0.60-0.71(m, 2H), 0.38-0.42 (m, 2H); MS-ESI: m/z 609.70 [M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole -4-Carbonyl)-1,4-homopyrazine-1-carboxylic acid methyl ester hydrochloride

The compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)-1,4-homoxazine-1-carboxylic acid methyl ester (95 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL), and HCl in ethyl acetate (4M) was added , 2mL), stirred at room temperature for 30min, the solvent was removed to obtain 79mg white solid, yield: 93%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.73-7.80 (m, 2H), 7.36 (d, J = 8.3 Hz, 1H), 6.94 (t, J _FH = 75.0 Hz, 1H), 5.01-5.09 (m,1H), 4.22-4.26(m,1H), 4.13-4.17(m,1H), 4.08(t, J =7.1Hz, 2H), 3.88-3.95(m,1H), 3.76-3.87(m , 2H), 3.74(s, 3H), 3.69(s, 1H), 3.60-3.66(m, 2H), 2.05-2.11(m, 1H), 1.93-2.01(m, 1H), 1.81(d, J =6.6Hz,3H),1.35-1.40(m,1H),0.70-0.73(m,2H),0.45-0.48(m,2H); MS-ESI: m/z 509.80[M+H-HCl] ⁺ .

Example 85: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyridin-4-carboxylic acid isopropyl ester hydrochloride

Step 1: Synthesis of compound 4-isopropoxycarbonyl pyridine hydrochloride

Compound 1-(tert-butoxycarbonyl)pyridin-4-carboxylic acid (260mg, 1.14mmol) and N , N' -carbonyldiimidazole (CDI) (275mg, 1.70mmol) were dissolved in anhydrous THF (10mL) at 60°C After 1h of reaction, it was cooled, DBU (0.33mL, 2.67mmol) and isopropanol (0.14mL, 1.70mmol) were added, the reaction was stopped after 4h reaction at 60°C, saturated aqueous ammonium chloride solution (10mL) was added, THF was swirled out, the aqueous phase It was extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 10/1) To obtain 90mg colorless liquid: 4-isopropoxycarbonylpyridine-1-carboxylic acid tert-butyl ester, yield: 29%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 4.97-5.04 (m, 1H), 3.94-4.05 (m, 2H), 2.83 (t, J =11.8Hz, 2H), 2.35-2.42 (m, 1H ), 1.80-1.88 (m, 2H), 1.56-1.66 (m, 2H), 1.45 (s, 9H), 1.22 (d, J = 6.3Hz, 6H); MS-ESI: m/z 216.10 [M- 55] ⁺ .

The compound 4-isopropoxycarbonylpyridine-1-carboxylic acid tert-butyl ester (150 mg, 0.55 mmol) was dissolved in dichloromethane (2 mL), HCl in ethyl acetate solution (4M, 2 mL) was added, and stirred at room temperature for 30 min After removing the solvent, 110 mg of pale yellow liquid was obtained: 4-isopropoxycarbonyl pyridine hydrochloride, yield: 96%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 5.00-5.06 (m, 1H), 3.33-3.42 (m, 2H), 2.99-3.09 (m, 2H), 2.51-2.60 (m, 1H), 2.06 -2.22 (m, 4H), 1.23 (d, J = 6.3 Hz, 6H); MS-ESI: m/z 172.30 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-1-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy Of propyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyridin-4-carboxylic acid isopropyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (250 mg, 0.53 mmol), compound 4-isopropoxycarbonylpyridinium hydrochloride (110 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (204mg, 1.07mmol) and N -hydroxy-7-azabenzotriazole (110mg, 0.8mmol) were dissolved in dichloromethane (10mL) at 0°C. N , N -diisopropylethylamine (0.4mL, 2.14mmol) was added dropwise to the solution, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution Column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) was performed to obtain 170 mg of colorless liquid, yield: 51%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.54-7.59 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.1 Hz, 1H), 6.05 (br. s,1H),5.15-5.22(m,1H),5.00-5.07(m,1H),4.37-4.49(m,2H),3.97(d, J =6.9Hz, 2H),3.23-3.40(m, 1H), 2.98-3.13(m, 1H), 2.54-2.61(m, 1H), 1.88-2.06(m, 2H), 1.72-1.85(m, 2H), 1.53(d, J = 7.0Hz, 3H) ,1.42(s,9H),1.28-1.35(m,1H),1.24(d, J =6.3Hz,6H),0.65-0.70(m,2H),0.37-0.42(m,2H); MS-ESI : M/z 622.30[M+H] ⁺ .

Step 3: Compound ( S )-1-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole Synthesis of -4-carbonyl)pyridine-4-carboxylic acid isopropyl ester hydrochloride

The compound ( S )-1-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )Phenyl)oxazole-4-carbonyl)pyridine-4-carboxylic acid isopropyl ester (160mg, 0.26mmol) was dissolved in dichloromethane (4mL), added HCl in ethyl acetate solution (4M, 4mL), room temperature After stirring for 50 min, the solvent was removed to obtain 140 mg of a white solid. Yield: 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.78 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.95 (t, J _FH =74.8Hz,1H),5.05-5.08(m,2H),4.76-4.86(m,1H),4.47-4.54(m,1H),4.08(d, J =6.9Hz,2H),3.47-3.54( m,1H),3.11-3.18(m,1H),2.72-2.77(m,1H),2.45-2.11(m,2H),1.74-1.88(m,2H),1.82(d, J =6.6Hz, 3H), 1.34-1.41 (m, 1H), 1.30 (d, J = 6.2Hz, 6H), 0.71-0.73 (m, 2H), 0.46-0.49 (m, 2H); MS-ESI: m/z 522.25 [M+H-HCl] ⁺ .

Example 86: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazol-4-yl)(4-(2,4-difluorophenyl)pyrazin-1-yl)methanone dihydrochloride

Step 1: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(2,4-di Synthesis of tert-butyl fluorophenyl)pyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (0.3g, 0.64mmol), 1-(2,4-difluorophenyl)pyrazine (152mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine Propyl)carbodiimide hydrochloride (183mg, 0.96mmol) and N -hydroxy-7-azabenzotriazole (131mg, 0.96mmol) were dissolved in dichloromethane (10mL), stirred at 0 ℃ for 30min Then, N , N -diisopropylethylamine (0.33 mL, 1.92 mmol) was added dropwise, stirred at room temperature for 17 h, washed with water (10 mL×3), the organic phase was dried with Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column Chromatographic separation (eluent: petroleum ether/ethyl acetate (v/v)=3/1) gave 300 mg of white solid in 72% yield.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.61 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.57 (d, J =1.8 Hz, 1H), 7.26 (d, J =8.3 Hz, 1H), 7.00-6.95 (m, 1H), 6.87-6.82 (m, 2H), 6.72 (t, J _FH = 74.7Hz, 1H), 5.28-5.24 (m, 1H), 4.20-4.10 (m , 2H), 4.01-3.92 (m, 2H), 3.99 (d, J = 7.0Hz, 2H), 3.16-3.10 (m, 4H), 1.58 (d, J = 7.0Hz, 3H), 1.44 (s, 9H), 1.33-1.30 (m, 1H), 0.71-0.69 (m, 2H), 0.43-0.42 (m, 2H).

Step 2: Compound ( S )-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4- )) (4- (2,4-difluorophenyl) pyrazin-1-yl) ketone dihydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-(2,4-difluorobenzene ))Pyrazine-1-carbonyl)oxazol-5-yl)ethyl)tert-butyl carbamate (0.3g, 0.46mmol) in dichloromethane (2mL) was added HCl in ethyl acetate (4M , 10mL), stirred at room temperature for 30min, the solvent was removed to obtain 250mg light yellow solid, yield: 93%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.76 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.20-7.17 (m, 1H), 7.02-6.97 (m, 2H), 6.92 (t, J _FH = 74.7Hz, 1H), 5.09-5.07 (m, 1H), 4.38-4.36 (m, 2H), 4.04 (d, J = 6.9 Hz, 2H), 3.99-3.96 (m, 2H), 3.23-3.19 (m, 4H), 1.80 (d, J = 6.8Hz, 3H), 1.35-1.32 (m, 1H), 0.71-0.66 (m, 2H), 0.46-0.43 (m, 2H); MS-ESI: m/z 549.20 [M+H-2HCl] ⁺ .

Example 87: Compound 1-(( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)-2-methylpentazin-1-yl)propane-1-one hydrochloride

Step 1: Synthesis of compound ( R )-1-(2-methylpyrazin-1-yl)propane-1-one hydrochloride

Compound ( R )-4-Boc-2-methylpyrazine (500mg, 2.50mmol), propionic acid (0.22mL, 3.00mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimine hydrochloride (718mg, 3.74mmol) and N -hydroxy-7-azabenzotriazole (850mg, 6.24mmol) were dissolved in dichloromethane (15mL) and added to this solution at 0°C N , N -diisopropylethylamine (1.7 mL, 9.99 mmol) was added dropwise, stirred at room temperature for 16 h, washed with water (10 mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was carried out Column chromatography separation (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 630 mg of colorless oil: ( R )-3-methyl-4-propionylpyrazine- 1-tert-Butyl formate, yield: 95%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 4.76, 4.36 (m, m, 0.5H, 0.5H), 4.00-3.94 (m, 1H), 3.85-3.76 (m, 1H), 3.53, 3.29 (m ,m,0.5H,0.5H),2.98-2.96(m,1H),2.83-2.74(m,2H),2.34-2.26(m,2H),1.45(s,9H),1.13(t, J = 7.0Hz, 6H).

To a solution of compound ( R )-3-methyl-4-propionylpyrazine-1-carboxylic acid tert-butyl ester (630 mg, 2.46 mmol) in dichloromethane (4 mL) was added a solution of HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 2h, and removed the solvent to obtain 473mg of white viscous material: ( R )-1-(2-methylpyrazin-1-yl)propane-1-one hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.14 (m, 1H), 3.11 (m, 1H), 3.07 (m, 1H), 2.97-2.94 (m, 2H), 2.82-2.76 (m, 2H ), 2.20-2.16 (m, 2H), 0.85 (t, J = 7.4 Hz, 6H); MS-ESI: m/z 157.2 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(2-(3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( R )-3- Synthesis of tert-butyl methyl-4-propionylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (250 mg, 0.53 mmol), ( R )-1-(2-methylpyrazin-1-yl)propane-1-one hydrochloride (123 mg, 0.64 mmol), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154mg, 0.80mmol) and N -hydroxy-7-azabenzotriazole (182mg, 1.33mmol) dissolved in di To methyl chloride (15mL), N , N -diisopropylethylamine (0.37mL, 2.14mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 5h, washed with water (10mL×2), organic The phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/2) to obtain 230 mg of a white solid, yield: 65 %.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.57 (d, J = 8.2Hz, 1H), 7.53 (s, 1H), 7.24 (d, J = 8.3Hz, 1H), 6.70 (t, J _FH = 75.0Hz, 1H), 5.29-5.21(m, 1H), 4.83-4.71(m, 1H), 4.62-4.50(m, 2H), 3.96(d, J = 6.9Hz, 2H), 3.69, 3.23(m , m, 0.5H, 0.5H), 3.47-3.44(m, 1H), 3.01-2.92(m, 2H), 2.35-2.30(m, 2H), 1.55(d, J = 6.8Hz, 3H), 1.41 (s,9H),1.32-1.30(m,1H),1.29-1.23(m,3H),1.17(t, J =6.6Hz,3H),0.71-0.64(m,2H),0.42-0.36(m , 2H); MS-ESI: m/z 607.8 [M+H] ⁺ .

Step 3: Compound 1-(( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazin-1-yl)propane-1-one hydrochloride

To the compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( R )-3-methyl-4 -Propionylpyrazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (220 mg, 0.36 mmol) in dichloromethane (4 mL) was added HCl in ethyl acetate solution ( 4M, 4mL), stirred at room temperature for 2h, the solvent was removed to obtain 190mg white solid, yield: 96%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.61-7.57 (m, 2H), 7.21-7.19 (m, 1H), 6.71 (t, J _FH = 74.9 Hz, 1H), 5.05 (br.s, 1H ), 5.04-4.89 (m, 1H), 4.50-4.48 (m, 1H), 4.42-4.35, 4.19-4.16 (m, m, 0.5H, 0.5H), 3.95 (d, J = 4.4Hz, 2H) , 3.74-3.71, 3.30-3.28 (m, m, 0.5H, 0.5H), 3.50-3.42 (m, 1H), 3.04-2.87 (m, 2H), 2.43-2.33 (m, 2H), 1.86-1.84 (m,3H),1.35-1.32(m,1H),1.16-1.13(m,3H),0.87-0.83(m,3H),0.65-0.64(m,2H),0.39-0.38(m,2H) ; MS-ESI: m/z 507.3 [M+H-HCl] ⁺ .

Example 88: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyrazine-2,6-dione hydrochloride

Step 1: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(3,5-dioxoquat Synthesis of tert-butyl 1-carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (250 mg, 0.53 mmol), pyrazine-2,6-dione (73 mg, 0.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Amine hydrochloride (153 mg, 0.80 mmol) and N -hydroxy-7-azabenzotriazole (182 mg, 1.33 mmol) were dissolved in methylene chloride (15 mL), and added dropwise to this solution at 0°C N , N -diisopropylethylamine (0.37mL, 2.14mmol), stirred at room temperature for 10h, washed with water (10mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography Analysis and separation (eluent: dichloromethane/methanol (v/v)=60/1) gave 156 mg of light yellow solid, yield: 51%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.59 (dd, J ₁ =8.3 Hz, J ₂ =1.7 Hz, 1H), 7.56 (d, J =1.6 Hz, 1H), 7.25 (d, J =8.2 Hz, 1H), 6.71(t, J _FH = 75.0Hz, 1H), 5.32-5.25(m, 1H), 5.01(br.s, 2H), 4.63(br.s, 2H), 3.98(d, J =6.9Hz, 2H), 1.54(d, J =7.0Hz, 3H), 1.40(s, 9H), 1.33-1.29(m, 1H), 0.71-0.66(m, 2H), 0.43-0.39(m, 2H); MS-ESI: m/z 465.2 [M+H-100] ⁺ .

Step 2: Compound ( S )-4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrazine-2,6-dione hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(3,5-dioxopyrazine- 1-carbonyl) oxazol-5-yl) ethyl) aminocarboxylic acid tert-butyl ester (149mg, 0.26mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL), room temperature Stir for 3h and remove the solvent to obtain 125mg of white solid. Yield: 94%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.78(d, J =1.8Hz,1H), 7.74(dd, J ₁ =8.3Hz, J ₂ =1.9Hz,1H),7.34(d, J = 8.3Hz, 1H), 6.92(t, J _FH = 74.7Hz, 1H), 5.19-5.18(m, 2H), 5.15-5.12(m, 1H), 4.62(br.s, 2H), 4.05(d, J = 6.9Hz, 2H), 1.79 (d, J = 7.0Hz, 3H), 1.35-1.33 (m, 1H), 0.71-0.68 (m, 2H), 0.46-0.43 (m, 2H); MS-ESI : M/z 465.8 [M+H-HCl] ⁺ .

Example 89: Compound ( S )-1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)cyclopropylaminocarboxylic acid (pyridin-4-yl) ester hydrochloride

Step 1: Synthesis of compound cyclopropylaminocarboxylic acid (pyridin-4-yl) ester hydrochloride

Under ice bath conditions, to a solution of N- Boc-4-pyridone (500mg, 2.51mmol) in absolute ethanol (15mL) was added sodium borohydride (190mg, 5.02mmol), reacted at room temperature for 1.5h, the ethanol was removed and added Ethyl acetate (15mL), saturated ammonium chloride solution (10mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated to obtain 500mg of colorless oil: N- Boc-4-hydroxypyridine, yield : 99%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.85-3.79 (m, 3H), 3.05-2.98 (m, 2H), 1.86-1.82 (m, 2H), 1.49-1.47 (m, 1H), 1.45 ( s, 9H), 1.42-1.40 (m, 1H); MS-ESI: m/z 102.3 [M-100+H] ⁺ .

At room temperature to N 'N - carbonyldiimidazole (623mg, 3.73mmol) in anhydrous DMF (5mL) was added dropwise triethylamine (0.35 mL, 2.48 mmol), stirred at room temperature, was slowly added dropwise N -Boc A solution of 4-hydroxypyridine (250mg, 1.24mmol) in anhydrous DMF (8mL), react at room temperature for 30min, add dropwise a solution of cyclopropylamine (0.26mL, 3.73mmol) in anhydrous DMF (2mL), react at 50°C for 24h, remove Solvent DMF, add ethyl acetate (15 mL), wash with water (10 mL×2), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrate by column chromatography (eluent: petroleum ether/ethyl acetate) (v/v)=3/1), 320 mg of colorless oil was obtained: 4-(cyclopropylaminomethyloxy) pyridine-1-carboxylic acid tert-butyl ester, yield: 90%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.90-4.80 (m, 2H), 3.70-3.62 (m, 2H), 3.20-3.15 (m, 2H), 2.58-2.55 (m, 1H), 1.86- 1.82 (m, 2H), 1.57-1.53 (m, 1H), 1.45 (s, 9H), 0.73-0.69 (m, 2H), 0.52-0.49 (m, 2H); MS-ESI: m/z 185.3[ M-100+H] ⁺ .

To a solution of the compound 4-(cyclopropylaminomethyloxy)pyridine-1-carboxylic acid tert-butyl ester (400 mg, 1.41 mmol) in dichloromethane (6 mL) was added a solution of HCl in ethyl acetate (4M, 5 mL) ), stirred at room temperature for 1 h, and removed the solvent to obtain 310 mg of yellow oil: cyclopropylaminocarboxylic acid (pyridin-4-yl) ester hydrochloride, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.92-4.90 (m, 1H), 3.36-3.34 (m, 1H), 3.32-3.30 (m, 1H), 3.24-3.20 (m, 2H), 2.55 -2.52(m,1H),2.15-2.12(m,2H),1.98-1.93(m,2H),0.71-0.69(m,2H),0.51-0.49(m,2H); MS-ESI: m/ z 185.1[M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(4-(4-(Cyclopropylaminomethyloxy)pyridin-1-carbonyl)-2-(3-(cyclopropyl Of methoxymethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (250 mg, 0.53 mmol), cyclopropylaminocarboxylic acid (pyridin-4-yl) ester hydrochloride (141 mg, 0.64 mmol), 1-ethyl-3-(3- Dimethylaminopropyl) carbodiimide hydrochloride (154mg, 0.80mmol) and N -hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (15mL), 0 N , N -diisopropylethylamine (0.37mL, 2.14mmol) was added dropwise to this solution at ℃, stirred at room temperature for 17h, washed with water (10mL×2), and the organic phase was dried over anhydrous Na ₂ SO ₄ After removing the solvent, the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 246 mg of colorless viscous material, yield: 72%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.57 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.54 (d, J =1.8 Hz, 1H), 7.22 (d, J =8.3 Hz, 1H), 6.69(t, J _FH = 75.1Hz, 1H), 5.21-5.18(m, 1H), 4.98-4.86(m, 2H), 4.05-4.00(m, 1H), 3.95(d, J =6.9Hz, 2H), 3.80-3.52(m, 2H), 2.60-2.57(m, 1H), 2.00-1.95(m, 2H), 1.75-1.71(m, 2H), 1.53(d, J =7.1 Hz, 3H), 1.42 (s, 9H), 1.33-1.30 (m, 1H), 0.74-0.72 (m, 2H), 0.69-0.66 (m, 2H), 0.54-0.51 (m, 2H), 0.41- 0.38 (m, 2H); MS-ESI: m/z 635.3 [M+H] ⁺ .

Step 3: Compound ( S )-1-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of hydroxy)oxazole-4-carbonyl)cyclopropylaminocarboxylic acid (pyridin-4-yl) ester hydrochloride

To the compound ( S )-(1-(4-(4-(cyclopropylaminomethyloxy) pyridine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamic acid tert-butyl ester (236mg, 0.37mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M , 4mL), stirred at room temperature for 2h, the solvent was removed to obtain 200mg white solid, yield: 94%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.59-7.57 (m, 2H), 7.19 (d, J = 7.9 Hz, 1H), 6.69 (t, J _FH = 74.9 Hz, 1H), 5.10-5.07 ( m,1H), 4.99-4.95 (m, 2H), 4.32-4.24 (m, 1H), 3.94 (d, J = 6.4Hz, 2H), 3.88-3.82 (m, 1H), 3.60-3.53 (m, 1H), 2.59-2.57(m, 1H), 2.00-1.92(m, 2H), 1.79-1.69(m, 2H), 1.30-1.28(m, 1H), 0.72-0.71(m, 2H), 0.65- 0.64 (m, 2H), 0.54-0.52 (m, 2H), 0.38-0.37 (m, 2H); MS-ESI: m/z 535.8 [M+H-HCl] ⁺ .

Example 90: Compound (1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester hydrochloride

Step 1: Synthesis of the compound methyl pyridin-3-ylcarbamate hydrochloride

At room temperature to N 'N - (5mL) was added dropwise a solution of carbonyl diimidazole (1.25g, 7.49mmol) in anhydrous THF triethylamine (0.70mL, 4.99mmol), stirred at room temperature, methanol was slowly added dropwise ( 0.30mL, 7.49mmol), react at room temperature for 30min, add dropwise a solution of 1-Boc-3-aminopyridine (500mg, 2.50mmol) in anhydrous THF (10mL), react at 75℃ for 13h, add dilute hydrochloric acid solution (1M) The pH value of the solution was adjusted to about 1, ethyl acetate (15mL×2) was extracted, the organic phase was washed with saturated sodium bicarbonate solution (10mL×2), the organic phases were combined and dried with anhydrous Na ₂ SO _{4 to} remove the solvent, The concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain 477 mg of colorless oil: 3-((methoxycarbonyl)amino)pyridinium- 1-tert-Butyl formate, yield: 74%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 3.66 (s, 3H), 3.58-3.55 (m, 1H), 3.36-3.32 (m, 1H), 3.27-3.23 (m, 1H), 1.83-1.81 ( m, 1H), 1.66-1.60 (m, 1H), 1.56-1.51 (m, 2H), 1.45 (s, 9H); MS-ESI: m/z 159.2 [M-100+H] ⁺ .

To a solution of the compound 3-((methoxycarbonyl)amino)pyridine-1-carboxylic acid tert-butyl ester (464 mg, 1.80 mmol) in dichloromethane (6 mL) was added a solution of HCl in ethyl acetate (4M, 6 mL), After stirring at room temperature for 2h, the solvent was removed to obtain 349mg of a white solid: methyl pyrido-3-ylcarbamate hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.11-4.04 (m, 1H), 3.65 (s, 3H), 3.36-3.32 (m, 1H), 3.21-3.12 (m, 3H), 1.91-1.75 ( m, 3H); MS-ESI: m/z 159.2 [M+H-HCl] ⁺ .

Step 2: Compound (1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-(( S )-1-(tert-butyl Synthesis of Oxycarbonylamino)ethyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (250 mg, 0.53 mmol), pyridin-3-ylaminocarbamic acid methyl ester hydrochloride (156 mg, 0.80 mmol), 1-ethyl-3-(3-dimethylaminopropyl Group) carbodiimide hydrochloride (154mg, 0.80mmol) and N -hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (16mL), at 0 ℃ to N , N -diisopropylethylamine (0.37mL, 2.14mmol) was added dropwise to this solution, stirred at room temperature for 17h, washed with water (10mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed, The concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 235 mg of white solid in a yield of 69%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.64-7.55 (m, 2H), 7.22 (d, J = 8.5Hz, 1H), 6.70 (t, J _FH = 75.1Hz, 1H), 5.22-5.17 ( m,1H),4.01-3.94(m, 1H),3.98(d, J =6.6Hz,2H),3.83-3.81(m,1H),3.67-3.64(m,3H),3.58-3.55(m, 1H), 3.27-3.15(m, 1H), 1.81-1.75(m, 2H), 1.55(d, J = 7.0Hz, 3H), 1.42(s, 9H), 1.33-1.29(m, 1H), 0.68 -0.66 (m, 2H), 0.41-0.40 (m, 2H); MS-ESI: m/z 609.2 [M+H] ⁺ .

Step 3: Compound (1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of methyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester hydrochloride

To the compound (1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-(( S )-1-(tert-butoxycarbonylamino) Ethyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester (226mg, 0.37mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL), After stirring at room temperature for 2h, the solvent was removed to obtain 202mg of white solid. Yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.85 (s, 1H), 7.75-7.74 (m, 1H), 7.33-7.31 (m, 1H), 6.92 (t, J _FH = 74.8 Hz, 1H) ,5.03-5.00(m,1H),4.55-4.45(m,1H),4.14-4.11(m,1H),4.04(d, J =6.6Hz,2H),3.77-3.75(m,1H),3.67 -3.58(m,4H),3.49-3.45(m,1H),2.05-2.03(m,1H),1.93-1.90(m,1H),1.78(d, J =6.4Hz,3H),1.70-1.64 (m, 2H), 1.35-1.33 (m, 1H), 0.69-0.68 (m, 2H), 0.45-0.44 (m, 2H); MS-ESI: m/z 509.9 [M+H-HCl] ⁺ .

Example 91: Compound (( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid isopropyl ester hydrochloride

Step 1: Synthesis of compound ( R )-isopropyl pyrrolidin-3-ylcarbamate hydrochloride

To a solution of compound ( R )-1-Boc-3-aminopyrrolidine (500mg, 2.68mmol) in dichloromethane (15mL) at room temperature, N , N -diisopropylethylamine (1.9 mL, 10.73 mmol), stirred at room temperature, isopropyl chloroformate (1.84 mL, 13.42 mmol) was added dropwise, reacted at room temperature for 18 h, washed with saturated sodium bicarbonate solution (10 mL×2), and the organic phase was washed with anhydrous Na ₂ SO ₄ Dry, remove the solvent, and separate the concentrated solution by column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain 735 mg of colorless liquid: ( R )-3-(isopropoxy Carbonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 98%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.92-4.88 (m, 1H), 4.71-4.70 (m, 1H), 4.21-4.20 (m, 1H), 3.61-3.57 (m, 1H), 3.40- 3.36 (m, 2H), 3.18-3.12 (m, 1H), 2.14-2.07 (m, 1H), 1.45 (s, 9H), 1.22 (d, J = 6.2Hz, 6H); MS-ESI: m/ z 173.2[M-100+H] ⁺ .

To a solution of the compound ( R )-3-(isopropoxycarbonylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (800mg, 2.94mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M, 6mL), stirred at room temperature for 1h, and removed the solvent to obtain 613mg of light yellow oil: ( R )-pyrrolidin-3-ylaminocarboxylic acid isopropyl ester hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.30-4.24 (m, 1H), 3.50-3.44 (m, 2H), 3.40-3.36 (m, 1H), 3.29-3.25 (m, 1H), 2.34 -2.25 (m, 1H), 2.07-2.03 (m, 1H), 1.25 (d, J = 6.7 Hz, 6H); MS-ESI: m/z 173.1 [M+H-HCl] ⁺ .

Step 2: Compound (( R )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)-5-(( S )-1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carbonyl)pyrrolidin-3-yl)aminocarboxylic acid isopropyl Ester synthesis

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (250 mg, 0.53 mmol), ( R )-pyrrolidine-3-ylaminocarboxylic acid isopropyl ester hydrochloride (134 mg, 0.64 mmol), 1-ethyl-3-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (153 mg, 0.80 mmol) and N -hydroxy-7-azabenzotriazole (182 mg, 1.33 mmol) were dissolved in dichloromethane (15 mL), To this solution was added N , N -diisopropylethylamine (0.37mL, 2.14mmol) dropwise at 0°C, stirred at room temperature for 14h, washed with water (10mL×2), and the organic phase was washed with anhydrous Na ₂ SO ₄ Dry, remove the solvent, and separate the concentrated solution by column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 174 mg of white solid in a yield of 52%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.58(dd, J ₁ =8.3Hz, J ₂ =1.8Hz,1H),7.54-7.53(m,1H),7.23(d, J =8.4Hz,1H ), 6.69 (t, J _FH = 75.1 Hz, 1H), 5.29-5.25 (m, 1H), 4.93-4.79 (m, 2H), 4.35-4.33 (m, 1H), 4.23-4.19 (m, 1H) , 4.00-3.95 (m, 1H), 3.97 (d, J = 6.9Hz, 2H), 3.77-3.73 (m, 1H), 2.24-2.19 (m, 1H), 1.99-1.88 (m, 1H), 1.55 -1.52(m,3H),1.43(s,9H),1.33-1.29(m,1H),1.24(d, J =6.0Hz,6H),0.71-0.66(m,2H),0.42-0.39(m , 2H); MS-ESI: m/z 623.4 [M+H] ⁺ .

Step 3: Compound (( R )-1-(5-((S)-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid isopropyl ester hydrochloride

To the compound (( R )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-(( S )-1-(tert-butoxy Carbonylamino)ethyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid isopropyl ester (169 mg, 0.27 mmol) in dichloromethane (4 mL) was added HCl in ethyl acetate solution ( 4M, 3mL), stirred at room temperature for 3h, the solvent was removed to obtain 151mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75-7.74 (m, 1H), 7.73-7.71 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH = 74.7Hz, 1H), 5.13-5.10(m, 1H), 4.36-4.33(m, 1H), 4.28-4.21(m, 2H), 4.09-4.06(m, 1H), 4.04(d, J = 6.6Hz , 2H), 3.90-3.86, 3.79-3.76 (m, m, 0.5H, 0.5H), 3.76-3.73, 3.61-3.58 (m, m, 0.5H, 0.5H), 2.29-2.20 (m, 1H) ,2.07-1.95(m,2H),1.78(d, J =7.0Hz,3H),1.36-1.32(m,1H),1.24(d, J =6.2Hz,6H),0.71-0.68(m,2H ), 0.45-0.43 (m, 2H); MS-ESI: m/z 523.3 [M+H-HCl] ⁺ .

Example 92: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-5-aminomethylpyrrolidin-3-yl)aminocarbamic acid hydrochloride Salt Synthesis

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid methyl ester (550 mg, 0.84 mmol) was dissolved in THF (8 mL ) And H ₂ O (4mL) mixed solvent, then add lithium hydroxide monohydrate (177mg, 4.21mmol), react at 45 ℃ for 1.5h, add HCl (1M) to adjust the pH of the solution to about 1, use acetic acid Ethyl ester (10 mL×3) was extracted, and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 538 mg of a white solid in a yield of 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.74-7.72 (m, 1H), 7.68-7.60 (m, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.89 (t, J _FH = 75.0Hz, 1H), 5.51-5.45(m, 1H), 5.34-5.29(m, 1H), 4.37-4.25(m, 1H), 4.02(d, J = 6.8Hz, 2H), 3.98-3.93(m ,1H),3.76-3.73(m,1H),3.67(s,3H),2.45-2.28(m,2H),1.52(d, J =7.0Hz,3H),1.43(s,9H),1.36- 1.34 (m, 1H), 0.71-0.66 (m, 2H), 0.45-0.42 (m, 2H); MS-ESI: m/z 639.7 [M+H] ⁺ .

Step 2: Compound ((3 R ,5 S )-5-aminomethylacetoyl-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Yl)phenyl)-5-(( S )-1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carbonyl)pyrrolidin-3-yl)aminomethyl Synthesis of methyl acid ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (220mg, 0.34mmol), ammonium chloride (55mg, 1.03mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (99mg, 0.52mmol) and N -hydroxy-7-azabenzotriazole (117mg, 0.86mmol) was dissolved in dichloromethane (16mL), N , N -diisopropylethylamine (0.36mL, 2.07mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 5h, water (10mL × 3) The organic phase was washed with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain 123 mg of a white solid. Yield: 55%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.57 (d, J = 8.5Hz, 1H), 7.55 (s, 1H), 7.24 (d, J = 8.5Hz, 1H), 6.70 (t, J _FH = 75.1Hz, 1H), 5.35-5.23 (m, 2H), 5.06-4.99 (m, 1H), 4.82-4.80 (m, 1H), 4.45-4.34 (m, 1H), 3.98 (d, J = 6.9Hz ,2H),3.66(s,3H),2.66-2.61(m,1H),2.23-2.15(m,1H),1.55(d, J =6.6Hz,3H),1.40(s,9H),1.33- 1.31 (m, 1H), 0.69-0.66 (m, 2H), 0.42-0.40 (m, 2H).

Step 3: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-5-aminomethylpyrrolidin-3-yl)aminocarbamate hydrochloride

To the compound ((3 R ,5 S )-5-aminocarbamoyl-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5 -(( S )-1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester (117 mg, 0.18 mmol) in dichloromethane (4 mL ) A solution of HCl in ethyl acetate (4M, 4mL) was added to the solution, stirred at room temperature for 1h, and the solvent was removed to obtain 105mg of a white solid, yield: 99%.

¹ H NMR(600MHz, d ₆ -DMSO): δ ppm 7.76(s,1H),7.66(d, J =8.1Hz,1H),7.37(d, J =8.5Hz,1H),7.10(t, J _FH = 63.4Hz, 1H), 5.24-5.23, 5.00-4.99 (m, m, 0.5H, 0.5H), 5.10-5.08, 4.53-4.50 (m, m, 0.5H, 0.5H), 4.21-4.20 ( m,1H), 4.10-4.07(m,1H), 4.03(d, J =6.5Hz, 2H), 4.00-3.96(m,1H), 3.56-3.53(m,3H), 2.28-2.14(m, 2H), 1.62-1.61(m, 3H), 1.29-1.26(m, 1H), 0.62-0.61(m, 2H), 0.42-0.40(m, 2H); MS-ESI: m/z 538.8[M+ H-HCl] ⁺ .

Example 93: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(cyclopropylaminomethylamide)pyrrolidin-3-yl)aminocarboxylic acid Synthesis of methyl ester hydrochloride

Step 1: Compound ((3 R ,5 S )-5-(cyclopropylaminomethylamide)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)-5-(( S )-1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carbonyl)pyrrolidin-3-yl)aminocarbamate

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (220mg, 0.34mmol), cyclopropylamine (0.04mL, 0.52mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (99mg, 0.52mmol) and N -hydroxy-7-azabenzotriazole (117mg, 0.86mmol) was dissolved in dichloromethane (16mL), N , N -diisopropylethylamine (0.24mL, 1.38mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 8h, water (10mL × 3) Wash, dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrated solution by column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 130 mg of white solid, Yield: 55%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.61-7.52 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 6.70 (t, J _FH = 75.1 Hz, 1H), 5.35-5.23 ( m,2H),4.76-4.73(m,1H),4.40-4.35(m,1H),4.05-4.02(m,1H),3.98(d, J =7.0Hz,2H),3.66(s,3H) , 2.72-2.66 (m, 2H), 2.23-2.15 (m, 1H), 1.54 (d, J = 7.0Hz, 3H), 1.42 (s, 9H), 1.33-1.31 (m, 1H), 0.77-0.73 (m, 2H), 0.69-0.66 (m, 2H), 0.54-0.46 (m, 2H), 0.42-0.40 (m, 2H); MS-ESI: m/z 678.8 [M+H] ⁺ .

Step 2: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Oxygen)phenyl)oxazole-4-carbonyl)-5-(cyclopropylaminocarboxamide)pyrrolidin-3-yl)carbamic acid methyl ester Synthesis of hydrochloride

To the compound ((3 R ,5 S )-5-(cyclopropylaminomethylamide)-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Phenyl)-5-(( S )-1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carbonyl)pyrrolidin-3-yl)aminocarbamate (128mg, 0.19mmol) To a solution of dichloromethane (4 mL) was added an ethyl acetate solution of HCl (4M, 4 mL), stirred at room temperature for 1.5 h, and the solvent was removed to obtain 116 mg of a white solid, yield: 100%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.75-7.69 (m, 2H), 7.33 (d, J = 8.2Hz, 1H), 6.92 (t, J _FH = 74.7Hz, 1H), 5.41-5.37 , 4.62-4.58(m,m,0.5H,0.5H),5.16-5.10(m,1H),4.39-4.37(m,1H),4.27-4.22(m,1H),4.16-4.11,4.02-3.97 (m,m,0.5H,0.5H),4.09-4.04(m,2H),3.67-3.65(m,3H),2.74-2.71,2.56-2.52(m,m,0.5H,0.5H),2.47 -2.42,2.20-2.15(m,m,0.5H,0.5H),2.34-2.25(m,1H),1.78(d, J =6.9Hz,3H),1.36-1.32(m,1H),0.77- 0.75 (m, 1H), 0.72-0.69 (m, 2H), 0.64-0.57 (m, 2H), 0.48-0.44 (m, 2H), 0.41-0.37, 0.29-0.25 (m, m, 0.5H, 0.5 H); MS-ESI: m/z 578.8 [M+H-HCl] ⁺ .

Example 94: Compound (( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester hydrochloride

Step 1: Synthesis of compound ( S )-methyl pyrido-3-ylcarbamate hydrochloride

At room temperature to N 'N - triethylamine was added dropwise a solution of carbonyl diimidazole (2.5g, 15.0mmol) in anhydrous THF (5mL) (1.4mL, 9.99mmol ), stirred at room temperature, methanol was slowly added dropwise ( 0.61mL, 15.0mmol), react at room temperature for 30min, add ( S )-1-Boc-3-aminopyridine (1.0g, 4.99mmol) in anhydrous THF (10mL), react at 75℃ for 5h, add dilute The pH of the solution was adjusted to about 1 with hydrochloric acid solution (1M), extracted with ethyl acetate (15mL×2), the organic phase was washed with saturated sodium bicarbonate solution (10mL×2), and the organic phases were combined and dried with anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain 1.07 g of colorless oil: ( S )-3-(( Methoxycarbonyl)amino)pyridine-1-carboxylic acid tert-butyl ester, yield: 83%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.77 (br.s, 1H), 3.66 (s, 3H), 3.58-3.55 (m, 1H), 3.36-3.32 (m, 1H), 3.28-3.24 ( m,1H),1.84-1.81(m,1H),1.65-1.61(m,1H),1.56-1.48(m,2H),1.45(s,9H); MS-ESI: m/z 159.2[M- 100+H] ⁺ .

To a solution of the compound ( S )-3-((methoxycarbonyl)amino)pyridine-1-carboxylic acid tert-butyl ester (1.04g, 4.04mmol) in dichloromethane (6mL) was added HCl in ethyl acetate ( 4M, 6mL), stirred at room temperature for 3h, the solvent was removed to obtain 711mg of white solid: ( S )- pyridine-3-ylaminocarboxylic acid methyl ester hydrochloride, yield: 90%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.81-3.75 (m, 1H), 3.67 (s, 3H), 3.43-3.39 (m, 1H), 3.30-3.28 (m, 1H), 2.99-2.93 (m,1H), 2.89-2.84(m,1H), 2.04-1.99(m,2H), 1.85-1.75(m,1H),1.64-1.56(m,1H); MS-ESI: m/z 159.3 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Methyl)-5-(( S )-1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester synthesis

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (250 mg, 0.53 mmol), ( S )-pyridin-3-ylaminocarboxylic acid methyl ester hydrochloride (156 mg, 0.80 mmol), 1-ethyl-3-(3- Dimethylaminopropyl) carbodiimide hydrochloride (154mg, 0.80mmol) and N -hydroxy-7-azabenzotriazole (182mg, 1.33mmol) were dissolved in dichloromethane (16mL), 0 To this solution, N , N -diisopropylethylamine (0.37mL, 2.14mmol) was added dropwise at ℃, stirred at room temperature for 9h, washed with water (10mL×2), and the organic phase was dried over anhydrous Na ₂ SO ₄ After removing the solvent, the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 302 mg of a white solid in a yield of 92%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.64-7.55 (m, 2H), 7.22 (d, J = 8.2Hz, 1H), 6.70 (t, J _FH = 75.1Hz, 1H), 5.21-5.17 ( m,1H), 4.09-3.97(m, 2H), 3.98(d, J =7.1Hz, 2H), 3.85-3.76(m, 2H), 3.70-3.68(m, 1H), 3.64(s, 3H) ,1.83-1.77(m,2H),1.66-1.64(m,1H),1.55(d, J =7.0Hz,3H),1.42(s,9H),1.34-1.31(m,1H),0.70-0.65 (m, 2H), 0.42-0.39 (m, 2H); MS-ESI: m/z 609.8 [M+H] ⁺ .

Step 3: Compound (( S )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester hydrochloride

To the compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-(( S )-1-(tert-butoxy To a solution of carbonylamino)ethyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester (298 mg, 0.49 mmol) in methylene chloride (4 mL) was added HCl in ethyl acetate (4M , 4mL), stirred at room temperature for 1.5h, the solvent was removed to obtain 266mg white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75-7.70 (m, 2H), 7.33-7.31 (m, 1H), 6.92 (t, J _FH = 74.8 Hz, 1H), 5.04-5.01 (m, 1H), 4.60-4.49(m, 1H), 4.15-4.11(m, 1H), 4.07-4.04(m, 2H), 3.77-3.75(m, 1H), 3.67-3.59(m, 4H), 3.49- 3.45(m,1H),2.05-2.03(m,1H),1.93-1.90(m,1H),1.78(d, J =7.0Hz,3H),1.71-1.63(m,2H),1.36-1.33( m, 1H), 0.70-0.67 (m, 2H), 0.46-0.43 (m, 2H); MS-ESI: m/z 509.3 [M+H-HCl] ⁺ .

Example 95: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid ethyl ester hydrochloride synthesis

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxylic acid ethyl Ester synthesis

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (200mg, 0.31mmol), ethanol (0.03mL, 0.47 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (90mg, 0.47mmol) and N -hydroxy-7-azabenzotriazole (107mg, 0.78 mmol) was dissolved in dichloromethane (16mL), N , N -diisopropylethylamine (0.22mL, 1.25mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 16h, and water (10mL×3) was added ) Wash, the organic phase is dried over anhydrous Na ₂ SO ₄ , the solvent is removed, and the concentrated solution is subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 111 mg of colorless viscous The yield is 53%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.59 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.53 (s, 1H), 7.24-7.20 (m, 1H), 6.69 (t , J _FH = 75.1Hz, 1H), 5.27-5.21(m, 1H), 4.38-4.28(m, 1H), 4.26-4.18(m, 2H), 4.15-4.09(m, 2H), 3.99-3.97( m,2H),3.68(s,3H),2.47-2.26(m,2H),1.52(d, J =7.1Hz,3H),1.42(s,9H),1.35-1.32(m,1H),1.26 (t, J = 7.2Hz, 3H), 0.71-0.67 (m, 2H), 0.43-0.39 (m, 2H); MS-ESI: m/z 667.7 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Oxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid ethyl ester hydrochloride to make

To compound (2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxylic acid ethyl ester (107mg, 0.16mmol) in dichloromethane (6mL) Add HCl in ethyl acetate (4M, 4mL), stir at room temperature for 1.5h, remove the solvent to obtain 96mg of white solid, yield: 99%.

¹ H NMR(400MHz,CD ₃ OD): δ ppm 7.76-7.73(m,1H),7.66(dd, J ₁ =8.3Hz, J ₂ =1.7Hz,1H),7.33(d, J =8.3Hz, 1H), 6.92 (t, J _FH = 74.7Hz, 1H), 5.54-5.51, 4.77-4.73 (m, m, 0.5H, 0.5H), 5.18-5.11 (m, 1H), 4.41-4.35 (m, 1H), 4.29-4.22 (m, 2H), 4.18-4.11 (m, 1H), 4.05 (d, J = 6.9Hz, 2H), 4.00-3.95 (m, 1H), 3.75-3.70 (m, 1H) , 3.67(s, 3H), 2.47-2.45(m, 1H), 1.78-1.76(m, 3H), 1.39-1.35(m, 1H), 1.33-1.27(m, 3H), 0.72-0.69(m, 2H), 0.46-0.42 (m, 2H).

Example 96: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of (oxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxylic acid (2-methoxy) ethyl ester hydrochloride

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxylic acid (2-methoxy)ethyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (230 mg, 0.36 mmol), ethylene glycol monomethyl ether (36mg, 0.47mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (104mg, 0.54mmol) and N -hydroxy-7-azabenzotriazole (123mg, 0.90mmol) was dissolved in dichloromethane (16mL), N , N -diisopropylethylamine (0.25mL, 1.44mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 7h, water was added (10mL×3) washed, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/2) to obtain 63mg colorless viscous material, yield: 25%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.60-7.53(m,1H),7.52(s,1H),7.24-7.20(m,1H),6.70(t, J _FH =75.1Hz,1H), 5.35-5.31(m,1H), 5.28-5.22(m,1H),4.76-4.73(m,1H),4.36-4.26(m,2H),4.23-4.19(m,1H),4.02-3.97(m , 2H), 3.69 (s, 3H), 3.65-3.60 (m, 1H), 3.51-3.49 (m, 1H), 3.39, 3.25 (s, s, 1.5H, 1.5H), 2.50-2.45 (m, 1H), 2.30-2.25(m, 1H), 1.52(d, J =7.1Hz, 3H), 1.42(s, 9H), 1.31-1.28(m, 1H), 0.70-0.67(m, 2H), 0.43 -0.39 (m, 2H); MS-ESI: m/z 697.7 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Oxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxylic acid (2-methoxy) ethyl salt Synthesis of acid salt

To compound (2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxylic acid (2-methoxy)ethyl ester (61 mg, 0.09 mmol) To a solution of methyl chloride (4 mL) was added a solution of HCl in ethyl acetate (4M, 3 mL), stirred at room temperature for 1.5 h, and the solvent was removed to obtain 50 mg of a white solid. Yield: 90%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.76-7.74 (m, 1H), 7.72 (s, 1H), 7.35-7.31 (m, 1H), 6.92 (t, J _FH = 74.8 Hz, 1H) , 5.58-5.56 (m, 1H), 5.19-5.16 (m, 1H), 4.37-4.34 (m, 1H), 4.32-4.27 (m, 2H), 4.21-4.17 (m, 1H), 4.09-4.04 ( m,2H), 4.00-3.97(m,1H),3.73-3.70(m,1H),3.67-3.66(m,3H),3.52-3.51(m,1H),3.40,3.21(s,s,1H , 2H), 2.50-2.48(m, 1H), 2.36-2.29(m, 1H), 1.78-1.76(m, 3H), 1.37-1.34(m, 1H), 0.71-0.68(m, 2H), 0.46 -0.43 (m, 2H); MS-ESI: m/z 597.8 [M+H-HCl] ⁺ .

Example 97: Compound ( S )-(1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyridin-4-yl)carbamic acid methyl ester hydrochloride

Step 1: Synthesis of the compound methyl pyridin-4-ylaminocarbamate hydrochloride

At room temperature to N 'N - (5mL) was added dropwise a solution of carbonyl diimidazole (2.50g, 15.0mmol) in anhydrous THF triethylamine (1.40 mL, 10.0 mmol), stirred at room temperature, methanol was slowly added dropwise ( 0.61mL, 15.0mmol), react at room temperature for 30min, add 1-Boc-4-aminopyridine (1.00g, 4.99mmol) in anhydrous THF (10mL), react at 75℃ for 16h, add dilute hydrochloric acid solution (1M) The pH value of the solution was adjusted to about 1, ethyl acetate (15mL×2) was extracted, the organic phase was washed with saturated sodium bicarbonate solution (10mL×2), the organic phases were combined and dried with anhydrous Na ₂ SO _{4 to} remove the solvent, The concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain 819 mg of colorless oil: 4-(methoxycarbonylamino)pyridin-1- Tert-butyl formate, yield: 63%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.59 (br.s, 1H), 4.02-3.95 (m, 2H), 3.66 (s, 3H), 3.65-3.61 (m, 1H), 2.88-2.82 ( m, 2H), 1.92-1.89 (m, 2H), 1.44 (s, 9H), 1.31-1.27 (m, 2H); MS-ESI: m/z 159.3 [M+H-100] ⁺ .

To a solution of the compound 4-(methoxycarbonylamino)pyridine-1-carboxylic acid tert-butyl ester (809 mg, 3.13 mmol) in dichloromethane (6 mL) was added a solution of HCl in ethyl acetate (4M, 5 mL) at room temperature Stir for 2.5h and remove the solvent to obtain 545mg white solid: methyl pyridin-4-ylcarbamate hydrochloride, yield: 89%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 3.73-3.69(m,1H),3.66(s,3H),3.43-3.39(m,2H),3.11(td, J ₁ =12.9Hz, J ₂ =3.1 Hz, 2H), 2.13-2.10 (m, 2H), 1.76-1.69 (m, 2H); MS-ESI: m/z 159.2 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-(1-(tert-butyl Synthesis of Oxycarbonylamino)ethyl)oxazole-4-carbonyl)pyridin-4-yl)carbamic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (220 mg, 0.47 mmol), pyridin-4-ylaminocarbamic acid methyl ester hydrochloride (119 mg, 0.61 mmol), 1-ethyl-3-(3-dimethylaminopropane Group) carbodiimide hydrochloride (135mg, 0.70mmol) and N -hydroxy-7-azabenzotriazole (160mg, 1.17mmol) were dissolved in dichloromethane (16mL), at 0 ℃ to N , N -diisopropylethylamine (0.33mL, 1.88mmol) was added dropwise to this solution, stirred at room temperature for 17h, washed with water (10mL×2), the organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed, The concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/2) to obtain 246 mg of white solid in a yield of 86%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.54 (s, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.69(t, J _FH = 75.1Hz, 1H), 5.23-5.16(m, 1H), 4.65-4.59(m, 1H), 4.54-4.50(m, 2H), 3.96(d, J = 6.9Hz, 2H ), 3.83-3.76 (m, 1H), 3.68 (s, 3H), 3.34-3.25 (m, 1H), 2.10-1.99 (m, 2H), 1.53 (d, J = 7.0Hz, 3H), 1.51- 1.45 (m, 2H), 1.42 (s, 9H), 1.33-1.29 (m, 1H), 0.70-0.66 (m, 2H), 0.42-0.38 (m, 2H); MS-ESI: m/z 609.8[ M+H] ⁺ .

Step 3: Compound ( S )-(1-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of methyl)oxazole-4-carbonyl)pyridin-4-yl)carbamic acid methyl ester hydrochloride

To the compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-(1-(tert-butoxycarbonylamino) Ethyl)oxazole-4-carbonyl)pyridin-4-yl)carbamic acid methyl ester (240mg, 0.39mmol) in dichloromethane (6mL) was added HCl in ethyl acetate (4M, 4mL), Stir at room temperature for 2.5h and remove the solvent to obtain 214mg of white solid. Yield: 99%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.73(s,1H),7.71(dd, J ₁ =8.3Hz, J ₂ =1.8Hz,1H),7.33(d, J =8.3Hz,1H) ,6.92(t, J _FH =74.7Hz,1H),5.04-4.99(m,1H),4.82-4.79(m,1H),4.53-4.51(m,1H),4.03(d, J =6.9Hz, 2H), 3.78-3.73 (m, 1H), 3.66 (s, 3H), 3.47-3.41 (m, 1H), 3.11-3.07 (m, 1H), 2.05-2.03 (m, 2H), 1.77 (d, J = 7.0Hz, 3H), 1.65-1.61(m, 1H), 1.55-1.51(m, 1H), 1.36-1.33(m, 1H), 0.71-0.68(m, 2H), 0.45-0.43(m, 2H); MS-ESI: m/z 509.3 [M+H-HCl] ⁺ .

Example 98: Compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxamide Synthesis of amine)-3-methylbutyrate

Step 1: Compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-)(3-(ring Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxamide)-3-methyl Synthesis of methyl butyrate

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (250 mg, 0.39 mmol), ( S )-2- Amino-3-methylbutyric acid methyl ester (85mg, 0.51mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (113mg, 0.59mmol) and N- Hydroxy-7-azabenzotriazole (133mg, 0.98mmol) was dissolved in dichloromethane (16mL), and N , N -diisopropylethylamine (0.27mL) was added dropwise to this solution at 0°C , 1.57 mmol), stirred at room temperature for 16 h, washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: dichloromethane/methanol (v /v)=40/1) to obtain 225 mg of white solid, yield: 76%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.58-7.51(m,2H),7.24-7.20(m,1H),6.70(t, J _FH =75.0Hz,1H),5.34-5.26(m,1H ), 5.01-4.96 (m, 1H), 4.88-4.85, 4.24-4.20 (m, m, 0.5H, 0.5H), 4.53-4.46 (m, 2H), 4.03-3.97 (m, 2H), 3.75, 3.44(s, s, 2H, 1H), 3.67(s, 3H), 2.72-2.61(m, 1H), 2.20-2.16(m, 1H), 1.55-1.51(m, 3H), 1.43-1.41(m , 9H), 1.35-1.31 (m, 1H), 0.94-0.91 (m, 3H), 0.90-0.85 (m, 3H), 0.71-0.66 (m, 2H), 0.44-0.39 (m, 2H); MS -ESI: m/z 752.4[M+H] ⁺ .

Step 2: Compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-)(3-(ring C Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-methyl Synthesis of acetamide)-3-methylbutyric acid

The compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-)(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxamide)-3-methylbutyric acid The methyl ester (217 mg, 0.29 mmol) was dissolved in a mixed solvent of THF (8 mL) and H ₂ O (4 mL), lithium hydroxide monohydrate (61 mg, 1.44 mmol) was added, reacted at 45°C for 1 h, and HCl (1M) was added. The pH of the solution was adjusted to about 1 and extracted with ethyl acetate (10 mL×3). After combining the organic phases, it was dried over anhydrous Na ₂ SO ₄ and the solvent was removed to obtain 212 mg of a white solid. Yield: 99%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (d, J = 8.5 Hz, 1H), 7.54-7.51 (m, 1H), 7.25-7.18 (m, 1H), 6.70 (t, J _FH = 75.1 Hz, 1H), 5.29-5.25 (m, 1H), 4.87-4.81 (m, 1H), 4.55-4.40 (m, 3H), 4.33-4.16 (m, 2H), 3.98 (d, J = 6.9Hz, 2H), 3.67(s, 3H), 2.63-2.55(m, 1H), 2.26-2.20(m, 1H), 1.55-1.50(m, 3H), 1.43-1.41(m, 9H), 1.33-1.31( m,1H),0.87(d, J =1.5Hz,1H),0.85(s,3H),0.71-0.66(m,2H),0.43-0.39(m,2H); MS-ESI: m/z 738.4 [M+H] ⁺ .

Step 3: Compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)- 4-(two Fluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxamide)-3-methylbutane Synthesis of hydrochloride

To the compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-)(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxamide)-3-methylbutyric acid To a solution of (212mg, 0.29mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 3mL), stirred at room temperature for 1.5h, and the solvent was removed to obtain 170mg of white solid, yield: 87%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.76-7.69 (m, 2H), 7.34-7.30 (m, 1H), 6.92 (t, J _FH = 74.8 Hz, 1H), 5.69-5.67, 4.20- 4.18(m,m,0.5H,0.5H),5.13-5.09(m,1H),4.40-4.36(m,2H),4.27-4.23(m,1H),4.07-4.04(m,3H),3.67 -3.66(m,3H), 2.60-2.53(m,1H),2.43-2.41,2.36-2.33(m,m,0.5H,0.5H),2.28-2.24(m,1H),1.76(d, J =6.8Hz, 3H), 1.37-1.34(m, 1H), 1.06-1.04(m, 3H), 0.77-0.75(m, 2H), 0.71-0.69(m, 3H), 0.46-0.43(m, 2H ); MS-ESI: m/z 638.8 [M+H-HCl] ⁺ .

Example 99: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

Step 1: Compound ((3 R ,5 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-(( S )- Synthesis of 1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)aminocarbamate

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (220 mg, 0.34 mmol), morpholine (36 mg, 0.41 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (99mg, 0.52mmol) and N -hydroxy-7-azabenzotriazole (117mg, 0.86 mmol) was dissolved in dichloromethane (16mL), N , N -diisopropylethylamine (0.24mL, 1.38mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 17h, and water (10mL×3) was added ) Washed, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: dichloromethane/methanol (v/v)=50/1) to obtain 228 mg of pale yellow solid, Yield: 93%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.58 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.53 (d, J =1.7 Hz, 1H), 7.23 (d, J =8.3 Hz, 1H), 6.70(t, J _FH = 74.9Hz, 1H), 5.25-5.21(m, 1H), 5.09-5.06(m, 1H), 4.52-4.48(m, 1H), 4.37-4.27(m , 2H), 3.97(d, J =7.1Hz, 2H), 3.90-3.86(m, 1H), 3.80-3.74(m, 2H), 3.67(s, 3H), 3.70-3.62(m, 3H), 3.56-3.49(m, 2H), 2.35-2.24(m, 2H), 1.54-1.49(m, 3H), 1.43-1.39(m, 9H), 1.33-1.31(m, 1H), 0.71-0.66(m , 2H), 0.43-0.40 (m, 2H); MS-ESI: m/z 708.7 [M+H] ⁺ .

Step 2: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Oxygen)phenyl)oxazole-4-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride Synthesis

To the compound ((3 R ,5 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-(( S )-1- (Tert-Butoxycarbonylamino)ethyl)oxazole-4-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)methylcarbamate (220 mg, 0.31 mmol) in dichloro To the methane (4 mL) solution was added HCl in ethyl acetate solution (4M, 3 mL), stirred at room temperature for 3 h, and the solvent was removed to obtain 188 mg of white solid, yield: 93%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.76 (d, J =1.6 Hz, 1H), 7.73 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.34 (d, J = 8.3Hz, 1H), 6.92 (t, J _FH = 74.7Hz, 1H), 5.21-5.19, 4.43-4.24 (m, m, 0.5H, 2.5H), 5.16-5.08 (m, 1H), 4.06-4.03 (m, 2H), 3.99-3.95, 3.86-3.83 (m, m, 0.5H, 0.5H), 3.79-3.75 (m, 1H), 3.74-3.70 (m, 2H), 3.68-3.63 (m, 3H ), 3.66 (s, 3H), 3.57-3.50, 3.21-3.17 (m, m, 1.5H, 0.5H), 2.57-2.53, 2.20-2.11 (m, m, 0.5H, 0.5H), 2.38-2.29 (m,1H), 1.77 (d, J = 7.0 Hz, 3H), 1.38-1.34 (m, 1H), 0.71-0.68 (m, 2H), 0.46-0.43 (m, 2H); MS-ESI: m /z 608.8[M+H-HCl] ⁺ .

Example 101: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxylic acid-(2-hydroxyethyl) ester Synthesis of hydrochloride

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxylic acid-(2-hydroxyethyl) ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (250 mg, 0.39 mmol), ethylene glycol (1.0 mL , 19.6mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (113mg, 0.59mmol) and N -hydroxy-7-azabenzotriazole (133mg , 0.98mmol) was dissolved in dichloromethane (16mL), N , N -diisopropylethylamine (0.24mL, 1.37mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 17h, water (10mL) was added ×3) Wash, dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrated solution by column chromatography (eluent: dichloromethane/methanol (v/v)=40/1) to obtain 187 mg of white solid , Yield: 70%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.59-7.51 (m, 2H), 7.23 (t, J = 8.3 Hz, 1H), 6.70 (t, J _FH = 75.0 Hz, 1H), 5.30-5.24( m,1H),5.05-4.90(m,1H),4.50-4.42(m,2H),4.35-4.23(m,2H),3.99(t, J =6.3Hz, 2H),3.90-3.76(m, 3H), 3.68 (s, 3H), 2.48-2.30 (m, 2H), 1.55-1.50 (m, 3H), 1.42 (s, 9H), 1.35-1.32 (m, 1H), 0.71-0.67 (m, 2H), 0.43-0.40 (m, 2H); MS-ESI: m/z 683.4 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Oxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxylic acid-(2-hydroxyethyl) ester hydrochloric acid Salt Synthesis

To compound (2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carboxylic acid-(2-hydroxyethyl) ester (182 mg, 0.27 mmol) To a solution of methyl chloride (4 mL) was added HCl in isopropanol (7M, 4 mL), stirred at room temperature for 2.5 h, and the solvent was removed to obtain 160 mg of a white solid. After preparation and purification, 10 mg of light yellow solid was obtained after treatment. .

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.75-7.71 (m, 1H), 7.65 (d, J = 8.2Hz, 1H), 7.31 (t, J = 9.1Hz, 1H), 6.91 (t, J _FH = 74.8Hz, 1H), 5.52-5.50(m, 1H), 4.78-4.75(m, 1H), 4.65-4.56(m, 1H), 4.27-4.20(m, 3H), 4.12-4.08(m , 1H), 4.06-4.02(m, 2H), 4.00-3.97(m, 1H), 3.80-3.77(m, 1H), 3.67(s, 3H), 2.49-2.46(m, 1H), 2.36-2.29 (m,1H),1.65-1.63(m,3H),1.36-1.33(m,1H),0.71-0.68(m,2H),0.46-0.43(m,2H); MS-ESI: m/z 583.7 [M+H-HCl] ⁺ .

Example 102: Compound 1-(( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carbonyl)pyridin-4-carboxylic acid hydrochloride

Step 1: Synthesis of compound ( S )-1-(pyrrolidine-2-carbonyl)pyridin-4-carboxylic acid methyl ester hydrochloride

The compound Boc- L -proline (500 mg, 2.32 mmol), methyl 4-pyridinecarboxylate (499 mg, 3.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Hydrochloride (1.11g, 5.81mmol) and N -hydroxy-7-azabenzotriazole (474mg, 3.48mmol) were dissolved in dichloromethane (16mL) and added dropwise to this solution at 0°C N , N -diisopropylethylamine (1.6 mL, 9.29 mmol), stirred at room temperature for 12 h, washed with water (10 mL×2), washed with dilute hydrochloric acid (1M, 10 mL×2), and the organic phase was washed with anhydrous Na ₂ SO ₄ Dry, remove the solvent, and separate the concentrated solution by column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/2) to obtain 605 mg of colorless oil: ( S )-1-(1 -Methyl tert-butoxycarbonylpyrrolidine-2-carbonyl)pyridine-4-carboxylate, yield: 76%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 4.70-4.65, 4.55-4.52 (m, m, 0.5H, 0.5H), 4.48-4.31 (m, 1H), 3.92-3.80 (m, 1H), 3.68 (s, 3H), 3.59-3.38(m, 2H), 3.23-3.04(m, 1H), 2.91-2.75(m, 1H), 2.59-2.52(m, 1H), 2.17-2.08(m, 1H) , 1.98-1.92(m, 3H), 1.87-1.80(m, 2H), 1.68-1.60(m, 1H), 1.45-1.38(m, 9H); MS-ESI: m/z 241.1[M+H- 100] ⁺ .

To a solution of the compound ( S )-1-(1-tert-butoxycarbonylpyrrolidine-2-carbonyl)pyridine-4-carboxylic acid methyl ester (595mg, 1.75mmol) in dichloromethane (4mL) was added HCl in ethyl acetate Ester solution (4M, 6mL), stirred at room temperature for 2h, the solvent was removed to give 483mg of a colorless oil: ( S )-1-(pyrrolidine-2-carbonyl) pyridine-4-carboxylic acid methyl ester hydrochloride, the Rate: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.74-4.66 (m, 1H), 4.37-4.29 (m, 1H), 3.89-3.83 (m, 1H), 3.71 (s, 3H), 3.47-3.35 (m, 2H), 3.31-3.24 (m, 1H), 3.06-2.95 (m, 1H), 2.77-2.69 (m, 1H), 2.58-2.49 (m, 1H), 2.17-2.01 (m, 3H) , 1.98-1.89 (m, 2H), 1.76-1.58 (m, 2H); MS-ESI: m/z 241.1 [M+H-HCl] ⁺ .

Step 2: Compound 1-(( S )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-)(3-(cyclopropylmethoxy Group)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carbonyl)pyridine-4-carboxylic acid methyl ester to make

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (250 mg, 0.53 mmol), ( S )-1-(pyrrolidin-2-carbonyl)pyridin-4-carboxylic acid methyl ester hydrochloride (192 mg, 0.69 mmol), 1-B 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (205mg, 1.07mmol) and N -hydroxy-7-azabenzotriazole (109mg, 0.80mmol) dissolved in dichloromethane In methane (16mL), N , N -diisopropylethylamine (0.37mL, 2.14mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 12h, washed with water (10mL×2), organic phase Dry with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrate by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1, dichloromethane/methanol (v/v) = 20/1), 243 mg of light yellow solid was obtained, yield: 65%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.58 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.54 (d, J =1.7 Hz, 1H), 7.22 (d, J =8.2 Hz, 1H), 6.69(t, J _FH = 75.2Hz, 1H), 5.67-5.58(m, 1H), 5.23-5.19(m, 1H), 5.07-5.03(m, 1H), 4.51-4.41(m ,1H),4.25-4.19(m,1H),3.96(d, J =6.9Hz,2H),3.94-3.88(m,2H),3.82-3.77(m,1H),3.71(s,3H), 3.00-2.85(m, 1H), 2.60-2.48(m, 1H), 2.36-2.31(m, 1H), 2.21-2.07(m, 2H), 2.00-1.90(m, 4H), 1.51(d, J =7.0Hz, 3H), 1.43(s, 9H), 1.33-1.31(m, 1H), 0.69-0.66(m, 2H), 0.43-0.40(m, 2H); MS-ESI: m/z 691.8[ M+H] ⁺ .

Step 3: Compound 1-(( S )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carbonyl)pyridine-4-carboxylic acid

Compound 1-(( S )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carbonyl)pyridin-4-carboxylic acid methyl ester (241 mg, 0.35 mmol) was dissolved in THF (8 mL) and H ₂ O (4 mL) In the mixed solvent, add lithium hydroxide monohydrate (73mg, 1.74mmol), react at 45℃ for 1h, add HCl (1M) to adjust the pH of the solution to about 1, and extract with ethyl acetate (10mL×3) After combining the organic phases, it was dried over anhydrous Na ₂ SO ₄ and the solvent was removed to obtain 236 mg of white solid in a yield of 99%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.71 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.30-7.27 (m, 1H), 6.90 (t, J _FH = 74.8Hz ,1H), 5.67-5.60(m,1H),5.41-5.31(m,1H),4.43-4.33(m,1H),4.15-4.07(m,2H),4.03(d, J =6.7Hz, 2H ), 3.87-3.79(m, 2H), 3.03-2.96(m, 1H), 2.83-2.77(m, 1H), 2.67-2.54(m, 1H), 2.47-2.41(m, 1H), 2.00-1.89 (m,3H),1.53-1.51(m,3H),1.44(s,9H),1.37-1.35(m,1H),0.71-0.66(m,2H),0.44-0.41(m,2H); MS -ESI: m/z 677.7[M+H] ⁺ .

Step 4: Compound 1-(( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl) phenyl) oxazole-4-carbonyl) pyrrolidine-2-carbonyl) pyridine-4-carboxylic acid hydrochloride

To compound 1-(( S )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carbonyl)pyridine-4-carboxylic acid (218 mg, 0.32 mmol) in dichloromethane (4 mL) was added HCl in ethyl acetate The solution (4M, 5mL) was stirred at room temperature for 1.5h, and the solvent was removed to obtain 197mg of light yellow solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.75 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.34-7.30 (m, 1H), 6.92 (t, J _FH = 74.8 Hz , 1H), 5.97-5.93 (m, 1H), 5.13-5.04 (m, 2H), 4.41-4.27 (m, 2H), 4.19-4.13 (m, 1H), 4.06-4.01 (m, 1H), 4.04 (d, J =6.6Hz, 2H), 3.83-3.77(m, 1H), 2.71-2.65(m, 1H), 2.57-2.53(m, 1H), 2.41-2.35(m, 1H), 2.13-2.07 (m,2H),1.94-1.90(m,2H),1.77(d, J =6.7Hz,3H),1.70-1.57(m,2H),1.36-1.34(m,1H),0.71-0.67(m , 2H), 0.45-0.43 (m, 2H); MS-ESI: m/z 577.8 [M+H-HCl] ⁺ .

Example 103: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(4-methylpyrazine-1-carbonyl)pyrrolidin-3-yl)aminocarboxylic acid Synthesis of methyl ester dihydrochloride

Step 1: Compound ((3 R ,5 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-(( S )- Synthesis of 1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carbonyl)-5-(4-methylpyrazine-1-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (200mg, 0.31mmol) and N , N' -carbonyl Diimidazole (79mg, 0.47mmol) was dissolved in anhydrous tetrahydrofuran (12mL), reacted at 60℃ for 50min, 1-methylpyrazine (0.09mL, 0.78mmol) was added dropwise, reacted at 60℃ for 12h, and washed with water (10mL×3) Extracted with ethyl acetate (15mL), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: dichloromethane/methanol (v/v)=10/1) to obtain 166mg white solid, yield: 73%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (dd, J ₁ =8.3 Hz, J ₂ =1.9 Hz, 1H), 7.53 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.69(t, J _FH = 75.1Hz, 1H), 5.25-5.18(m, 1H), 5.11-5.08(m, 1H), 4.50-4.45(m, 1H), 4.35-4.24(m, 2H), 3.96 (t, J =6.6Hz, 2H), 3.69-3.60(m, 2H), 3.68(s, 3H), 2.66-2.61(m, 1H), 2.52-2.48(m, 1H), 2.40-2.36(m , 1H), 2.33 (s, 3H), 2.24-2.20 (m, 2H), 1.54-1.49 (m, 3H), 1.43 (s, 9H), 1.33-1.30 (m, 1H), 0.71-0.67 (m , 2H), 0.43-0.41 (m, 2H); MS-ESI: m/z 721.7 [M+H] ⁺ .

Step 2: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Oxygen)phenyl)oxazole-4-carbonyl)-5-(4-methylpyrazine-1-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester Synthesis of dihydrochloride

To the compound ((3 R ,5 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-((S)-1- (Tert-butoxycarbonylamino)ethyl)oxazole-4-carbonyl)-5-(4-methylpyrazine-1-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester (162mg, 0.22mmol ) In dichloromethane (4mL) solution was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 2.5h, the solvent was removed to obtain 155mg white solid, yield: 99%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.77(s,1H),7.73(dd, J ₁ =8.3Hz, J ₂ =1.7Hz,1H),7.33(d, J =8.3Hz,1H) , 6.93(t, J _FH = 74.8Hz, 1H), 5.28-5.24(m, 1H), 5.17-5.11(m, 1H), 4.40-4.34(m, 3H), 4.28-4.26(m, 1H), 4.05(d, J = 6.9Hz, 2H), 3.99-3.95(m, 1H), 3.79-3.76(m, 1H), 3.67(s, 3H), 3.53-3.44(m, 2H), 3.24-3.15( m,1H), 3.00(s,3H), 2.86-2.80(m,1H), 2.60-2.55(m,1H), 2.39-2.35(m,1H),2.24-2.21(m,1H),1.78( d, J = 6.8Hz, 3H), 1.37-1.33(m, 1H), 0.71-0.68(m, 2H), 0.46-0.44(m, 2H); MS-ESI: m/z 621.8[M+H- 2HCl] ⁺ .

Example 104: Compound 4-((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carbonyl)morpholine Synthesis of -2-formate hydrochloride

Step 1: Compound 4-((2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-)(3-(cyclopropylmethoxy Of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carbonyl)morpholine-2-carboxylic acid methyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (350 mg, 0.55 mmol), morpholine-2-carboxylic acid Methyl ester hydrochloride (129mg, 0.71mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (263mg, 1.37mmol) and N -hydroxy-7-aza Benzotriazole (112mg, 0.82mmol) was dissolved in dichloromethane (16mL), and N , N -diisopropylethylamine (0.38mL, 2.19mmol) was added dropwise to this solution at 0°C. Stir at a temperature of 12.5h, wash with saturated sodium chloride solution (10mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrate by column chromatography (eluent: dichloromethane/methanol (v /v)=50/1), 320 mg of white solid was obtained, yield: 76%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.58 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.53 (s, 1H), 7.24-7.21 (m, 1H), 6.70 (t , J _FH =75.1Hz,1H),5.25-5.21(m,1H),5.16-5.08(m,1H),4.55-4.49(m,1H),4.35-4.29(m,2H),3.97(d, J =6.9Hz, 2H), 4.05-3.94(m, 2H), 3.87-3.84(m, 2H), 3.79-3.73(m, 2H), 3.68(s, 3H), 3.61-3.55(m, 1H) ,3.45-3.42,3.15-3.09(m,m,0.5H,0.5H),2.26-2.21(m,1H),1.54-1.48(m,3H),1.43(s,9H),1.34-1.31(m , 1H), 0.71-0.66 (m, 2H), 0.43-0.40 (m, 2H); MS-ESI: m/z 766.4 [M+H] ⁺ .

Step 2: Compound 4-((2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-)(3-(cyclopropyl (Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carbonyl) Synthesis of morpholine-2-carboxylic acid

Compound 4-((2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carbonyl)morpholine-2-carboxylic acid methyl ester (210mg, 0.28mmol ) Dissolved in a mixed solvent of THF (10 mL) and H ₂ O (5 mL), added lithium hydroxide monohydrate (60 mg, 1.42 mmol), reacted at 55° C. for 2 h, and added HCl (1M) to adjust the pH of the solution to 1 It was extracted with ethyl acetate (10 mL×3) and the organic phases were combined and dried with anhydrous Na ₂ SO _{4 to} remove the solvent to obtain 185 mg of white solid. Yield: 89%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.72 (s, 1H), 7.68-7.64 (m, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.89 (t, J _FH = 74.9 Hz , 1H), 5.40-5.35(m, 1H), 4.38-4.34(m, 1H), 4.27-4.21(m, 2H), 4.05-4.01(m, 3H), 3.97-3.89(m, 2H), 3.79 -3.73 (m, 2H), 3.67-3.65 (m, 3H), 1.52-1.50 (m, 3H), 1.43 (s, 9H), 1.35-1.33 (m, 1H), 0.69-0.67 (m, 2H) , 0.45-0.43 (m, 2H); MS-ESI: m/z 752.4 [M+H] ⁺ .

Step 3: Compound 4-((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di fluorine Methoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carbonyl)morpholine-2-carboxylate Synthesis of acid salt

To compound 4-((2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carbonyl)morpholine-2-carboxylic acid (180 mg, 0.24 mmol) To a solution of dichloromethane (4 mL) was added an ethyl acetate solution of HCl (4M, 4 mL), stirred at room temperature for 1.5 h, and the solvent was removed to obtain 164 mg of a white solid in a yield of 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.76 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH =74.7Hz,1H),5.12-5.07(m,1H),4.47-4.12(m,6H),4.05(d, J =6.9Hz,2H),4.01-3.86(m,2H),3.80-3.76( m,1H),3.68-3.66(m,3H),3.58-3.50(m,1H),3.25-3.21(m,1H),2.38-2.30(m,1H),2.21-2.15(m,1H), 1.78-1.77(m,3H),1.36-1.34(m,1H),0.71-0.68(m,2H), 0.46-0.43(m,2H); MS-ESI: m/z 652.4[M+H-HCl ] ⁺ .

Example 105: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(4-hydroxypyridin-1-carbonyl)pyrrolidin-3-yl)aminocarboxylic acid Synthesis of methyl ester hydrochloride

Step 1: Compound ((3 R ,5 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-((S)- Synthesis of 1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carbonyl)-5-(4-hydroxypyridin-1-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (280 mg, 0.44 mmol), 4-hydroxypyridinium salt Acid salt (78 mg, 0.57 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (210 mg, 1.10 mmol) and N -hydroxy-7-azabenzotriazine Nitrozole (90mg, 0.66mmol) was dissolved in dichloromethane (16mL), N , N -diisopropylethylamine (0.31mL, 1.75mmol) was added dropwise to this solution at room temperature, and stirred at room temperature for 15h , Washed with saturated sodium chloride solution (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: dichloromethane/methanol (v/v)= 20/1), 247 mg of white solid was obtained, yield: 78%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.53 (s, 1H), 7.23 (d, J =8.4 Hz, 1H), 6.69(t, J _FH = 75.1Hz, 1H), 5.16-5.11(m, 1H), 4.50-4.46(m, 1H), 4.37-4.32(m, 1H), 4.27-4.21(m, 1H), 3.97 (d, J = 6.9Hz, 2H), 3.95-3.94(m, 2H), 3.67(s, 3H), 3.34-3.26(m, 1H), 2.27-2.20(m, 2H), 1.95-1.85(m , 2H), 1.54-1.49 (m, 3H), 1.43 (s, 9H), 1.33-1.29 (m, 1H), 0.71-0.66 (m, 2H), 0.43-0.38 (m, 2H); MS-ESI : M/z 722.2[M+H] ⁺ .

Step 2: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Oxygen)phenyl)oxazole-4-carbonyl)-5-(4-hydroxypyridin-1-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester Synthesis of hydrochloride

To the compound ((3 R ,5 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-(( S )-1- (Tert-Butoxycarbonylamino)ethyl)oxazole-4-carbonyl)-5-(4-hydroxypyridin-1-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester (120mg, 0.16mmol) To the dichloromethane (4mL) solution was added HCl in isopropanol solution (7M, 4mL), stirred at room temperature for 1h, the solvent was removed to obtain 105mg white solid, yield: 95%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.76 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.92 (t, J _FH =74.8Hz,1H),5.26-5.23(m,1H),5.15-5.08(m,1H),4.45-4.24(m,3H),4.05(d, J =6.8Hz,2H),4.03-4.01( m,1H),3.95-3.92(m,2H),3.82-3.77(m,1H),3.67-3.65(m,3H),3.57-3.50(m,1H),2.35-2.27,1.95-1.90(m ,m,1.5H,1.5H),2.15-2.09(m,1H),1.77(d, J =5.6Hz,3H),1.73-1.67(m,1H),1.36-1.33(m,1H),0.71 -0.68 (m, 2H), 0.46-0.44 (m, 2H); MS-ESI: m/z 622.2 [M+H-HCl] ⁺ .

Example 106: Compound ( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of (oxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid (2-methoxy) ethyl ester hydrochloride

Step 1: Compound ( S )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid (2-methoxy)ethyl ester

The compound ( S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid (146 mg, 0.26 mmol), ethylene glycol monomethyl ether (0.20 mL, 2.58 mmol), 1-ethyl-3-( 3-Dimethylaminopropyl) carbodiimide hydrochloride (99 mg, 0.52 mmol) and N -hydroxy-7-azabenzotriazole (53 mg, 0.39 mmol) were dissolved in dichloromethane (16 mL) , at room temperature this solution was added dropwise to N, N - diisopropylethylamine (0.18 mL, 1.03 mmol), stirred at rt for 4h, washed with water and dried (15mL) the organic phase was dried over anhydrous Na ₂ SO _4, The solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 50 mg of a colorless viscous material, yield: 31%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.59 (dd, J ₁ =8.3 Hz, J ₂ =1.8 Hz, 1H), 7.53 (s, 1H), 7.23-7.20 (m, 1H), 6.69 (t , J _FH = 75.1Hz, 1H), 5.34-5.24(m, 2H), 4.35-4.20(m, 2H), 4.00-3.96(m, 2H), 3.91-3.86(m, 1H), 3.78-3.73( m,1H),3.65-3.60(m,1H),3.53-3.50(m,1H),3.39,3.27(s,s,1H,2H),2.34-2.25(m,2H),2.02-1.93(m , 2H), 1.53-1.50 (m, 3H), 1.43 (s, 9H), 1.33-1.29 (m, 1H), 0.70-0.66 (m, 2H), 0.43-0.40 (m, 2H); MS-ESI : M/z 624.2[M+H] ⁺ .

Step 2: Compound ( S )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid (2-methoxy) ethyl ester hydrochloride

To the compound ( S )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Oxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid (2-methoxy)ethyl ester (50mg, 0.08mmol) in dichloromethane (4mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 1h, the solvent was removed to obtain 44mg white solid, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.76-7.73 (m, 1H), 7.67 (dd, J ₁ = 8.4 Hz, J ₂ = 1.8 Hz, 1 H), 7.34-7.31 (m, 1 H), 6.92(t, J _FH = 74.8Hz, 1H), 5.47-5.45(m, 1H), 4.35-4.25(m, 2H), 4.21-4.17(m, 1H), 4.08-4.03(m, 2H), 3.86 -3.83(m,1H),3.80-3.77(m,1H),3.67-3.65(m,1H),3.53-3.52(m,1H),3.39,3.22(s,s,1H,2H),2.49- 2.44(m, 1H), 2.32-2.29(m, 1H), 2.15-2.01(m, 2H), 1.78-1.76(m, 3H), 1.37-1.35(m, 1H), 0.71-0.69(m, 2H ), 0.46-0.43 (m, 2H); MS-ESI: m/z 524.2 [M+H-HCl] ⁺ .

Example 107: Compound (5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazol-4-yl)(( S )-2-(morpholine-4-carbonyl)pyrrolidin-1-yl)methanone hydrochloride

Step 1: Compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( S )-2-( Of porphyrin-4-carbonyl)pyrrolidine-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-1-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidine-2-carboxylic acid (145 mg, 0.25 mmol), morpholine (0.03 mL, 0.38 mmol), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (74mg, 0.38mmol) and N -hydroxy-7-azabenzotriazole (87mg, 0.64mmol) were dissolved in dichloromethane (12mL) at 20℃ N , N -diisopropylethylamine (0.18mL, 1.03mmol) was added dropwise to this solution, stirred at room temperature for 15h, washed with saturated sodium chloride solution (15mL×2), and the organic phase was washed with anhydrous Na ₂ SO ₄ Dry, remove the solvent, and separate the concentrated solution by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/3, 0/1) to obtain 119 mg of colorless viscous material, yield: 73% .

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.59(dd, J ₁ =8.3Hz, J ₂ =1.7Hz,1H),7.54(d, J =1.7Hz,1H),7.25-7.21(m,1H ), 6.69 (t, J _FH = 75.1 Hz, 1H), 5.24-5.20 (m, 1H), 5.03-5.00 (m, 1H), 4.26-4.20 (m, 1H), 3.97-3.95 (m, 2H) , 3.91-3.74 (m, 3H), 3.71-3.66 (m, 3H), 3.61-3.53 (m, 3H), 2.40-2.30 (m, 1H), 2.21-2.16 (m, 1H), 2.00-1.94 ( m, 2H), 1.54-1.50 (m, 3H), 1.43 (s, 9H), 1.34-1.31 (m, 1H), 0.69-0.66 (m, 2H), 0.42-0.39 (m, 2H); MS- ESI: m/z 635.2[M+H] ⁺ .

Step 2: Compound (5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Synthesis of oxazol-4-yl)(( S )-2-(morpholine-4-carbonyl)pyrrolidin-1-yl)methanone hydrochloride

To the compound (( S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(( S )-2-(morpholine- 4-carbonyl)pyrrolidine-1-carbonyl)oxazol-5-yl)ethyl)tert-butyl carbamate (117 mg, 0.18 mmol) in methylene chloride (4 mL) was added HCl in ethyl acetate (4 mL) 4M, 4mL), stirred at room temperature for 2.5h, the solvent was removed to obtain 100mg white solid, yield: 95%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.75 (d, J = 1.8Hz, 1H), 7.73 (dd, J ₁ = 8.3Hz, J ₂ = 1.9Hz, 1H), 7.38-7.33 (m, 1H), 6.92 (t, J _FH = 74.8Hz, 1H), 5.15-5.09 (m, 1H), 4.40-4.37, 4.20-4.16 (m, m, 0.5H, 0.5H), 4.07-4.02 (m, 2H), 3.86-3.79 (m, 2H), 3.76-3.59 (m, 6H), 3.56-3.54 (m, 1H), 3.23-3.18 (m, 1H), 2.57-2.54, 2.39-2.35 (m, m ,0.5H,0.5H),2.15-2.08,1.99-1.93(m,m,1.5H,1.5H),1.77(d, J =7.0Hz,3H),1.36-1.34(m,1H),0.71- 0.68 (m, 2H), 0.46-0.43 (m, 2H); MS-ESI: m/z 535.3 [M+H-HCl] ⁺ .

Example 108: Compound 4-((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carbonyl)morpholine Synthesis of methyl-2-carboxylate hydrochloride

To compound 4-((2 S ,4 R )-1-(5-(( S )-1-(tert-butoxycarbonylamino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(methoxycarbonylamino)pyrrolidine-2-carbonyl)morpholine-2-carboxylic acid methyl ester (100 mg, 0.13 mmol ) In dichloromethane (4mL) solution was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 1.5h, the solvent was removed to obtain 91mg white solid, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.76 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH =74.8Hz,1H),5.27-5.09(m,2H),4.40-4.27(m,3H),4.22-4.13(m,1H),4.05(d, J =6.9Hz,2H),3.99-3.94( m,1H), 3.87-3.78(m,3H), 3.68-3.66(m,3H), 3.61-3.55(m,1H), 2.37-2.32(m,1H),2.26-2.12(m,1H), 1.77(d, J = 6.9Hz, 3H), 1.35-1.33(m, 1H), 0.72-0.67(m, 2H), 0.46-0.43(m, 2H); MS-ESI: m/z 666.4[M+ H-HCl] ⁺ .

Example 109: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Group) phenyl) oxazol-4-yl) (4-(cyclopropylmethyl)-1,4-diazacycloheptan-1-yl)methanone hydrochloride to make

Step 1: Synthesis of compound cyclopropyl (1,4-diazacycloheptan-1-yl)methanone hydrochloride

The compound cyclopropylcarboxylic acid (257 mg, 3.0 mmol), compound 1,4-homoxazine-1-carboxylic acid tert-butyl ester (500 mg, 2.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl ) Carbodiimide hydrochloride (957mg, 5.0mmol) and N -hydroxy-7-azabenzotriazole (680mg, 5.0mmol) dissolved in dichloromethane (15mL), at 0 ℃ to this N , N -diisopropylethylamine (1.3mL, 7.49mmol) was added dropwise to the solution, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution Column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) was performed to obtain 660 mg of colorless liquid: 4-(cyclopropylmethyl acetyl)-1,4-diazacycloheptane- 1-tert-butyl formate, yield: 98%.

¹ H NM R(400MHz, CDCl ₃ ): δ ppm 3.71-3.78(m, 1H), 3.61-3.67(m, 2H), 3.52-3.60(m, 2H), 3.43-3.47(m, 2H), 3.34 -3.42(m,1H),1.92-2.00(m,1H),1.72-1.83(m,2H),1.47(s,9H),0.95-1.02(m,2H),0.75-0.79(m,2H) ; MS-ESI: m/z 213.10 [M-55] ⁺ .

Dissolve the compound 4-(cyclopropylcarboxamide)-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (210 mg, 0.78 mmol) in dichloromethane (4 mL), add HCl in ethyl acetate The solution (4M, 4 mL) was stirred at room temperature for 30 min, and the solvent was removed to obtain 158 mg of a colorless liquid: cyclopropyl (1,4-diazacycloheptan-1-yl)methanone hydrochloride, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.08-4.11 (m, 1H), 3.91-3.95 (m, 1H), 3.84-3.87 (m, 1H), 3.70-3.73 (m, 1H), 3.45 -3.48(m,1H), 3.29-3.39(m,3H), 2.20-2.26(m,1H), 2.07-2.13(m,1H), 1.95-2.01(m,1H), 0.87-0.95(m, 4H); MS-ESI: m/z 169.30 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(4-(4-(Cyclopropylmethylamide)-1,4-diazacycloheptane-1-carbonyl)-2-(3-(ring Synthesis of propylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound cyclopropyl (1,4-diazacycloheptan-1-yl)methanone hydrochloride (157 mg, 0.77 mmol), 1-ethyl -3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (245mg, 1.28mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96mmol) dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 10h, washed with water (10mL×3), and the organic phase was anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 238 mg of a white solid in a yield of 60%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.53-7.57 (m, 2H), 7.23 (d, J = 8.2Hz, 1H), 6.69 (t, J _FH = 75.0Hz, 1H), 5.18-5.26 ( m,1H), 3.96 (d, J = 6.9Hz, 2H), 3.69-3.97 (m, 8H), 2.01-2.17 (m, 2H), 1.71-1.79 (m, 1H), 1.51-1.54 (m, 3H), 1.42 (s, 9H), 1.28-1.36 (m, 1H), 0.97-1.04 (m, 2H), 0.76-0.83 (m, 2H), 0.65-0.70 (m, 2H), 0.38-0.42 ( m, 2H); MS-ESI: m/z 619.80 [M+H] ⁺ .

Step 3: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of yl)oxazol-4-yl)(4-(cyclopropylformyl)-1,4-diazacycloheptan-1-yl)methanone hydrochloride

The compound ( S )-(1-(4-(4-(cyclopropylcarboxamide)-1,4-diazacycloheptane-1-carbonyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester (221mg, 0.36mmol) was dissolved in dichloromethane (4mL), added HCl in acetic acid Ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 192mg white solid, yield: 96%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.70-7.76 (m, 2H), 7.32 (d, J = 8.3Hz, 1H), 6.92 (t, J _FH = 75.0Hz, 1H), 4.98-5.06 (m,1H), 4.10-4.21(m,2H), 4.05(t, J =6.2Hz, 2H), 4.00-4.05(m,1H), 3.78-3.89(m,4H),3.64-3.72(m ,1H),2.06-2.10(m,1H),1.97-2.04(m,2H),1.79(d, J =4.2Hz,3H),1.31-1.37(m,1H),0.81-0.90(m,4H ), 0.66-0.70 (m, 2H), 0.42-0.45 (m, 2H); MS-ESI: m/z 519.30 [M+H-HCl] ⁺ .

Example 110: Compound ( S )-1-(4-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-1,4-diazacycloheptan-1-yl)-2-methylpropane-1-one hydrochloride synthesis

Step 1: Synthesis of compound 1-(1,4-diazacycloheptan-1-yl)-2-methylpropane-1-one hydrochloride

The compound isobutyric acid (158 mg, 1.8 mmol), compound 1,4-homoxazine-1-carboxylic acid tert-butyl ester (300 mg, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (574mg, 3.0mmol) and N -hydroxy-7-azabenzotriazole (305mg, 2.25mmol) were dissolved in dichloromethane (15mL) and added to this solution at 0°C N , N -diisopropylethylamine (0.76mL, 4.49mmol) was added dropwise, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography Separation (eluent: Petroleum ether/EtOAc (v/v) = 2/1), to obtain 313mg of colorless liquid: 4-isobutyryl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester, Rate: 71%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 3.32-3.65(m,8H), 2.73-2.81(m,1H),1.77-1.90(m,2H),1.45-1.47(m,9H),1.12- 1.15 (m, 6H); MS-ESI: m/z 215.10 [M-55] ⁺ .

The compound 4-isobutyryl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (300 mg, 1.1 mmol) was dissolved in dichloromethane (4 mL), and a solution of HCl in ethyl acetate (4M, 4 mL) was added ), stirred at room temperature for 30 min, and removed the solvent to obtain 219 mg of colorless liquid: 1-(1,4-diazacycloheptan-1-yl)-2-methylpropane-1-one hydrochloride, yield: 95 %.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.70-3.83 (m, 2H), 3.58-3.66 (m, 2H), 3.17-3.25 (m, 4H), 2.81-2.88 (m, 1H), 1.95 -2.10 (m, 2H), 1.03 (d, J = 6.7 Hz, 6H); MS-ESI: m/z 171.10 [M+H-HCl] ⁺ .

Step 2: Compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-isobutyl Synthesis of Acetyl-1,4-diazacycloheptane-1-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound 1-(1,4-diazacycloheptan-1-yl)-2-methylpropane-1-one hydrochloride (158 mg, 0.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (245mg, 1.28mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96 mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 10h, and water (10mL×3) was added ) Washed, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 258 mg of a white solid in a yield : 65%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.53-7.58 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.0 Hz, 1H), 5.18-5.25( m,1H), 3.97 (d, J = 6.9Hz, 2H), 3.87-4.03 (m, 2H), 3.54-3.85 (m, 6H), 2.77-2.84 (m, 1H), 1.96-2.08 (m, 2H), 1.51-1.55(m, 3H), 1.41(s, 9H), 1.27-1.35(m, 1H), 1.12-1.16(m, 6H), 0.65-0.71(m, 2H), 0.38-0.42( m, 2H); MS-ESI: m/z 621.35 [M+H] ⁺ .

Step 3: Compound ( S )-1-(4-(5-(1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)-1,4-diazacycloheptan-1-yl)-2-methylpropane-1-one hydrochloride

The compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(4-isobutylamide-1,4-di N-cycloheptane-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester (248 mg, 0.39 mmol) was dissolved in dichloromethane (4 mL), and HCl in ethyl acetate (4M) was added , 4mL), stirred at room temperature for 30min, remove the solvent to obtain 221mg white solid, yield: 99%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.69-7.77 (m, 2H), 7.34 (d, J = 8.2Hz, 1H), 6.92 (t, J _FH = 75.0Hz, 1H), 5.00-5.08 (m,1H), 4.21-4.29(m,1H), 4.09-4.17(m,1H), 4.03-4.06(m,2H), 3.91-4.00(m,1H),3.74-3.90(m,4H) ,3.66-3.72(m,1H),2.95-3.05(m,1H),1.92-2.05(m,2H),1.77(d, J =6.6Hz,3H),1.31-1.38(m,1H),1.08 -1.13 (m, 6H), 0.67-0.71 (m, 2H), 0.42-0.45 (m, 2H); MS-ESI: m/z 521.30 [M+H-HCl] ⁺ .

Example 111: Compound N -(( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)cyclopropylformamide hydrochloride

Step 1: Synthesis of compound ( S )-3-(cyclopropylcarboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

Cyclopropylcarboxylic acid (210 mg, 2.42 mmol), ( S )-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.61 mmol), 1-ethyl-3-(3-dimethylaminopropyl Group) carbodiimide hydrochloride (621mg, 3.22mmol) and N -hydroxy-7-azabenzotriazole (328mg, 2.42mmol) were dissolved in dichloromethane (15mL), at 0 ℃ to N , N -diisopropylethylamine (0.8 mL, 4.83 mmol) was added dropwise to this solution, stirred at room temperature for 10 h, washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and concentrated The liquid was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 215 mg of colorless liquid, yield: 52%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 5.81 (br.s, 1H), 4.43-4.50 (m, 1H), 3.59-3.62 (m, 1H), 3.37-3.47 (m, 2H), 3.13 3.25(m,1H),2.09-2.18(m,1H),1.77-1.89(m,1H),1.46(s,9H),1.29-1.35(m,1H),0.94-0.98(m,2H), 0.71-0.76 (m, 2H); MS-ESI: m/z 199.20 [M-55] ⁺ .

Synthesis of (pyrrolidin-3-yl) cyclopropyl methyl Amides hydrochloride - Compound (S) - N: Step 2

The compound ( S )-3-(cyclopropylcarboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester (205 mg, 0.86 mmol) was dissolved in dichloromethane (4 mL), and HCl in ethyl acetate was added ( 4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 151mg white solid, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.34-4.40 (m, 1H), 3.43-3.49 (m, 2H), 3.29-3.36 (m, 1H), 3.16-3.20 (m, 1H), 2.23 -2.32(m,1H),1.98-2.06(m,1H),1.55-1.62(m,1H),0.78-0.84(m,2H),0.72-0.77(m,2H); MS-ESI: m/ z 155.15[M+H-HCl] ⁺ .

Step 3: Compound (( S )-1-(4-(( S )-3-(cyclopropylcarboxamido)pyrrolidine-1-carbonyl)-2-(3-(cyclopropyl Of methoxymethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), ( S )- N -(pyrrolidin-3-yl)cyclopropylcarboxamide hydrochloride (145 mg, 0.77 mmol), 1-ethyl- 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (245 mg, 1.28 mmol) and N -hydroxy-7-azabenzotriazole (130 mg, 0.96 mmol) were dissolved in dichloromethane ( 15mL), N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution at 0℃, stirred at room temperature for 10h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 186 mg of a white solid in a yield of 48%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.51-7.58 (m, 1H), 7.23 (d, J = 8.3Hz, 1H), 6.69 (t, J _FH = 75.0Hz, 1H), 5.96-6.03 ( m,1H),5.25-5.30(m,1H),4.57-4.66(m,1H),4.12-4.19(m,1H),3.99-4.07(m,1H),3.96(d, J =6.9Hz, 2H), 3.71-3.82(m, 2H), 2.17-2.27(m, 1H), 1.89-2.02(m, 1H), 1.55(t, J =7.3Hz, 3H), 1.41(s, 9H), 1.29 -1.35(m,1H),0.94-1.00(m,2H),0.71-0.78(m,2H),0.66-0.70(m,2H),0.38-0.42(m,2H); MS-ESI: m/ z 605.80[M+H] ⁺ .

Step 4: Compound N -(( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)cyclopropylformamide hydrochloride

The compound (( S )-1-(4-(( S )-3-(cyclopropylcarboxamido)pyrrolidine-1-carbonyl)-2-(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamic acid tert-butyl ester (180mg, 0.30mmol) was dissolved in dichloromethane (2mL), ethyl acetate was added HCl The solution (4M, 4mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 146mg of a white solid, yield: 82%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.74-7.78 (m, 2H), 7.35-7.37 (m, 1H), 6.95 (t, J _FH = 75.0 Hz, 1H), 5.12-5.18 (m, 1H), 4.45-4.51 (m, 1H), 4.35-4.41 (m, 1H), 4.23-4.29, 4.10-4.15 (m, 0.5H, 0.5H), 4.08 (d, J = 6.9Hz, 2H), 3.85-3.95(m, 1H), 3.77-3.82, 3.62-3.67(m, 0.5H, 0.5H), 2.25-2.36(m, 1H), 2.02-2.14(m, 1H), 1.83(d, J = 6.8Hz, 3H), 1.65-1.70(m, 1H), 1.36-1.41(m, 1H), 0.89-0.94(m, 2H), 0.80-0.84(m, 2H), 0.71-0.74(m, 2H) , 0.46-0.49 (m, 2H); MS-ESI: m/z 505.30 [M+H-HCl] ⁺ .

Example 112: Compound N -(( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)cyclopropylformamide hydrochloride

Step 1: Synthesis of compound ( R )- N -(pyrrolidin-3-yl)cyclopropylformamide hydrochloride

Combine cyclopropylcarboxylic acid (210 mg, 2.42 mmol), ( R )-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.61 mmol), 1-ethyl-3-(3-dimethylaminopropyl Group) carbodiimide hydrochloride (621mg, 3.22mmol) and N -hydroxy-7-azabenzotriazole (328mg, 2.42mmol) were dissolved in dichloromethane (15mL), at 0 ℃ to N , N -diisopropylethylamine (0.8 mL, 4.83 mmol) was added dropwise to this solution, stirred at room temperature for 10 h, washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and concentrated The liquid was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 1/1) to obtain 215 mg of colorless liquid: ( R )-3-(cyclopropylmethylamido)pyrrolidine-1 -Tert-butyl formate, yield: 52%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 5.81 (br.s, 1H), 4.43-4.50 (m, 1H), 3.59-3.62 (m, 1H), 3.37-3.47 (m, 2H), 3.13 3.25(m,1H),2.09-2.18(m,1H),1.77-1.89(m,1H),1.46(s,9H),1.29-1.35(m,1H),0.94-0.98(m,2H), 0.71-0.76 (m, 2H); MS-ESI: m/z 199.20 [M-55] ⁺ .

The compound ( R )-3-(cyclopropylcarboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester (205mg, 0.86mmol) was dissolved in dichloromethane (4mL), and HCl in ethyl acetate was added ( 4M, 4 mL), stirred at rt for 30min, the solvent was removed to give a white solid 151mg :( R) - N - (pyrrolidin-3-yl) cyclopropyl carboxylic acyl amine hydrochloride, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.34-4.40 (m, 1H), 3.43-3.49 (m, 2H), 3.29-3.36 (m, 1H), 3.16-3.20 (m, 1H), 2.23 -2.32(m,1H), 1.98-2.06(m,1H), 1.55-1.62(m,1H), 0.78-0.84(m,2H), 0.72-0.77(m,2H);

MS-ESI: m/z 155.15 [M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(4-(( R )-3-(cyclopropylcarboxamido)pyrrolidine-1-carbonyl)-2-(3-(cyclopropyl Of methoxymethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), ( R )- N -(pyrrolidin-3-yl)cyclopropylmethanamide hydrochloride (145 mg, 0.77 mmol), 1-ethyl- 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (245 mg, 1.28 mmol) and N -hydroxy-7-azabenzotriazole (130 mg, 0.96 mmol) were dissolved in dichloromethane ( 15mL), N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution at 0℃, stirred at room temperature for 10h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 186 mg of a white solid in a yield of 48%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.51-7.58 (m, 1H), 7.23 (d, J = 8.3Hz, 1H), 6.69 (t, J _FH = 75.0Hz, 1H), 5.96-6.03 ( m,1H),5.25-5.30(m, 1H),4.57-4.66(m,1H),4.12-4.19(m,1H),3.99-4.07(m,1H),3.96(d, J =6.9Hz, 2H), 3.71-3.82(m, 2H), 2.17-2.27(m, 1H), 1.89-2.02(m, 1H), 1.55(t, J =7.3Hz, 3H), 1.41(s, 9H), 1.29 -1.35(m,1H),0.94-1.00(m,2H),0.71-0.78(m,2H),0.66-0.70(m,2H),0.38-0.42(m,2H); MS-ESI: m/ z 605.80[M+H] ⁺ .

Step 3: Compound N -(( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)cyclopropylformamide hydrochloride

The compound (( S )-1-(4-(( R )-3-(cyclopropylcarboxamido)pyrrolidine-1-carbonyl)-2-(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamic acid tert-butyl ester (180mg, 0.30mmol) was dissolved in dichloromethane (2mL), ethyl acetate was added HCl The solution (4M, 4mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 146mg of a white solid, yield: 82%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.74-7.78 (m, 2H), 7.35-7.37 (m, 1H), 6.95 (t, J _FH = 75.0 Hz, 1H), 5.12-5.18 (m, 1H), 4.45-4.51 (m, 1H), 4.35-4.41 (m, 1H), 4.23-4.29, 4.10-4.15 (m, 0.5H, 0.5H), 4.08 (d, J = 6.9Hz, 2H), 3.85-3.95(m, 1H), 3.77-3.82, 3.62-3.67(m, 0.5H, 0.5H), 2.25-2.36(m, 1H), 2.02-2.14(m, 1H), 1.83(d, J = 6.8Hz, 3H), 1.65-1.70(m, 1H), 1.36-1.41(m, 1H), 0.89-0.94(m, 2H), 0.80-0.84(m, 2H), 0.71-0.74(m, 2H) , 0.46-0.49 (m, 2H); MS-ESI: m/z 505.30 [M+H-HCl] ⁺ .

Example 113: Compound ( S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl) -N -cyclopropylpyrrolidine-2-carboxamide hydrochloride

Step 1: Synthesis of compound ( S ) -N -cyclopropylpyrrolidine-2-carboxamide hydrochloride

N- Boc- L -proline (500 mg, 2.32 mmol), cyclopropylamine (160 mg, 2.79 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride ( 890mg, 4.65mmol) and N -hydroxy-7-azabenzotriazole (475mg, 3.48mmol) were dissolved in dichloromethane (10mL), N , N -di diisopropylethylamine (1.2mL, 6.97mmol), stirred for 10H at room temperature, add water (10mL × 3), dried the organic phase over anhydrous Na ₂ SO _4, solvent was removed concentrate was separated by column chromatography (eluent : Petroleum ether/EtOAc (v/v) = 1/1), to obtain 494mg white solid: ( S )-2-(cyclopropylaminomethyl amide) pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 83%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.13-4.26 (m, 1H), 3.32-3.48 (m, 2H), 2.68-2.75 (m, 1H), 2.11-2.37 (m, 2H), 1.81- 1.96 (m, 2H), 1.47 (s, 9H), 0.73-0.81 (m, 2H), 0.44-0.51 (m, 2H); MS-ESI: m/z 155.25 [M+H-100] ⁺ .

Dissolve the compound ( S )-2-(cyclopropylaminomethylamide)pyrrolidine-1-carboxylic acid tert-butyl ester (485mg, 1.91mmol) in dichloromethane (4mL) and add HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, and removed the solvent to obtain 360mg of white solid: ( S ) -N -cyclopropylpyrrolidine-2-carboxamide hydrochloride, yield: 99%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 4.25 (t, J = 7.8Hz, 1H), 3.38-3.48 (m, 2H), 2.76-2.80 (m, 1H), 2.43-2.49 (m, 1H) ), 2.08-2.13(m, 2H), 1.99-2.05(m, 1H), 0.79-0.85(m, 2H), 0.57-0.63(m, 2H); MS-ESI: m/z 155.15[M+H -HCl] ⁺ .

Step 2: Compound (( S )-1-(4-(( S )-2-(Cyclopropylaminomethylamide)pyrrolidine-1-carbonyl)-2-(3-(ring Synthesis of propylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (300 mg, 0.64 mmol), ( S ) -N -cyclopropylpyrrolidine-2-carboxamide hydrochloride (146 mg, 0.77 mmol), 1-ethyl-3-( 3-dimethylaminopropyl) carbodiimide hydrochloride (245mg, 1.28mmol) and N -hydroxy-7-azabenzotriazole (130mg, 0.96mmol) were dissolved in dichloromethane (10mL) , N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution at 0℃, stirred at room temperature for 10h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 186 mg of a white solid in a yield of 48%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.60-7.68(m,1H),7.54-7.56(m,1H),7.23-7.26(m,1H),6.72(t, J _FH =75.1Hz,1H ), 5.21-5.39 (m, 1H), 4.95-4.97, 4.69-4.71 (m, 0.5H, 0.5H), 4.08-4.11, 3.86-3.93 (m, 0.5H, 0.5H), 3.98-4.06 (m , 2H), 3.72-3.84 (m, 1H), 2.69-2.76 (m, 1H), 2.34-2.44 (m, 1H), 2.17-2.25, 2.06-2.13 (m, 0.5H, 0.5H), 1.88- 2.03(m, 2H), 1.54-1.58(m, 3H), 1.44(s, 9H), 1.33-1.38(m, 1H), 0.65-0.79(m, 4H), 0.51-0.61(m, 1H), 0.34-0.67 (m, 3H); MS-ESI: m/z 605.30 [M+H] ⁺ .

Step 3: Compound ( S )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)-N-cyclopropylpyrrolidine-2-carboxamide hydrochloride

The compound (( S )-1-(4-(( S )-2-(cyclopropylaminomethylcarbonyl)pyrrolidine-1-carbonyl)-2-(3-(cyclopropylmethoxy) -4-(Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester (180mg, 0.30mmol) was dissolved in dichloromethane (2mL), ethyl acetate added HCl The ester solution (4M, 4mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 146mg of a white solid, yield: 82%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.69-7.75 (m, 2H), 7.32-7.34 (m, 1H), 6.92 (t, J _FH = 75.0 Hz, 1H), 5.27-5.29, 4.49- 4.52(m,0.5H,0.5H),5.09-5.15(m,1H),4.27-4.32,3.82-3.86(m,0.5H,0.5H),4.27-4.31,3.74-3.78(m,0.5H, 0.5H), 4.04-4.09 (m, 2H), 2.70-2.74, 2.53-2.57 (m, 0.5H, 0.5H), 2.39-2.45, 2.25-2.31 (m, 0.5H, 0.5H), 1.91-2.05 (m, 2H), 1.76-1.78 (m, 3H), 1.33-1.38 (m, 1H), 0.68-0.71 (m, 2H), 0.53-0.66 (m, 2H), 0.43-0.47 (m, 2H) , 0.27-0.40 (m, 2H); MS-ESI: m/z 505.90 [M+H-HCl] ⁺ .

Example 114: Compound ( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-ylcyclopropylcarbamate hydrochloride

Step 1: Synthesis of compound ( R )-pyrrolidin-3-ylcyclopropylcarbamate hydrochloride

Dissolve triethylamine (0.34mL, 2.41mmol) and N , N' -carbonyldiimidazole (CDI) (315mg, 1.93mmol) in anhydrous THF (5mL), add compound ( R )-3-hydroxypyrrolidine at room temperature Tert-Butyl-1-carboxylate (300 mg, 1.60 mmol), react for 20 min, add the compound cyclopropylamine (0.6 mL, 8.01 mmol), stop the reaction at 50 °C for 10 h, remove the solvent THF, add water (5 mL), ethyl acetate (10 mL ×3) Extraction, drying over anhydrous sodium sulfate, removal of solvent, and separation of the concentrated solution by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) to obtain 325 mg of white solid: ( R )-3 -((Cyclopropylaminocarboxamide)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 75%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 5.21(s, 1H), 4.80-4.95(m, 1H), 3.32-3.53(m, 4H), 2.52-2.60(m, 1H), 1.97-2.06( m, 2H), 1.45 (s, 9H), 0.65-0.74 (m, 2H), 0.46-0.55 (m, 2H); MS-ESI: m/z 215.20 [M-55] ⁺ .

The compound ( R )-3-((cyclopropylaminomethylcarbonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (300mg, 1.11mmol) was dissolved in dichloromethane (4mL), and HCl was added Ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 216mg white solid: ( R )-pyrrolidin-3-ylcyclopropylcarbamate hydrochloride, yield: 94% .

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 5.31 (s, 1H), 3.39-3.50 (m, 4H), 2.51-2.55 (m, 1H), 2.18-2.28 (m, 2H), 0.68-0.71 (m, 2H), 0.49-0.51 (m, 2H); MS-ESI: m/z 171.10 [M+H-HCl] ⁺ .

Step 2: Compound ( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-ylcyclopropylcarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300mg, 0.64mmol), compound ( R )-pyrrolidin-3-ylcyclopropylcarbamate hydrochloride (158mg, 0.77mmol), 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride (245 mg, 1.3 mmol) and N -hydroxy-7-azabenzotriazole (174 mg, 1.3 mmol) were dissolved in dichloromethane (10 mL ), N , N -diisopropylethylamine (0.45mL, 2.56mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 6h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/2) to obtain 235 mg of a white solid in a yield of 59%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.58 (d, J = 8.3Hz, 1H), 7.53 (s, 1H), 7.23 (d, J = 8.3Hz, 1H), 6.69 (t, J _FH = 75.1Hz, 1H), 5.30-5.38(m, 1H), 5.22-5.30(m, 1H), 4.88-4.99(m, 1H), 4.23-4.34(m, 1H), 4.06-4.17(m, 1H) , 3.95-3.98(m, 2H), 3.71-3.88(m, 2H), 2.53-2.61(m, 1H), 2.10-2.18(m, 2H), 1.54(d, J = 7.0Hz, 3H), 1.42 (s,9H), 1.29-1.37(m,1H), 0.66-0.73(m,4H), 0.49-0.55(m,2H), 0.38-0.42(m,2H); MS-ESI: m/z 621.80 [M+H] ⁺ .

Step 3: Compound ( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyrrolidin-3-ylcyclopropylcarbamate hydrochloride

The compound ( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-ylcyclopropylcarbamate (220mg, 0.35mmol) was dissolved in dichloromethane (4mL), ethyl acetate added HCl The ester solution (4M, 4mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 191mg of a white solid, yield: 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.23-7.76 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.93 (t, J _FH = 75.0 Hz, 1H), 5.30-5.35 (m,1H), 5.12-5.16(m,1H), 4.41-4.43(m,1H), 4.17-4.30(m,1H), 4.05-4.07(m,2H),3.72-3.91(m,2H) , 2.52-2.58 (m, 1H), 2.19-2.28 (m, 1H), 1.80 (d, J = 6.9Hz, 3H), 1.34-1.39 (m, 1H), 0.68-0.72 (m, 4H), 0.46 -0.51 (m, 4H); MS-ESI: m/z 521.80 [M+H-HCl] ⁺ .

Example 115: Compound 1-(( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-2-methylpentazin-1-yl)butane-1-one hydrochloride

Step 1: Synthesis of compound ( R )-1-(2-methylpyrazin-1-yl)butane-1-one hydrochloride

The compound ( R )-3-methylpyrazine-1-carboxylic acid tert-butyl ester (300 mg, 1.5 mmol), n-butyric acid (200 mg, 2.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl Group) carbodiimide hydrochloride (595mg, 3.0mmol) and N -hydroxy-7-azabenzotriazole (306mg, 2.3mmol) were dissolved in dichloromethane (10mL), at 0 ℃ to To this solution, N , N -diisopropylethylamine (0.76mL, 4.5mmol) was added dropwise, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed and concentrated The liquid was separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 370 mg of colorless liquid; ( R )-4-butyryl-3-methylpyrazine-1-carboxylic acid tert Butyl ester, yield: 91%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 4.74-4.81,4.34-4.41(m,0.5H,0.5H),3.80-4.12,3.53-3.60(m,2.5H,0.5H),3.26-3.35, 2.75-2.98(m,0.5H,2.5H),2.26-2.35(m,2H),1.61-1.69(m,2H),1.47(s,9H),1.13-1.24(m,3H),1.12(t , J = 7.3 Hz, 3H); MS-ESI: m/z 215.10[M-55] ⁺ .

The compound ( R )-4-butyryl-3-methylpyrazine-1-carboxylic acid tert-butyl ester (360mg, 1.33mmol) was dissolved in dichloromethane (4mL), and a solution of HCl in ethyl acetate (4M, 4mL) was added ), stirred at room temperature for 50 min, and removed the solvent to obtain 269 mg of light yellow liquid: ( R )-1-(2-methylpyrazin-1-yl)butane-1-one hydrochloride, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.88-5.02, 4.49-4.67 (m, 0.5H, 0.5H), 4.01-4.14, 3.49-3.64 (m, 0.5H, 0.5H), 3.34-3.41 (m,2H),3.09-3.24 (m,2H),2.38-2.49(m,2H),1.62-1.68(m,2H),1.30-1.45(m,3H),1.00(d, J =7.4Hz , 3H); MS-ESI: m/z 171.30 [M+H-HCl] ⁺ .

Step 2: The compound (( S )-1-(4-(( R )-4-butyryl-3-methylpyrazine-1-carbonyl)-2-(3-(cyclopropylmethyl Oxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (300 mg, 0.64 mmol), compound ( R )-1-(2-methylpyrazin-1-yl)butane-1-one hydrochloride (158 mg, 0.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (245 mg, 1.28 mmol) and N -hydroxy-7-azabenzotriazole (130 mg, 0.96 mmol) were dissolved In dichloromethane (15mL), N , N -diisopropylethylamine (0.44mL, 2.56mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 10h, and washed with water (10mL×3), The organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 275 mg of a white solid in a yield of 69% .

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 7.56-7.58(m,1H),7.53(s,1H),7.24(d, J =8.3Hz,1H),6.70(t, J _FH =75.0Hz, 1H), 5.21-5.28 (m, 1H), 4.93-5.00, 4.68-4.76 (m, 0.5H, 0.5H), 4.81-4.87, 4.46-4.55 (m, 0.5H, 0.5H), 4.59-4.62 ( m,1H),3.96(d, J =6.6Hz,2H),3.64-3.71(m,1H),3.36-3.49(m,1H),3.16-3.28(m,1H),2.93-3.07(m, 1H), 2.30-2.40(m, 2H), 1.64-1.71(m, 2H), 1.53-1.55(m, 3H), 1.40-1.42(m, 9H), 1.29-1.35(m, 1H), 1.16 1.26(m,3H),0.98(t, J =7.3Hz,3H),0.67-0.70(m,2H),0.38-0.41(m,2H); MS-ESI: m/z 621.20[M+H] ⁺ .

Step 3: Compound 1-(( R )-4-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-2-methylpentazin-1-yl)butane-1-one hydrochloride

To the compound (( S )-1-(4-(( R )-4-butyryl-3-methylpyrazine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (265mg, 0.43mmol) in dichloromethane (4mL) was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 50min, and removed the solvent to obtain 226mg white solid, yield: 96%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.71-7.76 (m, 2H), 7.34 (d, J = 8.2Hz, 1H), 6.92 (t, J _FH = 74.8Hz, 1H), 5.01-5.10 (m, 2H), 4.88-4.97, 3.89-3.98 (m, 0.5H, 0.5H), 4.40-4.57 (m, 2H), 4.05 (d, J = 6.2Hz, 2H), 3.45-3.60 (m, 1H), 3.07-3.19(m, 1H), 2.42-2.53(m, 2H), 1.80(s, 3H), 1.64-1.71(m, 2H), 1.21-1.39(m, 4H), 1.01(t, J = 7.1 Hz, 3H), 0.67-0.70 (m, 2H), 0.42-0.47 (m, 2H); MS-ESI: m/z 521.30 [M+H-HCl] ⁺ .

Example 116: Compound (( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

Step 1: Synthesis of compound ( R )-3-methoxycarbonylaminopyrrolidine hydrochloride

Dissolve triethylamine (162mg, 1.61mmol) and N , N' -carbonyldiimidazole (CDI) (208mg, 1.28mmol) in anhydrous DMF (5mL), add compound ( R )-3-aminopyrrolidine-1 -Tert-butyl formate (200mg, 1.07mmol), stirred at room temperature for 30min, added anhydrous methanol (5mL), the reaction was stopped after 24h at 60°C, the solvent DMF was removed, water (5mL) was added, ethyl acetate (10mL×3) was extracted, After drying over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 3/1) to obtain 230 mg of colorless liquid: ( R )-3-((methoxy Carbonyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 87%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 4.79(br.s,1H),4.18-4.24(m,1H),3.67(s,3H),3.57-3.62(m,1H),3.34-3.44( m,2H),3.12-3.24(m,1H),2.08-2.15(m,1H),1.76-1.86(m,1H),1.45(m,9H); MS-ESI: m/z 189.10[M- 55] ⁺ .

To a solution of the compound ( R )-3-((methoxycarbonyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (220mg, 0.90mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M , 2mL), stirred at room temperature for 30min, and removed the solvent to obtain 160mg of viscous solid: ( R )-3-methoxycarbonylaminopyrrolidine hydrochloride, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.26-4.31 (m, 1H), 3.69 (s, 3H), 3.44-3.52 (m, 2H), 3.36-3.42 (m, 1H), 3.24-3.32 (m, 1H), 2.27-2.36 (m, 1H), 2.01-2.10 (m, 1H); MS-ESI: m/z 145.20 [M+H-HCl] ⁺ .

Step 2: Compound (( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy Of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (400mg, 0.854mmol), compound ( R )-3-methoxycarbonylaminopyrrolidine hydrochloride (200mg, 1.11mmol), 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide hydrochloride (327mg, 1.71mmol) and N -hydroxy-7-azabenzotriazole (232mg, 1.71mmol) were dissolved in dichloromethane (10mL), 0 ℃ N , N -diisopropylethylamine (0.60mL,3.42mmol) was added dropwise to this solution under conditions, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and removed The solvent and the concentrated liquid were separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/1) to obtain 250 mg of a white solid in a yield of 49%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.52-7.59 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.0 Hz, 1H), 5.22-5.30 ( m,1H),4.86-4.94,4.16-4.22(m,0.5H,0.5H),4.29-4.39(m,1H),3.93-4.07(m,1H),3.95-3.97(m,2H),3.69 -3.82(m, 2H), 3.68(s, 3H), 2.17-2.28(m, 1H), 1.87-2.04(m, 1H), 1.51-1.55(m, 3H), 1.42(s, 9H), 1.28 -1.35 (m, 1H), 0.65-0.71 (m, 2H), 0.38-0.43 (m, 2H); MS-ESI: m/z 595.30 [M+H] ⁺ .

Step 3: Compound (( R )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

To compound (( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester (240 mg, 0.40 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 210mg of white solid, yield: 98%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.72-7.75 (m, 2H), 7.34 (d, J = 8.2Hz, 1H), 6.92 (t, J _FH = 74.8Hz, 1H), 5.11-5.15 (m,1H), 4.33-4.37, 4.08-4.14(m,0.5H,0.5H), 4.19-4.30(m,2H), 4.03-4.05(m,2H),3.71-3.90(m,1H), 3.68 (s, 3H), 2.21-2.31 (m, 1H), 1.98-2.09 (m, 1H), 1.80 (d, J = 6.8Hz, 3H), 1.32-1.37 (m, 1H), 0.68-0.71 ( m, 2H), 0.38-0.46 (m, 2H); MS-ESI: m/z 495.30 [M+H-HCl] ⁺ .

Example 117: Compound N -(( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)isobutylamide hydrochloride

Step 1: Compound (R) - Synthesis of Amides isobutyrate hydrochloride (pyrrolidin-3-yl) - N

Isobutyric acid (212mg, 2.42mmol), ( R )-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (300mg, 1.61mmol), 1-ethyl-3-(3-dimethylaminopropyl ) Carbodiimide hydrochloride (617mg, 3.22mmol) and N -hydroxy-7-azabenzotriazole (328mg, 2.42mmol) were dissolved in dichloromethane (10mL), this is 0 ℃ N , N -diisopropylethylamine (0.8 mL, 4.83 mmol) was added dropwise to the solution, stirred at room temperature for 10 h, washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution Column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 1/1) was performed to obtain 358 mg of white solid: ( R )-3-isobutylaminopyrrolidine-1-carboxylic acid tert-butyl ester , Yield: 86%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 5.62 (br.s, 1H), 4.40-4.46 (m, 1H), 3.58-3.62 (m, 1H), 3.35-3.45 (m, 2H), 3.10- 3.16(m,1H),2.26-2.36(m,1H),2.07-2.17(m,1H),1.74-1.83(m,1H),1.45(s,9H), 1.13(d, J =6.9Hz, 6H); MS-ESI: m/z 201.12 [M-55] ⁺ .

To a solution of the compound ( R )-3-isobutylamidopyrrolidine-1-carboxylic acid tert-butyl ester (160mg, 0.63mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M, 4mL), After stirring at room temperature for 30 min, the solvent was removed to obtain 110 mg of colorless liquid: ( R )- N -(pyrrolidin-3-yl)isobutylamide hydrochloride, yield: 92%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.30-4.36 (m, 1H), 3.39-3.47 (m, 2H), 3.24-3.32 (m, 1H), 3.11-3.17 (m, 1H), 2.38 -2.45(m,1H), 2.20-2.29(m,1H),1.93-2.01(m,1H),1.04(d, J =6.9Hz,6H); MS-ESI: m/z 157.20[M+H -HCl] ⁺ .

Step 2: Compound (( S )-1-(4-(( R )-3-(cyclopropylcarboxamido)pyrrolidine-1-carbonyl)-2-(3-(cyclopropyl Of methoxymethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene yl) oxazole-4-carboxylic acid (200mg, 0.43mmol), (R ) - N - ( pyrrolidin-3-yl) isobutyramide Amides hydrochloride (100mg, 0.52mmol), 1- ethyl-3- (3-Dimethylaminopropyl)carbodiimide hydrochloride (161mg, 0.85mmol) and N -hydroxy-7-azabenzotriazole (87mg, 0.64mmol) were dissolved in dichloromethane (10mL) In this solution, N , N -diisopropylethylamine (0.30mL, 1.71mmol) was added dropwise to the solution at 0℃, stirred at room temperature for 4h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ Dry, remove the solvent, and separate the concentrated solution by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 112 mg of white solid in a yield of 43%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.55-7.59(m,1H),7.51-7.54(m,1H),7.23(d, J =8.3Hz,1H),6.69(t, J _FH =74.8 Hz, 1H), 5.22-5.30 (m, 1H), 4.55-4.62 (m, 1H), 4.17-4.22, 4.04-4.09 (m, 0.5H, 0.5H), 3.92-4.02 (m, 1H), 3.96 (d, J =6.9Hz, 2H), 3.73-3.83(m, 2H), 2.31-2.39(m, 1H), 2.18-2.28(m, 1H), 1.86-2.01(m, 1H), 1.53-1.56 (m,3H),1.42(s,9H),1.29-1.35(m,1H),1.12-1.18(m,6H),0.66-0.71(m,2H),0.38-0.42(m,2H); MS -ESI: m/z 607.80[M+H] ⁺ .

Step 3: Compound N -(( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)isobutylamide hydrochloride

To the compound (( S )-1-(4-(( R )-3-(cyclopropylcarboxamido)pyrrolidine-1-carbonyl)-2-(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (100 mg, 0.16 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 88mg of white solid, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.70-7.74 (m, 2H), 7.33-7.35 (m, 1H), 6.92 (t, J _FH = 75.0 Hz, 1H), 5.09-5.15 (m, 1H), 4.40-4.45(m, 1H), 4.31-4.39(m, 1H), 4.19-4.25, 4.06-4.10(m, 0.5H, 0.5H), 4.04(d, J = 6.9Hz, 2H), 3.91-3.94, 3.80-3.85 (m, 0.5H, 0.5H), 3.73-3.48, 3.55-3.58 (m, 0.5H, 0.5H), 2.47-2.53 (m, 1H), 2.21-2.34 (m, 1H ), 1.96-2.10 (m, 1H), 1.79 (d, J = 6.9Hz, 3H), 1.33-1.37 (m, 1H), 1.11-1.35 (m, 6H), 0.68-0.71 (m, 2H), 0.43-0.46 (m, 2H); MS-ESI: m/z 507.90 [M+H-HCl] ⁺ .

Example 118: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazol-4-yl)(3-fluoroazetidin-1-yl)methanone hydrochloride

Step 1: Compound ( S )-(1-(2-(3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(3-fluoroazetidine Synthesis of tert-butyl -1-carbonyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (200 mg, 0.43 mmol), 3-fluoroazetidine (57 mg, 0.52 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Hydrochloride (163mg, 0.85mmol) and N -hydroxy-7-azabenzotriazole (87mg, 0.64mmol) were dissolved in dichloromethane (10mL), and N was added dropwise to this solution at 0°C , N -diisopropylethylamine (0.30mL, 1.71mmol), stirred at room temperature for 5h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was separated by column chromatography (Eluent: Petroleum ether/EtOAc (v/v)=2/1), 156 mg of white solid was obtained, yield: 70%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.51-7.58 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 6.70 (t, J _FH = 75.0 Hz, 1H), 5.43-5.50, 5.29-5.34(m,0.5H,0.5H),5.25-5.34(m,1H),4.93-5.08(m,1H),4.73-4.87(m,1H),4.42-4.52(m,1H),4.25 -4.35(m,1H), 3.97(d, J =6.9Hz, 2H), 3.74-3.81(m,6H), 1.50-1.53(m,3H), 1.43(s,9H),1.30-1.36(m , 1H), 0.67-0.71 (m, 2H), 0.39-0.43 (m, 2H); MS-ESI: m/z 526.30 [M+H] ⁺ .

Step 2: Compound ( S )-(5-(1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Of hydroxy)oxazol-4-yl)(3-fluoroazetidin-1-yl)methanone hydrochloride

The compound ( S )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(3-fluoroazetidine-1 -Carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (150mg, 0.29mmol) was dissolved in dichloromethane (4mL), added HCl in ethyl acetate solution (4M, 4mL), room temperature After stirring for 30 min, the solvent was removed to obtain 126 mg of white solid. Yield: 96%.

¹ H NMR(600MHz,CD ₃ OD): δ ppm 7.72-7.74(m,1H),7.71(dd, J ₁ =8.3Hz, J ₂ =1.7Hz,1H),7.34(d, J =8.2Hz, 1H), 6.93 (t, J _FH = 74.8Hz, 1H), 5.52-5.55, 5.42-5.46 (m, 0.5H, 0.5H), 5.10-5.20 (m, 2H), 4.80-4.83 (m, 1H) , 4.51-4.58 (m, 1H), 4.24-4.30 (m, 1H), 4.05 (d, J = 7.0Hz, 2H), 3.80 (s, 6H), 1.79 (d, J = 7.0Hz, 3H), 1.33-1.37 (m, 1H), 0.69-0.72 (m, 2H), 0.44-0.47 (m, 2H); MS-ESI: m/z 426.20 [M+H-HCl] ⁺ .

Example 119: Compound N -(( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)propionamide hydrochloride

Step 1: Synthesis of compound ( R )- N -(pyrrolidin-3-yl)propionamide hydrochloride

Propionic acid (240 mg, 3.22 mmol), ( R )-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.61 mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (617mg, 3.22mmol) and N -hydroxy-7-azabenzotriazole (328mg, 2.42mmol) were dissolved in dichloromethane (10mL), and the solution was added at 0℃ N , N -diisopropylethylamine (0.8 mL, 4.83 mmol) was added dropwise, stirred at room temperature for 10 h, washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was carried out Column chromatography separation (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 360 mg of white solid: ( R )-3-Propylaminopyrrolidine-1-carboxylic acid tert-butyl ester. Rate: 92%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 5.65 (s, 1H), 4.41-4.48 (m, 1H), 3.58-3.62 (m, 1H), 3.34-3.45 (m, 2H), 3.10-3.20 ( m,1H), 2.19(q, J =7.6Hz, 2H), 2.08-2.16(m,1H), 1.73-1.85(m,1H), 1.45(s,9H), 1.14(t, J =7.6Hz , 3H); MS-ESI: m/z 187.25 [M-55] ⁺ .

Compound ( R )-3-propionamidopyrrolidine-1-carboxylic acid tert-butyl ester (150mg, 0.62mmol) was dissolved in dichloromethane (4mL), HCl in ethyl acetate solution (4M, 2mL) was added, After stirring at room temperature for 30 min, the solvent was removed to obtain 103 mg of a viscous solid: ( R )- N -(pyrrolidin-3-yl)propionamide hydrochloride, yield: 93%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.25-4.31 (m, 1H), 3.33-3.40 (m, 2H), 3.20-3.27 (m, 1H), 3.08-3.12 (m, 1H), 2.14 -2.23(m,1H), 2.12(q, J =7.6Hz,2H),1.90-1.96(m,1H),1.14(t, J =7.6Hz,3H); MS-ESI: m/z 143.25[ M+H-HCl] ⁺ .

Step 2: Compound (( S )-1-(4-(( R )-3-propionamidopyrrolidine-1-carbonyl)-2-(3-(cyclopropylmethoxy Of 4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene yl) oxazole-4-carboxylic acid (200mg, 0.43mmol), (R ) - N - ( pyrrolidin-3-yl) propan-acyl amine hydrochloride (91mg, 0.52mmol), 1- ethyl-3- ( 3-dimethylaminopropyl) carbodiimide hydrochloride (165 mg, 0.86 mmol) and N -hydroxy-7-azabenzotriazole (87 mg, 0.64 mmol) were dissolved in dichloromethane (10 mL) To this solution, N , N -diisopropylethylamine (0.30mL, 1.71mmol) was added dropwise at 0℃, stirred at room temperature for 10h, washed with water (10mL×3), and the organic phase was washed with anhydrous Na ₂ SO ₄ After drying, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: ethyl acetate) to obtain 175 mg of a white solid in a yield of 69%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 4.1 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.69 ( t, J _FH = 75.1Hz, 1H), 5.22-5.30 (m, 1H), 4.56-4.64 (m, 1H), 4.02-4.20 (m, 1H), 3.91-4.00 (m, 1H), 3.96 (d , J = 6.9Hz, 2H), 3.65-3.80 (m, 2H), 2.22 (q, J = 7.6Hz, 2H), 2.19-2.29 (m, 1H), 1.87-2.02 (m, 1H), 1.54 ( t, J =7.3Hz,3H),1.42(s,9H),1.16(t, J =7.6Hz,3H),0.66-0.71(m,2H),0.38-0.43(m,2H); MS-ESI : M/z 593.80[M+H] ⁺ .

Step 3: Compound N -(( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)propionamide hydrochloride

The compound (( S )-1-(4-(( R )-3-propionamidopyrrolidine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (170 mg, 0.29 mmol) was dissolved in dichloromethane (4 mL), and a solution of HCl in ethyl acetate (4M, 4 mL) was added ), stirred at room temperature for 30 min, and removed the solvent to obtain 150 mg of white solid, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.70-7.74 (m, 2H), 7.32-7.34 (m, 1H), 6.92 (t, J _FH = 75.1 Hz, 1H), 5.09-5.15 (m, 1H), 4.39-4.46(m, 1H), 4.30-4.38(m, 1H), 4.19-4.24, 4.05-4.10(m, 0.5H, 0.5H), 4.04(d, J = 6.9Hz, 2H), 3.73-3.83 (m, 1H), 3.89-3.93, 3.56-3.59 (m, 0.5H, 0.5H), 2.25 (q, J = 7.6Hz, 2H), 2.21-2.33 (m, 1H), 1.96-2.10 (m,1H), 1.80 (d, J = 6.8Hz, 3H), 1.14 (t, J = 7.6Hz, 3H), 1.33-1.37 (m, 1H), 0.68-0.71 (m, 2H), 0.43- 0.45 (m, 2H); MS-ESI: m/z 493.10 [M+H-HCl] ⁺ .

Example 120: Compound (( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid ethyl ester hydrochloride

Step 1: Synthesis of compound ( R )-3-ethoxycarbonylaminopyrrolidine hydrochloride

Dissolve triethylamine (0.75mL, 5.37mmol) and N , N' -carbonyldiimidazole (CDI) (2.2g, 13.42mmol) in anhydrous THF (5mL), add compound ( R )-3-aminopyrrolidine Tert-Butyl-1-carboxylate (500mg, 2.69mmol), stirred at room temperature for 30min, added absolute ethanol (5mL), the reaction was stopped after reaction at 70℃ for 24h, the solvent THF was removed, water (5mL), ethyl acetate (10mL×3) was added ) Extraction, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 3/1) to obtain 420 mg of colorless liquid: ( R )-3-( (Ethoxycarbonyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 60%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.86 (br.s, 1H), 4.18-4.27 (m, 1H), 4.13 (q, J = 6.7 Hz, 2H), 3.59-3.63 (m, 1H) , 3.37-3.47(m, 2H), 3.14-3.24(m, 1H), 2.09-2.18(m, 1H), 1.78-1.88(m, 1H), 1.46(m, 9H), 1.25(t, J = 7.0 Hz, 3H); MS-ESI: m/z 203.20 [M-55] ⁺ .

The compound ( R )-3-((ethoxycarbonyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (200mg, 0.77mmol) was dissolved in dichloromethane (4mL), and a solution of HCl in ethyl acetate was added ( 4M, 4mL), stirred at room temperature for 30min, and removed the solvent to obtain 153mg of light brown liquid: ( R )-3-ethoxycarbonylaminopyrrolidine hydrochloride, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.19-4.25 (m, 1H), 4.05 (q, J = 6.7 Hz, 2H), 3.38-3.45 (m, 2H), 3.30-3.36 (m, 1H ), 3.19-3.24 (m, 1H), 2.20-2.29 (m, 1H), 1.96-2.15 (m, 1H), 1.20 (t, J = 7.0Hz, 3H); MS-ESI: m/z 159.20[ M+H-HCl] ⁺ .

Step 2: Compound (( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy Of ethyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid ethyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (250mg, 0.53mmol), compound ( R )-3-ethoxycarbonylaminopyrrolidine hydrochloride (125mg, 0.64mmol), 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide hydrochloride (204mg, 1.07mmol) and N -hydroxy-7-azabenzotriazole (110mg, 0.8mmol) were dissolved in dichloromethane (10mL), 0 ℃ N , N -diisopropylethylamine (0.36mL, 2.14mmol) was added dropwise to this solution under conditions, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and removed The solvent and the concentrated liquid were separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/1) to obtain 142 mg of a white solid in a yield of 44%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.53-7.59 (m, 2H), 7.24 (d, J = 8.3Hz, 1H), 6.69 (t, J _FH = 75.0Hz, 1H), 5.27-5.30 ( m,1H),4.29-4.30(m,1H),4.07-4.23(m,3H),3.94-4.00(m,1H),3.99(d, J =6.8Hz, 2H),3.64-3.82(m, 2H), 2.17-2.28(m, 1H), 1.87-2.00(m, 1H), 1.43-1.55(m, 3H), 1.42(s, 9H), 1.28-1.35(m, 1H), 1.25(t, J = 6.7 Hz, 3H), 0.66-0.71 (m, 2H), 0.39-0.43 (m, 2H); MS-ESI: m/z 609.30 [M+H] ⁺ .

Step 3: Compound (( R )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)aminocarbamate hydrochloride

The compound (( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid ethyl ester (135mg, 0.22mmol) was dissolved in dichloromethane (2mL), ethyl acetate was added HCl The solution (4M, 4mL) was stirred at room temperature for 2h, and the solvent was removed to obtain 118mg of a white solid, yield: 98%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.71-7.75 (m, 2H), 7.34 (d, J = 8.2Hz, 1H), 6.92 (t, J _FH = 74.8Hz, 1H), 5.09-5.14 (m,1H),4.33-4.36,4.08-4.14(m,0.5H,0.5H),4.19-4.31(m,2H),4.08-4.15(m,2H),4.03-4.05(m,2H), 3.87-3.91, 3.77-3.83 (m, 0.5H, 0.5H), 3.71-3.76, 3.59-3.61 (m, 0.5H, 0.5H), 2.19-2.32 (m, 1H), 1.95-2.10 (m, 1H) ), 1.80 (d, J = 6.8Hz, 3H), 1.33-1.37 (m, 1H), 1.25 (t, J = 7.1Hz, 3H), 0.68-0.71 (m, 2H), 0.43-0.46 (m, 2H); MS-ESI: m/z 509.10 [M+H-HCl] ⁺ .

Example 121: Compound (S) - N - (1- (5- (1- aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Yl)oxazole-4-carbonyl)azetidin-3-yl)cyclopropylcarboxamide hydrochloride

Step 1: Synthesis of compound N- (heterocyclobutan-3-yl)cyclopropylcarboxamide hydrochloride

Combine cyclopropylcarboxylic acid (224 mg, 2.61 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (300 mg, 1.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl) ) Carbodiimide hydrochloride (667mg, 3.48mmol) and N -hydroxy-7-azabenzotriazole (355mg, 2.61mmol) were dissolved in dichloromethane (10mL), this is 0 ℃ N , N -diisopropylethylamine (0.9mL, 5.23mmol) was added dropwise to the solution, stirred at room temperature for 6h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution Column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) was performed to obtain 386 mg of a white solid: 3-(cyclopropylcarboxamido)azetidine-1-carboxylic acid Tert-butyl ester, yield: 92%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 6.20 (s, 1H), 4.61-4.69 (m, 1H), 4.21-4.26 (m, 2H), 3.72-3.77 (m, 2H), 1.43 (s, 9H), 1.34-1.40 (m, 1H), 0.95-0.98 (m, 2H), 0.73-0.79 (m, 2H); MS-ESI: m/z 241.10 [M+H] ⁺ .

Compound 3-(cyclopropylcarboxamido)azetidine-1-carboxylic acid tert-butyl ester (180 mg, 0.75 mmol) was dissolved in dichloromethane (4 mL), and a solution of HCl in ethyl acetate (4M) was added , 4mL), stirred at room temperature for 50min, and removed the solvent to obtain 129mg of a colorless liquid: N- (heterocyclobutan-3-yl)cyclopropylmethanamide hydrochloride, yield: 97%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 5.08-5.13, 4.66-4.71 (m, 0.5H, 0.5H), 3.33-3.47 (m, 1H), 4.23-4.30 (m, 1H), 4.14 4.18(m,1H),3.34-3.40(m,1H),1.47-1.53(m,1H),0.98-1.01(m,1H),0.80-0.88(m,3H); MS-ESI: m/z 141.10[M+H] ⁺ .

Step 2: Compound ( S )-(1-(4-(3-(cyclopropylcarboxamido)azetidine-1-carbonyl)-2-(3-(cyclopropylmethoxy) Synthesis of tert-Butyl-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Yl)oxazole-4-carboxylic acid (250 mg, 0.53 mmol), N- (heterocyclo-3-yl)cyclopropylcarboxamide hydrochloride (112 mg, 0.64 mmol), 1-ethyl-3- (3-Dimethylaminopropyl)carbodiimide hydrochloride (205mg, 1.07mmol) and N -hydroxy-7-azabenzotriazole (110mg, 0.80mmol) were dissolved in dichloromethane (10mL) In this solution, N , N -diisopropylethylamine (0.36mL, 2.14mmol) was added dropwise to the solution at 0℃, stirred at room temperature for 12h, washed with water (10mL×3), and the organic phase was dried with anhydrous Na ₂ SO ₄ Dry, remove the solvent, and separate the concentrated solution by column chromatography (eluent: dichloromethane/ethyl acetate (v/v)=2/1) to obtain 175 mg of white solid in a yield of 56%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.57-7.60 (m, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.70 (t, J _FH = 75.0 Hz, 1H), 5.24-5.29 ( m,1H), 4.28-4.32(m,2H),3.96-4.01(m,1H),3.98(d, J =6.8Hz,2H),3.55-3.66(m,2H),1.52(d, J = 7.0Hz, 2H), 1.43(s, 9H), 1.29-1.35(m, 2H), 0.95-1.00(m, 2H), 0.85-0.90(m, 2H), 0.66-0.71(m, 2H), 0.39 -0.43 (m, 2H); MS-ESI: m/z 591.30 [M+H] ⁺ .

Step 3: Compound (S) - N - (1- (5- (1- aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy Of phenyl) phenyl) oxazole-4-carbonyl) azetidine-3-yl) cyclopropylcarboxamide hydrochloride

The compound ( S )-(1-(4-(3-(cyclopropylcarboxamido)azetidine-1-carbonyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamic acid tert-butyl ester (170 mg, 0.29 mmol) was dissolved in dichloromethane (4 mL), and HCl in ethyl acetate was added (4M, 4mL), stirred at room temperature for 2h, the solvent was removed to obtain 149mg of white solid, yield: 22%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.69-7.71 (m, 2H), 7.35 (d, J = 8.3Hz, 1H), 6.92 (t, J _FH = 75.0Hz, 1H), 5.07-5.17 (m, 2H), 4.64-4.70 (m, 2H), 4.49-4.52 (m, 1H), 4.09-4.12 (m, 1H), 4.03 (d, J = 6.9Hz, 2H), 1.77 (d, J =6.8Hz, 3H), 1.62-1.66(m, 1H), 1.33-1.37(m, 1H), 0.89-0.92(m, 2H), 0.81-0.84(m, 2H), 0.67-0.71(m, 2H ), 0.43-0.45 (m, 2H); MS-ESI: m/z 491.90 [M+H-HCl] ⁺ .

Example 122: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxamide hydrochloride

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid methyl ester (600 mg, 0.91 mmol) dissolved in THF ( 10mL) and water (5mL) mixed solvent, then add lithium hydroxide monohydrate (190mg, 4.53mmol), 45 ℃ reaction after 30min to stop, add concentrated hydrochloric acid to adjust the solution pH = 1, use ethyl acetate (10mL × 3 ) Extraction, after combining the organic phases, drying over anhydrous sodium sulfate and concentration to obtain 580 mg of white solid, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.72-7.75 (m, 1H), 7.61-7.69 (m, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.89 (t, J _FH = 75.0Hz, 1H), 5.45-5.51(m, 1H), 5.29-5.38(m, 1H), 4.50-4.60(m, 1H), 4.02(d, J = 6.9Hz, 2H), 3.95-4.04(m ,1H),3.67-3.76(m,1H),2.31-2.49(m,2H),1.58-1.64(m,1H),1.51-1.55(m,3H),1.43(s,9H),1.33-1.39 (m,1H),0.87-0.92(m,2H),0.76-0.82(m,2H),0.66-0.71(m,2H),0.42-0.46(m,2H); MS-ESI: m/z 649.30 [M+H] ⁺ .

Step 2: Compound (( S )-1-(4-((2 S ,4 R )-2-Aminomethylamido-4-(cyclopropylmethylamido)pyrrolidine -1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminomethyl Synthesis of tert-butyl acid

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid (250mg, 0.39mmol), ammonium chloride (61mg , 1.16mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (150mg, 0.77mmol) and N -hydroxy-7-azabenzotriazole (78mg , 0.58mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.4mL, 2.31mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, water (10mL) was added ×3) Washing, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH (v/v)=25/1) to obtain 173 mg of a white solid. Rate: 69%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.55-7.59 (m, 2H), 7.18-7.26 (m, 1H), 6.72 (t, J _FH = 75.0 Hz, 1H), 5.22-5.31 (m, 1H ), 4.84-4.99 (m, 1H), 4.62-4.72 (m, 1H), 4.17-4.21, 3.78-3.84, (m, 0.5H, 0.5H), 3.92-4.02 (m, 1H), 4.00 (d , J = 6.8Hz, 2H), 2.53-2.64 (m, 1H), 2.18-2.31 (m, 1H), 1.57 (d, J = 6.9Hz, 3H), 1.42 (s, 9H), 1.31-1.38 ( m, 2H), 0.92-1.01 (m, 2H), 0.66-0.78 (m, 4H), 0.41-0.44 (m, 2H); MS-ESI: m/z 648.80 [M+H] ⁺ .

Step 3: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxamide hydrochloride to make

The compound (( S )-1-(4-((2 S ,4 R )-2-aminomethylamido-4-(cyclopropylmethylamido)pyrrolidine-1-carbonyl)-2- (3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (165 mg, 0.26 mmol) was dissolved in dichloromethane To methane (4 mL), a solution of HCl in ethyl acetate (4M, 4 mL) was added, stirred at room temperature for 30 min, and the solvent was removed to obtain 62 mg of a white solid, yield: 49%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.73-7.74 (m, 1H), 7.65-7.68 (m, 1H), 7.26-7.29 (m, 1H), 6.91 (td, J _FH = 75.0, 7.8 Hz, 1H), 5.36-5.38, 4.62-4.65 (m, 0.5H, 0.5H), 4.70-4.74 (m, 1H), 4.49-4.55 (m, 1H), 4.31-4.34, 4.14-4.17 (m, 0.5H,0.5H),4.02-4.04(m,2H),3.98-4.03,3.66-3.69 (m,0.5H,0.5H),2.40-2.46(m,1H),2.25-2.36(m,1H) , 1.58-1.64 (m, 1H), 1.54 (d, J = 6.8Hz, 3H), 1.31-1.37 (m, 1H), 0.85-0.91 (m, 2H), 0.75-0.80 (m, 2H), 0.67 -0.70 (m, 2H), 0.43-0.46 (m, 2H); MS-ESI: m/z 548.80 [M+H-HCl] ⁺ .

Example 123: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido) -N -cyclopropylpyrrolidine Synthesis of 2-Methylamide Hydrochloride

Step 1: Compound (( S )-1-(4-((2 S ,4 R )-4-(cyclopropylmethylamidoamino)-2-(cyclopropylaminomethylamido)pyrrolidine- Synthesis of 1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid (250mg, 0.39mmol), cyclopropylamine (66mg, 1.16mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (150mg, 0.77mmol) and N -hydroxy-7-azabenzotriazole (78mg, 0.58mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.4mL, 2.31mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, water (10mL × 3) The organic phase was washed with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1) to obtain 182 mg of a white solid. Rate: 69%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.51-7.59 (m, 2H), 7.21-7.26 (m, 1H), 6.72 (t, J _FH = 75.0 Hz, 1H), 5.71-5.80 (m, 1H ), 5.22-5.37(m,1H),4.76-4.85(m,1H),4.59-4.65(m,1H),3.96-4.06,3.70-3.77(m,0.5H,0.5H), 4.00(d, J = 6.8Hz, 1H), 2.55-2.74 (m, 2H), 2.12-2.24 (m, 1H), 1.57 (d, J = 6.9Hz, 3H), 1.44 (s, 9H), 1.31-1.41 (m , 2H), 0.92-1.01 (m, 2H), 0.68-0.78 (m, 6H), 0.40-0.56 (m, 4H); MS-ESI: m/z 688.40 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido) -N -cyclopropylpyrrolidine-2-carboxamide Synthesis of hydrochloride

The compound (( S )-1-(4-((2 S ,4 R )-4-(cyclopropylmethylamidoamino)-2-(cyclopropylaminomethylamido)pyrrolidine-1- Carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester (130 mg, 0.20 mmol ) Was dissolved in dichloromethane (2mL), added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 115mg white solid, yield: 98%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.69-7.74 (m, 2H), 7.33 (d, J = 8.2Hz, 1H), 6.91 (t, J _FH = 75.0Hz, 1H), 5.40-5.44 , 4.61-4.66 (m, 0.5H, 0.5H), 5.10-5.15 (m, 1H), 4.53-4.59, 4.41-4.46 (m, 0.5H, 0.5H), 4.36-4.41, 4.26-4.30 (m, 0.5H, 0.5H), 4.03-4.08 (m, 2H), 3.99-4.02, 3.68-3.72 (m, 0.5H, 0.5H), 2.70-2.74, 2.50-2.55 (m, 0.5H, 0.5H), 2.44-2.50, 2.16-2.20 (m, 0.5H, 0.5H), 2.27-2.35 (m, 1H), 1.78 (d, J = 6.6Hz, 3H), 1.59-1.64 (m, 1H), 1.32-1.38 (m, 1H), 0.82-0.91 (m, 2H), 0.73-0.80 (m, 3H), 0.66-0.71 (m, 2H), 0.55-0.65 (m, 2H), 0.42-0.48 (m, 2H) , 0.35-0.41,0.23-0.27 (m, 0.5H, 0.5H); MS-ESI: m/z 588.80 [M+H] ⁺ .

Example 124: Compound (( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Synthesis of methoxy)phenyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester hydrochloride

Step 1: Synthesis of compound ( R )-3-methoxycarbonylaminopyridinium hydrochloride

Dissolve triethylamine (1.4mL, 10.0mmol) and N , N' -carbonyldiimidazole (CDI) (3.2g, 20.0mmol) in anhydrous THF (15mL), add anhydrous methanol (640mg, 20.0mmol), room temperature After stirring for 10 min, the compound ( R )-3-aminopyridine-1-carboxylic acid tert-butyl ester (1.0g, 5.0mmol) was added. After the reaction at 75°C for 12h, the reaction was stopped, the solvent was removed, water (15mL), ethyl acetate ( 10mL×3) extraction, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) to obtain 1.2g of colorless liquid: (R) -3-((Methoxycarbonyl)amino)pyridine-1-carboxylic acid tert-butyl ester, yield: 97%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.76 (br.s, 1H), 3.62-3.72 (m, 1H), 3.66 (s, 3H), 3.55-3.58 (m, 1H), 3.29-3.40 ( m, 2H), 3.22-3.29 (m, 1H), 1.78-1.86 (m, 1H), 1.61-1.68 (m, 1H), 1.47-1.59 (m, 2H), 1.45 (m, 9H); MS- ESI: m/z 203.10[M-55] ⁺ .

To a solution of the compound ( R )-3-((methoxycarbonyl)amino)pyridine-1-carboxylic acid tert-butyl ester (1.2g, 4.6mmol) in methylene chloride (6mL) was added HCl in ethyl acetate ( 4M, 6mL), stirred at room temperature for 30min, the solvent was removed to obtain 820mg white solid: ( R )-3-methoxycarbonylaminopyridinium hydrochloride, yield: 91%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 3.78-3.83 (m, 1H), 3.68 (s, 3H) 3.40-3.44 (m, 1H), 3.29-3.33 (m, 1H), 2.86-3.01 ( m, 2H), 2.01-2.05 (m, 2H), 1.77-1.87 (m, 1H), 1.57-1.65 (m, 1H); MS-ESI: m/z 159.10 [M+H-HCl] ⁺ .

Step 2: Compound (( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy Of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (200 mg, 0.43 mmol), ( R )-3-methoxycarbonylaminopyridinium hydrochloride (100 mg, 0.51 mmol), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (165mg, 0.86mmol) and N -hydroxy-7-azabenzotriazole (87mg, 0.64mmol) were dissolved in dichloromethane (10mL) at 0℃ N , N -diisopropylethylamine (0.3mL, 1.71mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed The concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) to obtain 205 mg of white solid in a yield of 79%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.59-7.68 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 6.72 (t, J _FH = 75.0 Hz, 1H), 5.17-5.30 ( m,1H),4.11-4.24(m,1H),3.97-4.03(m,1H),3.98-4.01(m,2H),3.78-3.87,3.55-3.60(m,0.5H,0.5H),3.68 (s,3H),3.13-3.22,2.12-2.22(m,0.5H,0.5H),1.65-1.87(m,3H),1.53-1.58(m,3H),1.42(s,9H),1.28- 1.35 (m, 1H), 0.66-0.72 (m, 2H), 0.39-0.43 (m, 2H); MS-ESI: m/z 609.80 [M+H] ⁺ .

Step 3: Compound (( R )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy Of phenyl)phenyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester hydrochloride

The compound (( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyridin-3-yl)carbamic acid methyl ester (200 mg, 0.33 mmol) was dissolved in dichloromethane (4 mL), and HCl ethyl acetate was added The solution (4M, 4mL) was stirred at room temperature for 2h, and the solvent was removed to obtain 175mg of white solid, yield: 97%.

¹ H NMR(600MHz, CD ₃ OD): δ ppm 7.86(s,1H),7.71-7.75(m,1H),7.33(d, J =7.8Hz,1H),6.93(t, J _FH =74.8Hz ,1H),5.01-5.04(m,1H),4.47-4.59(m,1H),4.40-4.43,4.12-4.16(m,0.5H,0.5H),4.04-4.07(m,2H),3.72- 3.80 (m, 1H), 3.61-3.68, 3.44-3.54 (m, 0.5H, 0.5H), 3.68 (s, 1H), 3.59 (s, 2H), 3.33-3.40, 3.03-3.10 (m, 0.5H , 0.5H), 2.03-2.08 (m, 1H), 1.89-1.94 (m, 1H), 1.79 (d, J = 6.9Hz, 3H), 1.63-1.72 (m, 2H), 1.33-1.37 (m, 1H), 0.68-0.71 (m, 2H), 0.43-0.46 (m, 2H); MS-ESI: m/z 509.85 [M+H-HCl] ⁺ .

Example 125: Compound 7-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ox Of oxazol-4-carbonyl)tetrahydro-1 H -oxazolo[3,4-a]pyrazine-3(5 H )-one hydrochloride

Step 1: Synthesis of compound tetrahydro-1 H -oxazolo[3,4-a]pyrazine-3(5 H )-one hydrochloride

The compound 3-methoxycarbonylpyrazine-1-carboxylic acid tert-butyl ester (1.0 g, 4.1 mmol), nickel chloride (640 mg, 4.9 mmol) and absolute ethanol (10 mL) were mixed and added to this solution at 0°C Sodium borohydride (380mg, 10.0mmol), after stirring for 4h, stop the reaction, add ice water (5mL), add concentrated hydrochloric acid to adjust pH=1, after the reaction system is clear, add aqueous sodium hydroxide solution (1.0M) to adjust pH=10, It was extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and concentrated to obtain 890 mg of light green solid: tert-butyl 3-(hydroxymethyl)pyrazine-1-carboxylate. Rate: 83%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 3.99-4.02 (m, 1H), 3.90-3.93 (m, 1H), 3.48-3.54 (m, 2H), 2.96-3.00 (m, 1H), 2.83 -2.93(m,1H), 2.66-2.72(m,2H), 2.56-2.66(m,1H), 1.48(m,9H); MS-ESI: m/z 217.10[M+H] ⁺ .

Dissolve triethylamine (670mg, 6.5mmol) and N , N' -carbonyldiimidazole (CDI) (2.6g, 16.2mmol) in anhydrous THF (5mL), add anhydrous methanol (520mg, 16.2mmol), and stir at room temperature 15min, add tert-butyl 3-(hydroxymethyl)pyrazine-1-carboxylate (700mg, 3.2mmol), stop the reaction after 6h reaction at 65°C, remove the solvent, add water (5mL), ethyl acetate (10mL×3) It was extracted, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 3/1) to obtain 202 mg of a white solid: 3-oxotetrahydro-1 H -oxazolo[3,4-a]pyrazine-7( 3H )-carboxylic acid tert-butyl ester, yield: 26%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 4.41-4.44 (m, 1H), 4.04-4.30 (m, 2H), 3.92-3.95 (m, 1H), 3.76-3.80 (m, 2H), 2.97- 3.02 (m, 1H), 2.63-2.80 (m, 2H), 1.46 (m, 9H); MS-ESI: m/z 187.05 [M-55] ⁺ .

The compound 3-oxotetrahydro-1 H -oxazolo[3,4-a]pyrazine-7(3 H )-carboxylic acid tert-butyl ester (100 mg, 0.41 mmol) was dissolved in dichloromethane (4 mL) , Add HCl in ethyl acetate solution (4M, 2mL), stir at room temperature for 50min, remove the solvent to obtain 68mg of viscous solid: tetrahydro- 1H -oxazolo[3,4-a]pyrazine-3( 5H )- Ketone hydrochloride, yield: 93%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 4.53-4.58 (m, 1H), 4.20-4.28 (m, 1H), 4.13-4.16 (m, 1H), 3.97-4.02 (m, 1H), 3.53 -3.57 (m, 1H), 3.37-3.45 (m, 2H), 3.08-3.14 (m, 2H); MS-ESI: m/z 143.20 [M+H-HCl] ⁺ .

Step 2: Compound ((1 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(3-oxo Synthesis of tert-butyl hexahydro- 1H -oxazolo[3,4-a]pyrazine-7-carbonyl)oxazol-5-yl)ethyl)aminocarbamate to make

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (150 mg, 0.32 mmol), tetrahydro-1 H -oxazolo[3,4-a]pyrazine-3(5 H )-one hydrochloride (68 mg, 0.38 mmol) , 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (125mg, 0.64mmol) and N -hydroxy-7-azabenzotriazole (64mg, 0.41mmol) Dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.22mL, 1.28mmol) was added dropwise to this solution at 0℃, stirred at room temperature for 12h, and washed with water (10mL×3) The organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/3) to obtain 116 mg of white solid, yield: 61 %.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.53-7.58 (m, 2H), 7.25 (d, J = 9.2Hz, 1H), 6.70 (t, J _FH = 75.0Hz, 1H), 5.17-5.27 ( m,1H), 4.68-4.85 (m, 2H), 4.36-4.52 (m, 1H), 3.83-4.05 (m, 3H), 3.96 (d, J = 6.9Hz, 2H), 3.08-3.23 (m, 2H), 2.70-2.88 (m, 1H), 1.55 (d, J = 7.0Hz, 3H), 1.41 (s, 9H), 1.28-1.36 (m, 1H), 0.67-0.71 (m, 2H), 0.38 -0.42 (m, 2H); MS-ESI: m/z 493.30 [M+H-100] ⁺ .

Step 3: Compound 7-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl)oxazole-4-carbonyl)tetrahydro-1 H -oxazolo[3,4-a]pyrazine-3(5 H )-one hydrochloride

The compound ((1 S )-1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-(3-oxohexahydro-1 H -Oxazolo[3,4-a]pyrazine-7-carbonyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (110 mg, 0.18 mmol) was dissolved in dichloromethane (4 mL) and added A solution of HCl in ethyl acetate (4M, 4mL), stirred at room temperature for 50min, and removed the solvent to obtain 97mg of white solid, yield: 99%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.73-7.76 (m, 2H), 7.34 (d, J = 8.2Hz, 1H), 6.93 (t, J _FH = 74.7Hz, 1H), 5.12-5.22 (m,1H),5.07-5.12(m,1H),4.82-4.86,4.69-4.72(m,1.5H,0.5H),4.52-4.57(m,1H),4.12-4.18,4.01-4.06(m , 1.5H, 0.5H), 4.05 (d, J = 6.9Hz, 2H), 3.86-3.91 (m, 1H), 3.18-3.32 (m, 1H), 2.87-2.98 (m, 1H), 1.80 (d , J = 6.9Hz, 3H), 1.34-1.38 (m, 1H), 0.69-0.72 (m, 2H), 0.44-0.46 (m, 2H); MS-ESI: m/z 493.80 [M+H-HCl ] ⁺ .

Example 126: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid ethyl Synthesis of ester hydrochloride

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid ethyl ester

The compound (2 S ,4 R )-1-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid (250mg, 0.39mmol), absolute ethanol (71mg, 1.54mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (150mg, 0.77mmol) and N -hydroxy-7-azabenzotriazole (78mg, 0.58mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.4mL, 2.31mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, water (10mL × 3) Wash, the organic phase is dried over anhydrous Na ₂ SO ₄ , the solvent is removed, and the concentrated solution is subjected to column chromatography (eluent: dichloromethane/ethyl acetate (v/v)=2/1) to obtain 204 mg of white Solid, yield: 78%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.52-7.61(m,2H),7.22-7.26(m,1H),6.72(t, J _FH =75.0Hz,1H),5.36-5.43(m,1H ), 5.21-5.26, 4.62-4.67 (m, 0.5H, 0.5H), 4.69-4.77 (m, 1H), 4.26-4.33 (m, 1H), 4.10-4.25 (m, 2H), 4.00 (d, J = 5.7Hz, 1H), 3.97-4.03, 3.80-3.86 (m, 0.5H, 0.5H), 2.31-2.52 (m, 2H), 1.52-1.57 (m, 3H), 1.44 (s, 9H), 1.33-1.41(m, 2H), 1.17-1.29(m, 3H), 0.96-1.01(m, 2H), 0.74-0.79(m, 2H), 0.68-0.72(m, 2H), 0.42-0.45(m , 2H); MS-ESI: m/z 677.20 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid ethyl ester hydrochloride synthesis

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid ethyl ester (200 mg, 0.29 mmol) was dissolved in dichloromethane To (4mL), add a solution of HCl in ethyl acetate (4M, 4mL), stir at room temperature for 30min, and remove the solvent to obtain 174mg of white solid.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.66-7.76 (m, 2H), 7.33 (d, J = 8.3Hz, 1H), 6.92 (t, J _FH = 74.7Hz, 1H), 5.55-5.58 , 4.77-4.84 (m, 0.5H, 0.5H), 5.10-5.21 (m, 1H), 4.52-4.59, 4.26-4.31 (m, 0.5H, 0.5H), 4.00-4.48 (m, 1H), 4.10 -4.30(m,2H),4.02-4.06(m,2H),3.97-4.02,3.70-3.75(m,0.5H,0.5H),2.45-2.51(m,1H),2.25-2.41(m,1H ), 1.76-1.79 (m, 3H), 1.59-1.66 (m, 1H), 1.32-1.38 (m, 1H), 1.16-1.33 (m, 3H), 0.85-0.91 (m, 2H), 0.75-0.81 (m, 2H), 0.66-0.71 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 577.20 [M+H-HCl] ⁺ .

Example 127: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropyl Synthesis of acetamido)- N , N -dimethylpyrrolidine-2-carboxamide hydrochloride

Step 1: Compound (( S )-1-(4-((2 S ,4 R )-4-(cyclopropylmethylamidoamino)-2-(dimethylaminomethylamido)pyrrolidine- Synthesis of 1-carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid (200 mg, 0.31 mmol), dimethylamine hydrochloride Salt (100 mg, 1.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (120 mg, 0.62 mmol) and N -hydroxy-7-azabenzotriazine Azole (61mg, 0.46mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.35mL, 1.85mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, Wash with water (10 mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrated solution by column chromatography (eluent: DCM/MeOH (v/v)=40/1) to obtain 176 mg of white Solid, yield: 84%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.52-7.57(m,1H),7.41-7.46(m,1H),7.19-7.23(m,1H),6.69(td, J _FH =75.0,2.5Hz , 1H), 5.55-5.58, 5.34-5.40 (m, 0.5H, 0.5H), 5.10-5.23 (m, 1H), 4.56-4.65 (m, 1H), 4.19-4.32 (m, 1H), 3.92 3.97 (m, 3H), 3.16 (s, 1.5H), 3.05 (s, 1.5H), 2.99 (s, 1.5H), 2.92 (s, 1.5H), 2.19-2.47 (m, 2H), 1.52- 1.55 (m, 3H), 1.41 (s, 9H), 1.29-1.37 (m, 2H), 0.93-0.97 (m, 2H), 0.66-0.76 (m, 4H), 0.37-0.43 (m, 2H); MS-ESI: m/z 676.70 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropyl Synthesis of acetamido)- N , N -dimethylpyrrolidine-2-carboxamide hydrochloride

The compound (( S )-1-(4-((2 S ,4 R )-4-(cyclopropylcarboxamido)-2-(dimethylaminocarboxamido)pyrrolidine-1- Carbonyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (170 mg, 0.25 mmol ) Was dissolved in dichloromethane (4mL), HCl in ethyl acetate solution (4M, 4mL) was added, stirred at room temperature for 30min, the solvent was removed to obtain 151mg white solid, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.71-7.74 (m, 1H), 7.62-7.67 (m, 1H), 7.31-7.36 (m, 1H), 6.91 (td, J _FH = 74.7, 6.2 Hz, 1H), 6.01-6.03, 5.22-5.24 (m, 0.5H, 0.5H), 5.08-5.15 (m, 1H), 4.55-4.58, 4.29-4.32 (m, 0.5H, 0.5H), 4.40- 4.47(m, 1H), 4.01-4.04(m, 2H), 3.95-4.00, 3.75-3.78(m, 0.5H, 0.5H), 3.24(s, 3H), 3.00(s, 1.5H), 2.86( s, 1.5H), 2.52-2.57, 2.35-2.39 (m, 0.5H, 0.5H), 2.28-2.32, 2.13-2.19 (m, 0.5H, 0.5H), 1.76 (d, J = 6.9Hz, 3H ), 1.60-1.65 (m, 1H), 1.32-1.36 (m, 1H), 0.84-0.88 (m, 2H), 0.75-0.79 (m, 2H), 0.67-0.70 (m, 2H), 0.41-0.44 (m, 2H); MS-ESI: m/z 576.35 [M+H-HCl] ⁺ .

Example 128: Compound (( R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxy Of methyl phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

Step 1: Synthesis of compound 3-(cyclopropylmethoxy)-4-methoxybenzoic acid methyl ester

Dissolve methyl 3-hydroxy-4-methoxybenzoate (5g, 27.47mmol) in DMF (30mL), add anhydrous potassium carbonate (7.58g, 54.95mmol) and bromomethylcyclopropane (3.8mL, 41.20) mmol), seal the tube and react at 60°C for 4.5h. Saturated NaCl solution (20 mL) was added and extracted with ethyl acetate (25 mL×3). The organic phases were combined and washed with water (30 mL×3). The organic phase was dried with anhydrous Na ₂ SO _{4 for} 1 h and the solvent was removed to obtain 6.26 g of white. Solid, yield: 96.5%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.66 (d, J =8.4 Hz, 1H), 7.52 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 3.89 (d, J = 7.0 Hz, 2H), 3.87 (s, 3H), 1.32-1.36 (m, 1H), 0.62-0.67 (m, 2H), 0.34-0.38 (m, 2H); MS-ESI: m/z 237.1[M+H] ⁺ .

Step 2: Synthesis of compound 3-(cyclopropylmethoxy)-4-methoxybenzoic acid

Compound 3-(cyclopropylmethoxy)-4-methoxybenzoic acid methyl ester (2g, 8.47mmol) was dissolved in ethanol (20mL), and then sodium hydroxide (1.70g, 42.37mmol) was added at 60 Reaction at ℃ for 1.5h, remove ethanol, dissolve the residue with water (20mL), then adjust the pH of the solution to about 1 with HCl (1M), and extract with ethyl acetate (25mL×3). After combining the organic phases, use anhydrous Na ₂ SO _{4 was} dried and the solvent was removed to obtain 1.81 g of white solid. Yield: 96.2%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.65 (d, J = 8.4Hz, 1H), 7.52 (s, 1H), 7.00 (d, J = 8.5Hz, 1H), 3.89 (s, 3H), 3.86 (d, J = 6.9Hz, 2H), 1.24-1.27 (m, 1H), 0.58-0.63 (m, 2H), 0.33-0.37 (m, 2H); MS-ESI: m/z 223.0 [M+ H] ⁺ .

Step 3: Synthesis of the compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenylamido)acetate

Compound 3-(cyclopropylmethoxy)-4-methoxybenzoic acid (4.5 g, 20.27 mmol), HOAT (2.76 g, 20.27 mmol) and EDCI (5.81 g, 30.41 mmol) were dissolved in DCM (30 mL ), after stirring at room temperature for 30 min, then add methyl glycinate hydrochloride (3.04g, 24.32mmol), slowly add DIPEA (14mL, 81.08mmol) dropwise under ice bath, continue at room temperature After stirring overnight, water (30 mL) was added, followed by extraction with CH ₂ Cl ₂ (25 mL×3). After the organic phases were combined, dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1), obtained 3.68 g of white solid, yield: 61.9%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.41 (s, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.57 (s, 1H), 4.23(d, J =5.0Hz, 2H), 3.92(s, 3H), 3.90(d, J = 7.0Hz, 2H), 3.80(s, 3H), 1.25-1.34(m, 1H), 0.62-0.66 (m, 2H), 0.35-0.38 (m, 2H); MS-ESI: m/z 294.2 [M+H] ⁺ .

Step 4: Synthesis of compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenylthioamido)acetate

Dissolve compound 2-(3-(cyclopropylmethoxy)-4-methoxyphenylamidoamino)acetate (4g, 13.64mmol) and Lawesson's reagent (5.52g, 13.64mmol) in tetrahydrofuran (30mL), react at 75°C for 2h, add a saturated solution of sodium bicarbonate (30mL), extract with ethyl acetate (20mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate the solution for column layer Separation (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) gave 2.89 g of a yellow solid, yield: 68%.

Step 5: Synthesis of compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetate

To a solution of trimethyloxonium tetrafluoroborate (2.68 g, 18.1 mmol) in methylene chloride (15 mL) at -78°C, add compound 2-(3-(cyclopropylmethoxy)-4- A solution of methyl methoxyphenylthioamido)acetate (2.8 g, 9.05 mmol) in methylene chloride (20 mL) was stirred at 0° C. for 3 h, and then washed with saturated sodium bicarbonate solution (25 mL×3). The organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed to obtain 2.8 g of yellow oil. Yield: 96%.

Step 6: Compound ( S )-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole- Synthesis of 4-methyl formate

Combine compound 2-(((3-(cyclopropylmethoxy)-4-methoxyphenyl)(methylthio)methylene)amino)acetate (2.8g, 8.66mmol) with compound ( S )-(1-fluoro-1-oxopropane-2-yl)aminocarboxylic acid tert-butyl ester (3.3 g, 17.32 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and this solution was added at -78°C A solution of potassium hexamethyldisilazide in tetrahydrofuran (21.65mL, 21.65mmol) was added dropwise, and the reaction was carried out at -78°C for 1h. The reaction was quenched with water (30mL), extracted with ethyl acetate (25mL×3), and the organic phases were combined , Dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 2.58 g of white solid, yield: 67%.

Step 7: Compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl) Synthesis of oxazole-4-carboxylic acid

The compound ( S )-5-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole-4- Methyl formate (2.58g, 5.78mmol) and lithium hydroxide monohydrate (1.21g, 28.9mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), reacted at 40℃ for 2h, adjusted with hydrochloric acid (1M) The pH value reached 1, extracted with ethyl acetate (20 mL×3), the organic phases were combined and dried with Na ₂ SO ₄ , and the solvent was removed to obtain 1.66 g of a yellow solid. Yield: 66%.

Step 8: Compound (( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy)-4 -Methoxyphenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)oxazole -4-carboxylic acid (250 mg, 0.58 mmol), compound ( R )-3-methoxycarbonylaminopyrrolidine hydrochloride (120 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl ) Carbodiimide hydrochloride (327mg, 1.71mmol) and N -hydroxy-7-azabenzotriazole (120mg, 0.87mmol) were dissolved in dichloromethane (10mL), this is 0 ℃ N , N -diisopropylethylamine (0.40mL, 2.31mmol) was added dropwise to the solution, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution Column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) was performed to obtain 115 mg of a white solid in a yield of 35%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.58(dd, J ₁ =8.4Hz, J ₂ =1.9Hz,1H),7.44-7.46(m,1H),6.92(d, J =8.5Hz,1H ), 5.19-5.30, 4.88-4.97 (m, 1.5H, 0.5H), 4.31-4.39 (m, 1H), 4.05-4.13, 4.04-4.12 (m, 0.5H, 0.5H), 3.90-4.01 (m , 1H), 3.94 (d, J = 2.5Hz, 2H), 3.93 (s, 3H), 3.69-3.80 (m, 2H), 3.68 (s, 3H), 2.17-2.26 (m, 1H), 1.89- 1.99 (m, 1H), 1.51-1.55 (m, 3H), 1.41 (s, 9H), 1.31-1.38 (m, 1H), 0.65-0.70 (m, 2H), 0.38-0.42 (m, 2H); MS-ESI: m/z 559.90 [M+H] ⁺ .

Step 9: Compound (( R )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-methoxybenzene Of methyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

The compound (( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-methyl Oxygen)phenyloxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester (110mg, 0.20mmol) was dissolved in dichloromethane (4mL), was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 30min, the solvent was removed to obtain 96mg white solid, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.70 (dd, J ₁ =8.4 Hz, J ₂ =1.6 Hz, 1H), 7.57-7.58 (m, 1H), 7.12 (d, J = 8.5 Hz, 1H),5.05-5.10(m,1H), 4.22-4.34(m,2H),4.16-4.22,4.04-4.09(m,0.5H,0.5 H),3.94(d, J =3.9Hz,2H), 3.93(s, 3H), 3.84-3.88, 3.69-3.80(m, 0.5H, 1.5H), 3.65-3.67(m, 3H), 2.17-2.30(m, 1H), 1.94-2.07(m, 1H) , 1.75(d, J = 6.9Hz, 3H), 1.29-1.35(m, 1H), 0.64-0.67(m, 2H), 0.38-0.40(m, 2H); MS-ESI: m/z 459.30[M +H-HCl] ⁺ .

Example 129: Compound 4-((((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy Of methyl)methyl)benzoate hydrochloride

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy Of phenyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid methyl ester (2.8 g, 4.3 mmol) was dissolved in THF ( 20mL) and H ₂ O (10mL) in a mixed solvent, then add lithium hydroxide monohydrate (900mg, 21.0mmol), 45 ℃ reaction for 1h after stopping, add concentrated hydrochloric acid to adjust the solution pH = 1, use ethyl acetate (15mL ×3) Extraction, after combining the organic phases, drying with anhydrous Na ₂ SO ₄ and removing the solvent to obtain 2.7 g of white solid, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.60-7.74 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 6.88 (t, J _FH = 75.0 Hz, 1H), 5.43-5.50 (m,1H),5.25-5.34(m,1H),4.27-4.38(m,1H),4.02(d, J =6.8Hz,2H),3.93-4.00(m,1H),3.63-3.70 (m ,1H),3.67(s,1H),2.28-2.47(m,2H),1.52(d, J =7.0Hz,3H),1.42(s,9H),1.33-1.39(m,1H),0.66- 0.71 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 639.35 [M+H] ⁺ .

Step 2: Compound 4-((((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(ring C Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2- Synthesis of carbonyl)oxy)methyl)benzoic acid

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (300mg, 0.47mmol) dissolved in THF (5mL) At room temperature, add N , N' -carbonyldiimidazole (CDI) (115mg, 0.71mmol), react at 60℃ for 30min, add 4-hydroxymethylbenzoic acid (143mg, 0.94mmol), stop at 70℃ for 24h, The solvent was sucked off, water (10 mL) was added, extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: DCM/MeOH( v/v)=30/1), 141 mg of white solid was obtained, yield: 38%.

Step 3: Compound 4-((((2 S ,4 R )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy)methyl)benzoic acid hydrochloride synthesis

The compound 4-((((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy)methyl)benzene Formic acid (140 mg, 0.18 mmol) was dissolved in dichloromethane (4 mL), HCl in ethyl acetate solution (4M, 4 mL) was added, stirred at room temperature for 50 min, and the solvent was removed to obtain 62 mg of white solid, yield: 48%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.51-7.75 (m, 3H), 7.32-7.42 (m, 2H), 7.15-7.26 (m, 2H), 6.69-7.10 (m, 1H), 5.57 -5.64(m,1H),5.11-5.30(m,3H),4.25-4.32(m,1H),3.86-4.06(m,3H),3.64-3.77(m,4H),2.48-2.56(m, 1H), 2.28-2.46(m, 1H), 1.73-1.78(m, 3H), 1.27-1.36(m, 1H), 0.64-0.72(m, 2H), 0.38-0.46(m, 2H); MS- ESI: m/z 673.20 [M+H-HCl] ⁺ .

Example 130: Compound (( R )-1-(5-(( S )-1-amino-2-methylpropyl)-2-(3-(cyclopropylmethoxy Of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

Step 1: Compound ( S )-5-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-( Synthesis of methyl difluoromethoxy)phenyl)oxazole-4-carboxylate

At room temperature, N , N' -carbonyldiimidazole (CDI) (1.20g, 7.5mmol) was dissolved in anhydrous THF (10mL), and the compound ( S )-2-((tert-butoxycarbonyl)amino group was slowly added )-3-methylbutyric acid (1.4g, 6.3mmol), stirred at room temperature for 20min, added 2-(((3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) (Methylthio)methylene)amino)acetic acid methyl ester (1.5g, 4.2mmol), at -78 ℃, slowly dropwise add hexamethyldisilazium potassium THF solution (1.0M, 13mL ), the reaction was stopped after 1.5h, water (25mL) was added to quench the reaction, and then extracted with ethyl acetate (25mL×3), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography Separation (eluent: Petroleum ether/EtOAc (v/v)=5/1) to obtain 1.0 g of white solid in a yield of 47%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.60-7.64 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 6.70 (t, J _FH = 75.1 Hz, 1H), 5.86-5.89 ( m,1H),5.07-5.12(m,1H),3.98(s,3H),3.97(d, J =7.1Hz,2H),2.12-2.19(m,1H),1.44(s,9H),1.29 -1.35(m,1H),1.05(d, J =6.5Hz,3H),0.89(d, J =6.6Hz,3H),0.65-0.70(m,2H),0.37-0.41(m,2H); MS-ESI: m/z 511.30 [M+H] ⁺ .

Step 2: Compound ( S )-5-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropylmethyl Synthesis of oxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxylic acid

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carboxylic acid methyl ester (1.00 g, 2.0 mmol) was dissolved in a mixed solvent of THF (10 mL) and water (5 mL), and then lithium hydroxide monohydrate (410 mg, 9.8 mmol) was added ), after 1 hour reaction at 45°C, stop the reaction, add concentrated hydrochloric acid to adjust the pH of the solution=1, remove THF, extract with ethyl acetate (15mL×3), combine the organic phases, dry with anhydrous Na ₂ SO ₄ and remove the solvent, 960 mg light red solid was obtained, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.81 (s, 1H), 7.67-7.69 (m, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.90 (t, J _FH = 74.9 Hz ,1H),5.25-5.28(m,1H),4.03(d, J =6.9Hz,2H),2.13-2.23(m,1H),1.44(s,9H),1.33-1.38(m,1H), 1.08 (d, J = 5.6Hz, 3H), 0.96 (d, J = 6.7Hz, 3H), 0.66-0.71 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 441.80 [M-55] ⁺ .

Step 3: Compound (( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropyl Methyl))-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester synthesis

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carboxylic acid (300 mg, 0.61 mmol), compound ( R )-3-methoxycarbonylaminopyrrolidine hydrochloride (130 mg, 0.73 mmol), 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride (230mg, 1.21mmol) and N -hydroxy-7-azabenzotriazole (120mg, 0.91mmol) were dissolved in dichloromethane (10mL ), N , N -diisopropylethylamine (0.41mL, 2.42mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 10h, washed with water (15mL×3), and the organic phase was washed with anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/1) to obtain 391 mg of a white solid in a yield of 99%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.53-7.59 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.1 Hz, 1H), 4.80-4.87, 4.18-4.23(m,1.5H,0.5H), 4.30-4.40(m,1H),3.95-4.04(m,1H),3.96-3.99(m,2H),3.63-3.84(m,2H),3.68 (s,3H),2.14-2.28(m,2H),1.86-2.03(m,1H),1.42(s,9H),1.28-1.35(m,1H),1.01-1.05(m,3H),0.82 -0.87 (m, 3H), 0.66-0.71 (m, 2H), 0.38-0.43 (m, 2H); MS-ESI: m/z 623.40 [M+H] ⁺ .

Step 4: Compound (( R )-1-(5-(( S )-1-Amino-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

To the compound (( R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester (360mg, 0.58mmol) in methylene chloride (4mL) was added HCl The ethyl acetate solution (4M, 4mL) was stirred at room temperature for 30min, the solvent was removed, to obtain 315mg white solid, yield: 97%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.70-7.74 (m, 2H), 7.32 (d, J = 8.3Hz, 1H), 6.92 (t, J _FH = 74.8Hz, 1H), 4.27-4.31 ,4.08-4.12(m,0.5H,0.5H),4.21-4.25(m,2H),4.02-4.04(m,2H),3.83-3.87,3.75-3.80(m,0.5H,0.5H),3.68 -3.72,3.56-3.59(m,0.5H,0.5H),3.64-3.66(m,3H),2.44-2.50(m,1H),2.18-2.30(m,1H),1.94-2.07(m,1H ), 1.31-1.36 (m, 1H), 1.18 (d, J = 6.7Hz, 3H), 1.00 (d, J = 6.7Hz, 3H), 0.66-0.69 (m, 2H), 0.42-0.44 (m, 2H); MS-ESI: m/z 523.85 [M+H-HCl] ⁺ .

Example 131: Compound ( R )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-ethyl Synthesis of methyl oxazol-4-carbonyl)pyrrolidin-3-yl)carbamate

Step 1: Synthesis of compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-ethyloxazole-4-carboxylic acid methyl ester

At room temperature, dissolve N , N' -carbonyldiimidazole (CDI) (1.50g, 9.2mmol) in anhydrous THF (10mL), slowly add propionic acid (620mg, 8.3mmol), stir at room temperature for 20min, add 2 -(((3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(methylthio)methylene)amino)acetic acid methyl ester (1.5 g, 4.2 mmol), Under the condition of -78℃, slowly add THF solution (1.0M, 13mL) of potassium hexamethyldisilazide potassium dropwise, stop the reaction after 1.5h, add water (25mL) to quench the reaction, and then use ethyl acetate (25mL×3) extraction, the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=6/1) to obtain 650mg white solid, yield: 42%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.65 (m, 1H), 7.59-7.62 (m, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.70 (t, J _FH = 75.1 Hz, 1H), 3.96 (d, J = 7.0Hz, 2H), 3.95 (s, 3H), 3.13 (q, J = 7.6Hz, 2H), 1.34 (t, J = 7.6Hz, 3H), 1.28-1.35 ( m, 1H), 0.63-0.69 (m, 2H), 0.35-0.39 (m, 2H); MS-ESI: m/z 368.90 [M+H] ⁺ .

Step 2: Compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-ethyloxazole-4-methyl Acid synthesis

The compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-ethyloxazole-4-carboxylic acid methyl ester (650 mg, 1.8 mmol) was dissolved in THF (10mL) and water (5mL) in a mixed solvent, then add lithium hydroxide monohydrate (370mg, 8.8mmol), 45 ℃ reaction for 1h to stop the reaction, add concentrated hydrochloric acid to adjust the pH of the solution = 1, remove THF, use acetic acid Ethyl ester (15 mL×3) was extracted. After the organic phases were combined, dried with anhydrous Na ₂ SO ₄ and the solvent was removed to obtain 590 mg of pale yellow solid. Yield: 94%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.78 (d, J = 1.8 Hz, 1H), 7.63 (dd, J ₁ = 8.4 Hz, J ₂ = 1.9 Hz, 1H), 7.29 (d, J = 8.4Hz, 1H), 6.90 (t, J _FH = 75.0Hz, 1H), 4.03 (d, J = 6.9Hz, 2H), 3.17 (q, J = 7.6Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H), 1.32-1.39 (m, 1H), 0.66-0.71 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 354.90 [M+H] ⁺ .

Step 3: Compound ( R )-(1-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-ethyloxan Synthesis of Methyl-4-oxo)pyrrolidin-3-yl)carbamate

Compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-5-ethyloxazole-4-carboxylic acid (200 mg, 0.56 mmol), compound ( R ) -3-methoxycarbonylaminopyrrolidine hydrochloride (122mg, 0.68mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (215mg, 1.13mmol) and N -Hydroxy-7-azabenzotriazole (115mg, 0.85mmol) was dissolved in dichloromethane (10mL), and N , N -diisopropylethylamine ( 0.40 mL, 2.26 mmol), stirred at room temperature for 10 h, washed with water (15 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc ( v/v) = 2/3), 180 mg of white solid was obtained, yield: 66%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.51-7.56 (m, 2H), 7.23 (d, J = 7.4 Hz, 1H), 6.68 (t, J _FH = 75.2 Hz, 1H), 4.96-5.05 ( m,1H), 4.28-4.38(m,1H), 4.18-4.21,3.90-3.95(m,0.5H,0.5H),4.03-4.02(m,1H),3.95-3.97(m,2H),3.82 -3.86,3.54-3.56(m,0.5H,0.5H),3.66-3.74(m,1H),3.66-3.69(m,3H),3.07-3.12(m,2H),2.16-2.23(m,2H ), 1.89-2.03 (m, 2H), 1.32 (t, J = 7.4Hz, 3H), 1.28-1.34 (m, 1H), 0.64-0.69 (m, 2H), 0.38-0.41 (m, 2H); MS-ESI: m/z 480.30 [M+H] ⁺ .

Example 134: Compound 1-((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)Xia Synthesis of pyridine-4-formate hydrochloride

Step 1: Compound 1-((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)pyridine-4-carboxylic acid Synthesis of methyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (300 mg, 0.47 mmol), 4-pyridinecarboxylic acid Methyl ester (101mg, 0.71mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (224mg, 1.17mmol) and N -hydroxy-7-azabenzotriazine Nitrozole (95mg, 0.71mmol) was dissolved in dichloromethane (10mL), and N , N -diisopropylethylamine (0.25mL, 1.41mmol) was added dropwise to this solution at 0°C, and stirred at room temperature for 10h , Washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/3) to obtain 255mg white solid, yield: 71%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.43-7.58 (m, 2H), 7.22 (d, J = 8.3Hz, 1H), 6.69 (t, J _FH = 75.1Hz, 1H), 5.05-5.30 ( m,2H),4.24-4.45(m,3H),3.88-3.99(m,3H),3.58-3.71(m,6H),3.10-3.38(m,1.5H),2.77-2.97(m,1H) , 2.56-2.70 (m, 1H), 2.37-2.50 (m, 1H), 2.16-2.30 (m, 1.5H), 1.88-2.03 (m, 2H), 1.72-1.85 (m, 1H), 1.57-1.65 (m,1H),1.49-1.56(m,3H),1.43(s,9H),1.28-1.36(m,1H),0.66-0.70(m,2H),0.39-0.43(m,2H); MS -ESI: m/z 764.70[M+H] ⁺ .

Step 2: Compound 1-((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2- Synthesis of carbonyl)pyridine-4-carboxylic acid

Compound 1-((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethyl Oxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)pyridine-4-carboxylic acid methyl ester (250mg, 0.33mmol) was dissolved in a mixed solvent of THF (10mL) and H ₂ O (5mL), then lithium hydroxide monohydrate (52mg, 3.3mmol) was added, the reaction was stopped after 45h at 45°C, adjusted with concentrated hydrochloric acid The solution had pH=1 and was extracted with ethyl acetate (10 mL×3). After the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed to obtain 243 mg of a white solid. Yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.56-7.72 (m, 2H), 7.27-7.35 (m, 1H), 6.68-7.09 (m, 1H), 5.31-5.41 (m, 1H), 5.69 -5.78, 5.18-5.25 (m, 0.5H, 0.5H), 4.20-4.38 (m, 3H), 3.98-4.05 (m, 2H), 3.98-4.10, 3.89-3.96 (m, 0.5H, 0.5H) , 3.65-3.67 (m, 3H), 3.16-3.30 (m, 1H), 2.92-3.04 (m, 1H), 2.63-2.81 (m, 1H), 2.38-2.55 (m, 1H), 2.10-2.31 ( m, 2H), 1.82-2.02 (m, 2H), 1.59-1.69 (m, 1H), 1.48-1.53 (m, 3H), 1.44 (s, 9H), 1.31-1.38 (m, 1H), 0.61- 0.71 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 750.40 [M+H] ⁺ .

Step 3: Compound 1-((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-( two Fluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)pyridine-4-carboxylic acid Synthesis of hydrochloride

Compound 1-((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethyl Oxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)pyridine-4-carboxylic acid (100mg , 0.13mmol) was dissolved in dichloromethane (4mL), was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 2h, the solvent was removed to obtain 90mg white solid, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.64-7.76 (m, 2H), 7.30-7.39 (m, 1H), 6.71-7.12 (m, 1H), 5.04-5.17 (m, 1H), 6.05 -6.10, 5.20-5.25 (m, 0.5H, 0.5H), 4.20-4.42 (m, 3H), 4.05 (d, J = 6.8Hz, 2H), 3.90-4.03 (m, 1H), 3.72-3.84 ( m,1H),3.65-3.68(m,3H),3.25-3.43(m,1H),2.87-3.04(m,1H),2.62-2.73(m,1H),2.48-2.60(m,1H), 2.21-2.38 (m, 1H), 2.10-2.19 (m, 1H), 1.83-2.00 (m, 1.5H), 1.77 (d, J = 6.9Hz, 3H), 1.52-1.70 (m, 1.5H), 1.31-1.38 (m, 1H), 0.67-0.71 (m, 2H), 0.43-0.45 (m, 2H); MS-ESI: m/z 650.80 [M+H-HCl] ⁺ .

Example 135: Compound (2 S ,4 R )-1-(5-(( S )-1-amino-2-methylpropyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (2- Synthesis of methoxy) ethyl ester hydrochloride

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclo Synthesis of methyl propylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carboxylic acid (300 mg, 0.61 mmol), compound (2 S ,4 R )-2-methoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine hydrochloride Salt (175mg, 0.73mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (290mg, 1.51mmol) and N -hydroxy-7-azabenzotriazine Zirconium (123mg, 0.91mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.42mL, 2.42mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, Wash with water (15 mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrated solution by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=3/1) to obtain 285 mg White solid, yield: 69%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.50-7.60 (m, 2H), 7.21-7.25 (m, 1H), 6.69 (t, J _FH = 75.1 Hz, 1H), 5.20-5.26, 4.42-4.51 (m,0.5H,0.5H),4.71-4.91(m,2H),4.30-4.40(m,1H),4.17-4.26,4.01-4.07(m,0.5H,0.5H),3.97-4.00(m ,2H),3.68-3.77(m,6H),2.32-2.51(m,1H),2.12-2.32(m,2H),1.43(s,9H),1.29-1.37(m,1H),0.99-1.04 (m, 3H), 0.81-0.86 (m, 3H), 0.67-0.71 (m, 2H), 0.40-0.44 (m, 2H); MS-ESI: m/z 681.40 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclo Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine Synthesis of -2-carboxylic acid

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid methyl ester (280 mg, 0.41 mmol) Dissolve in a mixed solvent of THF (5mL) and H ₂ O (3mL), then add lithium hydroxide monohydrate (172mg, 4.1mmol), stop the reaction at 45℃ for 1h, add concentrated hydrochloric acid to adjust the solution pH=1, use acetic acid Ethyl ester (15 mL×3) was extracted. After the organic phases were combined, dried with anhydrous Na ₂ SO ₄ and the solvent was removed to obtain 260 mg of white solid. Yield: 95%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.73-7.75 (m, 1H), 7.61-7.69 (m, 1H), 7.25-7.30 (m, 1H), 6.88 (t, J _FH = 75.0Hz, 1H), 5.27-5.32 (m, 1H), 5.19-5.21 (m, 1H), 4.30-4.33 (m, 1H), 4.02 (d, J = 6.8Hz, 2H), 3.93-4.05 (m, 1H) , 3.63-3.71 (m, 1H), 3.67 (s, 1H), 2.28-2.46 (m, 2H), 2.14-2.24 (m, 1H), 1.44 (s, 9H), 1.33-1.38 (m, 1H) , 1.01-1.07 (m, 3H), 0.87-0.92 (m, 3H), 0.66-0.71 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 667.75 [M+H] ⁺ .

Step 3: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclo Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine Synthesis of (2-methoxy) ethyl-2-carboxylate

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (250 mg, 0.37 mmol), ethyl Glycol monomethyl ether (142 mg, 1.88 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (215 mg, 1.13 mmol) and N -hydroxy-7-aza Benzotriazole (75 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL), and N , N -diisopropylethylamine (0.2 mL, 1.13 mmol) was added dropwise to this solution at 0°C. Stir at a warm temperature for 10 h, wash with water (15 mL×3), dry the organic phase over anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrate by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/1 ), 230 mg of white solid was obtained, yield: 84%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.53-7.60 (m, 2H), 7.20-7.25 (m, 1H), 6.69 (t, J _FH = 75.2 Hz, 1H), 5.28-5.35, 4.72-4.78 (m,0.5H,0.5H),4.78-4.90(m,2H),4.37-4.49(m,1H),4.25-4.36(m,2H),4.15-4.23(m,1H),3.95-4.03( m, 2H), 3.68 (s, 3H), 3.58-3.64, 3.48-3.50 (m, 0.5H, 1.5H), 3.38 (s, 1H), 3.25 (s, 2H), 2.39-2.51 (m, 1H ), 2.24-2.38 (m, 1H), 2.11-2.23 (m, 1H), 1.43 (s, 9H), 1.29-1.36 (m, 1H), 0.99-1.05 (m, 3H), 0.81-0.87 (m , 3H), 0.66-0.71 (m, 2H), 0.40-0.44 (m, 2H); MS-ESI: m/z 725.70 [M+H] ⁺ .

Step 4: Compound (2 S ,4 R )-1-(5-(( S )-1-amino-2-methylpropyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (2- Synthesis of methoxy) ethyl ester hydrochloride

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (2-methoxy)ethyl The ester (230 mg, 0.32 mmol) was dissolved in dichloromethane (4 mL), and a solution of HCl in ethyl acetate (4M, 4 mL) was added, stirred at room temperature for 1 h, and the solvent was removed to obtain 204 mg of a white solid, yield: 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.66-7.77 (m, 2H), 7.32-7.35 (m, 1H), 6.92 (t, J _FH = 74.8 Hz, 1H), 5.55-5.58, 4.77- 4.79(m,0.5H,0.5H),4.97(d, J =8.5Hz,1H),4.25-4.39(m,3H),4.18-4.22,3.97-4.00(m,0.5H,0.5H),4.02 -4.09(m,2H),3.63-3.71(m,1H),3.66-3.67(m,3H),3.51-3.53(m,1H),3.40(s,1H),3.21(s,2H),2.43 -2.49 (m, 2H), 2.28-2.37 (m, 1H), 1.33-1.39 (m, 1H), 1.17-1.20 (m, 3H), 0.99-1.02 (m, 3H), 0.68-0.71 (m, 2H), 0.44-0.46 (m, 2H); MS-ESI: m/z 625.80 [M+H-HCl] ⁺ .

Example 136: Compound ( S )-2-(((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy Of phenyl)-2-phenylacetic acid hydrochloride

Step 1: Compound ( S )-2-(((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3 -(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy ) Synthesis of 2-phenylacetic acid

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (250 mg, 0.39 mmol) dissolved in THF (5 mL) At room temperature, N , N' -carbonyldiimidazole (CDI) (95mg, 0.59mmol) was added, reacted at room temperature for 30min, compound ( S )-2-hydroxy-2-phenylacetic acid (89mg, 0.59mmol), 60 The reaction was stopped after 12h at ℃, the solvent was pumped off, water (10mL) was added and extracted with ethyl acetate (10mL×3). After the organic phases were combined, dried with anhydrous Na ₂ SO ₄ and the solvent was removed to obtain 280mg of pale yellow solid. Rate: 93%.

MS-ESI: m/z 773.70 [M+H] ⁺ .

Step 2: Compound ( S )-2-(((2 S ,4 R )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy)-2-phenylacetic acid hydrochloric acid Salt Synthesis

The compound ( S )-2-(((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy)- 2-Phenylacetic acid (310mg, 0.4mmol) was dissolved in dichloromethane (4mL), HCl in ethyl acetate solution (4M, 4mL) was added, stirred at room temperature for 50min, the solvent was removed, and the residue was separated by preparative chromatography to obtain 60mg White solid, yield: 21%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.61-7.75 (m, 2H), 7.51 (s, 1H), 7.32-7.44 (m, 5H), 6.71-7.04 (m, 1H), 5.96, 5.79 (s,0.3H,0.7H),5.73-5.75,5.06-5.11(m,0.7H,0.3H),5.12-5.18,4.90-4.92(m,0.7H,0.3H),4.36-4.45(m, 1H), 4.25-4.30 (m, 1H), 4.00-4.04, 3.78-3.81 (m, 1.4H, 0.6H), 3.69-3.76 (m, 1H), 3.64-3.67 (m, 3H), 2.73-2.77 , 2.48-2.53 (m, 0.7H, 0.3H), 2.56-2.62, 2.40-2.46 (m, 0.7H, 0.3H), 1.70-1.76 (m, 3H), 1.31-1.36 (m, 1H), 0.66 -0.70, 0.62-0.65 (m, 0.6H, 1.4H), 0.42-0.44, 0.33-0.36 (m, 0.6H, 1.4H); MS-ESI: m/z 673.30 [M+H] ⁺ .

Example 139: Compound 2-(((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy Synthesis of 2-methylpropionate hydrochloride

Step 1: Compound 2-(((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy)-2- Synthesis of methylpropionic acid

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (350 mg, 0.55 mmol) dissolved in THF (10 mL) At room temperature, N , N' -carbonyldiimidazole (CDI) (135mg, 0.82mmol) was added. After reacting at 60℃ for 30min, 2-hydroxy-2-methylpropionic acid (89mg, 0.59mmol) was added and reacting at 60℃ for 12h After stopping, the solvent was pumped off, water (10 mL) was added, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried with anhydrous Na ₂ SO ₄ , the solvent was removed, and the residue was subjected to preparative chromatography to obtain 253 mg of shallow Yellow solid, yield: 63%.

MS-ESI: m/z 725.70 [M+H] ⁺ .

Step 2: Compound 2-(((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy)-2-methylpropionate synthesis

Compound 2-(((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethyl Oxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)oxy)-2-methyl Propionic acid (240mg, 0.33mmol) was dissolved in dichloromethane (4mL), HCl in ethyl acetate solution (4M, 4mL) was added, stirred at room temperature for 50min, the solvent was removed, and the residue was separated by preparative chromatography to obtain 206mg white solid , Yield: 94%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.68-7.75 (m, 2H), 7.32-7.34 (m, 1H), 6.79-7.05 (m, 1H), 5.56-5.61, 4.74-4.78 (m, 0.5H, 0.5H), 5.08-5.17 (m, 1H), 4.25-4.42 (m, 2H), 4.02-4.06 (m, 2H), 3.97-4.01, 3.68-3.72 (m, 0.5H, 0.5H) ,3.63-3.72(m,3H),2.45-2.56(m,1H),2.31-2.39(m,1H),1.70-1.76(m,3H),1.64(s,1H),1.59(s,1H) , 1.47 (s, 2H), 1.41 (s, 2H), 1.33-1.36 (m, 1H), 0.66-0.70 (m, 2H), 0.42-0.46 (m, 2H); MS-ESI: m/z 625.40 [M+H-HCl] ⁺ .

Example 141: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(dimethylaminecarboxamido)pyrrolidin-3-yl)amino Synthesis of methyl formate hydrochloride

Step 1: Compound ((3 R ,5 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy Of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(dimethylaminecarboxamido)pyrrolidin-3-yl)carbamic acid methyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (200 mg, 0.31 mmol), dimethylamine hydrochloride Salt (73mg, 1.65mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (180mg, 0.94mmol) and N -hydroxy-7-azabenzotriazine Zirconium (63mg, 0.46mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.35mL, 2.0mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, Wash with water (10 mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrated solution by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/2) to obtain 146 mg White solid, yield: 70%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.44-7.59 (m, 2H), 7.20-7.24 (m, 1H), 6.69 (t, J _FH = 75.1 Hz, 1H), 5.55-5.64, 5.28-5.36 (m,0.5H,0.5H),5.16-5.27(m,1H),5.03-5.13(m,1H),4.38-4.48(m,1H),4.23-4.34(m,1H),3.93-3.98( m, 2H), 3.67(s, 3H), 3.17(s, 1.7H), 3.06(s, 1.3H), 3.00(s, 1.7H), 2.94(s, 1.3H), 2.19-2.42(m, 2H), 1.49-1.54 (m, 3H), 1.42-1.43 (m, 9H), 1.29-1.36 (m, 1H), 0.66-0.71 (m, 2H), 0.39-0.43 (m, 2H); MS- ESI: m/z 666.80[M+H] ⁺ .

Step 2: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-5-(dimethylaminecarboxamide)pyrrolidin-3-yl)carbamic acid methyl ester Synthesis of hydrochloride

The compound ((3 R ,5 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(dimethylaminecarboxamide)pyrrolidin-3-yl)carbamic acid methyl ester (146mg, 0.22mmol) Dissolve in dichloromethane (4mL), add HCl in ethyl acetate (4M, 4mL), stir at room temperature for 50min, remove the solvent to obtain 108mg white solid, yield: 81%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.70-7.75 (m, 1H), 7.62-7.66 (m, 1H), 7.32-7.36 (m, 1H), 6.91 (t, J _FH = 74.7, 4.9 Hz, 1H), 5.16-5.19, 5.96-5.98 (m, 0.5H, 0.5H), 5.07-5.13 (m, 1H), 4.36-4.41 (m, 1H), 4.23-4.31 (m, 1H), 4.01 -4.05(m,2H),3.72-3.77,3.95-3.98(m,0.5H,0.5H),3.64-3.66(m,3H),3.23(s,1.5H),3.22(s,1.5H), 3.00 (s, 1.5H), 2.86 (s, 1.5H), 2.50-2.55, 2.31-2.36 (m, 0.5H, 0.5H), 2.26-2.30, 2.12-2.17 (m, 0.5H, 0.5H), 1.76 (d, J = 6.9Hz, 3H), 1.33-1.36 (m, 1H), 0.67-0.70 (m, 2H), 0.41-0.45 (m, 2H); MS-ESI: m/z 566.40 [M+ H-HCl] ⁺ .

Example 142: Compound ((3 R ,S S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(methylaminomethylformyl)pyrrolidin-3-yl)amino Synthesis of methyl formate hydrochloride

Step 1: Compound ((3 R ,5 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy Of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(methylaminecarboxamido)pyrrolidin-3-yl)carbamic acid methyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (200 mg, 0.31 mmol), methylamine hydrochloride (105 mg, 1.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (180 mg, 0.94 mmol) and N -hydroxy-7-azabenzotriazole (63mg, 0.46mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.35mL, 2.0mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, water was added (10mL×3) washed, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/2) to obtain 160 mg of white Solid, yield: 78%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.48-7.58 (m, 2H), 7.21-7.25 (m, 1H), 6.70 (t, J _FH = 75.1 Hz, 1H), 4.78-4.80, 5.53-5.55 (m,0.5H,0.5H),5.23-5.32(m,1H),4.30-4.44(m,1H),3.95-4.02,4.06-4.14(m,0.5H,0.5H),3.98(d, J =6.9Hz, 2H), 3.81-3.91(m, 1H), 3.65(s, 3H), 2.83(d, J =4.7Hz, 2H), 2.58-2.60(m, 1H), 2.08-2.23(m, 1H), 1.53-1.57 (m, 3H), 1.42 (s, 9H), 1.29-1.36 (m, 1H), 0.66-0.71 (m, 2H), 0.39-0.43 (m, 2H); MS-ESI: m/z 652.40[M+H] ⁺ .

Step 2: Compound ((3 R ,5 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-5-(methylaminomethylcarboxamido)pyrrolidin-3-yl)carbamic acid methyl ester Synthesis of hydrochloride

The compound ((3 R ,5 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(methylaminecarboxamide)pyrrolidin-3-yl)carbamic acid methyl ester (155mg, 0.24mmol) dissolved In dichloromethane (4 mL), a solution of HCl in ethyl acetate (4M, 4 mL) was added, stirred at room temperature for 50 min, and the solvent was removed to obtain 137 mg of a white solid, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.67-7.76 (m, 2H), 7.31-7.34 (m, 1H), 6.92 (td, J _FH = 74.8, 2.2 Hz, 1H), 4.65-4.67, 5.36-5.38(m,0.5H,0.5H),5.11-5.17(m,1H),4.35-4.39(m,1H),4.23-4.30(m,1H),4.04-4.07(m,2H),3.64 -3.70,3.99-4.03(m,0.5H,0.5H),3.64-3.67(m,3H),2.79(m,1.5H),2.71(m,1.5H),2.35-2.45(m,1H), 2.18-2.32 (m, 1H), 1.78 (d, J = 6.9Hz, 3H), 1.33-1.38 (m, 1H), 0.67-0.71 (m, 2H), 0.43-0.47 (m, 2H); MS- ESI: m/z 552.80 [M+H-HCl] ⁺ .

Example 143: Compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxamido)-2-phenylacetate Synthesis of acid salt

Step 1: Synthesis of compound ( S )-2-(amino)-2-phenylacetic acid methyl ester hydrochloride

Dissolve N , N' -carbonyldiimidazole (CDI) (770mg, 4.8mmol) in anhydrous DMF (10mL), and add compound ( S )-2-((tert-butoxycarbonyl)amino)-2 at room temperature -Phenylacetic acid (1.0g, 4.0mmol), react at 60°C for 50min, add methanol (10mL), continue the reaction for 12h, then stop, draw off the solvent, add water (10mL), extract with ethyl acetate (10mL×3), organic The phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=8/1) to obtain 426 mg of pale yellow solid: ( S )-2 -((Tert-butoxycarbonyl)amino)-2-phenylacetic acid methyl ester, yield: 40%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.31-7.36 (m, 5H), 5.22 (s, 1H), 5.32 (d, J = 7.1 Hz, 1H), 3.72 (s, 3H), 1.43 (s , 9H); MS-ESI: m/z 288.00 [M+Na] ⁺ .

The compound ( S )-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid methyl ester (160mg, 0.61mmol) was dissolved in dichloromethane (4mL), and a solution of HCl in ethyl acetate was added ( 4M, 2mL), stirred at room temperature for 50min, and removed the solvent to obtain 119mg of light yellow solid: ( S )-2-(amino)-2-phenylacetic acid methyl ester hydrochloride, yield: 97%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.49-7.53 (m, 5H), 5.22 (s, 1H), 3.83 (s, 3H); MS-ESI: m/z 166.25 [M+H-HCl ] ⁺ .

Step 2: Compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3- (ring Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxamido)-2 -Synthesis of Methyl Phenylacetate

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (250 mg, 0.39 mmol), ( S )-2 -(Amino)-2-phenylacetic acid methyl ester hydrochloride (101mg, 0.5mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (180mg, 0.94mmol ) And N -hydroxy-7-azabenzotriazole (90mg, 0.59mmol) were dissolved in dichloromethane (10mL), N , N -diisopropyl ethyl was added dropwise to this solution at 0℃ amine (0.3 mL, 2.0 mmol), stirred for 10H at room temperature, add water (10mL × 3), dried the organic phase over anhydrous Na ₂ SO _4, subjected to column chromatography (eluent solvent was removed, the concentrate: Petroleum ether / EtOAc (v/v)=1/1), 230 mg of colorless solid was obtained, yield: 75%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.31-7.61 (m, 5H), 7.23-7.28 (m, 1H), 7.10-7.19 (m, 1H), 6.99-7.06 (m, 1H), 6.52 6.90 (m, 1H), 5.53-5.61 (m, 1H), 5.28-5.41 (m, 1H), 5.16-5.27 (m, 1H), 4.91-4.99 (m, 1H), 4.37-4.50 (m, 1H) ), 4.08-4.21 (m, 1H), 3.94-4.06 (m, 2H), 3.64-3.76 (m, 6H), 2.58-2.74 (m, 1H), 2.05-2.26 (m, 1H), 1.53-1.59 (m,3H),1.44(m,9H),1.31-1.39(m,1H),0.66-0.73(m,2H),0.37-0.44(m,2H); MS-ESI: m/z 786.70[M +H] ⁺ .

Step 3: Compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3- (ring Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine Synthesis of -2-methylamino)-2-phenylacetic acid

The compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(ring Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxamido)-2 -Methyl phenylacetate (220 mg, 0.28 mmol) was dissolved in a mixed solvent of THF (5 mL) and H ₂ O (3 mL), and then lithium hydroxide monohydrate (60 mg, 1.43 mmol) was added, and the reaction was stopped after 1 hour at 45°C. Add concentrated hydrochloric acid to adjust the solution pH=4, extract with ethyl acetate (10 mL×3), combine the organic phases, dry with anhydrous Na ₂ SO ₄ , remove the solvent to obtain 212 mg of white solid, yield: 98%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.64-7.71 (m, 1H), 7.43-7.53 (m, 2H), 7.33-7.41 (m, 1H), 7.19-7.30 (m, 3H), 7.07 -7.12(m,1H), 6.68-7.04(m,1H), 5.41-5.49(m,1H), 5.31-5.40(m,1H), 4.28-4.36(m,1H), 3.90-4.05(m, 2H), 3.80-3.86(m, 1H), 3.63-3.69(m, 3H), 2.35-2.50(m, 2H), 1.47-1.54(m, 2H), 1.43(s, 9H), 1.28-1.36( m, 1H), 0.65-0.71 (m, 2H), 0.40-0.45 (m, 2H); MS-ESI: m/z 772.40 [M+H] ⁺ .

Step 4: Compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxamide Of phenyl)-2-phenylacetic acid hydrochloride

The compound ( S )-2-((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(ring Propylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxamido)-2 -Phenylacetic acid (220mg, 0.28mmol) was dissolved in dichloromethane (4mL), HCl in ethyl acetate solution (4M, 4mL) was added, stirred at room temperature for 50min, the solvent was removed to obtain 202mg white solid, yield: 100% .

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.65-7.74 (m, 1.5H), 7.44-7.54 (m, 1.5H), 7.29-7.41 (m, 2H), 7.12-7.21 (m, 3H) , 6.73-7.10(m, 1H), 5.59-5.70(m, 1H), 5.25(s, 1H), 5.00-5.15(m, 1H), 4.23-4.40(m, 2H), 3.98-4.05(m, 2H), 3.89-3.94, 3.73-3.80 (m, 0.5H, 0.5H), 3.63-3.76 (m, 3H), 2.44-2.64 (m, 1H), 2.23-2.35 (m, 1H), 1.71-1.79 (m, 3H), 1.29-1.37 (m, 1H), 0.64-0.71 (m, 2H), 0.39-0.46 (m, 2H); MS-ESI: m/z 672.20 [M+H-HCl] ⁺ .

Example 145: Compound 4-((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)? Synthesis of methyl quinoline-3-carboxylate hydrochloride

Step 1: Compound 4-((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropyl Methoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)morpholine-3-carboxylic acid methyl Ester synthesis

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (300 mg, 0.47 mmol), methyl 3-carboxylate Morpholine (81 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (271 mg, 1.41 mmol) and N -hydroxy-7-azabenzotriazine Nitrozole (95mg, 0.70mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.3mL, 2.0mmol) was added dropwise to this solution at 0°C, and stirred at room temperature for 10h , Washed with water (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v)=1/3) to obtain 34mg white solid, yield: 9%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.43-7.57 (m, 2H), 7.18-7.22 (m, 1H), 6.68 (t, J _FH = 75.1 Hz, 1H), 5.75-5.82, 5.28-5.34 (m,0.5H,0.5H),5.13-5.27(m,2H),5.00-5.03,4.83-4.86(m,0.5H,0.5H),4.32-4.43(m,2H),4.17-4.28(m , 1H), 3.91-3.96 (m, 2H), 3.85-3.91 (m, 1H), 3.72-3.81 (m, 5H), 3.62-3.69 (m, 3H), 3.48-3.60 (m, 1H), 3.22 -3.44(m,1H), 2.23-2.50(m,2H),1.47-1.53(m,3H),1.38-1.41(m,9H),1.28-1.33(m,1H),0.64-0.70(m, 2H), 0.37-0.41 (m, 2H); MS-ESI: m/z 766.35 [M+H] ⁺ .

Step 2: Compound 4-((2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-( two Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)morpholine-3-carboxylic acid methyl ester hydrochloride

The compound 4-((2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy Methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carbonyl)morpholine-3-carboxylic acid methyl ester ( 30mg, 0.04mmol) was dissolved in dichloromethane (2mL), HCl in ethyl acetate solution (4M, 2mL) was added, stirred at room temperature for 1h, the solvent was removed to obtain 26mg white solid, yield: 94%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.73-7.77 (m, 2H), 7.34-7.40 (m, 1H), 6.94 (td, J = 74.9, 9.9 Hz, 1H), 6.19-6.23, 5.31 -5.34(m,0.5H,0.5H),5.07-5.16(m,1H),4.89-4.97(m,2H),4.74-4.83(m,1H),4.23-4.46(m,3H),4.03- 4.07(m, 2H), 3.91-4.00(m, 2H), 3.66-3.84(m, 7H), 3.49-3.59(m, 1H), 2.29-2.59(m, 2H), 1.78(d, J = 6.9 Hz, 3H), 1.31-1.40 (m, 1H), 0.68-0.73 (m, 2H), 0.45-0.47 (m, 2H); MS-ESI: m/z 666.30 [M+H-HCl] ⁺ .

Example 147: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (4- Synthesis of hydroxy) cyclohexyl ester hydrochloride

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (4-hydroxy)cyclohexyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (280 mg, 0.43 mmol), 1,4-cyclo Hexanediol (254 mg, 2.19 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (340 mg, 1.77 mmol) and N -hydroxy-7-azabenzo Triazole (90mg, 0.66mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.3mL, 2.0mmol) was added dropwise to this solution at 0°C, and stirred at room temperature 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/3), 41 mg of white solid was obtained, yield: 12%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.52-7.62 (m, 2H), 7.24-7.28 (m, 1H), 6.72 (t, J _FH = 75.1 Hz, 1H), 5.25-5.38 (m, 2H ), 4.68-4.86(m, 2H), 4.37-4.49(m, 1H), 3.98-4.02(m, 2H), 3.70-3.81(m, 5H), 2.22-2.49(m, 2H), 1.87-2.04 (m,4H),1.66-1.85(m,4H),1.50-1.56(m,3H),1.44(s,9H),1.33-1.39(m,1H),0.69-0.73(m,2H),0.42 -0.46 (m, 2H); MS-ESI: m/z 737.30 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (4-hydroxy)cyclohexyl ester Synthesis of hydrochloride

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (4-hydroxy)cyclohexyl ester (35 mg, 0.05 mmol ) Was dissolved in dichloromethane (2mL), added HCl in isopropanol solution (4M, 2mL), stirred at room temperature for 2h, the solvent was removed to obtain 32mg white solid, yield: 99%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.65-7.76 (m, 2H), 7.33-7.36 (m, 1H), 6.93 (t, J _FH = 75.1 Hz, 1H), 4.95-5.20 (m, 2H), 4.71-4.84 (m, 2H), 4.24-4.41 (m, 1H), 4.06 (d, J = 6.9Hz, 2H), 3.57-3.73 (m, 5H), 2.22-2.50 (m, 2H) ,1.83-2.04(m,4H),1.77(d, J =6.9Hz,3H),1.40-1.63(m,4H),1.31-1.38(m,1H),0.68-0.74(m,2H),0.43 -0.47 (m, 2H); MS-ESI: m/z 637.50 [M+H-HCl] ⁺ .

Example 148: Compound (( R )-1-(5-(( R )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of fluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

Step 1: Compound ( R )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy ) Synthesis of phenyl)oxazole-4-carboxylic acid methyl ester

At room temperature, dissolve N , N' -carbonyldiimidazole (CDI) (540mg, 3.33mmol) in anhydrous THF (10mL), slowly add N- Boc- D -alanine (530mg, 2.80mmol), room temperature Stir for 20min, add methyl 2-(((3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(methylthio)methylene)amino)acetate (500mg, 1.39mmol), at -78 ℃, slowly add dropwise hexamethyldisilazide potassium THF solution (1.0M, 5mL), the reaction was stopped after 1.5h, water (25mL) was added to quench the reaction, then Extract with ethyl acetate (25 mL×3), combine the organic phases, dry with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrated solution by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=6/ 1), 286 mg of white solid was obtained, yield: 42%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.60-7.64 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 6.70 (t, J _FH = 75.1 Hz, 1H), 5.67 (br. s,1H),5.41-5.49(m,1H),3.98(s,3H),3.96(d, J =7.0Hz,2H),1.54(d, J =7.0Hz,3H),1.43(s,9H ), 1.29-1.35 (m, 1H), 0.65-0.70 (m, 2H), 0.36-0.40 (m, 2H); MS-ESI: m/z 483.20 [M+H] ⁺ .

Step 2: Compound ( R )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy ) Synthesis of phenyl)oxazole-4-carboxylic acid

The compound ( R )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid methyl ester (280g, 0.58mmol) was dissolved in a mixed solvent of THF (10mL) and H ₂ O (5mL), and then lithium hydroxide monohydrate (92mg, 2.19mmol) was added at 45 The reaction was carried out at ℃ for 2h, dilute hydrochloric acid was added to adjust the pH of the solution to about 1, THF was removed, extracted with ethyl acetate (15mL×3), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ and the solvent was removed to obtain 243mg of white solid, yield : 89%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.81 (d, J = 1.7 Hz, 1H), 7.67 (dd, J ₁ = 8.4 Hz, J ₂ = 1.8 Hz, 1 H), 7.30 (d, J = 8.3Hz, 1H), 6.90 (t, J _FH = 74.9Hz, 1H), 5.47-5.53 (m, 1H), 4.04 (d, J = 7.0Hz, 2H), 1.54 (d, J = 7.1Hz, 3H ), 1.44 (s, 9H), 1.33-1.40 (m, 1H), 0.66-0.71 (m, 2H), 0.42-0.45 (m, 2H); MS-ESI: m/z 467.10 [MH] ^- .

Step 3: Compound (( R )-1-(5-(( R )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy Of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester

The compound ( R )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene Group) oxazole-4-carboxylic acid (200mg, 0.43mmol), compound ( R )-3-methoxycarbonylaminopyrrolidine hydrochloride (92mg, 0.51mmol), 1-ethyl-3-(3-di Methylaminopropyl) carbodiimide hydrochloride (245mg, 1.28mmol) and N -hydroxy-7-azabenzotriazole (87mg, 0.64mmol) were dissolved in dichloromethane (15mL), 0 ℃ To this solution, N , N -diisopropylethylamine (0.30mL, 2.0mmol) was added dropwise, stirred at room temperature for 10h, washed with water (10mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and removed The solvent and the concentrated solution were separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v)=2/3) to obtain 208 mg of white solid in a yield of 8%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.52-7.59 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 6.69 (t, J _FH = 75.0 Hz, 1H), 5.22-5.30 ( m,1H),4.27-4.37(m,1H),4.11-4.22(m,1H),4.00-4.07,3.84-3.91(m,0.5H,0.5H),3.96(d, J =7.0Hz,2H ), 3.70-3.80(m, 2H), 3.65-3.70(m, 3H), 2.12-2.28(m, 1H), 1.97-2.08(m, 1H), 1.52-1.55(m, 3H), 1.42(s , 9H), 1.28-1.35 (m, 1H), 0.66-0.71 (m, 2H), 0.38-0.42 (m, 2H); MS-ESI: m/z 595.25 [M+H] ⁺ .

Step 4: Compound (( R )-1-(5-(( R )-1-Aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester hydrochloride

The compound (( R )-1-(5-(( R )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)oxazole-4-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester (200mg, 0.34mmol) was dissolved in dichloromethane (4mL), ethyl acetate was added HCl The solution (4M, 4mL) was stirred at room temperature for 30min, and the solvent was removed to obtain 176mg of white solid, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.71-7.74 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.92 (t, J _FH = 74.8 Hz, 1H), 5.09-5.13 (m,1H), 4.30-4.34, 4.09-4.14(m,0.5H,0.5H), 4.23-4.28(m,2H), 4.03-4.05(m,2H),3.77-3.90(m,1H), 3.70-3.75, 3.57-3.61 (m, 0.5H, 0.5H), 3.66-3.68 (m, 3H), 2.19-2.31 (m, 1H), 1.95-2.09 (m, 1H), 1.79 (d, J = 6.8 Hz, 3H), 1.32-1.37 (m, 1H), 0.68-0.71 (m, 2H), 0.43-0.45 (m, 2H); MS-ESI: m/z 495.10 [M+H-HCl] ⁺ .

Example 149: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (4- Synthesis of methoxycarbonyl)benzyl ester hydrochloride

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy )-4-(Difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (4-methoxycarbonyl)benzyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (200 mg, 0.31 mmol), 4-hydroxymethyl Methyl benzoate (66mg, 0.4mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (187mg, 0.98mmol) and N -hydroxy-7-azabenzene Pyrogallazole (68mg, 0.5mmol) was dissolved in dichloromethane (10mL), N , N -diisopropylethylamine (0.3mL, 2.0mmol) was added dropwise to this solution at 0°C, room temperature Stir for 10 h, wash with water (10 mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrate by column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/1) , To obtain 133mg colorless solid, yield: 33%.

MS-ESI: m/z 787.30 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (4-methoxycarbonyl)benzyl ester hydrochloride

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (4-methoxycarbonyl)benzyl ester (70mg, 0.09 mmol) was dissolved in dichloromethane (2mL), HCl in ethyl acetate solution (4M, 2mL) was added, stirred at room temperature for 40min, the solvent was removed to obtain 59mg white solid, yield: 91%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 8.00-8.02, 7.68-7.73 (m, 0.5H, 0.5H), 7.50-7.60 (m, 2H), 7.30-7.34 (m, 2H), 7.11 7.21 (m, 2H), 6.67-7.08 (m, 1H), 5.76-5.61 (m, 1H), 5.06-5.31 (m, 3H), 4.22-4.28 (m, 1H), 3.96-4.02 (m, 1H) ), 3.81-4.02(m, 2H), 3.85(s, 3H), 3.70-3.74(m, 1H), 3.63-3.65(m, 3H), 2.47-2.52(m, 1H), 2.26-2.35(m ,1H),1.71-1.76(m,3H),1.29-1.37(m,1H),0.64-0.68(m,2H),0.38-0.42(m,2H); MS-ESI: m/z 687.40[M +H-HCl] ⁺ .

Example 150: Compound ( S )-5-(5-(5-(1-aminoethyl)-4-(4-(cyclopropylcarbonyl)pyrazine-1-carbonyl) Synthesis of oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valeric acid methyl ester hydrochloride

Step 1: Synthesis of compound 3-(benzyloxy)-4-(difluoromethoxy)benzoic acid methyl ester

Dissolve methyl 3-hydroxy-4-(difluoromethoxy)benzoate (5.0 g, 22.94 mmol), potassium carbonate (6.33 g, 45.88 mmol) and benzyl bromide (3.3 mL, 27.53 mmol) in N , N -dimethylformamide (60mL), reacted at 60°C for 4.5h, added water (40mL), extracted with ethyl acetate (50mL×3), combined organic phases, dried over anhydrous Na ₂ SO ₄ and removed The solvent and the concentrated liquid were separated by column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=5/1) to obtain 6.99 g of white solid in a yield of 99%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.75 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.48-7.38 (m, 5H), 7.24 (d, J = 8.3 Hz, 1H ), 6.67 (t, J _FH = 74.6 Hz, 1H), 5.20 (s, 2H), 3.93 (s, 3H); MS-ESI: 309.0 [M+H] ⁺ .

Step 2: Synthesis of compound 3-(benzyloxy)-4-(difluoromethoxy)benzoic acid

Compound 3-(benzyloxy)-4-(difluoromethoxy)benzoic acid methyl ester (6.99g, 22.69mmol) and sodium hydroxide (2.27g, 56.74mmol) were dissolved in ethanol (60mL) and water ( 30mL) in a mixed solvent, react at 60°C for 1.5h, remove ethanol, adjust the pH to 1 with hydrochloric acid (1M), extract with ethyl acetate (50mL×3), combine the organic phases and dry with anhydrous Na ₂ SO ₄ , Removal of the solvent gave 6.70 g of white solid, yield: 99%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.80 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 7.0 Hz, 2H), 7.43-7.35 (m, 3H ), 7.26 (d, J = 8.4 Hz, 1H), 6.88 (t, J _FH = 74.5 Hz, 1H), 5.23 (s, 2H); MS-ESI: 293.1 [MH] ^- .

Step 3: Synthesis of compound 2-(3-(benzyloxy)-4-(difluoromethoxy)benzylamino)acetate

The compound 3-(benzyloxy)-4-(difluoromethoxy)benzoic acid (6.70 g, 22.79 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide salt The acid salt (6.60g, 34.19mmol) and 1-hydroxybenzotriazole (4.62g, 34.19mmol) were dissolved in dichloromethane (60mL), stirred at room temperature for 0.5h, and methylglycine hydrochloride was added at 0°C Salt (3.44g, 27.35mmol) and N , N -diisopropylethylamine (12.25mL, 68.37mmol), stirred at room temperature for 12h, washed with water (40mL×3), the organic phase was dried with Na ₂ SO ₄ and removed The solvent and the concentrated liquid were separated by column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 7.95 g of white solid in a yield of 96%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.62 (s, 1H), 7.47-7.33 (m, 6H), 7.24 (d, J = 8.3 Hz, 1H), 6.67 (br.s, 1H), 6.65 (t, J _FH = 74.5Hz, 1H), 5.20(s, 2H), 4.25(d, J = 5.0Hz, 2H), 3.83(s, 3H); MS-ESI: m/z 366.2[M+H ] ⁺ .

Step 4: Synthesis of compound 2-(3-(benzyloxy)-4-(difluoromethoxy)phenylthioamide)acetate

Compound 2-(3-(benzyloxy)-4-(difluoromethoxy)benzylamino)acetate (7.95g, 21.80mmol) was dissolved in Lawson's reagent (8.80g, 21.80mmol) Stir in tetrahydrofuran (60 mL) at 75°C under reflux for 2 h. After adding saturated sodium bicarbonate solution (40 mL), extract with ethyl acetate (50 mL × 3). Combine the organic phases and dry with Na ₂ SO _4. Remove the solvent and concentrate. The liquid was subjected to column separation (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain 8.33 g of a yellow solid in a yield of 99%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 8.08 (br.s, 1H), 7.69 (s, 1H), 7.50-7.28 (m, 6H), 7.21 (d, J = 8.3 Hz, 1H), 6.64 (t, J _FH = 74.7Hz, 1H), 5.21(s, 2H), 4.57(d, J = 4.5Hz, 2H), 3.88(s, 3H); MS-ESI: m/z 380.0[MH] ^- .

Step 5: Compound 2-(((3-(benzyloxy)-4-(difluoromethoxy)phenyl)(methylthio)methylene)amino) Synthesis of methyl acetate

At -78°C, the compound 2-(3-(benzyloxy)-4-(difluoromethoxy)phenylthioamide)acetate (8.33g, 21.87mmol) in dichloromethane ( 30mL) solution was slowly added dropwise to a solution of trimethyloxonium tetrafluoroborate (6.47g, 43.74mmol) in methylene chloride (20mL). After stirring at 0°C for 3h, a saturated sodium bicarbonate solution (25mL×3) was added ) Washed, the organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was removed to obtain 8.55 g of yellow oil, yield: 99%. MS-ESI: m/z 396.2 [M+H] ⁺ .

Step 6: Compound ( S )-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl) Synthesis of oxazole-4-carboxylic acid methyl ester

The compound 2-(((3-(benzyloxy)-4-(difluoromethoxy)phenyl)(methylthio)methylene)amino)acetic acid methyl ester (3.45g, 8.74mmol), Compound ( S )-(1-fluoro-1-oxopropan-2-yl)aminocarboxylic acid tert-butyl ester (4.45g, 23.30mmol) was dissolved in anhydrous tetrahydrofuran (30mL), and added dropwise at -78℃ A solution of potassium hexamethyldisilazide in tetrahydrofuran (30.00mL, 30.00mmol), react at -78℃ for 1h, add ice water (20mL) to quench the reaction, extract with ethyl acetate (15mL×3), and combine After the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain 3.78 g of a yellow solid. Rate: 83%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.80 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.50-7.36 (m, 5H), 7.29 (d, J = 8.3 Hz, 1H ), 6.66 (t, J _FH = 74.7 Hz, 1H), 5.68 (br.s, 1H), 5.53-5.45 (m, 1H), 5.23 (s, 2H), 4.01 (s, 3H), 1.57 (d , J = 7.0Hz, 3H), 1.45 (s, 9H).

Step 7: Compound ( S )-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl) Synthesis of oxazole-4-carboxylic acid

Compound ( S )-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole Methyl-4-carboxylate (0.55g, 1.06mmol) and lithium hydroxide monohydrate (0.22g, 5.30mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL), reacted at 40°C for 3h, removed Tetrahydrofuran, add hydrochloric acid (1M) to adjust the pH value to 1, extract with ethyl acetate (30mL×3), combine the organic phases and dry with Na ₂ SO ₄ , remove the solvent to obtain 0.53mg white solid, yield: 99%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.80 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.51-7.35 (m, 5H), 7.29 (d, J = 8.4 Hz, 1H ), 6.66 (t, J _FH = 74.7Hz, 1H), 5.68 (br.s, 1H), 5.53-5.46 (m, 1H), 5.23 (s, 2H), 1.57 (d, J = 7.0Hz, 3H ), 1.45 (s, 9H); MS-ESI: m/z 449.2 [M-55].

Step 8: Compound ( S )-(1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-(4-(cyclopropylcarbonyl) Synthesis of tert-Butyl Phenazine-1-carbonyl)oxazol-5-yl)ethyl)aminocarbamate

Compound ( S )-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole -4-carboxylic acid (1.0 g, 1.98 mmol), N -cyclopropylcarbonylpyrazine hydrochloride (454 mg, 2.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Hydrochloride (570mg, 2.97mmol) and N -hydroxy-7-azabenzotriazole (404mg, 2.97mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, at 0 ℃ N , N -diisopropylethylamine (1.4mL, 7.93mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (25mL×3), extracted with dichloromethane (25mL×3), and the organic phases were combined, The organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 875 mg of white solid in a yield of: 69%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.66 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.4 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.36-7.39 (m, 1H), 7.29 (d, J = 8.1 Hz, 1H), 6.66 (t, J _FH = 74.6 Hz, 1H), 5.23-5.32 (m, 1H), 5.24 ( s, 2H), 3.75-3.97 (m, 8H), 1.68-1.71 (m, 1H), 1.57 (d, J = 7.2Hz, 3H), 1.44 (s, 9H), 1.30-1.33 (m, 1H) , 1.05-1.07 (m, 2H), 0.84-0.91 (m, 2H); MS-ESI: m/z 641.20 [M+2H] ⁺ .

Step 9: Compound ( S )-(1-(4-(4-(Cyclopropylcarbonyl)pyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3- Synthesis of tert-butyl hydroxyphenyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-(1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-(4-(cyclopropylcarbonyl)pyrazine-1- Carbonyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester (875mg, 1.37mmol) and nickel chloride (377mg, 2.91mmol) were dissolved in tetrahydrofuran (5mL), to this solution at 0 ℃ Add dropwise a solution of sodium borohydride (459mg, 12.1mmol) in tetrahydrofuran (15mL), stir at room temperature for 8.5h, add hydrochloric acid (1M) to adjust pH=1, stir until clear, add sodium hydroxide solution (1M) to adjust pH= 14. Extraction with ethyl acetate (25 mL×3), the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/ v)=1/1), 200 mg of white solid was obtained, yield: 28%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.61 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.65 (t, J _FH = 73.2Hz, 1H), 5.25-5.27(m, 1H), 3.77-4.05(m, 8H), 1.74-1.82(m, 1H), 1.57(d, J = 6.6Hz, 3H), 1.44(s, 9H ), 1.29-1.35 (m, 1H), 1.05-1.07 (m, 2H), 0.85-0.90 (m, 2H); MS-ESI: m/z 551.25 [M+H] ⁺ .

Step 10: Compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-4-(4-(cyclopropylcarbonyl) Synthesis of methylpyrazine-1-carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valerate

The compound ( S )-(1-(4-(4-(cyclopropylcarbonyl)pyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole 5-yl)ethyl)tert-butyl carbamate (200 mg, 0.36 mmol), methyl 5-bromovalerate (106 mg, 0.55 mmol) and potassium carbonate (100 mg, 0.73 mmol) were dissolved in DMF (10 mL), The tube was sealed at 60°C for 5 hours, suction filtered to remove potassium carbonate, the filtrate was concentrated, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 200 mg of white Solid, yield: 83%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.60 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 6.64 ( t, J _FH =74.4Hz,1H),5.24-5.27(m,1H),4.15(t, J =6.0Hz,2H),3.76-3.83(m,8H),3.71(s,3H),2.46( t, J =7.1Hz,2H),1.88-1.95(m,5H),1.57(d, J =7.2Hz,3H),1.44(s,9H),1.33-1.35(m,1H),1.04-1.06 (m, 2H), 0.84-0.91 (m, 2H); MS-ESI: m/z 665.30 [M+H] ⁺ .

Step 11: Compound ( S )-5-(5-(5-(1-aminoethyl)-4-(4-(cyclopropylcarbonyl)pyrazine-1-carbonyl)oxo Synthesis of oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valeric acid methyl ester hydrochloride

The compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-(4-(cyclopropylcarbonyl)pyrazine-1-carbonyl)ox Oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valeric acid methyl ester (200mg, 0.30mmol) was dissolved in dichloromethane (2mL), and a solution of HCl in isopropanol (25%) was added , 3mL), stirred at room temperature for 40min, the solvent was removed, to obtain 170mg white solid, yield: 94%, preparative chromatography separation, to obtain 20mg white solid.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.77 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.88 (t, J _FH =74.4Hz,1H),5.05-5.09(m,1H),4.20(t, J =5.8Hz,2H),3.74-3.96(m,8H),3.68(s,3H),2.48(t, J = 7.1Hz, 2H), 2.00-2.06 (m, 1H), 1.85-1.95 (m, 4H), 1.79 (d, J = 6.9Hz, 3H), 1.33-1.36 (m, 1H), 0.93-0.96 (m , 2H), 0.89-0.92 (m, 2H); MS-ESI: m/z 565.20 [M+H-HCl] ⁺ .

Example 151: Compound ( S )-4-(5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl Synthesis of methyl-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate hydrochloride

Step 1: Compound ( S )-4-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino) Synthesis of ethyl)oxazole-4-carbonyl)methylazine-1-carboxylate

Compound ( S )-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole -4-carboxylic acid (500 mg, 0.99 mmol), methyl 1-pyrazinecarboxylate (171 mg, 1.19 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (285 mg , 1.49mmol) and N -hydroxy-7-azabenzotriazole (202mg, 1.49mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, added dropwise to this solution at 0 ℃ N , N -diisopropylethylamine (0.52mL, 2.97mmol), stirred at room temperature for 10h, washed with water (25mL×3), extracted with dichloromethane (25mL×3), combined organic phases, the organic phase was dried over anhydrous Na ₂ SO _{4 was} dried, the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 567 mg of a white solid in a yield of 91%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.66 (d, J =2.0 Hz, 1H), 7.62 (dd, J ₁ =8.0 Hz, J ₂ =2.0 Hz, 1H), 7.49 (d, J =7.4 Hz, 2H), 7.43 (t, J = 7.5Hz, 2H), 7.36-7.39 (m, 1H), 7.28 (d, J = 8.0Hz, 1H), 6.66 (t, J _FH = 74.8Hz, 1H) , 5.23-5.32 (m, 1H), 3.25 (s, 2H), 3.94 (br.s, 3H), 3.77 (s, 3H), 3.60 (br.s, 5H), 1.56 (d, J = 7.2Hz , 3H), 1.44 (s, 9H); MS-ESI: m/z 631.20 [M+H] ⁺ .

Step 2: Compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3- Synthesis of methyl hydroxyphenyl)oxazole-4-carbonyl)pyrazine-1-carboxylate

The compound ( S )-4-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl ) Oxazole-4-carbonyl) methylpyrazine-1-carboxylate (567 mg, 0.90 mmol) and nickel chloride (175 mg, 1.35 mmol) were dissolved in tetrahydrofuran (5 mL), and the solution was dropped at 0°C. Add sodium borohydride (459mg, 12.1mmol) in ethanol (20mL) solution, stir at room temperature for 8.5h, add hydrochloric acid (1M) to adjust pH=1, stir until clear, add sodium hydroxide aqueous solution (1M) to adjust pH=14, Extracted with ethyl acetate (25mL×3), combined the organic phase, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: MeOH/EtOAc(v/v)=1/ 20), 442 mg of white solid was obtained, yield: 91%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.61 (d, J =1.6 Hz, 1H), 7.48 (dd, J ₁ =8.4 Hz, J ₂ =1.6 Hz, 1H), 7.18 (d, J =8.4 Hz, 1H), 6.64 (t, J _FH = 73.2Hz, 1H), 5.22-5.26 (m, 1H), 3.95 (br.s, 2H), 3.77 (s, 3H), 3.60 (br.s, 4H ), 1.56 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H); MS-ESI: m/z 541.25 [M+H] ⁺ .

Step 3: Compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-methyl Synthesis of methyloxy-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate

The compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole- 4-Carbonyl)pyrazine-1-carboxylic acid methyl ester (442mg, 0.82mmol), methyl 5-bromovalerate (239mg, 1.23mmol) and potassium carbonate (226mg, 1.64mmol) dissolved in DMF (15mL), 60℃ The tube was sealed and reacted for 4 hours, suction filtered to remove potassium carbonate, the filtrate was concentrated, and the concentrated liquid was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 454 mg of colorless oil , Yield: 85%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.60 (dd, J ₁ =8.4 Hz, J ₂ =1.8 Hz, 1H), 7.56 (d, J =1.8 Hz, 1H), 7.26 (d, J =8.4 Hz,1H),6.64(t, J _FH =75.0Hz,1H),5.23-5.27(m,1H),4.14-4.15(m,2H),3.94-3.99(m,2H),3.76(s,3H ), 3.71(s,3H), 3.60(brs,4H),2.45-2.47(m,2H),1.86-1.95(m,4H),1.56(d, J =7.2Hz,3H),1.43(s, 9H); MS-ESI: m/z 655.25 [M+H] ⁺ .

Step 4: Compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-)(4-(methoxycarbonyl)pyrazine Synthesis of -1-carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid

The compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-methoxy -5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate (150mg, 0.23mmol) and sodium hydroxide (45mg, 1.15mmol) dissolved in water (10mL ) In a mixed solvent of ethanol (20mL), react at 40°C for 1.5h, remove ethanol by rotary evaporation, add hydrochloric acid (1M) to adjust pH=1, extract with ethyl acetate (25mL×3), combine organic phases, anhydrous Na ₂ SO _4. Dry and remove the solvent to obtain 128 mg of light yellow oil. Yield: 87%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.72 (d, J =1.6 Hz, 1H), 7.65 (dd, J ₁ =8.4 Hz, J ₂ =1.8 Hz, 1H), 7.30 (d, J = 8.4Hz, 1H), 6.86(t, J _FH = 74.8Hz, 1H), 5.13-5.17(m, 1H), 4.18-4.21(m, 2H), 3.84(br.s, 2H), 3.74(s, 3H), 3.61 (br.s, 4H), 2.42-2.45 (m, 2H), 1.82-2.01 (m, 4H), 1.55 (d, J = 7.2Hz, 3H), 1.43 (s, 9H); MS -ESI: m/z 641.30[M+H] ⁺ .

Step 5: Compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-? Synthesis of Molinoyl-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)pyrazine-1-carboxylic acid methyl ester

The compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-(4-(methoxycarbonyl)pyrazine-1-carbonyl)oxazole -2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (128mg, 0.20mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloric acid Salt (57mg, 0.30mmol) and N -hydroxy-7-azabenzotriazole (40mg, 0.30mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, morpholine (26mg, 0.30mmol) was added ), N , N -diisopropylethylamine (0.10mL, 0.60mmol) was added dropwise to this solution at 0℃, stirred at room temperature for 10h, washed with water (25mL×3), dichloromethane (25mL× 3) Extraction, combining organic phases, drying the organic phase with anhydrous Na ₂ SO ₄ , removing the solvent, and separating the concentrated solution by column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1), 129 mg of white solid was obtained, yield: 91%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 7.57-7.61(m,2H),7.25(d, J =8.3Hz,1H),6.63(t, J _FH =74.6Hz,1H),5.22-5.27( m,2H),4.16-4.18(m,2H),3.94-3.99(m,3H),3.77(s,3H),3.69-3.83(m,6H),3.61-3.65(m,5H),3.51- 3.52(m,2H),2.46-2.48(m,2H),1.89-1.98(m,4H),1.57(d, J =7.1Hz,3H),1.44(s,9H); MS-ESI: m/ z 710.30[M+H] ⁺ .

Step 6: Compound ( S )-4-(5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl-5-oxo Synthesis of methylpentyl)oxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate hydrochloride

To the compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl -5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate (129 mg, 0.18 mmol) in methylene chloride (2 mL) was added HCl in ethyl acetate The solution (4M, 3mL) was stirred at room temperature for 40min, and the solvent was removed to obtain 110mg of white solid, yield: 94%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.77 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.90 (t, J _FH =74.4Hz, 1H), 5.05-5.08(m, 1H), 4.21-4.23(m, 2H), 3.80(br.s, 2H), 375(s, 3H), 3.59-3.69(m, 14H), 2.53-2.55 (m, 2H), 1.93-1.96 (m, 2H), 1.84-1.89 (m, 2H), 1.78 (d, J = 6.6Hz, 3H); MS-ESI: m/z 610.20 [M+ H-HCl] ⁺ .

Example 152: Compound ( S )-4-(5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl Synthesis of -5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl) -N -cyclopropylpyrazine-1-carboxamide hydrochloride

Step 1: Synthesis of compound 4-(cyclopropylaminomethylamide)pyrazine-1-carboxylic acid tert-butyl ester

Dissolve N , N -carbonyldiimidazole (682mg, 4.20mmol) and triethylamine (1.22mL, 8.76mmol) in anhydrous N , N -dimethylformamide (5mL), add dropwise to this solution A solution of propylmethylamine (200mg, 3.50mmol) in N , N -dimethylformamide (5mL), stirred at room temperature for 30 minutes, and then added 1-Boc-pyrazine (0.651g, 3.50mmol) N , N -A solution of dimethylformamide (5mL), stirred at 60°C for 1 hour, remove the solvent, add water (25mL), extract with ethyl acetate (25mL×3), combine the organic phases, and dry the organic phase with anhydrous Na ₂ SO ₄ After removing the solvent, the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 674 mg of white solid in a yield of 71%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 3.40-3.41 (m, 4H), 3.35-3.37 (m, 4H), 2.53-2.58 (m, 1H), 1.48 (s, 9H), 0.65-0.70 (m, 2H), 0.45-0.49 (m, 2H); MS-ESI: m/z 214.15 [M-55] ⁺ .

Step 2: Synthesis of compound N -cyclopropylpyrazine-1-carboxamide hydrochloride

To a solution of the compound 4-(cyclopropylaminocarboxamide)pyrazine-1-carboxylic acid tert-butyl ester (947 mg, 2.50 mmol) in dichloromethane (4 mL) was added a solution of HCl in ethyl acetate (4M, 6 mL) After stirring at room temperature for 40 min, the solvent was removed to obtain 516 mg of white solid. Yield: 100%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 3.64 (t, J = 7.8Hz, 4H), 3.21 (t, J = 7.8Hz, 4H), 2.55-2.59 (m, 1H), 0.68-0.72 ( m, 2H), 0.47-0.51 (m, 2H); MS-ESI: m/z 170.20 [M+H-HCl] ⁺ .

Step 3: Compound ( S )-(1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-(4-(cyclopropylamino Synthesis of Tert-Butyl Methyl) Pyrazin-1-carbonyl) Oxazol-5-yl) Ethyl) Carbamate

Compound ( S )-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole -4-carboxylic acid (250 mg, 0.496 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (142 mg, 0.743 mmol) and N -hydroxy-7-azabenzene Pyrogallazole (101 mg, 0.743 mmol) was dissolved in dichloromethane (20 mL), stirred at room temperature for 30 min, and N -cyclopropylpyrazine-1-carboxamide hydrochloride (122 mg, 0.595 mmol) was added at N , N -diisopropylethylamine (0.35mL, 1.98mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 10h, washed with water (25mL×3), and extracted with dichloromethane (25mL×3) , The organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/3) to obtain 282 mg of colorless Oily substance, yield: 89%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.66(d, J =1.6Hz,1H),7.61(dd, J ₁ =8.4Hz, J ₂ =1.6Hz,1H),7.36-7.51(m,5H ), 7.28 (d, J = 8.4Hz, 1H), 6.66 (t, J _FH = 74.8Hz, 1H), 5.21-5.32 (m, 1H), 5.25 (s, 2H), 3.77-4.01 (m, 4H ), 3.49-3.51 (m, 4H), 2.70-2.72 (m, 1H), 1.56 (d, J = 7.2Hz, 3H), 1.44 (s, 9H), 0.76-0.80 (m, 2H), 0.50- 0.53 (m, 2H); MS-ESI: m/z 656.30 [M+H] ⁺ .

Step 4: Compound ( S )-(1-(4-(4-(Cyclopropylaminomethylcarbonyl)pyrazine-1-carbonyl)-2-(4-(difluoromethyl Oxy)-3-hydroxyphenyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester

The compound ( S )-(1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-(4-(cyclopropylaminomethylamide)) Azine-1-carbonyl)oxazol-5-yl)ethyl)tert-butylaminocarbamate (200mg, 0.305mmol) and nickel chloride (79mg, 0.610mmol) dissolved in ethanol (5mL) at 0°C To this solution was added dropwise a solution of sodium borohydride (116mg, 3.05mmol) in ethanol (20mL), stirred at room temperature for 6h, added hydrochloric acid (1M) to adjust pH=1, stirred until clear, and added sodium hydroxide solution (1M) Adjust pH=14, extract with ethyl acetate (25mL×3), combine the organic phases, dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrated solution by column chromatography (eluent: methanol/ethyl acetate ( v/v)=1/20), 157 mg of white solid was obtained, yield: 91%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.59 (d, J =2.0 Hz, 1H), 7.52 (dd, J ₁ =8.4 Hz, J ₂ =2.0 Hz, 1H), 7.25 (d, J = 8.4Hz, 1H), 6.89(t, J _FH = 74.6Hz, 1H), 5.11-5.14(m, 1H), 3.51-3.81(m, 8H), 2.56-2.59(m, 1H), 1.55(d, J = 7.2 Hz, 3H), 1.42 (s, 9H), 0.67-0.70 (m, 2H), 0.47-0.51 (m, 2H); MS-ESI: m/z 566.20 [M+H] ⁺ .

Step 5: Compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-4-(4-(cyclopropylaminomethyl Synthesis of Acetyl)Pyrazin-1-carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valeric acid methyl ester

The compound ( S )-(1-(4-(4-(cyclopropylaminomethylcarbonyl)pyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-hydroxybenzene (Yl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (157 mg, 0.278 mmol), methyl 5-bromovalerate (81 mg, 0.416 mmol) and potassium carbonate (76 mg, 0.555 mmol) dissolved in DMF (15mL), sealed tube at 60℃ for 4 hours, suction filtered to remove potassium carbonate, concentrated the filtrate, and the concentrated liquid was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) , 130 mg of colorless oil was obtained, yield: 69%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.56-7.60 (m, 2H), 7.25 (d, J = 8.4 Hz, 1H), 6.64 (t, J _FH = 74.8 Hz, 1H), 5.23-5.27 ( m,1H),4.13-4.16(m,2H),3.73-3.98(m,4H),3.69(s,3H),3.49(br.s,4H),2.68-2.70(m,1H),2.44- 2.48 (m, 2H), 1.87-1.95 (m, 4H), 1.56 (d, J = 6.8Hz, 3H), 1.44 (s, 9H), 0.75-0.79 (m, 2H), 0.49-0.52 (m, 2H); MS-ESI: m/z 680.35 [M+H] ⁺ .

Step 6: Compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-4-(4-(cyclopropylaminomethyl Synthesis of Acyl)Pyrazin-1-carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid

The compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-)(4-(cyclopropylaminomethylamide)pyrazine-1 -Carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valeric acid methyl ester (130mg, 0.191mmol) and sodium hydroxide (38mg, 0.956mmol) dissolved in water (10mL) In a mixed solvent with ethanol (20mL), react at 60°C for 1.5h, remove ethanol by rotary evaporation, add hydrochloric acid (1M) to adjust pH=1, extract with ethyl acetate (25mL×3), combine organic phases, anhydrous Na ₂ SO ₄ Dry and remove the solvent to obtain 123 mg of light yellow oil. Yield: 97%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.66-7.84(m,2H),7.25(d, 1H),6.63(t, J _FH =74.8Hz,1H),5.32-5.37(m,1H), 4.22-4.28(m, 2H), 3.49-1.99(m, 8H), 2.69-2.71(m, 1H), 2.49-2.51(m, 2H), 1.76-1.85(m, 4H), 1.57(d, J =6.8Hz, 3H), 1.45(s, 9H), 0.75-0.80(m, 2H), 0.50-0.53(m, 2H).

Step 7: Compound ( S )-(1-(4-(4-(Cyclopropylaminomethylamide)pyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3- Synthesis of ((5-morpholinyl-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-)(4-(cyclopropylaminomethylamide)pyrazine-1 -Carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valeric acid (123 mg, 0.185 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimine hydrochloride (55mg, 0.277mmol) and N -hydroxy-7-azabenzotriazole (39mg, 0.277mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, and morpholine was added (25mg, 0.277mmol), N , N -diisopropylethylamine (0.10mL, 0.554mmol) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, washed with water (25mL × 3), two Chloromethane (25mL×3) was extracted, the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: methanol/ethyl acetate (v/v)=1 /20), 101 mg of white solid was obtained, yield: 74%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 7.58-7.60(m,2H),7.25(d, J =8.3Hz,1H),6.63(t, J _FH =75.0Hz,1H),5.24-5.27( m,1H),4.15-4.18(m,2H),3.96-4.05(m,3H),3.74-3.86(m,2H),3.64-3.70(m,5H),3.50-3.51(m,5H), 2.60-2.70(m, 1H), 2.46-2.48(m, 2H), 1.89-1.98(m, 4H), 1.57(d, J =7.2Hz, 3H), 1.44(s, 9H), 0.76-0.79( m, 2H), 0.50-0.52 (m, 2H); MS-ESI: m/z 735.30 [M+H] ⁺ .

Step 8: Compound ( S )-4-(5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl-5-oxy Synthesis of pentyl)oxy)phenyl)oxazole-4-carbonyl) -N -cyclopropylpyrazine-1-carboxamide hydrochloride

To the compound ( S )-(1-(4-(4-(cyclopropylaminomethylcarbonyl)pyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-(( 5-Morpholin-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (91 mg, 0.124 mmol) in dichloromethane (2 mL) A solution of HCl in ethyl acetate (4M, 3mL) was added, and the mixture was stirred at room temperature for 40min. The solvent was removed to obtain 82mg of a white solid. Yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.76 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.90 (t, J _FH =74.4Hz, 1H), 5.06-5.07(m, 1H), 4.19-4.23(m, 2H), 3.65-3.77(m, 8H), 3.53-3.59(m, 8H), 2.57-2.60(m, 1H) ), 2.53-2.56 (m, 2H), 1.94-1.95 (m, 2H), 1.85-1.89 (m, 2H), 1.78 (d, J = 6.6Hz, 3H), 0.69-0.72 (m, 2H), 0.49-0.51 (m, 2H); MS-ESI: m/z 635.35 [M+H-HCl] ⁺ .

Example 153: Compound ( S )-4-(5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-(4-methyl Pyrazin-1-yl)-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)pivalzine-1-carboxylic acid methyl ester dihydrochloride synthesis

Step 1: Compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-( Synthesis of methyl 4-methylpyrazin-1-yl)-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)pyrazin-1-carboxylate

The compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-(4-(methoxycarbonyl)pyrazine-1-carbonyl)oxazole -2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (130mg, 0.203mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloric acid Salt (58mg, 0.304mmol) and N -hydroxy-7-azabenzotriazole (41mg, 0.31mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, 1-methylpyrazine ( 26mg, 0.30mmol), N , N -diisopropylethylamine (0.11mL, 0.609mmol) was added dropwise to this solution at 0℃, stirred at room temperature for 10h, washed with water (25mL×3), dichloromethane Methane (25mL×3) was extracted, the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: methanol/ethyl acetate (v/v)=1/ 20), 117 mg of white solid was obtained, yield: 80%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.72 (d, J =2.0 Hz, 1H), 7.65 (dd, J ₁ =8.0 Hz, J ₂ =2.0 Hz, 1H), 7.29 (d, J = 8.0Hz, 1H), 6.87(t, J _FH = 74.8Hz, 1H), 5.13-5.18(m, 1H), 4.19-4.22(m, 2H), 3.84(br.s, 3H), 3.74(m, 3H), 3.59-3.62 (m, 8H), 2.52-2.56 (m, 2H), 2.47-2.50 (m, 2H), 2.42-2.44 (m, 2H), 2.33 (s, 3H), 1.91-1.96 ( m, 2H), 1.83-1.89 (m, 2H), 1.55 (d, J = 7.2 Hz, 3H), 1.43 (s, 9H); MS-ESI: m/z 723.30 [M+H] ⁺ .

Step 2: Compound ( S )-4-(5-(1-Aminoethyl)-2-(4-(difluoromethoxy)-3-((5-(4-methylpyrazine Synthesis of methyl-1-yl)-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)pyrazine-1-carboxylate dihydrochloride

To the compound ( S )-4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-(4- Methylpyrazin-1-yl)-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)methylazine-1-carboxylate (117mg, 0.162mmol) in dichloromethane (2mL ) A solution of HCl in ethyl acetate (4M, 3mL) was added to the solution, stirred at room temperature for 40min, and the solvent was removed to obtain 101mg of a white solid.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.79 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.91 (t, J _FH =74.4Hz, 1H), 5.05-5.08(m, 1H), 4.23-4.25(m, 2H), 4.20(br.s, 2H), 3.79(br.s, 2H), 3.76(s, 3H), 3.46-3.64 (m, 7H), 3.02-3.26 (m, 3H), 2.95 (s, 3H), 2.60-2.62 (m, 2H), 1.95-1.97 (m, 2H), 1.87-1.90 (m, 2H ), 1.79 (d, J = 7.2 Hz, 3H); MS-ESI: m/z 623.20 [M+H-2HCl] ⁺ .

Example 154: Compound ( S )-5-(5-(4-(4-(4-(1-Naphthalenemethyl)pyrazine-1-carbonyl)-5-(1-aminoethyl) Synthesis of oxazol-2-yl)-2-(difluoromethoxy)phenoxy)-1-morpholinylpentane-1-one hydrochloride

Step 1: Compound ( S )-(1-(4-(4-(1-Naphthylmethyl)pyrazine-1-carbonyl)-2-(3-(benzyloxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazol-5-yl)ethyl)aminocarbamic acid tert-butyl ester

Compound ( S )-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole -4-carboxylic acid (300 mg, 0.595 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.170 g, 0.892 mmol) and N -hydroxy-7-aza Benzotriazole (125mg, 0.89mmol) was dissolved in dichloromethane (20mL), stirred at room temperature for 30min, and added naphthalene-1-yl(pentazin-1-yl)methanone hydrochloride (198mg, 0.714mmol) ), N , N -diisopropylethylamine (0.31mL, 1.78mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 10h, washed with water (25mL×3), dichloromethane (25mL) ×3) Extraction, combining organic phases, drying the organic phase with anhydrous Na ₂ SO ₄ , removing the solvent, and separating the concentrated solution by column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) , 378mg white solid was obtained, yield: 88%.

MS-ESI: m/z 727.25 [M+H] ⁺ .

Step 2: Compound ( S )-(1-(4-(4-(1-Naphthylmethyl)pyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-hydroxybenzene Synthesis of tert-Butyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-(1-(4-(4-(1-naphthylmethyl)pyrazine-1-carbonyl)-2-(3-(benzyloxy)-4-(difluoromethoxy )Phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (378mg, 0.52mmol) and nickel chloride (80mg, 0.52mmol) dissolved in ethanol (5mL), at 0 ℃ to To this solution was added dropwise a solution of sodium borohydride (100 mg, 2.60 mmol) in ethanol (20 mL), stirred at room temperature for 19 h, added hydrochloric acid (1M) to adjust the pH=1, stirred until clear, and added sodium hydroxide solution (1M) to adjust the pH =14, ethyl acetate (25mL×3) extraction, the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v /v)=1/1), 209 mg of white solid was obtained, yield: 63%.

MS-ESI: m/z 637.25 [M+H] ⁺ .

Step 3: Compound ( S )-5-(5-(4-(4-(1-Naphthylmethyl)pyrazine-1-carbonyl)-5-(1-((tert-butoxycarbonyl)amino) Synthesis of methyl ethyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valerate

The compound ( S )-(1-(4-(4-(1-naphthylmethyl)pyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl) Oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (209 mg, 0.329 mmol), methyl 5-bromovalerate (80 mg, 0.395 mmol) and potassium carbonate (90 mg, 0.658 mmol) were dissolved in DMF (10 mL ), the tube was sealed at 60°C for 4 hours, suction filtered to remove potassium carbonate, the filtrate was concentrated, and the concentrated liquid was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/2) to obtain 224mg white solid, yield: 91%.

MS-ESI: m/z 751.35 [M+H] ⁺ .

Step 4: Compound ( S )-5-(5-(4-(4-(1-(Naphthalenemethyl)pyrazine-1-carbonyl)-5-(1-((tert-butoxycarbonyl)amino) Synthesis of ethyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid

The compound ( S )-5-(5-(4-(4-(1-(naphthylmethyl)pyrazine-1-carbonyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl ) Oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valeric acid methyl ester (220mg, 0.293mmol) and sodium hydroxide (58mg, 1.47mmol) dissolved in water (10mL) and ethanol (20mL) in a mixed solvent, react at 60°C for 90min, remove ethanol by rotary evaporation, add hydrochloric acid (1M) to adjust pH=1, extract with ethyl acetate (25mL×3), combine organic phases, dry with anhydrous Na ₂ SO ₄ and remove Solvent, to obtain 209mg white solid, yield: 97%.

MS-ESI: m/z 737.25 [M+H] ⁺ .

Step 5: Compound ( S )-(1-(4-(4-(1-Naphthylmethyl)pyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-(( Synthesis of 5-morpholinyl-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(5-(4-(4-(1-(naphthylmethyl)pyrazine-1-carbonyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl )Oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (209mg, 0.284mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Amine hydrochloride (93mg, 0.425mmol) and N -hydroxy-7-azabenzotriazole (61mg, 0.425mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, morpholine (40mg) was added , 0.425mmol), N , N -diisopropylethylamine (0.15mL, 0.851mmol) was added dropwise to this solution at 0℃, stirred at room temperature for 10h, washed with water (25mL×3), dichloromethane (25mL×3) extraction, the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated liquid was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/ 1), 147 mg of white solid was obtained, yield: 64%.

MS-ESI: m/z 806.30 [M+H] ⁺ .

Step 6: Compound ( S )-5-(5-(4-(4-(1-Naphthalenemethyl)pyrazine-1-carbonyl)-5-(1-aminoethyl)oxazole-2- Synthesis)-2-(difluoromethoxy)phenoxy)-1-morpholinylpentane-1-one hydrochloride

To compound ( S )-(1-(4-(4-(1-naphthylmethyl)pyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-((5- To a solution of morpholinyl-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester (147 mg, 0.182 mmol) in dichloromethane (2 mL) was added HCl Ethyl acetate solution (4M, 3mL), stirred at room temperature for 40min, the solvent was removed to obtain 123mg white solid, yield: 91%.

¹ H NMR (400MHz, CDCl ₃ ): δ ppm 7.98-8.01 (m, 2H), 7.88 (d, J = 8.0Hz, 1H), 7.70-7.76 (m, 1H), 7.56-7.65 (m, 4H) , 7.53-7.55(m, 1H), 7.24-7.37(m, 1H), 6.72-7.05(m, 1H), 4.99-5.03(m, 1H), 4.03-4.13(m, 4H), 3.72-3.75( m, 2H), 3.55-3.68 (m, 10H), 3.33-3.44 (m, 2H), 2.48-2.55 (m, 2H), 1.88-1.89 (m, 4H), 1.76 (m, 3H); MS- ESI: m/z 706.30 [M+H-HCl] ⁺ .

Example 155: Compound 1-(5-(( S )-1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl-5- Synthesis of oxopentyl)oxy)phenyl)oxazole-4-carbonyl)pyrazine-2-carboxamide dihydrochloride

Step 1: Compound 4-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(( S )-1-((tert-butoxycarbonyl)amino) Synthesis of tert-butyl ethyl)oxazole-4-carbonyl)-3-aminomethylacetophenazine-1-carboxylate

Compound ( S )-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole -4-carboxylic acid (300 mg, 0.595 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (170 mg, 0.892 mmol) and N -hydroxy-7-azabenzene Pyrogallazole (125mg, 0.892mmol) was dissolved in dichloromethane (20mL), stirred at room temperature for 30min, after adding 1-tert-butoxycarbonyl-3-pyrazinecarboxamide (164mg, 0.714mmol), at 0 To this solution was added N , N -diisopropylethylamine (0.31mL, 1.78mmol) dropwise at ℃, stirred at room temperature for 10h, washed with water (25mL×3), and extracted with dichloromethane (25mL×3). The organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 330 mg of a white solid , Yield: 77%.

MS-ESI: m/z 716.30 [M+H] ⁺ .

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3- Synthesis of tert-butyl hydroxyphenyl)oxazole-4-carbonyl)-3-aminomethylacetophenazine-1-carboxylate

Compound 4-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl ) Oxazole-4-carbonyl)-3-aminomethylacetophenazine-1-carboxylic acid tert-butyl ester (330mg, 0.461mmol) and nickel chloride (60mg, 0.461mmol) were dissolved in ethanol (5mL), in To this solution was added dropwise a solution of sodium borohydride (91mg, 2.31mmol) in ethanol (20mL) at 0°C, stirred at room temperature for 3h, adjusted to pH=1 by adding hydrochloric acid (1M), stirred until clear, and added sodium hydroxide solution (1M) Adjust pH=14, extract with ethyl acetate (25mL×3), combine organic phases, dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrated solution by column chromatography (eluent: petroleum ether/ Ethyl acetate (v/v) = 1/2), to obtain 241 mg of white solid, yield: 84%.

MS-ESI: m/z 626.20 [M+H] ⁺ .

Step 3: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-methyl Synthesis of tert-Butyloxy-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-3-aminomethylcarboxamazine-1-carboxylate

The compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole- 4-Carbonyl)-3-aminocarbamoylpyrazine-1-carboxylic acid tert-butyl ester (241 mg, 0.385 mmol), methyl 5-bromovalerate (90 mg, 0.087 mmol) and potassium carbonate (106 mg, 0.14 mmol) Dissolved in DMF (10mL), sealed tube at 60℃ for 4 hours, suction filtered to remove potassium carbonate, concentrated the filtrate, and the concentrated liquid was separated by column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1 /1), 229 mg of white solid was obtained, yield: 80%.

MS-ESI: m/z 740.20 [M+H] ⁺ .

Step 4: Compound 5-(5-(4-(4-(tert-butoxycarbonyl)-2-aminomethylacetophenazine-1-carbonyl)-5-(( S )-1-((tert-butyl Synthesis of oxycarbonyl)amino)ethyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid

Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-methoxy -5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-3-aminomethylamylpyrazine-1-carboxylic acid tert-butyl ester (229 mg, 0.310 mmol) and sodium hydroxide (60 mg , 1.55mmol) was dissolved in a mixed solvent of water (10mL) and ethanol (20mL), reacted at 60 ℃ for 90min, ethanol was removed by rotary evaporation, hydrochloric acid (1M) was added to adjust pH = 1, ethyl acetate (25mL × 3) extraction, The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed to obtain 214 mg of white solid. Yield: 95%.

MS-ESI: m/z 726.30 [M+H] ⁺ .

Step 5: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-? Synthesis of terolinyl-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-3-aminomethylamylpyrazine-1-carboxylic acid tert-butyl ester

The compound 5-(5-(4-(4-(tert-butoxycarbonyl)-2-aminomethylacetophenazine-1-carbonyl)-5-(( S )-1-((tert-butoxycarbonyl )Amino)ethyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (214 mg, 0.295 mmol), 1-ethyl-3-(3-dimethylamine Propyl)carbodiimide hydrochloride (93mg, 0.442mmol) and N -hydroxy-7-azabenzotriazole (61mg, 0.442mmol) were dissolved in dichloromethane (20mL) and stirred at room temperature for 30min , Add morpholine (40mg, 0.442mmol), add N , N -diisopropylethylamine (18mg, 0.14mmol) dropwise to this solution at 0℃, stir at room temperature for 10h, add water (25mL×3) After washing, extraction with dichloromethane (25mL×3), the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: dichloromethane/methanol (v/v )=10/1), and then separated by preparing a silica gel plate (developing agent: dichloromethane/methanol (v/v)=15/1) to obtain 110 mg of white solid in a yield of 47%.

MS-ESI: m/z 795.20 [M+H] ⁺ .

Step 6: Compound 1-(5-(( S )-1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl-5-oxopentyl Yl)oxy)phenyl)oxazole-4-carbonyl)pyrazine-2-carboxamide dihydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl -5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-3-aminomethyl acetophenazine-1-carboxylic acid tert-butyl ester (110 mg, 0.035 mmol) in dichloromethane (2 mL ) A solution of HCl in ethyl acetate (4M, 3mL) was added to the solution, stirred at room temperature for 40min, and the solvent was removed to obtain 87mg of a white solid, yield: 100%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.70-7.77 (m, 2H), 7.35 (d, J = 8.0 Hz, 1H), 6.91 (t, J _FH = 74.4 Hz, 1H), 5.36-5.40 (m,1H),5.17-5.20(m,1H),4.21-4.23(m,2H),3.78-3.92(m,2H),3.63-3.70(m,4H),3.57-3.60(m,4H) , 3.42-3.47 (m, 4H), 2.53-2.56 (m, 2H), 1.83-1.97 (m, 4H), 1.80-1.83 (m, 3H); MS-ESI: m/z 595.20 [M+H- HCl] ⁺ .

Example 156: Compound 4-(5-(( S )-1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl-5- Synthesis of methyl oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-3-aminomethylcarboxamazine-1-carboxylate hydrochloride

Step 1: Compound 4-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(( S )-1-((tert-butoxycarbonyl)amino) Synthesis of Methyl Ethyl)oxazole-4-carbonyl)-3-aminomethylacetophenazine-1-carboxylate

Compound ( S )-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole -4-carboxylic acid (300 mg, 0.595 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (171 mg, 0.892 mmol) and N -hydroxy-7-azabenzene Pyrogallazole (121g, 0.892mmol) was dissolved in dichloromethane (20mL), stirred at room temperature for 30min, after adding methyl 1-carboxylate-3-pyrazinecarboxamide (191mg, 0.892mmol), at 0 ℃ N , N -diisopropylethylamine (308mg, 2.38mmol) was added dropwise to the solution under conditions, stirred at room temperature for 10h, washed with water (25mL×3), extracted with dichloromethane (25mL×3), combined organic Phase, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 161 mg of a white solid. Rate: 40%.

MS-ESI: m/z 674.30 [M+H] ⁺ .

Step 2: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)ox Synthesis of Methyl-4-oxo)-3-aminomethylacetophenazine-1-carboxylate

Compound 4-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl ) Oxazole-4-carbonyl)-3-aminomethyl acetophenazine-1-carboxylic acid methyl ester (161mg, 0.239mmol) and nickel chloride (31mg, 0.239mmol) were dissolved in ethanol (5mL) in 0 To this solution was added dropwise a solution of sodium borohydride (0.045g, 1.19mmol) in ethanol (20mL) at room temperature, stirred at room temperature for 3h, added hydrochloric acid (1M) to adjust pH=1, stirred until clear, and added sodium hydroxide solution (1M) Adjust pH=14, extract with ethyl acetate (25mL×3), combine organic phases, dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrated solution by column chromatography (eluent: petroleum ether/ Ethyl acetate (v/v) = 1/2) to obtain 128 mg of white solid, yield: 92%.

MS-ESI: m/z 584.20 [M+H] ⁺ .

Step 3: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-methyl Synthesis of Methyl Oxo-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-3-aminomethylcarbamoylazine-1-carboxylate

The compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole- 4-Carbonyl)-3-aminomethylacetophenazine-1-carboxylic acid methyl ester (128mg, 0.219mmol), methyl 5-bromovalerate (51mg, 0.263mmol) and potassium carbonate (60mg, 0.439mmol) were dissolved Seal the tube with DMF (10mL) at 60℃ for 4 hours, filter with suction, remove the potassium carbonate, concentrate the filtrate, and concentrate the liquid for column separation (eluent: petroleum ether/ethyl acetate (v/v)=1/1) , 61 mg of white solid was obtained, yield: 40%.

MS-ESI: m/z 698.25 [M+H] ⁺ .

Step 4: Compound 5-(5-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-4-(2-aminomethylamide-4-(methoxycarbonyl ) Synthesis of pyrazin-1-carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid

Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-methoxy -5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-3-aminomethylcarbamoylazine-1-carboxylic acid methyl ester (61 mg, 0.087 mmol) and lithium hydroxide monohydrate (18mg, 0.44mmol) was dissolved in a mixed solvent of water (10mL) and tetrahydrofuran (20mL), reacted at 40℃ for 90min, added hydrochloric acid (1M) to adjust pH=1, extracted with ethyl acetate (25mL×3), and combined organic phases , Dried over anhydrous Na ₂ SO ₄ , the solvent was removed to obtain 56 mg of white solid, yield: 94%.

MS-ESI: m/z 684.25 [M+H] ⁺ .

Step 5: Compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-? Synthesis of Molinoyl-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-3-aminomethylcarboxamazine-1-carboxylate

The compound 5-(5-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-4-)(2-aminomethylamino-4-(methoxycarbonyl)) Azine-1-carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (56mg, 0.082mmol), 1-ethyl-3-(3-dimethylaminopropyl Group) carbodiimide hydrochloride (24mg, 0.12mmol) and N -hydroxy-7-azabenzotriazole (17mg, 0.12mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min , Add morpholine (20mg, 0.12mmol), add N , N -diisopropylethylamine (32mg, 0.25mmol) dropwise to this solution at 0℃, stir at room temperature for 10h, add water (25mL×3) After washing, extraction with dichloromethane (25mL×3), the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: dichloromethane/methanol (v/v )=10/1), and then separated by preparing a silica gel plate (developing agent: dichloromethane/methanol (v/v)=20/1) to obtain 35 mg of white solid in a yield of 57%.

MS-ESI: m/z 753.30 [M+H] ⁺ .

Step 6: Compound 4-(5-(( S )-1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl-5-oxopentyl Of methyl)oxy)phenyl)oxazole-4-carbonyl)-3-aminomethylcarboxamethylene-1-carboxylate hydrochloride

To compound 4-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl -5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-3-aminomethylcarboxamidoazine-1-carboxylic acid methyl ester (35mg, 0.046mmol) in dichloromethane (2mL) A solution of HCl in ethyl acetate (4M, 3mL) was added to the solution, stirred at room temperature for 40min, the solvent was removed, and dried to obtain 21mg of a white solid, yield: 66%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.78 (s, 1H), 7.68-7.74 (m, 1H), 7.32-7.36 (m, 1H), 6.89 (t, J _FH = 74.4 Hz, 1H) , 5.05-5.12 (m, 2H), 4.56-4.59 (m, 1H), 4.48-4.51 (m, 0.5H), 4.28-4.38 (m, 0.5H), 4.19-4.23 (m, 2H), 3.95 4.05(m, 2H), 3.74(s, 2H), 3.65-3.69(m, 4H), 3.54-3.59(m, 6H), 2.53-2.56(m, 2H), 1.93-1.96(m, 2H), 1.84-1.87 (m, 2H), 1.74-1.80 (m, 3H); MS-ESI: m/z 653.30 [M+H-HCl] ⁺ .

Example 157: Compound ( S )-4-(5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl Synthesis of -5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)pyrazine-1-carboxamide hydrochloride

Step 1: Compound ( S )-(1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-(4-aminomethylamylpyrazine-1 -Synthesis of carbonyl)oxazol-5-yl)ethyl)aminocarbamate

Compound ( S )-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole -4-carboxylic acid (300 mg, 0.595 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (171 mg, 0.892 mmol) and N -hydroxy-7-azabenzene Pyrogallazole (121mg, 0.892mmol) was dissolved in dichloromethane (20mL), stirred at room temperature for 30min, after adding 1-oxazine methanamide hydrochloride (200mg, 0.892mmol), at 0 N , N -diisopropylethylamine (1.5mL, 9.52mmol) was added dropwise to this solution, stirred at room temperature for 10h, washed with water (25mL×3), extracted with dichloromethane (25mL×3), and the organic phases were combined, The organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 176 mg of white solid in a yield of: 48%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.66(d, J =2.0Hz,1H),7.61(d, J ₁ =8.4Hz, J ₂ =2.0Hz,1H),7.36-7.50(m,5H ), 7.29 (d, J = 8.4Hz, 1H), 6.66 (t, J _FH = 74.4Hz, 1H), 5.25-5.28 (m, 1H), 5.25 (s, 2H), 4.56 (s, 2H), 3.83-4.00 (m, 4H), 3.53-3.55 (m, 4H), 1.57 (d, J = 6.8Hz, 3H), 1.44 (s, 9H); MS-ESI: m/z 616.30 [M+H] ⁺ .

Step 2: Compound ( S )-(1-(4-(4-Aminomethylpyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3- Synthesis of tert-butyl hydroxyphenyl)oxazol-5-yl)ethyl)aminocarbamate

The compound ( S )-(1-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4-(4-aminomethylpyrazine-1-carbonyl ) Oxazol-5-yl) ethyl) aminocarboxylic acid tert-butyl ester (176mg, 0.286mmol) and nickel chloride (40mg, 0.286mmol) were dissolved in ethanol (5mL), to this solution at 0 ℃ Add dropwise a solution of sodium borohydride (60mg, 1.43mmol) in ethanol (20mL), stir at room temperature for 3h, add hydrochloric acid (1M) to adjust the pH=1, stir until clear, add sodium hydroxide solution (1M) to adjust the pH=14, Extraction with ethyl acetate (25mL×3), the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated liquid was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) to obtain 128 mg of white solid in a yield of 85%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.62 (d, J =1.6 Hz, 1H), 7.48 (dd, J ₁ =8.7 Hz, J ₂ =1.2 Hz, 1H), 7.19 (d, J =8.4 Hz, 1H), 6.66 (t, J _FH = 73.5Hz, 1H), 5.21-5.28 (m, 1H), 4.90 (s, 2H), 3.82-4.02 (m, 4H), 3.53-3.59 (m, 4H ), 1.56 (d, J = 6.8 Hz, 3H), 1.44 (s, 9H); MS-ESI: m/z 526.20 [M+H] ⁺ .

Step 3: Compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-4-(4-aminomethylacetamide Synthesis of Methylazine-1-carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valerate

The compound ( S )-(1-(4-(4-aminomethylacetophenazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole- 5-yl)ethyl)tert-butyl carbamate (128 mg, 0.219 mmol), methyl 5-bromovalerate (51 mg, 0.263 mmol) and potassium carbonate (60 mg, 0.439 mmol) dissolved in DMF (10 mL), 60 The tube was sealed at ℃ for 4 hours, suction filtered to remove potassium carbonate, the filtrate was concentrated, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 61 mg of white solid , Yield: 40%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.00 (s, 1H), 7.71 (d, J =2.0 Hz, 1H), 7.65 (dd, J ₁ =8.4 Hz, J ₂ =2.0 Hz, 1H) ,7.30(d, J =8.4Hz,1H),6.86(t, J _FH =74.4Hz,1H),5.11-5.19(m,1H),4.18(t, J =5.8Hz,2H),3.81-3.88 (m,2H),3.68(s,3H),3.56-3.59(m,4H),2.47(t, J =7.0Hz,2H),1.86-1.93(m,4H),1.56(d, J =7.2 Hz, 3H), 1.43 (s, 9H); MS-ESI: m/z 640.30 [M+H] ⁺ .

Step 4: Compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-4-(4-aminomethylamide Synthesis of azine-1-carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid

The compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-)(4-aminomethylpyrazine-1-carbonyl)oxazole -2-yl)-2-(difluoromethoxy)phenoxy)valeric acid methyl ester (61mg, 0.087mmol) and lithium hydroxide monohydrate (18mg, 0.44mmol) dissolved in water (10mL) and tetrahydrofuran In a mixed solvent of (20mL), react at 40°C for 90min, add hydrochloric acid (1M) to adjust the pH to 1, extract with ethyl acetate (25mL×3), combine the organic phases, dry with anhydrous Na ₂ SO ₄ and remove the solvent to obtain 56mg White solid, yield: 94%.

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.72 (d, J = 1.7 Hz, 1H), 7.65 (dd, J ₁ = 8.4 Hz, J ₂ = 1.7 Hz, 1 H), 7.30 (d, J = 8.3Hz, 1H), 6.86 (t, J _FH = 74.4Hz, 1H), 5.15-5.17 (m, 1H), 4.19 (t, J = 5.8Hz, 2H), 3.85 (br.s, 4H), 3.56 -3.59(m,4H),2.43(t, J =6.9Hz,2H),1.83-1.95(m,4H),1.56(d, J =7.2Hz,3H),1.43(s,9H); MS- ESI: m/z 626.30 [M+H] ⁺ .

Step 5: Compound ( S )-(1-(4-(4-Aminomethylpyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-((5- Synthesis of terolinyl-5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)aminocarboxylic acid tert-butyl ester

The compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-)(4-aminomethylpyrazine-1-carbonyl)oxazole -2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (56mg, 0.082mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric acid Salt (24mg, 0.12mmol) and N -hydroxy-7-azabenzotriazole (17mg, 0.12mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, added morpholine (20g, 0.12mmol) ), N , N -diisopropylethylamine (32mg, 0.25mmol) was added dropwise to this solution at 0℃, stirred at room temperature for 10h, washed with water (25mL×3), dichloromethane (25mL×3) ) Extraction, the organic phases are combined, the organic phases are dried over anhydrous Na ₂ SO ₄ , the solvent is removed, the concentrated liquid is subjected to column chromatography (eluent: dichloromethane/methanol (v/v)=10/1), and then Prepare a silica gel plate for separation (developing agent: dichloromethane/methanol (v/v)=20/1) to obtain 35 mg of white solid in a yield of 57%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.58-7.60 (m, 2H), 7.25 (d, J = 8.4 Hz, 1H), 6.63 (t, J _FH = 74.4 Hz, 1H), 5.23-5.28 ( m,1H),4.6(s,2H),4.18(t, J =6.0Hz,2H),4.01-4.06(m,2H),3.79-3.85(m,2H),3.69-3.72(m,4H) ,3.63-3.65(m,2H),3.52-3.58(m,4H),3.50-3.52(m,2H),2.47(t, J =7.3Hz,2H),1.90-1.97(m,4H),1.57 (d, J = 7.2 Hz, 3H), 1.44 (s, 9H); MS-ESI: m/z 695.35 [M+H] ⁺ .

Step 6: Compound ( S )-4-(5-(1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl-5-oxo Synthesis of pentyl)oxy)phenyl)oxazole-4-carbonyl)pyrazine-1-carboxamide hydrochloride

To the compound ( S )-(1-(4-(4-Aminomethylpyrazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-((5-morpholinyl -5-oxopentyl)oxy)phenyl)oxazol-5-yl)ethyl)tert-butyl carbamate (78 mg, 0.11 mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate The ester solution (4M, 3mL) was stirred at room temperature for 40min, the solvent was removed, slurried with ethyl acetate/petroleum ether (v/v=1/20), and dried to obtain 69mg of white solid, yield: 97%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.78 (d, J =1.2 Hz, 1H), 7.73 (dd, J ₁ =8.4 Hz, J ₂ =1.2 Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 6.90 (t, J _FH = 74.4Hz, 1H), 5.06-5.10 (m, 1H), 4.26 (br.s, 2H), 4.23 (t, J = 5.8Hz, 2H), 3.83 (br.s, 2H), 3.64-3.70 (m, 8H), 3.58-3.60 (m, 4H), 2.55 (t, J = 7.4Hz, 2H), 1.93-1.97 (m, 2H), 1.84-1.89 (m, 2H), 1.80 (d, J = 7.2 Hz, 3H); MS-ESI: m/z 595.30 [M+H-HCl] ⁺ .

Example 158: Compound 4-(5-(( S )-1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-(4-(methoxy Carbonyl)pyrazin-1-yl)-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl Synthesis of ester hydrochloride

Step 1: Compound 4-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-((S)-1-((tert-butoxycarbonyl)amino) Synthesis of methyl ethyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylate

Compound (S)-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)oxazole -4-carboxylic acid (300 mg, 0.595 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (171 mg, 0.892 mmol) and N-hydroxy-7-azabenzene Pyrogallazole (121mg, 0.892mmol) was dissolved in dichloromethane (20mL), stirred at room temperature for 30min, after adding 1-methoxycarbonyl-2-methylpyrazine hydrochloride (217mg, 0.595mmol), To this solution was added N,N-diisopropylethylamine (0.85mL, 4.76mmol) dropwise at 0°C, stirred at room temperature for 10h, washed with water (25mL×3), and extracted with dichloromethane (25mL×3) , The organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 383 mg of white Solid, yield: 99%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.60-7.66 (m, 2H), 7.36-7.50 (m, 5H), 7.28 (d, J=8.4 Hz, 1H), 6.66 (t, J _FH = 74.8 Hz, 1H), 5.28-5.32(m, 1H), 5.25(s, 2H), 4.39-4.67(m, 3H), 3.95-4.12(m, 1H), 3.77(s, 3H), 3.31-3.30( m, 2H), 2.88-2.98(m, 1H), 1.57(d, J=7.2Hz, 3H), 1.44(s, 9H), 1.26(d, J=6.8Hz, 3H); MS-ESI: m /z 645.10[M+H] ⁺ .

Step 2: Compound 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)ox Of oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester

Compound 4-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-((S)-1-((tert-butoxycarbonyl)amino)ethyl ) Oxazol-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester (383mg, 0.594mmol) and nickel chloride (77mg, 0.594mmol) were dissolved in ethanol (5mL) at 0°C To this solution was added dropwise a solution of sodium borohydride (113mg, 2.97mmol) in ethanol (20mL), stirred at room temperature for 2h, added hydrochloric acid (1M) to adjust pH=1, stirred until clear, and adjusted with sodium hydroxide solution (1M) pH=14, ethyl acetate (25mL×3) extraction, the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate ( v/v)=1/1), 308 mg of white solid was obtained, yield: 94%.

¹ H NMR(600MHz,CDCl ₃ ): δ ppm 7.63-7.65(m,1H),7.51-7.54(m,1H),7.20-7.22(m,1H),6.64(t,J _FH =73.2Hz,1H ), 5.24-5.32 (m, 1H), 4.69-4.73 (m, 1H), 4.48-4.60 (m, 2H), 3.98-4.03 (m, 1H), 3.76 (s, 3H), 3.24-3.26 (m , 2H), 2.92-3.07 (m, 1H), 1.56 (m, 3H), 1.44 (s, 9H), 1.26-1.28 (m, 3H); MS-ESI: m/z 555.30 [M+H] ⁺ .

Step 3: Compound 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5- Synthesis of methyl methoxy-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylate

The compound 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole- 4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester (308mg, 0.555mmol), methyl 5-bromovalerate (130mg, 0.667mmol) and potassium carbonate (154mg, 1.11mmol) were dissolved in DMF ( 10mL), sealed tube at 60℃ for 4 hours, suction filtered to remove potassium carbonate, concentrated the filtrate, and the concentrated liquid was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1), 326 mg of white solid was obtained, yield: 88%.

MS-ESI: m/z 669.30 [M+H] ⁺ .

Step 4: Compound 5-(5-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-4-(4-(methoxycarbonyl)-3-methylpyrazine Synthesis of -1-carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid

Compound 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-methoxy -5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester (326 mg, 0.488 mmol) and lithium hydroxide monohydrate (102 mg, 2.44mmol) dissolved in a mixed solvent of water (10mL) and tetrahydrofuran (20mL), react at 40°C for 1h, add hydrochloric acid (1M) to adjust the pH to 1, extract with ethyl acetate (25mL×3), combine organic phases, anhydrous Na ₂ SO _{4 was} dried and the solvent was removed to obtain 313 mg of white solid. Yield: 98%.

MS-ESI: m/z 655.30 [M+H] ⁺ .

Step 5: Compound 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-( Synthesis of 4-(methoxycarbonyl)pyrazin-1-yl)-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester

Compound 5-(5-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-4-)(4-(methoxycarbonyl)-3-methylpyrazine-1 -Carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)valeric acid (157 mg, 0.240 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimine hydrochloride (71mg, 0.360mmol) and N-hydroxy-7-azabenzotriazole (49mg, 0.360mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, added 1- Methoxycarbonylpyrazine hydrochloride (65mg, 0.360mmol), N,N-diisopropylethylamine (0.17mL, 0.595mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 10h, and water was added (25mL×3) washed, extracted with dichloromethane (25mL×3), combined the organic phases, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, the concentrated liquid was subjected to column chromatography (eluent: petroleum ether/acetic acid) Ethyl ester (v/v)=1/1) to obtain 171 mg of white solid, yield: 91%.

MS-ESI: m/z 781.20 [M+H] ⁺ .

Step 6: Compound 4-(5-((S)-1-aminoethyl)-2-(4-(difluoromethoxy)-3-((5-(4-(methoxycarbonyl)qua Synthesis of oxazin-1-yl)-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester hydrochloride

To compound 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-(4- (Methoxycarbonyl)pyrazin-1-yl)-5-oxopentyl)oxy)phenyl)oxazole-4-carbonyl)-2-methylpyrazine-1-carboxylic acid methyl ester (165 mg, 0.211 A solution of mmol) in dichloromethane (2 mL) was added HCl in ethyl acetate (4M, 3 mL), stirred at room temperature for 40 min, the solvent was removed, and dried to obtain 133 mg of a white solid, yield: 88%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.78-7.79 (m, 1H), 7.71-7.74 (m, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.91 (t, J _FH = 74.4Hz, 1H), 5.05-5.12 (m, 1H), 4.96-5.03 (m, 1H), 4.42-4.53 (m, 2H), 4.23 (m, 2H), 4.03-4.05 (m, 1H), 3.75 (s,3H),3.73(s,3H),3.57-3.61(m,4H),3.53-3.46(m,4H),3.26-3.38(m,2H),3.00-3.17(m,1H),2.56 (t, J=7.3Hz, 2H), 1.93-1.96(m, 2H), 1.84-1.89(m, 2H), 1.80(d, J=6.6Hz, 3H), 1.23-1.32(m, 3H); MS-ESI: m/z 681.20 [M+H-HCl] ⁺ .

Example 159: Compound (2R, 4S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid methyl Synthesis of ester hydrochloride

Step 1: Synthesis of compound (2 R ,4 R )-2-methoxycarbonyl-4-p-toluenesulfonylpyrrolidine-1-carboxylic acid tert-butyl ester

The compound (2 R ,4 R )-1-tert-butoxycarbonyl-4-hydroxyproline methyl ester (1.0 g, 4.08 mmol), 4-dimethylaminopyridine (50 mg, 0.408 mmol) and triethylamine (1.42mL, 10.2mmol) was dissolved in dichloromethane (20mL), p-toluenesulfonyl chloride (1.17g, 6.12mmol) in dichloromethane (10mL) was slowly added dropwise, stirred at room temperature for 15h, and saturated chlorination was added Sodium solution (20mL×3), dichloromethane (20mL×3) was extracted, the organic phase was dried over Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v /v)=3/1), 1.39 g of yellow oil was obtained, yield: 85%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.76-7.79 (m, 2H), 7.35-7.37 (m, 2H), 5.03-5.08 (m, 1H), 4.33-4.45 (m, 1H), 3.69- 3.70(m,3H),3.57-3.67(m,2H),2.46(s,3H),2.36-2.43(m,2H),1.41-1.45(m,9H); MS-ESI: m/z 300.00[ M+H-100] ⁺ .

Step 2: Synthesis of compound (2 R ,4 S )-2-methoxycarbonyl-4-azidopyrrolidine-1-carboxylic acid tert-butyl ester

Compound (2 R , 4 R )-2-methoxycarbonyl-4-p-toluenesulfonylpyrrolidine-1-carboxylic acid tert-butyl ester (1.37 g, 3.43 mmol) and sodium azide (1.15 g , 17.1mmol) was dissolved in N , N -dimethylformamide (10mL), stirred at 80 ℃ for 5h, added water (30mL), ethyl acetate (20mL × 3) extraction, the organic phase was dried over anhydrous Na ₂ SO ₄ After removing the solvent, the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=2/1) to obtain 803 mg of a white solid in a yield of 87%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.32-4.44 (m, 1H), 4.18-4.22 (m, 1H), 3.75 (m, 3H), 3.69-3.73 (m, 1H), 3.46-3.61 ( m, 1H), 2.28-2.38 (m, 1H), 2.18-2.21 (m, 1H), 1.42-1.47 (m, 9H); MS-ESI: m/z 171.25 [M+H-100] ⁺ .

Step 3: Synthesis of compound (2 R ,4 S )-2-methoxycarbonyl-4-aminopyrrolidine-1-carboxylic acid tert-butyl ester

Compound (2 R ,4 S )-2-methoxycarbonyl-4-azidopyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.390 mmol) and Pd/C (150 mg, 0.390 mmol) were added to methanol ( 150mg, 0.390mmol), filled with hydrogen, ventilated twice, stirred at room temperature for 15h, and removed the solvent to obtain 643mg gray oil, yield: 89%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.38-4.41 (m, 1H), 3.74-3.75 (m, 3H), 3.64-3.69 (m, 1H), 3.58-3.61 (m, 1H), 3.16 -3.21 (m, 1H), 2.08-2.13 (m, 2H), 1.42-1.48 (m, 9H); MS-ESI: m/z 145.20 [M+H-100] ⁺ .

Step 4: Compound (2 R ,4 S )-2-methoxycarbonyl-4-methoxycarbonylaminopyrrolidine-1-carboxylic acid tert-butyl ester Synthesis

The compound (2 R ,4 S )-2-methoxycarbonyl-4-aminopyrrolidine-1-carboxylic acid tert-butyl ester (112 mg, 0.212 mmol), N , N′ -carbonyldiimidazole (52 mg, 0.318 mmol) And triethylamine (0.15mL, 0.848mmol) were dissolved in anhydrous DMF (10mL), stirred at 40 °C for 0.5 hours, added anhydrous methanol (10mL), stirred at 60 °C for 6 hours, the solvent was removed, the concentrated solution was subjected to column chromatography Separated (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 245 mg of colorless oil, yield: 66%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.84-4.88 (m, 1H), 4.29-4.33 (m, 1H), 3.78-3.83 (m, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.29-3.40 (m, 1H), 2.23-2.26 (m, 2H), 1.43-1.47 (m, 9H); MS-ESI: m/z 203.20 [M+H-100] ⁺ .

Step 5: Synthesis of compound (2 R ,4 S )-2-methoxycarbonyl-4-methoxycarbonylaminopyrrolidine hydrochloride

To a solution of compound (2 R ,4 S )-2-methoxycarbonyl-4-methoxycarbonylaminopyrrolidine-1-carboxylic acid tert-butyl ester (245 mg, 0.810 mmol) in dichloromethane (2 mL) was added HCl Ethyl acetate solution (4M, 4mL), stirred at room temperature for 1h, the solvent was removed to obtain 189mg white solid, yield: 98%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.65-4.68 (m, 1H), 4.31-4.33 (m, 1H), 3.89 (s, 3H), 3.68 (s, 3H), 3.64-3.67 (m , 1H), 3.39-3.42 (m, 1H), 2.44-2.46 (m, 2H); MS-ESI: m/z 203.10 [M+H-HCl] ⁺ .

Step 6: Compound (2 R ,4 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethyl Oxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid Synthesis of methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (300 mg, 0.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (180 mg, 0.96 mmol) and N -hydroxy-7 -Azabenzotriazole (130mg, 0.96mmol) was added to dichloromethane (20mL), stirred at room temperature for 30min, compound ( 2R , 4S )-2-methoxycarbonyl-4-methoxycarbonylamine was added Pyrrolidine hydrochloride (140mg, 0.64mmol), N , N -diisopropylethylamine (0.45mL, 2.60mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 10h, and water (25mL) was added ×3) Washing, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 198 mg of white Solid, yield: 47%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.52-7.61 (m, 2H), 7.23-7.28 (m, 1H), 6.72 (t, J _FH = 75.2 Hz, 1H), 5.23-5.32 (m, 1H ), 4.32-4.44 (m, 2H), 3.99-4.01 (m, 2H), 3.68-3.80 (m, 8H), 2.21-2.46 (m, 2H), 1.54-1.57 (m, 3H), 1.42-1.45 (m, 9H), 1.34-1.35 (m, 1H), 0.68-0.73 (m, 2H), 0.42-0.45 (m, 2H); MS-ESI: m/z 653.15 [M+H] ⁺ .

Step 7: Compound (2 R ,4 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

To compound (2 R ,4 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid methyl ester (198 mg, 0.303 mmol) in methylene chloride ( 2mL) solution was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 1h, the solvent was removed to obtain 157mg white solid, yield: 94%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.64-7.77 (m, 2H), 7.33 (d, J = 8.4Hz, 1H), 6.93 (t, J _FH = 75.0Hz, 1H), 5.18-5.21 (m,1H),4.35-4.43(m,1H),4.24-4.31(m,1H),4.05-4.07(m,2H),3.96-4.00(m,1H),3.79(s,1H),3.73 (s,2H), 3.69-3.73(m,1H),3.66-3.67(m,3H),2.45-2.47(m,1H),2.24-2.36(m,1H),1.33-1.36(m,3H) , 1.30-1.31 (m, 1H), 0.69-0.72 (m, 2H), 0.44-0.46 (m, 2H); MS-ESI: m/z 553.30 [M+H-HCl] ⁺ .

Example 160: Compound (2 R ,4 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid methyl Synthesis of ester hydrochloride

Step 1: Synthesis of compound (2 R ,4 S )-2-methoxycarbonyl-4-cyclopropylcarboxamidopyrrolidine-1-carboxylic acid tert-butyl ester

Combine cyclopropylcarboxylic acid (150 mg, 1.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (501 mg, 2.61 mmol) and N -hydroxy-7-aza Benzotriazole (356mg, 2.61mmol) was added to dichloromethane (20mL), stirred at room temperature for 30min, compound ( 2R , 4S )-2-methoxycarbonyl-4-aminopyrrolidine-1- Tert-Butyl formate (346mg, 1.42mmol), N , N -diisopropylethylamine (1.2mL, 6.9mmol) was added dropwise to this solution at 0℃, stirred at room temperature for 10h, and water (25mL×3) was added ) Washed, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/2) to obtain 311 mg of a white solid, Yield: 70%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 4.54-4.58 (m, 1H), 4.31-4.43 (m, 1H), 3.79-3.81 (m, 1H), 3.75 (s, 3H), 3.30-3.44( m,1H),2.22-2.28(m,2H),1.42-1.48(m,9H),1.30-1.36(m,1H),0.98-0.99(m,2H),0.76-0.79(m,2H); MS-ESI: m/z 213.20 [M+H-100] ⁺ .

Step 2: Synthesis of compound (2 R ,4 S )-4-cyclopropylcarboxamidopyrrolidine-2-carboxylic acid methyl ester hydrochloride

To a solution of the compound (2 R ,4 S )-2-methoxycarbonyl-4-cyclopropylcarboxamidopyrrolidine-1-carboxylic acid tert-butyl ester (311 mg, 0.996 mmol) in dichloromethane (2 mL) was added A solution of HCl in ethyl acetate (4M, 4mL) was stirred at room temperature for 1h, and the solvent was removed to obtain 246mg of a white solid, yield: 99%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 4.70-4.73 (m, 1H), 4.44-4.45 (m, 1H), 3.89 (s, 3H), 3.61-3.69 (m, 1H), 3.35-3.38 (m,1H),2.45-2.50(m,2H),1.61-1.65(m,1H),0.88-0.92(m,2H),0.81-0.83(m,2H); MS-ESI: m/z 213.20 [M+H-HCl] ⁺ .

Step 3: Compound (2 R ,4 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethyl Oxy)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid Synthesis of methyl ester

The compound ( S )-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene )Oxazole-4-carboxylic acid (150 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (92 mg, 0.48 mmol) and N -hydroxy-7 - aza-benzotriazole (65mg, 0.48mmol) was added dichloromethane (20mL), the room temperature was stirred 30min, was added compound (2 R, 4 S) -4- cyclopropyl-pyrrolidine carboxylic acyl group - 2-Methyl formate hydrochloride (79mg, 0.32mmol), N , N -diisopropylethylamine (0.22mL, 1.28mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 10h, and water was added (25mL×3) washed, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/1) to obtain 189mg white solid, yield: 89%.

¹ H NMR(400MHz,CDCl ₃ ): δ ppm 7.49-7.60(m,2H),7.22-7.28(m,1H),6.72(t, J _FH =75.2Hz,1H),5.27-5.34(m,1H ), 4.74-4.78, 4.26-4.34(m, 0.5H, 0.5H), 4.60-4.70(m, 1H), 4.01-4.10(m, 1H), 3.96-4.00(m, 2H), 3.80(s, 1.5H), 3.64 (s, 1.5H), 2.44-2.48 (m, 1H), 2.36-2.42, 2.21-2.28 (m, 0.5H, 0.5 H), 1.55-1.57 (m, 3H), 1.42-1.46 (m,9H),1.34-1.37(m,1H),1.29-1.32(m,1H),0.96-1.02(m,2H),0.85-0.90(m,2H),0.68-0.74(m,2H) , 0.43-0.45 (m, 2H); MS-ESI: m/z 663.40 [M+H] ⁺ .

Step 4: Compound (2 R ,4 S )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid methyl ester hydrochloride synthesis

To compound (2 R ,4 S )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-(cyclopropylcarboxamido)pyrrolidine-2-carboxylic acid methyl ester (189 mg, 0.285 mmol) in methylene chloride ( 2mL) solution was added HCl in ethyl acetate solution (4M, 4mL), stirred at room temperature for 1h, the solvent was removed to obtain 169mg white solid, yield: 99%.

¹ H NMR (600MHz, CD ₃ OD): δ ppm 7.65-7.76 (m, 2H), 7.33 (d, J = 7.8Hz, 1H), 6.93 (t, J _FH = 75.0Hz, 1H), 5.52-5.54 (m,1H),5.16-5.20(m,1H),4.53-4.57,4.29-4.31(m,0.5H,0.5H),4.41-4.49(m,1H),4.04-4.07(m,2H), 3.99-4.02(m, 1H), 3.79(s, 1H), 3.73(s, 2H), 2.47-2.50(m, 1H), 2.28-2.39(m, 1H), 1.76-1.79(m, 3H), 1.59-1.66(m, 1H), 1.36-1.39(m, 1H), 0.86-0.89(m, 2H), 0.79-0.80(m, 2H), 0.69-0.72(m, 2H), 0.45-0.46(m , 2H); MS-ESI: m/z 563.35 [M+H-HCl] ⁺ .

Example 161: Compound ( S )-4-(5-(5-(5-(1-(Aminoethyl)-4-(4-Aminomethylacetophenazine-1-carbonyl Group) oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentyl)pentazine-1-carboxylic acid methyl ester hydrochloride to make

Step 1: Compound ( S )-4-(5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-4-(4-aminomethylamylpyrazine-1 -Synthesis of carbonyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentyl)pentazine-1-carboxylate

The compound ( S )-5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-)(4-aminomethylpyrazine-1-carbonyl)oxazole -2-yl)-2-(difluoromethoxy)phenoxy)pentanoic acid (51mg, 0.082mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloric acid Salt (23mg, 0.12mmol) and N -hydroxy-7-azabenzotriazole (17mg, 0.12mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, 1-methoxycarbonylpyrazine was added Hydrochloride (25mg, 0.12mmol), N , N -diisopropylethylamine (0.05mL, 0.25mmol) was added dropwise to this solution at 0℃, stirred at room temperature for 10h, and water (25mL×3) was added After washing, extraction with dichloromethane (25mL×3), the organic phases were combined, the organic phase was dried over anhydrous Na ₂ SO ₄ , the solvent was removed, and the concentrated solution was subjected to column chromatography (eluent: dichloromethane/methanol (v/v )=20/1), 51 mg of white solid was obtained, yield: 83%.

¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.57-7.60 (m, 2H), 7.24 (d, J = 8.4 Hz, 1H), 6.63 (t, J _FH = 75.0 Hz, 1H), 5.24-5.32 ( m,1H), 4.17 (t, J = 6.0 Hz, 2H), 4.00-4.08 (m, 2H), 3.82 (br.s, 2H), 3.75 (s, 3H), 3.61-3.65 (m, 2H) , 3.49-3.55 (m, 10H), 2.49 (t, J = 7.3Hz, 2H), 1.94-1.97 (m, 2H), 1.88-1.92 (m, 2H), 1.56 (d, J = 6.6Hz, 3H ), 1.43 (s, 9H); MS-ESI: m/z 752.40 [M+H] ⁺ .

Step 2: Compound ( S )-4-(5-(5-(5-(5-(1-Aminoethyl)-4-(4-aminomethanylpyrazine-1-carbonyl)oxo Synthesis of oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentyl)pyrazine-1-carboxylic acid methyl ester hydrochloride

To the compound ( S )-4-(5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)ethyl)-4-(4-aminomethylacetophenazine-1-carbonyl ) Oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentyl)pentazine-1-carboxylic acid methyl ester (47mg, 0.063mmol) in methylene chloride (2mL) was added A solution of HCl in ethyl acetate (4M, 3mL), stirred at room temperature for 40min, and removed the solvent to obtain 39mg of white solid, yield: 91%.

¹ H NMR (600 MHz, CD ₃ OD): δ ppm 7.78 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.91 (t, J _FH =74.4Hz,1H),5.06-5.09(m,1H),4.23(t, J =6.0Hz,2H),4.20(br.s,2H),3.80(br.s,2H),3.73(s, 3H), 3.59-3.60 (m, 8H), 3.53 (br.s, 2H), 3.47 (br.s, 2H), 4.57 (t, J = 7.3Hz, 2H), 1.94-1.96 (m, 2H) , 1.85-1.88 (m, 2H), 1.80 (d, J = 7.2 Hz, 3H); MS-ESI: m/z 652.20 [M+H-HCl] ⁺ .

Example 162: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy Yl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid ((4- Synthesis of Hydroxycyclohexyl)methyl)methyl ester hydrochloride

Step 1: Compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy )-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid ((4-hydroxycyclohexyl)methyl) Synthesis of methyl ester

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy) -4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (250 mg, 0.39 mmol), 6-hydroxymethyl Cyclohexanol (61 mg, 0.47 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (300 mg, 1.56 mmol) and N -hydroxy-7-azabenzo Triazole (79mg, 0.59mmol) was dissolved in dichloromethane (10mL), and N , N -diisopropylethylamine (0.67mL, 1.56mmol) was added dropwise to this solution at 0°C, and stirred at room temperature 10h, wash with water (10mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , remove the solvent, and separate the concentrate by column chromatography (eluent: Petroleum ether/EtOAc (v/v) = 2/5), 97 mg of colorless solid was obtained, yield: 24%.

MS-ESI: m/z 751.70 [M+H] ⁺ .

Step 2: Compound (2 S ,4 R )-1-(5-(( S )-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethyl Synthesis of oxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid ((4-hydroxycyclohexyl)methyl) methyl ester hydrochloride

The compound (2 S ,4 R )-1-(5-(( S )-1-((tert-butoxycarbonyl)amino)ethyl)-2-)(3-(cyclopropylmethoxy)- 4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidine-2-carboxylic acid ((4-hydroxycyclohexyl)methyl)methyl ester (70mg, 0.09mmol) was dissolved in dichloromethane (2mL), a solution of hydrogen chloride in isopropanol (25%, 4mL) was added, stirred at room temperature for 40min, the solvent was removed to obtain 79mg white solid, yield: 96%.

¹ H NMR (400MHz, CD ₃ OD): δ ppm 7.67-7.78(m, 2H), 7.34-7.37(m, 1H), 6.94(t, J _FH = 75.1Hz, 1H), 5.12-5.24(m, 1H), 4.40-4.46(m, 1H), 4.25-4.33(m, 1H), 4.06(d, J = 7.0Hz, 2H), 3.97-4.05(m, 2H), 3.85-3.89, 3.71-3.76( m,0.5H,0.5H),3.68-3.70(m,3H),3.36-3.55(m,1H),2.24-2.52(m,2H),1.97-2.07(m,1H),1.81-1.88(m , 2H), 1.79 (d, J = 6.9Hz, 3H), 1.50-1.68 (m, 3H), 1.36-1.42 (m, 2H), 0.90-1.07 (m, 3H), 0.69-0.75 (m, 2H ), 0.44-0.48 (m, 2H); MS-ESI: m/z 651.70 [M+H-HCl] ⁺ .

Through similar synthetic methods of the embodiments of the present invention and the synthetic methods described in the present invention, with suitable optional starting materials, the compounds shown in Table 1 are prepared:

Biological test Biological Example 1

The present invention adopts the following methods to conduct biological tests on the compounds represented by formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf):

1. Using the BPS production kit (BPS, 603343), according to the instructions provided by the manufacturer, using fluorescent polarization method to detect the inhibitory effect of the compound on the PDE4B2 enzyme.

2. The concentration of PDE4B2 enzyme was 83.33pg/μL, the final concentration was 27.78pg/μL; the concentration of substrate FAM-Cyclic-3', 5'-AMP was 300nM, the final concentration of the reaction was 100nM, the enzyme and substrate were diluted The solution uses the kit's own buffer PDE Assay buffer; the Binding Agent uses the kit's own Binding Agent Diluent to perform a 100-fold dilution and set aside. The reaction system is shown in Table 2 below.

3. A 384-well plate is used for the test. The test sample wells, positive control wells, negative control wells and blank control wells are set up in the experiment. Each sample is tested for the inhibitory effect of PDE4B2 enzyme concentration at 10 concentrations using double duplicate wells and PDE4B2. The enzyme and FAM-Cyclic-3', 5'-AMP substrate reaction wells served as positive controls, FAM-Cyclic-3', 5'-AMP substrate wells served as negative controls, and buffer wells served as blank controls. After adding the corresponding samples, enzymes, substrates and buffers to each well in the order shown in Table 2, incubate for 1 hour at 25°C incubator, then add 15μL of the configured Binding Agent to each well and shake it at 25°C for 1 hour. The PHER Astar FS multifunctional microplate reader (BMG) was used for detection at FP485/525 wavelength. Graph Pad Prism 5 software was used to plot the inhibitory effect of the compound on the PDE4B2 enzyme at different concentrations to calculate the IC ₅₀ .

The inhibitory effect of the compound provided by the present invention on the PDE4B2 enzyme was determined according to the above method. The results are shown in Table 3.

The data in Table 3 shows that the compounds of the present invention generally show higher inhibitory activity in the in vitro screening test for PDE4B2 enzyme inhibition.

It will be apparent to those skilled in the art that the present disclosure is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from its essential characteristics. Therefore, it is expected that the embodiments are regarded as illustrative and non-limiting in all respects, and reference should be made to the scope of the attached patent application rather than the foregoing embodiments. Therefore, the meaning and scope of equivalent contents in the scope of the attached patent application All changes within are included in this article.

In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples" or "some examples" means specific features described in conjunction with the embodiment or examples, The structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, the schematic expression of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and cannot be understood as limitations to the present invention, and those of ordinary skill in the art will not deviate from the principles and purposes of the present invention The above embodiments can be changed, modified, replaced and modified within the scope of the present invention.

Claims (25)

A compound which is a compound represented by formula (I) or a stereoisomer, racemate, nitrogen oxide, or pharmaceutically acceptable salt of a compound represented by formula (I):

Wherein: R ¹ is H, deuterium, alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkyl-C(=O)-, alkyl-S(=O ^{_{) 2 -, R a -C (}} = O) - ^{alkylene, R a -S (= O)} 2 - alkylene, alkenyl, alkynyl, cycloalkylalkyl, heterocyclylalkyl, aryl Alkyl or heteroarylalkyl; each R ^{2 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , COOH, -C(=O)-NH ₂ , -S(=O) ₂ -NH ₂ , alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkoxy, haloalkoxy or alkylamino; R ³ is H, deuterium, alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkyl-C(=O)-, alkyl-S(=O) ₂ -, alkyl -C(=O)-alkylene, alkyl-OC(=O)-alkylene, alkyl-S(=O) ₂ -alkylene, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl-C(=O)-alkylene or heterocyclyl -C(=O)-alkylene; R ⁴ is NH ₂ , C _2-10 alkyl, haloalkyl, aminoalkyl, hydroxy substituted alkyl, cyano substituted alkyl, R ^a -C( = O) - ^{alkylene, R a -S (= O)} 2 - alkylene group, an alkenyl group, an alkynyl group, an alkoxy group, an alkoxy group, -C (= O) -NH _2, or -S (= O) ₂ -NH ₂ ; X is N(R ^b ), O or S; Y is O or S; A is a heterocyclic group containing at least one nitrogen atom; each R ^{5 is} independently H, deuterium, F, Cl , Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)-, R ⁶ -C(=O)-alkylene, R ⁶ -C(=O)-alkenylene , R ⁶ -C(=O)-alkylene-OC(=O)-, R ⁶ -C(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O)O -Alkylene-OC(=O)-, R ⁶ -C(=O)O-alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC( =O)-O-, R ^c R ^b NC(=O)-alkylene, R ^c R ^b NC(=O)-alkenylene, R ^c R ^b NC(=O)-alkylene-OC (=O)-, R ^c R ^b NC(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O)-N(R ^b )-, R ⁶ -C(=O )-N(R ^b )-alkylene, R ⁶ -C(=O)-N(R ^b )-alkenylene, R ⁶ -C(=O)-alkylene-N(R ^b )- , R ⁶ -C(=O)-alkenylene-N(R ^b )-, R ^c R ^b NC (=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-alkylene, R ^c R ^b NC(=O)-N(R ^b )-ene Group, R ^c R ^b NC(=O)-alkylene-N(R ^b )-, R ^c R ^b NC(=O)-alkenylene-N(R ^b )-, R ⁶ -C(= O)-N(R ^b )-C(=O)-, R ⁶ -C(=O)-N(R ^b )-C(=O)-alkylene, R ⁶ -C(=O)- N(R ^b )-C(=O)-alkenylene, R ^6a -O-alkylene, R ^6a -O-alkenylene, oxo, alkyl, haloalkyl, aminoalkyl, hydroxyl substituted Alkyl, cyano-substituted alkyl, carboxy-substituted alkyl, alkoxyalkyl, hydroxy-substituted alkoxyalkyl, carboxy-substituted alkoxyalkyl, alkylaminoalkyl, aryloxy Substituted alkyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, alkylaminoalkylamino, alkylaminoalkoxy, alkoxyalkylamino, alkylthio, alkene Group, carboxy substituted alkenyl, alkynyl, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -alkylene, R ⁶ -S(=O) ₂ -alkenylene, R ⁶ -S(=O) ₂ -N(R ^b )-, R ⁶ -S(=O) ₂ -N(R ^b )-alkylene, R ⁶ -S(=O) ₂ -N(R ^b )-alkenylene, R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -alkylene, R ^c R ^b NS(=O) ₂ -alkenylene, ring Alkyl, cycloalkyloxy, cycloalkylamine, cycloalkylalkyl, cycloalkenyl, cycloalkenyloxy, cycloalkenylamine, cycloalkenylalkyl, heterocyclyl, heterocyclyl Oxygen, heterocyclylamino, heterocyclylalkyl, aryl, aryloxy, arylamino, arylalkyl, heteroaryl, heteroaryloxy, heteroarylamino or hetero Arylalkyl; each R ^a and R ^{6 are} independently H, deuterium, OH, NH ₂ , alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, alkoxy Alkyl, alkoxy, haloalkoxy, hydroxy substituted alkoxy, carboxy substituted alkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkoxy Group, heteroarylalkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, aryl Alkyl, aryloxy, heteroaryl, heteroaryloxy or heteroarylalkyl; each R ^{6a is} independently H, alkyl, haloalkyl, hydroxy substituted alkyl, carboxy substituted alkyl, Alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; each R ^b and R ^c Independently H, deuterium, alkyl, haloalkyl, hydroxy substituted alkyl, carboxy substituted alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl Alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; or R ^b , R ^c together with the nitrogen atom to which they are connected to form a ring of 3-12 atoms; m is 0, 1 , 2 or 3; n is 0, ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , 9 or 10; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ^a , R ^b and R ^c alkyl, haloalkyl, aminoalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, carboxy-substituted alkyl, alkyl-C (= O)-, alkyl-S(=O) ₂ -, alkyl-C(=O)-alkylene, alkyl-OC(=O)-alkylene, alkyl-S(=O) ₂ - alkylene ^{group, R a -C (= O)} - ^{alkylene, R a -S (= O)} 2 - alkylene, alkenylene, carboxyl-substituted alkenyl group, alkynyl group, alkoxy group, haloalkoxy Group, hydroxy-substituted alkoxy group, carboxy-substituted alkoxy group, alkylamino group, cycloalkyl-C(=O)-alkylene group, heterocyclic group-C(=O)-alkylene group, C _{2 -10} alkyl, R ⁶ -C(=O)-, R ⁶ -C(=O)-alkylene, R ⁶ -C(=O)-alkenylene, R ⁶ -C(=O)- Alkylene-OC(=O)-, R ⁶ -C(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O)O-alkylene-OC(=O) -, R ⁶ -C(=O)O-alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-alkylene, R ^c R ^b NC(=O)-alkenylene, R ^c R ^b NC(=O)-alkylene-OC(=O)-, R ^c R ^b NC(=O)-alkenylene-OC(=O)-, R ⁶ -C(=O)-N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-alkylene Group, R ⁶ -C(=O)-N(R ^b )-alkenylene, R ⁶ -C(=O)-alkylene-N(R ^b )-, R ⁶ -C(=O)- Alkenylene-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-alkylene, R ^c R ^b NC(=O)-N(R ^b )-alkenylene, R ^c R ^b NC(=O)-alkylene-N(R ^b )-, R ^c R ^b NC(=O)-ene Alkenyl-N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-C(=O)-, R ⁶ -C(=O)-N(R ^b )-C(= O)-alkylene, R ⁶ -C(=O)-N(R ^b )-C(=O)-alkenylene, R ^6a -O-alkylene, R ^6a -O-alkenylene, Alkoxyalkyl, hydroxy-substituted alkoxyalkyl, carboxyl -Substituted alkoxyalkyl, alkylaminoalkyl, aryloxy-substituted alkyl, alkoxyalkoxy, alkylaminoalkylamino, alkylaminoalkoxy, alkoxyalkylamino , Alkylthio, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -alkylene, R ⁶ -S(=O) ₂ -alkenylene, R ⁶ -S(= O) ₂ -N(R ^b )-, R ⁶ -S(=O) ₂ -N(R ^b )-alkylene, R ⁶ -S(=O) ₂ -N(R ^b )-alkenylene , R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -alkylene, R ^c R ^b NS(=O) ₂ -alkenylene, cycloalkyl, cycloalkyl Oxygen, cycloalkylamino, cycloalkylalkyl, cycloalkylalkoxy, cycloalkenyl, cycloalkenyloxy, cycloalkenylamine, cycloalkenylalkyl, heterocyclyl, 3- 12-atom ring, heterocyclyloxy, heterocyclylamino, heterocyclylalkyl, heterocyclylalkoxy, aryl, aryloxy, arylamino, arylalkyl, Arylalkoxy, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylalkyl or heteroarylalkoxy are independently optionally substituted by one or more R ⁷ ; wherein each R ⁷ Independently for H, deuterium, F, Cl, Br, I, CN, NO ₂ , OH, NH ₂ , COOH, -C(=O)-NH ₂ , -S(=O) ₂ -NH ₂ , oxygen Substituted, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _1-6 alkyl-C(=O)- or C _1-6 alkyl-OC(=O)-. The compound as described in item 1 of the patent scope, wherein R ¹ is H, deuterium, C _1-4 alkyl, halogenated C _1-4 alkyl, amine C _1-3 alkyl, hydroxy substituted C _{1 -3} alkyl, cyano-substituted C _1-3 alkyl, C _1-3 alkyl-C(=O)-, C _1-3 alkyl-S(=O) ₂ -, C _2-4 alkene Radical or C _2-4 alkynyl; each R ^{2 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , COOH, -C(=O)-NH ₂ ,- S(=O) ₂ -NH ₂ , C _1-3 alkyl, halogenated C _1-3 alkyl, amino C _1-3 alkyl, hydroxy substituted C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkoxy or C _1-3 alkylamino; R ⁴ is NH ₂ , C _2-4 alkyl, halogenated C _{1- 4} alkyl, amino C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, fluoro substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{1 -3} alkoxy, C _1-3 alkylamino, -C(=O)-NH ₂ or -S(=O) ₂ -NH ₂ ; m is 0, 1, 2 or 3. The compound as described in item 2 of the patent application scope, wherein R ¹ is H, deuterium, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ )CH ₃ , -CH ₂ Cl, -CHCl ₂ , -CCl ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ Cl, -CH ₂ CHCl ₂ , -CH ₂ CH ₂ F, or -CH ₂ CHF ₂ ; each R ^{2 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , COOH, -C(=O)-NH ₂ , -S(=O) ₂ -NH ₂ , Methyl or methoxy; R ⁴ is NH ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ NH ₂ , -CH(CH ₃ )NH ₂ , -CH ₂ CH ₂ CH ₂ NH ₂ , -CH(CH ₂ CH ₃ )NH ₂ , -CH ₂ CH(CH ₃ )NH ₂ , -CH(CH(CH ₃ ) ₂ )NH ₂ , -C(=O)-NH ₂ or -S(=O) ₂ -NH ₂ . The compound according to item 1 of the patent application scope, wherein R ³ is H, deuterium, C _1-6 alkyl, halogenated C _1-6 alkyl, amine C _1-6 alkyl, hydroxy substituted C _{1 -6} alkyl, cyano substituted C _1-6 alkyl, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O) ₂ -, C _1-6 alkyl -C(=O)-C _1-6 alkylene, C _1-6 alkyl-OC(=O)-C _1-8 alkylene, C _1-6 alkyl-S(=O) ₂ -C _1-6 alkylene, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, C _1-9 Heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 alkyl, C _1-9 hetero Aryl C _1-6 alkyl, C _3-8 cycloalkyl-C(=O)-C _1-6 alkylene or C _2-10 heterocyclyl-C(=O)-C _1-8 alkyl alkyl. The compound as described in item 4 of the patent application, wherein R ³ is C _1-3 alkyl, halogenated C _1-3 alkyl, C _1-3 alkyl-C(=O)-C _1-6 Alkyl, C _1-3 alkyl-OC(=O)-C _1-6 alkylene, C _1-3 alkyl-S(=O) ₂ -C _1-6 alkylene, C _3-6 Cycloalkyl, C _2-6 heterocyclyl, C _6-10 aryl, C _1-5 heteroaryl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _{1 -3} alkyl, C _6-10 aryl C _1-3 alkyl, C _1-5 heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl-C(=O)-C _1-6 Alkylene or C _2-6 heterocyclyl-C(=O)-C _1-6 alkylene. The compound as described in item 5 of the patent application, wherein R ³ is CH ₃ -OC(=O)-C _1-6 alkylene, CH ₃ CH ₂ -OC(=O)-C _1-6 alkylene Group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, pyridinyl, pyrazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thio? Porphyrinyl, 1,1-dioxo-thiomorpholinyl, tetrahydropyranyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl , Cyclohexylmethyl, pyrrolidinylmethyl, tetrahydrofuranylmethyl, pyridinylmethyl, pyrazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, 1-oxo-thio Morpholinylmethyl, 1,1-dioxo-thiomorpholinylmethyl, tetrahydropyranylmethyl, benzyl, phenethyl, cyclohexyl-C(=O)-C _1-6 Alkylene, pyridinyl-C(=O)-C _1-6 alkylene, morpholinyl-C(=O)-C _1-6 alkylene, pyrazinyl-C(=O)- C _1-6 alkylene group, thiomorpholino group -C (= O) -C _1-6 alkylene, 1-oxo - thiomorpholinyl -C (= O) -C _1-6 alkylene Alkyl or 1,1-dioxo-thiomorpholinyl-C(=O)-C _1-6 alkylene. The compound according to item 1 of the patent application scope, wherein A is a heterocyclic group composed of 3-12 atoms containing at least one nitrogen atom. The compound as described in item 7 of the patent application, wherein A is the following substructure formula:

Where: each Z is independently CH ₂ , NH, O, S, S(=O) or S(=O) ₂ ; each Z ^{1 is} independently NH, O, S, S(=O) or S(= O) ₂ ; each W is independently CH ₂ , NH or O; each V is independently CH ₂ or NH; each E is independently CH or N; each G is independently O or NH; each p is independently 0 , 1, 2 or 3; each q is independently 1 or 2; each r is independently 0, 1, 2 or 3; each s is independently 1, 2, or 3. The compound as described in item 8 of the patent application, wherein A is the following substructure formula:

The compound as described in item 1 of the patent application scope, which is a compound represented by formula (II) or a stereoisomer, racemate, nitrogen oxide or pharmaceutically acceptable compound of the compound represented by formula (II) salt:

Wherein: each Z is independently CH ₂ , NH, O, S, S(=O) or S(=O) ₂ ; t is 0, 1, 2 or 3. The compound as described in item 1 of the patent application scope, which is a compound represented by formula (IIa) or a stereoisomer, racemate, nitrogen oxide or pharmaceutically acceptable compound of formula (IIa) salt:

The compound as described in item 1 of the patent application scope, which is a compound represented by formula (IIb) or formula (IIc) or a stereoisomer or racemate of a compound represented by formula (IIb) or formula (IIc) , Nitrogen oxides or pharmaceutically acceptable salts:

The compound according to any one of the first, tenth, eleventh and twelfth items of the patent application scope, wherein the pharmaceutically acceptable salts are hydrochloride, hydrobromide, sulfate, nitrate , Phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, hydroxy Acetate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate Acid salt, besylate, methanesulfonate, ethanesulfonate, triflate or a combination thereof. The compound as described in any one of the first, tenth, eleventh and twelfth items of the patent application scope, wherein each R ^{5 is} independently H, deuterium, F, Cl, Br, I, CN, OH , NO ₂ , NH ₂ , R ⁶ -C(=O)-, R ⁶ -C(=O)-C _1-6 alkylene, R ⁶ -C(=O)-C _2-6 alkenylene , R ⁶ -C(=O)-C _1-6 alkylene-OC(=O)-, R ⁶ -C(=O)-C _2-6 alkenylene-OC(=O)-, R ⁶ -C(=O)OC _1-6 alkylene-OC(=O)-, R ⁶ -C(=O)OC _2-6 alkenylene-OC(=O)-, R ^c R ^b NC (=O)-, R ^c R ^b NC(=O)-O-, R ^c R ^b NC(=O)-C _1-6 alkylene, R ^c R ^b NC(=O)-C _{2- 6} alkenylene, R ^c R ^b NC(=O)-C _1-6 alkylene-OC(=O)-, R ^c R ^b NC(=O)-C _2-6 alkenylene-OC( =O)-, R ⁶ -C(=O)-N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-C _1-6 alkylene, R ⁶ -C(= O)-N(R ^b )-C _2-6 alkenylene, R ⁶ -C(=O)-C _1-6 alkylene-N(R ^b )-, R ⁶ -C(=O)- C _2-6 alkenylene-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-C _{1 -6} alkylene, R ^c R ^b NC(=O)-N(R ^b )-C _2-6 alkenylene, R ^c R ^b NC(=O)-C _1-6 alkylene-N( R ^b )-, R ^c R ^b NC(=O)-C _2-6 alkenylene-N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-C(=O) -, R ⁶ -C(=O)-N(R ^b )-C(=O)-C _1-6 alkylene, R ⁶ -C(=O)-N(R ^b )-C(=O )-C _2-6 alkenylene, R ^6a -OC _1-8 alkylene, R ^6a -OC _2-8 alkenylene, oxo, C _1-8 alkyl, halo C _1-6 alkyl , Amine C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, cyano substituted C _1-6 alkyl, carboxy substituted C _1-6 alkyl, C _1-6 alkoxy C _{1 -6} alkyl, hydroxy substituted C _1-6 alkoxy C _1-6 alkyl, carboxy substituted C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylamino C _1-6 Alkyl, C _6-10 aryloxy substituted C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 alkoxy C _1-6 Alkoxy, C _1-6 alkylamino, C _1-6 alkylamino C _1-6 alkylamino, C _1-6 alkylamino C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkylamino, C _1-6 alkylthio, C _2-6 alkenyl, carboxy substituted C _2-6 alkenyl, C _2-6 alkynyl, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -C _1-6 alkylene, R ⁶ -S(=O) ₂ -C _2-6 alkenylene, R ⁶ -S(=O) ₂ -N(R ^b )-, R ⁶ -S(=O) ₂ -N(R ^b )-C _1-6 alkylene, R ⁶ -S(=O) ₂ -N(R ^b )-C _2-6 alkenylene , R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -C _1-6 alkylene, R ^c R ^b NS(=O) ₂ -C _2-6 alkenylene , C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, C _3-8 cycloalkylamino, C _3-8 cycloalkyl C _1-6 alkyl, C _3-8 cycloalkenyl , C _3-8 cycloalkenyloxy, C _3-8 cycloalkenylamino, C _3-8 cycloalkenyl C _1-6 alkyl, C _2-10 heterocyclyl, C _2-10 heterocyclyl Oxygen, C _2-10 heterocyclylamino, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl, C _6-10 aryloxy, C _6-10 arylamine Group, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl, C _1-9 heteroaryloxy, C _1-9 heteroarylamino or C _1-9 heteroaryl C _1-6 alkyl; each R ^{6 is} independently H, deuterium, OH, NH ₂ , C _1-8 alkyl, halogenated C _1-6 alkyl, amine C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-8 alkoxy, halogenated C _1-6 alkoxy, Hydroxy substituted C _1-8 alkoxy, carboxy substituted C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _3-8 cycloalkyl C _1-6 alkoxy Group, C _2-10 heterocyclyl C _1-6 alkoxy, C _6-10 aryl C _1-6 alkoxy, C _1-9 heteroaryl C _1-6 alkoxy, C _1-6 Alkylamino, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _3-8 cycloalkyloxy, C _2-10 heterocyclyl, C _2-10 heterocyclic Group C _1-6 alkyl, C _2-10 heterocyclyloxy, C _6-10 aryl, C _6-10 aryl C _1-6 alkyl, C _6-10 aryloxy, C _{1- 9} Heteroaryl, C _1-9 heteroaryloxy or C _1-9 heteroaryl C _1-6 alkyl; each R ^{6a is} independently H, C _1-8 alkyl, halo C _1-8 Alkyl, hydroxy substituted C _1-8 alkyl, carboxy substituted C _1-8 alkyl, C _{1 -6} alkoxy C _1-6 alkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl C _1-6 alkyl, C _6-10 aryl C _1-6 Alkyl, C _1-9 heteroaryl C _1-6 alkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl; each R ^b and R ^{c are} independently H, deuterium, C _1-8 alkyl, halogenated C _1-6 alkyl, hydroxy substituted C _1-8 alkyl, carboxy substituted C _1-8 alkyl, C _{1- 6} alkoxy C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl, C _2-10 heterocyclyl C _{1 -6} alkyl, C _6-10 aryl, C _6-10 aryl C _1-6 alkyl, C _1-9 heteroaryl or C _1-9 heteroaryl C _1-6 alkyl; or R ^b , R ^c and the nitrogen atom connected to it form a ring composed of 3-8 atoms. The compound as described in item 14 of the patent application scope, wherein each R ^{5 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)- , R ⁶ -C(=O)-C _1-3 alkylene, R ⁶ -C(=O)-C _2-4 alkenylene, R ⁶ -C(=O)OC _1-4 alkylene -OC(=O)-, R ⁶ -C(=O)OC _2-4 alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O )-O-, R ^c R ^b NC(=O)-C _1-3 alkylene, R ^c R ^b NC(=O)-C _2-4 alkenylene, R ⁶ -C(=O)- N(R ^b )-, R ⁶ -C(=O)-N(R ^b )-C _1-3 alkylene, R ⁶ -C(=O)-N(R ^b )-C _2-4 alkylene Alkenyl, R ^c R ^b NC(=O)-N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-C _1-3 alkylene, R ^c R ^b NC( =O)-N(R ^b )-C _2-4 alkenylene, R ^6a -OC _1-6 alkylene, R ^6a -OC _2-6 alkenylene, oxo, C _1-6 alkyl, Halogenated C _1-4 alkyl, amine C _1-4 alkyl, hydroxy substituted C _1-6 alkyl, cyano substituted C _1-4 alkyl, carboxy substituted C _1-4 alkyl, C _1-6 alkoxy C _1-3 alkyl, hydroxy substituted C _1-6 alkoxy C _1-3 alkyl, carboxy substituted C _1-6 alkoxy C _1-4 alkyl, C _{1- 3} alkylamino C _1-3 alkyl, C _6-10 aryloxy substituted C _1-3 alkyl, C _1-3 alkoxy, C _2-4 alkenyl, carboxy substituted C _2-4 alkenyl Group, C _2-4 alkynyl, R ⁶ -S(=O) ₂ -, R ⁶ -S(=O) ₂ -C _1-3 alkylene, R ⁶ -S(=O) ₂ -C _{2 -4} alkenylene, R ^c R ^b NS(=O) ₂ -, R ^c R ^b NS(=O) ₂ -C _1-3 alkylene, R ^c R ^b NS(=O) ₂ -C _{2 -4} alkenylene, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _1-3 alkyl, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, C _1-6 heteroaryl or C _1-6 heteroaryl C _1-3 alkyl; each R ^{6 is} independently H, Deuterium, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, hydroxy substituted C _1-6 alkoxy, carboxy substituted C _1-6 alkoxy, C _1-3 alkoxy C _1-4 alkoxy, C _3-6 cycloalkyl C _1-3 alkoxy, C _2-6 heterocyclyl C _1-3 alkoxy, C _6-10 aryl C _1-3 alkoxy, C _1-5 heteroaryl C _1-3 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-3 alkyl, C _3-8 cycloalkyloxy, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _1-3 alkyl, C _2-6 heterocyclyloxy, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, C _6-10 aryloxy, C _1-6 heteroaryl, C _1-5 heteroaryloxy or C _1-6 heteroaryl C _1-3 Alkyl; each R ^{6a is} independently H, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, carboxy substituted C _1-6 alkyl, C _{1- 3} alkoxy C _1-4 alkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl C _1-3 alkyl, C _6-10 aryl C _1-3 alkyl Group, C _1-5 heteroaryl C _1-3 alkyl, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _6-10 aryl or C _1-5 heteroaryl; each R ^b And R ^{c are} independently H, deuterium, C _1-6 alkyl, halogenated C _1-3 alkyl, hydroxy substituted C _1-6 alkyl, carboxy substituted C _1-6 alkyl, C _1-3 Alkoxy C _1-4 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl C _1-3 alkyl, C _2-6 heterocyclyl, C _2-6 heterocyclyl C _{1- 3} alkyl, C _6-10 aryl, C _6-10 aryl C _1-3 alkyl, C _1-5 heteroaryl or C _1-5 heteroaryl C _1-3 alkyl; or R ^b , R ^c and the nitrogen atom connected to it form a ring composed of 3-6 atoms. The compound as described in item 15 of the patent application scope, wherein each R ^{5 is} independently H, deuterium, F, Cl, Br, I, CN, OH, NO ₂ , NH ₂ , R ⁶ -C(=O)- , R ⁶ -C(=O)-C _1-3 alkylene, R ⁶ -C(=O)-C _2-4 alkenylene, R ⁶ -C(=O)OC _1-4 alkylene -OC(=O)-, R ⁶ -C(=O)OC _2-4 alkenylene-OC(=O)-, R ^c R ^b NC(=O)-, R ^c R ^b NC(=O )-O-, R ^c R ^b NC(=O)-C _1-3 alkylene, R ^c R ^b NC(=O)-C _2-4 alkenylene, R ⁶ -C(=O)- N(R ^b )-, R ^c R ^b NC(=O)-N(R ^b )-, R ^6a -OC _1-6 alkylene, R ^6a -OC _2-6 alkenylene, oxo, methyl Group, cyano substituted methyl, carboxymethyl, ethyl, cyano substituted ethyl, carboxyethyl, propyl, cyano substituted propyl, carboxypropyl, isopropyl, butyl, isobutyl Group, sec-butyl, tert-butyl, hydroxy substituted C _1-4 alkyl, phenoxymethyl, phenoxyethyl, C _1-5 alkoxy C _1-3 alkyl, hydroxy substituted C _1-5 alkoxy C _1-3 alkyl, carboxy substituted C _1-4 alkoxy C _1-3 alkyl, methoxy, ethoxy, propoxy, isopropoxy, halogenated C _1-3 alkyl, vinyl, carboxy substituted vinyl, propenyl, carboxy substituted propenyl, ethynyl, propynyl, R ⁶ -S(=O) ₂ -, R ^c R ^b NS(=O ) ₂ -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, pyrrolidinyl, tetrahydrofuranyl, pyridine , Pyrazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl Methyl, tetrahydrofurylmethyl, pyridylmethyl, pyrazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, 1-oxo-thiomorpholinylmethyl, 1,1 -Dioxo-thiomorpholinylmethyl, tetrahydropyranylmethyl, phenyl, indenyl, naphthyl, benzyl, phenethyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl , Oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridylmethyl, pyridylethyl Group, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl or pyridazinylethyl; each R ^{6 is} independently H, deuterium, OH, NH ₂ , Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, hydroxy substituted methoxy, carboxy substituted methoxy, ethoxy , Hydroxy substituted ethoxy, carboxy substituted ethoxy, propoxy, hydroxy substituted propoxy, carboxy substituted propoxy, isopropoxy, hydroxy substituted Isopropoxy, carboxy substituted isopropoxy, butoxy, hydroxy substituted butoxy, carboxy substituted butoxy, isobutoxy, hydroxy substituted isobutoxy, carboxy substituted isobutoxy Oxy, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy, benzyloxy, phenylethoxy, cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethyl Oxygen, cyclohexylmethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, pyrrolidinyl, tetrahydrofuranyl, pyridinyl, pyrazinyl, morpholinyl , Thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydropyranyl, pyrrolidinylmethyl, tetrahydrofuranylmethyl, Xia Pyridylmethyl, pyrazinylmethyl, morpholinylmethyl, thiomorpholinylmethyl, 1-oxo-thiomorpholinylmethyl, 1,1-dioxo-thiomorpholine Methyl, tetrahydropyranylmethyl, phenyl, indenyl, naphthyl, benzyl, phenethyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl , Oxadiazolyl, thiazolyl, isothiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridylmethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazine Methyl, pyrazinylethyl, pyridazinylmethyl or pyridazinylethyl; each R ^{6a is} independently H, methyl, ethyl, propyl, isopropyl, butyl, hydroxymethyl, Hydroxyethyl, hydroxypropyl, hydroxy-substituted isopropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, carboxymethyl, carboxyethyl, carboxypropyl, 2-carboxy-2-methyl Ethyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl Methyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, phenyl , Pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; each R ^b and R ^{c is} independently H, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl Group, tert-butyl, hydroxy substituted C _1-5 alkyl, carboxy substituted C _1-4 alkyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, Ethoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclo Amylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, phenyl, benzyl, phenethyl or phenylpropyl; or R ^b , R ^c together with the nitrogen atom to which they are attached Azetidine, pyrrolidine, pyridine, pyrazine, morpholine, thiomorpholine, 1-oxo-thiomorpholine or 1,1-dioxo-thiomorpholine are formed. The compound as described in item 1 of the patent application scope is a compound having one of the following structures or a stereoisomer, nitrogen oxide or pharmaceutically acceptable salt of a compound having one of the following structures:

A pharmaceutical composition comprising the compound according to any one of patent application items 1 to 17. The pharmaceutical composition according to item 18 of the patent application scope further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle. The pharmaceutical composition according to Item 18 or Item 19 of the patent application scope, further comprising additional therapeutic agents, which are drugs, pharmacologically active agents or their used for the treatment of chronic obstructive pulmonary disease (COPD) combination. The pharmaceutical composition as described in item 20 of the patent application scope, wherein the additional therapeutic agents are: sodium pyruvate, doxofylline, roflumilast, aprost, tetomilast, and Tyrus , Theophylline, formoterol, salmeterol, fluticasone propionate, salmeterol/fluticasone propionate compound, rolipram, pyrimide, cilostrin, CDP-840, indacate Luo, Odaterol, QVA149, Midestan, Qi Liu, Salbutamol, Carmoxicil, Budesonide and their anisotropy Conjugate, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, roflunide, ciclesonide, ipratropium bromide, ipratropium bromide and albuterol compound, oxygen Tortropium bromide, tiotropium bromide, glycopyrronium bromide, urdebronium bromide, vilanterol, urdeonium bromide/vilanterol compound, aclidinium bromide, aclidinium bromide/formum fumarate Tero Compound, LAS40464, LAS100977 (abediterol), AZD-8999, RPL-554, OCID-2987, CHF-6001, CR-3465, HPP-737, fluticasone furoate/vilanterol compound, Benralizumab, tralokinumab, Swiss Vaparate or a combination thereof. A compound according to any one of patent application items 1 to 17 or a pharmaceutical composition according to any patent application item 18 to 21 in the preparation of a medicament, wherein The medicine is used for preventing, treating, treating or alleviating diseases related to phosphodiesterase type 4 (PDE 4). The use as described in item 22 of the patent application, wherein the diseases related to phosphodiesterase type 4 (PDE 4) are respiratory diseases, allergies and inflammations, central nervous system (CNS) diseases, pulmonary fibrosis or Non-insulin dependent diabetes. The use as described in item 23 of the patent application scope, wherein the respiratory diseases are: chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, allergic Bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, diffuse panbronchiolitis, obliterative bronchiolitis, acute respiratory distress syndrome (ARDS) or inflammation of the respiratory tract. The use as described in item 23 of the patent application, wherein the inflammation is allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcer Colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis.