CN105085429B

CN105085429B - Aromatic heterocyclic derivative and application thereof in medicines

Info

Publication number: CN105085429B
Application number: CN201510200741.9A
Authority: CN
Inventors: 刘兵; 余天柱; 张英俊; 张翔宇; 张仕国; 郑常春; 张健存
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2014-04-25
Filing date: 2015-04-24
Publication date: 2019-12-10
Anticipated expiration: 2035-04-24
Also published as: WO2015161830A1; CN105085429A; CN105085428B; CN105085428A

Abstract

The invention provides aromatic heterocyclic compounds or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutical composition containing the compounds. The invention also discloses the use of a compound of the invention or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of respiratory diseases, particularly Chronic Obstructive Pulmonary Disease (COPD).

Description

Aromatic heterocyclic derivative and application thereof in medicines

Technical Field

The invention belongs to the field of medicines, and particularly relates to an aromatic heterocyclic compound, a composition containing the compound, and application and a using method of the compound. In particular, the compounds of the invention are PDE4 inhibitors for the treatment of Chronic Obstructive Pulmonary Disease (COPD).

Background

Cyclic nucleotide Phosphodiesterases (PDEs) are an important super enzyme family, which effectively control the intracellular concentrations of cAMP and cGMP by hydrolyzing cAMP and cGMP, thereby regulating the biochemical effects conducted by second messengers in vivo. PDEs are widely distributed in mammalian tissues, and the diversity of PDEs causes different PDE enzymes to have specific distribution at cellular and subcellular levels, can selectively regulate various cellular functions, and is a good drug design and treatment target.

Phosphodiesterase 4(PDE4) has been shown to be a major regulator of cyclic AMP in respiratory smooth muscle and inflammatory cells. Inhibitors of PDE4 are useful in the treatment of a variety of diseases, including allergic and inflammatory diseases, diabetes, central nervous system disorders, pain, and TNF producing viruses.

Cyclic adenosine-3 ', 5' -monophosphate (cAMP) is known to exhibit an important intracellular secondary messenger role (Sutherland and Roll, pharmacol. rev,1960,12: 265). Intracellular hydrolysis of cAMP to adenosine 5 '-monophosphate (AMP) results in a number of inflammatory conditions 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 Phosphodiesterases (PDEs) are a highly varied superfamily of biochemical and functional properties of this enzyme, and are important factors for controlling cAMP (and cGMP) levels. There are 11 distinct families of phosphodiesterases with over 25 gene products. While PDE1, PDE2, PDE3, PDE4 and PDE7 all use cAMP as a substrate, only PDE4 and PDE7 types are highly selective for cAMP hydrolysis. Therefore, PDE inhibitors, in particular PDE4 inhibitors (e.g. ciclopirox (rolipram) or Ro-1724) are considered cAMP enhancers. The immune cells contain PDE3 and PDE4, with PDE4 being ubiquitous in human monocytes. Thus, inhibition of phosphodiesterase type iv is a goal of therapeutic intervention that modulates and thereby is useful in a variety of disease processes. Studies have shown that administration of PDE4 inhibitors has a memory loss-restoring effect in animal models, including those of alzheimer's disease (expetopein ther. targets,2005,9(6): 1283-1305; Drug Discovery Today,2005,10(22): 1503-19).

It was initially observed that xanthine derivatives, theophylline and caffeine inhibit cAMP hydrolysis leading to the discovery of the hydrolytic activity required for cyclic nucleotide Phosphodiesterases (PDEs). Recently, various types of PDEs have been identified (Beavo and Reifsnyder, Trends pharmacol. sci.,1990,11:150) whose selective inhibitory action improves the pharmacotherapeutic effect (Nicholus, Challiss and Shahid, Trends pharmacol. sci.,1991,12: 19). Thus, it is recognized that inhibition of PDE4 inhibits the release of inflammatory mediators (Verghese et al, J.mol.cell.Cardiol.,1989,12 (suppl II): S61).

WO 2004046095 discloses certain arylthiourea derivatives and related compounds having antiviral activity. WO 00/35891 discloses the use as human alpha_1aCertain morpholinones (morpholinones) and morpholinone derivatives that are selective antagonists of the receptor. WO 200450024 discloses 3-aminopyrrolidine derivatives and their use as modulators of chemokine receptors. WO 2005/21515 relates to isoxazoline derivatives which act as selective inhibitors of Phosphodiesterase (PDE) type iv. WO2005/051931 discloses inhibitors of phosphodiesterase type IV.

Summary of the invention

The present invention relates to novel aromatic heterocyclic derivatives and methods of treating chronic respiratory obstruction. The compound or the pharmaceutical composition containing the compound has better affinity effect on PDE4, and particularly has better treatment effect on chronic respiratory obstruction.

In one aspect, the present invention relates to a compound that is a compound of formula (i) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (i):

Wherein:

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

p is 0, 1 or 2;

Each e is independently 0,1 or 2;

Each f is independently 0,1 or 2;

X is-N (R)⁸) -, -O-or-S-;

Y is O or S;

A is a bond or-N (R)⁷)-；

B is- (CR)^aR^b)_p-；

R¹Is D, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_2-10Heterocyclyl, halo C_1-6Alkyl radical, R^9aR⁹N-C_1-6Alkyl-, C_1-6alkyl-C (═ O) -, -C (═ O) OR^9c，-C(＝O)-NR⁹R^9a，R⁹R^9aN-S(＝O)₂-，R^9d-S(＝O)₂-，R^9d-S(＝O)-C_1-6Alkyl-, R⁹R^9aN-C(＝O)-C_1-6alkyl-, C_6-10Aryl radical, C_1-9Heteroaryl group, C_3-8cycloalkyl radical C_1-6alkyl radical, C_2-10Heterocyclyl radical C_1-6Alkyl radical, C_6-10Aryl radical C_1-6Alkyl or C_1-9Heteroaryl C_1-6An alkyl group;

Each R²Independently H, D, F, Cl, Br, I, CN, NO₂，OH，NH₂，-S(＝O)₂Cl，R^9aR⁹N-，-C(＝O)-R^9d，-C(＝O)-NR⁹R^9a，-OC(＝O)-NR⁹R^9a，-OC(＝O)OR^9c，-N(R⁹)-C(＝O)-NR⁹R^9a，-N(R⁹)-C(＝O)OR^9c，R^9d-S(＝O)₂-，R^9d-S(＝O)₂-N(R^9a)-，HOC(＝O)-C_1-6alkoxy-C_1-6alkoxy- (CH)₂)_e-C(＝O)-C_1-6alkoxy-C_2-10heterocyclyl-NH-C_1-6alkoxy-C_2-10Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6alkoxy-C_2-10Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6alkoxy-C_3-8Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6alkoxy-C_6-10Aryl- (CR)^cR^d)_f-NH-C_1-6alkoxy-C_1-6alkyl-NH-C (═ O) -C_1-6Alkoxy-, R^eR^fN-C(＝O)-C_1-6alkoxy-C_1-9heteroaryl-C_2-10heterocyclyl-C (═ O) -C_1-6alkoxy-C_3-8cycloalkyl-C (═ O) -C_2-10heterocyclyl-C (═ O) -C_1-6Alkoxy-, NH₂-C(＝O)-C_1-6alkoxy-C_1-6alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6Alkoxy-, NH₂-NH-C(＝O)-C_1-6Alkoxy-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6alkoxy-C_1-6alkyl-S (═ O)₂-NH-C(＝O)-C_1-6alkoxy-C_1-6alkyl-O-C (═ O) -C_1-6Alkoxy-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6alkoxy-C_2-10heterocyclyl-C (═ O) -C_1-6alkoxy-C_6-10Aryl radical, C_1-9Heteroaryl group, C_1-6Alkoxy, amino-substituted C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl radical, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-10Heterocyclyloxy, C_6-10Aryl radical C_1-6Alkoxy radical, C_3-8Cycloalkyloxy or C_3-8Cycloalkyl radical C_1-6An alkoxy group; each R²Independently optionally substituted by one or more R¹²Substitution;

R³Is D, F, Cl, Br, I, CN, NO₂，NH₂，OH，COOH，C_1-6Alkylamino radical, NH₂-C_1-6alkyl-C_1-9Heteroaryl-, NH₂-C_1-6alkyl-C_1-9heteroaryl-C_1-6Alkyl-, NH₂-C_1-6alkyl-C_6-10Aryl-, NH₂-C_1-6alkyl-C_6-10aryl-C_1-6alkyl-, C_1-6alkyl-C (═ O) -NH-, R¹³O-C(＝O)-C_1-6alkyl-C (═ O) -NH-, C_3-8cycloalkyl-C (═ O) -NH-or-C (═ O) -NR⁹R^9a；

Each R⁵And R⁶Independently H, D, F, Cl, Br, I, CN, NO₂，NH₂，OH，COOH，C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkylamino radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl, mercapto-substituted C_1-6Alkyl, carboxyl substituted C_1-6alkyl radical, NH₂-C_1-6alkyl-C_1-9Heteroaryl-, NH₂-C_1-6alkyl-C_1-9heteroaryl-C_1-6Alkyl-, NH₂-C_1-6alkyl-C_6-10Aryl-, NH₂-C_1-6alkyl-C_6-10aryl-C_1-6alkyl-, C_3-6Cycloalkyl radical, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_3-8cycloalkyl-C (═ O) -NH-, -C (═ O) -NR⁹R^9a，C_6-10Aryl or C_1-9A heteroaryl group;

or optionally R³、R⁵And R⁶Any two of which, together with the C atom to which they are attached, form C ═ O;

R⁴Is C_6-10Aryl radical, C_6-10aryl-S (═ O)₂-，C_1-9Heteroaryl group, C_1-9heteroaryl-S (═ O)₂-，C_6-10Aryl radical C_1-6Alkyl or C_1-9Heteroaryl C_1-6An alkyl group; r⁴Optionally substituted by one or more R¹⁴Substitution;

Each R⁷And R⁸Independently is H, D or C_1-6An alkyl group;

Each R^aAnd R^bIndependently H, D, F, Cl, Br, I, CN, OH, NO₂，NH₂，-COOR^9c，C_1-6Alkyl, -C (═ O) -NR⁹R^9a，-C_1-6alkyl-C (═ O) -NR⁹R^9a，-C(＝S)-NH₂Amino-substituted C_1-6Alkyl, -NH-C (═ O) -R^9b，-C_1-6alkyl-NH-C (═ O) -R^9b，-NH-S(＝O)₂-C_1-6Alkyl radical, -C_1-6alkyl-NH-S (═ O)₂-C_1-6alkyl, -NH-S (═ O)₂-C_3-8Cycloalkyl, -C_1-6alkyl-NH-S (═ O)₂-C_3-8Cycloalkyl, -S (═ O)₂-C_1-6Alkyl radical, -C_1-6alkyl-S (═ O)₂-C_1-6alkyl radical, C_6-10Aryl or C_1-9A heteroaryl group; or R^a，R^bTogether with the carbon atom to which they are attached form a ring of 3 to 8 atoms;

Each R^cAnd R^dIndependently is H, OH, CN, F, Cl, Br, I or C_1-6An alkyl group;

each R^eAnd R^fIndependently is H, OH or C_1-6An alkyl group;

Each R⁹，R^9a，R^9bAnd R^9dIndependently is H, D, OH, NH₂，-S(＝O)₂-NH₂，-C(＝O)-NH₂，-C_1-6alkyl-C (═ O) -NH₂，-C_1-6alkyl-C (═ O) O-C_1-6Alkyl radical, -C_1-6alkyl-O-C (═ O) -C_1-6Alkyl radical, C_1-6Alkyl, -S (═ O)₂-C_1-6Alkyl, -S (═ O)₂-C_3-8Cycloalkyl, halo C_1-6Alkyl, amino-substituted C_1-6Alkyl radical, C_1-6alkoxy radical, C_1-6Alkylamino radical, C_6-10Aryl radical, C_2-10Heterocyclic radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkylamino radical, C_3-8cycloalkyl radical C_1-6Alkyl radical, C_6-10Aryl radical C_1-6Alkyl radical, C_6-10aryloxy radical, C_2-10Heterocyclyloxy, C_3-8Cycloalkyloxy radical, C_6-10Arylamino, C_2-10Heterocyclylamino radical, C_3-8Cycloalkylamino, C_1-9Heteroaryl or C_3-8A carbocyclic group; or R⁹，R^9atogether with the nitrogen atom to which they are attached form a ring of 3 to 8 atoms; said ring of 3 to 8 atoms, R⁹、R^9a、R^9bAnd R^9dEach independently optionally substituted with one or more R¹⁵Substitution;

Each R^9cIndependently of one another, are H, D, -C_1-6alkyl-C (═ O) -NH₂，-C_1-6alkyl-C (═ O) O-C_1-6Alkyl radical, -C_1-6alkyl-O-C (═ O) -C_1-6Alkyl radical, C_1-6Alkyl, halo C_1-6Alkyl, amino-substituted C_1-6Alkyl radical, C_6-10Aryl radical, C_1-9Heteroaryl group, C_3-8Cycloalkyl radical, C_2-10Heterocyclic radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_6-10aryl radical C_1-6Alkyl or C_3-8A carbocyclic group;

Each R¹²Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogeno C_1-6Alkyl, halo C_1-6Alkoxy, halo C_1-6Alkylamino, hydroxy-substituted C_1-6Alkyl, hydroxy-substituted C_1-6Alkoxy or hydroxy substituted C_1-6An alkylamino group;

R¹³Is H, D or C_1-6An alkyl group;

Each R¹⁴Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，-C(＝O)-NH₂，-C_1-6alkyl-C (═ O) -NH₂，-C_1-6alkyl-C (═ O) O-C_1-6Alkyl radical, -C_1-6alkyl-O-C (═ O) -C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogeno C_1-6Alkyl, halo C_1-6Alkoxy, halo C_1-6Alkylamino, hydroxy-substituted C_1-6Alkyl, hydroxy-substituted C_1-6Alkoxy, hydroxy-substituted C_1-6Alkylamino or C_3-6A cycloalkyl group;

Each R¹⁵Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-6Alkyl radical, C_6-10Aryl radical, C_1-9Heteroaryl group, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_2-10Heterocyclic radical, C_2-10Heterocyclyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl carbonyl radical, C_2-10Heterocyclylcarbonyl, C_6-10Aryl carbonyl or C_1-9A heteroaryl carbonyl group; and

The R is¹，R³，R⁵，R⁶，R⁷，R⁸，R^9c，R^a，R^b，R^c，R^d，R^e，R^f，R¹²，R¹³，R¹⁴And R¹⁵Each independently optionally substituted with one or more R; wherein each R is independently H, D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-6alkyl or C_1-6An alkoxy group.

In some of these embodiments, R is¹Is D, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_2-6Heterocyclic radical, C_2-6Heterocyclyl radical C_1-4Alkyl, halo C_1-4Alkyl, -C (═ O) -C_1-4Alkyl, -C (═ O) OR^9c，-C(＝O)-NR⁹R^9a，R⁹R^9aN-C(＝O)-C_1-4Alkyl-, C_6-10Aryl radical, C_6-10Aryl radical C_1-4Alkyl radical, C_1-9heteroaryl or C_3-6cycloalkyl radical C_1-4An alkyl group.

In some of these embodiments, each R is²Independently H, D, F, Cl, Br, I, CN, NO₂，OH，NH₂，HOC(＝O)-C_1-6alkoxy-C_1-4Alkoxy- (CH)₂)_e-C(＝O)-C_1-6alkoxy-C_2-6heterocyclyl-NH-C_1-6alkoxy-C_2-6Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6alkoxy-C_2-6Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6alkoxy-C_3-6cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6alkoxy-C_6-10Aryl- (CR)^cR^d)_f-NH-C_1-6alkoxy-C_1-4alkyl-NH-C (═ O) -C_1-6Alkoxy-, R^eR^fN-C(＝O)-C_1-6alkoxy-C_1-5heteroaryl-C_2-6heterocyclyl-C (═ O) -C_1-6alkoxy-C_3-6cycloalkyl-C (═ O) -C_2-6heterocyclyl-C (═ O) -C_1-6Alkoxy-, NH₂-C(＝O)-C_1-6alkoxy-C_1-6alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6Alkoxy-, NH₂-NH-C(＝O)-C_1-6Alkoxy-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6alkoxy-C_1-4alkyl-S (═ O)₂-NH-C(＝O)-C_1-6alkoxy-C_1-4alkyl-O-C (═ O) -C_1-6Alkoxy-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6alkoxy-C_2-6heterocyclyl-C (═ O) -C_1-6alkoxy-C_6-10Aryl radical, C_1-5Heteroaryl group, C_1-6Alkoxy, amino-substituted C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl radical, C_1-4Alkyl, halo C_1-4Alkyl radical, C_2-6Heterocyclyloxy, C_6-10Aryl radical C_1-4Alkoxy radical, C_3-6Cycloalkyloxy or C_3-6Cycloalkyl radical C_1-4An alkoxy group; each R²Independently optionally substituted by one or more R¹²Substitution;

Each R^cAnd R^dIndependently is H, OH, CN, F, Cl, Br, I or C_1-4An alkyl group;

Each R^eAnd R^fIndependently is H, OH or C_1-4An alkyl group; and

Each R¹²Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4alkylamino, halogeno C_1-4Alkyl, halo C_1-4alkoxy, halo C_1-4Alkylamino, hydroxy-substituted C_1-4Alkyl, hydroxy-substituted C_1-4Alkoxy or hydroxy substituted C_1-4An alkylamino group.

In some of these embodiments, R is³Is D, F, Cl, Br, I, CN, NO₂，NH₂，OH，COOH，C_1-4Alkylamino radical, NH₂-C_1-4alkyl-C_1-5Heteroaryl-, NH₂-C_1-4alkyl-C_1-5heteroaryl-C_1-4Alkyl-, NH₂-C_1-4alkyl-C_6-10Aryl-, NH₂-C_1-4alkyl-C_6-10aryl-C_1-4Alkyl-, C_1-4alkyl-C (═ O) -NH-, R¹³O-C(＝O)-C_1-4alkyl-C (═ O) -NH-, C_3-6cycloalkyl-C (═ O) -NH-or-C (═ O) -NR⁹R^9a；

Each R⁵And R⁶Independently H, D, F, Cl, Br, I, CN, NO₂，NH₂，OH，COOH，C_1-4alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4alkylamino radical, C_1-4Alkoxy, halo C_1-4Alkoxy, hydroxy-substituted C_1-4Alkyl, mercapto-substituted C_1-4Alkyl, carboxyl substituted C_1-4Alkyl radical, NH₂-C_1-4alkyl-C_1-5Heteroaryl-, NH₂-C_1-4alkyl-C_1-5heteroaryl-C_1-4Alkyl-, NH₂-C_1-4alkyl-C_6-10Aryl-, NH₂-C_1-4alkyl-C_6-10aryl-C_1-4Alkyl-, C_3-6Cycloalkyl radical, C_6-10Aryl radical C_1-4Alkyl radical, C_3-6cycloalkyl-C (═ O) -NH-, -C (═ O) -NR⁹R^9a，C_6-10Aryl or C_1-5A heteroaryl group;

each R⁷And R⁸Independently is H, D or C_1-4An alkyl group; and

R¹³Is H, D or C_1-4An alkyl group.

In some embodiments, the present invention relates to a compound of formula (i ') or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound of formula (i'):

Wherein:

X、R₁、R₂、R₄、R₅、R₆、R₇、R_a、R_bAnd p has the meaning as described in the present invention;

R¹¹Is H, C_1-4Alkyl radical, C_1-4alkyl-C (═ O) -, R¹³O-C(＝O)-C_1-4alkyl-C (═ O) -or C_3-6cycloalkyl-C (═ O) -.

in some embodiments, the present invention relates to a compound of formula (ii) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound of formula (ii):

Wherein:

X、R₁、R₂、R₄、R₅、R₆、R_aand R_bHave the meaning as described herein;

m is 0, 1,2 or 3;

R¹⁰Is H, HOC (═ O) -C_1-6Alkyl-, C_1-6Alkoxy- (CH)₂)_e-C(＝O)-C_1-6Alkyl-, C_2-10heterocyclyl-NH-C_1-6Alkyl-, C_2-10Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6Alkyl-, C_2-10Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, C_3-8Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, C_6-10Aryl- (CR)^cR^d)_f-NH-C_1-6Alkyl-, C_1-6alkyl-NH-C (═ O) -C_1-6Alkyl-, R^eR^fN-C(＝O)-C_1-6Alkyl-, C_1-9heteroaryl-C_2-10heterocyclyl-C (═ O) -C_1-6Alkyl-, C_3-8cycloalkyl-C (═ O) -C_2-10heterocyclyl-C (═ O) -C_1-6Alkyl-, NH₂-C(＝O)-C_1-6Alkyl-, C_1-6alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, NH₂-NH-C(＝O)-C_1-6Alkyl-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, C_1-6alkyl-S (═ O)₂-NH-C(＝O)-C_1-6Alkyl-, C_1-6alkyl-O-C (═ O) -C_1-6Alkyl-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6Alkyl-,C_2-10heterocyclyl-C (═ O) -C_1-6Alkyl-, amino-substituted C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkyl radical, C_2-10Heterocyclic radical, C_6-10Aryl radical C_1-6Alkyl radical, C_3-8Cycloalkyl or C_3-8Cycloalkyl radical C_1-6An alkyl group; r¹⁰Optionally substituted by one or more R¹²Substitution; and

In some embodiments, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate or a combination thereof.

In some of these embodiments, R is¹Is methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl ethyl, tetrahydrofuryl methyl, tetrahydrofuryl ethyl, phenyl, benzyl, phenethyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

In some of these embodiments, each R is²Independently H, D, F, Cl, Br, I, CN, NO₂，OH，NH₂Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutyloxyButylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy, cyclohexylmethoxy, cyclohexylethoxy, oxetanyloxy, tetrahydrofuryloxy, benzyloxy, phenylethoxy, HOC (═ O) -C_1-6alkoxy-C_1-3Alkoxy- (CH)₂)_e-C(＝O)-C_1-6alkoxy-C_1-4alkyl-O-C (═ O) -C_1-6alkoxy-C_2-4Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6alkoxy-C_2-4heterocyclyl-C (═ O) -C_1-6alkoxy-C_1-4heteroaryl-C_2-4heterocyclyl-C (═ O) -C_1-6alkoxy-C_3-6cycloalkyl-C (═ O) -C_2-4heterocyclyl-C (═ O) -C_1-6alkoxy-, NH₂-C(＝O)-C_1-6Alkoxy-, NH₂-NH-C(＝O)-C_1-6Alkoxy-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6Alkoxy-, R^eR^fN-C(＝O)-C_1-6alkoxy-C_1-4alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6Alkoxy-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6alkoxy-C_1-3alkyl-S (═ O)₂-NH-C(＝O)-C_1-6alkoxy-C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6alkoxy-C_2-4Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkoxy-, amino-substituted C_1-6Alkoxy radical, C_2-4heterocyclyl-NH-C_1-6Alkoxy-or phenyl- (CR)^cR^d)_f-NH-C_1-6Alkoxy-; each R²Independently optionally substituted by one or more R¹²Substitution;

Each R^cAnd R^dIndependently is H, OH, CN, F, Cl, Br, I or C_1-3An alkyl group;

Each R^eAnd R^fIndependently is H, OH or C_1-3An alkyl group; and

each R¹²Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂COOH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, hydroxy-substituted methyl or halomethyl.

In some of these embodiments, each R is⁵And R⁶Independently H, D, F, Cl, Br, I, NH₂Methyl, ethyl, propyl, isopropyl, hydroxy-substituted methyl, phenyl, benzyl or phenethyl.

In some of these embodiments, R is⁴Is C_6-10Aryl radical, C_6-10aryl-S (═ O)₂-，C_1-9Heteroaryl group, C_1-9heteroaryl-S (═ O)₂-，C_6-10Aryl radical C_1-4Alkyl or C_1-9Heteroaryl C_1-4An alkyl group; r⁴Optionally substituted by one or more R¹⁴Substitution; and

Each R¹⁴Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，-C(＝O)-NH₂，-C_1-4alkyl-C (═ O) -NH₂，-C_1-4alkyl-C (═ O) O-C_1-4Alkyl radical, -C_1-4alkyl-O-C (═ O) -C_1-4Alkyl radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, halogeno C_1-4Alkyl, halo C_1-4Alkoxy, halo C_1-4Alkylamino, hydroxy-substituted C_1-4Alkyl, hydroxy-substituted C_1-4Alkoxy, hydroxy-substituted C_1-4Alkylamino or C_3-6A cycloalkyl group.

In still other embodiments, R is⁴Is phenyl, naphthyl, thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrid-2-yl, pyrid-4-yl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl, naphthyridinyl, furo [3,2-c ] group]Pyridyl, furo [3,2-b ] compounds]Pyridyl, furo [2,3-b ] compounds]Pyridyl, furo [2,3-c ]]Pyridyl, benzoxadiazolyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzopyrazinyl, benzofuranyl, pyridopyrazinyl, 3, 4-dihydro-pyridine [3,2-b ]][1,4]Oxazinyl, 1, 3-benzodioxolyl, 2, 3-dihydrobenzofuranyl, thieno [3,2-b ]]Pyridyl, thieno [2,3-c ]]Pyridyl, thieno [2,3-b ]]Pyridyl, 1, 4-benzodioxanyl, 1,2,3, 4-tetrahydroquinolin-2-yl or benzenesulfonyl; r⁴Optionally substituted by one or more R¹⁴Substitution; and

Each R¹⁴Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，-C(＝O)-NH₂，-C_1-3alkyl-C (═ O) -NH₂，-C_1-3alkyl-C (═ O) O-C_1-4Alkyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, methylamino or ethylamino.

In some of these embodiments, each R is^aAnd R^bIndependently H, D, F, Cl, Br, I, CN, OH, NO₂，NH₂，-COOR^9c，C_1-4Alkyl, -C (═ O) -NR⁹R^9a，-C_1-4alkyl-C (═ O) -NR⁹R^9a，-C(＝S)-NH₂Amino-substituted C_1-4Alkyl, -NH-C (═ O) -R^9b，-C_1-4alkyl-NH-C (═ O) -R^9b，-NH-S(＝O)₂-C_1-4Alkyl radical, -C_1-4alkyl-NH-S (═ O)₂-C_1-4Alkyl, -NH-S (═ O)₂-C_3-6Cycloalkyl, -C_1-4alkyl-NH-S (═ O)₂-C_3-6cycloalkyl, -S (═ O)₂-C_1-4Alkyl radical, -C_1-4alkyl-S (═ O)₂-C_1-4Alkyl radical, C_6-10Aryl or C_1-5A heteroaryl group; or R^a，R^bTogether with the carbon atom to which they are attached form a ring of 3 to 6 atoms;

Each R⁹，R^9aAnd R^9bIndependently is H, D, OH, NH₂，-S(＝O)₂-NH₂，-C(＝O)-NH₂，-C_1-4alkyl-C (═ O) -NH₂，-C_1-4alkyl-C (═ O) O-C_1-6Alkyl radical, -C_1-4alkyl-O-C (═ O) -C_1-6Alkyl radical, C_1-4Alkyl, -S: (＝O)₂-C_1-4Alkyl, -S (═ O)₂-C_3-6Cycloalkyl, halo C_1-4Alkyl, amino-substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-6Alkylamino radical, C_6-10Aryl radical, C_2-6Heterocyclic radical, C_3-6cycloalkyl radical, C_3-6Cycloalkyl radical C_1-4Alkylamino radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_6-10Aryl radical C_1-4Alkyl radical, C_6-10Aryloxy radical, C_2-6Heterocyclyloxy, C_3-6Cycloalkyloxy radical, C_6-10Arylamino, C_2-6Heterocyclylamino radical, C_3-6Cycloalkylamino, C_1-5Heteroaryl or C_3-6A carbocyclic group; or R⁹，R^9aTogether with the nitrogen atom to which they are attached form a ring of 3 to 6 atoms; said ring of 3 to 6 atoms, R⁹、R^9aAnd R^9bEach independently optionally substituted with one or more R¹⁵Substitution;

Each R^9cIndependently of one another, are H, D, -C_1-4alkyl-C (═ O) -NH₂，-C_1-4alkyl-C (═ O) O-C_1-4Alkyl radical, -C_1-4alkyl-O-C (═ O) -C_1-6Alkyl radical, C_1-5Alkyl, halo C_1-4Alkyl, amino-substituted C_1-4Alkyl radical, C_6-10Aryl radical, C_1-5Heteroaryl group, C_3-6Cycloalkyl radical, C_2-6Heterocyclic radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_6-10Aryl radical C_1-4Alkyl or C_3-6A carbocyclic group; and

Each R¹⁵Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-4Alkyl radical, C_6-10Aryl radical, C_1-5Heteroaryl group, C_6-10Aryl radical C_1-4Alkyl radical, C_1-5Heteroaryl C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-6Heterocyclic radical, C_2-6Heterocyclyl radical C_1-4Alkyl radical, C_3-6Cycloalkyl carbonyl radical, C_2-6Heterocyclylcarbonyl, C_6-10Aryl carbonyl or C_1-5A heteroaryl carbonyl group.

In still other embodiments, each R is^aAnd R^bIndependently H, D, F, Cl, Br, I, CN, OH, NO₂，NH₂，-COOR^9cMethyl, ethyl, propyl, isopropyl, -C (═ O) -NR⁹R^9a，-C(＝S)-NH₂Aminomethyl, aminoethyl, -C_1-3alkyl-NH-C (═ O) -R^9b，-C_1-3alkyl-NH-S (═ O)₂-C_3-6Cycloalkyl, -C_1-3alkyl-S (═ O)₂-C_1-3Alkyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, phenyl, pyridyl or pyrimidinyl; or R^a，R^bTogether with the carbon atom to which they are attached form an oxetane or 1, 3-dioxolane;

Each R⁹，R^9aAnd R^9bIndependently is H, D, OH, NH₂，-S(＝O)₂-NH₂，-C(＝O)-NH₂，-C_1-3alkyl-C (═ O) -NH₂，-C_1-4alkyl-C (═ O) O-C_1-4Alkyl radical, -C_1-3alkyl-O-C (═ O) -C_1-3Alkyl, methyl, ethyl, propyl, isopropyl, -S (═ O)₂-C_1-3Alkyl, -S (═ O)₂-cyclopropyl, -S (═ O)₂-cyclobutyl, -S (═ O)₂-cyclopentyl, -S (═ O)₂-cyclohexyl, halo C_1-4Alkyl, amino-substituted C_1-4alkyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, phenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, benzyl, phenethyl, phenoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, phenylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R⁹，R^9aAnd the nitrogen atom connected with the ring form a ring with 3-6 atoms, and the ring with 3-6 atoms is azetidine, pyrrolidine, piperidinePiperazine, morpholine, thiomorpholine, 1-oxo-thiomorpholine or 1, 1-dioxo-thiomorpholine; said ring of 3 to 6 atoms, R⁹、R^9aAnd R^9beach independently optionally substituted with one or more R¹⁵Substitution;

Each R^9cIndependently of one another, are H, D, -C_1-3alkyl-C (═ O) -NH₂，-C_1-3alkyl-C (═ O) O-C_1-3Alkyl radical, -C_1-3alkyl-O-C (═ O) -C_1-4Alkyl, methyl, ethyl, propyl, isopropyl, halogeno C_1-4Alkyl, amino-substituted C_1-4Alkyl, phenyl, benzyl, phenethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and

Each R¹⁵Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂COOH, methyl, ethyl, propyl, phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, benzyl, phenethyl, pyridylmethyl, pyrimidinylmethyl, pyridylethyl, pyrimidylethyl, benzoyl, cyclopropylcarbonyl, cyclobutylcarbonyl or cyclopentylcarbonyl.

In still other embodiments, R is¹⁰Is H, HOC (═ O) -C_1-6Alkyl-, C_1-4Alkoxy- (CH)₂)_e-C(＝O)-C_1-6Alkyl-, C_2-6heterocyclyl-NH-C_1-6Alkyl-, C_2-6Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6Alkyl-, C_2-6Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, C_6-10Aryl- (CR)^cR^d)_f-NH-C_1-6Alkyl-, C_1-4alkyl-NH-C (═ O) -C_1-6Alkyl-, R^eR^fN-C(＝O)-C_1-6Alkyl-, C_1-5heteroaryl-C_2-6heterocyclyl-C (═ O) -C_1-6Alkyl-, C_3-6cycloalkyl-C (═ O) -C_2-6heterocyclyl-C (═ O) -C_1-6Alkyl-, NH₂-C(＝O)-C_1-6Alkyl-, C_1-6alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, NH₂-NH-C(＝O)-C_1-6Alkyl-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, C_1-4alkyl-S (═ O)₂-NH-C(＝O)-C_1-6Alkyl-, C_1-4alkyl-O-C (═ O) -C_1-4Alkyl-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6alkyl-, C_2-6heterocyclyl-C (═ O) -C_1-6Alkyl-, amino-substituted C_1-6Alkyl, halo C_1-6Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C_2-6Heterocyclic radical, C_6-10Aryl radical C_1-4Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-4An alkyl group; r¹⁰Optionally substituted by one or more R¹²Substitution;

Each R^cAnd R^dIndependently is H, OH, CN, F, Cl, Br, I or C_1-3An alkyl group;

Each R^eAnd R^fIndependently is H, OH or C_1-3An alkyl group; and

Each R¹²Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylamino, halogeno C_1-3Alkyl, halo C_1-3Alkoxy, halo C_1-3Alkylamino, hydroxy-substituted C_1-3Alkyl, hydroxy-substituted C_1-3Alkoxy or hydroxy substituted C_1-3An alkylamino group.

In still other embodiments, R is¹⁰Is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, oxetanyl, tetrahydroxyethylFuryl, benzyl, phenethyl, HOC (═ O) -C_1-6Alkyl-, C_1-3Alkoxy- (CH)₂)_e-C(＝O)-C_1-6Alkyl-, C_2-4Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6Alkyl-, C_1-4alkyl-O-C (═ O) -C_1-4alkyl-, C_2-4heterocyclyl-C (═ O) -C_1-6Alkyl-, C_1-4heteroaryl-C_2-4heterocyclyl-C (═ O) -C_1-6Alkyl-, C_3-6cycloalkyl-C (═ O) -C_2-4heterocyclyl-C (═ O) -C_1-6Alkyl-, NH₂-C(＝O)-C_1-6Alkyl-, NH₂-NH-C(＝O)-C_1-6Alkyl-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, R^eR^fN-C(＝O)-C_1-6Alkyl-, C_1-4alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6Alkyl-, C_1-3alkyl-S (═ O)₂-NH-C(＝O)-C_1-6Alkyl-, C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, C_2-4Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, amino-substituted C_1-6Alkyl radical, C_2-4heterocyclyl-NH-C_1-6Alkyl-or phenyl- (CR)^cR^d)_f-NH-C_1-6Alkyl-; r¹⁰Optionally substituted by one or more R¹²Substitution;

Each R^cAnd R^dIndependently H, OH, CN, F, Cl, Br, I, methyl, ethyl or propyl;

each R^eAnd R^fIndependently H, OH, methyl, ethyl or propyl; and

In one aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.

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 embodiments, the pharmaceutical compositions of the present invention further comprise an additional therapeutic agent that is a drug, an active agent, or a combination thereof for the treatment of chronic respiratory obstruction.

In still other embodiments, the pharmaceutical composition of the invention, wherein the additional therapeutic agent is: sodium pyruvate, Doxofylline (Doxofylline), Roflumilast (Roflumilast), Apremilast (Apremilast), Tetomilast (Tetomilast), Tipelukast, Theophylline (Theophylline), Formoterol (Formoterol), Salmeterol (Salmeterol), Fluticasone Propionate (Fluticasone Propionate), Salmeterol/Fluticasone Propionate complex (Salmeterol Xinafoate/Fluticasone Propionate), Rolipram (Rolipram), pirlamilast (Piclamist), Cilomilast (Cilomilast), CDP-840, Indacaterol (Indacaterol), odaterol (olopaterol), QVA149, Midesine (Mideinine), zileseton (Zileseton), salbutamine, carbamazepine, and its epimers, triamcinolone acetonide, isobromate, isobromethamate, isobromethasone, triamcinolone acetonide, isobromate, isobromethasone, isobromate, isobromethasone, isobromethamate, isobromate, isobrometharate, isoetharate, isobrom, glycopyrronium bromide, Umeclidinium bromide, vilanterol, Umeclidinium bromide/vilanterol, aclidinium bromide/formoterol fumarate, LAS40464, LAS100977(abediterol), AZD-8999, RPL-554, OCID-2987, CHF-6001, CR-3465, HPP-737, fluticasone furoate/vilanterol (fluticasone furoate/vilanterol, FF/VI), Benralizumab, revapryltolate or combinations thereof.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a disorder related to phosphodiesterase type 4(PDE 4).

In some embodiments, the diseases associated with phosphodiesterase type 4 (PDE 4) are respiratory diseases, allergies and inflammation, Central Nervous System (CNS) diseases, pulmonary fibrosis or non-insulin dependent diabetes.

In still other embodiments, the respiratory disorder is: chronic respiratory obstruction (COPD), chronic bronchitis, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, allergic bronchitis, bronchiectasis, tuberculosis fibrotic lesions, pulmonary cystic fibrosis, diffuse panbronchiolitis, bronchiolitis obliterans, Acute Respiratory Distress Syndrome (ARDS) or respiratory inflammation.

In still other embodiments, the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis.

In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I), formula (I') or formula (II).

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

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

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

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

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

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

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

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

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

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

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

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

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

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

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

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

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

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

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

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

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may 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 a particular substituent. Unless otherwise indicated An optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, deuterium, hydroxy, amino, fluoro, chloro, bromo, iodo, cyano, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, carboxy, haloalkyl, hydroxy-substituted alkyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (═ O) -, alkyl-S (═ O) —, alkyl-S (═ O)₂-, hydroxy-substituted alkyl-S (═ O)₂Carboxyalkoxy and the like.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other. With R⁹For example, the formula "-N (R)⁹)-C(＝O)-NR⁹R^9a"and structural formula" R^9aR⁹N-C_1-6Alkyl- "R between the two⁹Are not affected by each other, and are in the same chemical formula "-N (R)⁹)-C(＝O)-NR⁹R^9a"inner, plural R⁹Are not affected by each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₆Alkyl "or" C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl, aryl, heteroaryl, and heteroaryl,C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

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

the term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein, wherein the substituents are deuterium, hydroxy, amino, fluoro, chloro, bromo, iodo, cyano, azido, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, carboxy, haloalkyl, hydroxy-substituted alkyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (═ O) -, alkyl-S (═ O)₂-, hydroxy-substituted alkyl-S (═ O)₂Carboxyalkoxy and the like. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH)(CH₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "alkylene" denotes a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of such include methyleneRadical (-CH)₂-, ethylene (-CH)₂CH₂-, propylene (-CH)₂CH₂CH₂-, isopropylidene (-CH (CH)₃)CH₂-) and the like.

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

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

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO₂H or-COOH; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", denotes- (C ═ O) -. The terms "cycloalkylcarbonyl," "heterocyclylcarbonyl," "arylcarbonyl," or "heteroarylcarbonyl" refer to a cycloalkyl, heterocyclyl, aryl, or heteroaryl group attached to the remainder of the molecule through a carbonyl group (i.e., (C ═ O)).

The term "H" represents a single hydrogen atom. Such radicals may be attached to other groups, such as oxygen atoms, to form hydroxyl groups.

The term "D" or "²H "represents a single deuterium atom. For example, one such atom replaces one hydrogen atom in a methyl group to form a mono-deuterated methyl (-CDH)₂) Two deuterium atoms replace two hydrogen atoms in a methyl group to form a bis-deuterated methyl (-CD)₂H) And three deuterium atoms are substituted for three hydrogen atoms in the methyl group to form a tri-deuterated methyl (-CD)₃)。

The term "azido" or "N₃"represents an azide structure. Such groups may be linked to other groups, e.g. to a methyl group to form azidomethane (Men)₃) Or linked to a phenyl group to form azidobenzene (PhN)₃)。

The term "heteroalkyl" means that one or more heteroatoms may be inserted in the alkyl chain, wherein the alkyl group and the heteroatoms have the meaning as described herein. Unless otherwise specified, a heteroalkyl group contains from 1 to 12 carbon atoms, in some embodiments from 1 to 10 carbon atoms, in other embodiments from 1 to 5 carbon atoms, and in yet other embodiments from 1 to 4 carbon atoms. Examples include, but are not limited to, CH₃OCH₂-，CH₃CH₂OCH₂-，CH₃SCH₂-，(CH₃)₂NCH₂-，(CH₃)₂CH₂OCH₂-，CH₃OCH₂CH₂-，CH₃CH₂OCH₂CH₂-，CH₃C(＝O)CH₂-，CH₃C(＝O)OCH₂-，CH₃S(＝O)₂OCH₂-and the like.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

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

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

The terms "hydroxy-substituted alkyl", "hydroxy-substituted alkoxy" or "hydroxy-substituted alkylamino" denote alkyl groups, alkoxy groups or alkylamino groups substituted with one or more hydroxy groups, wherein alkyl groups, alkoxy groups and alkylamino groups have the meaning as described herein. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, hydroxymethoxy, hydroxyethoxy, hydroxymethylamino, hydroxyethylamino, and the like.

The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy and the like.

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

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy)、-OCH₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butyloxy (-OC (CH)₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

the term "alkylthio" includes C_1-6The linear or branched alkyl group is attached to a divalent sulfur atom. In some of these embodiments, alkylthio is lower C_1-4Alkylthio groups, and such examples include, but are not limited to, methylthio (CH)₃S-)。

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C_1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C_1-3Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.

The term "aminoalkyl" or "amino-substituted alkyl" includes C substituted with one or more amino groups_1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups_1-6"lower aminoalkyl" such examples include, but are not limited toWithout limitation, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

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

the term "ring" includes carbocycles, heterocycles, aromatic rings, heteroaromatic rings, spirocycles, spiroheterocycles, fused rings, and the like, wherein the carbocycles, heterocycles, aromatic rings, heteroaromatic rings, spirocycles, spiroheterocycles, fused rings, fused heterocyclic groups have the meaning as described herein.

The terms "fused bicyclic ring," "fused bicyclic group," and "fused ring group" are used interchangeably herein and all refer to a monovalent or multivalent saturated or partially unsaturated bridged ring system, which refers to a non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturated systems, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may be substituted thereon).

The terms "spirocyclic", "spiro", "spirobicyclic" or "spirobicyclic" are used interchangeably herein to refer to a monovalent or multivalent saturated or partially unsaturated ring system in which one ring is derived from a specific ring carbon atom on another ring. For example, as described below, one saturated bridged ring system (rings B and B') is referred to as "fused bicyclic ring", while ring a and ring B share one carbon atom in two saturated ring systems, referred to as "spiro" or "spirobicyclic ring". Each ring in the fused bicyclic and spirobicyclic groups may be a carbocyclic or heterocyclic group, and each ring is optionally substituted with one or more substituents described herein.

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

The term "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of carbocyclyl groups further include, cyclopropane, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

The term "cycloalkylalkyl" denotes an alkyl group substituted with one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group have the meaning as described herein, examples of which include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, and the like.

The term "cycloalkyloxy" or "carbocyclyloxy" includes optionally substituted cycloalkyl or carbocyclyl as defined herein, attached to an oxygen atom and linked to the remaining molecules by an oxygen atom, examples of which include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy and the like.

The term "cycloalkylamino" denotes an amino group substituted with one or two optionally substituted cycloalkyl groups, wherein cycloalkyl has the meaning as described herein, examples of which include, but are not limited to, cyclopropylamino, cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino and the like.

the term "cycloalkylalkoxy" ("carbocyclylalkoxy") means that the alkoxy group is substituted with one or more cycloalkyl ("carbocyclyl") groups, wherein the cycloalkyl ("carbocyclyl") groups and alkoxy groups have the meaning as described herein, examples of which include, but are not limited to, cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy, cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy, and the like.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, wherein no aromatic ring is included in the monocyclic, bicyclic, or tricyclic ring, and at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaoxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, 2-oxa-5-azabicyclo [ 2.2.1.1 ]]Hept-5-yl. In heterocyclic radicals of-CH₂Examples of the substitution of the-group by-C (═ O) -includeBut are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

In one embodiment, heterocyclyl is a 4-7 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 4 to 7 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 to 7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. Said heterocyclyl group of 4 to 7 atoms may be optionally substituted by one or more substituents as described herein.

In another embodiment, heterocyclyl is a 4-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms in which at least one ring atom is substituted by a member selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise indicatedIllustratively, a heterocyclic group of 4 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In another embodiment, heterocyclyl is a 5 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 5-atom heterocyclic group may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may 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, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In another embodiment, heterocyclyl is a 6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 6 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Hetero 6 atomsExamples of cyclic groups include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In yet another embodiment, heterocyclyl is a 7-12 atom heterocyclyl and refers to a saturated or partially unsaturated spiro-or fused-bicyclic ring containing 7-12 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group of 7 to 12 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 7 to 12 atoms include, but are not limited to: 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. Said heterocyclyl group of 7 to 12 atoms may be optionally substituted by one or more substituents as described herein.

The term "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group; wherein heterocyclyl and alkyl groups have the meaning as indicated in the present invention. Examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-ylmethyl, pyrrolidin-2-ylmethyl, morpholin-4-ylmethyl and the like.

The term "heterocyclylalkoxy" includes heterocyclyl-substituted alkoxy groups in which an oxygen atom is attached to the remainder of the molecule; the term "heterocyclylalkylamino" includes heterocyclyl-substituted alkylamino groups in which the nitrogen atom is attached to the remainder of the molecule. Wherein heterocyclyl, alkoxy and alkylamino have the meanings as described herein, such examples include, but are not limited to pyrrolidin-2-ylmethoxy, morpholin-2-ylethoxy, morpholin-3-ylethoxy, piperazin-2-ylethoxy, piperidin-4-ylethylamino and the like.

the term "heterocyclyloxy" includes optionally substituted heterocyclyl groups, as defined herein, attached to an oxygen atom, wherein the oxygen atom is attached to the rest of the molecule, examples of which include, but are not limited to, pyrrolidin-2-yloxy, pyrrolidin-3-yloxy, piperidin-2-yloxy, piperidin-3-yloxy, piperazin-2-yloxy, piperidin-4-yloxy, and the like.

The term "heterocyclylamino" means that the amino group is substituted with one or two heterocyclyl groups in which the nitrogen atom is attached to the rest of the molecule and the heterocyclyl group has the meaning described herein, examples of which include, but are not limited to, pyrrolidin-2-ylamino, pyrrolidin-3-ylamino, piperidin-2-ylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperazin-2-ylamino and the like.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "aralkyl" or "arylalkyl" includes aryl-substituted alkyl groups. In some embodiments, an aralkyl group refers to a "lower aralkyl" group, i.e., the aryl group is attached to C_1-6On the alkyl group of (a). In still other embodiments, an aralkyl group refers to a group containing C_1-4The "phenylalkyl" of an alkyl group of (1). Specific examples thereof include benzyl, diphenylmethyl, phenethyl. The aryl group on the aralkyl group may be further substituted with halogen, alkyl, alkoxy, haloalkyl and haloalkoxy.

The term "aryloxy" includes optionally substituted aryl groups, as defined herein, attached to an oxygen atom and linked to the rest of the molecule by an oxygen atom, wherein the aryl group has the meaning described herein, examples of which include, but are not limited to, phenoxy, tolyloxy, ethylbenzene oxy, and the like.

The term "arylamino" denotes an amino group substituted with one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group may be further substituted.

The term "arylalkylamino" means an alkylamino group substituted with one or more optionally substituted aryl groups, wherein aryl and alkylamino have the meaning described herein, examples of which include, but are not limited to, phenylmethylamino, phenylethylamino, phenylpropylamino, p-tolylmethylamino, and the like.

The term "arylalkoxy" means an alkoxy group substituted with one or more optionally substituted aryl groups, wherein aryl and alkoxy have the meaning described herein, examples of which include, but are not limited to, phenylmethoxy, phenylethoxy, p-tolylmethoxy, phenylpropoxy, and the like.

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

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

As described herein, a ring system formed by a substituent on a ring that is bonded to the center (as shown below) represents that the substituent may be substituted at any substitutable position on the ring. For example, formula e represents any possible substituted position on the A or B ring, such as formula f¹-f⁷Shown in the figure:

The term "heteroarylamino" means that the amino group is substituted with one or two optionally substituted heteroaryl groups, wherein heteroaryl has the meaning as described herein, examples of which include, but are not limited to, N-thienylamino, pyridin-4-ylamino, m-fluoropyridinylamino, dipyridylamino and the like.

The term "heteroaryloxy" or "heteroaryloxy" includes optionally substituted heteroaryl groups, as defined herein, attached to an oxygen atom and linked to the rest of the molecule by an oxygen atom, wherein the heteroaryl group has the meaning as described herein, examples of which include, but are not limited to, pyridyloxy, pyrimidyloxy, and the like.

the term "heteroarylalkyl" denotes an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl groups have the meaning described herein, and examples include, but are not limited to, imidazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl, and the like.

The term "heteroarylalkylamino" includes heteroarylalkyl groups containing a nitrogen atom attached to other groups through the nitrogen atom, wherein heteroarylalkyl has the meaning as described herein, and examples include, but are not limited to, pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino and the like.

The term "heteroarylalkoxy" includes heteroarylalkyl groups containing an oxygen atom attached to other groups through an oxygen atom, wherein heteroarylalkyl has the meaning as described herein, examples of which include, but are not limited to, pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, and the like.

The term "prodrug", as used herein, means a compound which is converted in vivo to a compound of formula (I), formula (I') or formula (II). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl groupI.e. it can be acylated to give the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Discovery,2008,7, 255-.

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

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, J.pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartatesExamples of suitable organic solvents include, but are not limited to, the salts of hydrochloric, benzoic, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

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

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl-yl, -trifluoroacetyl, -t-butyloxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。

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

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

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, and the like.

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 of groups I to XII of the periodic table. In certain embodiments, the salts are 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. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

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

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

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

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present³H，¹⁴c and¹⁸Those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³C. The isotopically enriched compounds can be used for metabolic studies (use)¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques, e.g. Positron Emission Tomography (PET) or tissue distribution involving drugs or substratesMeasured Single Photon Emission Computed Tomography (SPECT), or can be used in radiotherapy of a patient.¹⁸F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (i), (i') or (ii) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using suitable isotopically labelled reagents in place of the original unlabelled reagents used.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²Substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the context of the present invention is to be considered as a substituent of a compound of formula (I), formula (I') or formula (II). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), 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% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D₂O, acetone-d₆、DMSO-d₆Those solvates of (a).

Description of the Compounds of the invention

The aromatic heterocyclic derivatives, the pharmaceutically acceptable salts thereof and the pharmaceutical preparation thereof have the antagonistic effect on PDE4 and have potential application in treatment of chronic respiratory obstruction.

Wherein:

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

p is 0,1 or 2;

Each e is independently 0, 1 or 2;

Each f is independently 0,1 or 2;

X is-N (R)⁸) -, -O-or-S-;

Y is O or S;

A is a bond or-N (R)⁷)-；

B is- (CR)^aR^b)_p-；

Each R⁷And R⁸Independently is H, D or C_1-6An alkyl group;

Each R^cAnd R^dIndependently is H, OH, CN, F, Cl, Br, I or C_1-6An alkyl group;

Each R^eAnd R^fIndependently is H, OH or C_1-6An alkyl group;

Each R⁹，R^9a，R^9bAnd R^9dIndependently is H, D, OH, NH₂，-S(＝O)₂-NH₂，-C(＝O)-NH₂，-C_1-6alkyl-C (═ O) -NH₂，-C_1-6alkyl-C (═ O) O-C_1-6Alkyl radical, -C_1-6alkyl-O-C (═ O) -C_1-6Alkyl radical, C_1-6Alkyl, -S (═ O)₂-C_1-6Alkyl, -S (═ O)₂-C_3-8cycloalkyl, halo C_1-6An alkyl group, a carboxyl group,amino-substituted C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_6-10Aryl radical, C_2-10Heterocyclic radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkylamino radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_6-10Aryl radical C_1-6Alkyl radical, C_6-10Aryloxy radical, C_2-10Heterocyclyloxy, C_3-8Cycloalkyloxy radical, C_6-10Arylamino, C_2-10Heterocyclylamino radical, C_3-8Cycloalkylamino, C_1-9Heteroaryl or C_3-8A carbocyclic group; or R⁹，R^9atogether with the nitrogen atom to which they are attached form a ring of 3 to 8 atoms; said ring of 3 to 8 atoms, R⁹、R^9a、R^9bAnd R^9dEach independently optionally substituted with one or more R¹⁵Substitution;

R¹³Is H, D or C_1-6An alkyl group;

In some of these embodiments, each R is²Independently H, D, F, Cl, Br, I, CN, NO₂，OH，NH₂，HOC(＝O)-C_1-6alkoxy-C_1-4Alkoxy- (CH)₂)_e-C(＝O)-C_1-6alkoxy-C_2-6heterocyclyl-NH-C_1-6alkoxy-C_2-6Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6alkoxy-C_2-6Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6alkoxy-C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6alkoxy-C_6-10Aryl- (CR)^cR^d)_f-NH-C_1-6alkoxy-C_1-4alkyl-NH-C (═ O) -C_1-6Alkoxy-, R^eR^fN-C(＝O)-C_1-6alkoxy-C_1-5heteroaryl-C_2-6heterocyclyl-C (═ O) -C_1-6alkoxy-C_3-6cycloalkyl-C (═ O) -C_2-6heterocyclyl-C (═ O) -C_1-6Alkoxy-, NH₂-C(＝O)-C_1-6alkoxy-C_1-6alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6Alkoxy-, NH₂-NH-C(＝O)-C_1-6Alkoxy-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6alkoxy-C_1-4alkyl-S (═ O)₂-NH-C(＝O)-C_1-6alkoxy-C_1-4alkyl-O-C (═ O) -C_1-6Alkoxy-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6alkoxy-C_2-6heterocyclyl-C (═ O) -C_1-6alkoxy-C_6-10Aryl radical, C_1-5Heteroaryl group, C_1-6Alkoxy, amino-substituted C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-4Alkylamino radical, C_3-6Cycloalkyl radical, C_1-4alkyl, halo C_1-4Alkyl radical, C_2-6Heterocyclyloxy, C_6-10Aryl radical C_1-4alkoxy radical, C_3-6cycloalkyloxy or C_3-6Cycloalkyl radical C_1-4An alkoxy group; each R²Independently optionally substituted by one or more R¹²And (4) substitution.

In some of these embodiments, each R is^cAnd R^dIndependently is H, OH, CN, F, Cl, Br, I or C_1-4An alkyl group.

In some of these embodiments, each R is^eAnd R^fIndependently is H, OH or C_1-4An alkyl group.

in some of these embodiments, each R is¹²Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, halogeno C_1-4Alkyl, halo C_1-4Alkoxy, halo C_1-4Alkylamino, hydroxy-substituted C_1-4Alkyl, hydroxy-substituted C_1-4Alkoxy or hydroxy substituted C_1-4An alkylamino group.

In some of these embodiments, R is³Is D, F, Cl, Br, I, CN, NO₂，NH₂，OH，COOH，C_1-4Alkylamino radical, NH₂-C_1-4alkyl-C_1-5heteroaryl-, NH₂-C_1-4alkyl-C_1-5heteroaryl-C_1-4Alkyl-, NH₂-C_1-4alkyl-C_6-10Aryl-, NH₂-C_1-4alkyl-C_6-10aryl-C_1-4Alkyl-, C_1-4alkyl-C (═ O) -NH-, R¹³O-C(＝O)-C_1-4alkyl-C (═ O) -NH-, C_3-6cycloalkyl-C (═ O) -NH-or-C (═ O) -NR⁹R^9a。

In some of these embodiments, each R is⁵And R⁶Independently H, D, F, Cl, Br, I, CN, NO₂，NH₂，OH，COOH，C_1-4Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4alkynyl, C_1-4Alkylamino radical, C_1-4Alkoxy, halo C_1-4Alkoxy, hydroxySubstituted C_1-4Alkyl, mercapto-substituted C_1-4Alkyl, carboxyl substituted C_1-4Alkyl radical, NH₂-C_1-4alkyl-C_1-5heteroaryl-, NH₂-C_1-4alkyl-C_1-5heteroaryl-C_1-4Alkyl-, NH₂-C_1-4alkyl-C_6-10Aryl-, NH₂-C_1-4alkyl-C_6-10aryl-C_1-4Alkyl-, C_3-6Cycloalkyl radical, C_6-10Aryl radical C_1-4Alkyl radical, C_3-6cycloalkyl-C (═ O) -NH-, -C (═ O) -NR⁹R^9a，C_6-10aryl or C_1-5A heteroaryl group.

Wherein some embodiments are, optionally R³、R⁵And R⁶Any two of which, together with the C atom to which they are attached, form C ═ O.

In some of these embodiments, each R is⁷And R⁸Independently is H, D or C_1-4An alkyl group.

In some of these embodiments, R is¹³Is H, D or C_1-4an alkyl group.

Wherein:

X、R¹、R²、R⁴、R⁵、R⁶、R⁷、R^a、R^bAnd p has the meaning as described in the present invention;

Wherein:

X、R¹、R²、R⁴、R⁵、R⁶、R^aAnd R^bHave the meaning as described herein;

m is 0,1, 2 or 3;

R¹⁰Is H, HOC (═ O) -C_1-6Alkyl-, C_1-6Alkoxy- (CH)₂)_e-C(＝O)-C_1-6Alkyl-, C_2-10heterocyclyl-NH-C_1-6Alkyl-, C_2-10Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6Alkyl-, C_2-10Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, C_3-8Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, C_6-10Aryl- (CR)^cR^d)_f-NH-C_1-6Alkyl-, C_1-6alkyl-NH-C (═ O) -C_1-6Alkyl-, R^eR^fN-C(＝O)-C_1-6Alkyl-, C_1-9heteroaryl-C_2-10heterocyclyl-C (═ O) -C_1-6Alkyl-, C_3-8cycloalkyl-C (═ O) -C_2-10heterocyclyl-C (═ O) -C_1-6Alkyl-, NH₂-C(＝O)-C_1-6Alkyl-, C_1-6alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, NH₂-NH-C(＝O)-C_1-6Alkyl-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, C_1-6alkyl-S (═ O)₂-NH-C(＝O)-C_1-6Alkyl-, C_1-6alkyl-O-C (═ O) -C_1-6Alkyl-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6Alkyl-, C_2-10heterocyclyl-C (═ O) -C_1-6alkyl-, amino-substituted C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkyl radical, C_2-10Heterocyclic radical, C_6-10Aryl radical C_1-6Alkyl radical, C_3-8Cycloalkyl or C_3-8Cycloalkyl radical C_1-6An alkyl group; r¹⁰Optionally substituted by one or more R¹²Substitution; and

In some of these embodiments, each R is²Independently H, D, F, Cl, Br, I, CN, NO₂，OH，NH₂methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxyAlkyl, cyclohexyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy, cyclohexylmethoxy, cyclohexylethoxy, oxetanyloxy, tetrahydrofuryloxy, benzyloxy, phenylethoxy, HOC (═ O) -C_1-6alkoxy-C_1-3Alkoxy- (CH)₂)_e-C(＝O)-C_1-6alkoxy-C_1-4alkyl-O-C (═ O) -C_1-6alkoxy-C_2-4Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6alkoxy-C_2-4heterocyclyl-C (═ O) -C_1-6alkoxy-C_1-4heteroaryl-C_2-4heterocyclyl-C (═ O) -C_1-6alkoxy-C_3-6cycloalkyl-C (═ O) -C_2-4heterocyclyl-C (═ O) -C_1-6Alkoxy-, NH₂-C(＝O)-C_1-6Alkoxy-, NH₂-NH-C(＝O)-C_1-6Alkoxy-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6Alkoxy-, R^eR^fN-C(＝O)-C_1-6alkoxy-C_1-4alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6alkoxy-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6alkoxy-C_1-3alkyl-S (═ O)₂-NH-C(＝O)-C_1-6alkoxy-C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6alkoxy-C_2-4Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkoxy-, amino-substituted C_1-6alkoxy radical, C_2-4heterocyclyl-NH-C_1-6Alkoxy-or phenyl- (CR)^cR^d)_f-NH-C_1-6Alkoxy-; each R²Independently optionally substituted by one or more R¹²And (4) substitution.

In some of these embodiments, each R is^cAnd R^dindependently is H, OH, CN, F, Cl, Br, I or C_1-3An alkyl group.

In some of these embodiments, each R is^eAnd R^fIndependently is H, OHOr C_1-3An alkyl group.

In some of these embodiments, each R is¹²Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂COOH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, hydroxy-substituted methyl or halomethyl.

In some of these embodiments, R is⁴Is C_6-10Aryl radical, C_6-10aryl-S (═ O)₂-，C_1-9Heteroaryl group, C_1-9heteroaryl-S (═ O)₂-，C_6-10Aryl radical C_1-4Alkyl or C_1-9Heteroaryl C_1-4An alkyl group; r⁴optionally substituted by one or more R¹⁴And (4) substitution.

In some of these embodiments, each R is¹⁴Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，-C(＝O)-NH₂，-C_1-4alkyl-C (═ O) -NH₂，-C_1-4alkyl-C (═ O) O-C_1-4Alkyl radical, -C_1-4alkyl-O-C (═ O) -C_1-4Alkyl radical, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4alkylamino, halogeno C_1-4Alkyl, halo C_1-4Alkoxy, halo C_1-4Alkylamino, hydroxy-substituted C_1-4Alkyl, hydroxy-substituted C_1-4Alkoxy, hydroxy-substituted C_1-4Alkylamino or C_3-6A cycloalkyl group.

In still other embodiments, R is⁴Is phenyl, naphthyl, thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrid-2-yl, pyrid-4-yl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl, naphthyridinyl, furo [3,2-c ] group]Pyridyl, furo [3,2-b ] compounds]Pyridyl, furo [2,3-b ] compounds]Pyridyl group, furanAnd [2,3-c ]]Pyridyl, benzoxadiazolyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzopyrazinyl, benzofuranyl, pyridopyrazinyl, 3, 4-dihydro-pyridine [3,2-b ]][1,4]Oxazinyl, 1, 3-benzodioxolyl, 2, 3-dihydrobenzofuranyl, thieno [3,2-b ]]Pyridyl, thieno [2,3-c ]]Pyridyl, thieno [2,3-b ]]Pyridyl, 1, 4-benzodioxanyl, 1,2,3, 4-tetrahydroquinolin-2-yl or benzenesulfonyl; r⁴Optionally substituted by one or more R¹⁴And (4) substitution.

In still other embodiments, each R is¹⁴Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，-C(＝O)-NH₂，-C_1-3alkyl-C (═ O) -NH₂，-C_1-3alkyl-C (═ O) O-C_1-4Alkyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, methylamino or ethylamino.

in some of these embodiments, each R is^aAnd R^bIndependently H, D, F, Cl, Br, I, CN, OH, NO₂，NH₂，-COOR^9c，C_1-4Alkyl, -C (═ O) -NR⁹R^9a，-C_1-4alkyl-C (═ O) -NR⁹R^9a，-C(＝S)-NH₂amino-substituted C_1-4Alkyl, -NH-C (═ O) -R^9b，-C_1-4alkyl-NH-C (═ O) -R^9b，-NH-S(＝O)₂-C_1-4Alkyl radical, -C_1-4alkyl-NH-S (═ O)₂-C_1-4Alkyl, -NH-S (═ O)₂-C_3-6Cycloalkyl, -C_1-4alkyl-NH-S (═ O)₂-C_3-6Cycloalkyl, -S (═ O)₂-C_1-4Alkyl radical, -C_1-4alkyl-S (═ O)₂-C_1-4Alkyl radical, C_6-10Aryl or C_1-5A heteroaryl group.

In some of these embodiments, R is^a，R^bTogether with the carbon atoms to which they are attached form a ring of 3-6 atoms.

In some of these embodiments, each R is⁹，R^9aAnd R^9bIndependently is H, D, OH, NH₂，-S(＝O)₂-NH₂，-C(＝O)-NH₂，-C_1-4alkyl-C (═ O) -NH₂，-C_1-4alkyl-C (═ O) O-C_1-6Alkyl radical, -C_1-4alkyl-O-C (═ O) -C_1-6Alkyl radical, C_1-4alkyl, -S (═ O)₂-C_1-4Alkyl, -S (═ O)₂-C_3-6Cycloalkyl, halo C_1-4Alkyl, amino-substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-6Alkylamino radical, C_6-10Aryl radical, C_2-6Heterocyclic radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-4Alkylamino radical, C_3-6cycloalkyl radical C_1-4Alkyl radical, C_6-10aryl radical C_1-4Alkyl radical, C_6-10Aryloxy radical, C_2-6Heterocyclyloxy, C_3-6Cycloalkyloxy radical, C_6-10Arylamino, C_2-6Heterocyclylamino radical, C_3-6Cycloalkylamino, C_1-5Heteroaryl or C_3-6A carbocyclic group; r⁹、R^9aAnd R^9bEach independently optionally substituted with one or more R¹⁵And (4) substitution.

In some of these embodiments, R is⁹，R^9aTogether with the nitrogen atom to which they are attached form a ring of 3 to 6 atoms; said ring of 3 to 6 atoms being optionally substituted by one or more R¹⁵And (4) substitution.

In some of these embodiments, each R is^9cIndependently of one another, are H, D, -C_1-4alkyl-C (═ O) -NH₂，-C_1-4alkyl-C (═ O) O-C_1-4Alkyl radical, -C_1-4alkyl-O-C (═ O) -C_1-6Alkyl radical, C_1-5Alkyl, halo C_1-4Alkyl, amino-substituted C_1-4alkyl radical, C_6-10Aryl radical, C_1-5Heteroaryl group, C_3-6Cycloalkyl radical, C_2-6Heterocyclic radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_6-10Aryl radical C_1-4Alkyl or C_3-6A carbocyclic group.

In some of these embodiments, each R is¹⁵Independently D, F, Cl, Br, I, CN,NO₂，OH，NH₂，COOH，C_1-4Alkyl radical, C_6-10Aryl radical, C_1-5Heteroaryl group, C_6-10Aryl radical C_1-4Alkyl radical, C_1-5Heteroaryl C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_2-6Heterocyclic radical, C_2-6Heterocyclyl radical C_1-4Alkyl radical, C_3-6Cycloalkyl carbonyl radical, C_2-6Heterocyclylcarbonyl, C_6-10Aryl carbonyl or C_1-5A heteroaryl carbonyl group.

In still other embodiments, each R is^aAnd R^bIndependently H, D, F, Cl, Br, I, CN, OH, NO₂，NH₂，-COOR^9cMethyl, ethyl, propyl, isopropyl, -C (═ O) -NR⁹R^9a，-C(＝S)-NH₂Aminomethyl, aminoethyl, -C_1-3alkyl-NH-C (═ O) -R^9b，-C_1-3alkyl-NH-S (═ O)₂-C_3-6Cycloalkyl, -C_1-3alkyl-S (═ O)₂-C_1-3Alkyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, phenyl, pyridyl or pyrimidinyl.

In still other embodiments, R is^a，R^bTogether with the carbon atom to which they are attached form an oxetane or 1, 3-dioxolane.

In still other embodiments, each R is⁹，R^9aAnd R^9bIndependently is H, D, OH, NH₂，-S(＝O)₂-NH₂，-C(＝O)-NH₂，-C_1-3alkyl-C (═ O) -NH₂，-C_1-4alkyl-C (═ O) O-C_1-4Alkyl radical, -C_1-3alkyl-O-C (═ O) -C_1-3Alkyl, methyl, ethyl, propyl, isopropyl, -S (═ O)₂-C_1-3Alkyl, -S (═ O)₂-cyclopropyl, -S (═ O)₂-cyclobutyl, -S (═ O)₂-cyclopentyl, -S (═ O)₂-cyclohexyl, halo C_1-4Alkyl, amino-substituted C_1-4Alkyl, methoxy, ethoxy, propoxy, isopropoxy, methylaminoDimethylamino, ethylamino, propylamino, isopropylamino, phenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, benzyl, phenethyl, phenoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, phenylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; r⁹、R^9aAnd R^9bEach independently optionally substituted with one or more R¹⁵And (4) substitution.

In still other embodiments, R is⁹，R^9aAnd the nitrogen atom to which it is attached form a 3-6 atom ring, said 3-6 atom ring being azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1-oxo-thiomorpholine or 1, 1-dioxo-thiomorpholine; said ring of 3 to 6 atoms being optionally substituted by one or more R¹⁵And (4) substitution.

In still other embodiments, each R is^9cIndependently of one another, are H, D, -C_1-3alkyl-C (═ O) -NH₂，-C_1-3alkyl-C (═ O) O-C_1-3Alkyl radical, -C_1-3alkyl-O-C (═ O) -C_1-4Alkyl, methyl, ethyl, propyl, isopropyl, halogeno C_1-4Alkyl, amino-substituted C_1-4Alkyl, phenyl, benzyl, phenethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In still other embodiments, each R is¹⁵Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂COOH, methyl, ethyl, propyl, phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, benzyl, phenethyl, pyridylmethyl, pyrimidinylmethyl, pyridylethyl, pyrimidylethyl, benzoyl, cyclopropylcarbonyl, cyclobutylcarbonyl or cyclopentylcarbonyl.

In still other embodiments, R is¹⁰Is H, HOC (═ O) -C_1-6Alkyl-, C_1-4Alkoxy- (CH)₂)_e-C(＝O)-C_1-6Alkyl-, C_2-6heterocyclyl-NH-C_1-6Alkyl-, C_2-6Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6Alkyl-, C_2-6Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, C_6-10Aryl- (CR)^cR^d)_f-NH-C_1-6Alkyl-, C_1-4alkyl-NH-C (═ O) -C_1-6Alkyl-, R^eR^fN-C(＝O)-C_1-6Alkyl-, C_1-5heteroaryl-C_2-6heterocyclyl-C (═ O) -C_1-6alkyl-, C_3-6cycloalkyl-C (═ O) -C_2-6heterocyclyl-C (═ O) -C_1-6alkyl-, NH₂-C(＝O)-C_1-6Alkyl-, C_1-6alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, NH₂-NH-C(＝O)-C_1-6Alkyl-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, C_1-4alkyl-S (═ O)₂-NH-C(＝O)-C_1-6alkyl-, C_1-4alkyl-O-C (═ O) -C_1-4Alkyl-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6Alkyl-, C_2-6heterocyclyl-C (═ O) -C_1-6Alkyl-, amino-substituted C_1-6Alkyl, halo C_1-6Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C_2-6Heterocyclic radical, C_6-10Aryl radical C_1-4Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-4An alkyl group; r¹⁰Optionally substituted by one or more R¹²And (4) substitution.

in still other embodiments, each R is^cAnd R^dIndependently is H, OH, CN, F, Cl, Br, I or C_1-3An alkyl group.

In still other embodiments, each R is^eAnd R^findependently is H, OH or C_1-3An alkyl group.

In still other embodiments, each R is¹²Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylamino, halogeno C_1-3Alkyl, halo C_1-3Alkoxy, halo C_1-3Alkylamino, hydroxy-substituted C_1-3Alkyl, hydroxy-substituted C_1-3Alkoxy or hydroxy substituted C_1-3An alkylamino group.

In still other embodiments, R is¹⁰Is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, oxetanyl, tetrahydrofuranyl, benzyl, phenethyl, HOC (═ O) -C_1-6Alkyl-, C_1-3Alkoxy- (CH)₂)_e-C(＝O)-C_1-6Alkyl-, C_2-4Heterocyclyl- (CH)₂)_e-OC(＝O)-C_1-6Alkyl-, C_1-4alkyl-O-C (═ O) -C_1-4Alkyl-, C_2-4heterocyclyl-C (═ O) -C_1-6Alkyl-, C_1-4heteroaryl-C_2-4heterocyclyl-C (═ O) -C_1-6Alkyl-, C_3-6cycloalkyl-C (═ O) -C_2-4heterocyclyl-C (═ O) -C_1-6Alkyl-, NH₂-C(＝O)-C_1-6Alkyl-, NH₂-NH-C(＝O)-C_1-6Alkyl-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, R^eR^fN-C(＝O)-C_1-6Alkyl-, C_1-4alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-6Alkyl-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-6Alkyl-, C_1-3alkyl-S (═ O)₂-NH-C(＝O)-C_1-6Alkyl-, C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, C_2-4Heterocyclyl- (CH)₂)_e-NH-C(＝O)-C_1-6Alkyl-, amino-substituted C_1-6Alkyl radical, C_2-4heterocyclyl-NH-C_1-6Alkyl-or phenyl- (CR)^cR^d)_f-NH-C_1-6Alkyl-; r¹⁰Optionally substituted by one or more R¹²And (4) substitution.

In still other embodiments, each R is^cAnd R^dIndependently H, OH, CN, F, Cl, Br, I, methyl, ethyl or propyl.

In still other embodiments, each R is^eAnd R^fIndependently H, OH, methyl, ethyl or propyl.

In still other embodiments, each R is¹²Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂COOH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, hydroxy-substituted methyl or halomethyl.

Some of these embodiments are, the present invention includes, but is in no way limited to, compounds having one of the following structures or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds having one of the following structures:

(Note that the numbers of the compounds having the above-mentioned specific structures correspond to those of the examples and those of the compounds obtained as a result of the measurement of the inhibitory activity on PDE4B2 enzyme. for example, Compound 13 of example 1 and Compound 13 obtained as a result of the measurement of the inhibitory activity on PDE4B2 enzyme correspond to Compound 13 herein.)

The invention also comprises the use of the compounds of the invention and pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical product for the treatment of respiratory diseases, particularly chronic respiratory obstruction, allergy and inflammation, Central Nervous System (CNS) diseases, pulmonary fibrosis or non-insulin dependent diabetes mellitus including those described herein.

The compounds of the invention are likewise useful for the production of a medicament for the alleviation, prevention, control or treatment of PDE 4-mediated disorders, in particular chronic respiratory obstruction.

The present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (i), formula (i') or formula (ii) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the present invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated.

Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of, intermediates used in the preparation or purification of the compounds of formula (I), (I ') or (II) or isolated enantiomers of the compounds of formula (I), (I') or (II).

If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Or using 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; pyranonic acids, such as glucuronic acid and galacturonic acid; alpha-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, ethanesulfonic acid, and the like.

If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

compounds of the invention and pharmaceutical compositions, formulations and administrations thereof

The compounds of the invention may be manufactured and formulated as racemic mixtures, enantiomers, diastereomers, rotamers, N-oxides, polymorphs, solvates and pharmaceutically acceptable salts thereof and as active metabolite forms; pharmaceutical compositions comprising a compound of formula (I), formula (I') or formula (II) or a metabolite, enantiomer, diastereomer, N-oxide, polymorph, solvate or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier and optionally excipients may also be produced.

The pharmaceutical compositions of the invention may be manufactured and administered in dosage units, each unit containing an amount of at least one compound according to the invention and/or at least one physiologically acceptable addition salt thereof. The dosage can vary over a very wide range, since the compounds are effective even at low dosage levels and are relatively non-toxic. The compounds can be administered in therapeutically effective low micromolar doses, and the dosage can be increased as needed to the maximum dose that the patient can tolerate.

When useful in therapy, a therapeutically effective amount of a compound of formula (I), formula (I') or formula (II), and pharmaceutically acceptable salts thereof, may be administered as the raw chemical or as an active ingredient in a pharmaceutical composition. Accordingly, the present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (i), formula (Γ), or formula (ii), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

In practice, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions may be presented as discrete units suitable for oral administration, e.g., capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the composition may be present in the following form: powder, granules, solution, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion. In addition to the usual dosage forms shown above, the compounds, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any method known in the pharmaceutical industry. Generally, such methods include the step of combining the active ingredient with a carrier, which constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently brought into the desired form.

The pharmaceutical carrier employed may be a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, 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 herein refers to the total amount of each active ingredient sufficient to show meaningful patient benefit. When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sequentially or simultaneously. Compounds of formula (I), (I') or (II) and pharmaceutically acceptable salts 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 deleterious to the recipient thereof. According to another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation which comprises mixing a compound of formula (i), formula (i') or formula (ii), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.

In general, the compounds of the present invention are administered in therapeutically effective amounts by any conventional means of administration for substances that exert similar effects. Suitable dosage ranges are typically from 1 to 500mg per day, preferably from 1 to 100mg per day, most preferably from 1 to 30mg per day, depending on a variety of factors such as the severity of the disease being treated, the age and relative health of the subject being administered, the potency of the compound used, the route and form of administration, the indication for which administration is being made, and the preferences and experience of the relevant medical practitioner. One of ordinary skill in the art of treating such diseases will be able to determine, without undue experimentation and relying on personal knowledge and the disclosure of this application, a therapeutically effective amount of a compound of the present invention for a given disease.

Administration of the compounds of the present invention may be carried out as desired by the patient, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, transdermally and ocularly.

Various solid oral dosage forms can be used for administration of the compounds of the present invention, such as solid dosage forms of tablets, soft gelatin capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention may be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavoring agents, lubricants, and the like. Timed release capsules, tablets and gels are also advantageous for administration of the compounds of the present invention.

Tablets may be prepared by compression or moulding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.l mg to about 500mg of active ingredient; and each sachet or capsule preferably contains from about 0.1mg to about 500mg of active ingredient. Thus, in the case of one or two tablets, cachets or capsules (once, twice or three times daily), the tablets, cachets or capsules conveniently contain 0.l mg, 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg or 500mg of the active ingredient.

The compounds of the present invention may also be administered in a variety of liquid oral dosage forms, including aqueous and non-aqueous 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 compounds of the invention may be administered by injection in the form of an isotonic sterile solution, for example, by intravenous injection. Other preparations are also possible.

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

Formulations for vaginal administration may be in the form of creams, gels, pastes, foams or sprays containing in addition to the active ingredient such suitable carriers as are known in the art.

For topical administration, the pharmaceutical compositions may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays and drops suitable for administration to the skin, eyes, ears or nose. Topical administration may also include transdermal administration by way of, for example, a transdermal patch.

For the treatment of respiratory diseases, the compounds of the invention are preferably administered by inhalation.

Inhalable preparations include inhalable powders, propellant-containing metered aerosol formulations or propellant-free inhalable formulations. For this purpose, they can be administered directly as powders, preferably in micronized form, or via spray solutions or suspensions containing them.

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

Inhalation aerosols comprising a gaseous propellant, for example a hydrofluoroalkane, may comprise the compounds of the invention in solution or in dispersed form. The propellant-driven formulation may also comprise other ingredients, such as co-solvents, stabilizers, and optionally other excipients.

The propellant-free inhalable formulations containing the compounds according to the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they may be delivered by means of jet atomizers or ultrasonic atomizers known from the prior art, or by means of fine-mist atomizers (soft-mist atomizers), for exampleAnd (4) delivering.

the compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients, including those currently used in the treatment of respiratory disorders, e.g., β 2-agonists, such as salbutamol, formoterol, salmeterol and carmoterol (TA 2005); corticosteroids such as budesonide and its epimers, beclomethasone dipropionate, triamcinolone acetonide, fluticasone propionate, flunisolide, mometasone furoate, rofleponide and ciclesonide; and anticholinergics or antimuscarinics, such as ipratropium bromide, oxitropium bromide, tiotropium bromide, glycopyrrolate, revaproxil or the compounds disclosed in WO 03/053966.

Preferably, the compounds of formula (I), formula (I') or formula (II), alone or in combination with other active ingredients, are administered for the prevention and or treatment of respiratory diseases characterized by airway obstruction, such as asthma, chronic bronchitis or Chronic Obstructive Pulmonary Disease (COPD).

A method of treatment comprising administering a compound or pharmaceutical composition of the invention, further comprising administering to the patient an additional anti-chronic respiratory obstruction drug (combination therapy), wherein the additional anti-chronic respiratory obstruction drug is sodium pyruvate, Doxofylline (Doxofylline), Roflumilast (Roflumilast), Apremilast (Apremilast), Tetomilast (Tetomilast), Tipelukast, Theophylline (Theophylline), Formoterol (Formoterol), Salmeterol (Salmeterol), Fluticasone Propionate (Fluticasone Propionate), Salmeterol/Fluticasone Propionate (Salmeterol Xinafoate/Fluticasone Propionate), rolipramine (Rolipram), piracetamide (Piclamist), Cilomilast (Ciloast), CDP-840, Indacaterol (stepaloterol), olorate (149), ketoroletamol, ketoroletasone (QVA 149), epimeric acid, and epimeric acid (dexamethasone), triamcinolone acetonide, flunisolide, mometasone furoate, rofleponide, ciclesonide, Ipratropium Bromide (Ipratropium Bromide), Ipratropium Bromide complexed with albuterol, oxitropium Bromide, Tiotropium Bromide (Tiotropium Bromide), glycopyrronium Bromide, Umeclidinium Bromide (Umeclidinium Bromide), vilanterol (vilanterol), Umeclidinium/vilanterol complexed (Umeclidinium/vilanterol), aclidinium Bromide (aclidinium Bromide), aclidinium/formoterol fumarate complexed, LAS40464, LAS100977(abediterol), AZD-8999, RPL-554, OCID-2987, CHF-6001, CR-3465, fluticasone furoate/velutin (flutemazuron Bromide), beryllate/flavonid, bervalazurin/flavonide, or combinations thereof.

The term "combined use" or "combination" is to be understood as meaning: the components may be administered simultaneously or more or less simultaneously, or separately and sequentially. In some of these embodiments, one therapeutic agent/pharmaceutically active ingredient may be administered in the morning and the other at a later time of the day. In other embodiments, one therapeutic agent/pharmaceutically active ingredient may be administered once a day and the other once a week. As will be appreciated, if the components are administered directly in succession, the delay in administration of the second component should not be such as to lose the beneficial effect of the combination.

Simultaneous administration may be by any suitable route, and preferably is such as by administering the therapeutic agents to a subject in need thereof by oral or intravenous route or by intramuscular route or subcutaneous injection, such that the administration form has a fixed ratio of each therapeutic agent.

More or less simultaneous or sequential administration of each therapeutic agent may be by any appropriate route, including but not limited to oral route, intravenous route, intramuscular route, and absorption via mucosal tissue. These therapeutic agents may be administered by the same route or by different routes. For example, both therapeutic agents of the combination may be administered orally.

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

The compositions include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in a given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

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

Pharmaceutical compositions suitable for parenteral administration may be prepared as solutions or suspensions of the active ingredient in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof (in oils). In addition, preservatives may be included to prevent the unwanted growth of microorganisms.

Those pharmaceutical compositions suitable for injectable use include sterile aqueous solutions or dispersions. The compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid to enable easy injection.

The pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, protection should preferably be against the contaminating action of microorganisms (e.g., bacteria and fungi). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, 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 an aerosol, cream, ointment, lotion, dusting powder and the like. In addition, the compositions may be in a form suitable for use in a transdermal device, and these formulations may be prepared by conventional processing methods using the compounds or pharmaceutically acceptable salts thereof. By way of example, creams and ointments are prepared in the following manner: mixing the hydrophilic material and water and about 5 wt% to about 10 wt% of the compound to produce a cream or ointment having a desired consistency.

The present invention provides a method of treating a pulmonary disorder (e.g., COPD, asthma or fibrocystic disorder) in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of at least one compound of formula (i), formula (Γ), or formula (ii), or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one compound selected from the group consisting of: steroids (e.g., glucocorticoids), 5-lipoxygenase inhibitors, beta-2 adrenoceptor (adrenoreceptor) agonists, alpha-adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-b agonists, nociceptin agonists, expectorants, mucolytics, decongestants, mast cell stabilizers, antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, and anti-TNF-gamma, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, growth hormone and other PDE4 inhibitors.

Non-limiting examples of anti-hindered amine agents useful in combination with compounds of formula (I), (I') or (II) include: astemizole (astemizole), azatadine (azatadine), azelastine (azelastine), acrivastine (acrivastine), brompheniramine (bropheramine), cetirizine (certirizine), chlorpheniramine (chlorpheniramine), clemastine (clemostine), cyclizine (cyclizine), carithamine (carithazine), cyproheptadine (cyproheptadine), carithamine (caroxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), dimethidine (dimethinide), ebastine (epinastine), epinastine (epinastine), efletirizine (efletirizine), mefenadine (sulfadiazine), pyritinosine (clavine), pyrilamine (clavine), pyrilamine (e), pyrilamine (clavine), pyrilamine (e (clavine), pyrilamine (e), pyrilamine (e), pyrilamine (e), pyrilamine), pyribenoxazimine (e), pyrilamine, Terfenadine (terfenadine), tripelennamine (tripelennamine), temastine (temelastine), alimemazine (trimeprazine) and triprolidine (triprolidine).

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

The term "leukotriene inhibitor" includes any agent or compound that inhibits, arrests, 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-quinolinyl) vinyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropaneacetic acid and its sodium salt, described in U.S. Pat. No. 5,270,324, 1- (((1(R) -3(3- (2, 3-dichlorothieno [3,2-b ] pyridin-5-yl) - (E) -vinyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) thio) methyl) cyclopropaneacetic acid and its sodium salt, described in U.S. Pat. No. 5,472,964, pranlukast (pranlukast), zalukast (zarlukast), and [2- [ [2 (4-tert-butyl-2-thia ] acetic acid and its sodium salt Azolyl) -5-benzofuranyl ] oxymethyl ] phenyl ] acetic acid, which is described in U.S. Pat. No. 5,296,495.

Non-limiting examples of beta-adrenoceptor agonists include: salbutamol, bitolterol, isoetharine, mataproterenol, perbutyrol, salmeterol, terbutaline, isoproterenol, ephedrine, and epinephrine. Non-limiting examples of alpha-adrenoceptor agonists include arylalkylamines (e.g., phenylpropanolamine and pseudoephedrine), imidazoles (e.g., naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline), and cycloalkylamines (e.g., hexahydrodeoxyephedrine).

A non-limiting example of a mast cell stabilizer is nedocromil sodium (nedocromil sodium). A non-limiting example of an expectorant is guaifenesin (guaifenesin). Non-limiting examples of decongestants are pseudoephedrine (pseudoephedrine), phenylpropanolamine (phenylpropanolamine), and phenylephrine (phenyleephrine).

Non-limiting examples of NK1, NK2, and NK3 tachykinin receptor antagonists include CP-99, 994, and SR 48968. Non-limiting examples of muscarinic antagonists include ipratropium bromide (ipratropium bromide) and tiaatropium bromide.

GABA_BNon-limiting examples of agonists include baclofen (baclofen) and 3-aminopropyl-phosphonic acid. Dopamine agonists include quinpirole (quinpirole), ropinirole (ropinairole), pramipexole (pramipexole), pergolide (pergolide) and bromocriptine (bromocriptine).

"5-lipoxygenase inhibitor" includes any agent or compound that inhibits, retards, or interacts with the enzymatic action of 5-lipoxygenase. Non-limiting examples of 5-lipoxygenase inhibitors include zileuton (zileuton), doxobenzone (docbenone), piraprost (piripost), ICI-D2318, and ABT 761.

The dosage of the compounds of the invention will depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of dosage intervals, the particular compound used, the potency of the compound, the toxicological profile and the pharmacokinetic profile.

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

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

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

Use of the Compounds and pharmaceutical compositions of the invention

The pharmaceutical composition of the invention is characterized by comprising a compound represented by formula (I), formula (I') or formula (II) or a compound listed in the invention, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

The amount of compound in the compositions of the invention is effective to detectably antagonize PDE4 to treat: pain (e.g., 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, gram negative septicemia, toxic shock syndrome, stroke, ischemia reperfusion injury, kidney reperfusion injury, glomerulonephritis, Parkinson's disease, Alzheimer's disease, Mild Cognitive Impairment (MCI), depression, anxiety, graft-to-host reaction (i.e., graft-versus-host disease), allograft rejection (e.g., acute and chronic allograft rejection), acute respiratory distress syndrome, delayed type hypersensitivity reaction, chronic inflammatory bowel disease, and neuropathic pain, Atherosclerosis, cerebral ischemia, osteoarthritis, multiple sclerosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, kaposi's sarcoma-associated virus (i.e. kaposi's sarcoma), meningitis, fibrocysts, premature labor, cough, pruritus, multiple organ dysfunction, psoriatic arthritis, herpes, encephalitis, traumatic brain injury, CNS tumors, interstitial pneumonia, allergy, crystallization-induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, ocular inflammation, corneal neovascularization, polymyositis, acne, esophagitis, glossitis, airflow obstruction, airway allergy (i.e. 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, hyperinflation (hyperinflation), hypoxemia, hyperoxia-induced inflammation, hypoxia, pulmonary fibrosis, pulmonary hypertension, peritonitis associated with continuous emergency peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway (small airway) disease, airway obstruction, disorders of ventilation and blood flow, wheezing, colds, gout, alcoholic liver disease, lupus, periodontitis, cancer, graft reperfusion injury, early graft rejection (e.g., acute allograft rejection), airway hyperreactivity, allergic contact dermatitis, allergic rhinitis, non-allergic rhinitis, alopecia areata, autoimmune ear (including, e.g., meniere's disease), Autoimmune hemolytic syndrome, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune vasculitis, autoimmune thrombocytopenia, chronic inflammatory demyelinating polyneuropathy, cirrhosis, dermatomyositis, diabetes mellitus, drug-induced autoimmunity, endometriosis, fibrotic diseases, gastritis, Goodpasture's syndrome, graves' disease, guillain-Barre disease, hashimoto's thyroiditis, hepatitis-related autoimmunity, HIV-related autoimmune syndrome and blood diseases, hypophyseal hyposecretion (hypophysis), interstitial cystitis, juvenile arthritis, langerhans' cell proliferation, lichen planus, metal-induced autoimmunity, myocarditis (including viral myocarditis), myositis, neuropathy (including, e.g., IgA neuropathy, cell membrane neuropathy and idiopathic neuropathy), Nephritis syndrome, optic neuritis, pancreatitis, post-infection autoimmunity, primary gallbladder cirrhosis, reactive arthritis, ankylosing spondylitis, reiter's syndrome, reperfusion injury, scleritis, scleroderma, a blood disorder secondary to an autoimmune disease (e.g., anemia), a polysiloxane (silicone) implant-associated autoimmune disease, sjogren's syndrome, systemic lupus erythematosus, transverse myelitis, tubulointerstitial nephritis, uveitis, and vitiligo, the method comprising administering to the disease an effective amount of at least one compound of formula (i), formula (i ') or formula (ii), or a pharmaceutically acceptable salt or solvate thereof.

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.

General Synthesis of Compounds of the invention

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

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

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Lingkai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

The anhydrous tetrahydrofuran is obtained by refluxing and drying the metallic sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide and petroleum ether were used as they were dried over anhydrous sodium sulfate in advance.

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

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. The test conditions of the nuclear magnetic resonance hydrogen spectrum are as follows: brookfield (Bruker) nuclear magnetic instrument at 400MHz or 600MHz in CDC1 at room temperature₃，DMSO-d₆，CD₃OD or acetone-d₆as solvent (reported in ppm) TMS (0ppm) or chloroform (7.26ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), m (multiplet, multiplet), br (broad ), dd (doublet of doublets, quartet), dt (doublet of triplets, doublet). Coupling constants are expressed in hertz (Hz).

Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

Low resolution Mass Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.

both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:

TABLE 1 gradient elution conditions

Time (min)	A(CH₃CN,0.1％HCOOH)	B(H₂O,0.1％HCOOH)
			0-3	5-100	95-0

Time (min)	A(CH₃CN,0.1％HCOOH)	B(H₂O,0.1％HCOOH)
			3-6	100	0
6-6.1	100-5	0-95
			6.1-8	5	95

Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm,10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.

The purity of the compound is characterized in the following way: 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) with UV detection at 210nm/254 nm.

The following acronyms are used throughout the invention:

HOAc acetic acid

MeCN,CH₃CN acetonitrile

Boc₂Di-tert-butyl O dicarbonate

CHCl₃chloroform

CDC1₃Deuterated chloroform

DMSO dimethyl sulfoxide

DMF N, N-dimethylformamide

DIPEA N, N-diisopropylethylamine

DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene

KHMDS potassium bis (trimethylsilyl) amide

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EtOAc, EA ethyl acetate

EtOH ethanol

Et₂O Ether

Fmoc-OSU 9-fluorenylmethyl-N-succinimidyl carbonate

Me-methyl group

Et-,CH₃CH₂-ethyl radical

Ph-,C₆H₅-phenyl radical

Bn-benzyl

HCl hydrogen chloride

HOAT N-hydroxy-7-azabenzotriazole

HOBT 1-hydroxybenzotriazole

THF tetrahydrofuran

MgSO₄Magnesium sulfate

MgCl₂Magnesium chloride

MeOH,CH₃OH methanol

CD₃OD deuterated methanol

HCHO Formaldehyde

CH₂Cl₂DCM dichloromethane

mL, m mL

M, mol/L mol/liter

PE Petroleum ether (60-90 deg.C)

K Potassium

RT Room temperature

rt Retention time

NaBH₃CN Cyanoborohydride sodium salt

NaOH sodium hydroxide

Na₂CO₃sodium carbonate

K₂CO₃Potassium carbonate

NaHCO₃Sodium bicarbonate

Na₂SO₄Sodium sulfate

H₂O water

The following synthetic schemes describe the procedures for preparing the compounds of the present invention. Unless otherwise stated, each p, R^a，R^b，R¹，R⁵，R⁶，R⁹，R^9a，R^9b，R^9c，R¹⁰，R¹¹，R¹⁴And R¹⁵Have the meaning as described in the present invention.

The first synthesis method comprises the following steps:

Target compound (A)21) And a target compound (a)22) Can be prepared by a first synthesis method, wherein n is 0,1, 2,3,4 or 5, and x is 1,2 or 3. Compound (A) to (B)1) Condensing with glycine methyl ester hydrochloride to obtain a compound (2) Compound (A) to (B)2) Sulfurization by Lawson's reagent to give compound (A)3) Compound (A) to (B)3) Formation of a thiomethyl group under the conditions of trimethyloxonium tetrafluoroborate to give a compound (A)4) Compound (A) to (B)4) Under basic conditions (e.g., KHMDS, etc.), (5-1) Reaction to give a compound (5) Compound (A) to (B)5) Under alkaline conditions (e.g. LiOH. H)₂O、NH₃MeOH, etc.) to yield compound (A)6) Compound (A) to (B)6) And a compound of (A)20-1) Condensation to give the compound (A)20) Compound (A) to (B)20) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound21)。

Compound (A) to (B)21) Further treatment with a base (e.g., sodium hydroxide, etc.) to give the objective compound (A)22)。

And a second synthesis method comprises the following steps:

Target compound (A)23) Can be prepared by a second synthesis method, wherein n is 0, 1,2,3,4 or 5. Compound (A) to (B)22) And R¹¹OH to obtain the target compound (23)。

The third synthesis method comprises the following steps:

Target compound (A)25) Can be prepared by a third synthesis method, wherein q is 0,1, 2,3 or 4. Compound (A) to (B)5) And 4-methylpyridine derivatives (24-1) Reaction to give a compound (24) Compound (A) to (B)24) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound25)。

The synthesis method comprises the following steps:

Target compound (A)28) Can be prepared by a synthesis method IV, wherein q is 0,1, 2,3 or 4. Compound (A) to (B)6) With cyanuric fluoride to give a compound26) Compound (A) to (B)26) Reacting with a 4-aminopyridine derivative to obtain a compound (A)27) Compound (A) to (B)27) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound28)。

The synthesis method comprises the following steps:

Target compound (A)30) Can be prepared by synthesis method five, wherein q is 0, 1,2,3 or 4. Compound (A) to (B)6) And a compound of (A)29-1) Reaction to give a compound (29) Compound (A) to (B)29) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound30)。

The synthesis method comprises the following steps:

Target compound (A)33) Can be used for dredgingPrepared by a sixth synthetic method, wherein q is 0,1, 2,3 or 4, R^14xIs D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，-C(＝O)O-C_1-6Alkyl, -C (═ O) -NH₂，-C_1-6alkyl-C (═ O) -NH₂，-C_1-6alkyl-C (═ O) O-C_1-6Alkyl radical, -C_1-6alkyl-O-C (═ O) -C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogeno C_1-6Alkyl, halo C_1-6Alkoxy, halo C_1-6Alkylamino, hydroxy-substituted C_1-6Alkyl, hydroxy-substituted C_1-6Alkoxy, hydroxy-substituted C_1-6Alkylamino or C_3-6A cycloalkyl group. Compound (A) to (B)6) And a compound of (A)31-1) Reaction to give a compound (31) Compound (A) to (B)31) Hydrolyzing under alkaline condition to obtain compound (A)32) Compound (A) to (B)32) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound33)。

The synthesis method comprises the following steps:

Target compound (A)33) Can be prepared by a synthesis method seven, wherein q is 0,1, 2,3 or 4. Compound (A) to (B)6) And a compound of (A)32-1) Reaction to give a compound (32) Compound (A) to (B)32) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound33)。

The synthesis method comprises the following steps:

Target compound (A)35) Can be prepared by a synthesis method eight, wherein n is 0,1, 2,3,4 or 5. Compound (A) to (B)26) With a phenylamine derivative to give a compound34) Compound (A) to (B)34) In an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.)) Deprotection to give the target Compound (35)。

The synthesis method comprises the following steps:

Target compound (A)37) Can be prepared by a ninth synthesis method. Compound (A) to (B)6) And a compound of (A)36-1) Reaction to give a compound (36) Compound (A) to (B)36) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound37)。

The synthesis method comprises the following steps:

Target compound (A)39) Can be prepared by a synthesis method, wherein n is 0, 1,2,3,4 or 5. Compound (A) to (B)6) With a benzenesulfonamide derivative to give a compound (38) Compound (A) to (B)38) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound39)。

The synthesis method comprises the eleven steps:

Target compound (A)42-1) A target compound (a)42-3) And a target compound (a)42-5) Can be prepared by a synthesis method eleven, wherein n is 0, 1,2,3,4 or 5, R^xIs C_1-6Alkyl or C_3-8A cycloalkyl group.

compound (A) to (B)6) And a compound of (A)40-1) Reaction to give a compound (40) Compound (A) to (B)40) Under catalytic conditions to give compounds41) Compound (A) to (B)41) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound42-1)。

Compound (A) to (B)41) And R^9bReaction of-COOH to give the compound(42-2) Compound (A) to (B)42-2) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound42-3)。

Compound (A) to (B)41) And R^x-SO₃H reaction to give the compound (42-4) Compound (A) to (B)42-4) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound42-5)。

The synthesis method comprises the following steps:

Target compound (A)46-1) And a target compound (a)46) Can be prepared by a synthesis method twelve, wherein n is 0,1, 2,3,4 or 5.

Compound (A) to (B)6) And a compound of (A)43-1) Reaction to give a compound (43) Compound (A) to (B)43) Hydrolyzing under alkaline condition to obtain compound (A)44) Compound (A) to (B)44) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound46-1)。

Compound (A) to (B)44) And NHR⁹R^9aReaction to give a compound (45) Compound (A) to (B)45) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound46)。

thirteen synthetic methods:

target compound (A)48) Can be prepared by a thirteen synthetic method, wherein n is 0, 1,2,3,4 or 5, the ring Hy is a ring consisting of 3 to 8 atoms, s is 0, 1,2,3,4, 5, 6,7, 8, 9, 10, 11, 12, 13 or 14, and x is 1,2 or 3. Compound (A) to (B)44) And a compound of (A)47-1) Reaction to give a compound (47) Compound (A) to (B)47) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound48)。

The synthesis method is fourteen:

Target compound (A)50) Can be prepared by a synthesis method fourteen, wherein n is 0, 1,2,3,4 or 5. Compound (A) to (B)44) And R^9cOH to give the compound (A)49) Compound (A) to (B)49) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound50)。

The synthesis method comprises the following fifteen:

Target compound (A)52) Can be prepared by a synthesis method fifteen, wherein x is 1,2 or 3. Compound (A) to (B)6) And a compound of (A)50-1) Reaction to give a compound (51) Compound (A) to (B)51) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound52)。

The synthesis method is sixteen:

Target compound (A)57) Can be prepared by a sixteen synthetic method, n is 0,1, 2,3,4 or 5, x is 1,2 or 3. Compound (A) to (B)4) And a compound of (A)53-1) Cyclizing under alkaline conditions to obtain a compound (A)53) Compound (A) to (B)53) Under alkaline conditions (e.g. LiOH. H)₂O、NH₃MeOH, etc.) to yield compound (A)54) Compound (A) to (B)54) And a compound of (A)20-1) Condensation to give the compound (A)55) Compound (A) to (B)55) Reduction and debenzylation to obtain the compound (A)56) Compound (A) to (B)56) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound57)。

Seventeen synthetic methods are as follows:

Target compound (A)62) Can be prepared by a seventeenth synthesis method, wherein n is 0, 1,2,3,4 or 5. Compound (A) to (B)4) And a compound of (A)58-1) Cyclizing under alkaline conditions to obtain a compound (A)58) Compound (A) to (B)58) Under alkaline conditions (e.g. LiOH. H)₂O、NH₃MeOH, etc.) to yield compound (A)59) Compound (A) to (B)59) And a compound of (A)20-1) Condensation to give the compound (A)60) Compound (A) to (B)60) Reduction and debenzylation to obtain the compound (A)61) Compound (A) to (B)61) Oxidation to obtain the target compound (62)。

Eighteen synthetic methods:

Target compound (A)67) Can be prepared by eighteen synthetic methods, n is 0,1, 2,3,4 or 5, and x is 1,2 or 3. Compound (A) to (B)2) And a compound of (A)5-1) Under alkaline conditions to obtain a compound (A)63) Compound (A) to (B)63) Cyclizing to give a compound (64) Compound (A) to (B)64) Under alkaline conditions (e.g. LiOH. H)₂O、NH₃MeOH, etc.) to yield compound (A)65) Compound (A) to (B)65) And a compound of (A)20-1) Condensation to give the compound (A)66) Compound (A) to (B)66) Deprotection in organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain target compound67)。

The synthesis method comprises the following steps:

TargetingA composition of (A), (B), (C), (82) Can be prepared by a nineteen synthetic method, wherein n is 0, 1,2,3,4 or 5. Compound (A) to (B)68) Reaction with benzyl bromide to give compound (b)69) Compound (A) to (B)69) Hydrolyzing under alkaline condition (such as NaOH) to obtain compound(s) ((s))70) Compound (A) to (B)70) Condensing with glycine methyl ester hydrochloride to obtain a compound (71) Compound (A) to (B)71) Sulfurization by Lawson's reagent to give compound (A)72) Compound (A) to (B)72) Formation of a thiomethyl group under the conditions of trimethyloxonium tetrafluoroborate to give a compound (A)73) Compound (A) to (B)73) Under basic conditions (e.g., KHMDS, etc.), (5-1) Reaction to give a compound (74) Compound (A) to (B)74) Under alkaline conditions (e.g. LiOH. H)₂O、NH₃MeOH, etc.) to yield compound (A)75) Compound (A) to (B)75) And a compound of (A)20-1) Condensation to give the compound (A)76) Compound (A) to (B)76) Reduction to give the compound (A)77) Compound (A) to (B)77) Reacting with 4-bromobutyl acetate to obtain a compound (A)78) Compound (A) to (B)78) Hydrolyzing under alkaline condition to obtain compound (A)79) Compound (A) to (B)79) Reacting with 4-toluenesulfonyl chloride to obtain a compound (A)80) Compound (A) to (B)80) And a compound of (A)80-1) Under alkaline conditions to obtain a compound (A)81) Compound (A) to (B)81) Reacting under acidic condition to obtain a target compound (82)。

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

Examples

Example 1: the compound (S) -5- (1-aminoethyl) -N- (2-chloro-6-fluorobenzyl) -2- (3- (cyclopropylmethoxy) - Synthesis of 4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound methyl 2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzamide) acetate

Reacting 3- (cyclopropylmethoxy) -4- (difluoromethoxy)Methyl) benzoic acid (10g,38.76mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (11.1g,58.14mmol) and N-hydroxy-7-azabenzotriazole (5.28g,38.76mmol) were added to dichloromethane (50mL), stirred at room temperature for 30min, methyl aminoacetate hydrochloride (5.813g,46.51mmol) was added, N-diisopropylethylamine (27.06mL,155.04mmol) was added dropwise to the solution at 0 deg.C, stirred at room temperature for 10h, washed with water (25 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 11.12g of a white solid, yield: 87 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.47(s,1H),7.29(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.18(d,J＝8.3Hz,1H),6.68(t,J_F-H＝75.0Hz,1H),4.22(d,J＝5.0Hz,2H),3.92(d,J＝7.0Hz,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 methyl 2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenylthiocarboxamide) acetate

The compound methyl 2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzamide) acetate (11.12g,33.77mmol) and lawson's reagent (13.66g,33.77mmol) were added to tetrahydrofuran (50mL), reacted at 75 ℃ for 2h, saturated sodium bicarbonate solution (60mL) was added, ethyl acetate (20mL × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 10.5g yellow solid, yield: 90 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.07(s,1H),7.55(d,J＝2.0Hz,1H),7.24(d,J＝2.1Hz,1H),7.16(d,J＝8.3Hz,1H),6.68(t,J_F-H＝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]⁺。

And step 3: synthesis of compound methyl 2- (((3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) (methylthio) methylene) amino) acetate

To a solution of trimethyloxonium tetrafluoroborate (4.28g,28.96mmol) in dichloromethane (20mL) at-78 deg.C was added dropwise a solution of the compound methyl 2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenylthiocarboxamide) acetate (5g,14.48mmol) in dichloromethane (40mL), stirred at 0 deg.C for 5h, washed with saturated sodium bicarbonate solution (25 mL. times.3) and the organic phase washed with anhydrous Na₂SO₄drying and removal of the solvent gave 5g of a yellow oil, yield: 96 percent.

¹H NMR(400MHz,CDCl_3，Z/E＝1:1):δppm 7.16-7.20(m,2H),7.10-7.13(m,2H),6.83-6.87(m,2H),6.65(t,J_F-H＝75.2Hz,2H),4.44(s,2H),4.15(s,2H),3.90(d,J＝6.9Hz,2H),3.85(d,J＝6.9Hz,2H),3.79(s,3H),3.72(s,3H),2.45(s,3H),2.16(s,3H),1.27-1.29(m,2H),0.62-0.67(m,4H),0.34-0.36(m,4H)；

MS-ESI:m/z 360.1[M+H]⁺。

And 4, step 4: synthesis of Compound (S) - (1-fluoro-1-oxopropan-2-yl) carbamic acid tert-butyl ester

N-Boc L-alanine (6.5g,34.4mmol) and triethylamine (5.27mL,37.83mmol) were dissolved in dichloromethane (60mL) at-40 deg.C, to this solution was added dropwise melamine fluoride (5.62mL,68.8mmol) and reacted at-10 deg.C for 2h, washed with ice water (20 mL. times.5) and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 5.84g of a white solid, yield: 89 percent.

And 5: synthesis of the compound (S) -methyl 5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylate

Dissolving the compound methyl 2- (((3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) (methylthio) methylene) amino) acetate (5.2g,14.48mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (4.15g,21.72mmol) in anhydrous tetrahydrofuran (25mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (36.2mL,36.2mmol) at-78 deg.C, reacting at 78 deg.C for 1h, adding water (20mL), quenching the reaction, extracting with ethyl acetate (25 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removing the solvent,The concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give 5.13g of a yellow solid, yield: 73 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.64(s,1H),7.62(d,J＝8.4Hz,1H),7.23(d,J＝8.3Hz,1H),6.70(t,J_F-H＝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 6: synthesis of the compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid

the compound methyl (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylate (5.13g,10.63mmol) and lithium hydroxide monohydrate (2.23g,53.16mmol) were dissolved in a mixed solvent of tetrahydrofuran (40mL) and water (20mL) to react at 40 ℃ for 2h, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added to extract (20 mL. times.3), the organic phases were combined and Na was added thereto₂SO₄Drying and removal of the solvent gave 4.8g of a yellow solid, yield: 96 percent.

¹H NMR(600MHz,CD₃OD):δppm 7.80(d,J＝1.8Hz,1H),7.66(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.29(d,J＝8.3Hz,1H),6.90(t,J_F-H＝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[M-H]^-。

And 7: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2-chloro-6-fluorobenzyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (130.56mg,0.96mmol) were dissolved inTo dichloromethane (10mL) was added dropwise 2-chloro-6-fluorobenzylamine (0.1mL,0.77mmol) and N, N-diisopropylethylamine (0.33mL,1.92mmol) at 0 ℃ to the solution, followed by stirring at room temperature for 22h, washing with water (20 mL. times.3), and adding anhydrous Na to the organic phase₂SO₄drying, removal of solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) gave 264mg of a white solid, yield: 67%.

¹H NMR(400MHz,CDCl₃):δppm 7.59(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.54(d,J＝1.8Hz,1H),7.47–7.45(m,1H),7.27(d,J＝4.6Hz,1H),7.24(d,J＝8.4Hz,1H),7.10–7.06(m,1H),6.71(t,J_F-H＝75.0Hz,1H),5.32–5.25(m,1H),4.87–4.84(m,2H),3.98(d,J＝6.9Hz,2H),1.56(d,J＝7.0Hz,3H),1.45–1.43(m,9H),1.38–1.34(m,1H),0.73–0.68(m,2H),0.44–0.40(m,2H)。

And 8: synthesis of Compound (S) -5- (1-aminoethyl) -N- (2-chloro-6-fluorobenzyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (S) - (1- (4- ((2-chloro-6-fluorobenzyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.26g,0.43mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 16h, filtered and washed with ethyl acetate (15 mL. times.3) to give 128mg of a white solid, yield: and 55 percent.

Compound 13:¹H NMR(400MHz,CD₃OD):δppm 7.76(d,J＝1.9Hz,1H),7.70(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.39–7.35(m,1H),7.31(d,J＝8.2Hz,2H),7.18–7.13(m,1H),6.91(t,J_F-H＝74.8Hz,1H),5.19–5.14(m,1H),4.81–4.82(br.s,2H),4.01(d,J＝6.9Hz,2H),1.76(d,J＝7.0Hz,3H),1.34–1.31(m,1H),0.69–0.66(m,2H),0.43–0.41(m,2H)；

MS-ESI:m/z 510.2[M+H-HCl]⁺。

Example 2: the compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (3, 4-dimethoxyphenyl) Synthesis of oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound 3, 4-dimethoxybenzoic acid methyl ester

Methyl 3-hydroxy-4-methoxybenzoate (10g,54.94mmol) was dissolved in acetone (50mL), anhydrous potassium carbonate (15.2g,110.0mmol) and iodomethane (6.8mL,109.2mmol) were added in this order, the tube was sealed, and the reaction was carried out at 60 ℃ for 4.5 h. Saturated NaCl solution (20mL) was added, extracted with ethyl acetate (25 mL. times.3), the organic phases combined and the organic phase extracted with anhydrous Na₂SO₄Drying for 1h, removal of solvent gave 10.23g of white solid, yield: 95 percent.

MS-ESI:m/z 197.1[M+H]⁺。

step 2: synthesis of compound 3, 4-dimethoxybenzoic acid

Dissolving compound methyl 3, 4-dimethoxybenzoate (10.23g,52.17mmol) in a mixed solvent of ethanol (20mL) and water (10mL), adding sodium hydroxide (10.43g,260.87mmol), reacting at 60 deg.C for 1.5h, removing ethanol, dissolving the residue with water (20mL), adjusting the pH of the solution to about 1 with HCl (1M), extracting with ethyl acetate (25 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying and removal of the solvent gave 9.16g of a white solid, yield: 96.4 percent.

MS-ESI:m/z 181.1[M-H]^-。

And step 3: synthesis of methyl 2- (3, 4-dimethoxyphenylamido) acetate compound

The compounds 3, 4-dimethoxybenzoic acid (9.16g,50.33mmol), HOAT (6.85g,50.33mmol) and EDCI (14.47g,75.50mmol) were dissolved in DCM (50mL) and after stirring at room temperature for 30min, glycine methyl ester hydrochloride (7.58g,60.40mmol) was added, DIPEA (35.16mL,201.32mmol) was slowly added dropwise in an ice bath, stirring was continued at room temperature overnight, water (30mL) was added and CH was used₂Cl₂Extraction (25 mL. times.3), combining the organic phases and then applying anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (Petroleum ether/EtOAc (v/v) ═ 1/1) afforded 10.82g of a white solid, yield: 85 percent.

MS-ESI:m/z 254.1[M+H]⁺。

And 4, step 4: synthesis of methyl 2- (3, 4-dimethoxyphenylthioamido) acetate compound

The compound methyl 2- (3, 4-dimethoxyphenylamido) acetate (2g,7.90mmol) and Lawson's reagent (3.19g,7.89mmol) were dissolved in THF (30mL) and after 2h of reaction at 75 deg.C, THF was removed and saturated NaHCO was added₃The solution (30mL) was extracted with ethyl acetate (25 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (Petroleum ether/EtOAc (v/v) ═ 2/1) afforded 1.81g of a yellow solid, yield: 85 percent.

MS-ESI:m/z 270.1[M+H]⁺。

And 5: synthesis of methyl 2- (((3, 4-dimethoxyphenyl) (methylthio) methylene) amino) acetate, a compound

A solution of the compound methyl 2- (3, 4-dimethoxyphenylthioamido) acetate (2g,7.43mmol) in dichloromethane (30mL) was slowly added dropwise at-78 ℃ to a solution of trimethyloxonium tetrafluoroborate (2.20g,14.87mmol) in dichloromethane (20mL), stirring was continued at 0 ℃ for 3h, then a saturated sodium bicarbonate solution was added and the organic phase was washed (25 mL. times.3) with anhydrous Na₂SO₄Drying and removal of the solvent gave 1.89g of a yellow oil, yield: 90 percent.

MS-ESI:m/z 284.1[M+H]⁺。

Step 6: synthesis of methyl (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxylate, a compound

Dissolving the compound methyl 2- (((3, 4-dimethoxyphenyl) (methylthio) methylene) amino) acetate (2.5g,8.83mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (2.53g,13.25mmol) in anhydrous tetrahydrofuran (20mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (22.08mL,22.08mmol) at 78 deg.C, reacting at-78 deg.C for 1h, adding ice water (20mL), quenching the reaction, extracting with ethyl acetate (15 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removing solvent, and separating the concentrated solution with column (petroleum ether/ethyl acetate)(v/v) ═ 3/1), 1.61g of a yellow solid was obtained, yield: 45 percent.

MS-ESI:m/z 407.2[M+H]⁺。

And 7: synthesis of the Compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxylic acid

The compound methyl (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxylate (2g,4.92mmol) and lithium hydroxide monohydrate (1.03g,24.6mmol) were dissolved in a mixed solvent of tetrahydrofuran (30mL) and water (15mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added for extraction (20 mL. times.3), the organic phases were combined and then extracted with anhydrous Na₂SO₄Drying and removal of the solvent gave 1.8g of a yellow solid, yield: 95 percent.

And 8: synthesis of the Compound (S) - (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxylic acid (0.3g,0.76mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (220mg,1.15mmol) and N-hydroxy-7-azabenzotriazole (156mg,1.15mmol) were dissolved in dichloromethane (10mL), stirred at 0 ℃ for 30min, then 2, 4-difluorobenzylamine (0.11mL,0.92mmol) and N, N-diisopropylethylamine (0.4mL,2.3mmol) were added dropwise, stirred at room temperature for 7h, washed with water (10 mL. times.3), and the organic phase was Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 249mg of yellow oil, yield: and 63 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.61(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.50(d,J＝1.9Hz,1H),7.47–7.41(m,1H),6.95(d,J＝8.4Hz,1H),6.93–6.84(m,2H),5.32–5.28(m,1H),4.69–4.66(m,2H),3.99(s,3H),3.96(s,3H),1.56(d,J＝7.0Hz,3H),1.45(s,9H)；

MS-ESI:m/z 518.3[M+H]⁺。

And step 9: synthesis of Compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.24g,0.46mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 2h, filtered, washed with ethyl acetate (15 mL. times.3) to give 142mg of a white solid, yield: 68 percent.

Compound 21:¹H NMR(400MHz,CD₃OD):δppm 7.73(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.67(d,J＝2.0Hz,1H),7.52–7.46(m,1H),7.13(d,J＝8.5Hz,1H),7.02–6.94(m,2H),5.17–5.13(m,1H),4.65(s,2H),3.93(d,J＝3.3Hz,6H),1.77(d,J＝7.0Hz,3H)；

MS-ESI:m/z 418.2[M+H-HCl]⁺。

Example 3: the compound (S) -5- (1-aminoethyl) -N- (2, 6-difluorobenzyl) -2- (3, 4-dimethoxyphenyl) Synthesis of oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound (S) - (1- (4- ((2, 6-difluorobenzyl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxylic acid (0.2g,0.51mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (146mg,0.77mmol) and N-hydroxy-7-azabenzotriazole (104mg,0.77mmol) were dissolved in dichloromethane (10mL), stirred at 0 ℃ for 30min, then 2, 6-difluorobenzylamine (0.07mL,0.61mmol) and N, N-diisopropylethylamine (0.27mL,1.53mmol) were added dropwise, stirred at room temperature for 7h, washed with water (10 mL. times.3), and the organic phase was Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 127mg of a white solid, yield: 48 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.49(d,J＝1.9Hz,1H),7.33–7.29(m,1H),6.99–6.93(m,3H),5.32–5.26(m,1H),4.83–4.71(m,2H),3.99(s,3H),3.96(s,3H),1.55(d,J＝7.0Hz,3H),1.45(s,9H)；

MS-ESI:m/z 518.3[M+H]⁺。

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -N- (2, 6-difluorobenzyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2, 6-difluorobenzyl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.12g,0.23mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 7h, filtered, washed with ethyl acetate (15 mL. times.3) to give 85mg of a white solid, yield: 82 percent.

Compound 22:¹H NMR(400MHz,CD₃OD):δppm 7.71(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.65(d,J＝2.0Hz,1H),7.42–7.36(m,1H),7.12(d,J＝8.5Hz,1H),7.02(t,J＝8.1Hz,2H),5.17–5.11(m,1H),4.73(s,2H),3.93(d,J＝2.9Hz,6H),1.76(d,J＝7.0Hz,3H)；

MS-ESI:m/z 418.3[M+H-HCl]⁺。

Example 4: the compound (S) -5- (1-aminoethyl) -N- (2-chloro-6-fluorobenzyl) -2- (3, 4-dimethoxyphenyl) Synthesis of oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2-chloro-6-fluorobenzyl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamate

the compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxylic acid (0.3g,0.764mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (219.65mg,1.15mmol) and N-hydroxy-7-azabenzotriazole (156.4mg,1.15mmol) were dissolved in dichloromethane (15mL), stirred at 0 ℃ for 30min, then 2-chloro-6-fluorobenzylamine (0.12mL,0.92mmol) and N, N-diisopropylethylamine (0.4mL,2.3mmol) were added dropwise, respectively, stirred at room temperature for 12h,Washed with water (20 mL. times.3) and the organic phase with Na₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 188mg of a white solid, yield: 46 percent.

Step 2: synthesis of the compound (S) -5- (1-aminoethyl) -N- (2-chloro-6-fluorobenzyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2-chloro-6-fluorobenzyl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.18g,0.35mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 17h, filtered, washed with ethyl acetate (15 mL. times.3) to give 138mg of a white solid, yield: 61 percent.

compound 23:¹H NMR(400MHz,CD₃OD):δppm 7.70(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.64(d,J＝2.0Hz,1H),7.54–7.52(m,1H),7.31–7.26(m,1H),7.18–7.13(m,1H),7.12(d,J＝8.5Hz,1H),5.17–5.12(m,1H),4.82(s,2H),4.36(d,J＝1.8Hz,2H),3.92(s,6H),1.76(d,J＝7.0Hz,3H)；

MS-ESI:m/z 434.2[M+H-HCl]⁺。

Example 5: the compound (S) -5- (1-aminoethyl) -N- (2, 6-difluorobenzyl) -2- (3-ethoxy-4-methoxy Synthesis of phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound 3-ethoxy-4-methoxybenzoic acid methyl ester

Methyl 3-hydroxy-4-methoxybenzoate (10g,54.9mmol) was dissolved in acetone (50mL), anhydrous potassium carbonate (15.2g,109.9mmol) and bromoethane (6.1mL,82.42mmol) were added sequentially, the tube was sealed, and reaction was carried out at 60 ℃ for 4.5 h. Saturated NaCl solution (20mL) was added, extracted with ethyl acetate (25 mL. times.3), the organic phases combined and the organic phase extracted with anhydrous Na₂SO₄Drying for 1h, removal of solvent gave 11.07g of white solid, yield: 95.9 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.65(d,J＝8.4Hz,1H),7.53(s,1H),6.87(d,J＝8.4Hz,1H),4.12-4.17(m,2H),3.91(s,3H),3.87(s,3H),1.47(t,J＝7.0Hz,3H)；

MS-ESI:m/z 211.2[M+H]⁺。

Step 2: synthesis of compound 3-ethoxy-4-methoxybenzoic acid

Dissolving the compound methyl 3-ethoxy-4-methoxybenzoate (11.66g,55.5mmol) in a mixed solvent of ethanol (20mL) and water (10mL), adding sodium hydroxide (11.1g,277.5mmol), reacting at 60 ℃ for 1.5h, removing ethanol, dissolving the residue with water (20mL), adjusting the pH of the solution to about 1 with HCl (1M), extracting with ethyl acetate (25 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying and removal of the solvent gave 10.25g of a white solid in yield: 94.5 percent.

MS-ESI:m/z 197.2[M+H]⁺。

And step 3: synthesis of compound methyl 2- (3-ethoxy-4-methoxybenzamido) acetate

The compounds 3-ethoxy-4-methoxybenzoic acid (11.86g,60.5mmol), HOAT (8.229g,60.51mmol) and EDCI (17.336g,90.76mmol) were dissolved in DCM (50mL), stirred at room temperature for 30min, glycine methyl ester hydrochloride (9.076g,72.61mmol) was added, DIPEA (42.2mL,242.0mmol) was slowly added dropwise in an ice bath, stirring was continued at room temperature overnight, water (30mL) was added, and CH was used₂Cl₂Extraction (25 mL. times.3), combining the organic phases and then applying anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (Petroleum ether/EtOAc (v/v) ═ 1/1) afforded 12.88g of a white solid, yield: 79.7 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.42(s,1H),7.33(d,J＝8.3Hz,1H),6.87(d,J＝8.4Hz,1H),6.60(s,1H),4.23(d,J＝5.0Hz,2H),4.12-4.17(m,2H),3.91(s,3H),3.80(s,3H),1.47(t,J＝7.0Hz,3H)；

MS-ESI:m/z 268.1[M+H]⁺。

And 4, step 4: synthesis of compound methyl 2- (3-ethoxy-4-methoxyphenyl thioamido) acetate

The compound 2- (3-ethoxy-4-methoxybenzene)amido) methyl acetate (2g,7.49mmol) and Lawson's reagent (3.03g,7.49mmol) were dissolved in THF (30mL), after 2h of reaction at 75 ℃ continued, THF was removed and saturated NaHCO was added₃The solution (30mL) was extracted with ethyl acetate (25 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (Petroleum ether/EtOAc (v/v) ═ 2/1) afforded 1.7046g of a yellow solid, yield: 80.4 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.05(s,1H),7.54(s,1H),7.33(d,J＝8.4Hz,1H),6.83(d,J＝8.4Hz,1H),4.56(d,J＝4.4Hz,2H),4.13-4.18(m,2H),3.90(s,3H),3.83(s,3H),1.47(t,J＝7.0Hz,3H)；

MS-ESI:m/z 284.1[M+H]⁺。

And 5: synthesis of compound methyl 2- (((3-ethoxy-4-methoxyphenyl) (methylthio) methylene) amino) acetate

a solution of the compound methyl 2- (3-ethoxy-4-methoxyphenylthioamido) acetate (2g,7.06mmol) in dichloromethane (30mL) was slowly added dropwise at-78 ℃ to a solution of trimethyloxonium tetrafluoroborate (2.08g,14.12mmol) in dichloromethane (20mL), stirring was continued at 0 ℃ for 3h, then a saturated sodium bicarbonate solution was added and the organic phase was washed (25 mL. times.3) with anhydrous Na₂SO₄Drying and removal of the solvent gave 1.89g of a yellow oil, yield: 90 percent.

Step 6: synthesis of Compound (S) -methyl 5- (1- (t-butoxycarbonylamino) ethyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxylate

Dissolving the compound methyl 2- (((3-ethoxy-4-methoxyphenyl) (methylthio) methylene) amino) acetate (2.47g,8.31mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (2.38g,12.46mmol) in anhydrous tetrahydrofuran (20mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (20.78mL,20.78mmol) at 78 deg.C, reacting at-78 deg.C for 1h, adding ice water (20mL), quenching the reaction, extracting with ethyl acetate (15 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 1g of a yellow solid, yield:28％。

And 7: synthesis of Compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxylic acid

the compound methyl (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxylate (0.73g,1.736mmol) and lithium hydroxide monohydrate (364.25mg,8.681mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added for extraction (20 mL. times.3), the organic phases were combined and then extracted with anhydrous Na₂SO₄Drying and removal of the solvent gave 668mg of a yellow solid, yield: 95 percent.

And 8: synthesis of the Compound (S) - (1- (4- ((2, 6-difluorobenzyl) carbamoyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxylic acid (0.7g,1.732mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (496.22mg,2.60mmol) and N-hydroxy-7-azabenzotriazole (353.33mg,2.60mmol) were dissolved in dichloromethane (30mL), stirred at 0 ℃ for 30min, and then 2, 6-difluorobenzylamine (0.25mL,2.08mmol) and N, N-diisopropylethylamine (0.91mL,5.2mmol) were added dropwise, and stirred at room temperature for 12h, washed with water (20 mL. times.3), and the organic phase was washed with Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 834.6mg of a white solid, yield: 91 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.58(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.49(d,J＝1.9Hz,1H),7.32–7.30(m,1H),6.98–6.92(m,3H),5.30–5.25(m,1H),4.83–4.74(m,2H),4.23–4.17(m,2H),3.94(s,3H),1.55–1.51(m,6H),1.45(s,9H)；

MS-ESI:m/z 532.2[M+H]⁺。

and step 9: synthesis of compound (S) -5- (1-aminoethyl) -N- (2, 6-difluorobenzyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxamide hydrochloride

to a solution of compound (S) tert-butyl (1- (4- ((2, 6-difluorobenzyl) carbamoyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.83g,1.56mmol) in dichloromethane (10mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 3h, filtered, washed with ethyl acetate (20 mL. times.3) to give 699.3mg of a white solid, yield: 96 percent.

Compound 24:¹H NMR(400MHz,CD₃OD):δppm 7.70(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.63(d,J＝2.0Hz,1H),7.43–7.35(m,1H),7.12(d,J＝8.5Hz,1H),7.02(t,J＝8.1Hz,2H),5.16–5.11(m,1H),4.73(s,2H),4.18–4.13(m,2H),3.93(s,3H),1.76(d,J＝7.0Hz,3H),1.46(t,J＝7.0Hz,3H)；

MS-ESI:m/z 432.3[M+H-HCl]⁺。

Example 6: the compound (S) -1- (5- (1-aminoethyl) -2- (3, 4-dimethoxyphenyl) oxazol-4-yl) -2- Synthesis of (3, 5-dichloropyridin-4-yl) ethanone dihydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (4- (2- (3, 5-dichloropyridin-4-yl) acetyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamate

The compound methyl (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxylate (0.2g,0.49mmol) and 3, 5-dichloro-4-methylpyridine (119.6mg,0.74mmol) were dissolved in tetrahydrofuran (5mL), stirred at 0 deg.C, a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.476mL,1.476mmol) was added dropwise, stirred at room temperature for 4 hours, a saturated ammonium chloride solution (15mL) was added, extracted with ethyl acetate (15 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) afforded 120mg of a yellow solid, yield: 45 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.55(s,2H),7.68(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.58(d,J＝1.9Hz,1H),6.98(d,J＝8.5Hz,1H),5.36–5.30(m,1H),4.85–4.75(m,2H),4.03(s,3H),3.99(s,3H),1.51(d,J＝7.1Hz,3H),1.42(s,9H)；

MS-ESI:m/z 536.2[M+H]⁺。

Step 2: synthesis of Compound (S) -1- (5- (1-aminoethyl) -2- (3, 4-dimethoxyphenyl) oxazol-4-yl) -2- (3, 5-dichloropyridin-4-yl) ethanone dihydrochloride

To a solution of compound (S) tert-butyl (1- (4- (2- (3, 5-dichloropyridin-4-yl) acetyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.11g,0.21mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 5h, filtered, washed with ethyl acetate (15 mL. times.3) to give 86mg of a yellow solid, yield: 86 percent.

Compound 25:¹H NMR(400MHz,CD₃OD):δppm 8.62(s,2H),7.80(dd,J₁＝8.4Hz,J₂＝1.8Hz,1H),7.71(d,J＝1.8Hz,1H),7.16(d,J＝8.4Hz,1H),5.21–5.16(m,1H),5.00–4.92(m,2H),3.97(s,3H),3.95(s,3H),1.76(d,J＝6.9Hz,3H)。

example 7: the compound (S) -1- (5- (1-aminoethyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4- Synthesis of 2- (3, 5-dichloropyridin-4-yl) ethanone dihydrochloride

Step 1: synthesis of Compound (S) - (1- (4- (2- (3, 5-dichloropyridin-4-yl) acetyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound methyl (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxylate (0.2g,0.48mmol) and 3, 5-dichloro-4-methylpyridine (116.65mg,0.72mmol) were dissolved in tetrahydrofuran (5mL), stirred at 0 deg.C, a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.44mL,1.44mmol) was added dropwise, stirred at room temperature for 2.5 hours, then a saturated ammonium chloride solution (15mL) was added, dichloromethane was extracted (20mL), and the organic phase was extracted with anhydrous Na₂SO₄Drying, removal of solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 0 as a pale yellow solid.16g, yield: 61 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.55(s,2H),7.66(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.58(d,J＝1.9Hz,1H),6.98(d,J＝8.5Hz,1H),5.34–5.29(m,1H),4.85–4.74(m,2H),4.28–4.22(m,2H),3.97(s,3H),1.56(t,J＝7.0Hz,3H),1.51(d,J＝7.1Hz,3H),1.42(s,9H)；

MS-ESI:m/z 550.1[M+H]⁺。

Step 2: synthesis of Compound (S) -1- (5- (1-aminoethyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-4-yl) -2- (3, 5-dichloropyridin-4-yl) ethanone dihydrochloride

to a solution of compound (S) tert-butyl (1- (4- (2- (3, 5-dichloropyridin-4-yl) acetyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.16g,0.29mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 2h, filtered, washed with ethyl acetate (15 mL. times.3) to give 50mg of a yellow solid, yield: 40 percent.

Compound 26:¹H NMR(400MHz,CD₃OD):δppm 8.57(s,2H),7.76(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.67(d,J＝2.0Hz,1H),7.14(d,J＝8.5Hz,1H),5.18–5.13(m,1H),4.90–4.87(m,2H),4.20–4.15(m,2H),3.92(s,3H),1.72(d,J＝7.0Hz,3H),1.46(t,J＝7.0Hz,3H)。

Example 8: the compound (S) -5- (1-aminoethyl) -N- (3, 5-dichloropyridin-4-yl) -2- (3, 4-dimethoxy Synthesis of phenyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (1- (2- (3, 4-dimethoxyphenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxylic acid (0.86g,2.2mmol) and triethylamine (0.34mL,2.42mmol) were dissolved in dichloromethane (15mL), and to this solution was added dropwise melamine (0.36mL,4.4mmol) at-40 deg.C, reacted at-10 deg.C for 2h, and ice was addedWashed with water (20 mL. times.4), and the combined organic phases were washed with Na₂SO₄Drying and removal of the solvent gave 0.82g of red solid, yield: 95 percent.

¹H NMR(400MHz,d₆-DMSO):δppm 7.61(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.49(d,J＝2.0Hz,1H),7.17(d,J＝8.5Hz,1H),5.21–5.16(m,1H),3.86(d,J＝5.1Hz,6H),1.48(d,J＝7.1Hz,3H),1.37(s,9H)；

MS-ESI:m/z 395.2[M+H]⁺。

Step 2: synthesis of the Compound (S) - (tert-butyl 1- (4- ((3, 5-dichloropyridin-4-yl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamate

3, 5-dichloro-4-aminopyridine (537.9mg,3.3mmol) and sodium hydride (60%, 132mg,3.3mmol) were dissolved in tetrahydrofuran (6mL) and stirred at room temperature for 1h, to this solution was added dropwise a solution of tert-butyl compound (S) - (1- (2- (3, 4-dimethoxyphenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamate (0.86g,2.2mmol) in tetrahydrofuran (9mL) at 0 ℃ and stirred at room temperature for 23h, followed by addition of a saturated ammonium chloride solution (20mL) and extraction with ethyl acetate (20 mL. times.3). The combined organic phases are washed with Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) gave 325mg of a light yellow oil, yield: 27 percent.

And step 3: synthesis of the Compound (S) -5- (1-aminoethyl) -N- (3, 5-dichloropyridin-4-yl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((3, 5-dichloropyridin-4-yl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.32g,0.59mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 1.5h, filtered, washed with ethyl acetate (20 mL. times.3) to give 220mg of a yellow solid, yield: recrystallization from methanol/ethyl acetate (v/v ═ 1/20) at 81% gave 110mg of a yellow solid.

Compound 27:¹H NMR(400MHz,CD₃OD):δppm 8.72(s,2H),7.81(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.74(d,J＝2.0Hz,1H),7.16(d,J＝8.5Hz,1H),5.29–5.24(m,1H),3.96(d,J＝6.8Hz,6H),1.80(d,J＝7.0Hz,3H)；

MS-ESI:m/z 438.2[M+H-2HCl]⁺。

Example 9: the compound (S) -5- (1-aminoethyl) -N- (3, 5-dichloropyridin-4-yl) -2- (3-ethoxy-4-methyl Synthesis of oxyphenyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (1- (2- (3-ethoxy-4-methoxyphenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxylic acid (0.65g,1.6 mmol) and triethylamine (0.25mL,1.76mmol) were dissolved in dichloromethane (10mL), to the solution was slowly added dropwise melamine fluoride (0.26mL,3.2mmol) at-40 deg.C, reacted at-10 deg.C for 2h, washed 4-5 times with ice water (50mL), and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 577mg of a yellow solid, yield: 88 percent.

¹H NMR(400MHz,d₆-DMSO):δppm 7.60(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.48(d,J＝2.0Hz,1H),7.17(d,J＝8.6Hz,1H),5.26–5.18(m,1H),4.14–4.06(m,2H),3.85(s,3H),1.47(d,J＝7.1Hz,3H),1.40–1.38(m,3H),1.36–1.31(m,9H)；

MS-ESI:m/z 409.3[M+H]⁺。

Step 2: synthesis of the Compound (S) - (1- (4- ((3, 5-dichloropyridin-4-yl) carbamoyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

3, 5-dichloro-4-aminopyridine (341.23mg,2.1mmol) and sodium hydride (60%, 84mg,2.1mmol) were dissolved in tetrahydrofuran (6mL), stirred at room temperature for 1h, a solution of compound (S) - (1- (2- (3-ethoxy-4-methoxyphenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (0.57g,1.4mmol) in tetrahydrofuran (9mL) was added dropwise at 0 deg.C, stirred at room temperature for 14h, a saturated ammonium chloride solution (20mL) was added, and ethyl acetate was extracted (20mL)X 3). The combined organic phases are washed with Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) gave 240mg of a light yellow solid, yield: 31 percent.

¹H NMR(400MHz,CDCl₃):δppm 9.04(s,1H),8.62(s,2H),7.68–7.65(m,1H),7.55(d,J＝1.9Hz,1H),6.98(d,J＝8.5Hz,1H),5.34–5.30(m,1H),4.26–4.21(m,2H),3.97(s,3H),1.60(d,J＝7.0Hz,3H),1.44(s,9H),1.28(t,J＝7.1Hz,3H)；

MS-ESI:m/z 552.3[M+H]⁺。

and step 3: synthesis of compound (S) -5- (1-aminoethyl) -N- (3, 5-dichloropyridin-4-yl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxamide dihydrochloride

To a solution of the compound tert-butyl (S) - (1- (4- ((3, 5-dichloropyridin-4-yl) carbamoyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.23g,0.42mmol) in dichloromethane (2mL) was added an ethyl acetate solution of HCl (4M,7mL), stirred at room temperature for 2.5h, filtered, washed with ethyl acetate (15mL × 3) to give 170mg of a yellow solid, which was recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 27.7mg of a yellow solid.

Compound 28:¹H NMR(400MHz,CD₃OD):δppm 8.70(s,2H),7.79(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.72(d,J＝1.9Hz,1H),7.16(d,J＝8.5Hz,1H),5.28–5.23(m,1H),4.22–4.17(m,2H),3.95(s,3H),1.79(d,J＝7.0Hz,3H),1.48(t,J＝7.2Hz,3H)；

MS-ESI:m/z 452.9[M+H-2HCl]⁺。

Example 10: the compound (S) -5- (1-aminoethyl) -N- (2-chloro-6-fluorobenzyl) -2- (3-ethoxy-4-methoxy Synthesis of phenyl group) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (1- (4- ((2-chloro-6-fluorobenzyl) carbamoyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxylic acid (0.3g,0.74mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (212mg,1.11mmol) and N-hydroxy-7-azabenzotriazole (151mg,1.11mmol) were dissolved in dichloromethane (10mL), stirred at 0 ℃ for 30min, then 2-fluoro-6-chlorobenzylamine (0.11mL,0.89mmol) and N, N-diisopropylethylamine (0.39mL,2.21mmol) were added dropwise, stirred at room temperature for 12h, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 190mg of a white solid, yield: and 47 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.52(d,J＝1.8Hz,1H),7.39–7.29(m,1H),7.27–7.25(m,1H),7.10–7.05(m,1H),6.94(d,J＝8.5Hz,1H),5.30–5.25(m,1H),4.91–4.84(m,2H),4.23–4.18(m,2H),3.95(s,1H),1.57–1.51(m,6H),1.45(s,9H)；

MS-ESI:m/z 549.2[M+H]⁺。

Step 2: synthesis of compound (S) -5- (1-aminoethyl) -N- (2-chloro-6-fluorobenzyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2-chloro-6-fluorobenzyl) carbamoyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.19g,0.35mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 3h, filtered, washed with ethyl acetate (15 mL. times.3) to give 92mg of a white solid, yield: 56 percent.

Compound 29:¹H NMR(400MHz,CD₃OD):δppm 7.69(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.62(d,J＝2.0Hz,1H),7.38–7.35(m,1H),7.33–7.31(m,1H),7.18–7.13(m,1H),7.11(d,J＝8.5Hz,1H),5.17–5.12(m,1H),4.81(s,2H),4.17–4.12(m,2H),3.92(s,3H),1.76(d,J＝7.0Hz,3H),1.45(t,J＝7.0Hz,3H)；

MS-ESI:m/z 448.2[M+H-HCl]⁺。

Example 11: the compound (S) -5- (1-aminoethyl) -2- (2: (1-aminoethyl)3-cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (2, 6-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 6-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (130.56mg,0.96mmol) were dissolved in dichloromethane (10mL), 2, 6-difluorobenzylamine (0.1mL,0.77mmol) and N, N-diisopropylethylamine (0.33mL,1.92mmol) were added dropwise to the solution at 0 ℃ and stirred at room temperature for 4 hours, then water was added (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 203mg of a white solid, yield: 53 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.55(d,J＝1.9Hz,1H),7.35–7.30(m,1H),7.24(d,J＝8.3Hz,1H),6.98–6.94(m,2H),6.71(t,J_F-H＝75.0Hz,1H),5.35–5.28(m,1H),4.80–4.70(m,2H),3.99(d,J＝6.9Hz,2H),1.55(d,J＝7.0Hz,3H),1.38–1.36(m,1H),1.45–1.43(m,9H),0.72–0.68(m,2H),0.43–0.41(m,2H)；

MS-ESI:m/z 594.2[M+H]⁺。

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 6-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 6-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.2g,0.34mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 14h, filtered, washed with ethyl acetate (15 mL. times.3) to afford 152mg of a white solid, yield: 83 percent.

Compound 30:¹H NMR(400MHz,CD₃OD):δppm 7.69(d,J＝1.9Hz,1H),7.61(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.32–7.28(m,1H),7.23(d,J＝8.4Hz,1H),6.93(t,J＝8.0Hz,2H),6.83(t,J_F-H＝74.8Hz,1H),5.10–5.05(m,1H),4.64(s,2H),3.94(d,J＝7.0Hz,2H),1.67(d,J＝7.0Hz,3H),1.27–1.24(m,1H),0.61–0.59(m,2H),0.35–0.32(m,2H)；

MS-ESI:m/z 494.3[M+H-HCl]⁺。

Example 12: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (2-fluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2-fluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (130.56mg,0.96mmol) were dissolved in dichloromethane (10mL), 2-fluorobenzylamine (0.09mL,0.77mmol) and N, N-diisopropylethylamine (0.33mL,1.92mmol) were added dropwise to the solution at 0 ℃ and stirred at room temperature for 7h, washed with water (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 256mg of a white solid, yield: and 69 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.56(d,J＝1.8Hz,1H),7.47–7.43(m,1H),7.33–7.29(m,1H),7.25(d,J＝8.3Hz,1H),7.18–7.09(m,2H),6.72(t,J_F-H＝75.0Hz,1H),5.32–5.28(m,1H),4.74–4.71(m,2H),3.99(d,J＝7.0Hz,2H),1.56(d,J＝7.0Hz,3H),1.45(s,9H),1.41–1.37(m,1H),0.73–0.68(m,2H),0.44–0.40(m,2H)；

MS-ESI:m/z 576.1[M+H]⁺。

Step 2: synthesis of compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2-fluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2-fluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.25g,0.43mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 2h, filtered, washed with ethyl acetate (20 mL. times.3) to give 191mg of a white solid, yield: 87 percent.

Compound 31:¹H NMR(400MHz,CD₃OD):δppm 7.80(d,J＝1.9Hz,1H),7.73(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.45(td,J₁＝7.6Hz,J₂＝1.5Hz,1H),7.33(d,J＝8.3Hz,2H),7.19–7.12(m,2H),6.92(t,J_F-H＝74.8Hz,1H),5.20–5.14(m,1H),4.69(s,2H),4.03(d,J＝6.9Hz,2H),1.77(d,J＝7.0Hz,3H),1.38–1.34(m,1H),0.71–0.66(m,2H),0.44–0.41(m,2H)；

MS-ESI:m/z 476.3[M+H-HCl]⁺。

Example 13: the compound (S) -5- (1-aminoethyl) -2- (3-butoxy-4-methoxyphenyl) -N- (2, 4-difluoro Synthesis of benzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound methyl 3-butoxy-4-methoxybenzoate

Methyl 3-hydroxy-4-methoxybenzoate (10.0g,54.95mmol), potassium carbonate (15.15g,109.78mmol) and N-butyl bromide (8.85mL,66.07mmol) were dissolved in N, N-dimethylformamide (60mL), reacted at 60 ℃ for 4.5h, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined andwith anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 12.89g of a white solid in yield: 99 percent.

Step 2: synthesis of Compound 3-butoxy-4-methoxybenzoic acid

The compound methyl 3-butoxy-4-methoxybenzoate (12.89g,54.16mmol) and sodium hydroxide (6.5g,162.48mmol) were dissolved in a mixed solvent of ethanol (150mL) and water (50mL), reacted at 60 ℃ for 1.5h, ethanol was removed, pH was adjusted to 1 with hydrochloric acid (1M), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and then extracted with anhydrous Na₂SO₄Drying and removal of the solvent gave 12.02g of a white solid, yield: 99 percent.

And step 3: synthesis of Compound methyl 2- (3-butoxy-4-methoxybenzamide) acetate

The compounds 3-butoxy-4-methoxybenzoic acid (12.02g,53.66mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (15.45g,80.49mmol) and 1-hydroxybenzotriazole (10.87g,80.49mmol) were dissolved in dichloromethane (80mL), stirred at room temperature for 0.5h, glycine methyl ester hydrochloride (8.11g,64.39mmol) and N, N-diisopropylethylamine (28.8mL,160.98mmol) were added at 0 deg.C, stirred at room temperature for 12h, washed with water (40 mL. times.3), and the organic phase was Na₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 14.74g of a white solid in yield: 93 percent.

And 4, step 4: synthesis of methyl 2- (3-butoxy-4-methoxyphenylthioamide) acetate, a compound

The compound methyl 2- (3-butoxy-4-methoxybenzamide) acetate (5.0g,16.95mmol) and Lawson's reagent (6.85g,16.95mmol) were dissolved in anhydrous treated tetrahydrofuran (40mL), refluxed at 75 ℃ for 2 hours, added with a saturated sodium bicarbonate solution (40mL), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and Na was used₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 5.16g of a yellow solid, yield: 98 percent.

And 5: synthesis of methyl 2- (((3-butoxy-4-methoxyphenyl) (methylthio) methylene) amino) acetate, a compound

A solution of the compound methyl 2- (3-butoxy-4-methoxyphenylthioamide) acetate (5.16g,16.60mmol) in dichloromethane (30mL) was slowly added dropwise at-78 ℃ to a solution of trimethyloxonium tetrafluoroborate (4.88g,33.20mmol) in dichloromethane (20mL), stirring was continued at 0 ℃ for 3h, then a saturated sodium bicarbonate solution was added and the organic phase was washed (25 mL. times.3) with anhydrous Na₂SO₄Drying and removal of the solvent gave 5.35g of a yellow oil, yield: 99 percent.

Step 6: synthesis of methyl (S) -2- (3-butoxy-4-methoxyphenyl) -5- (1- (tert-butoxycarbonylamino) ethyl) oxazole-4-carboxylate, a compound

Dissolving the compound methyl 2- (((3-butoxy-4-methoxyphenyl) (methylthio) methylene) amino) acetate (5.35g,16.36mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (7.47g,39.1mmol) in anhydrous tetrahydrofuran (20mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (32.0mL,32.0mmol) at 78 deg.C, reacting at-78 deg.C for 1h, quenching the reaction with ice water (20mL), extracting with ethyl acetate (15 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 5.02g of a yellow solid, yield: 68 percent.

And 7: synthesis of the Compound (S) -2- (3-butoxy-4-methoxyphenyl) -5- (1- (t-butoxycarbonylamino) ethyl) oxazole-4-carboxylic acid

The compound methyl (S) -2- (3-butoxy-4-methoxyphenyl) -5- (1- (t-butoxycarbonylamino) ethyl) oxazole-4-carboxylate (2.47g,5.52mmol) and lithium hydroxide monohydrate (1.16g,27.27mmol) were dissolved in a mixed solvent of tetrahydrofuran (40mL) and water (20mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added for extraction (30 mL. times.3), the organic phases were combined and then anhydrous Na was used₂SO₄drying and removal of the solvent gave 1.66g of a yellow solid, yield: 70 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.65(d,J＝8.4Hz,1H),7.60(s,1H),6.94(d,J＝8.4Hz,1H),5.50-5.42(m,1H),4.12(t,J＝6.8Hz,2H),3.94(s,3H),1.92-1.85(m,2H),1.59(d,J＝7.1Hz,3H),1.57-1.51(m,2H),1.44(s,9H),1.01(t,J＝7.3Hz,3H)；

MS-ESI:m/z 435.2[M+H]⁺。

And 8: synthesis of Compound (S) - (tert-butyl 1- (2- (3-butoxy-4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -2- (3-butoxy-4-methoxyphenyl) -5- (1- (t-butoxycarbonylamino) ethyl) oxazole-4-carboxylic acid (1.66g,3.82mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.10g,5.73mmol) and N-hydroxy-7-azabenzotriazole (0.77g,5.73mmol) were dissolved in dichloromethane (30mL), stirred at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.55mL,0.90mmol) and N, N-diisopropylethylamine (2.05mL,11.46mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, washed with water (20 mL. times.3), and the organic phase was washed with Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 694.5mg of a white solid in yield: 40 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.58(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.48(d,J＝1.9Hz,1H),7.46-7.40(m,1H),6.93(d,J＝8.4Hz,1H),6.91-6.82(m,2H),5.32-5.28(m,1H),4.68-4.61(m,2H),4.11(t,J＝6.8Hz,2H),3.93(s,3H),1.92-1.85(m,2H),1.55(d,J＝7.1Hz,3H),1.45(s,9H),1.40-1.38(m,2H),1.02(t,J＝7.4Hz,3H)；

MS-ESI:m/z 560.2[M+H]⁺。

And step 9: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3-butoxy-4-methoxyphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (S) - (1- (2- (3-butoxy-4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (695mg,1.24mmol) in dichloromethane (3mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 344mg of a white solid, yield: 60 percent.

Compound 33:¹H NMR(400MHz,d₆-DMSO):δppm 7.67(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.63(d,J＝1.9Hz,1H),7.49-7.43(m,1H),7.26-7.20(m,1H),7.18(d,J＝8.6Hz,1H),7.08(td,J₁＝8.5Hz,J₂＝1.9Hz,1H),5.12-5.08(m,1H),4.49(d,J＝6.1Hz,2H),4.05(t,J＝6.4Hz,2H),3.86(s,3H),1.78-1.71(m,2H),1.63(d,J＝6.9Hz,3H),1.47-1.44(m,2H),0.95(t,J＝7.4Hz,3H)；

MS-ESI:m/z 460.3[M+H-HCl]⁺。

Example 14: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of yl) -N- ((3, 5-dichloropyridin-4-yl) methyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (130.56mg,0.96mmol) were dissolved in dichloromethane (10mL), a solution of the compound (3, 5-dichloropyridin-4-yl) methylamine (136mg,0.77mmol) in DCM (7mL) and N, N-diisopropylethylamine (0.33mL,1.92mmol) were added dropwise to the solution at 0 ℃ under stirring at room temperature for 17h, followed by washing with water (20 mL. times.3), anhydrous Na for organic phase₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 263mg of a white solid, yield: 65 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.56(s,2H),7.59(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.55(d,J＝1.9Hz,1H),7.25(d,J＝8.3Hz,1H),6.71(t,J_F-H＝75.0Hz,1H),5.32–5.26(m,1H),4.96(d,J＝5.7Hz,2H),3.98(d,J＝7.0Hz,2H),1.56(d,J＝7.0Hz,3H),1.44(s,9H),1.36–1.32(m,1H),0.71–0.68(m,2H),0.44–0.41(m,2H)。

step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((3, 5-dichloropyridin-4-yl) methyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) -tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.26g,0.41mmol) in dichloromethane (5mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 17h, filtered, washed with ethyl acetate (20 mL. times.3) to give 209mg of a white solid, yield: 85 percent.

Compound 34:¹H NMR(400MHz,CD₃OD):δppm 8.57(s,2H),7.77(d,J＝1.9Hz,1H),7.70(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.32(d,J＝8.4Hz,1H),6.91(t,J_F-H＝74.8Hz,1H),5.18–5.14(m,1H),4.92(s,2H),4.02(d,J＝6.9Hz,2H),1.76(d,J＝7.0Hz,3H),1.36–1.32(m,1H),0.70–0.66(m,2H),0.44–0.40(m,2H)；

MS-ESI:m/z 528.2[M+H-2HCl]⁺。

Example 15: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (3-fluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((3-fluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (130.56mg,0.96mmol) were dissolved in dichloromethane (10mL) and the solution was added dropwise at 0 ℃ to each solutionAdding 3-fluorobenzylamine (0.09mL,0.77mmol) and N, N-diisopropylethylamine (0.33mL,1.92mmol), stirring at room temperature for 5h, washing with water (20 mL. times.3), and adding anhydrous Na to the organic phase₂SO₄drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) gave 254mg of a white solid, yield: and 69 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.55(d,J＝1.9Hz,1H),7.37–7.33(m,1H),7.25(d,J＝8.3Hz,1H),7.17(d,J＝7.7Hz,1H),7.12–7.09(m,1H),7.04–7.00(m,1H),6.71(t,J_F-H＝75.0Hz,1H),5.32–5.28(m,1H),4.67(d,J＝6.2Hz,2H),3.98(d,J＝7.0Hz,2H),1.56(s,3H),1.45(s,9H),1.36–1.32(m,1H),0.71–0.68(m,2H),0.44–0.41(m,2H)。

Step 2: synthesis of compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (3-fluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((3-fluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.25g,0.43mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 24h, filtered, washed with ethyl acetate (20 mL. times.3) to give 149mg of a white solid, yield: 68 percent.

Compound 35:¹H NMR(400MHz,CD₃OD):δppm 7.72(d,J＝1.8Hz,1H),7.64(dd,J₁＝8.4Hz,J₂＝1.9 Hz,1H),7.31–7.23(m,2H),7.13(d,J＝7.7Hz,1H),7.07–7.04(m,1H),6.95–6.90(m,1H),6.83(t,J_F-H＝74.8Hz,1H),5.12–5.06(m,1H),4.54(s,2H),3.95(d,J＝6.9Hz,2H),1.69(d,J＝7.0Hz,3H),1.29–1.25(m,1H),0.62–0.58(m,2H),0.36–0.32(m,2H)；

MS-ESI:m/z 476.3[M+H-HCl]⁺。

Example 16: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (4-fluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((4-fluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (130.56mg,0.96mmol) were dissolved in dichloromethane (10mL), 4-fluorobenzylamine (0.09mL,0.77mmol) and N, N-diisopropylethylamine (0.33mL,1.92mmol) were added dropwise to the solution at 0 ℃ and stirred at room temperature for 3h, washed with water (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) gave 250mg of a colorless oil, yield: 68 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.56(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.52(d,J＝1.9Hz,1H),7.37–7.33(m,2H),7.22(d,J＝8.3Hz,1H),7.05(t,J＝8.7Hz,2H),6.69(t,J_F-H＝75.0Hz,1H),5.32–5.26(m,1H),4.61(d,J＝6.1Hz,2H),3.96(d,J＝7.0Hz,2H),1.54(d,J＝7.0Hz,3H),1.43(s,9H),1.36–1.32(m,1H),0.70–0.65(m,2H),0.41–0.37(m,2H)。

Step 2: synthesis of compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (4-fluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((4-fluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.25g,0.43mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 24h, filtered, washed with ethyl acetate (20 mL. times.3) to give 187mg of a white solid, yield: 78 percent.

Compound 36:¹H NMR(400MHz,CD₃OD):δppm 7.79(d,J＝1.9Hz,1H),7.72(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.45–7.41(m,2H),7.33(d,J＝8.4Hz,1H),7.10–7.06(m,2H),6.92(t,J_F-H＝65.5Hz,1H),5.20–5.15(m,1H),4.59(s,2H),4.03(d,J＝7.0Hz,2H),1.78(d,J＝7.0Hz,3H),1.37–1.32(m,1H),0.70–0.66(m,2H),0.44–0.42(m,2H)；

MS-ESI:m/z 476.1[M+H-HCl]⁺。

Example 17: the compound (S) -5- (1-aminoethyl) -N-benzyl-2- (3- (cyclopropylmethoxy) -4- (difluoromethyl) Synthesis of oxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (1- (4- (benzylcarbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (183.36mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (130.56mg,0.96mmol) were dissolved in dichloromethane (10mL), to this solution was added dropwise benzylamine (0.08mL,0.77mmol) and N, N-diisopropylethylamine (0.33mL,1.92mmol) respectively at 0 ℃ and stirred for 3h at room temperature, followed by addition of water (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 200mg of a white solid, yield: 56 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.55(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.52(d,J＝1.8Hz,1H),7.40–7.38(m,4H),7.36–7.31(m,1H),7.21(d,J＝8.3Hz,1H),6.69(t,J_F-H＝75.0Hz,1H),5.18–5.15(m,1H),4.65(d,J＝6.0Hz,2H),3.95(d,J＝7.0Hz,2H),1.55(d,J＝7.0Hz,3H),1.43(s,9H),1.36–1.33(m,1H),0.69–0.65(m,2H),0.41–0.37(m,2H)；

MS-ESI:m/z 558.2[M+H]⁺。

Step 2: synthesis of compound (S) -5- (1-aminoethyl) -N-benzyl-2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) - (1- (4- (benzylcarbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (0.2g,0.36mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,7mL), stirred at room temperature for 18h, filtered, washed with ethyl acetate (15 mL. times.3) to give 136mg of a white solid, yield: 77 percent.

Compound 37:¹H NMR(400MHz,CD₃OD):δppm 7.80(d,J＝1.9Hz,1H),7.72(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.42–7.39(m,2H),7.37–7.31(m,3H),7.30–7.26(m,1H),6.91(t,J_F-H＝74.8Hz,1H),5.20–5.15(m,1H),4.62(s,2H),4.03(d,J＝7.0Hz,2H),1.78(d,J＝7.0Hz,3H),1.37–1.32(m,1H),0.71–0.66(m,2H),0.44–0.40(m,2H)；

MS-ESI:m/z 458.1[M+H-HCl]⁺。

Example 18: the compound (S) -5- (1-aminoethyl) -N- ((3, 5-dichloropyridin-4-yl) methyl) -2- (3-ethoxycarbonyl) Synthesis of phenyl-4-methoxyphenyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (1- (4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxylic acid (0.25g,0.62mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (178mg,0.93mmol) and N-hydroxy-7-azabenzotriazole (127mg,0.93mmol) were dissolved in dichloromethane (10mL), and after stirring at 0 ℃ for 30min, a solution of the compound (3, 5-dichloropyridin-4-yl) methylamine (132mg,0.74mmol) in DCM (4mL) and N, N-diisopropylethylamine (0.32mL,1.86mmol) were added dropwise, followed by stirring at room temperature for 22h, water washing (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 140mg of a white solid, yield: 40 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.53(s,2H),7.57(dd,J₁＝8.4Hz,J₂＝1.8Hz,1H),7.47(d,J＝1.7Hz,1H),6.91(d,J＝8.5Hz,1H),5.30–5.24(m,1H),4.93(d,J＝5.5Hz,2H),4.20–4.15(m,2H),3.93(s,3H),1.54–1.49(m,6H),1.42(s,9H)。

Step 2: synthesis of compound (S) -5- (1-aminoethyl) -N- ((3, 5-dichloropyridin-4-yl) methyl) -2- (3-ethoxy-4-methoxyphenyl) oxazole-4-carboxamide dihydrochloride

To a solution of the compound tert-butyl (S) - (1- (4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) -2- (3-ethoxy-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.14g,0.25mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 3h, filtered and washed with ethyl acetate (15 mL. times.3) to give 100mg of a white solid, yield: 75 percent.

Compound 38:¹H NMR(400MHz,CD₃OD):δppm 8.50(s,2H),7.60(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.52(d,J＝2.0Hz,1H),7.01(d,J＝8.5Hz,1H),5.07–5.04(m,1H),4.82(s,2H),4.07–4.02(m,2H),3.82(s,3H),1.65(d,J＝7.0Hz,3H),1.35(t,J＝7.0Hz,3H)；

MS-ESI:m/z 466.2[M+H-2HCl]⁺。

Example 19: the compound (S) -5- (1-aminoethyl) -N- ((3, 5-dichloropyridin-4-yl) methyl) -2- (3, 4-di Synthesis of methoxyphenyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (1- (4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxylic acid (0.3g,0.77 m)mol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (220.6mg,1.16mmol) and N-hydroxy-7-azabenzotriazole (157.1mg,1.16mmol) are dissolved in dichloromethane (10mL), a DCM (5mL) solution of the compound (3, 5-dichloropyridin-4-yl) methylamine (163mg,0.77mmol) and N, N-diisopropylethylamine (0.4mL,2.31mmol) are added dropwise to the solution at 0 deg.C, the mixture is stirred at room temperature for 22h, washed with water (20 mL. times.3), and the organic phase is washed with anhydrous Na₂SO₄drying, removal of solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 378mg of a white solid, yield: 89 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.53(s,2H),7.58(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.46(d,J＝1.9Hz,1H),6.92(d,J＝8.5Hz,1H),5.30–5.24(m,1H),4.93(d,J＝5.8Hz,2H),3.95(d,J＝8.7Hz,6H),1.54(d,J＝7.0Hz,3H),1.42(s,9H)；

MS-ESI:m/z 552.1[M+H]⁺。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -N- ((3, 5-dichloropyridin-4-yl) methyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamide dihydrochloride

To a solution of the compound tert-butyl (S) - (1- (4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) -2- (3, 4-dimethoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.37g,0.67mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,9mL), stirred at room temperature for 17h, filtered and washed with ethyl acetate (20 mL. times.3) to give 326mg of a white solid, yield: 93 percent.

compound 39:¹H NMR(400MHz,CD₃OD):δppm 8.50(s,2H),7.55(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.48(d,J＝1.9Hz,1H),6.96(d,J＝8.5Hz,1H),5.03–4.98(m,1H),4.77(s,2H),3.76(s,6H),1.61(d,J＝7.0Hz,3H)；

MS-ESI:m/z 452.2[M+H-2HCl]⁺。

Example 20: the compound (S) -6- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) Synthesis of oxazole-4-carboxamido) methyl) picolinic acid dihydrochloride

Step 1: synthesis of compound 3- (cyclopropylmethoxy) -4-methoxybenzoic acid methyl ester

Methyl 3-hydroxy-4-methoxybenzoate (5g,27.4725mmol) was dissolved in DMF (30mL), anhydrous potassium carbonate (7.58g,54.945mmol) and bromomethylcyclopropane (3.8mL,41.204mmol) were added sequentially, the tube was sealed, and reaction was carried out at 60 ℃ for 4.5 h. Saturated NaCl solution (20mL) was added, extraction was performed with ethyl acetate (25 mL. times.3), the organic phases were combined and washed with water (30 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying for 1h, removal of solvent gave 6.26g of white solid, yield: 96.5 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.66(d,J＝8.4Hz,1H),7.52(s,1H),6.87(d,J＝8.4Hz,1H),3.92(s,3H),3.89(d,J＝7.0Hz,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

The compound methyl 3- (cyclopropylmethoxy) -4-methoxybenzoate (2g,8.47mmol) was dissolved in ethanol (20mL), sodium hydroxide (1.695g,42.37mmol) was added, the reaction was carried out at 60 ℃ for 1.5h, ethanol was removed, the residue was dissolved in water (20mL), the solution was adjusted to pH 1 with HCl (1M), extracted with ethyl acetate (25 mL. times.3), the organic phases were combined and dried over anhydrous Na₂SO₄drying and removal of the solvent gave 1.81g of a white solid in yield: 96.2 percent.

¹H NMR(400MHz,CDCl₃):δppm 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]⁺。

And step 3: synthesis of Compound methyl 2- (3- (cyclopropylmethoxy) -4-methoxyphenylamido) acetate

The compound 3- (cyclopropylmethoxy) -4-methoxybenzoic acid (4.5g,20.27mmol), HOAT (2.7 mmol)59g,20.27mmol) and EDCI (5.807g,30.405mmol) were dissolved in DCM (30mL) and stirred at room temperature for a further 30min, then glycine methyl ester hydrochloride (3.04g,24.324mmol) was added and, after dropwise addition of DIPEA (14mL,81.08mmol) in an ice bath, stirring was continued at room temperature overnight, after addition of water (30mL), with CH₂Cl₂Extraction (25 mL. times.3), combining the organic phases and then applying anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (Petroleum ether/EtOAc (v/v) ═ 1/1) afforded 3.68g of a white solid, yield: 61.9 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.41(s,1H),7.34(d,J＝8.3Hz,1H),6.88(d,J＝8.4Hz,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]⁺。

And 4, step 4: synthesis of compound methyl 2- (3- (cyclopropylmethoxy) -4-methoxyphenyl thioamido) acetate

The compound methyl 2- (3- (cyclopropylmethoxy) -4-methoxyphenylamido) acetate (4g,13.64mmol) and lawson's reagent (5.52g,13.64mmol) were dissolved in tetrahydrofuran (30mL), reacted at 75 ℃ for 2h, a saturated solution of sodium bicarbonate (30mL) was added, extracted with ethyl acetate (20mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 2.89g of a yellow solid, yield: 68 percent.

And 5: synthesis of compound methyl 2- (((3- (cyclopropylmethoxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate

To a solution of trimethyloxonium tetrafluoroborate (2.68g,18.1mmol) in dichloromethane (15mL) at-78 deg.C was added dropwise a solution of the compound methyl 2- (3- (cyclopropylmethoxy) -4-methoxyphenylthioamido) acetate (2.8g,9.05mmol) in dichloromethane (20mL), after stirring for 3h at 0 deg.C, a saturated sodium bicarbonate solution was added and the organic phase was washed (25 mL. times.3) with anhydrous Na₂SO₄Drying and removal of the solvent gave 2.8g of a yellow oil, yield: 96 percent.

Step 6: synthesis of Compound (S) -methyl 5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate

Dissolving the compound methyl 2- (((3- (cyclopropylmethoxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate (2.8g,8.66mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (3.3g,17.32mmol) in anhydrous tetrahydrofuran (15mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (21.65mL,21.65mmol) to the solution at-78 deg.C, reacting at 78 deg.C for 1h, adding water (30mL) to quench the reaction, extracting with ethyl acetate (25 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 2.58g of a white solid, yield: 67%.

And 7: synthesis of the Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid

The compound methyl (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate (2.58g,5.78mmol) and lithium hydroxide monohydrate (1.21g,28.9mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL) to react at 40 ℃ for 2h, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added to extract (20 mL. times.3), the organic phases were combined and Na was added thereto₂SO₄drying and removal of the solvent gave 1.66g of a yellow solid, yield: 66 percent.

and 8: synthesis of Compound ethyl (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxamido) methyl) picolinate

compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid (0.35g,0.81mmol), compound ethyl 6- (aminomethyl) picolinate (175mg,0.97mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (232mg,1.21mmol) and N-hydroxy-7-azabenzotriazole (165mg,1.21mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.42mL,2.43mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 4 hours,Washed with water (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 240mg of a yellow solid, yield: 50 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.18(br.s,1H),8.07(d,J＝7.6Hz,1H),7.87(t,J＝7.7Hz,1H),7.64(d,J＝7.7Hz,1H),7.60(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.51(d,J＝1.9Hz,1H),6.94(d,J＝8.5Hz,1H),5.32–5.29(m,1H),4.90–4.88(m,2H),4.54–4.49(m,2H),3.98(d,J＝7.0Hz,2H),3.96(s,3H),1.54(d,J＝7.0Hz,3H),1.49–1.47(m,3H),1.45(s,9H),1.41–1.39(m,1H),0.73–0.68(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 595.4[M+H]⁺。

And step 9: synthesis of compound (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid

The compound ethyl (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxamido) methyl) picolinate (0.24g,0.4mmol) and lithium hydroxide monohydrate (0.085g,2.0mmol) were dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (5mL) and reacted at 40 ℃ for 2 hours, the pH was adjusted to 1 with hydrochloric acid (1M), extraction was performed with ethyl acetate (10 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 0.22g of a yellow oil, yield: 95 percent.

¹H NMR(400MHz,CD₃OD):δppm 8.01–7.92(m,2H),7.63–7.49(m,3H),6.98(d,J＝8.4Hz,1H),5.35–5.32(m,1H),4.68(s,2H),3.83–3.80(m,2H),3.81(s,3H),1.40(d,J＝6.4Hz,3H),1.31–1.30(m,9H),1.23–1.22(m,1H),0.57–0.52(m,2H),0.30–0.26(m,2H)；

MS-ESI:m/z 567.2[M+H]⁺。

Step 10: synthesis of compound (S) -6- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid dihydrochloride

to a solution of compound (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid (0.22g,0.39mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 15min, filtered, washed with ethyl acetate (20 mL. times.3) to give 90mg of a white solid, yield: and 43 percent.

Compound 49:¹H NMR(400MHz,CD₃OD):δppm 8.35–8.31(m,1H),8.23(d,J＝7.6Hz,1H),7.92(d,J＝7.8Hz,1H),7.62–7.59(m,1H),7.52(s,1H),7.00(d,J＝8.5Hz,1H),5.05–5.02(m,1H),4.84(s,2H),3.82–3.80(m,2H),3.81(s,3H),1.63(d,J＝6.8Hz,3H),1.20–1.17(m,1H),0.55–0.51(m,2H),0.27–0.23(m,2H)；

MS-ESI:m/z 467.3[M+H-2HCl]⁺。

Example 21: the compound (S) -6- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) Synthesis of bi-hydrochloride of phenyl) oxazole-4-formamido) methyl) pyridine carboxylic acid

Step 1: synthesis of ethyl (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) picolinate, a compound

Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.35g,0.75mmol), compound ethyl 6- (aminomethyl) picolinate (162mg,0.90mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (214mg,1.12mmol) and N-hydroxy-7-azabenzotriazole (152mg,1.12mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.4mL,2.24mmol) was added dropwise to the solution at 0 deg.C, the solution was stirred at room temperature for 4h, washed with water (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 250mg of a white solid, yield: 52 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.22(br.s,1H),8.08(d,J＝7.5Hz,1H),7.90–7.87(m,1H),7.60(d, J＝8.7Hz,2H),7.25(d,J＝8.1Hz,1H),6.73(t,J_F-H＝75.1Hz,1H),5.35–5.30(m,1H),4.89(s,2H),4.55–4.49(m,2H),4.02(d,J＝6.8Hz,2H),1.55(d,J＝7.0Hz,3H),1.45(s,9H),1.37–1.34(m,1H),1.28(t,J＝7.1Hz,1H),0.73–0.68(m,2H),0.46–0.43(m,2H)。

Step 2: synthesis of compound (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) picolinic acid

Ethyl (0.25g,0.4mmol) of the compound (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) picolinate and lithium hydroxide monohydrate (0.08g,2.0mmol) were dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (5mL) and reacted at 40 ℃ for 2 hours, the pH was adjusted to 1 with hydrochloric acid (1M), extraction was performed with ethyl acetate (10 mL. times.3), and the organic phases were combined and then extracted with Na₂SO₄drying and removal of the solvent gave 0.23g of a yellow oil, yield: 98 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.99(d,J＝7.5Hz,1H),7.93–7.90(m,1H),7.63–7.55(m,3H),7.17(d,J＝9.1Hz,1H),6.78(t,J_F-H＝74.9Hz,1H),5.38–5.32(m,1H),4.67(s,2H),3.90(d,J＝6.9Hz,2H),1.41(d,J＝6.9Hz,3H),1.31–1.28(m,9H),1.26–1.23(m,1H),0.59–0.54(m,2H),0.33–0.29(m,2H)；

MS-ESI:m/z 603.4[M+H]⁺。

And step 3: synthesis of Compound (S) -6- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) picolinic acid dihydrochloride

to a solution of compound (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) methyl) picolinic acid (0.23g,0.38mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 15min, filtered, washed with ethyl acetate (15 mL. times.3) to give 150mg of a white solid, yield: and 69 percent.

Chemical combinationSubstance 51:¹H NMR(400MHz,CD₃OD):δppm 8.40(t,J＝7.9Hz,1H),8.28(d,J＝7.7Hz,1H),8.19–8.15(m,1H),7.99(d,J＝8.0Hz,1H),7.70(s,1H),7.64–7.61(m,1H),7.22(d,J＝8.4Hz,1H),6.81(t,J_F-H＝74.7Hz,1H),5.12–5.07(m,1H),4.89,4.80(s,s,1H,1H),3.92(d,J＝6.9Hz,2H),1.66(d,J＝7.0Hz,3H),1.26–1.23(m,1H),0.60–0.55(m,2H),0.33–0.29(m,2H)；

MS-ESI:m/z 503.3[M+H-2HCl]⁺。

Example 22: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- Synthesis of ((3, 5-dichloropyridin-4-yl) methyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid (0.35g,0.81mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (232mg,1.21mmol) and N-hydroxy-7-azabenzotriazol (165mg,1.21mmol) were dissolved in dichloromethane (10mL), a DCM (5mL) solution of the compound (3, 5-dichloropyridin-4-yl) methylamine (172mg,0.97mmol) and N, N-diisopropylethylamine (0.42mL,2.43mmol) were added dropwise to this solution at 0 ℃ under stirring at room temperature for 4 hours, followed by washing with water (20 mL. times.3), anhydrous Na for organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 280mg of a white solid, yield: 58 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.53(s,2H),7.58(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.46(d,J＝1.9Hz,1H),6.93(d,J＝8.5Hz,1H),5.30–5.26(m,1H),4.94(d,J＝5.7Hz,2H),3.94(s,3H),3.92(d,J＝7.0Hz,2H),1.55(d,J＝7.0Hz,3H),1.44(s,9H),1.39–1.37(m,1H),0.71–0.66(m,2H),0.42–0.38(m,2H)。

step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- ((3, 5-dichloropyridin-4-yl) methyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) -tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.28g,0.47mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 23h, filtered, washed with ethyl acetate (20 mL. times.3) to give 240mg of a white solid, yield: 86 percent.

Compound 52:¹H NMR(400MHz,CD₃OD):δppm 8.62(s,2H),7.70(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.61(d,J＝2.0Hz,1H),7.12(d,J＝8.6Hz,1H),5.18–5.13(m,1H),4.92(s,2H),3.93(s,3H),3.92(d,J＝7.2Hz,2H),1.76(d,J＝7.0Hz,3H),1.33–1.30(m,1H),0.68–0.63(m,2H),0.40–0.37(m,2H)；

MS-ESI:m/z 492.1[M+H-2HCl]⁺。

example 23: the compound (S) -6- ((5- (1-aminoethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamide Synthesis of Yl) methyl) picolinic acid dihydrochloride

step 1: synthesis of ethyl (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamido) methyl) picolinate

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxylic acid (0.35g,0.89mmol), the compound ethyl 6- (aminomethyl) picolinate (193mg,1.07mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (256mg,1.34mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.34mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.47mL,2.68mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 12 hours, washed with water (15 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 360mg of a yellow oil, yield: 72 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.05(d,J＝7.6Hz,1H),7.85(t,J＝7.6Hz,1H),7.60(t,J＝8.6Hz,2H),7.54(s,1H),6.92(d,J＝8.4Hz,1H),5.30–5.26(m,1H),4.87–4.85(m,2H),4.51–4.45(m,2H),4.00(s,3H),3.94(s,3H),1.52(d,J＝7.0Hz,3H),1.44(d,J＝7.2Hz,3H),1.43(s,9H)；

MS-ESI:m/z 555.4[M+H]⁺。

Step 2: synthesis of (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid

The compound ethyl (S) -6- ((5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamido) methyl) picolinate (0.36g,0.4mmol) and lithium hydroxide monohydrate (0.14g,3.25mmol) were dissolved in a mixed solvent of tetrahydrofuran (14mL) and water (7mL) and reacted at 40 ℃ for 2 hours, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added and extracted (10 mL. times.3), and the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 0.27g of a yellow oil, yield: 79 percent.

¹H NMR(400MHz,CD₃OD):δppm 8.09(d,J＝7.4Hz,1H),8.00(t,J＝7.7Hz,1H),7.71(d,J＝7.6Hz,1H),7.67(dd,J₁＝8.4Hz,J₂＝1.8Hz,1H),7.63(s,1H),7.09(d,J＝8.4Hz,1H),5.46–5.44(m,1H),4.79(s,2H),3.92(d,J＝7.2Hz,6H),1.53(d,J＝7.1Hz,3H),1.42(s,9H)；

MS-ESI:m/z 527.4[M+H]⁺。

And step 3: synthesis of Compound (S) -6- ((5- (1-aminoethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid dihydrochloride

To a solution of compound (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3, 4-dimethoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid (0.27g,0.51mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,9mL), stirred at room temperature for 15min, filtered, washed with ethyl acetate (20 mL. times.3) to give 210mg of a white solid, yield: 82 percent.

Compound 53:¹H NMR(400MHz,CD₃OD):δppm 8.57(t,J＝7.9Hz,1H),8.44(d,J＝7.5Hz,1H),8.15(d,J＝8.0Hz,1H),7.77–7.75(m,1H),7.69(s,1H),7.14(d,J＝8.5Hz,1H),5.21–5.18(m,1H),3.94(s,6H),3.37(s,2H),1.77(d,J＝7.0Hz,3H)；

MS-ESI:m/z 427.3[M+H-2HCl]⁺。

Example 24: the compound (S) -5- (1-aminoethyl) -N- ((3, 5-dichloropyridin-4-yl) methyl) -2- (3, 4-di Synthesis of ethoxyphenyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of compound 3, 4-diethoxybenzoic acid methyl ester

A100 mL two-necked flask was charged with methyl 3, 4-dihydroxybenzoate (2.0g,11.90mmol), potassium carbonate (4.93g,35.70mmol), N, N-dimethylformamide (30mL) and bromoethane (2.22mL,29.75mmol), reacted at 60 deg.C, stopped after 4.5h, extracted with ethyl acetate (50 mL. times.3), the organic phases combined and then treated with anhydrous Na₂SO₄Drying and removal of the solvent gave 2.0g of a white solid in yield: 76 percent.

Step 2: synthesis of compound 3, 4-diethoxybenzoic acid

A100 mL two-necked flask was charged with methyl 3, 4-diethoxybenzoate (2.0g,8.92mmol), sodium hydroxide (1.79g,44.64 mmol), ethanol (30mL) and water (15mL) and reacted at 60 deg.C for 1.5h, after which the reaction was stopped, ethanol was removed, pH was adjusted to 1 with hydrochloric acid (1M), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and dried over anhydrous Na₂SO₄Drying and removal of the solvent gave 1.85 white solid, yield: 99 percent.

¹H NMR(400MHz,CDCl₃):δppm 10.95(br.s,1H),7.73(d,J＝8.4Hz,1H),7.59(s,1H),6.89(d,J＝8.4Hz,1H),4.17-4.14(m,4H),1.50-1.45(m,6H)；

MS-ESI:m/z 211.1[M+H]⁺。

And step 3: synthesis of compound methyl 2- (3, 4-diethoxybenzoylamino) acetate

the compounds 3, 4-Diethoxybenzoic acid (6.37g,30.3mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (8.72g,45.5mmol) and 1-hydroxybenzotriazole (6.15g,45.5mmol) were dissolved in dichloromethane (80mL), stirred at ambient temperature for 0.5h, glycine methyl ester hydrochloride (4.57g,36.4mmol) and N, N-diisopropylethylamine (15.9mL,91.0mmol) were added at 0 deg.C, stirred at room temperature for 12h, washed with water (40 mL. times.3), and the organic phase was washed with Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 6.73g of a white solid in yield: 79 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.41(s,1H),7.31(d,J＝8.3Hz,1H),6.84(d,J＝8.3Hz,1H),6.72(br.s,1H),4.19(s,2H),4.14-4.08(m,4H),3.77(s,3H),1.46-1.41(m,6H)；

MS-ESI:m/z 282.1[M+H]⁺。

And 4, step 4: synthesis of compound methyl 2- (3, 4-diethoxyphenylthioamide) acetate

The compound methyl 2- (3, 4-diethoxybenzoylamino) acetate (4g,14.23mmol) and lawson's reagent (5.75g,14.23mmol) were added to tetrahydrofuran (60mL), reacted at 75 ℃ for 4h, saturated sodium bicarbonate solution (60mL) was added, ethyl acetate (20mL × 2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 4g yellow solid, yield: 95 percent.

And 5: synthesis of compound methyl 2- (((3, 4-diethoxyphenyl) (methylthio) methylene) amino) acetate

To a solution of trimethyloxonium tetrafluoroborate (3.98g,26.90mmol) in dichloromethane (20mL) at-78 deg.C was added dropwise a solution of the compound methyl 2- (3, 4-diethoxyphenylthioamide) acetate (4g,13.45mmol) in dichloromethane (30mL), after stirring at 0 deg.C for 4h, a saturated solution of sodium bicarbonate was added and the organic phase was washed (25 mL. times.3) with anhydrous Na₂SO₄drying and removal of the solvent gave 4g of a yellow oil, yield: 95 percent.

Step 6: synthesis of Compound (S) -methyl 5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxylate

Dissolving the compound methyl 2- (((3, 4-diethoxyphenyl) (methylthio) methylene) amino) acetate (4g,12.85mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (4.91g,25.7mmol) in anhydrous tetrahydrofuran (20mL), adding dropwise a tetrahydrofuran solution of potassium hexamethyldisilazide (32.1mL,32.1mmol) to the solution at-78 deg.C, reacting at 78 deg.C for 1h, adding water (30mL) to quench the reaction, extracting with ethyl acetate (25 mL. times.3), combining the organic phases, and extracting with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 3.9g of a yellow solid, yield: 70 percent.

And 7: synthesis of Compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxylic acid

The compound methyl (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxylate (1.8g,4.14mmol) and lithium hydroxide monohydrate (0.87g,20.71mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL) to react at 40 ℃ for 3 hours, the pH was adjusted to 1 by adding hydrochloric acid (1M), extraction was performed with ethyl acetate (20 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 1.67g of a yellow solid, yield: 96 percent.

And 8: synthesis of Compound (S) - (1- (4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) -2- (3, 4-diethoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxylic acid (0.35g,0.83mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (239mg,1.25mmol) and N-hydroxy-7-azabenzotriazole (170mg,1.25mmol) were dissolved in dichloromethane (6mL), a solution of the compound (3, 5-dichloropyridin-4-yl) methylamine (177mg,1.0mmol) in DCM (9mL) and N, N-diisopropylethylamine (0.44mL,2.5mmol) were added dropwise to the solution at 0 ℃ and stirred at room temperature for 4h, water was added thereto (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removing solvent, and separating the concentrated solution with column (petroleum)Ether/ethyl acetate (v/v) ═ 2/1), yielding 270mg of a white solid, yield: 56 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.55(s,2H),7.57(dd,J₁＝8.3Hz,J₂＝1.8Hz,2H),7.48(d,J＝1.8Hz,1H),6.93(d,J＝8.4Hz,1H),5.30–5.26(m,1H),4.95(d,J＝5.6Hz,2H),4.21–4.13(m,4H),1.55(d,J＝7.0Hz,3H),1.51(td,J₁＝7.0Hz,J₂＝2.4Hz,6H),1.44(s,9H)。

And step 9: synthesis of compound (S) -5- (1-aminoethyl) -N- ((3, 5-dichloropyridin-4-yl) methyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxamide dihydrochloride

To a solution of the compound tert-butyl (S) - (1- (4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) -2- (3, 4-diethoxyphenyl) oxazol-5-yl) ethyl) carbamate (0.27g,0.47mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,10mL), stirred at room temperature for 20min, filtered and washed with ethyl acetate (20 mL. times.3) to give 230mg of a yellow solid, yield: 89 percent.

Compound 54:¹H NMR(400MHz,CD₃OD):δppm 8.65(s,2H),7.68(dd,J₁＝8.4Hz,J₂＝2.0Hz,2H),7.63(d,J＝2.0Hz,1H),7.09(d,J＝8.5Hz,1H),5.18–5.13(m,1H),4.93(s,2H),4.19–4.13(m,4H),1.75(d,J＝7.0Hz,3H),1.46(td,J₁＝7.0Hz,J₂＝1.3Hz,6H)；

MS-ESI:m/z 480.1[M+H-2HCl]⁺。

Example 25: the compound (S) -6- ((5- (1-aminoethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxamide Synthesis of Yl) methyl) picolinic acid dihydrochloride

Step 1: synthesis of ethyl 6- ((5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxamido) methyl) picolinate, a compound

The compound (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxylic acid (0.35g,0.83mmol) was converted toEthyl 6-aminomethylpicolinate (180mg,1.0mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (239mg,1.25mmol) and N-hydroxy-7-azabenzotriazole (170mg,1.25mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.44mL,2.5mmol) was added dropwise to the solution at 0 deg.C, stirred at room temperature for 7h, washed with water (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 270mg of a white solid, yield: 56 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.21(br.s,1H),8.08(d,J＝7.6Hz,1H),7.88(t,J＝7.7Hz,1H),7.65(d,J＝7.8Hz,1H),7.58(dd,J₁＝8.4Hz,J₂＝1.8Hz,1H),7.55(d,J＝1.7Hz,1H),6.93(d,J＝8.4Hz,1H),5.32–5.30(m,1H),4.90–4.89(m,2H),4.54–4.49(m,2H),4.25–4.13(m,4H),1.55–1.47(m,12H),1.45(s,9H)；

MS-ESI:m/z 583.4[M+H]⁺。

Step 2: synthesis of compound (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid

the compound ethyl (S) -6- ((5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxamido) methyl) picolinate (0.27g,0.46mmol) and lithium hydroxide monohydrate (0.097g,2.32mmol) were dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (5mL) and reacted at 40 ℃ for 2 hours, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added and extracted (10 mL. times.3), and the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 0.24g of a yellow oil, yield: 93 percent.

¹H NMR(400MHz,CD₃OD):δppm 8.12(d,J＝7.4Hz,1H),8.05(t,J＝7.6Hz,1H),7.74(d,J＝7.2Hz,1H),7.66–7.63(m,2H),7.07(d,J＝8.3Hz,1H),5.45–5.43(m,1H),4.80(s,2H),4.19–4.13(m,4H),1.54(d,J＝4.5Hz,3H),1.48–1.43(m,6H),1.42(s,9H)；

MS-ESI:m/z 555.2[M+H]⁺。

And step 3: synthesis of Compound (S) -6- ((5- (1-aminoethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid dihydrochloride

To a solution of compound (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid (0.24g,0.43mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,9mL), stirred at room temperature for 15min, filtered, washed with ethyl acetate (20 mL. times.3) to give 190mg of a yellow solid, yield: 83 percent.

Compound 55:¹H NMR(400MHz,CD₃OD):δppm 8.52(t,J＝7.9Hz,1H),8.40(d,J＝7.5Hz,1H),8.11(d,J＝7.8Hz,1H),7.72(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.68(d,J＝1.9Hz,1H),7.12(d,J＝8.5Hz,1H),5.20–5.18(m,1H),5.01(s,2H),4.20–4.15(m,4H),1.77(d,J＝7.0Hz,3H),1.47(td,J₁＝6.9Hz,J₂＝1.1Hz,6H)；

MS-ESI:m/z 455.3[M+H-2HCl]⁺。

Example 26: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (2, 4-dichlorobenzyl) oxazole-4-carboxamide hydrochloride

step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-dichlorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

the compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.35g,0.75mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (214mg,1.12mmol) and N-hydroxy-7-azabenzotriazole (153mg,1.12mmol) were dissolved in dichloromethane (10mL), 2, 4-difluorobenzylamine (0.12mL,0.90mmol) and N, N-diisopropylethylamine (0.4mL,2.24mmol) were added dropwise to this solution at 0 ℃ and stirred at room temperature for 5 hours, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄drying, removing solvent, and separating the concentrated solution with column (petroleum ether/ethyl acetate (v/v) ═ 6-1) To yield 350mg of a colorless oil, yield: 75 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.56(d,J＝1.9Hz,1H),7.45(d,J＝2.1Hz,1H),7.42(d,J＝8.3Hz,1H),7.27–7.25(m,1H),6.72(t,J_F-H＝75.0Hz,1H),5.32–5.28(m,1H),4.73–4.71(m,2H),3.99(d,J＝7.0Hz,2H),1.55(d,J＝7.0Hz,3H),1.45(s,9H),1.38–1.35(m,1H),0.73–0.69(m,2H),0.44–0.40(m,2H)。

step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-dichlorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-dichlorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.35g,0.56mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,10mL), stirred at room temperature for 20min, and the solvent was removed to give 250mg of a white solid, yield: 79 percent.

Compound 56:¹H NMR(400MHz,CD₃OD):δppm 7.81(d,J＝1.6Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.7Hz,1H),7.47(d,J＝1.9Hz,1H),7.44(d,J＝8.4Hz,1H),7.34–7.31(m,2H),6.93(t,J_F-H＝74.8Hz,1H),5.21–5.19(m,1H),4.68(s,2H),4.03(d,J＝6.9Hz,2H),1.80(d,J＝7.0Hz,3H),1.64(dd,J₁＝7.2Hz,J₂＝2.8Hz,6H),1.37–1.33(m,1H),0.68–0.65(m,2H),0.44–0.40(m,2H)；

MS-ESI:m/z 527.2[M+H-HCl]⁺。

Example 27: the compound (S) -5- (1-aminoethyl) -N- (2-chlorobenzyl) -2- (3- (cyclopropylmethoxy) -4- Synthesis of (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

step 1: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2-chlorobenzyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.35g,0.75mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (214mg,1.12mmol) and N-hydroxy-7-azabenzotriazole (153mg,1.12mmol) were dissolved in dichloromethane (10mL), 2-chlorobenzylamine (0.11mL,0.90mmol) and N, N-diisopropylethylamine (0.4mL,2.24mmol) were added dropwise to the solution at 0 ℃ and the solution was stirred at room temperature for 5 hours, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) gave 310mg of a colorless oil, yield: 70 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.56(d,J＝1.9Hz,1H),7.49–7.47(m,1H),7.44–7.42(m,1H),7.30–7.28(m,1H),7.25(d,J＝8.3Hz,1H),6.72(t,J_F-H＝75.0Hz,1H),5.32–5.28(m,1H),4.78–4.76(m,2H),3.99(d,J＝7.0Hz,2H),1.56(d,J＝7.0Hz,3H),1.45(s,9H),1.39–1.34(m,1H),0.73–0.68(m,2H),0.44–0.40(m,2H)。

Step 2: synthesis of compound (S) -5- (1-aminoethyl) -N- (2-chlorobenzyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2-chlorobenzyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.31g,0.52mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,10mL), stirred at room temperature for 20min, the solvent was removed to give 250mg of a white solid, yield: 90 percent.

Compound 57:¹H NMR(400MHz,CD₃OD):δppm 7.81(d,J＝1.9Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.46–7.42(m,2H),7.33–7.29(m,3H),6.92(t,J_F-H＝74.8Hz,1H),5.22–5.17(m,1H),4.72(s,2H),4.03(d,J＝7.0Hz,2H),1.79(d,J＝7.0Hz,3H),1.37–1.33(m,1H),0.69–0.66(m,2H),0.44–0.40(m,2H)；

MS-ESI:m/z 492.1[M+H-HCl]⁺。

Example 28: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (2, 6-dichlorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 6-dichlorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.35g,0.75mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (214mg,1.12mmol) and N-hydroxy-7-azabenzotriazole (153mg,1.12mmol) were dissolved in dichloromethane (10mL), 2, 6-dichlorobenzylamine (0.12mL,0.90mmol) and N, N-diisopropylethylamine (0.4mL,2.24mmol) were added dropwise to this solution at 0 ℃ and stirred at room temperature for 4 hours, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 337mg of a white solid, yield: 72 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.61(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.56(d,J＝1.9Hz,1H),7.45(dd,J₁＝8.0Hz,J₂＝1.5Hz,1H),7.40(dd,J₁＝7.7Hz,J₂＝1.5Hz,1H),7.27–7.22(m,2H),6.73(t,J_F-H＝75.0Hz,1H),5.32–5.30(m,1H),4.79–4.77(m,2H),3.99(d,J＝7.0Hz,2H),1.55(d,J＝7.0Hz,3H),1.44(s,9H),1.37–1.34(m,1H),0.73–0.68(m,2H),0.44–0.40(m,2H)。

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 6-dichlorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 6-dichlorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.33g,0.53mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,10mL), stirred at room temperature for 20min, the solvent was removed to give 290mg of a white solid, yield: 97 percent.

Compound 58:¹H NMR(400MHz,CD₃OD):δppm 7.81(d,J＝1.9Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.50(dd,J₁＝7.9Hz,J₂＝1.5Hz,1H),7.41–7.39(m,1H),7.34–7.29(m,2H),6.92(t,J_F-H＝74.8Hz,1H),5.21–5.16(m,1H),4.75(s,2H),4.04(d,J＝6.9Hz,2H),1.78(d,J＝7.0Hz,3H),1.37–1.34(m,1H),0.71–0.66(m,2H),0.45–0.41(m,2H)；

MS-ESI:m/z 527.1[M+H-HCl]⁺。

Example 29: the compound (S) -5- (1- (cyclopropylcarboxamido) ethyl) -2- (3- (cyclopropylmethoxy) -4- Synthesis of (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.5g,1.07mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (307.51mg,1.61mmol) and N-hydroxy-7-azabenzotriazole (219mg,1.61mmol) were dissolved in dichloromethane (10mL), 2, 4-difluorobenzylamine (0.15mL,1.28mmol) and N, N-diisopropylethylamine (0.56mL,3.21mmol) were added dropwise to this solution at 0 ℃ and stirred at room temperature for 4h, then water was added (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 389mg of white solid, yield: 61 percent.

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.39g,0.66mmol) in dichloromethane (3mL) was added a solution of HCl in ethyl acetate (4M,12mL), stirred at room temperature for 5h, filtered, washed with ethyl acetate (20 mL. times.3) to afford 269mg of a white solid, yield: 77 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.79(d,J＝1.9Hz,1H),7.72(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.51–7.45(m,1H),7.33(d,J＝8.4Hz,1H),7.02–6.95(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.19–5.14(m,1H),4.65(s,2H),4.03(d,J＝7.0Hz,2H),1.77(d,J＝7.0Hz,3H),1.38–1.33(m,1H),0.70–0.67(m,2H),0.44–0.41(m,2H)；

MS-ESI:m/z 494.3[M+H-HCl]⁺。

And step 3: synthesis of compound (S) -5- (1- (cyclopropylcarboxamido) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide

The compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride (0.25g,0.47mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (135mg,0.71mmol) and N-hydroxy-7-azabenzotriazole (96mg,0.71mmol) were dissolved in dichloromethane (10mL), cyclopropylformic acid (0.05mL,0.57mmol) and N, N-diisopropylethylamine (0.33mL,1.89mmol) were added dropwise to the solution at 0 ℃ and stirred at room temperature for 4h, then washed with water (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/2) afforded 220mg of a white solid, yield: 83 percent.

Compound 59:¹H NMR(400MHz,CDCl₃):δppm 8.79(d,J＝9.1Hz,1H),7.65(t,J＝6.1Hz,1H),7.58(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.54(d,J＝1.8Hz,1H),7.45–7.39(m,1H),7.25(d,J＝8.3Hz,1H),6.93– 6.87(m,2H),6.72(t,J_F-H＝64.4Hz,1H),5.64–5.60(m,1H),4.68(d,J＝6.1Hz,2H),3.98(d,J＝7.0Hz,2H),1.55(d,J＝7.0Hz,3H),1.50–1.46(m,1H),1.36–1.30(m,1H),1.01–0.95(m,2H),0.80–0.72(m,2H),0.71–0.68(m,2H),0.44–0.40(m,2H)。

Example 30: the compound (S) -5- (1-aminoethyl) -N- (4-chloro-2-fluorobenzyl) -2- (3- (cyclopropylmethoxy) Synthesis of yl) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound (S) - (tert-butyl 1- (4- ((4-chloro-2-fluorobenzyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (184mg,0.96mmol) and N-hydroxy-7-azabenzotriazole (131mg,0.96mmol) were dissolved in dichloromethane (10mL), 4-chloro-2-fluorobenzylamine (0.1mL,0.77mmol) and N, N-diisopropylethylamine (0.34mL,1.92mmol) were added dropwise to the solution at 0 ℃ and stirred at room temperature for 15 hours, then water was added (10 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) gave 286mg of white solid, yield: 73 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.56(d,J＝1.9Hz,1H),7.40(t,J＝8.2Hz,1H),7.25(d,J＝8.3Hz,1H),7.17–7.13(m,2H),6.72(t,J_F-H＝75.0Hz,1H),5.32(s,1H),4.69–4.66(m,2H),3.99(d,J＝6.9Hz,2H),1.55(d,J＝7.0Hz,3H),1.45(s,9H),1.37–1.34(m,1H),0.73–0.68(m,2H),0.44–0.41(m,2H)。

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -N- (4-chloro-2-fluorobenzyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) -tert-butyl (1- (4- ((4-chloro-2-fluorobenzyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.28g,0.46mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,10mL), stirred at room temperature for 20min, the solvent was removed to give 230mg of a white solid, yield: 92 percent.

Compound 60:¹H NMR(400MHz,CD₃OD):δppm 7.80(d,J＝1.9Hz,1H),7.73(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.45(t,J＝8.3Hz,1H),7.33(d,J＝8.4Hz,1H),7.24–7.20(m,2H),6.92(t,J_F-H＝74.8Hz,1H),5.18–5.15(m,1H),4.65(s,2H),4.03(d,J＝7.0Hz,2H),1.78(d,J＝7.0Hz,3H),1.37–1.34(m,1H),0.71–0.66(m,2H),0.45–0.41(m,2H)；

MS-ESI:m/z 510.2[M+H-HCl]⁺。

example 31: the compound (S) -5- (1-aminopropyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- Synthesis of (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound (S) -2- (tert-butoxycarbonylamino) butanoic acid

Dissolving L-2-aminobutyric acid (2.0g,19.40mmol) and di-tert-butyl dicarbonate (4.67g,21.4mmol) in tetrahydrofuran (25mL), dropping sodium hydroxide solution (1M,23mL) at 0 deg.C, reacting at room temperature for 12h, adjusting pH to 1 with hydrochloric acid (1M), extracting with ethyl acetate (20 mL. times.3), combining organic phases, and adding anhydrous Na₂SO₄Drying and removal of the solvent gave 4.4g of a white solid, yield: 99 percent.

¹H NMR(400MHz,CDCl₃):δppm 10.52(s,1H),4.32-4.08(m,1H),1.95-1.89(m,1H),1.78-1.69(m,1H),1.45(s,9H),1.00-0.96(m,3H)。

Step 2: synthesis of Compound (S) - (1-fluoro-1-oxobutan-2-yl) carbamic acid tert-butyl ester

reacting (S) -2- (tert-butyloxycarbonyl)Dissolving amino) butyric acid (1.0g,4.93mmol) and triethylamine (0.8mL,5.43mmol) in dichloromethane (20mL), slowly adding dropwise cyanuric fluoride (1.0mL,9.86mmol) at-40 deg.C, reacting at-10 deg.C for 1h, washing with ice water (20mL × 3), and mixing the organic phase with anhydrous Na₂SO₄Drying and removal of the solvent gave 0.89g of a white solid, yield: 88 percent.

¹H NMR(400MHz,d₆-DMSO):δppm 4.15-4.13(m,1H),1.78-1.71(m,2H),1.40(s,9H),0.95-0.89(m,3H)；

MS-ESI:m/z 206.2[M+H]⁺。

And step 3: synthesis of Compound (S) -methyl 5- (1- (tert-butoxycarbonylamino) propyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate

Dissolving the compound methyl 2- (((3- (cyclopropylmethoxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate (0.50g,1.55mmol), the compound tert-butyl (S) - (1-fluoro-1-oxobutan-2-yl) carbamate (0.89g,4.33mmol) in anhydrous tetrahydrofuran (15mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (6.0mL,6.00mmol) at-78 deg.C, reacting at-78 deg.C for 1h, quenching the reaction with ice water (20mL), extracting with ethyl acetate (15 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) afforded 0.37g of a yellow solid, yield: 53 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.65(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.56(d,J＝2.0Hz,1H),6.94(d,J＝8.5Hz,1H),5.31-5.25(m,1H),4.00(s,3H),3.95(d,J＝7.0Hz,2H),3.95(s,3H),1.93-1.88(m,2H), 1.46(s,9H),1.40-1.35(m,1H),0.97(t,J＝7.3Hz,3H),0.72-0.67(m,2H),0.43-0.39(m,2H)；

MS-ESI:m/z 461.3[M+H]⁺。

And 4, step 4: synthesis of Compound (S) -5- (1- (tert-butoxycarbonylamino) propyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid

The compound (S) -5- (1- (tert-butoxycarbonylamino) propyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazoleDissolving methyl-4-carboxylate (0.37g,0.81mmol) and lithium hydroxide monohydrate (0.17g,0.45mmol) in a mixed solvent of tetrahydrofuran (30mL) and water (15mL), reacting at 40 deg.C for 3h, removing tetrahydrofuran, adjusting pH to 1 with hydrochloric acid (1M), extracting with ethyl acetate (30 mL. times.3), combining the organic phases, and adding Na₂SO₄drying and removal of the solvent gave 0.34g of a white solid, yield: 95 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.65(d,J＝8.4Hz,1H),7.57(s,1H),6.95(d,J＝8.4Hz,1H),5.26-5.24(m,1H),3.96(s,3H),3.95(d,J＝6.8Hz,2H),1.96-1.91(m,2H),1.45(s,9H),1.41-1.36(m,1H),0.99(t,J＝7.0Hz,3H),0.71-0.67(m,2H),0.42-0.39(m,2H)；

MS-ESI:m/z 447.1[M+H]⁺。

And 5: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) propyl) carbamate

The compound (S) -5- (1- (t-butoxycarbonylamino) propyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid (0.15g,0.34mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.10g,0.51mmol) and N-hydroxy-7-azabenzotriazole (0.07g,0.51mmol) were dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.05mL,0.41mmol) and N, N-diisopropylethylamine (0.18mL,1.02mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, water (20mL) was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 0.15g of a white solid in yield: 78 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.48(d,J＝2.0Hz,1H),7.46-7.40(m,1H),6.95(d,J＝8.5Hz,1H),6.92-6.84(m,2H),5.13-5.05(m,1H),4.67(t,J＝5.8Hz,2H),3.96(d,J＝7.0Hz,2H),3.96(s,3H),1.94-1.86(m,2H),1.46(s,9H),1.39-1.36(m,1H),0.96(t,J＝7.3Hz,3H),0.72-0.68(m,2H),0.45-0.41(m,2H)；

MS-ESI:m/z 572.2[M+H]⁺。

Step 6: synthesis of Compound (S) -5- (1-aminopropyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (S) - (1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) propyl) carbamate (0.15g,0.26mmol) in dichloromethane (2mL) was added an ethyl acetate solution of HCl (4M,6mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 117mg of a white solid, yield: 93 percent.

Compound 66:¹H NMR(400MHz,CD₃OD):δppm 7.72(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.64(d,J＝1.9Hz,1H),7.51-7.45(m,1H),7.13(d,J＝8.5Hz,1H),7.01-6.94(m,2H),5.04-5.01(m,1H),4.64(s,2H), 3.94(d,J＝6.8Hz,2H),3.94(s,3H),2.21-2.12(m,2H),1.03(t,J＝7.5Hz,3H),0.93-0.86(m,1H),0.68-0.64(m,2H),0.41-0.37(m,2H)；

MS-ESI:m/z 472.1[M+H-HCl]⁺。

Example 32: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (2, 4-difluorophenyl) oxazole-4-carboxamide hydrochloride

step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.48g,1.02mmol) and triethylamine (0.16mL,1.1mmol) were dissolved in dichloromethane (10mL) at-40 ℃ and cyanuric fluoride (0.18mL,2.05mmol) was added dropwise to the solution, which was reacted at-10 ℃ for 3 hours, washed with ice water (20 mL. times.4), and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 0.46g of a yellow oil, yield: 96 percent.

Step 2: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorophenyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

2, 4-difluoroaniline (0.16mL,1.53mmol) and sodium hydride (60%, 61mg,1.53mmol) were dissolved in tetrahydrofuran (5mL), stirred at room temperature for 0.5h, a solution of compound (S) - (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (0.46g,0.98mmol) in tetrahydrofuran (10mL) was added dropwise at 0 ℃ and stirred at room temperature for 23h, then saturated ammonium chloride solution (20mL) was added, ethyl acetate (15 mL. times.3) was extracted, the organic phases were combined, and anhydrous Na was used₂SO₄drying, removal of solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 8/1) gave 289mg of white solid, yield: 49 percent.

¹H NMR(400MHz,CDCl₃):δppm 9.08(s,1H),8.44–8.38(m,1H),7.66(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.61(d,J＝1.9Hz,1H),7.29(d,J＝7.4Hz,1H),6.99–6.94(m,2H),6.74(t,J_F-H＝75.0Hz,1H),5.41–5.37(m,1H),4.03(d,J＝6.9Hz,2H),1.59(d,J＝7.0Hz,3H),1.46(s,9H),1.38–1.35(m,1H),0.75–0.70(m,2H),0.47–0.43(m,2H)。

And step 3: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorophenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorophenyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.28g,0.48mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,12mL), stirred at room temperature for 20min, the solvent was removed to give 238mg of a white solid, yield: 92 percent.

Compound 73:¹H NMR(400MHz,CDCl₃):δppm 7.82(d,J＝1.7Hz,1H),7.75(dd,J₁＝8.4Hz,J₂＝1.7Hz,1H),7.54–7.49(m,1H),7.33(d,J＝8.4Hz,1H),7.34–7.26(m,1H),7.16–7.11(m,2H),6.91(t,J_F-H＝74.7Hz,1H),5.26–5.23(m,1H),4.04(d,J＝6.9Hz,2H),1.78(d,J＝7.0Hz,3H),1.34–1.31(m,1H),0.68–0.66(m,2H),0.42–0.41(m,2H)；

MS-ESI:m/z 480.2[M+H-HCl]⁺。

Example 33: the compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) -3- Synthesis of ethoxyphenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound 4- (difluoromethoxy) -3-ethoxybenzoic acid methyl ester

To the tube was added methyl 4-difluoromethoxy-3-hydroxybenzoate (5g,22.92mmol), potassium carbonate (6.33g,45.84mmol), bromoethane (2.58mL,34.38mmol) and N, N' -dimethylformamide (30mL), reacted at 60 ℃ for 4h, filtered with suction and the filtrate was dried by spinning to give 5.6g brown oil, yield: 96 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60–7.58(m,2H),7.15(d,J＝8.7Hz,1H),6.65(t,J_F-H＝74.8Hz,1H),3.88(s,3H),4.15–4.10(m,2H),1.44(t,J＝7.0Hz,3H)。

Step 2: synthesis of compound 4- (difluoromethoxy) -3-ethoxybenzoic acid

the compound methyl 4- (difluoromethoxy) -3-ethoxybenzoate (5.6g,22.92mmol), sodium hydroxide (2.73g,68.23mmol) were dissolved in a mixed solvent of ethanol (30mL) and water (10mL), reacted at 60 ℃ for 13 hours, the reaction was stopped, ethanol was removed, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate (20 mL. times.3) was added for extraction, and the organic phase was extracted with anhydrous Na₂SO₄Drying and concentration gave 4.75g of a pale yellow solid, yield: 90 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.71(d,J＝1.9Hz,1H),7.65(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.23(d,J＝8.3Hz,1H),6.87(t,J_F-H＝74.7Hz,1H),4.21–4.15(m,2H),1.46(t,J＝7.0Hz,3H)。

And step 3: synthesis of compound methyl 2- (4- (difluoromethoxy) -3-ethoxybenzoylamino) acetate

4- (difluoromethoxy)4.75g of phenyl) -3-ethoxybenzoic acid (20.46 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.86g,30.69mmol) and N-hydroxy-7-azabenzotriazole (4.17g,30.69mmol) were dissolved in dichloromethane (35mL), stirred at room temperature for 30min, glycine methyl ester hydrochloride (3.08g,24.55mmol) was added, N-diisopropylethylamine (11mL,61.38mmol) was added dropwise at 0 deg.C, stirred at room temperature for 16h, washed with water (40 mL. times.3), and the organic phase was Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 6.2g of a light yellow oil, yield: 98 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.99(s,1H),7.49(d,J＝2.0Hz,1H),7.31(dd,J₁＝8.3Hz,J₂＝2.0Hz,1H),7.14(d,J＝8.3Hz,1H),6.62(t,J_F-H＝74.9Hz,1H),4.19(d,J＝3.4Hz,2H),4.14–4.08(m,2H), 1.43(t,J＝7.0Hz,3H)；

MS-ESI:m/z 304.0[M+H]⁺。

And 4, step 4: synthesis of compound methyl 2- (4- (difluoromethoxy) -3-ethoxyphenylthioamide) acetate

The compound methyl 2- (4- (difluoromethoxy) -3-ethoxybenzoylamino) acetate (6g,19.8mmol) and Lawson's reagent (8g,19.8mmol) were dissolved in tetrahydrofuran (40mL) and reacted at 75 ℃ for 4h, then saturated sodium bicarbonate solution (30mL) was added, ethyl acetate was extracted (20 mL. times.3), the organic phases were combined, and anhydrous Na was added₂SO₄Drying and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 6g of a yellow oil, yield: 95 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59(d,J＝2.1Hz,1H),7.28–7.25(m,1H),7.17(d,J＝8.3Hz,1H),6.64(t,J_F-H＝74.9Hz,1H),4.57(d,J＝4.6Hz,2H),4.21–4.16(m,2H),3.87(s,3H),1.48(t,J＝7.0Hz,3H)；

MS-ESI:m/z 320.2[M+H]⁺。

And 5: synthesis of compound methyl 2- (((4- (difluoromethoxy) -3-ethoxyphenyl) (methylthio) methylene) amino) acetate

Trimethyloxonium tetrafluoroborate (5.84g,39.46mmol) was dissolved in dichloromethane (10 m)L), a solution of the compound methyl 2- (4- (difluoromethoxy) -3-ethoxyphenylthioamide) acetate (6.3g,19.73mmol) in dichloromethane (30mL) was added dropwise at-78 deg.C, the mixture was stirred at 0 deg.C for 5 hours, then washed with saturated sodium bicarbonate solution (25 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 6g of a yellow oil, yield: 91 percent.

Step 6: synthesis of Compound (S) -methyl 5- (1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxylate

Dissolving compound methyl 2- (((4- (difluoromethoxy) -3-ethoxyphenyl) (methylthio) methylene) amino) acetate (6g,18mmol), compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (6.88g,36mmol) in anhydrous tetrahydrofuran (20mL), stirring at 78 deg.C, adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (45mL,45mmol), reacting at-78 deg.C for 2h, adding saturated sodium bicarbonate solution (35mL), quenching the reaction, extracting with ethyl acetate (25 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄drying, removal of solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) gave 3.1g of a light yellow solid, yield: 38 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.66(d,J＝1.9Hz,1H),7.62(dd,J₁＝8.3Hz,J₂＝2.0Hz,1H),7.23(d,J＝8.3Hz,1H),6.64(t,J_F-H＝74.9Hz,1H),5.48–5.44(m,1H),4.22–4.17(m,2H),3.99(s,3H),1.54(d,J＝7.0Hz,3H),1.48(t,J＝7.0Hz,3H),1.42(s,9H)；

MS-ESI:m/z 457.3[M+H]⁺。

And 7: synthesis of Compound (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxylic acid

The compound methyl (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxylate (3.17g,6.95mmol) and lithium hydroxide monohydrate (1.46g,34.73mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL) and reacted at 40 ℃ for 2h, the solvent tetrahydrofuran was removed, hydrochloric acid (1M) was added to adjust the pH to 1, and extraction was carried out with ethyl acetate: (extraction:. RTM.), (20 mL. times.3), combine the organic phases and add Na₂SO₄Drying and removal of the solvent gave 3g of a yellow solid, yield: 90 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.82(d,J＝1.9Hz,1H),7.67(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.29(d,J＝8.4Hz,1H),6.87(t,J_F-H＝74.7Hz,1H),5.52–5.50(m,1H),4.25–4.22(m,2H),1.54(d,J＝7.1Hz,3H),1.49(t,J＝7.0Hz,3H),1.45(s,9H)。

And 8: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxylic acid (0.3g,0.68mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (194mg,1.02mmol) and N-hydroxy-7-azabenzotriazole (138mg,1.02mmol) were dissolved in dichloromethane (10mL), stirred at 0 deg.C, 2, 4-difluorobenzylamine (0.1mL,0.81mmol) and N, N-diisopropylethylamine (0.35mL,2.04mmol) were added dropwise, respectively, stirred at room temperature for 4h, washed with water (20 mL. times.3), and the organic phase was Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 264mg of a colourless oil, yield: and 69 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60–7.57(m,1H),7.58(s,1H),7.56–7.52(m,1H),7.45–7.41(m,1H),7.25(d,J＝8.7Hz,1H),6.91–6.85(m,2H),6.66(t,J_F-H＝74.8Hz,1H),5.34–5.31(m,1H),4.68–4.66(m,2H),4.25–4.19(m,2H),1.56(d,J＝7.0Hz,3H),1.52(t,J＝7.0Hz,3H),1.45(s,9H)。

And step 9: synthesis of Compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (S) - (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazol-5-yl) ethyl) carbamate (260mg,0.46mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,10mL), stirred at room temperature for 20min, the solvent was removed to give 218mg of a white solid, yield: 94 percent.

Compound 74:¹H NMR(400MHz,CD₃OD):δppm 7.81(d,J＝1.5Hz,1H),7.73(dd,J₁＝8.3Hz,J₂＝1.6Hz,1H),7.51–7.46(m,1H),7.32(d,J＝8.4Hz,1H),7.00–6.94(m,2H),6.88(t,J_F-H＝74.6Hz,1H),5.20–5.15(m,1H),4.65(s,2H),4.27–4.22(m,2H),1.78(d,J＝6.9Hz,3H),1.49(t,J＝7.0Hz,3H)；

MS-ESI:m/z 468.0[M+H-HCl]⁺。

Example 34: the compound (S) -6- ((5- (1-aminoethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxa Synthesis of oxazole-4-carboxamide) methyl) picolinic acid dihydrochloride

Step 1: synthesis of ethyl 6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxamide) methyl) picolinate, a compound

Compound (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxylic acid (0.4g,0.90mmol), compound 6- (aminoethyl) picolinic acid ethyl ester (196mg,1.085mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (259mg,1.36mmol) and N-hydroxy-7-azabenzotriazole (184mg,1.36mmol) were dissolved in dichloromethane (15mL), stirred at 0 deg.C, N-diisopropylethylamine (0.47mL,2.71mmol) was added dropwise, stirred at room temperature for 4h, washed with water (15 mL. times.3), and the organic phase was Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 279mg of a white solid, yield: 51 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.12(d,J＝7.2Hz,1H),7.98–7.94(m,1H),7.75–7.72(m,1H),7.67–7.66(m,1H),7.61–7.59(m,1H),7.25(d,J＝8.3Hz,1H),6.67(t,J_F-H＝74.9Hz,1H),5.34–5.31(m,1H),4.97–4.95(m,2H),4.56–4.50(m,2H),4.28–4.23(m,2H),1.54(t,J＝6.5Hz,6H),1.47(d,J＝7.2Hz,3H),1.45(s,9H)；

MS-ESI:m/z 605.3[M+H]⁺。

Step 2: synthesis of compound (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxamide) methyl) picolinic acid

The compound ethyl (S) -6- ((5- (1- (t-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxamide) methyl) picolinate (0.28g,0.46mmol) and lithium hydroxide monohydrate (97mg,2.32mmol) were added to a mixed solvent of tetrahydrofuran (10mL) and water (5mL) and reacted at 40 ℃ for 2 hours, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added and extracted (10 mL. times.3), the organic phases were combined and Na was added thereto₂SO₄Drying and removal of the solvent gave 0.26g of a white solid, yield: 98 percent.

¹H NMR(400MHz,CD₃OD):δppm 8.11(d,J＝7.6Hz,1H),8.05–8.02(br,1H),7.74–7.72(m,2H),7.66(d,J＝8.2Hz,1H),7.28(d,J＝8.2Hz,1H),6.86(t,J_F-H＝74.7Hz,1H),5.47–5.44(m,1H),4.80(s,2H),4.25–4.20(m,2H),1.53(d,J＝6.8Hz,3H),1.49(t,J＝7.1Hz,3H),1.42(s,9H)；

MS-ESI:m/z 577.2[M+H]⁺。

And step 3: synthesis of Compound (S) -6- ((5- (1-aminoethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxamide) methyl) picolinic acid dihydrochloride

To a solution of compound (S) -6- ((5- (1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxamide) methyl) picolinic acid (260mg,0.45mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,10mL), stirred at room temperature for 20min, filtered, washed with ethyl acetate (20 mL. times.3) to give 210mg of a white solid, yield: 85 percent.

Compound 75:¹H NMR(400MHz,CD₃OD):δppm 8.49–8.47(m,1H),8.38(d,J＝7.5Hz,1H),8.08(d,J＝7.2Hz,1H),7.83(d,J＝1.7Hz,1H),7.75(dd,J₁＝8.4Hz,J₂＝1.8Hz,1H),7.34(d,J＝8.3Hz,1H),6.90(t,J_F-H＝74.6Hz,1H),5.22–5.20(m,1H),5.00(s,2H),4.28–4.23(m,2H),1.78(d,J＝6.9Hz,3H),1.50(t,J＝6.9Hz,3H)；

MS-ESI:m/z 477.1[M+H-2HCl]⁺。

Example 35: the compound (S) -5- (1-aminoethyl) -N- (benzofuran-3-ylmethyl) -2- (3- (cyclopropylmethyl) methyl Synthesis of oxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound (S) - (tert-butyl 1- (4- ((benzofuran-3-ylmethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), the compound benzofuran-3-ylmethylamine hydrochloride (141mg,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), stirred at 0 ℃ for 30min, N-diisopropylethylamine (0.33mL,1.92mmol) was added dropwise, stirred at room temperature for 22h, washed with water (10 mL. times.3), the organic phase was then washed with Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 230mg of a white solid, yield: 60 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.72–7.70(m,2H),7.58–7.55(m,1H),7.54–7.52(m,2H),7.38–7.34(m,1H),7.30(dd,J₁＝7.6Hz,J₂＝1.0Hz,1H),7.23(d,J＝8.3Hz,1H),6.71(t,J_F-H＝75.0Hz,1H),5.34–5.30(m,1H),4.79(d,J＝5.8Hz,2H),3.96(d,J＝7.0Hz,2H),1.59(d,J＝6.4Hz,3H),1.47(s,9H),1.35–1.32(m,1H),0.71–0.66(m,2H),0.42–0.38(m,2H)。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -N- (benzofuran-3-ylmethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((benzofuran-3-ylmethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.23g,0.38mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,10mL), stirred at room temperature for 20min, the solvent was removed to give 200mg of a white solid, yield: 98 percent.

Compound 81:¹H NMR(400MHz,CD₃OD):δppm 7.80(s,1H),7.78–7.76(m,2H),7.70(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.48(d,J＝8.2Hz,1H),7.34–7.30(m,2H),7.27–7.23(m,1H),6.90(t,J_F-H＝74.7Hz,1H),5.22–5.17(m,1H),4.75(s,2H),4.01(d,J＝6.9Hz,2H),1.79(d,J＝7.0Hz,3H),1.34–1.30(m,1H),0.69–0.66(m,2H),0.42–0.40(m,2H)；

MS-ESI:m/z 498.3[M+H-HCl]⁺。

Example 36: the compound (S) -5- (1-aminoethyl) -N- (benzofuran-3-ylmethyl) -2- (4- (difluoromethoxy) Synthesis of 3-ethoxyphenyl-3-oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound (S) - (tert-butyl 1- (4- ((benzofuran-3-ylmethyl) carbamoyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxylic acid (0.3g,0.68mmol), the compound benzofuran-3-ylmethylamine hydrochloride (150mg,0.81mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (194mg,1.02mmol) and N-hydroxy-7-azabenzotriazole (138mg,1.02mmol) were dissolved in dichloromethane (10mL), stirred at 0 ℃ for 30min, N-diisopropylethylamine (0.35mL,2.04mmol) was added dropwise, stirred at room temperature for 21h, washed with water (10 mL. times.3), and the organic phase was Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) gave 220mg of a colorless oil, yield: 57 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.72–7.70(m,2H),7.57–7.55(m,2H),7.55–7.53(m,1H),7.38–7.34(m,1H),7.31–7.29(m,1H),7.23(d,J＝8.8Hz,1H),6.65(t,J_F-H＝74.8Hz,1H),5.36–5.32(m,1H),4.80(d,J＝5.7Hz,2H),4.22–4.17(m,2H),1.59(d,J＝7.0Hz,3H),1.48(s,9H),1.28(t,J＝7.1Hz,3H)。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -N- (benzofuran-3-ylmethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (S) - (1- (4- ((benzofuran-3-ylmethyl) carbamoyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazol-5-yl) ethyl) carbamate (220mg,0.38mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 20min, the solvent was removed to give 190mg of a light yellow solid, yield: 97 percent.

Compound 87:¹H NMR(400MHz,CD₃OD):δppm 7.80(s,1H),7.77–7.75(m,2H),7.69(dd,J₁＝8.4Hz,J₂＝1.6Hz,1H),7.46(d,J＝8.1Hz,1H),7.31–7.28(m,2H),7.24(td,J₁＝7.5Hz,J₂＝0.9Hz,1H),6.87(t,J_F-H＝74.6Hz,1H),5.22–5.20(m,1H),4.74(s,2H),4.22–4.17(m,2H),1.81(d,J＝6.9Hz,3H),1.46(t,J＝6.9Hz,3H)；

MS-ESI:m/z 472.3[M+H-HCl]⁺。

Example 37: the compound (S) -5- (1-aminoethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) -N- (2, Synthesis of 4-difluorophenethyl) oxazole-4-formamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (4- (difluoromethoxy) -3-ethoxyphenyl) -4- ((2, 4-difluorophenethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) oxazole-4-carboxylic acid (0.3g,0.68mmol), the compound 2- (2, 4-difluorophenyl) ethylamine (128mg,0.81mmol),Dissolving 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (194mg,1.02mmol) and N-hydroxy-7-azabenzotriazole (138mg,1.02mmol) in dichloromethane (10mL), stirring at 0 deg.C for 30min, adding N, N-diisopropylethylamine (0.35mL,2.04mmol), stirring at room temperature for 17h, washing with water (10 mL. times.3), and adding Na to organic phase₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) gave 230mg of a yellow oil, yield: 58 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59–7.57(m,2H),7.27–7.22(m,2H),6.87–6.81(m,2H),6.67(t,J_F-H＝70.0Hz,1H),5.29–5.25(m,1H),4.25–4.20(m,2H),3.71–3.67(m,2H),2.99(t,J＝7.0Hz,2H), 1.53(t,J＝7.5Hz,6H),1.46(s,9H)；

MS-ESI:m/z 582.3[M+H]⁺。

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (4- (difluoromethoxy) -3-ethoxyphenyl) -N- (2, 4-difluorophenethyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (S) - (1- (2- (4- (difluoromethoxy) -3-ethoxyphenyl) -4- ((2, 4-difluorophenethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (230mg,0.40mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 20min, the solvent was removed to give 180mg of a white solid, yield: 88 percent.

Compound 88:¹H NMR(400MHz,CD₃OD):δppm 7.79(d,J＝1.9Hz,1H),7.71(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.36–7.32(m,2H),6.93–6.90(m,2H),6.89(t,J_F-H＝74.6Hz,1H),5.12–5.11(m,1H),4.27–4.22(m,2H),3.66(t,J＝7.1Hz,2H),2.99(t,J＝7.1Hz,2H),1.75(d,J＝7.0Hz,3H),1.50(t,J＝7.0Hz,3H)；

MS-ESI:m/z 482.1[M+H-HCl]⁺。

Example 38: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl) -N- ((2, 4-difluorophenyl) sulfonyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((2, 4-difluorophenyl) sulfonyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol) and N, N' -carbonyldiimidazole (312mg,1.92mmol) were dissolved in anhydrous tetrahydrofuran (10mL) and reacted at 60 ℃ for 30min, after cooling to room temperature, the internal gas was purged with nitrogen, and 2, 4-difluorobenzenesulfonamide (247mg,1.28mmol) and 1, 8-diazabicyclo [5.4.0 ] were added dropwise]Adding anhydrous tetrahydrofuran (10mL) solution of undec-7-ene (0.14mL,0.96mmol), reacting at 60 deg.C for 12h, stopping reaction, adding saturated ammonium chloride solution (15mL), extracting with EA (15mL × 3), and extracting organic phase with anhydrous Na₂SO₄Drying and column separation of the concentrate (dichloromethane/methanol (v/v) ═ 20/1) gave 0.4g of a yellow solid, yield: 99 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)8.26–8.22(m,1H),7.59–7.54(m,2H),7.27–7.26(m,1H),7.14–7.10(m,1H),7.02–6.97(m,1H),6.75(t,J_F-H＝74.9Hz,1H),5.28–5.25(m,1H),4.04(d,J＝6.9Hz,2H),1.50(d,J＝7.1Hz,3H),1.39(s,9H),1.34–1.33(m,1H),0.74–0.72(m,2H),0.49–0.45(m,2H)。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((2, 4-difluorophenyl) sulfonyl) oxazole-4-carboxamide hydrochloride

To a solution of compound tert-butyl (S) - (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((2, 4-difluorophenyl) sulfonyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.12g,0.19mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,6mL), stirred at room temperature for 20min, and the solvent was removed to give 100mg of a pale yellow solid, yield: 93 percent.

Compound 89:¹H NMR(400MHz,CD₃OD):δ(ppm)8.22–8.18(m,1H),7.85(d,J＝1.8Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.34(d,J＝8.4Hz,1H),7.30–7.23(m,2H),6.93(t,J_F-H＝74.7Hz,1H),5.14–5.12(m,1H),4.06(d,J＝7.0Hz,2H),1.70(d,J＝7.0Hz,3H),1.38–1.35(m,1H),0.73–0.68(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 544.2[M+H-HCl]⁺。

Example 39: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl) -N- (1- (2, 4-difluorophenyl) -2- (methylsulfonyl) ethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound 1- (2, 4-difluorophenyl) -2- (methylsulfonyl) ethylamine hydrochloride

A solution of n-butyllithium in n-hexane (2.4M,7mL,16.8mmol) was added dropwise to a solution of dimethyl sulfone (1.59g,16.9mmol) in anhydrous tetrahydrofuran (30mL) at-78 deg.C, and the mixture was stirred at-78 deg.C for 30 min. Further, a THF solution of lithium hexamethyldisilazide (1M,16.9mL,16.9mmol) was added dropwise to a tetrahydrofuran (15mL) solution of 2, 4-difluorobenzaldehyde (2g,14.07mmol) at 0 deg.C, the mixture was stirred for 15min, boron trifluoride diethyl etherate (3.82mL,31mmol) was added dropwise at 0 deg.C, the resulting solution was stirred for 10min, then the previous solution was added dropwise to a solution of dimethyl sulfone and n-butyllithium at-78 deg.C, the reaction was stopped by stirring at room temperature for 24h, water (30mL) and potassium carbonate (3g,21.7mmol) were added to the resulting solution under ice bath, ethyl acetate was extracted (20 mL. times.3), the organic phases were combined, and anhydrous Na was used₂SO₄Drying, concentrating, adding dichloromethane (6mL), HCl. EA solution (4M,12mL), stirring at room temperature for 20min, removing solvent, adding water (20mL), washing with petroleum ether (15mL), adjusting pH of the aqueous phase to 12 with sodium hydroxide solution (1M), extracting with ethyl acetate (20 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying and concentration gave 0.9g of a tan oil, which was stirred at room temperature for 20min with addition of HCl in ethyl acetate (4M,10mL), and solvent was removed to give 1g of a tan oil, yield: 27 percent.

¹H NMR(400MHz,CD₃OD):δ(ppm)7.71–7.65(m,1H),7.22–7.14(m,2H),5.23–5.19(m,1H),4.00–3.89(m,2H),3.09(s,3H)；

MS-ESI:m/z 236.2[M+H-HCl]⁺。

Step 2: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (methylsulfonyl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.25g,0.53mmol), compound 1- (2, 4-difluorophenyl) -2- (methylsulfonyl) ethylamine hydrochloride (174mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (109mg,0.80 mmol) were dissolved in dichloromethane (10mL), stirred at 0 ℃ for 30min, N-diisopropylethylamine (0.28mL,1.60mmol) was added dropwise, stirred at room temperature for 17h, washed with water (10 mL. times.3), na for organic phase₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 94mg of a yellow oil, yield: 26 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.64–7.61(m,1H),7.60–7.58(m,2H),7.54–7.51(m,1H),7.26(d,J＝8.3Hz,1H),6.98–6.91(m,2H),6.73(t,J_F-H＝75.0Hz,1H),5.95–5.91(m,1H),5.37–5.31(m,1H),4.01–3.99(m,2H),3.86–3.81(m,1H),3.63–3.56(m,1H),2.87–2.84(m,3H),1.56–1.50(m,3H),1.45(s,9H),1.36–1.33(m,1H),0.73–0.70(m,2H),0.46–0.43(m,2H)。

And step 3: synthesis of the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (methylsulfonyl) ethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (methylsulfonyl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (94mg,0.14mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 30min, the solvent was removed to give 77mg of a pale yellow solid, yield: 91 percent.

Compound 92:¹H NMR(400MHz,CD₃OD):δ(ppm)7.81(d,J＝1.9Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.66–7.60(m,1H),7.34(d,J＝8.4Hz,1H),7.07–7.02(m,2H),6.92(t,J_F-H＝74.7Hz,1H),6.11–6.06(m,1H),5.19–5.14(m,1H),3.72–3.68(m,1H),3.08–3.05(m,3H),2.01(s,3H),1.76(d,J＝7.0Hz,3H),1.40–1.34(m,1H),0.72–0.67(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 586.3[M+H-HCl]⁺。

example 40: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) Synthesis of (yl) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound methyl 3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) benzoate

To the tube was added methyl 3-cyclopropylmethoxy-4-hydroxybenzoate (5g,22.5mmol), 1-bromo-2, 2-difluoroethane (4.89g,33.75mmol), potassium carbonate (6.22g,45mmol) and DMF (30mL), reacted at 60 ℃ for 7h, filtered with suction and the filtrate was concentrated to give 5.5g of a brown liquid, yield: 85 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.62(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.56(d,J＝1.9Hz,1H),6.92(d,J＝8.4Hz,1H),6.31–6.01(m,1H),4.28(td,J₁＝13.1Hz,J₂＝4.2Hz,2H),3.89(d,J＝8.7Hz,2H),3.88(s,3H),1.35–1.25(m,1H),0.67–0.60(m,2H),0.38–0.34(m,2H)；

MS-ESI:m/z 287.2[M+H]⁺。

Step 2: synthesis of compound 3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) benzoic acid

The compound methyl 3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) benzoate (5.5g,19.21mmol) and sodium hydroxide (2.31g,57.64mmol) were dissolved in ethanol (30mL) and water (15mL)The mixture of (1) was reacted at 60 ℃ for 3 hours, the solvent ethanol was removed, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added to extract (25mL × 3), and the organic phase was extracted with anhydrous Na₂SO₄drying and concentration gave 5.2g of a white solid, yield: 98 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.75(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.64(d,J＝1.9Hz,1H),6.99(d,J＝8.4Hz,1H),6.35–6.05(m,1H),4.34(td,J₁＝13.0Hz,J₂＝4.2Hz,2H),3.94(d,J＝6.9Hz,2H),1.36–1.30(m,1H),0.71–0.66(m,2H),0.42–0.37(m,2H)；

MS-ESI:m/z 273.2[M+H]⁺。

And step 3: synthesis of compound methyl 2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) benzoylamino) acetate

Dissolving the compounds 3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) benzoic acid (5.2g,19.1mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.47g,28.65mmol) and N-hydroxy-7-azabenzotriazole (3.9g,28.65mmol) in dichloromethane (40mL), stirring at room temperature for 30min, adding glycine methyl hydrochloride (2.88g,22.92mmol), adding N, N-diisopropylethylamine (10mL,57.30mmol) dropwise at 0 deg.C, stirring at room temperature for 10h, washing with water (30mL), and adding Na to the organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 6.19g of a white solid in yield: 94 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.45(d,J＝2.0Hz,1H),7.33(dd,J₁＝8.3Hz,J₂＝2.1Hz,1H),6.96(d,J＝8.3Hz,1H),6.67–6.63(m,1H),6.33–6.03(m,1H),4.30(td,J₁＝13.1Hz,J₂＝4.2Hz,2H),4.24(d,J＝5.1Hz,2H),3.92(d,J＝6.9Hz,2H),3.82(s,3H),1.34–1.29(m,1H),0.69–0.64(m,2H),0.39–0.35(m,2H)；

MS-ESI:m/z 344.1[M+H]⁺。

And 4, step 4: synthesis of compound methyl 2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) thiophenylamido) acetate

Reacting compound 2- (3- (cyclopropylmethoxy)Methyl (6.2g,18.06mmol) of (E) -4- (2, 2-difluoroethoxy) benzoylamino) acetate and Lawson's reagent (7.3g,18.06mmol) were dissolved in tetrahydrofuran (35mL) and reacted at 75 ℃ for 2h, after addition of a saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (20 mL. times.3), and the combined organic phases were treated with anhydrous Na₂SO₄Drying and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 6.49g of a yellow solid, yield: 92 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)8.09(br.s,1H),7.56(d,J＝2.2Hz,1H),7.32(dd,J₁＝8.4Hz,J₂＝2.2Hz,1H),6.92(d,J＝8.4Hz,1H),6.32–6.02(m,1H),4.58(d,J＝4.5Hz,2H),4.29(td,J₁＝13.1Hz,J₂＝4.2Hz,2H),3.93(d,J＝7.0Hz,2H),3.87(s,3H),1.34–1.29(m,1H),0.69–0.64(m,2H),0.40–0.37(m,2H)；

MS-ESI:m/z 360.2[M+H]⁺。

And 5: synthesis of the compound methyl 2- (((3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) phenyl) (methylthio) methylene) amino) acetate

To a solution of trimethyloxonium tetrafluoroborate (3.1g,20.87mmol) in dichloromethane (10mL) at-78 deg.C was added dropwise a solution of the compound methyl 2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) phenylthioamido) acetate (3g,8.35mmol) in dichloromethane (20mL), stirred at 0 deg.C for 3h, washed with saturated sodium bicarbonate solution (25mL), and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 3g of a yellow oil, yield: 98 percent.

Step 6: synthesis of Compound (S) -methyl 5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) phenyl) oxazole-4-carboxylate

Methyl 2- (((3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) phenyl) (methylthio) methylene) amino) acetate (3.1g,8.3mmol) and tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (4g,20.75mmol) were dissolved in anhydrous tetrahydrofuran (15mL) at-78 deg.C, a solution of potassium hexamethyldisilazide in tetrahydrofuran (29.05mL,29.05mmol) was added dropwise to the solution, the reaction was carried out at-78 deg.C for 1h, and saturated chloride was addedAfter the sodium solution (30mL), it was extracted with ethyl acetate (20 mL. times.3), the organic phases were combined and washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) afforded 1.91g of a yellow solid, yield: 48 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.64–7.61(m,2H),7.01(d,J＝8.3Hz,1H),6.34–6.04(m,1H),5.49–5.45(m,1H),4.32(td,J₁＝13.1Hz,J₂＝4.2Hz,2H),4.00(s,3H),3.96(d,J＝7.0Hz,2H),1.57(d,J＝2.8Hz,3H),1.45(s,9H),1.35–1.30(m,1H),0.71–0.66(m,2H),0.42–0.38(m,2H)；

MS-ESI:m/z 497.2[M+H]⁺。

And 7: synthesis of Compound (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) phenyl) oxazole-4-carboxylic acid

The compound methyl (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) phenyl) oxazole-4-carboxylate (1.91g,3.85mmol) and lithium hydroxide monohydrate (0.81g,19.23mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL) and reacted at 40 ℃ for 2 hours, the pH was adjusted to 1 with hydrochloric acid (1M), and extraction was carried out with ethyl acetate (20 mL. times.3), and the organic phases were combined and then extracted with Na₂SO₄drying and removal of the solvent gave 1.62g of a yellow solid, yield: 87 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.71(d,J＝2.0Hz,1H),7.65(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.15(d,J＝8.4Hz,1H),6.39–6.11(m,1H),5.50–5.48(m,1H),4.34(td,J₁＝13.7Hz,J₂＝3.9Hz,2H),3.98(d,J＝6.9Hz,2H),1.53(d,J＝7.1Hz,3H),1.45(s,9H),1.34–1.32(m,1H),0.69–0.64(m,2H),0.43–0.39(m,2H)；

MS-ESI:m/z 481.6[M-H]^-。

And 8: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.62mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (178mg,0.93mmol) and N-hydroxy-7-azabenzotriazole (127mg,0.93mmol) were dissolved in dichloromethane (10mL), stirred at 0 ℃ for 30min, 2, 4-difluorobenzylamine (0.09mL,0.75mmol) was added dropwise, after stirring at 0 ℃ for 30min, N-diisopropylethylamine (0.33mL,1.87mmol) was added dropwise, stirred at room temperature for 12h, washed with water (20 mL. times.3), and the organic phase was Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) afforded 230mg of a yellow solid, yield: 61 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.57(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.51(d,J＝1.9Hz,1H),7.46–7.40(m,1H),7.00(d,J＝8.4Hz,1H),6.91–6.83(m,2H),6.33–6.04(m,1H),5.32–5.30(m,1H),4.67–4.65(m,2H),4.31(td,J₁＝13.1Hz,J₂＝4.2Hz,2H),3.95(d,J＝7.0Hz,2H),1.55(d,J＝7.0Hz,3H),1.45(s,9H),1.36–1.32(m,1H),0.71–0.67(m,2H),0.43–0.39(m,2H)。

And step 9: synthesis of compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound (S) - (1- (2- (3- (cyclopropylmethoxy) -4- (2, 2-difluoroethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (220mg,0.36mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,5mL), stirred at room temperature for 15min, filtered, washed with ethyl acetate (15mL × 3) to give 76mg of a white solid, yield: 40 percent.

compound 96:¹H NMR(400MHz,CD₃OD):δ(ppm)7.66–7.64(m,2H),7.45–7.39(m,1H),7.12(d,J＝8.8Hz,1H),6.95–6.88(m,2H),6.33–6.05(m,1H),5.12–5.07(m,1H),4.58(s,2H),4.30(td,J₁＝13.7Hz,J₂＝3.8Hz,2H),3.92(d,J＝6.9Hz,2H),1.71(d,J＝6.9Hz,3H),1.29–1.24(m,1H),0.62–0.58(m,2H),0.36–0.32(m,2H)；

MS-ESI:m/z 508.1[M-HCl+H]⁺。

Example 41: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene synthesis of phenyl-N- (1- (2, 4-difluorophenyl) ethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

the compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 1- (2 ', 4' -difluorophenyl) ethylamine (121mg,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), stirred at 0 ℃ for 30min, N-diisopropylethylamine (0.34mL,1.92mmol) was added dropwise, washed with water at room temperature for 14h, added (10 mL. times.3), and the organic phase was Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 270mg of a colorless oil, yield: and 69 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.63(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.57(d,J＝1.8Hz,1H),7.38–7.36(m,1H),7.26(d,J＝8.4Hz,1H),6.92–6.83(m,2H),6.73(t,J_F-H＝75.0Hz,1H),5.45–5.42(m,1H),4.60–4.54(m,1H),4.01(d,J＝6.9Hz,2H),1.65–1.64(m,3H),1.55–1.49(m,3H),1.46(s,9H),1.32–1.30(m,1H),0.74–0.69(m,2H),0.46–0.42(m,2H)。

Step 2: synthesis of compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) ethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (270mg,0.44mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,5mL), stirred at room temperature for 2h and the solvent was removed to give 230mg of a white solid, yield: 95 percent.

Compound 100:¹H NMR(400MHz,CD₃OD):δ(ppm)7.83(d,J＝1.7Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.7Hz,1H),7.55–7.53(m,1H),7.33(d,J＝8.3Hz,1H),6.99–6.93(m,2H),6.92(t,J_F-H＝74.8Hz,1H),5.52–5.50(m,1H),5.16–5.11(m,1H),4.06(d,J＝6.9Hz,2H),1.76(dd,J₁＝7.0Hz,J₂＝2.7Hz,3H),1.63(d,J＝7.0Hz,3H),1.36–1.32(m,1H),0.71–0.67(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 508.3[M+H-HCl]⁺。

Example 42: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2- (methylsulfonyl) ethyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-amino Ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2- (methanesulfonate) Synthesis of acyl) ethyl) oxazole-4-carboxamide hydrochloride

The compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (methylsulfonyl) ethyl) oxazole-4-carboxamide hydrochloride of example 39 was resolved to give the compounds 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2- (methylsulfonyl) ethyl) oxazole-4-carboxamide hydrochloride (pale yellow solid) and 5- ((S) -1-aminoethyl) -2- (3- (cyclo-sulfonyl) ethyl) oxazole-4-carboxamide hydrochloride (pale yellow solid) Propylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2- (methylsulfonyl) ethyl) oxazole-4-carboxamide hydrochloride (light red solid).

Compound 101:¹H NMR(400MHz,CD₃OD):δ(ppm)7.81(d,J＝1.9Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.66–7.60(m,1H),7.34(d,J＝8.4Hz,1H),7.08–7.02(m,2H),6.92(t,J_F-H＝74.7Hz,1H), 6.11–6.07(m,1H),5.19–5.14(m,1H),4.07–4.01(m,1H),4.05(d,J＝6.9Hz,2H),3.73–3.68(m,1H),3.06(s,3H),1.75(d,J＝7.0Hz,3H),1.37–1.33(m,1H),0.72–0.68(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 586.2[M+H-HCl]⁺；

Compound 102:¹H NMR(400MHz,CD₃OD):δ(ppm)7.81(d,J＝1.8Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.63–7.61(m,1H),7.34(d,J＝8.4Hz,1H),7.08–7.02(m,2H),6.92(t,J_F-H＝74.7Hz,1H),6.12–6.08(m,1H),5.17–5.15(m,1H),4.08–4.02(m,1H),4.05(d,J＝6.9Hz,2H),3.72–3.68(m,1H),3.07(s,3H),1.76(d,J＝7.0Hz,3H),1.37–1.33(m,1H),0.72–0.68(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 586.3[M+H-HCl]⁺。

Example 43: the compound (S) -5- (1-aminoethyl) -2- (3, 4-bis (cyclopropylmethoxy) phenyl) -N- (2, 4-) Synthesis of difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound methyl 3, 4-bis (cyclopropylmethoxy) benzoate

To the sealed tube was added methyl 3-cyclopropylmethoxy-4-hydroxybenzoate (5g,22.5mmol), bromomethylcyclopropane (4.56g,33.75mmol), potassium carbonate (6.22g,45mmol) and N, N-dimethylformamide (30mL), reacted at 60 ℃ for 4.5h, filtered with suction and the solvent removed from the filtrate to give 5.47g of a white solid, yield: 88 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.64(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.57(d,J＝2.0Hz,1H),6.89(d,J＝8.4Hz,1H),3.94–3.91(m,4H),3.89(s,3H),1.38–1.31(m,2H),0.68–0.62(m,4H),0.41–0.37(m,4H)；

MS-ESI:m/z 277.1[M+H]⁺。

Step 2: synthesis of compound 3, 4-di (cyclopropylmethoxy) benzoic acid

The compound methyl 3, 4-bis (cyclopropylmethoxy) benzoate (5.47g,19.8mmol) and sodium hydroxide (2.38g,59.4mmol) were dissolved in a mixed solvent of ethanol (40mL) and water (20mL), reacted at 60 ℃ for 3 hours, the solvent ethanol was removed, hydrochloric acid (1M) was added to adjust pH to 1, ethyl acetate was added and extracted (25mL × 3), and the organic phase was extracted with anhydrous Na₂SO₄Drying and removal of the solvent gave 4.75g of a white solid, yield: 91 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.74(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.63(d,J＝2.0Hz,1H), 6.93(d,J＝8.5Hz,1H),3.98–3.94(m,4H),1.38–1.33(m,2H),0.70–0.64(m,4H),0.43–0.38(m,4H)；

MS-ESI:m/z 263.2[M+H]⁺。

And step 3: synthesis of compound methyl 2- (3, 4-di (cyclopropylmethoxy) benzamido) acetate

Dissolving compound 3, 4-bis (cyclopropylmethoxy) benzoic acid (4.75g,18.1mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.21g,27.2mmol) and N-hydroxy-7-azabenzotriazole (3.7g,27.2mmol) in dichloromethane (35mL), stirring at room temperature for 30min, adding methyl aminoacetate hydrochloride (2.73g,21.7mmol), adding N, N-diisopropylethylamine (13mL,72.4mmol) dropwise at 0 deg.C, stirring at room temperature for 10h, washing with water (20 mL. times.3), and adding anhydrous Na to the organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 5.56g of a white solid in yield: 92 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.45(d,J＝2.1Hz,1H),7.35(dd,J₁＝8.4Hz,J₂＝2.1Hz,1H),6.91(d,J＝8.4Hz,1H),6.59(br.s,1H),4.25(d,J＝4.8Hz,2H),3.93(d,J＝6.9Hz,4H),3.82(s,3H),1.38–1.31(m,2H),0.68–0.62(m,4H),0.41–0.36(m,4H)；

MS-ESI:m/z 334.3[M+H]⁺。

And 4, step 4: synthesis of compound methyl 2- (3, 4-bis (cyclopropylmethoxy) phenylthioamide) acetate

reacting the compound 2- (3, 4-di (cyclopropylmethoxy) benzamido)Methyl acetate (5.56g,16.7mmol) and Lawson's reagent (6.75g,16.7mmol) were added to tetrahydrofuran (35mL) and reacted at 75 ℃ for 2h, after addition of saturated sodium bicarbonate solution (40mL), ethyl acetate was extracted (20 mL. times.3), the combined organic phases were extracted with anhydrous Na₂SO₄Drying and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) gave 5.8g of a yellow solid, yield: 99 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)8.06(br.s,1H),7.56(d,J＝2.2Hz,1H),7.37(dd,J₁＝8.4Hz,J₂＝2.2Hz,1H),6.87(d,J＝8.4Hz,1H),4.59(d,J＝4.5Hz,2H),3.95–3.92(m,4H),3.87(s,3H),1.38–1.31(m,2H),0.68–0.63(m,4H),0.41–0.37(m,4H)；

MS-ESI:m/z 350.2[M+H]⁺。

And 5: synthesis of compound methyl 2- (((3, 4-bis (cyclopropylmethoxy) phenyl) (methylthio) methylene) amino) acetate

To a solution of trimethyloxonium tetrafluoroborate (3.0g,20mmol) in dichloromethane (10mL) at-78 deg.C was added dropwise a solution of the compound methyl 2- (3, 4-bis (cyclopropylmethoxy) phenylthioamide) acetate (2.55g,7.30mmol) in dichloromethane (20mL) at 0 deg.C for 3h, washed with saturated sodium bicarbonate solution (45mL) and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 2.39g of a yellow oil, yield: 90 percent.

Step 6: synthesis of compound (S) -methyl 2- (3, 4-bis (cyclopropylmethoxy) phenyl) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) oxazole-4-carboxylate

Dissolving the compound methyl 2- (((3, 4-bis (cyclopropylmethoxy) phenyl) (methylthio) methylene) amino) acetate (2.38g,6.55mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (3.6g,19mmol) in anhydrous tetrahydrofuran (10mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (26mL,26mmol) at-78 deg.C, reacting at-78 deg.C for 2.5h, adding a saturated solution of sodium chloride (30mL), quenching the reaction, extracting with ethyl acetate (20 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removing solvent, and separating the concentrated solution with column (petroleum ether/ethyl acetate (v)/v) ═ 4/1), 1g of a yellow solid was obtained, yield: 31 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.63(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.59(d,J＝2.0Hz,1H),6.94(d,J＝8.4Hz,1H),5.47–5.40(m 1H),3.99(s,3H),3.95(t,J＝6.6Hz,4H),1.55(d,J＝7.0Hz,3H),1.45(s,9H),1.34–1.30(m,2H),0.71–0.64(m,4H),0.41–0.39(m,4H)；

MS-ESI:m/z 487.2[M+H]⁺。

And 7: synthesis of Compound (S) -2- (3, 4-bis (cyclopropylmethoxy) phenyl) -5- (1- (tert-butoxycarbonylamino) ethyl) oxazole-4-carboxylic acid

The compound methyl (S) -2- (3, 4-bis (cyclopropylmethoxy) phenyl) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) oxazole-4-carboxylate (1g,2.1mmol) and lithium hydroxide monohydrate (0.43g,10mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL) and reacted at 40 ℃ for 2 hours, pH was adjusted to 1 by addition of hydrochloric acid (1M), extraction was performed with ethyl acetate (20 mL. times.3), and the organic phases were combined and Na was added thereto₂SO₄Drying and removal of the solvent gave 0.97g of a yellow solid, yield: 81 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.59–7.55(m,2H),6.99(d,J＝8.4Hz,1H),5.42–5.41(m,1H),3.90–3.87(m,4H),1.46(d,J＝7.1Hz,3H),1.39(s,9H),1.29–1.26(m,2H),0.60–0.56(m,4H),0.34–0.33(m,4H)；

MS-ESI:m/z 471.1[M-H]^-。

And 8: synthesis of Compound (S) - (tert-butyl 1- (2- (3, 4-bis (cyclopropylmethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -2- (3, 4-bis (cyclopropylmethoxy) phenyl) -5- (1- (t-butoxycarbonylamino) ethyl) oxazole-4-carboxylic acid (0.34g,0.73mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (183mg,0.95mmol) and N-hydroxy-7-azabenzotriazole (130mg,0.95mmol) were dissolved in dichloromethane (13mL), stirred at 0 deg.C, 30min later 2, 4-difluorobenzylamine (0.1mL,0.76mmol) was added dropwise, N-diisopropylethylamine (0.33mL,1.90mmol) was added dropwise at 0 deg.C, stirred at room temperature for 4h, washed with water (10 mL. times.3), and the organic phase was Na₂SO₄Drying, removal of the solvent, and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) gave 230mg of a yellow oil, yield: 52 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)7.56(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.51(d,J＝1.9Hz,1H),7.44–7.40(m,1H),6.94(d,J＝8.5Hz,1H),6.91–6.84(m,2H),5.32–5.26(m,1H),4.66(t,J＝5.2Hz,2H),3.95(t,J＝6.9Hz,4H),1.54(d,J＝7.0Hz,3H),1.45(s,9H),1.37–1.32(m,2H),0.69–0.65(m,4H),0.42–0.38(m,4H)。

And step 9: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3, 4-bis (cyclopropylmethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3, 4-bis (cyclopropylmethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.23g,0.38mmol) in dichloromethane (1.5mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 40min, the solvent was removed to give 100mg of a white solid, yield: and 47 percent.

Compound 103:¹H NMR(400MHz,CD₃OD):δ(ppm)7.69(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.66(d,J＝1.9Hz,1H),7.51–7.47(m,1H),7.10(d,J＝8.4Hz,1H),7.01–6.94(m,2H),5.15–5.13(m,1H),4.64(s,2H),3.97–3.95(m,4H),1.76(d,J＝7.0Hz,3H),1.35–1.30(m,2H),0.68–0.64(m,4H),0.43–0.38(m,2H)；

MS-ESI:m/z 498.3[M-HCl+H]⁺。

Example 44: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene synthesis of yl) -N- ((3, 5-difluoropyridin-2-yl) methyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((3, 5-difluoropyridin-2-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 3, 5-difluoropyridine-2-methanamine hydrochloride (139mg,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), stirred at 0 ℃ for 30min, N-diisopropylethylamine (0.45mL,2.56mmol) was added dropwise, stirred at room temperature for 14h, washed with water (10 mL. times.3), and the organic phase was washed with Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) afforded 120mg of a white solid, yield: 32 percent.

¹H NMR(400MHz,CDCl₃):δ(ppm)8.38(d,J＝2.3Hz,1H),8.13–8.11(m,1H),7.64(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.60(d,J＝1.9Hz,1H),7.27(d,J＝8.4Hz,1H),6.73(t,J_F-H＝75.0Hz,1H),5.32–5.30(m,1H),4.86–4.83(m,2H),4.01(d,J＝6.9Hz,2H),1.55(d,J＝7.0Hz,3H),1.45(s,9H),1.36–1.33(m,1H),0.74–0.69(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 595.1[M+H]⁺。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((3, 5-difluoropyridin-2-yl) methyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((3, 5-difluoropyridin-2-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (120mg,0.20mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 2h, the solvent was removed to give 65mg of a white solid, yield: 61 percent.

Compound 106:¹H NMR(400MHz,CD₃OD):δ(ppm)8.34(d,J＝2.2Hz,1H),7.77(d,J＝1.5Hz,1H), 7.70(dd,J₁＝8.3Hz,J₂＝1.5Hz,1H),7.63–7.58(m,1H),7.30(d,J＝8.3Hz,1H),6.89(t,J_F-H＝74.8Hz,1H),5.17–5.12(m,1H),4.78(s,2H),4.01(d,J＝6.9Hz,2H),1.75(d,J＝7.0Hz,3H),1.36–1.29(m,1H),0.68–0.63(m,2H),0.42–0.38(m,2H)；

MS-ESI:m/z 495.1[M+H-2HCl]⁺。

Example 45: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (2, 4-difluorobenzyl) -N-methyloxazole-4-carboxamide hydrochloride

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (1.17g,2.5mmol), 2, 4-difluorobenzylamine (0.536g,3.75mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.72g,3.75mmol) and N-hydroxy-7-azabenzotriazole (0.51g,3.75mmol) were dissolved in dichloromethane (20mL), stirred at 0 ℃ for 30min, N-diisopropylethylamine (1.31mL,7.5mmol) was added dropwise, stirred at room temperature for 5h, washed with water (20 mL. times.3), and the organic phase was washed with Na₂SO₄drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 800mg of a yellow oil, yield: 54 percent.

Step 2: synthesis of compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) -N-methyloxazole-4-carboxamide hydrochloride

The compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.3g,0.51mmol) and sodium hydride (60%, 30mg,0.76mmol) were added to anhydrous tetrahydrofuran (10mL), stirred at 0 ℃ after 1h, brought to room temperature after 1h, a solution of iodomethane in tetrahydrofuran (0.76mmol,10mL) was added dropwise, stirred at room temperature after 5h, the reaction was stopped, water (30mL) was added, extracted with ethyl acetate (15 mL. times.3), the combined organic phases were extracted with anhydrous Na₂SO₄Drying and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) gave 227mg of a pale yellow solid, yield: 74 percent.

To a solution of 227mg of the pale yellow solid obtained in the above step in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,6mL), and after stirring at room temperature for 1.5h, the reaction was stopped and the solvent was removed to give 200mg of a white solid, yield: 99% as a mixture of two compounds, which after resolution gives the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) -N-methyloxazole-4-carboxamide hydrochloride: pale yellow solid 20 mg.

Compound 114:¹H NMR(400MHz,CD₃OD):δ(ppm)7.70–7.67(m,1H),7.58–7.46(m,2H),7.31–7.26(m,1H),7.07–6.98(m,2H),7.02–6.67(m,1H),5.22–5.21(m,1H),4.56–4.54(m,2H),3.99(d,J＝6.7Hz,1H),3.87(d,J＝7.0Hz,1H),3.45(s,3H),1.75(d,J＝6.9Hz,3H),1.19–1.15(m,1H),0.66–0.64(m, 2H),0.41–0.37(m,2H)；

MS-ESI:m/z 508.3[M+H-HCl]⁺。

Example 46: the compound (S) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-bis Synthesis of fluorobenzyl) -N-methyl-5- (1- (methylamino) ethyl) oxazole-4-carboxamide hydrochloride

To a solution of 227mg of the pale yellow solid obtained in the above step in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,6mL), and after stirring at room temperature for 1.5h, the reaction was stopped and the solvent was removed to give 200mg of a white solid, yield: 99% as a mixture of two compounds, which after resolution gives the compound (S) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) -N-methyl-5- (1- (methylamino) ethyl) oxazole-4-carboxamide hydrochloride: pale yellow solid 20 mg.

Compound 115:¹H NMR(400MHz,CD₃OD):δ(ppm)7.74–7.71(m,1H),7.63–7.49(m,2H),7.34–7.29(m,1H),7.10–7.01(m,2H),7.08–6.70(m,1H),5.25–5.24(m,1H),5.07–4.97(m,2H),4.03(d,J＝6.9Hz,1H),3.91(d,J＝7.0Hz,1H),3.48(s,3H),2.76(s,3H),1.79(d,J＝7.0Hz,3H),1.42–1.39(m,1H),0.69–0.67(m,2H),0.44–0.40(m,2H)；

MS-ESI:m/z 522.2[M+H-HCl]⁺。

Example 47: the compound N- (2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl Phenyl-2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride and N- (2-amino-1-) (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) Synthesis of yl) phenyl) oxazole-4-carboxamide

step 1: synthesis of Compound 2-amino-2- (2, 4-difluorophenyl) acetamide

To a mixture of 2, 4-difluorobenzaldehyde (1g,7.04mmol) and trimethylsilane (0.91g,9.2mmol) was added zinc iodide (0.22g,0.70mmol) under nitrogen, the mixture was stirred at room temperature for 15min, a methanol solution of ammonia (7M,10mL) was added under ice bath, the mixture was reacted at 40 ℃ for 4h under nitrogen, the solvent was removed, ethyl acetate (20mL) was added, the mixture was washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, concentrating, adding HCl in ethyl acetate (4M,5mL), precipitating a solid, adding ethyl acetate (15mL), filtering, washing with petroleum ether 3 times to obtain a white solid 0.78g,Yield: 66 percent.

¹H NMR(600MHz,CD₃OD):δppm 7.81–7.77(m,1H),7.31–7.22(m,2H),6.03(s,1H)；

MS-ESI:m/z 169.1[M+H]⁺。

The above white solid (0.25g,1.49mmol) was added to water (0.1g) and concentrated sulfuric acid (2g) under ice bath, reacted at 55 ℃ for 4 hours, transferred to ice bath, slowly added dropwise with ammonia (15mL), water (10mL), ethyl acetate (15mL), the organic phase separated and washed with saturated sodium chloride solution (10 mL. times.3), followed by anhydrous Na₂SO₄Drying and concentration gave 190mg of a yellow solid, yield: 72 percent.

¹H NMR(600MHz,CD₃OD):δppm 7.39–7.35(m,1H),7.02(br.s,1H),6.92–6.89(m,1H),6.88–6.84(m,1H),5.75(br.s,1H),4.73(s,1H)；

MS-ESI:m/z 187.0[M+H]⁺。

Step 2: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.25g,0.53mmol), compound 2-amino-2- (2, 4-difluorophenyl) acetamide (180mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (109mg,0.80mmol) were dissolved in dichloromethane (10mL), n, N-diisopropylethylamine (0.28mL,1.60mmol) was added dropwise to the solution at 0 deg.C, stirred at room temperature for 20h, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na.₂SO₄Drying, removal of solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 184mg of white solid, yield: 54 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.64(dt,J₁＝8.3Hz,J₂＝2.0Hz,1H),7.61(s,1H),7.54–7.49(m,1H),7.27(d,J＝8.3Hz,1H),6.96–6.92(m,2H),6.74(t,J_F-H＝75.0Hz,1H),5.94–5.93(m,1H),5.60(br.s,1H),5.34–5.30(m,1H),4.03(d,J＝7.0Hz,2H),1.53–1.48(m,3H),1.45–1.37(m,9H),1.36–1.33(m,1H),0.73–0.70(m,2H),0.46–0.44(m,2H)；

MS-ESI:m/z 637.1[M+H]⁺。

And step 3: synthesis of the Compound N- (2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.18g,0.29mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 20min, and the solvent was removed to give 160mg of a white solid, yield: 97 percent.

Compound 132:¹H NMR(600MHz,CD₃OD):δppm 7.79(s,1H),7.73(d,J＝8.3Hz,1H),7.61–7.58(m,1H),7.33(d,J＝8.3Hz,1H),7.06–7.02(m,2H),6.92(t,J_F-H＝75.0Hz,1H),5.92(s,1H),5.19–5.17(m,1H),4.04–4.03(m,2H),1.76(d,J＝6.8Hz,3H),1.36–1.32(m,1H),0.69–0.68(m,2H),0.44–0.43(m,2H)；

MS-ESI:m/z 537.9[M+H-HCl]⁺。

And 4, step 4: synthesis of the compound N- (2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide

The compound N- (2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (85mg,0.15mmol) was dissolved in water (10mL), the pH was adjusted to 9 with NaOH solution (1.0M), dichloromethane was extracted (10 mL. times.3), and the organic phase was extracted with anhydrous Na₂SO₄Drying and removal of the solvent gave 75mg of a white solid, yield: 94 percent.

Compound 325: 1H NMR (400MHz, CD)₃OD):δppm 7.67(s,1H),7.59(d,J＝8.3Hz,1H),7.46(m,1H),7.21(d,J＝8.3Hz,1H),6.92(m,2H),6.81(t,JF-H＝75.0Hz,1H),5.82(s,1H),4.65(m,1H),3.91(m,2H),1.45(d,J＝6.9Hz,3H),1.23(m,1H),0.54–0.63(m,2H),0.28–0.37(m,2H)；

MS-ESI:m/z 509.15[M+H]⁺。

Example 48: the compound N- (2-amino-1- (2, 4-difluorophenyl) ethyl) -5- ((S) -1-aminoethyl) -2- (3- Synthesis of (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (4- ((cyano (2, 4-difluorophenyl) methyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.4g,0.85mmol), compound 2-amino-2- (2, 4-difluorophenyl) acetonitrile (210mg,1.03mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (245mg,1.28mmol) and N-hydroxy-7-azabenzotriazole (174mg,1.28mmol) were dissolved in dichloromethane (10mL), n, N-diisopropylethylamine (0.6mL,3.42mmol) was added dropwise to the solution at 0 deg.C, stirred at room temperature for 5h, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na.₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 218mg of a white solid, yield: 41 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.69–7.66(m,1H),7.60–7.57(m,2H),7.26(d,J＝8.2Hz,1H),7.04–6.96(m,2H),6.73(t,J_F-H＝74.9Hz,1H),6.40(d,J＝8.6Hz,1H),5.32–5.30(m,1H),4.56–4.53(m,1H),4.04–3.99(m,2H),1.58–1.54(m,3H),1.45(s,9H),1.34–1.32(m,1H),0.73–0.71(m,2H),0.45–0.42(m,2H)。

Step 2: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

To a solution of tert-butyl ((1S) -1- (4- ((cyano (2, 4-difluorophenyl) methyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (215mg,0.35mmol) and nickel chloride (45mg,0.35mmol) in ethanol (15mL) was added dropwise a solution of sodium borohydride (42mg,1.04mmol) in ethanol (10mL) under ice-bath conditions, the mixture was stirred at room temperature for 8 hours, then hydrochloric acid (1M,10mL) was added thereto to adjust the pH to about 1, then a solution of sodium hydroxide (2M) was added thereto to adjust the pH to about 12, then ethyl acetate (15mL) was added thereto, the upper layer was separated after standing, the organic solvent was removed, extracted with ethyl acetate (15 mL. times.3), the combined organic phases were dried, the concentrated solution was subjected to column separation (dichloromethane/methanol (v/v) ═ 20/1), to give 82mg of a pale yellow solid, yield: 38 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.61–7.56(m,2H),7.46–7.42(m,1H),7.25–7.21(m,1H),6.88–6.84(m,2H),6.85–6.60(m,1H),5.40–5.35(m,1H),4.16–4.12(m,1H),4.00–3.95(m,2H),1.53–1.50(m,3H),1.44–1.35(m,9H),1.34–1.31(m,1H),0.70–0.67(m,2H),0.43–0.40(m,2H)；

MS-ESI:m/z 623.2[M+H]⁺。

And step 3: synthesis of the Compound N- (2-amino-1- (2, 4-difluorophenyl) ethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.08g,0.12mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,1mL), stirred at room temperature for 20min, the solvent was removed to give 70mg of a white solid, yield: 97 percent.

Compound 133:¹H NMR(600MHz,CD₃OD):δppm 7.85–7.83(m,1H),7.76–7.75(m,1H),7.66–7.65(m,1H),7.34(d,J＝8.2Hz,1H),7.11–7.05(m,2H),6.93(t,J_F-H＝74.7Hz,1H),5.81–5.78(m,1H),5.23–5.16(m,1H),4.07(d,J＝6.8Hz,2H),3.65–3.62(m,1H),3.46–3.44(m,1H),1.77(t,J＝5.6Hz,3H),1.42–1.37(m,1H),0.70–0.69(m,2H),0.45–0.44(m,2H)。

Example 49: the compound 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) Synthesis of phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid methyl ester hydrochloride

Step 1: synthesis of compound methyl 2-amino-2- (2, 4-difluorophenyl) acetate hydrochloride

To a solution of 2-amino-2- (2, 4-difluorophenyl) acetonitrile (0.35g,2.08mmol) in methanol (20mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 7h, then refluxed for 24h to remove the solvent to give 0.4g of a yellow solid, yield: 95 percent.

¹H NMR(600MHz,CD₃OD):δppm 7.60–7.56(m,1H),7.21–7.13(m,2H),3.85(s,3H)；

MS-ESI:m/z 202.1[M+H]⁺。

Step 2: synthesis of methyl 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate, a compound

Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.73g,1.56mmol), compound methyl 2-amino-2- (2, 4-difluorophenyl) acetate hydrochloride (410mg,1.73mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (430mg,2.24mmol) and N-hydroxy-7-azabenzotriazole (310mg,2.24mmol) were dissolved in dichloromethane (25mL), to this solution was added dropwise N, N-diisopropylethylamine (1mL,5.98mmol) at 0 ℃ and stirred at room temperature for 5h, followed by washing with water (10 mL. times.3), anhydrous Na for organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 290mg of a white solid, yield: 29 percent.

¹H NMR(600MHz,CDCl₃):δppm 8.15(br.s,1H),7.64–7.62(m,1H),7.59(s,1H),7.51–7.46(m,1H),7.26(d,J＝8.3Hz,1H),6.94–6.88(m,2H),6.73(t,J_F-H＝75.0Hz,1H),5.99(t,J＝6.5Hz,1H),5.32–5.29(m,1H),4.03–4.01(m,2H),3.82(s,3H),1.54–1.49(m,3H),1.45(s,9H),1.37–1.34(m,1H),0.73–0.70(m,2H),0.46–0.43(m,2H)。

And step 3: synthesis of methyl 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate hydrochloride

to a solution of the compound methyl 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate (0.1g,0.15mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 1.5h and the solvent removed to afford 90mg of a white solid, yield: 99 percent.

Compound 134:¹H NMR(600MHz,CD₃OD):δppm 7.80(s,1H),7.74(d,J＝8.4Hz,1H),7.59–7.55(m,1H),7.34(d,J＝8.3Hz,1H),7.09–7.02(m,2H),6.93(t,J_F-H＝74.7Hz,1H),6.05(s,1H),5.20–5.17(m,1H),4.04(d,J＝7.0Hz,2H),3.81(s,3H),1.76(d,J＝7.0Hz,3H),1.38–1.34(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H)；

MS-ESI:m/z 552.9[M+H-HCl]⁺。

Example 50: the compound 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) Synthesis of phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid hydrochloride

Step 1: synthesis of the compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid

The compound methyl 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate (190mg,0.29mmol) and lithium hydroxide monohydrate (61mg,1.46mmol) were dissolved in tetrahydro-lReacting furan (20mL) and water (10mL) in a mixed solvent at 40 ℃ for 2h, adding hydrochloric acid (1M) to adjust the pH value to 1, adding ethyl acetate for extraction (10mL multiplied by 3), combining the organic phases, and adding Na₂SO₄Drying and removal of the solvent gave 185mg of a yellow solid, yield: 99 percent.

¹H NMR(600MHz,CD₃OD):δppm 7.75(s,1H),7.69–7.67(m,1H),7.58–7.56(m,1H),7.30(d,J＝8.3Hz,1H),7.05–7.00(m,2H),6.90(t,J_F-H＝74.9Hz,1H),5.93–5.91(m,1H),5.41–5.40(m,1H),4.02(d,J＝6.9Hz,2H),1.50(d,J＝7.1Hz,3H),1.46–1.36(m,9H),1.34–1.32(m,1H),0.70–0.67(m,2H),0.43–0.41(m,2H)。

Step 2: synthesis of Compound 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid hydrochloride

To a solution of the compound 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.185g,0.29mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 1.5h and the solvent removed to afford 165mg of a white solid, yield: 99 percent.

Compound 135:¹H NMR(600MHz,CD₃OD):δppm 7.79(s,1H),7.74(dd,J₁＝8.3Hz,J₂＝1.5Hz,1H),7.60–7.56(m,1H),7.33(d,J＝8.3Hz,1H),7.06–7.02(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.95(d,J＝2.2Hz,1H),5.20–5.15(m,1H),4.04(d,J＝6.9Hz,2H),1.76(d,J＝7.0Hz,3H),1.37–1.33(m,1H),0.70–0.67(m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 538.9[M+H-HCl]⁺。

Example 51: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene phenyl) -N- (2- ((2, 4-difluorobenzyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) oxazole-4-carboxamide hydrochloride Synthesis of (2)

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2- ((2, 4-difluorobenzyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.24g,0.38mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (108mg,0.56mmol) and N-hydroxy-7-azabenzotriazole (77mg,0.56mmol) were dissolved in dichloromethane (10mL), 2, 4-difluorobenzylamine (0.06mL,0.45mmol) and N, N-diisopropylethylamine (0.2mL,1.13mmol) were added dropwise to the solution at 0 ℃ and stirred at room temperature for 15 hours, the solvent was removed, the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give 210mg of a white solid, yield: 74 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.62(d,J＝8.3Hz,1H),7.60(s,1H),7.50–7.48(m,1H),7.26(d,J＝8.2Hz,1H),7.26–7.24(m,1H),6.94–6.89(m,2H),6.86–6.79(m,2H),6.74(t,J_F-H＝74.7Hz,1H),6.40–6.36(m,1H),5.89(d,J＝6.8Hz,1H),5.33–5.29(m,1H),4.49–4.49(m,2H),4.02(d,J＝6.8Hz,2H),1.52–1.47(m,3H),1.44–1.38(m,9H),1.36–1.30(m,1H),0.73–0.70(m,2H),0.46–0.45(m,2H)。

Step 2: synthesis of the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2- ((2, 4-difluorobenzyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2- ((2, 4-difluorobenzyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.21g,0.27mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 20min, the solvent was removed to give 190mg of a white solid, yield: 99 percent.

Compound 136:¹H NMR(600MHz,CD₃OD):δppm 7.78(d,J＝1.4Hz,1H),7.72(dd,J₁＝8.4Hz,J₂＝1.8Hz,1H),7.55–7.52(m,1H),7.34–7.32(m,2H),7.06–7.00(m,2H),6.94–6.90(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.96(s,1H),5.20–5.17(m,1H),4.51–4.40(m,2H),4.02(d,J＝6.9Hz,2H),1.76(t,J＝6.9Hz,3H),1.36–1.32(m,1H),0.70–0.66(m,2H),0.44–0.41(m,2H)；

MS-ESI:m/z 663.9[M+H-HCl]⁺。

Example 52: the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopropylcarboxamido) -1- (2, 4-difluorobenzene Synthesis of yl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2- (cyclopropylcarboxamido) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.16g,0.26mmol), cyclopropylcarboxylic acid (0.03mL,0.31mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (74mg,0.39mmol) and N-hydroxy-7-azabenzotriazole (53mg,0.39mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.13mL,0.77mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 12h to remove the solvent, the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 100mg of a white solid, yield: 56 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.65–7.58(m,2H),7.41–7.37(m,1H),7.26(d,J＝8.7Hz,1H),6.92–6.86(m,2H),6.73(t,J_F-H＝75.0Hz,1H),6.17–6.15(m,1H),5.48–5.46(m,1H),5.32–5.30(m,1H),4.04–3.99(m,2H),3.87–3.85(m,1H),3.68–3.65(m,1H),1.67–0.61(m,1H),1.56–1.48(m,3H),1.45–1.35(m,9H),1.09–1.05(m,1H),0.96–0.90(m,2H),0.76–0.70(m,4H),0.45–0.44(m,2H)；

MS-ESI:m/z 691.2[M+H]⁺。

Step 2: synthesis of Compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopropylcarboxamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound tert-butyl ((1S) -1- (4- ((2- (cyclopropylcarboxamido) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.10g,0.14mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, and the solvent was removed to give 90mg of a white solid, yield: 99 percent.

Compound 137:¹H NMR(400MHz,CD₃OD):δppm 7.84(s,1H),7.74(d,J＝8.4Hz,1H),7.48–7.46(m,1H),7.35(d,J＝8.4Hz,1H),7.04–6.97(m,2H),6.93(t,J_F-H＝74.7Hz,1H),5.49–5.47(m,1H),5.13–5.06(m,1H),4.08(d,J＝6.9Hz,2H),3.79–3.63(m,2H),1.74–1.72(m,3H),1.60–1.55(m,1H),1.38–1.36(m,1H),0.92–0.88(m,2H),0.77–0.69(m,4H),0.48–0.44(m,2H)；

MS-ESI:m/z 591.2[M+H-HCl]⁺。

Example 53: the compound N- (2-acetamido-1- (2, 4-difluorophenyl) ethyl) -5- ((S) -1-aminoethyl) - Synthesis of 2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2-acetylamino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.20g,0.32mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (92mg,0.48mmol) and N-hydroxy-7-azabenzotriazole (66mg,0.48mmol) were dissolved in dichloromethane (10mL), glacial acetic acid (30mg,0.39mmol) and N, N-diisopropylethylamine (0.17mL,0.96mmol) were added dropwise to this solution at 0 ℃ respectively, stirring was carried out at room temperature for 15h, the solvent was removed, the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give 90mg of a yellow oil, yield: 42 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.64–7.63(m,2H),7.39-7.41(m,1H),7.26(d,J＝8.7Hz,1H),6.93–6.87(m,2H),6.73(t,J_F-H＝75.0Hz,1H),6.13–6.10(m,1H),5.49–5.48(m,1H),5.32–5.28(m,1H),4.02(d,J＝6.8Hz,2H),3.84–3.82(m,1H),3.68–3.66(m,1H),2.00(s,3H),1.54–1.50(m,3H),1.44–1.41(m,9H),1.39–1.37(m,1H),0.73–0.70(m,2H),0.45–0.43(m,2H)。

Step 2: synthesis of the compound N- (2-acetylamino-1- (2, 4-difluorophenyl) ethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound tert-butyl ((1S) -1- (4- ((2-acetylamino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.09g,0.13mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 20min, the solvent was removed to give 80mg of a pale yellow solid, yield: 98 percent.

compound 138:¹H NMR(400MHz,CD₃OD):δppm 7.85(s,1H),7.77(d,J＝8.4Hz,1H),7.52–7.48(m,1H),7.34(d,J＝8.3Hz,1H),7.03–6.98(m,2H),6.93(t,J_F-H＝74.8Hz,1H),5.53–5.50(m,1H),5.15–5.10(m,1H),4.08(d,J＝6.9Hz,2H),3.76–3.62(m,2H),1.95(s,3H),1.75(d,J＝6.2Hz,3H),1.42–1.37(m,1H),0.72–0.67(m,2H),0.47–0.43(m,2H)；

MS-ESI:m/z 565.2[M+H-HCl]⁺。

Example 54: the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopropylsulfonamido) -1- (2, 4-difluorobenzene Yl) Ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoro)Methoxy) phenyl) oxazole-4-carboxamide hydrochloride, 5- ((S) -1- Aminoethyl) -N- ((S) -2- (cyclopropylsulfonamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) 4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -N- ((R) -2- (cyclopropylsulfonyl) amide Amino) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-methyl Synthesis of amide hydrochloride

Step 1: synthesis of compound 2-amino-2- (2, 4-difluorophenyl) acetonitrile hydrochloride

Adding zinc iodide (0.68g,2.11mmol) and a cyanotrimethylsilane solution (7M,30mL) into 2, 4-difluorobenzaldehyde (3.0g,21.1mmol) and cyanotrimethylsilane (2.8g,27.4mmol) at 0 ℃ under the protection of nitrogen, stirring at 40 ℃ for 4h, removing the solvent, extracting with ethyl acetate (10 mL. times.3), combining the organic phases, and adding Na₂SO₄Drying, removal of solvent, addition of HCl in ethyl acetate (4M,5mL), precipitation of solid, filtration, washing of solid with ethyl acetate (5 mL. times.3) gave 2.9g of light yellow solid, yield: 68 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.76–7.82(m,1H),7.21–7.31(m,2H),6.03(s,1H)；

MS-ESI:m/z 169.15[M+H-HCl]⁺。

Step 2: synthesis of the Compound tert-butyl ((1S) -1- (4- ((cyano (2, 4-difluorophenyl) methyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.60g,1.28mmol), compound 2-amino-2- (2, 4-difluorophenyl) acetonitrile hydrochloride (320mg,1.56mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (380mg,2.00mmol) and N-hydroxy-7-azabenzotriazole (270mg,2.00mmol) were dissolved in dichloromethane (20mL) and N, N-diiso-tolylazole was added dropwise to the solution at 0 deg.CPropylethylamine (0.91mL,5.20mmol), stirred at room temperature for 5h, washed with water (10 mL. times.3), and the organic phase over anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 330mg of a white solid, yield: 42 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.63–7.69(m,1H),7.58(d,J＝9.5Hz,2H),7.25(d,J＝8.2Hz,1H),6.94–7.03(m,2H),6.72(t,J_F-H＝75.0Hz,1H),6.40(d,J＝8.5Hz,1H),5.25–5.35(m,1H),4.00(d,J＝6.7Hz,2H),1.53–1.58(m,3H),1.45(s,9H),1.30–1.34(m,1H),0.68–0.72(m,2H),0.40–0.43(m,2H)；

MS-ESI:m/z 641.15[M+Na]⁺。

And step 3: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((cyano (2, 4-difluorophenyl) methyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (330mg,0.53mmol) and nickel chloride (68mg,0.53mmol) were dissolved in absolute ethanol (15mL), stirred at 0 ℃, a mixture of absolute ethanol (10mL) and sodium borohydride (101mg,2.67mmol) was added, reacted at room temperature for 4h, diluted hydrochloric acid was added to adjust pH to 1, stirred to clear, NaOH solution (1M) was added to adjust pH to 9, ethyl acetate was added for extraction (10mL × 3), the organic phases were combined and Na was used for subsequent organic phase separation₂SO₄Drying and removal of the solvent gave 300mg of a white solid, yield: 91 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.00(br.s,1H),7.65(dd,J₁＝8.3Hz,J₂＝1.7Hz,1H),7.59(d,J＝1.6Hz,1H),7.33–7.42(m,1H),7.27(d,J＝10.2Hz,1H),6.86–6.90(m,2H),6.73(t,J_F-H＝74.9Hz,1H),5.30–5.41(m,1H),5.25–5.30(m,1H),4.02(d,J＝6.9Hz,2H),1.57–1.78(m,2H),1.49–1.55(m,3H),1.41–1.44(m,9H),1.31–1.37(m,1H),0.69–0.74(m,2H),0.42–0.46(m,2H)；

MS-ESI:m/z 623.20[M+H]⁺。

And 4, step 4: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2- (cyclopropylsulfonamido) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (300mg,0.48mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (138mg,0.72mmol) and N-hydroxy-7-azabenzotriazole (98mg,0.72mmol) were dissolved in dichloromethane (15mL), cyclopropanesulfonic acid (71mg,0.58mmol) and N, N-diisopropylethylamine (0.25mL,1.44mmol) were added dropwise to the solution at 0 ℃ respectively, stirring was carried out at room temperature for 12h, the solvent was removed, the concentrated solution was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 90mg of a white solid, yield: 26 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.15(br.s,1H),7.59–7.63(m,2H),7.43–7.45(m,2H),7.26(d,J＝8.3Hz,1H),6.91–6.95(m,2H),6.73(t,J_F-H＝75Hz,1H),5.50–5.56(m,1H),5.27–5.34(m,1H),4.01(d,J＝6.9Hz,2H),3.65–3.70(m,2H),2.42–2.50(m,1H),1.50–1.55(m,3H),1.42–1.45(m,9H),1.18–1.22(m,1H),1.00–1.06(m,2H),0.85–0.91(m,2H),0.68–0.73(m,2H),0.41–0.45(m,2H)；

MS-ESI:m/z 749.20[M+Na]⁺。

And 5: synthesis of the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopropylsulfonamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

The compound tert-butyl ((1S) -1- (4- ((2- (cyclopropylsulfonamido) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (90mg,0.124mmol) was dissolved in dichloromethane (2mL), HCl in ethyl acetate (4M,4mL) was added, stirring was carried out at room temperature for 30min, the solvent was removed to give 70mg of a white solid, yield: 85 percent.

Compound 139:¹H NMR(400MHz,CD₃OD):δppm 7.86(s,1H),7.73(d,J＝8.2Hz,1H),7.51–7.58(m,1H),7.34(d,J＝8.3Hz,1H),6.97–7.06(m,2H),6.92(t,J_F-H＝74.8Hz,1H),5.51(t,J＝6.2Hz,1H),5.09–6.18(m,1H),4.05(d,J＝6.8Hz,2H),3.67–3.59(m,2H),2.55–2.63(m,1H),1.75(d,J＝6.5Hz,3H),1.07–1.09(m,1H),0.99–1.05(m,2H),0.86–0.94(m,2H),0.67–0.73(m,2H),0.43–0.47(m,2H)；

MS-ESI:m/z 627.15[M+H-HCl]⁺。

Step 6: synthesis of the compounds 5- ((S) -1-aminoethyl) -N- ((S) -2- (cyclopropylsulfonamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -N- ((R) -2- (cyclopropylsulfonamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

Preparative chromatography of the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopropylsulfonamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (300mg,0.45mmol) was carried out, the preparations in S and R configurations were concentrated, adjusted to pH 9 with NaOH solution (1M), extracted with ethyl acetate (10mL × 3), the organic phases combined and Na-treated₂SO₄Dried, the solvent removed, HCl in ethyl acetate (4M,2mL) added, this gave 5- ((S) -1-aminoethyl) -N- ((S) -2- (cyclopropylsulfonamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (90mg as a pale yellow solid) and 5- ((S) -1-aminoethyl) -N- ((R) -2- (cyclopropylsulfonamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (85mg as a pale yellow solid).

Example 55: the compound N- ((S) -2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-amino Ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride and N- ((R) -2-amino 1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoro) Synthesis of methoxy) phenyl) oxazole-4-carboxamide hydrochloride

The compound of example 47N- (2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride was resolved to give, after resolution, N- ((S) -2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride and N- ((R) -2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride.

Compound 140:¹H NMR(600MHz,CD₃OD):δppm 7.79(d,J＝1.9Hz,1H),7.73(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.62–7.58(m,1H),7.33(d,J＝8.3Hz,1H),7.07–7.02(m,2H),6.92(t,J_F-H＝75.0Hz,1H),5.92(s,1H),5.20–5.17(m,1H),4.04(d,J＝7.0Hz,2H),1.76(d,J＝6.8Hz,3H),1.38–1.33(m,1H),0.71–0.68(m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 537.2[M+H-HCl]⁺；

Compound 141:¹H NMR(600MHz,CD₃OD):δppm 7.79(d,J＝1.9Hz,1H),7.73(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.61–7.59(m,1H),7.33(d,J＝8.3Hz,1H),7.07–7.03(m,2H),6.92(t,J_F-H＝75.0Hz,1H),5.92(s,1H),5.18–5.14(m,1H),4.03(d,J＝7.0Hz,2H),1.75(d,J＝6.8Hz,3H),1.37–1.33(m,1H),0.71–0.67 (m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 537.1[M+H-HCl]⁺。

Example 56: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (1- (2, 4-difluorophenyl) -2- (methylamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (methylamino) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.23g,0.36mmol), methylamine hydrochloride (29mg,0.43mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (104mg,0.54mmol) and N-hydroxy-7-azabenzotriazole (74mg,0.54mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.25mL,1.44mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 15 hours, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1), 133mg of white solid are obtained, yield: 56 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.55–7.53(m,1H),7.52(s,1H),7.44–7.39(m,1H),7.17(d,J＝8.3Hz,1H),6.86–6.81(m,2H),6.65(t,J_F-H＝75.0Hz,1H),5.86–5.85(m,1H),5.79–5.77(m,1H),5.24–5.20(m,1H),3.94(d,J＝6.8Hz,2H),2.82–2.80(m,3H),1.44–1.39(m,3H),1.36–1.28(m,9H),1.27–1.24(m,1H),0.64–0.61(m,2H),0.38–0.33(m,2H)；

MS-ESI:m/z 651.9[M+H]⁺。

step 2: synthesis of the Compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (methylamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (methylamino) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.13g,0.20mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 20min, the solvent was removed to give 110mg of a white solid, yield: 94%, sent to preparation for further purification, to yield 80mg of a white solid.

Compound 144:¹H NMR(600MHz,CD₃OD):δppm 7.79(s,1H),7.72(d,J＝8.3Hz,1H),7.59–7.55(m,1H),7.34(d,J＝8.3Hz,1H),7.07–7.02(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.90(s,1H),5.19–5.15(m,1H),4.04(d,J＝6.9Hz,2H),2.80(s,3H),1.75(d,J＝7.0Hz,3H),1.37–1.34(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H)；

MS-ESI:m/z 551.1[M+H-HCl]⁺。

Example 57: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Base) -N- (1- (2, 4-difluorophenyl) -2- (4-methylpiperazin-1-yl) -2-oxoethyl) oxazole-4-carboxamide dihydrochloride Synthesis of (2)

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (4-methylpiperazin-1-yl) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.16g,0.25mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (72mg,0.38mmol) and N-hydroxy-7-azabenzotriazole (60mg,0.38mmol) were dissolved in dichloromethane (10mL), to this solution was added dropwise 1-methylpiperazine (0.03mL,0.30mmol) and N, N-diisopropylethylamine (0.13mL,0.75mmol), respectively, at 0 ℃ with stirring at room temperature for 15h, the solvent was removed, the concentrated solution was subjected to column separation (dichloromethane/methanol (v/v) ═ 20/1) to give 60mg of a white solid, yield: 33 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.60–7.58(m,1H),7.57–7.56(m,1H),7.53–7.49(m,1H),7.23(d,J＝8.0Hz,1H),6.95(t,J＝7.2Hz,1H),6.90(t,J＝9.3Hz,1H),6.71(t,J_F-H＝75.0Hz,1H),6.29–6.26(m,1H),5.30–5.25(m,2H),3.98(d,J＝6.9Hz,2H),3.85–3.75(m,2H),2.85–2.75(m,2H),2.62–2.50(m,4H),1.51–1.47(m,3H),1.42–1.38(m,9H),1.35–1.33(m,1H),0.71–0.68(m,2H),0.43–0.41(m,2H)。

Step 2: synthesis of the Compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (4-methylpiperazin-1-yl) -2-oxoethyl) oxazole-4-carboxamide dihydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (4-methylpiperazin-1-yl) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.06g,0.08mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,2mL), stirred at room temperature for 20min, the solvent was removed to give 50mg of a white solid, yield: 91 percent.

Compound 146:¹H NMR(600MHz,CD₃OD):δppm 7.79(d,J＝1.8Hz,1H),7.73(dd,J₁＝8.3Hz,J₂＝1.5Hz,1H),7.60–7.57(m,1H),7.34(d,J＝8.3Hz,1H),7.14–7.08(m,2H),6.92(t,J_F-H＝74.7Hz,1H),6.34(s,1H),5.21–5.17(m,1H),4.04(d,J＝6.9Hz,2H),3.70–3.40(m,4H),3.30–3.10(m,4H),2.93(s,3H),1.75(d,J＝6.8Hz,3H),1.36–1.33(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H)；

MS-ESI:m/z 620.2[M+H-2HCl]⁺。

Example 58: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Phenyl) -N- (1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyrimidin-2-yl) piperazin-1-yl) ethyl) oxazole-4-carboxamide bis synthesis of hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyrimidin-2-yl) piperazin-1-yl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.19g,0.30mmol), 1- (2-pyrimidinyl) piperazine (60mg,0.36mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (86mg,0.45mmol) and N-hydroxy-7-azabenzotriazole (61mg,0.45mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.16mL,0.89mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 15 hours, the solvent was removed and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 220mg of a colorless oil, yield: 94 percent.

¹H NMR(600MHz,CDCl₃):δppm 8.56(d,J＝7.3Hz,1H),8.33(d,J＝4.7Hz,2H),7.63(d,J＝8.4Hz,1H),7.60(s,1H),7.56–7.55(m,1H),7.25(d,J＝8.3Hz,1H),6.94–6.91(m,2H),6.73(t,J_F-H＝75.0Hz,1H),6.57(t,J＝4.7Hz,1H),6.34(d,J＝7.1Hz,1H),5.32–5.29(m,1H),4.02(d,J＝6.9Hz,2H),4.00–3.85(m,4H),3.72–3.70(m,2H),3.66–3.42(m,4H),1.53–1.49(m,3H),1.45–1.38(m,9H),1.39–1.37(m,1H),0.73–0.70(m,2H),0.46–0.44(m,2H)；

MS-ESI:m/z 684.1[M+H-100]⁺。

Step 2: synthesis of the Compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyrimidin-2-yl) piperazin-1-yl) ethyl) oxazole-4-carboxamide dihydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyrimidin-2-yl) piperazin-1-yl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.22g,0.28mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 20min, the solvent was removed to give 200mg of a white solid, yield: 99 percent.

Compound 147:¹H NMR(600MHz,CD₃OD):δppm 8.56(d,J＝4.5Hz,2H),7.79(d,J＝1.8Hz,1H),7.73(dd,J₁＝8.4Hz,J₂＝1.7Hz,1H),7.65–7.59(m,1H),7.34(d,J＝8.3Hz,2H),7.14–7.09(m,2H),6.96–6.94(m,1H),6.92(t,J_F-H＝74.7Hz,1H),6.35–6.34(m,1H),5.20–5.16(m,1H),4.10–3.99(m,4H),3.87–3.83(m,4H),3.58–3.56(m,2H),1.76(d,J＝6.9Hz,3H),1.41–1.39(m,1H),0.72–0.67(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 342.7[M+2H-2HCl]²⁺。

Example 59: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl) -N- ((2, 4-difluorophenyl) (2H-tetrazol-5-yl) methyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((2, 4-difluorophenyl) (2H-tetrazol-5-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

To a solution of tert-butyl ((1S) -1- (4- ((cyano (2, 4-difluorophenyl) methyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (160mg,0.26mmol) and ammonium chloride (20mg,0.31mmol) in N, N-dimethylformamide (15mL) was added sodium azide (20mg,0.31mmol), the reaction was carried out at 100 ℃ for 8 hours, the solvent was removed, water (10mL) was added, the pH was adjusted to about 1 with dilute hydrochloric acid (1M), ethyl acetate was extracted (15 mL. times.3), and the combined organic phases were extracted with anhydrous Na₂SO₄Drying and concentration gave 160mg of yellow oil, yield: 93 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.59–7.57(m,3H),7.25(d,J＝8.2Hz,1H),7.06–7.00(m,1H),6.96–6.84(m,2H),6.73(t,J_F-H＝74.7Hz,1H),5.61–5.51(m,1H),5.25–5.10(m,1H),3.99(d,J＝6.9Hz,2H),1.59–1.51(m,3H),1.41–1.39(m,9H),1.35–1.33(m,1H),0.71–0.69(m,2H),0.44–0.43(m,2H)；

MS-ESI:m/z 562.1[M-100+H]⁺。

Step 2: synthesis of the Compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((2, 4-difluorophenyl) (2H-tetrazol-5-yl) methyl) oxazole-4-carboxamide dihydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((2, 4-difluorophenyl) (2H-tetrazol-5-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.16g,0.24mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, and the solvent was removed to afford 140mg of a yellow solid, yield: 96 percent.

Compound 148:¹H NMR(600MHz,CD₃OD):δppm 7.71(s,1H),7.64(d,J＝8.2Hz,1H),7.49–7.45(m,1H),7.23(d,J＝8.2Hz,1H),7.02–6.96(m,2H),6.91(s,1H),6.82(t,J_F-H＝74.7Hz,1H),5.14–5.11(m,1H),3.93(d,J＝6.8Hz,2H),1.68(d,J＝6.5Hz,3H),0.82–0.77(m,1H),0.60–0.57(m,2H),0.33–0.32(m,2H)；

MS-ESI:m/z 562.1[M+H-2HCl]⁺。

Example 60: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Phenyl) -N- (1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyridin-4-ylmethyl) piperazin-1-yl) ethyl) oxazole-4-carboxylic acid Synthesis of amine trihydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyridin-4-ylmethyl) piperazin-1-yl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.23g,0.36mmol), 1- (4-picolyl) piperazine (77mg,0.43mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (103mg,0.54mmol) and N-hydroxy-7-azabenzotriazole (74mg,0.54mmol) were dissolved in dichloromethane (10mL), N-diisopropylethylamine (0.19mL,1.08mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 11h, the solvent was removed and the concentrate was subjected to column separation (ethyl acetate/methanol (v/v) ═ 20/1) to give 260mg of a colorless oil, yield: 90 percent.

¹H NMR(600MHz,CDCl₃):δppm 8.60(d,J＝4.1Hz,2H),8.52(d,J＝6.4Hz,1H),7.62(d,J＝8.4Hz,1H),7.59(s,1H),7.55–7.49(m,1H),7.36(d,J＝3.8Hz,2H),7.25(d,J＝8.3Hz,1H),6.96–6.86(m,2H),6.73(t,J_F-H＝75.0Hz,1H),6.28(d,J＝7.5Hz,1H),5.32–5.29(m,1H),4.01(d,J＝6.9Hz,2H),3.75–3.72(m,2H),3.66–3.63(m,1H),3.57(s,2H),3.50–3.45(m,1H),2.53–2.46(m,4H),1.53–1.48(m,3H),1.44(s,9H),1.33–1.29(m,1H),0.73–0.68(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 797.2[M+H]⁺。

Step 2: synthesis of the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyridin-4-ylmethyl) piperazin-1-yl) ethyl) oxazole-4-carboxamide trihydrochloride

To a solution of compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyridin-4-ylmethyl) piperazin-1-yl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.26g,0.33mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 20min, the solvent was removed to afford 220mg of a white solid, yield: 96 percent.

Compound 150:¹H NMR(400MHz,CD₃OD):δppm 8.98(s,2H),8.37(d,J＝5.4Hz,2H),7.79(s,1H),7.73(d,J＝8.4Hz,1H),7.61–7.55(m,1H),7.34(d,J＝8.4Hz,1H),7.13–7.07(m,2H),6.92(t,J_F-H＝70.6Hz,1H),6.33(s,1H),5.20–5.16(m,1H),4.58(s,2H),4.04(d,J＝6.9Hz,2H),3.33–3.20(m,8H),1.75(d,J＝7.0Hz,3H),1.36–1.34(m,1H),0.72–0.67(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 697.2[M+H-3HCl]⁺。

Example 61: the compound (S) -2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethyl) Oxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid hydrochloride and (R) -2- (5- ((S) -1-aminoethyl) Yl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) Process for preparing acetic acid hydrochlorideSynthesis of

The compound 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid hydrochloride of example 50 was submitted to preparative resolution to give, after resolution, the compounds (S) -2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid hydrochloride and (R) -2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) Oxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid hydrochloride.

Compound 153:¹H NMR(600MHz,CD₃OD):δppm 8.76(s,1H),7.71(s,1H),7.68(d,J＝8.3Hz,1H),7.40–7.34(m,2H),7.24(t,J_F-H＝75.0Hz,1H),7.12(t,J＝8.7Hz,1H),6.97(t,J＝7.7Hz,1H),5.21(s,1H),5.02–4.98(m,1H),4.02(d,J＝6.8Hz,2H),1.55(d,J＝6.7Hz,3H),1.28–1.24(m,1H),0.61–0.60(m,2H),0.41–0.40(m,2H)；

MS-ESI:m/z 538.2[M+H-HCl]⁺；

Compound 154:¹H NMR(400MHz,d₆-DMSO):δppm 8.67(s,1H),7.65–7.63(m,2H),7.35(d,J＝8.8Hz,1H),7.31–7.27(m,1H),7.23(t,J_F-H＝74.0Hz,1H),7.12(dd,J₁＝10.0Hz,J₂＝2.5Hz,1H),6.99–6.95(m,1H),5.16–5.15(m,1H),5.04–4.99(m,1H),3.98(d,J＝7.0Hz,2H),1.51(d,J＝6.9Hz,3H),1.29–1.25(m,1H),0.63–0.58(m,2H),0.41–0.38(m,2H)；

MS-ESI:m/z 538.2[M+H-HCl]⁺。

Example 62: the compound N- ((S) -2-acetamido-1- (2, 4-difluorophenyl) ethyl) -5- ((S) -1-aminoethyl Yl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride and N- ((R) -2-acetyl Amino-1- (2, 4-difluorophenyl) ethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) Synthesis of phenyl) oxazole-4-carboxamide hydrochloride

The compound N- (2-acetylamino-1- (2, 4-difluorophenyl) ethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride from example 53 was resolved by preparative chromatography to give, after resolution, N- ((S) -2-acetylamino-1- (2, 4-difluorophenyl) ethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (pale yellow solid) and N- ((R) -2-acetylamino-1- (2, 4-difluorophenyl) ethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (light yellow solid).

Compound 158:¹H NMR(400MHz,CD₃OD):δppm 7.78(s,1H),7.71(d,J＝8.4Hz,1H),7.46–7.41(m,1H),7.29(d,J＝8.4Hz,1H),6.98–6.91(m,2H),6.87(t,J_F-H＝74.7Hz,1H),5.47–5.44(m,1H),5.11–5.05(m,1H),4.02(d,J＝6.9Hz,2H),3.70–3.56(m,2H),1.89(s,3H),1.68(d,J＝7.0Hz,3H),1.35–1.30(m,1H),0.67–0.62(m,2H),0.41–0.37(m,2H)；

MS-ESI:m/z 565.2[M+H-HCl]⁺；

Compound 159:¹H NMR(600MHz,CD₃OD):δppm 7.85(s,1H),7.76(d,J＝8.3Hz,1H),7.50–7.48(m,1H),7.35(d,J＝8.3Hz,1H),7.03–6.98(m,2H),6.93(t,J_F-H＝74.7Hz,1H),5.53–5.51(m,1H),5.11–5.08(m,1H),4.07(d,J＝7.0Hz,2H),3.75–3.63(m,2H),1.95(s,3H),1.74(d,J＝7.0Hz,3H),1.39–1.37(m,1H),0.72–0.69(m,2H),0.46–0.44(m,2H)；

MS-ESI:m/z 565.2[M+H-HCl]⁺。

example 63: the compound (S) -2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethyl) Oxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid methyl ester hydrochloride and (R) -2- (5- ((S) -1-amino) Ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorobenzene Based) preparation of methyl acetate hydrochlorideSynthesis of

The compound methyl 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate hydrochloride of example 49 was resolved by preparative chromatography to give the compound methyl (S) -2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate hydrochloride (white solid) and the compound (R) -2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid methyl ester hydrochloride (white solid).

Compound 164:¹H NMR(600MHz,CD₃OD):δppm 7.80(s,1H),7.74(d,J＝8.3Hz,1H),7.59–7.55(m,1H),7.34(d,J＝8.3Hz,1H),7.10–7.03(m,2H),6.93(t,J_F-H＝74.7Hz,1H),6.06(s,1H),5.21–5.17(m,1H),4.04(d,J＝6.9Hz,2H),3.81(s,3H),1.75(d,J＝7.0Hz,3H),1.39–1.36(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H)；

MS-ESI:m/z 552.2[M+H-HCl]⁺；

compound 165:¹H NMR(600MHz,CD₃OD):δppm 7.80(s,1H),7.74(d,J＝8.3Hz,1H),7.59–7.55(m, 1H),7.34(d,J＝8.3Hz,1H),7.10–7.03(m,2H),6.93(t,J_F-H＝74.7Hz,1H),6.06(s,1H),5.19–5.16(m,1H),4.04(d,J＝6.9Hz,2H),3.81(s,3H),1.75(d,J＝7.0Hz,3H),1.38–1.35(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H)；

MS-ESI:m/z 552.2[M+H-HCl]⁺。

Example 64: the compound 5- ((S) -1-aminoethyl) -N- ((S) -2- (cyclopropylcarboxamido) -1- (2, 4-difluoro) Phenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -N- ((R) -2- (cyclopropylcarboxamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethyl) Oxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochlorideSynthesis of salts

The compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopropylcarboxamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride from example 52 was resolved by preparative chromatography to give, after resolution, the compound 5- ((S) -1-aminoethyl) -N- ((S) -2- (cyclopropylcarboxamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (white solid) and 5- ((S) -1-aminoethyl) -N- ((R) -2- (cyclopropylcarboxamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (white solid).

Compound 166:¹H NMR(600MHz,CD₃OD):δppm 7.84(s,1H),7.75(d,J＝8.3Hz,1H),7.50–7.46(m,1H),7.35(d,J＝8.3Hz,1H),7.04–6.98(m,2H),6.94(t,J_F-H＝74.7Hz,1H),5.49–5.47(m,1H),5.15–5.12(m,1H),4.07(d,J＝7.0Hz,2H),3.79–3.75(m,1H),3.66–3.63(m,1H),1.72(d,J＝7.0Hz,3H),1.58–1.55(m,1H),1.42–1.39(m,1H),0.93–0.90(m,2H),0.79–0.75(m,2H),0.73–0.70(m,2H),0.47–0.45(m,2H)；

MS-ESI:m/z 591.2[M+H-HCl]⁺；

Compound 167:¹H NMR(600MHz,CD₃OD):δppm 7.84(s,1H),7.74(d,J＝8.3Hz,1H),7.48–7.46(m,1H),7.35(d,J＝8.3Hz,1H),7.03–6.98(m,2H),6.94(t,J_F-H＝74.7Hz,1H),5.49–5.47(m,1H),5.10–5.08(m,1H),4.07(d,J＝7.0Hz,2H),3.77–3.74(m,1H),3.67–3.65(m,1H),1.73(d,J＝7.0Hz,3H),1.57–1.55(m,1H),1.41–1.38(m,1H),1.02–0.99(m,2H),0.80–0.75(m,2H),0.72–0.71(m,2H),0.47–0.46(m,2H)；

MS-ESI:m/z 591.2[M+H-HCl]⁺。

Example 65: the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopropylamino) -1- (2, 4-difluorophenyl) -2- oxoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoro)Synthesis of methoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of methyl 2-amino-2- (2, 4-difluorophenyl) acetate compound

The compound 2-amino-2- (2, 4-difluorophenyl) acetonitrile hydrochloride (1.0g,4.89mmol) was dissolved in anhydrous methanol (30mL), a solution of HCl in ethyl acetate (4M,8mL) was added, the reaction was carried out at 65 ℃ for 24h, the solvent was dried by spinning, and the remaining solid was washed with dichloromethane (10mL × 5) to give 1.05g of a pale yellow solid, yield: 91 percent.

¹H NMR(600MHz,CD₃OD):δppm 7.76–7.82(m,1H),7.21–7.31(m,2H),6.03(s,1H),3.84(s,3H)；

MS-ESI:m/z 202.20[M+H-HCl]⁺。

Step 2: synthesis of the compound methyl 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate

Compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.50g,1.07mmol), compound methyl 2-amino-2- (2, 4-difluorophenyl) acetate (380mg,1.60mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (409mg,2.13mmol) and N-hydroxy-7-azabenzotriazole (218mg,1.60mmol) were dissolved in dichloromethane (20mL), N-diisopropylethylamine (0.75mL,4.28mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 5 hours, followed by water washing (10 mL. times.3), anhydrous Na for organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 170mg of a white solid, yield: 25 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.16(br.s,1H),7.62–7.64(m,1H),7.59(d,J＝1.8Hz,1H),7.46–7.51(m,1H),7.26(d,J＝8.3Hz,1H),6.88–6.95(m,2H),6.73(t,J_F-H＝75.1Hz,1H),5.98–6.01(m,1H),5.25–5.32(m,1H),4.02(dd,J＝6.9,1.6Hz,2H),3.82(s,3H),1.49–1.54(m,3H),1.41–1.45(m,9H),1.34–1.37(m,1H),0.69–0.74(m,2H),0.43–0.47(m,2H)；

MS-ESI:m/z 674.10[M+Na]⁺。

And step 3: synthesis of the compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid

The compound methyl 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate (240mg,0.37mmol) was reacted with LiOH. H₂O (77mg,1.84mmol) was dissolved in THF (10mL) and water (5mL), the reaction was stirred at 40 ℃ for 30min, diluted hydrochloric acid (1M) was added to adjust pH to 1, ethyl acetate was added and extraction (20mL × 3) was performed, the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 230mg of a white solid, yield: 98 percent.

¹H NMR(600MHz,CD₃OD):δppm 7.70(s,1H),7.61–7.63(m,1H),7.50–7.54(m,1H),7.24(d,J＝8.3Hz,1H),6.94–7.00(m,2H),6.84(t,J_F-H＝74.9Hz,1H),5.87(d,J＝13.8Hz,1H),5.30–5.38(m,1H),3.97(dd,J＝6.9,2.4Hz,2H),1.45(d,J＝7.1Hz,3H),1.34–1.36(m,9H),1.27–1.31(m,1H),0.61–0.65(m,2H),0.36–0.39(m,2H)；

MS-ESI:m/z 660.15[M+Na]⁺。

And 4, step 4: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2- (cyclopropylamino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (230mg,0.36mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (138mg,0.72mmol) and N-hydroxy-7-azabenzotriazole (74mg,0.54mmol) were dissolved in dichloromethane (15mL), to this solution cyclopropylammonia (31mg,0.54mmol) and N, N-diisopropylethylamine (0.19mL,1.08mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, and water was addedWashed (10 mL. times.3) and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of the solvent, and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) gave 180mg of a white solid in yield: 74 percent.

¹H NMR(600MHz,CDCl₃):δppm 8.42(br.s,1H),7.61–7.64(m,2H),7.48–7.52(m,1H),7.26(d,J＝8.3Hz,1H),6.88–6.94(m,2H),6.74(t,J_F-H＝75.1Hz,1H),6.07(s,1H),5.80(d,J＝6.8Hz,1H),5.26–5.33(m,1H),4.04(d,J＝6.9Hz,2H),2.70–2.76(m,1H),1.46–1.53(m,3H),1.40–1.44(m,9H),1.34–1.39(m,1H),0.77–0.87(m,2H),0.70–0.73(m,2H),0.48–0.59(m,2H),0.44–0.47(m,2H)；

MS-ESI:m/z 699.20[M+Na]⁺。

And 5: synthesis of the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopropylamino) -1- (2, 4-difluorophenyl) -2-oxoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (4- ((2- (cyclopropylamino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (175mg,0.26mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 30min, and the solvent was removed to give 160mg of a white solid in yield: 99 percent.

Compound 168:¹H NMR(600MHz,CD₃OD):δppm 7.79(s,1H),7.72(d,J＝8.4Hz,1H),7.54–7.58(m,1H),7.34(d,J＝8.3Hz,1H),7.03–7.07(m,2H),6.92(t,J_F-H＝74.9Hz,1H),5.85(d,J＝4.6Hz,1H),5.15–5.20(m,1H),4.04(d,J＝6.9Hz,2H),2.72–2.75(m,1H),1.75(d,J＝7.0Hz,3H),1.32–1.38(m,1H),0.74–0.77(m,2H),0.68–0.71(m,2H),0.46–0.56(m,2H),0.42–0.45(m,2H)；

MS-ESI:m/z 577.20[M+H-HCl]⁺。

example 66: the compound 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) Synthesis of phenyl) oxazole-4-formylamino) -2- (2, 4-difluorophenyl) benzyl acetate hydrochloride

Step 1: synthesis of benzyl 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate, compound

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (230mg,0.36mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (138mg,0.72mmol) and N-hydroxy-7-azabenzotriazole (74mg,0.54mmol) were dissolved in dichloromethane (15mL), to this solution were added dropwise benzyl alcohol (58mg,0.54mmol) and N, N-diisopropylethylamine (0.19mL,1.08mmol) respectively at 0 ℃ with stirring at room temperature for 12 hours, followed by washing with water (10 mL. times.3), anhydrous Na for organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (ethyl acetate/petroleum ether (v/v) ═ 8/1) afforded 63mg of a white solid, yield: 24 percent.

¹H NMR(600MHz,CDCl₃):δppm 8.20(br.s,1H),7.60–7.63(m,1H),7.58–7.59(m,1H),7.31–7.35(m,5H),7.24–7.26(m,2H),6.87–6.91(m,2H),6.73(t,J_F-H＝74.9Hz,1H),6.03(d,J＝7.7Hz,1H),5.27–5.30(m,1H),5.25(s,2H),4.01(d,J＝6.9Hz,2H),1.52(d,J＝7.0Hz,3H),1.46(s,9H),1.31–1.39(m,1H),0.70–0.74(m,2H),0.42–0.45(m,2H)；

MS-ESI:m/z 750.20[M+Na]⁺。

Step 2: synthesis of benzyl 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate hydrochloride

To a solution of the compound benzyl 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate (63mg,0.087mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 30min, and the solvent was removed to give 55mg of a white solid in yield: 96 percent.

Compound 170:¹H NMR(400MHz,CD₃OD):δppm 7.80(s,1H),7.72–7.74(m,1H),7.50–7.56(m,1H),7.28–7.35(m,5H),6.97–7.08(m,2H),6.92(t,J_F-H＝74.8Hz,1H),6.08(s,1H),5.21–5.32(m,2H),5.15–5.21(m,1H),4.05(d,J＝6.8Hz,2H),1.75(d,J＝6.6Hz,3H),1.31–1.35(m,1H),0.66–0.72(m,2H),0.41 –0.45(m,2H)；

MS-ESI:m/z 628.10[M+H-HCl]⁺。

Example 67: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2- (methylamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorobenzene) Synthesis of yl) -2- (methylamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

The compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (methylamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride of example 56 was resolved by chiral preparative chromatography to give the compounds 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2- (methylamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride (white solid) and 5- ((S) -one 1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2- (methylamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride (white solid).

Compound 171:¹H NMR(600MHz,CD₃OD):δppm 7.79(s,1H),7.73(d,J＝8.3Hz,1H),7.58–7.55(m,1H),7.34(d,J＝8.3Hz,1H),7.07–7.02(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.90(s,1H),5.20–5.16(m,1H),4.04(d,J＝6.9Hz,2H),2.80(s,3H),1.75(d,J＝7.0Hz,3H),1.38–1.35(m,1H),0.71–0.68(m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 551.2[M+H-HCl]⁺；

Compound 172:¹H NMR(600MHz,CD₃OD):δppm 7.79(s,1H),7.72(d,J＝8.3Hz,1H),7.58–7.55(m,1H),7.34(d,J＝8.3Hz,1H),7.08–7.03(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.89(s,1H),5.17–5.14(m,1H),4.04(d,J＝6.9Hz,2H),2.80(s,3H),1.75(d,J＝7.0Hz,3H),1.36–1.34(m,1H),0.71–0.68(m,2H),0.45–0.43(m,2H)；

MS-ESI:m/z 551.2[M+H-HCl]⁺。

Example 68: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (1- (2, 4-difluorophenyl) -2- (dimethylamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (dimethylamino) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.35g,0.55mmol), dimethylamine hydrochloride (54mg,0.66mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (158mg,0.82mmol) and N-hydroxy-7-azabenzotriazole (112mg,0.82mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.38mL,2.20mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 4 hours, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 3/1), 140mg of a colorless oil are obtained, yield: 38 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.62(d,J＝8.4Hz,1H),7.60(s,1H),7.55–7.51(m,1H),7.24(d,J＝8.3Hz,1H),6.94–6.87(m,2H),6.73(t,J_F-H＝75.1Hz,1H),6.30–6.28(m,1H),5.32–5.28(m,1H),4.02(d,J＝7.0Hz,2H),3.05–3.04(m,6H),1.55–1.48(m,3H),1.37–1.34(m,1H),0.73–0.70(m,2H),0.44–0.40(m,2H)；

MS-ESI:m/z 665.2[M+H]⁺。

Step 2: synthesis of the Compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (dimethylamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (dimethylamino) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.13g,0.20mmol) in dichloromethane (5mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 1.5h, the solvent was removed to give 110mg of a white solid, yield: 99 percent.

Compound 173:¹H NMR(400MHz,CD₃OD):δppm 7.78(s,1H),7.72(d,J＝8.3Hz,1H),7.55–7.51(m,1H),7.33(d,J＝8.4Hz,1H),7.10–7.03(m,2H),6.92(t,J_F-H＝74.7Hz,1H),6.26(s,1H),5.18–5.14(m,1H),4.04(d,J＝6.9Hz,2H),3.03–3.01(m,6H),1.75(d,J＝6.9Hz,3H),1.35–1.32(m,1H),0.71–0.66(m,2H),0.45–0.43(m,2H)；

MS-ESI:m/z 565.2[M+H-HCl]⁺。

Example 69: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Process for preparation of phenyl) -N- (2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) oxazole-4-carboxamide hydrochloride Synthesis of

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.35g,0.55mmol), cyclopropylmethylamine (0.06mL,0.66mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (158mg,0.82mmol) and N-hydroxy-7-azabenzotriazole (112mg,0.82mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.29mL,1.65mmol) was added dropwise to the solution at 0 ℃, stirred at room temperature for 4h, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 4/1), 145mg of a pale yellow solid are obtained, yield: 38 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.63(d,J＝8.3Hz,1H),7.61(m,1H),7.53–7.50(m,1H),7.26(d,J＝8.3Hz,1H),6.95–6.90(m,2H),6.74(t,J_F-H＝75.0Hz,1H),6.02–6.00(m,1H),5.88–5.87(m,1H),5.33–5.29(m,1H),4.03(d,J＝7.0Hz,2H),3.24–3.21(m,1H),3.15–3.11(m,1H),1.53–1.48(m,3H),1.45–1.40(m,9H),1.37–1.34(m,1H),0.98–0.94(m,1H),0.73–0.70(m,2H),0.54–0.52(m,2H),0.47–0.44(m,2H),0.21–0.20(m,2H)；

MS-ESI:m/z 691.2[M+H]⁺。

Step 2: synthesis of the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.13g,0.20mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 2.5h, the solvent was removed to give 110mg of a white solid, yield: 95 percent.

compound 174:¹H NMR(600MHz,CD₃OD):δppm 7.79(s,1H),7.72(d,J＝8.3Hz,1H),7.60–7.57(m,1H),7.34(d,J＝8.3Hz,1H),7.08–7.03(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.92(d,J＝2.7Hz,1H),5.19–5.15(m,1H),4.04(d,J＝6.9Hz,2H),3.15–3.09(m,2H),1.75(d,J＝7.0Hz,3H),1.36–1.33(m,1H),1.00–0.97(m,1H),0.71–0.68(m,2H),0.49–0.47(m,2H),0.45–0.42(m,2H),0.22–0.20(m,2H)；

MS-ESI:m/z 591.2[M+H-HCl]⁺。

Example 70: the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopentylcarboxamide) -1- (2, 4-difluorophenyl) Synthesis of ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2- (cyclopentylcarboxamide) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.30g,0.48mmol), cyclopentanecarboxylic acid (66mg,0.58mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (140mg,0.72mmol) and N-hydroxy-7-azabenzotriazole (100mg,0.72mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.34mL,1.93mmol) was added dropwise to the solution at 0 deg.C, the solution was stirred at room temperature for 15h, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 3/1) 190mg of a colorless oil are obtained, yield: 54 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.65–7.64(m,2H),7.40–7.37(m,1H),7.26(d,J＝8.7Hz,1H),6.92–6.86(m,2H),6.74(t,J_F-H＝75.0Hz,1H),5.95–5.93(m,1H),5.49–5.48(m,1H),5.31–5.28(m,1H),4.03(d,J＝6.9Hz,2H),3.85–3.81(m,2H),2.53–2.50(m,1H),1.84–1.73(m,4H),1.58–1.55(m,2H),1.53–1.52(m,2H),1.49–1.47(m,3H),1.46(s,9H),1.38–1.35(m,1H),0.73–0.70(m,2H),0.44–0.43(m,2H)；

MS-ESI:m/z 719.2[M+H]⁺。

Step 2: synthesis of the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopentylcarboxamide) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound tert-butyl ((1S) -1- (4- ((2- (cyclopentylcarboxamide) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.19g,0.26mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 1h, the solvent was removed to give 170mg of a white solid, yield: 99 percent.

Compound 180:¹H NMR(400MHz,CD₃OD):δppm 7.85(s,1H),7.76(d,J＝8.3Hz,1H),7.50–7.45(m,1H),7.35(d,J＝8.4Hz,1H),7.03–7.03(m,2H),6.93(t,J_F-H＝74.7Hz,1H),5.52–5.48(m,1H),5.15–5.08(m,1H),4.08(d,J＝7.0Hz,2H),3.80–3.72(m,1H),3.67–3.62(m,1H),2.63–2.60(m,1H),1.83–1.79(m,2H),1.74–1.73(m,3H),1.72–1.69(m,4H),1.60–1.56(m,2H),1.41–1.38(m,1H),0.73–0.68(m,2H),0.47–0.43(m,2H)；

MS-ESI:m/z 619.2[M+H-HCl]⁺。

Example 71: the compound N- (2- ((S) -2-amino-2-cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethane 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide disalt Synthesis of acid salts

Step 1: synthesis of the Compound tert-butyl ((1S) -1-cyclopropyl-2- ((2- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -5- ((S) -1- (tert-butoxycarbonylamino) ethyl) oxazole-4-carboxamide) -2- (2, 4-difluorophenyl) ethyl) amino) -2-oxoethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.30g,0.48mmol), Boc-L-cyclopropylglycine (124mg,0.58mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (138mg,0.72mmol) and N-hydroxy-7-azabenzotriazole (98mg,0.72mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.25mL,1.45mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 4h, the solvent was removed and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give 210mg of a white solid, yield: 53 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.65–7.62(m,2H),7.43–7.37(m,1H),7.27(d,J＝8.3Hz,1H),6.92–6.87(m,2H),6.73(t,J_F-H＝75.0Hz,1H),5.54–5.50(m,1H),5.32–5.20(m,2H),4.02(d,J＝6.9Hz,2H),3.86–3.71(m,3H),3.45–3.41(m,1H),1.55–1.49(m,3H),1.46–1.41(m,18H),1.36–1.32(m,1H),1.29–1.27(m,2H),0.73–0.70(m,2H)；

MS-ESI:m/z 820.2[M+H]⁺。

Step 2: synthesis of the compound N- (2- ((S) -2-amino-2-cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound tert-butyl ((1S) -1-cyclopropyl-2- ((2- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -5- ((S) -1- (tert-butoxycarbonylamino) ethyl) oxazole-4-carboxamide) -2- (2, 4-difluorophenyl) ethyl) amino) -2-oxoethyl) carbamate (0.21g,0.25mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 1h, the solvent removed to afford 170mg of a white solid, yield: 98 percent.

Compound 182:¹H NMR(400MHz,CD₃OD):δppm 7.84(s,1H),7.77(d,J＝8.3Hz,1H),7.59–7.57(m,1H),7.35(d,J＝8.2Hz,1H),7.05–6.99(m,2H),6.93(t,J_F-H＝74.7Hz,1H),5.66–5.61(m,1H),5.19–5.11(m,1H),4.07(d,J＝6.8Hz,2H),4.03–3.94(m,1H),3.70–3.63(m,1H),3.20–3.17(m,1H),1.75(d,J＝7.0Hz,3H),1.36–1.32(m,1H),0.93–0.87(m,1H),0.71–0.68(m,2H),0.65–0.60(m,2H),0.53–0.50(m,1H),0.47–0.43(m,2H)；

MS-ESI:m/z 620.2[M+H-2HCl]⁺。

Example 72: the compound 5- ((S) -1-aminoethyl) -N- (2- ((S) -2-aminopropionylamino) -1- (2, 4-difluoro) Phenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoro)Synthesis of methoxy) phenyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- ((S) -2- (tert-butoxycarbonylamino) propionamido) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.30g,0.48mmol), Boc-L-alanine (109mg,0.58mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (140mg,0.72mmol) and N-hydroxy-7-azabenzotriazole (100mg,0.72mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.34mL,1.93mmol) was added dropwise to this solution at 0 ℃ and stirred at room temperature for 20h to remove the solvent, the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 195mg of a white solid, yield: 51 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.65–7.63(m,2H),7.40–7.37(m,1H),7.27(d,J＝8.7Hz,1H),6.92–6.86(m,2H),6.73(t,J_F-H＝75.0Hz,1H),5.50–5.48(m,1H),5.34–5.30(m,1H),4.17–4.12(m,1H),4.02(d,J＝6.9Hz,2H),3.81–3.77(m,1H),1.46–1.45(m,3H),1.41–1.40(m,9H),1.38–1.35(m,1H),1.33–1.30(m,3H),1.28–1.23(m,9H),0.74–0.69(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 794.2[M+H]⁺。

Step 2: synthesis of compound 5- ((S) -1-aminoethyl) -N- (2- ((S) -2-aminopropionylamino) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide dihydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- ((S) -2- (tert-butoxycarbonylamino) propionamido) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.19g,0.24mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 0.5h, the solvent was removed to give 159mg of a white solid, yield: 99 percent.

Compound 183:¹H NMR(600MHz,CD₃OD):δppm 7.84(s,1H),7.76(d,J＝8.3Hz,1H),7.58–7.57(m,1H),7.35(d,J＝8.3Hz,1H),7.06–7.01(m,2H),6.93(t,J_F-H＝74.8Hz,1H),5.64–5.60(m,1H),5.16–5.11(m,1H),4.07(d,J＝6.9Hz,2H),3.95–3.89(m,2H),3.70–3.65(m,1H),1.75(d,J＝5.9Hz,3H),1.44–1.40(m,3H),1.38–1.36(m,1H),0.72–0.67(m,2H),0.46–0.44(m,2H)；

MS-ESI:m/z 594.2[M+H-2HCl]⁺。

Example 73: the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopentylamino) -1- (2, 4-difluorophenyl) -2- Synthesis of oxoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2- (cyclopentylamino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (280mg,0.44mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (253mg,1.32mmol) and N-hydroxy-7-azabenzotriazole (89mg,0.66mmol) were dissolved in dichloromethane (25mL), cyclopentylamine (75mg,0.88mmol) and N, N-diisopropylethylamine (0.23mL,1.32mmol) were added dropwise to the solution at 0 ℃ respectively, stirring was carried out at room temperature for 12 hours, washing was carried out with water (10 mL. times.3), anhydrous Na for organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (ethyl acetate/petroleum ether (v/v) ═ 4/1) afforded 130mg of a white solid, yield: 42 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.40–8.43(m,1H),7.60–7.65(m,2H),7.47–7.53(m,1H),7.26(d,J＝8.3Hz,1H),6.87–6.95(m,2H),6.72(t,J_F-H＝75.1Hz,1H),5.81(d,J＝6.8Hz,1H),5.27–5.35(m,1H),4.17–4.25(m,1H),4.04(d,J＝6.9Hz,2H),1.90–2.06(m,2H),1.56–1.72(m,6H),1.44–1.53(m,3H),1.40–1.44(m,9H),1.31–1.37(m,1H),0.69–0.74(m,2H),0.43–0.47(m,2H)；

MS-ESI:m/z 727.20[M+Na]⁺。

Step 2: synthesis of the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopentylamino) -1- (2, 4-difluorophenyl) -2-oxoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound tert-butyl ((1S) -1- (4- ((2- (cyclopentylamino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (130mg,0.18mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 30min, the solvent was removed to give 115mg of a white solid, yield: 97 percent.

compound 184:¹H NMR(600MHz,CD₃OD):δppm 7.78(s,1H),7.71–7.73(m,1H),7.54–7.58(m,1H),7.34(d,J＝8.3Hz,1H),7.04–7.07(m,2H),6.92(t,J_F-H＝74.8Hz,1H),5.90(d,J＝4.6Hz,1H),5.15–5.20(m,1H),4.15–4.20(m,1H),4.04(d,J＝6.9Hz,2H),1.90–2.06(m,2H),1.75(d,J＝7.0Hz,3H),1.51–1.74(m,5H),1.39–1.44(m,1H),1.37–1.43(m,1H),0.68–0.71(m,2H),0.42–0.45(m,2H)；

MS-ESI:m/z 605.20[M+H-HCl]⁺。

Example 74: the compound 5- ((S) -1-aminoethyl) -N- (2- (2-cyclopropylacetamido) -1- (2, 4-difluorobenzene Yl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride, 5- ((S) -1- Aminoethyl) -N- ((S) -2- (2-cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) Phenyl-4- (difluoromethoxy) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -N- ((R) -2- (2-cyclopropyl) Acetylamino) -1-(2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxa Synthesis of oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2- (2-cyclopropylacetylamino) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.30g,0.48mmol), cyclopropylacetic acid (58mg,0.58mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (140mg,0.72mmol) and N-hydroxy-7-azabenzotriazole (100mg,0.72mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.34mL,1.93mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 15h, the solvent was removed, the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give 168mg of a white solid, yield: 49 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.65–7.63(m,2H),7.42–7.38(m,1H),7.26(d,J＝8.8Hz,1H),6.93–6.87(m,2H),6.73(t,J_F-H＝75.0Hz,1H),6.36–6.34(m,1H),5.53–5.50(m,1H),5.32–5.28(m,1H),4.03(d,J＝7.0Hz,2H),3.85–3.81(m,1H),3.76–3.71(m,1H),2.18–2.14(m,2H),1.55–1.48(m,3H),1.45–1.41(m,9H),1.37–1.34(m,1H),1.33–1.30(m,1H),0.92–0.88(m,2H),0.74–0.69(m,2H),0.57–0.55(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 705.2[M+H]⁺。

Step 2: the compounds 5- ((S) -1-aminoethyl) -N- (2- (2-cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride, 5- ((S) -1-aminoethyl) -N- ((S) -2- (2-cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -N- ((R) -2- (2- Synthesis of cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl ((1S) -1- (4- ((2- (2-cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.16g,0.23mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 0.5h, and the solvent was removed to give 5- ((S) -1-aminoethyl) -N- (2- (2-cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4- Formamide hydrochloride salt: white solid 170mg, yield: 99 percent.

The compound 5- ((S) -1-aminoethyl) -N- (2- (2-cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride was resolved by chiral preparative chromatography to give the compound 5- ((S) -1-aminoethyl) -N- ((S) -2- (2-cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (pale yellow solid) and 5- ((S) -1-aminoacetamide Ethyl) -N- ((R) -2- (2-cyclopropylacetamido) -1- (2, 4-difluorophenyl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (white solid).

Compound 187:¹H NMR(400MHz,CD₃OD):δppm 7.79(s,1H),7.71(d,J＝8.4Hz,1H),7.46–7.40(m,1H),7.29(d,J＝8.3Hz,1H),6.98–6.91(m,2H),6.87(t,J_F-H＝74.7Hz,1H),5.49–5.46(m,1H),5.06–5.01(m,1H),4.02(d,J＝6.9Hz,2H),3.72–3.62(m,2H),2.04(d,J＝7.1Hz,2H),1.68(d,J＝6.9Hz,3H),1.35–1.30(m,1H),1.30–1.26(m,1H),0.67–0.62(m,2H),0.45–0.37(m,4H),0.10–0.06(m,2H)；

MS-ESI:m/z 605.2[M+H-HCl]⁺；

Compound 188:¹H NMR(400MHz,CD₃OD):δppm 7.79(s,1H),7.71(d,J＝8.4Hz,1H),7.46–7.40(m,1H),7.29(d,J＝8.3Hz,1H),6.98–6.91(m,2H),6.87(t,J_F-H＝74.7Hz,1H),5.49–5.46(m,1H),5.06–5.01(m,1H),4.02(d,J＝6.9Hz,2H),3.72–3.62(m,2H),2.04(d,J＝7.1Hz,2H),1.68(d,J＝6.9Hz,3H),1.35–1.30(m,1H),1.30–1.26(m,1H),0.67–0.62(m,2H),0.45–0.37(m,4H),0.10–0.06(m,2H)；

MS-ESI:m/z 605.2[M+H-HCl]⁺。

Example 75: the compound (2S) -2- (2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (bis) Synthesis of fluoromethoxy) phenyl) oxazole-4-carboxamide) -2- (2, 4-difluorophenyl) acetamido) propionic acid isopropyl ester hydrochloride

Step 1: synthesis of compound L-alanine isopropyl ester hydrochloride

Boc-L-alanine (1g,5.29mmol), isopropanol (0.49mL,6.34mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.52g,7.93mmol) and N-hydroxy-7-azabenzotriazole (1.08g,7.93mmol) were dissolved in dichloromethane (20mL), N-diisopropylethylamine (3.7mL,21.14mmol) was added dropwise to this solution at 0 deg.C, stirred at room temperature for 16h, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 10/1) gave 630mg of colorless liquid isopropyl N-Boc-L-alaninate, yield: 51 percent.

¹H NMR(400MHz,CDCl₃):δppm 5.05–5.01(m,1H),4.24–4.21(m,1H),1.44(s,9H),1.34(d,J＝ 7.2Hz,3H),1.23(t,J＝6.6Hz,6H)；

MS-ESI:m/z 254.1[M+23]。

To a solution of the compound isopropyl N-Boc-L-alaninate (0.25g,1.08mmol) in dichloromethane (3mL) was added a solution of HCl in ethyl acetate (4M,8mL), stirred at room temperature for 5h, and the solvent was removed to give 181mg of a colorless oil, yield: 99 percent.

¹H NMR(400MHz,CD₃OD):δppm 5.06–5.00(m,1H),4.00–3.94(m,1H),1.45(d,J＝7.2Hz,3H),1.24–1.22(m,6H)；

MS-ESI:m/z 132.2[M+H-HCl]⁺。

Step 2: synthesis of the compound isopropyl (2S) -2- (2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide) -2- (2, 4-difluorophenyl) acetylamino) propionate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.23g,0.36mmol), L-alanine isopropyl ester hydrochloride (72mg,0.43mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (104mg,0.54mmol) and N-hydroxy-7-azabenzotriazole (74mg,0.54mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.25mL,1.44mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 12h to remove the solvent, the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give 118mg of a pale yellow solid, yield: and 43 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.65–7.62(m,1H),7.61–7.60(m,1H),7.52–7.48(m,1H),7.26(d,J＝8.2Hz,1H),6.95–6.90(m,2H),6.73(t,J_F-H＝74.5Hz,1H),6.53–6.52(m,1H),5.92(d,J＝7.2Hz,1H),5.33–5.29(m,1H),5.09–4.99(m,1H),4.57–4.49(m,1H),4.03(d,J＝6.9Hz,2H),1.53–1.50(m,3H),1.42–1.36(m,9H),1.28(t,J＝7.1Hz,6H),1.24–1.20(m,3H),0.74–0.69(m,2H),0.47–0.43(m,2H)；

MS-ESI:m/z 751.2[M+H]⁺。

And step 3: synthesis of the compound (2S) -isopropyl 2- (2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide) -2- (2, 4-difluorophenyl) acetylamino) propionate hydrochloride

To a solution of compound (2S) -2- (2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide) -2- (2, 4-difluorophenyl) acetylamino) propionic acid isopropyl ester (0.11g,0.15mmol) in dichloromethane (3mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 3h, and the solvent was removed to give 100mg of a pale yellow solid, yield: 97 percent.

Example 76: the compound 5- ((S) -1-aminoethyl) -N- (2- (4- (cyclopropylcarbonyl) piperazin-1-yl) -1- (2, 4-difluorophenyl) -2-oxoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid amide Synthesis of hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2- (4- (cyclopropylcarbonyl) piperazin-1-yl) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (210mg,0.33mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (126mg,0.66mmol) and N-hydroxy-7-azabenzotriazole (67mg,0.49mmol) were dissolved in dichloromethane (15mL), to this solution was added dropwise cyclopropyl (piperazin-1-yl) methanone hydrochloride (94mg,0.49mmol) and N, N-diisopropylethylamine (0.23mL,0.99mmol) at 0 ℃, stirred at room temperature for 12h, washed with water (10 mL. times.3), and the organic phase over anhydrous Na₂SO₄drying, removal of solvent, column separation of the concentrate (ethyl acetate/petroleum ether (v/v) ═ 2/1) afforded 160mg of a white solid in yield: and 63 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.51(d,J＝6.6Hz,1H),7.60–7.64(m,2H),7.52–7.57(m,1H),7.26(d,J＝8.3Hz,1H),6.88–6.95(m,2H),6.73(t,J_F-H＝75.1Hz,1H),6.32(d,J＝7.3Hz,1H),5.27–5.34(m,1H),4.02(d,J＝6.9Hz,2H),3.35–3.82(m,8H),1.67–1.74(m,1H),1.48–1.53(m,3H),1.40–1.45(m,9H),1.32–1.36(m,1H),0.86–0.93(m,2H),0.78–0.83(m,2H),0.69–0.73(m,2H),0.42–0.47(m,2H)；

MS-ESI:m/z 796.20[M+Na]⁺。

Step 2: synthesis of the compound 5- ((S) -1-aminoethyl) -N- (2- (4- (cyclopropylcarbonyl) piperazin-1-yl) -1- (2, 4-difluorophenyl) -2-oxoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (4- ((2- (4- (cyclopropylcarbonyl) piperazin-1-yl) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (85mg,0.11mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 30min, the solvent removed to give 75mg of a white solid, yield: 96 percent.

Compound 199:¹H NMR(400MHz,CD₃OD):δppm 7.77–7.79(m,1H),7.71–7.74(m,1H),7.61–7.55(m,1H),7.33(d,J＝8.3Hz,1H),7.08–7.14(m,2H),6.92(t,J_F-H＝75.1Hz,1H),6.31(s,1H),5.14–5.21(m,1H),4.04(d,J＝6.8Hz,2H),3.18–3.87(m,8H),1.89–2.00(m,1H),1.76(d,J＝6.8Hz,3H),1.34–1.39 (m,1H),0.81–0.91(m,4H),0.67–0.71(m,2H),0.42–0.46(m,2H)；

MS-ESI:m/z 674.20[M+H-HCl]⁺。

Example 77: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of yl) -N- (1- (2, 4-difluorophenyl) -2-hydrazino-2-oxoethyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-hydrazino-2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

To a solution of the compound methyl 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate (250mg,0.38mmol) in methanol (20mL) was added hydrazine hydrate (80%, 1mL) and reacted at 60 ℃ for 2.5h to give 240mg of a white solid after removal of the solvent, yield: 96 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.63–7.61(m,1H),7.60(s,1H),7.53–7.48(m,1H),7.26(d,J＝8.3Hz,1H),6.95–6.88(m,2H),6.74(t,J_F-H＝75.0Hz,1H),5.92(d,J＝7.6Hz,1H),5.35–5.30(m,1H),4.02–4.01(m,2H),1.54–1.47(m,3H),1.46–1.41(m,9H),1.37–1.34(m,1H),0.73–0.70(m,2H),0.46–0.40(m,2H)；

MS-ESI:m/z 552.2[M+H-100]⁺。

Step 2: synthesis of the Compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-hydrazino-2-oxoethyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-hydrazino-2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.24g,0.37mmol) in dichloromethane (4mL) was added a solution of HCl in isopropanol (7M,4mL), stirred at room temperature for 1.5h, the solvent was removed to afford 220mg of a light yellow solid, yield: 95 percent.

compound 202:¹H NMR(400MHz,CD₃OD):δppm 7.80–7.79(m,1H),7.75-7.72(m,1H),7.68–7.63(m,1H),7.33(d,J＝8.4Hz,1H),7.14–7.07(m,2H),6.92(t,J_F-H＝74.7Hz,1H),6.09–6.08(m,1H),5.24–5.19(m,1H),4.04(d,J＝6.9Hz,2H),1.79–1.76(m,3H),1.38–1.33(m,1H),0.71–0.66(m,2H),0.45–0.41(m,2H)；

MS-ESI:m/z 552.2[M+H-2HCl]⁺。

Example 78: the compound (S) -2- (5- (5- (5- ((S) -1-aminoethyl) -4- ((2, 4-difluorobenzyl) carbamic acid methyl) Synthesis of acyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanamide) propionic acid isopropyl ester hydrochloride

Step 1: synthesis of compound methyl 3- (benzyloxy) -4- (difluoromethoxy) benzoate

Methyl 3-hydroxy-4- (difluoromethoxy) benzoate (5.0g,22.94mmol), potassium carbonate (6.33g,45.88mmol) andBenzyl bromide (3.3mL,27.53mmol) was dissolved in N, N-dimethylformamide (60mL) and reacted at 60 ℃ for 4.5h, water (40mL) was added and extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and dried over anhydrous Na₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 6.99g of a white solid in yield: 99 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.75(s,1H),7.68(d,J＝8.2Hz,1H),7.48-7.38(m,5H),7.24(d,J＝8.3Hz,1H),6.67(t,J_F-H＝74.6Hz,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

the compound methyl 3- (benzyloxy) -4- (difluoromethoxy) benzoate (6.99g,22.69mmol) and sodium hydroxide (2.27g,56.74mmol) were dissolved in a mixed solvent of ethanol (60mL) and water (30mL), reacted at 60 ℃ for 1.5h, ethanol was removed, pH was adjusted to 1 with hydrochloric acid (1M), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and dried over anhydrous Na₂SO₄Drying and removal of the solvent gave 6.70g of a white solid in yield: 99 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.80(s,1H),7.68(d,J＝8.4Hz,1H),7.49(d,J＝7.0Hz,2H),7.43-7.35(m,3H),7.26(d,J＝8.4Hz,1H),6.88(t,J_F-H＝74.5Hz,1H),5.23(s,2H)；

MS-ESI:293.1[M-H]^-。

And step 3: synthesis of Compound methyl 2- (3- (benzyloxy) -4- (difluoromethoxy) benzoylamino) acetate

The compounds 3- (benzyloxy) -4- (difluoromethoxy) benzoic acid (6.70g,22.79mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.60g,34.19mmol) and 1-hydroxybenzotriazole (4.62g,34.19mmol) were dissolved in dichloromethane (60mL), stirred at ambient temperature for 0.5h, glycine methyl ester hydrochloride (3.44g,27.35mmol) and N, N-diisopropylethylamine (12.25mL,68.37mmol) were added at 0 deg.C, stirred at room temperature for 12h, washed with water (40 mL. times.3), the organic phase was Na₂SO₄Drying, removing solvent, and separating the concentrated solution with column (petroleum)Ether/ethyl acetate (v/v) ═ 1/1), 7.95g of white solid was obtained, yield: 96 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.62(s,1H),7.47-7.33(m,6H),7.24(d,J＝8.3Hz,1H),6.67(br.s,1H),6.65(t,J_F-H＝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]⁺。

And 4, step 4: synthesis of Compound methyl 2- (3- (benzyloxy) -4- (difluoromethoxy) phenylthioamide) acetate

the compound methyl 2- (3- (benzyloxy) -4- (difluoromethoxy) benzoylamino) acetate (7.95g,21.80mmol) and Lawson's reagent (8.80g,21.80mmol) were dissolved in tetrahydrofuran (60mL), stirred at 75 ℃ under reflux for 2h, saturated sodium bicarbonate solution (40mL) was added, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 8.33g of a yellow solid, yield: 99 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.08(br.s,1H),7.69(s,1H),7.50-7.28(m,6H),7.21(d,J＝8.3Hz,1H),6.64(t,J_F-H＝74.7Hz,1H),5.21(s,2H),4.57(d,J＝4.5Hz,2H),3.88(s,3H)；

MS-ESI:m/z 380.0[M-H]^-。

And 5: synthesis of compound methyl 2- (((3- (benzyloxy) -4- (difluoromethoxy) phenyl) (methylthio) methylene) amino) acetate

A solution of the compound methyl 2- (3- (benzyloxy) -4- (difluoromethoxy) phenylthioamide) acetate (8.33g,21.87mmol) in dichloromethane (30mL) was slowly added dropwise at-78 ℃ to a solution of trimethyloxonium tetrafluoroborate (6.47g,43.74mmol) in dichloromethane (20mL), stirring was continued at 0 ℃ for 3h, then a saturated sodium bicarbonate solution was added and the organic phase was washed (25 mL. times.3) with anhydrous Na₂SO₄Drying and removal of the solvent gave 8.55g of a yellow oil, yield: 99 percent.

MS-ESI:m/z 396.2[M+H]⁺。

step 6: synthesis of methyl (S) -2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) oxazole-4-carboxylate, a compound

Dissolving the compound methyl 2- (((3- (benzyloxy) -4- (difluoromethoxy) phenyl) (methylthio) methylene) amino) acetate (3.45g,8.74mmol), the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (4.45g,23.30mmol) in anhydrous tetrahydrofuran (30mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (30.00mL,30.00mmol) at-78 deg.C, reacting at-78 deg.C for 1h, quenching the reaction with ice water (20mL), extracting with ethyl acetate (15 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) afforded 3.78g of a yellow solid, yield: 83 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.80(s,1H),7.68(d,J＝8.4Hz,1H),7.50-7.36(m,5H),7.29(d,J＝8.3Hz,1H),6.66(t,J_F-H＝74.7Hz,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)。

And 7: synthesis of the Compound (S) -2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -5- (1- ((t-butoxycarbonyl) amino) ethyl) oxazole-4-carboxylic acid

The compound (S) -methyl 2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) oxazole-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) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, the pH was adjusted to 1 with hydrochloric acid (1M), ethyl acetate was added and extracted (30 mL. times.3), and the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 0.53mg of a white solid, yield: 99 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.80(s,1H),7.68(d,J＝8.4Hz,1H),7.51–7.35(m,5H),7.29(d,J ＝8.4Hz,1H),6.66(t,J_F-H＝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]。

And 8: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) oxazole-4-carboxylic acid (0.53g,1.05mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.31g,1.60mmol) and N-hydroxy-7-azabenzotriazole (0.22g,1.60mmol) were dissolved in dichloromethane (15mL), stirred at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.15mL,1.26mmol) and N, N-diisopropylethylamine (0.58mL,3.20mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, water (15mL) was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 211.0mg of a white solid in yield: 38 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.69(s,1H),7.63(d,J＝8.4Hz,1H),7.56(br.s,1H),7.50-7.36(m,6H),7.28(d,J＝8.3Hz,1H),6.92-6.85(m,2H),6.56(t,J_F-H＝74.6Hz,1H),5.32(br.s,1H),5.24(s,2H),4.73-4.63(m,2H),1.56(d,J＝7.0Hz,3H),1.45(s,9H)；

MS-ESI:m/z 574.1[M-55]⁺。

And step 9: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl (S) - (1- (2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (2.53g,4.02mmol) and nickel chloride (782mg,6.03mmol) were dissolved in ethanol (20mL), a solution of sodium borohydride (688mg,18.09mmol) in ethanol (20mL) was added, stirring was carried out at room temperature for 3h, the pH was adjusted to 1 with hydrochloric acid (1M) and then with sodium hydroxide, filtration was carried out to remove ethanol, extraction was carried out with ethyl acetate (20 mL. times.3), the organic phases were combined and then extracted with Na₂SO₄Drying, removal of solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) gave 1.719g of white solid, yield: 80 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60-7.57(m,2H),7.45-7.38(m,2H),7.16(d,J＝8.3Hz,1H),6.88-6.84(m,2H),6.65(t,J_F-H＝73.6Hz,1H),5.31(s,1H),4.69-4.59(m,2H),1.53(d,J＝7.0Hz,3H),1.44(s,9H)；

MS-ESI:540.3[M+H]⁺。

Step 10: synthesis of methyl 5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate, compound (S)

To a solution of tert-butyl (S) - (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate (560mg,1.04mmol) and methyl 5-bromovalerate (304mg,1.56mmol) in DMF (10mL) was added potassium carbonate (290mg,2.07mmol), the reaction was blocked at 60 ℃ for 5h, the solvent was removed, water (10mL) was added, ethyl acetate was extracted (15mL), and the organic phase was extracted with anhydrous Na₂SO₄The concentrate was dried and subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give 448mg of a colorless oil, yield: 66 percent.

Step 11: synthesis of compound (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid

To a mixed solvent of tetrahydrofuran (16mL) and water (8mL) of the compound methyl (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate (250mg,0.38mmol) was added lithium hydroxide monohydrate (80mg,1.91mmol), reacted at 40 ℃ for 2 hours, added hydrochloric acid solution (1M) to adjust pH to about 1, added ethyl acetate to extract (15 mL. times.3), and organic phase was Na anhydrous₂SO₄Dried and concentrated to give 240mg of a colorless oil, yield: 98 percent.

Step 12: synthesis of the Compound isopropyl (S) -2- (5- (5- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanamide) propionate

The compound (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazole-2-Phenyl) -2- (difluoromethoxy) phenoxy) pentanoic acid (0.25g,0.39mmol), the compound L-alanine isopropyl ester hydrochloride (80mg,0.47mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (112mg,0.59mmol) and N-hydroxy-7-azabenzotriazole (80mg,0.59mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.27mL,1.56mmol) was added dropwise to this solution at 0 deg.C, stirred at room temperature for 4h, washed with water (10 mL. times.3), the organic phase was washed with anhydrous Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) gave 235mg of a colorless oil, yield: 80 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60–7.58(m,2H),7.47-7.41(m,1H),7.24(d,J＝8.0Hz,1H),6.91–6.84(m,2H),6.65(t,J_F-H＝74.5Hz,1H),6.14–6.12(m,1H),5.09–5.03(m,1H),4.69–4.67(m,2H),4.58–4.54(m,1H),4.17–4.13(m,2H),2.36(t,J＝6.9Hz,2H),1.95–1.89(m,4H),1.56(d,J＝7.0Hz,3H),1.45(s,9H),1.40(d,J＝7.2Hz,3H),1.27(t,J＝5.8Hz,6H)；

MS-ESI:m/z 753.2[M+H]⁺。

Step 13: synthesis of the Compound isopropyl (S) -2- (5- (5- (5- ((S) -1-aminoethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanamide) propanoate hydrochloride

To a solution of the compound (S) -isopropyl 2- (5- (5- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanamide) propionate (0.22g,0.29mmol) in dichloromethane (3mL) was added a solution of HCl in isopropanol (4M,3mL), stirred at room temperature for 40min, and the solvent was removed to give 192mg of a white solid, yield: 94 percent.

Compound 198:¹H NMR(400MHz,CD₃OD):δppm 7.82(s,1H),7.73(d,J＝8.4Hz,1H),7.52–7.46(m,1H),7.33(d,J＝8.3Hz,1H),7.01–6.94(m,2H),6.89(t,J_F-H＝74.5Hz,1H),5.21–5.15(m,1H),5.01–4.95(m,1H),4.65(s,2H),4.36–4.30(m,1H),4.20(t,J＝6.0Hz,2H),2.38–2.34(m,2H),1.94–1.83(m,4H),1.78(d,J＝7.0Hz,3H),1.37(d,J＝7.3Hz,3H),1.24(t,J＝6.6Hz,6H)；

MS-ESI:m/z 653.3[M+H-HCl]⁺。

Example 79: the compound 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) Synthesis of phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) ethyl acetate hydrochloride

Step 1: synthesis of ethyl 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate, compound

The compound 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.25g,0.39mmol) and N, N' -carbonyldiimidazole (197mg,1.17mmol) were added to anhydrous tetrahydrofuran (20mL) and, after reaction at 60 ℃ for 0.5h, cooled to room temperature, anhydrous ethanol (22mg,0.47mmol) and 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (0.09mL,0.59mmol), reacted at 60 ℃ for 8h, saturated ammonium chloride solution (15mL) was added, extracted with ethyl acetate (10 mL. times.3), and the organic phase was added Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 4/1) afforded 200mg of a white solid, yield: 76 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.63(d,J＝8.3Hz,1H),7.59(s,1H),7.51–7.48(m,1H),7.26(d,J＝8.3Hz,1H),6.94–6.88(m,2H),6.73(t,J_F-H＝75.0Hz,1H),5.98–5.96(m,1H),5.32–5.30(m,1H),5.20–5.18(m,1H),4.56–4.54(m,1H),4.32–4.25(m,2H),4.02(d,J＝6.7Hz,2H),1.56–1.49(m,3H),1.46(s,9H),1.38–1.35(m,1H),1.28–1.27(m,3H),0.73–0.70(m,2H),0.46–0.45(m,2H)；

MS-ESI:m/z 566.2[M+H-100]⁺。

Step 2: synthesis of ethyl 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate hydrochloride

To a solution of the compound ethyl 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate (0.2g,0.30mmol) in dichloromethane (4mL) was added a solution of HCl in isopropanol (7M,2mL), stirred at room temperature for 40min, the solvent was removed to give 180mg of a white solid, yield: 99 percent.

Compound 207:¹H NMR(600MHz,CD₃OD):δppm 7.80(s,1H),7.74(d,J＝8.3Hz,1H),7.60–7.56(m,1H),7.33(d,J＝8.3Hz,1H),7.09–7.03(m,2H),6.92(t,J_F-H＝74.7Hz,1H),6.01(s,1H),5.20–5.18(m,1H),4.63–4.62(m,1H),4.28(q,J＝7.1Hz,2H),4.05(d,J＝6.9Hz,2H),1.76(d,J＝6.7Hz,3H),1.62(d,J＝7.2Hz,3H),1.36–1.34(m,1H),1.25(t,J＝7.2Hz,3H),0.70–0.67(m,2H),0.45–0.43(m,2H)；

MS-ESI:m/z 566.2[M+H-HCl]⁺。

Example 80: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Yl) -N- ((S) -1- (2, 4-difluorophenyl) -2-hydrazino-2-oxoethyl) oxazole-4-carboxamide dihydrochloride and 5- ((S) - 1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2- Synthesis of hydrazino-2-oxoethyl) oxazole-4-carboxamide dihydrochloride

the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-hydrazino-2-oxoethyl) oxazole-4-carboxamide dihydrochloride from example 77 was resolved by chiral preparative chromatography to give the compounds 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2-hydrazino-2-oxoethyl) oxazole-4-carboxamide dihydrochloride (white solid) and 5- ((S) -1- Aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2-hydrazino-2-oxoethyl) oxazole-4-carboxamide dihydrochloride (as a pale yellow solid).

Compound 208:¹H NMR(600MHz,CD₃OD):δppm 7.79(s,1H),7.73(d,J＝8.3Hz,1H),7.66–7.62(m,1H),7.34(d,J＝8.3Hz,1H),7.13–7.08(m,2H),6.92(t,J_F-H＝74.7Hz,1H),6.08(s,1H),5.25–5.23(m,1H),4.03(d,J＝6.9Hz,2H),1.76(d,J＝7.0Hz,3H),1.36–1.33(m,1H),0.71–0.68(m,2H),0.44–0.42(m,2H)；

MS-ESI:m/z 552.2[M+H-2HCl]⁺；

Compound 209:¹H NMR(600MHz,CD₃OD):δppm 7.79(s,1H),7.73(d,J＝8.3Hz,1H),7.67–7.63(m,1H),7.33(d,J＝8.3Hz,1H),7.13–7.08(m,2H),6.92(t,J_F-H＝74.7Hz,1H),6.07(s,1H),5.21–5.17(m,1H),4.03(d,J＝6.9Hz,2H),1.76(d,J＝6.8Hz,3H),1.35–1.31(m,1H),0.70–0.67(m,2H),0.44–0.42(m,2H)；

MS-ESI:m/z 552.2[M+H-2HCl]⁺。

Example 81: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (1- (2, 4-difluorophenyl) -2- (methoxyamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.25g,0.39mmol), methoxyamine hydrochloride (40mg,0.47mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (112mg,0.59mmol) and N-hydroxy-7-azabenzotriazole (80mg,0.59mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.27mL,1.57mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 15 hours, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1), 130mg of a colorless oil are obtained, yield: 49 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.63–7.60(m,2H),7.56–7.55(m,1H),7.26(d,J＝8.2Hz,1H),6.96–6.88(m,2H),6.74(t,J_F-H＝75.0Hz,1H),5.87–5.84(m,1H),5.36–5.31(m,1H),4.02(d,J＝6.8Hz,2H),3.81(s,3H),1.54–1.49(m,3H),1.45–1.41(m,9H),1.36–1.33(m,1H),0.73–0.70(m,2H),0.45–0.44(m,2H)；

MS-ESI:m/z 567.1[M+H-100]⁺。

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (methoxyamino) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.13g,0.19mmol) in dichloromethane (3mL) was added a solution of HCl in isopropanol (7M,2mL), stirred at room temperature for 30min, and the solvent was removed to give 110mg of a pale yellow solid, yield: 95%, sent to preparation for further purification, to yield 80mg of a white solid.

Compound 211:¹H NMR(400MHz,CD₃OD):δppm 7.79(s,1H),7.73(d,J＝8.3Hz,1H),7.63–7.61(m,1H),7.34(d,J＝8.3Hz,1H),7.07–7.03(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.87–5.86(m,1H),5.20–5.17(m,1H),4.04(d,J＝6.8Hz,2H),3.72(s,3H),1.77–1.75(m,3H),1.36–1.31(m,1H),0.70–0.67(m,2H),0.44–0.43(m,2H)；

MS-ESI:m/z 567.2[M+H-HCl]⁺。

Example 82: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (1- (2, 4-difluorophenyl) -2- (2-isopropylhydrazine) -2-oxoethyl) oxazole-4-carboxamide dihydrochloride

step 1: synthesis of Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (2-isopropylhydrazine) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.25g,0.39mmol), isopropylhydrazine hydrochloride (59mg,0.47mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (112mg,0.59mmol) and N-hydroxy-7-azabenzotriazole (80mg,0.59mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.27mL,1.57mmol) was added dropwise to the solution at 0 ℃, stirred at room temperature for 20 hours, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1), 148mg of a colorless oil are obtained, yield: 54 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.63(d,J＝8.3Hz,1H),7.60(s,1H),7.55–7.51(m,1H),7.26(d,J＝8.3Hz,1H),6.96–6.90(m,2H),6.74(t,J_F-H＝75.0Hz,1H),5.89(d,J＝7.4Hz,1H),5.34–5.31(m,1H),4.02(d,J＝6.7Hz,2H),1.53–1.49(m,3H),1.45–1.41(m,9H),1.35-1.38(m,1H),1.04(d,J＝5.9Hz,3H),0.99(d,J＝6.2Hz,3H),0.73–0.70(m,2H),0.46–0.43(m,2H)；

MS-ESI:m/z 694.2[M+H]⁺。

Step 2: synthesis of the Compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (2-isopropylhydrazine) -2-oxoethyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (2-isopropylhydrazine) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.14g,0.21mmol) in dichloromethane (3mL) was added a solution of HCl in isopropanol (7M,2mL), stirred at room temperature for 40min, the solvent was removed to give 120mg of a white solid, yield: 92% to preparative further purification to yield 63mg of a white solid.

Compound 212:¹H NMR(400MHz,CD₃OD):δppm 7.79(s,1H),7.74–7.66(m,2H),7.33(d,J＝8.0Hz,1H),7.13–7.10(m,2H),6.91(t,J_F-H＝74.7Hz,1H),6.06–6.05(m,1H),5.21–5.18(m,1H),4.03(d,J＝6.6Hz,2H),3.70–3.67(m,1H),1.78–1.76(m,3H),1.35–1.33(m,1H),1.33–1.30(m,6H),0.69–0.67(m,2H),0.43–0.42(m,2H)；

MS-ESI:m/z 594.3[M+H-2HCl]⁺。

Example 83: the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopropylsulfonamide) -1- (2, 4-difluorophenyl) -2- Synthesis of oxoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2- (cyclopropylsulfonamide) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.3g,0.47mmol) and N, N' -carbonyldiimidazole (236mg,1.41mmol) were added to anhydrous tetrahydrofuran (15mL), reacted at 60 ℃ for 0.5h, cooled to room temperature, cyclopropanesulfonamide (114mg,0.94mmol) and 1, 8-diazabicyclo [5.4.0 ] were added]undec-7-ene (0.11mL,0.71mmol), reacted at 60 ℃ for 15h, added with saturated ammonium chloride solution (15mL), extracted with ethyl acetate (10 mL. times.3), and the organic phase added with Na₂SO₄Drying and removal of the solvent gave 340mg of a yellow oil, yield: 97 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.61–7.58(m,2H),7.53–7.50(m,1H),7.30(d,J＝8.3Hz,1H),7.25–7.21(m,2H),6.80–6.78(m,1H),6.85–6.59(m,1H),5.73–5.72(m,1H),5.37–5.36(m,1H),4.03–3.98(m,2H),2.61–2.58(m,1H),1.50(d,J＝6.9Hz,3H),1.42–1.39(m,9H),1.33–1.30(m,1H),1.21–1.19(m,2H),1.15–1.13(m,1H),1.05–1.03(m,2H),0.70–0.66(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 641.1[M+H-100]⁺。

Step 2: synthesis of the compound 5- ((S) -1-aminoethyl) -N- (2- (cyclopropylsulfonamide) -1- (2, 4-difluorophenyl) -2-oxoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound tert-butyl ((1S) -1- (4- ((2- (cyclopropylsulfonamide) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.34g,0.46mmol) in dichloromethane (4mL) was added a solution of HCl in isopropanol (7M,3mL), stirred at room temperature for 1.5h, solvent removed to give 310mg of oil, yield: 99% to prepare and purify to obtain 100mg of white solid.

Compound 214:¹H NMR(600MHz,CD₃OD):δppm 7.78(s,1H),7.72(d,J＝8.3Hz,1H),7.59–7.55(m,1H),7.32(d,J＝8.3Hz,1H),7.12–7.08(m,2H),6.91(t,J_F-H＝74.7Hz,1H),5.97(d,J＝7.0Hz,1H),5.23–5.19(m,1H),4.02(d,J＝6.8Hz,2H),3.03–2.99(m,1H),1.77(d,J＝6.7Hz,3H),1.35–1.32(m,1H),1.30–1.29(m,2H),1.23–1.19(m,1H),1.18–1.14(m,2H),0.69–0.66(m,2H),0.42–0.41(m,2H)；

MS-ESI:m/z 641.1[M+H-HCl]⁺。

Example 84: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene synthesis of phenyl-N- (1- (2, 4-difluorophenyl) -2-ureidoethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-ureidoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (200mg,0.32mmol) and triethylamine (0.44mL,3.2mmol) were dissolved in anhydrous tetrahydrofuran (10mL), to this solution was added dropwise trimethylsilyl isocyanate (0.43mL,3.2mmol), stirred at room temperature for 2h, added ice water (5mL), extracted with ethyl acetate (10mL × 3), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column separation (dichloromethane/methanol (v/v) ═ 40/1) to give 90mg of a white solid, yield: 42 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.75–7.78(m,1H),7.69–7.71(m,1H),7.50–7.54(m,1H),7.30(d,J＝8.3Hz,1H),6.98–7.03(m,2H),6.90(t,J_F-H＝75.0Hz,1H),5.36–5.45(m,2H),4.03–4.06(m,2H),3.58–3.72(m,2H),1.47–1.50(m,3H),1.42(s,9H),1.31–1.37(m,1H),0.68–0.71(m,2H),0.43–0.46(m,2H)；

MS-ESI:m/z 666.20[M+H]⁺。

Step 2: synthesis of compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-ureidoethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-ureidoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (190mg,0.31mmol) in dichloromethane (4mL) was added an ethyl acetate solution of HCl (3.7M,2mL), stirred at room temperature for 30min, the solvent was removed to give 170mg of a white solid, yield: 99 percent.

Compound 215:¹H NMR(600MHz,CD₃OD):δppm 7.84(s,1H),7.77–7.79(m,1H),7.49–7.53(m,1H),7.33–7.35(m,1H),6.98–7.02(m,2H),6.93(t,J_F-H＝75.1Hz,1H),5.45–5.48(m,1H),5.09–5.16(m,1H),4.08(d,J＝6.8Hz,2H),3.58–3.68(m,2H),1.73–1.75(m,3H),1.35–1.39(m,1H),0.68–0.71(m,2H),0.44–0.47(m,2H)；

MS-ESI:m/z 566.20[M+H-HCl]⁺。

Example 85: the compound (2S) -2- (2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (bis) Fluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetamido) propionic acid methyl esterSynthesis of ester hydrochloride

Step 1: synthesis of methyl (2S) -2- (2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetylamino) propanoate, compound

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (230mg,0.36mmol), alanine methyl ester hydrochloride (75mg,0.54mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (138mg,0.72mmol) and N-hydroxy-7-azabenzotriazole (74mg,0.54mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.19mL,1.08mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 12 hours, followed by washing with water (10 mL. times.3), anhydrous Na for organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (ethyl acetate/petroleum ether (v/v) ═ 8/1) afforded 190mg of a white solid in yield: 79 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.30–8.35(m,1H),7.60–7.64(m,2H),7.47–7.53(m,1H),7.26(d,J＝8.3Hz,1H),6.89–6.93(m,2H),6.73(t,J_F-H＝74.9Hz,1H),5.93(d,J＝7.3Hz,1H),5.28–5.34(m,1H),4.57–4.63(m,1H),4.02(d,J＝6.9Hz,2H),3.78(s,1.5H),3.72(s,1.5H),1.77(s,3H),1.46–1.53(m,3H),1.39–1.44(m,9H),1.27–1.35(m,1H),0.69–0.73(m,2H),0.43–0.47(m,2H)；

MS-ESI:m/z 723.15[M+H]⁺。

Step 2: synthesis of compound methyl (2S) -2- (2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetylamino) propionate hydrochloride

To a solution of the compound methyl (2S) -2- (2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetylamino) propanoate (190mg,0.26mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 30min, the solvent was removed to give 170mg of a white solid, yield: 98 percent.

Compound 217:¹H NMR(600MHz,CD₃OD):δppm 7.77–7.78(m,1H),7.70–7.73(m,1H),7.59–7.64(m,1H),7.32–7.34(m,1H),7.03–7.06(m,2H),6.92(td,J＝74.8,3.4Hz,1H),5.99(d,J＝1.8Hz,1H),5.16–5.21(m,1H),4.45–4.51(m,1H),4.02–4.04(m,2H),3.75(s,1.5H),3.69(s,1.5H),1.78(d,J＝6.8Hz,3H),1.38(dd,J₁＝23.3Hz,J₂＝7.3Hz,3H),1.32–1.35(m,1H),0.67–0.70(m,2H),0.41–0.45(m,2H)；

MS-ESI:m/z 623.20[M+H-HCl]⁺。

Example 86: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Yl) -N- (1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) oxazole-4-carboxamide hydrochloride, 5- ((S) -1- aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2- (methyl) Sulfonamide) -2-oxoethyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) - 4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) oxazole-4-methyl Synthesis of amide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.25g,0.39mmol), N, N' -carbonyldiimidazole (197mg,1.17mmol) were added to anhydrous tetrahydrofuran (10mL), reacted at 60 ℃ for 0.5h, cooled to room temperature, and methylsulfonyl was addedAmine (75mg,0.78mmol), 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (0.09mL,0.59mmol), anhydrous tetrahydrofuran (8mL), reacted at 60 ℃ for 10h, saturated ammonium chloride solution (15mL) was added, extraction was performed with ethyl acetate (10 mL. times.3), and Na was added to the organic phase₂SO₄Drying and removal of the solvent gave 280mg of a white solid, yield: 99 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.59–7.57(m,1H),7.53–7.51(m,1H),7.24–7.21(m,1H),7.20(s,1H),6.75(br.s,1H),6.85–6.59(m,1H),5.74–5.73(m,1H),4.00–3.97(m,2H),3.11–3.00(m,3H),1.45(d,J＝6.0Hz,3H),1.43–1.39(m,9H),1.33–1.30(m,1H),0.70–0.65(m,2H),0.42–0.36(m,2H)；

MS-ESI:m/z 615.1[M-100+H]⁺。

Step 2: the compounds 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) oxazole-4-carboxamide hydrochloride, 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy-methoxy-4-carboxamide hydrochloride ) Synthesis of (E) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.32g,0.45mmol) in dichloromethane (4mL) was added a solution of HCl in isopropanol (7M,3mL), stirred at room temperature for 1h, and the solvent was removed to give the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) oxazole -4-carboxamide hydrochloride salt: white solid 291mg, yield: 99 percent.

The compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) oxazole-4-carboxamide hydrochloride was submitted to preparative chromatographic resolution to give the compounds 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) oxazole-4-carboxamide hydrochloride (65 mg as a pale yellow solid) and 5- ((S) -1-aminoethyl) Ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2- (methanesulfonamide) -2-oxoethyl) oxazole-4-carboxamide hydrochloride (70 mg of white solid).

Compound 219:¹H NMR(400MHz,CD₃OD):δppm 7.78(s,1H),7.72(d,J＝8.4Hz,1H),7.58–7.52(m,1H),7.32(d,J＝8.3Hz,1H),7.12–7.06(m,2H),6.91(t,J_F-H＝75.0Hz,1H),5.97(s,1H),5.23–5.21(m,1H),4.01(d,J＝6.9Hz,2H),1.78(d,J＝6.9Hz,3H),1.35–1.32(m,1H),0.70–0.65(m,2H),0.43–0.40(m,2H)；

MS-ESI:m/z 615.2[M+H-HCl]⁺；

Compound 220:¹H NMR(400MHz,CD₃OD):δppm 7.78(d,J＝1.7Hz,1H),7.72(dd,J₁＝8.3Hz,J₂＝1.8Hz,1H),7.58–7.52(m,1H),7.33(d,J＝8.4Hz,1H),7.13–7.06(m,2H),6.91(t,J_F-H＝75.0Hz,1H),5.96(s,1H),5.23–5.18(m,1H),4.01(d,J＝6.9Hz,2H),1.77(d,J＝7.0Hz,3H),1.36–1.32(m,1H),0.70–0.65(m,2H),0.43–0.39(m,2H)；

MS-ESI:m/z 615.1[M+H-HCl]⁺。

Example 87: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (1- (2, 4-difluorophenyl) -2- (3-methylurea) ethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (3-methylureido) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

Triethylamine (39mg,0.39mmol) and N, N' -Carbonyldiimidazole (CDI) (78mg,0.48mmol) were dissolved in anhydrous DMF (2mL), a solution of the compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (200mg,0.32mmol) in anhydrous DMF (3mL) was added, after stirring at room temperature for 30min, methylamine hydrochloride (26mg,0.38mmol) was added, the reaction was stopped after 1h at 60 ℃, the solvent DMF was removed, water (5mL) was added, ethyl acetate was extracted (10 mL. times.3), anhydrous sodium sulfate was dried, the solvent was removed, the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 1/1), 100mg of white solid are obtained, yield: 46 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60–7.64(m,2H),7.38–7.44(m,1H),7.24–7.26(m,1H),6.87–6.92(m,2H),6.73(t,J_F-H＝75.0Hz,1H),5.35–5.46(m,2H),4.00–4.03(m,2H),3.70–3.77(m,1H),3.59–3.64(m,1H),2.77(d,J＝4.7Hz,3H),1.49–1.54(m,3H),1.41–1.45(m,9H),1.32–1.36(m,1H),0.69–0.73(m,2H),0.41–0.45(m,2H)；

MS-ESI:m/z 680.20[M+H]⁺。

Step 2: synthesis of compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2- (3-methylureido) ethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (3-methylureido) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (95mg,0.14mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,2mL), stirred at room temperature for 30min, the solvent was removed to give 85mg of a white solid, yield: 99 percent.

Compound 221:¹H NMR(600MHz,CD₃OD):δppm 7.86(s,1H),7.77(d,J＝8.2Hz,1H),7.46–7.50(m,1H),7.34(d,J＝8.2Hz,1H),6.96–7.01(m,2H),6.93(t,J_F-H＝74.8Hz,1H),5.41–5.44(m,1H),5.08–5.13(m,1H),4.08(d,J＝6.8Hz,2H),3.59–3.66(m,2H),2.71(s,3H),1.73–1.75(m,3H),1.34–1.39(m,1H),0.68–0.71(m,2H),0.43–0.46(m,2H)；

MS-ESI:m/z 580.20[M+H-HCl]⁺。

Examples88: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl) -N- (2- (3- (cyclopropylmethyl) ureido) -1- (2, 4-difluorophenyl) ethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2- (3- (cyclopropylmethyl) ureido) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

Triethylamine (0.1mL,0.72mmol) and N, N' -Carbonyldiimidazole (CDI) (120mg,0.72mmol) were dissolved in anhydrous DMF (2mL), a solution of the compound ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (300mg,0.48mmol) in anhydrous DMF (3mL) was added, cyclopropylmethylamine (52mg,0.72mmol) was added after stirring at room temperature for 30min, the reaction was stopped after 1h at 60 ℃, the solvent DMF was removed, water (5mL) was added, ethyl acetate was extracted (10 mL. times.3), anhydrous sodium sulfate was dried, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 1/1), 170mg of white solid are obtained, yield: 49 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.63–7.66(m,2H),7.38–7.44(m,1H),7.26(d,J＝8.8Hz,1H),6.81–6.89(m,2H),6.92(t,J_F-H＝75.1Hz,1H),5.26–5.46(m,2H),4.02–4.04(m,2H),3.70–3.77(m,1H), 3.59–3.64(m,1H),3.01–3.10(m,2H),1.49–1.54(m,3H),1.40–1.45(m,9H),1.31–1.38(m,2H),0.69–0.73(m,2H),0.40–0.43(m,4H),0.14–0.17(m,2H)。

Step 2: synthesis of compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2- (3- (cyclopropylmethyl) ureido) -1- (2, 4-difluorophenyl) ethyl) oxazole-4-carboxamide hydrochloride

to a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2- (3- (cyclopropylmethyl) ureido) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (165mg,0.27mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,2mL), stirred at room temperature for 30min, and the solvent was removed to give 150mg of a white solid, yield: 97 percent.

Compound 222:¹H NMR(600MHz,CD₃OD):δppm 7.86(s,1H),7.77(d,J＝8.2Hz,1H),7.46–7.50(m,1H),7.34(d,J＝8.2Hz,1H),6.96–7.01(m,2H),6.93(t,J_F-H＝75.1Hz,1H),5.40–5.43(m,1H),5.10–5.16(m,1H),4.08(d,J＝6.8Hz,2H),3.58–3.68(m,2H),2.96–3.06(m,2H),1.74(d,J＝6.5Hz,3H),1.33–1.40(m,2H),0.68–0.71(m,2H),0.44–0.47(m,2H),0.37–0.43(m,2H),0.13–0.17(m,2H)；

MS-ESI:m/z 620.20[M+H-HCl]⁺。

Example 89: the compound N- (2- ((2-amino-2-oxoethyl) amino) -1- (2, 4-difluorophenyl) -2-oxo Ethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide salt Synthesis of acid salts

Step 1: synthesis of the compound methyl 2- (2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide) -2- (2, 4-difluorophenyl) acetamide) acetate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.25g,0.39mmol), glycine methyl ester hydrochloride (60mg,0.47mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (113mg,0.59mmol) and N-hydroxy-7-azabenzotriazole (80mg,0.59mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.27mL,1.57mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 16h, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1) To yield 187mg of a colorless oil, yield: 67%.

¹H NMR(400MHz,CDCl₃):δppm 7.64–7.61(m,2H),7.53–7.51(m,1H),7.26(d,J＝8.6Hz,1H), 6.94–6.91(m,2H),6.74(t,J_F-H＝71.6Hz,1H),6.48–6.45(m,1H),5.98–5.96(m,1H),5.32–5.30(m,1H),4.12–4.08(m,2H),4.03(d,J＝6.8Hz,2H),3.77(s,3H),1.54–1.48(m,3H),1.44–1.38(m,9H),1.35–1.32(m,1H),0.74–0.71(m,2H),0.46–0.44(m,2H)；

MS-ESI:m/z 609.2[M+H-100]⁺。

Step 2: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2- ((2-amino-2-oxoethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

To a solution of the compound methyl 2- (2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide) -2- (2, 4-difluorophenyl) acetamide) acetate (0.25g,0.35mmol) in dry methanol (7mL) was added a methanol solution of ammonia (7M,8mL), the reaction was sealed at 75 ℃ for 5h, the solvent was removed, and the concentrate was subjected to column separation (dichloromethane/methanol (v/v) ═ 20/1) to give 170mg of a pale yellow solid, yield: and 69 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.59–7.57(m,1H),7.56(s,1H),7.50–7.46(m,1H),7.24(d,J＝8.2Hz,1H),6.93–6.89(m,1H),6.86–6.83(m,1H),6.72(t,J_F-H＝75.0Hz,1H),6.41–6.39(m,1H),5.89(t,J＝7.4Hz,1H),5.65–5.63(m,1H),5.41–5.39(m,1H),4.04–3.97(m,2H),3.95–3.93(m,2H),1.56–1.51(m,3H),1.46–1.41(m,9H),1.34–1.31(m,1H),0.70–0.69(m,2H),0.41–0.40(m,2H)；

MS-ESI:m/z 594.1[M+H-100]⁺。

And step 3: synthesis of the compound N- (2- ((2-amino-2-oxoethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a mixed solution of the compound tert-butyl ((1S) -1- (4- ((2- ((2-amino-2-oxoethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.16g,0.24mmol) in dichloromethane (4mL) and methanol (4mL) was added a solution of HCl in isopropanol (7M,3mL), stirred at room temperature for 2h, the solvent was removed to give 148mg of a white solid, yield: 97% to preparative further purification to yield 60mg of a white solid.

Compound 223:¹H NMR(600MHz,CD₃OD):δppm 7.79–7.78(m,1H),7.73–7.71(m,1H),7.65–7.62(m,1H),7.33(d,J＝8.3Hz,1H),7.07–7.03(m,2H),6.92(t,J_F-H＝74.7Hz,1H),6.01(s,1H),5.20–5.17(m,1H),4.04–3.99(m,3H),3.85–3.82(m,1H),1.76(d,J＝7.0Hz,3H),1.36–1.33(m,1H),0.70–0.67(m,2H),0.44–0.41(m,2H)；

MS-ESI:m/z 594.2[M+H-HCl]⁺。

Example 90: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of yl) -N- (quinolin-2-ylmethyl) oxazole-4-carboxamide dihydrochloride

And 7: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((quinolin-2-ylmethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (0.3g,0.64mmol), 2-quinolinemethylamine (121mg,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), N-diisopropylethylamine (0.45mL,2.56mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 16 hours, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 3/1), 366mg of white solid are obtained, yield: 94 percent.

¹H NMR(600MHz,CDCl₃):δppm 8.20(d,J＝8.4Hz,1H),8.13(d,J＝8.5Hz,1H),7.86(d,J＝8.0Hz,1H),7.79–7.76(m,1H),7.66–7.65(m,2H),7.59(t,J＝7.4Hz,1H),7.48(d,J＝8.4Hz,1H),7.28(d,J＝8.6Hz,2H),7.12–7.11(m,1H),6.74(t,J_F-H＝75.0Hz,1H),5.34–5.30(m,1H),4.98–4.97(m,2H),4.03(d,J＝7.0Hz,2H),1.58(d,J＝7.0Hz,3H),1.46(s,9H),1.41–1.37(m,1H),0.74–0.71(m,2H),0.46–0.44(m,2H)；

MS-ESI:m/z 609.3[M+H]⁺。

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (quinolin-2-ylmethyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((quinolin-2-ylmethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.36g,0.59mmol) in dichloromethane (8mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 40min, the solvent was removed to give 77mg of a white solid, yield: 24 percent.

Compound 225:¹H NMR(600MHz,CD₃OD):δppm 9.15(d,J＝8.5Hz,1H),8.37–8.35(m,2H),8.22(t,J＝7.7Hz,1H),8.11(d,J＝8.5Hz,1H),8.00(t,J＝7.6Hz,1H),7.84(s,1H),7.77(d,J＝8.3Hz,1H),7.35(d,J＝8.3Hz,1H),6.93(t,J_F-H＝74.7Hz,1H),5.20–5.19(m,2H),4.05(d,J＝6.8Hz,2H),1.77(d,J＝6.8Hz,3H),1.37–1.34(m,1H),0.71–0.68(m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 509.2[M+H-2HCl]⁺。

Example 91: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Phenyl) -N- (1- (2, 4-difluorophenyl) -2-oxo-2- (aminosulfonylamino) ethyl) oxazole-4-carboxamide hydrochloride, 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorobenzene) Yl) -2-oxo-2- (aminosulfonylamino) ethyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2-oxo-2- (aminosulfonyl) Synthesis of amino) ethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-oxo-2- (sulfamoylamino) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.25g,0.39mmol) and N, N' -carbonyldiimidazole (197mg,1.17mmol) were added to anhydrous tetrahydrofuran (20mL), reacted at 60 ℃ for 0.5h, cooled to room temperature, and then sulfonamide (151mg,1.57mmol), 1, 8-diazabicyclo [5.4.0 ] was added]Undec-7-ene (0.09mL,0.59mmol), reacted at 60 ℃ for 15h, after addition of saturated ammonium chloride solution (15mL), extracted with ethyl acetate (10 mL. times.3), and the organic phase added Na₂SO₄Drying, removal of the solvent and column separation of the concentrate (dichloromethane/methanol (v/v) ═ 40/1) gave 212mg of a colorless oil, yield: 75 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.54-7.60(m,3H),7.23(d,J＝8.3Hz,1H),6.91(s,1H),6.80-6.85(m,1H),6.72(t,J_F-H＝74.7Hz,1H),6.00(s,1H),5.32(s,1H),3.93-4.00(m,2H),1.51-1.57(m,3H),1.32-1.35(m,1H),1.26-1.30(m,9H),0.67-0.72(m,2H),0.41-0.43(m,2H)；

MS-ESI:m/z 616.0[M+H-100]⁺。

Step 2: the compounds 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-oxo-2- (aminosulfonylamino) ethyl) oxazole-4-carboxamide hydrochloride, 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2-oxo-2- (aminosulfonylamino) ethyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) Synthesis of methoxymethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2-oxo-2- (aminosulfonylamino) ethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-oxo-2- (sulfamoylamino) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.20g,0.27mmol) in dichloromethane (4mL) was added a solution of HCl in isopropanol (7M,3mL), stirred at room temperature for 3h, and the solvent was removed to give 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-oxo-2- (sulfamoylamino) ethyl) oxazole -4-carboxamide hydrochloride salt: oil 167mg, yield: 93 percent.

The compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-oxo-2- (aminosulfonylamino) ethyl) oxazole-4-carboxamide hydrochloride was submitted to preparative resolution to give the compounds 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2-oxo-2- (aminosulfonylamino) ethyl) oxazole-4-carboxamide hydrochloride (54 mg as a white solid) and 5- ((S) -1- Aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2-oxo-2- (sulfamoylamino) ethyl) oxazole-4-carboxamide hydrochloride (55 mg of white solid).

Compound 226:¹H NMR(600MHz,CD₃OD):δppm 7.78(s,1H),7.71(d,J＝8.3Hz,1H),7.56-7.59(m,1H),7.32(d,J＝8.3Hz,1H),7.05-7.09(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.96(s,1H),5.20-5.22(m,1H),4.01(d,J＝6.9Hz,2H),1.77(d,J＝7.0Hz,3H),1.33-1.35(m,1H),0.66-0.69(m,2H),0.41-0.43(m,2H)；

MS-ESI:m/z 616.1[M+H-HCl]⁺；

Compound 227:¹H NMR(600MHz,CD₃OD):δppm 7.78(s,1H),7.71(d,J＝8.3Hz,1H),7.56-7.58(m,1H),7.33(d,J＝8.3Hz,1H),7.05-7.10(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.95(s,1H),5.19-5.20(m,1H),4.01(d,J＝7.0Hz,2H),1.77(d,J＝7.0Hz,3H),1.33-1.36(m,1H),0.66-0.70(m,2H),0.40-0.43(m,2H)；

MS-ESI:m/z 616.1[M+H-HCl]⁺。

Example 92: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy)) -4- (difluoromethoxy) benzene Yl) -N- ((S) -1- (2, 4-difluorophenyl) -2- (hydroxyamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorobenzene) Synthesis of yl) -2- (hydroxyamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (hydroxyamino) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

Adding potassium hydroxide (52mg,0.92mmol) to a solution of hydroxylamine hydrochloride (43mg,0.61mmol) in methanol (20mL) to react at 40 ℃ for 0.5h, stopping the reaction, adding the compound methyl 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate (200mg,0.31mmol) to the mixture under ice bath, reacting at 65 ℃ for 4h, filtering, removing the solvent from the filtrate, adding hydrochloric acid (1M) to adjust the pH to about 2, adding ethyl acetate to extract (10 mL. times.3), and using anhydrous Na as the organic phase₂SO₄Drying and removal of the solvent gave 180mg of a yellow solid, yield: 89 percent.

¹H NMR(600MHz,d₆-DMSO):δppm 7.67–7.62(m,2H),7.60–7.57(m,1H),7.40–7.37(m,1H),7.31–7.27(m,1H),7.22(t,J_F-H＝74.0Hz,1H),7.13–7.09(m,1H),5.36–5.30(m,1H),4.01–3.98(m,2H),1.42–1.35(m,9H),1.30–1.28(m,1H),0.62–0.60(m,2H),0.41–0.39(m,2H)；

MS-ESI:m/z 553.2[M+H-100]⁺。

Step 2: synthesis of the compounds 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2- (hydroxyamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2- (hydroxyamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride.

To a solution of compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2- (hydroxyamino) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.24g,0.36mmol) in dichloromethane (4mL) was added a solution of HCl in isopropanol (7M,3mL), stirred at room temperature for 1.5h, the solvent was removed to give 216mg of a yellow solid, yield: 99% to preparative chromatography gave the compounds 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2- (hydroxyamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride (50mg, white solid) and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2- (hydroxyamino) -2-oxoethyl) oxazole-4-carboxamide hydrochloride (90mg, a yellow solid).

Compound 229:¹H NMR(600MHz,CD₃OD):δppm 7.79(s,1H),7.72(d,J＝8.0Hz,1H),7.64–7.62(m,1H),7.33(d,J＝8.3Hz,1H),7.07–7.02(m,2H),6.92(t,J_F-H＝74.7Hz,1H),5.90(s,1H),5.20–5.19(m,1H),4.03(d,J＝6.9Hz,2H),1.76(d,J＝6.7Hz,3H),1.36–1.33(m,1H),0.70–0.67(m,2H),0.45–0.41(m,2H)；

MS-ESI:m/z 553.1[M+H-HCl]⁺；

Compound 230: MS-ESI: M/z 553.1[ M + H-HCl ]]⁺。

Example 93: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (1- (2, 4-difluorophenyl) -2-oxo-2-ureidoethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-oxo-2-ureidoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

Reacting the compound 2- (5- ((S) -1- ((tert-butyloxycarbonyl)Yl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.25g,0.39mmol), N, N-carbonyldiimidazole (197mg,1.17mmol) were added to anhydrous tetrahydrofuran (20mL), reacted at 60 ℃ for 0.5h, cooled to room temperature, added urea (94mg,1.57mmol) and 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (0.09mL,0.59mmol), reacted at 60 ℃ for 24h, after addition of saturated ammonium chloride solution (15mL), extracted with ethyl acetate (10 mL. times.3), and the organic phase added Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 80mg of a yellow solid, yield: 30 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.26–8.21(m,1H),7.67(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.61(d,J＝1.9Hz,1H),7.31(d,J＝8.3Hz,1H),7.14–7.09(m,1H),7.04–6.98(m,1H),6.75(t,J_F-H＝74.9Hz,1H),5.38–5.34(m,1H),4.03(d,J＝7.0Hz,2H),1.60(d,J＝7.2Hz,3H),1.44(s,9H),1.38–1.36(m,1H),0.76–0.71(m,2H),0.48–0.44(m,2H)。

Step 2: synthesis of the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-oxo-2-ureidoethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-oxo-2-ureidoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.07g,0.11mmol) in dichloromethane (4mL) was added a solution of HCl in isopropanol (7M,3mL), stirred at room temperature for 1h, and the solvent was removed to give 65mg of a pale yellow solid, yield: 93 percent.

Compound 231:¹H NMR(600MHz,CD₃OD):δppm 8.02–7.98(m,1H),7.75(s,1H),7.74–7.72(m,1H),7.34(d,J＝8.3Hz,1H),7.27–7.23(m,1H),7.13(t,J＝8.3Hz,1H),6.95(t,J_F-H＝74.6Hz,1H),5.37–5.34(m,1H),4.04(d,J＝6.8Hz,2H),1.82(d,J＝7.0Hz,3H),1.37–1.35(m,1H),0.73–0.69(m,2H),0.47–0.45(m,2H)；

MS-ESI:m/z 580.1[M+H-HCl]⁺。

Example 94: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl) -N- (2- (3-cyclopropylureido) -1- (2, 4-difluorophenyl) ethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2- (3-cyclopropylureido) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

Triethylamine (101mg,1.01mmol) and N, N' -Carbonyldiimidazole (CDI) (162mg,1.01mmol) were dissolved in anhydrous DMF (2mL), a solution of ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) ethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) tert-butyl carbamate (250mg,0.4mmol) in anhydrous DMF (3mL) was added, the reaction was stopped after stirring at room temperature for 30min, cyclopropylamine (57mg,1.01mmol) was added, the reaction was stopped after 1h at 60 ℃, DMF solvent was removed, water (5mL) was added, ethyl acetate was extracted (10 mL. times.3), anhydrous sodium sulfate was dried, solvent was removed, the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 1/1), 180mg of white solid are obtained in yield: and 64 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.50(br.s,1H),7.62–7.67(m,2H),7.37–7.43(m,1H),7.26(d,J＝8.3Hz,1H),6.68–6.92(m,2H),6.73(t,J_F-H＝75.0Hz,1H),5.48–5.53(m,1H),5.32–5.40(m,1H),5.23–5.34(m,1H),4.74–4.79(m,1H),4.02(d,J＝6.9Hz,2H),3.71–3.84(m,2H),2.37–2.41(m,1H),1.47–1.54(m,3H),1.41–1.45(m,9H),1.32–1.40(m,1H),0.67–0.76(m,4H),0.48–0.57(m,2H),0.42–0.46(m,2H)；

MS-ESI:m/z 706.25[M+H]⁺。

Step 2: synthesis of compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2- (3-cyclopropylureido) -1- (2, 4-difluorophenyl) ethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2- (3-cyclopropylureido) -1- (2, 4-difluorophenyl) ethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (170mg,0.24mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,2mL), stirred at room temperature for 30min, the solvent was removed to give 150mg of a white solid, yield: 97 percent.

Compound 232:¹H NMR(600MHz,CD₃OD):δppm 7.86(s,1H),7.78(d,J＝8.3Hz,1H),7.49–7.53(m,1H),7.34(d,J＝8.2Hz,1H),6.96–7.02(m,2H),6.93(t,J_F-H＝74.8Hz,1H),5.47–5.50(m,1H),5.09–5.16(m,1H),4.08(d,J＝6.8Hz,2H),3.63–3.73(m,2H),2.42–2.45(m,1H),1.75(d,J＝6.6Hz,3H),1.33–1.39(m,1H),0.66–0.71(m,4H),0.42–0.47(m,4H)；

MS-ESI:m/z 606.30[M+H-HCl]⁺。

Example 95: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (1- (2, 4-difluorophenyl) -2-morpholinyl-2-oxoethyl) oxazole-4-carboxamide hydrochloride

step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-morpholinyl-2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (0.25g,0.39mmol), morpholine (41mg,0.47mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (112mg,0.59mmol) and N-hydroxy-7-azabenzotriazole (133mg,0.98mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.27mL,1.57mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 15 hours, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 2/1), 267mg of a colorless oil are obtained, yield: 96 percent.

¹H NMR(600MHz,CDCl₃):δppm 8.51(d,J＝7.4Hz,1H),7.62(d,J＝8.4Hz,1H),7.60(s,1H),7.56–7.53(m,1H),7.25(d,J＝8.3Hz,1H),6.96–6.94(m,1H),6.92–6.88(m,1H),6.73(t,J_F-H＝75.1Hz,1H),6.29–6.28(m,1H),5.32–5.29(m,1H),4.02(d,J＝6.9Hz,2H),3.73–3.60(m,6H),3.44–3.36(m,2H),1.53–1.48(m,3H),1.45–1.38(m,9H),1.35–1.33(m,1H),0.73–0.70(m,2H),0.46–0.44(m,2H)；

MS-ESI:m/z 707.3[M+H]⁺。

Step 2: synthesis of the Compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-morpholinyl-2-oxoethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1- (2, 4-difluorophenyl) -2-morpholinyl-2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.25g,0.35mmol) in dichloromethane (4mL) was added a solution of HCl in isopropanol (7M,3mL), stirred at room temperature for 1h, the solvent was removed to give 210mg of a white solid, yield: 91 percent.

Compound 233:¹H NMR(600MHz,CD₃OD):δppm 7.78–7.77(m,1H),7.73–7.71(m,1H),7.58–7.55(m,1H),7.33(d,J＝8.3Hz,1H),7.11–7.06(m,2H),6.92(t,J_F-H＝74.7Hz,1H),6.27(s,1H),5.19–5.16(m,1H),4.03(d,J＝6.9Hz,2H),3.71–3.58(m,6H),3.37–3.35(m,1H),3.29–3.27(m,1H),1.77–1.75(m,3H),1.36–1.34(m,1H),0.70–0.68(m,2H),0.44–0.43(m,2H)；

MS-ESI:m/z 607.2[M+H-HCl]⁺。

example 96: the compound (S) -2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethyl) Oxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid ethyl ester hydrochloride and (R) -2- (5- ((S) -1-amino) Ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorobenzene Yl) Synthesis of Ethyl acetate hydrochloride

Ethyl 2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate hydrochloride, which was the compound of example 79, was subjected to preparative chromatographic resolution to give, after resolution, the compounds ethyl (S) -2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate hydrochloride and (R) -2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid ethyl ester hydrochloride.

Compound 238:¹H NMR(600MHz,CD₃OD):δppm 7.80(s,1H),7.74(d,J＝8.3Hz,1H),7.60–7.56(m,1H),7.34(d,J＝8.3Hz,1H),7.07–7.03(m,2H),6.92(t,J_F-H＝75.0Hz,1H),6.02(s,1H),5.20–5.19(m,1H),4.28(q,J＝7.1Hz,2H),4.05(d,J＝6.9Hz,2H),1.76(d,J＝6.9Hz,3H),1.36–1.34(m,1H),1.25(t,J＝7.1Hz,3H),0.71–0.68(m,2H),0.44–0.43(m,2H)；

MS-ESI:m/z 566.2[M+H-HCl]⁺；

Compound 239:¹H NMR(600MHz,CD₃OD):δppm 7.80(s,1H),7.74(d,J＝8.3Hz,1H),7.59–7.57(m,1H),7.34(d,J＝8.3Hz,1H),7.09–7.03(m,2H),6.92(t,J_F-H＝75.0Hz,1H),6.02(s,1H),5.18–5.16(m,1H),4.28(q,J＝7.1Hz,2H),4.04(d,J＝6.9Hz,2H),1.76(d,J＝6.9Hz,3H),1.37–1.34(m,1H),1.25(t,J＝7.1Hz,3H),0.71–0.68(m,2H),0.45–0.43(m,2H)；

MS-ESI:m/z 566.2[M+H-HCl]⁺。

Example 97: the compound N- (2-amino-1- (2, 4-difluorophenyl) -2-thioethyl) -5- ((S) -1-aminoethyl Yl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride, N- ((S) -2-amino- 1- (2, 4-difluorophenyl) -2-thioethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) Phenyl) oxazole-4-carboxamide hydrochloride and N- ((R) -2-amino-1- (2, 4-difluorophenyl) -2-thioethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy)) Synthesis of (E) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride Become into

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound methyl 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetate (240mg,0.37mmol), methanolic ammonia solution (7M,5.3mL,37mmol) was dissolved in anhydrous methanol (10mL), the reaction was stirred at 60 ℃ for 1h in a 100mL stoppered tube, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give 157mg of a white solid, yield: 67%.

¹H NMR(600MHz,CD₃OD):δppm 8.34–8.38(m,1H),7.61–7.64(m,2H),7.48–7.54(m,1H),7.27(d,J＝8.3Hz,1H),6.91–6.95(m,2H),6.74(t,J_F-H＝75.0Hz,1H),5.93–6.00(m,2H),5.58(br.s,1H),5.29–5.34(m,1H),4.04(d,J＝6.9Hz,2H),1.48–1.53(m,3H),1.40–1.45(m,9H),1.28–1.36(m,1H),0.70–0.74(m,2H),0.44–0.47(m,2H)；

MS-ESI:m/z 637.20[M+H]⁺。

Step 2: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-thioethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (200mg,0.32mmol) and thionine (Lawesson' S reagent) (140mg,0.35mmol) were dissolved in tetrahydrofuran (10mL), stirred at 75 ℃ under reflux for 30min, the solvent was removed, water (10mL) was added to the residue, ethyl acetate was extracted (10 mL. times.3), and the organic phase was extracted with anhydrous Na₂SO₄Drying, removal of the solvent, column separation of the concentrate (ethyl acetate/petroleum ether (v/v) ═ 4/1) gave 118mg of a pale yellow solid, yield: 58 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.78–8.82(m,1H),7.59–7.67(m,2H),7.28(d,J＝8.3Hz,1H), 6.88–6.94(m,2H),6.74(t,J_F-H75.0Hz,1H), 6.19-6.26 (m,1H), 5.30-5.42 (m,1H),4.04(d, J ═ 6.9Hz,2H), 1.48-1.52 (m,3H), 1.39-1.45 (m,9H), 1.28-1.36 (m,1H), 0.70-0.74 (m,2H), 0.43-0.47 (m, 2H). And step 3: synthesis of the compound N- (2-amino-1- (2, 4-difluorophenyl) -2-thioethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-thioethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (110mg,0.17mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,2mL), stirred at room temperature for 20min, the solvent was removed to give 95mg of a pale yellow solid, yield: 96 percent.

Compound 236:¹H NMR(600MHz,CD₃OD):δppm 7.80(s,1H),7.73–7.75(m,1H),7.66–7.70(m,1H),7.34(d,J＝8.3Hz,1H),6.98–7.04(m,2H),6.92(t,J_F-H＝75.0Hz,1H),6.19(s,1H),5.14–5.20(m,1H),4.04(d,J＝6.9Hz,2H),1.77(d,J＝7.0Hz,3H),1.32–1.37(m,1H),0.67–0.70(m,2H),0.42–0.45(m,2H)；

MS-ESI:m/z 553.20[M+H-HCl]⁺。

And 4, step 4: synthesis of the compounds N- ((S) -2-amino-1- (2, 4-difluorophenyl) -2-thioethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride and N- ((R) -2-amino-1- (2, 4-difluorophenyl) -2-thioethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

The compound N- (2-amino-1- (2, 4-difluorophenyl) -2-thioethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (270mg,0.46 m)mol), concentrating the respective preparations with S and R configuration, adjusting the pH to 9 with NaOH solution (1M), extracting with ethyl acetate (10 mL. times.3), combining the organic phases and then adding Na₂SO₄Drying, removing solvent, adding HCl in ethyl acetate (4M,2mL) to obtain S configuration compound N- ((S) -2-amino-1- (2, 4-difluorophenyl) -2-thioethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (68mg as pale yellow solid); r configuration the compound N- ((R) -2-amino-1- (2, 4-difluorophenyl) -2-thioethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (100mg as a pale yellow solid).

Compound 244: MS-ESI: M/z 553.20[ M + H-HCl ]]⁺；

Compound 245: MS-ESI: M/z 553.20[ M + H-HCl ]]⁺。

Example 98: the compound (2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) Synthesis of phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetoxy) methyltrimethylacetate hydrochloride Become into

Step 1: synthesis of the compound (2- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetoxy) methyltrimethylacetate

The compound 2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (500mg,0.78mmol) and potassium hydroxide (44mg,0.78mmol) were dissolved in anhydrous ethanol (5mL) and reacted at 40 ℃ for 15min, the solvent was removed, DMF (5mL) and chloromethyl pivalate (0.34mL,2.34mmol) were added, stirring was carried out at room temperature for 4h, ice water (10mL) was added, ethyl acetate was extracted (10 mL. times.3), and the organic phase was extracted with anhydrous Na₂SO₄Drying, removing solvent, and separating the concentrated solution with column (petroleum ether/ethyl acetate (v/v) ═ 10/1)) 450mg of a pale yellow solid are obtained in yield: 76 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.11–8.15(m,1H),7.59–7.63(m,2H),7.46–7.52(m,1H),7.26(d,J＝8.3Hz,1H),6.88–6.94(m,2H),6.73(t,J_F-H＝75.0Hz,1H),6.02–6.03(m,1H),5.93(d,J＝5.5Hz,1H),5.77(d,J＝5.5Hz,1H),5.29–5.33(m,1H),4.01–4.04(m,2H),1.48–1.54(m,3H),1.41–1.45(m,9H),1.31–1.35(m,1H),1.16(s,9H),0.69–0.74(m,2H),0.41–0.47(m,2H)；

MS-ESI:m/z 774.20[M+Na]⁺。

Step 2: synthesis of hydrochloride of compound (2- (5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetoxy) methyltrimethylacetate

To a solution of compound (2- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetoxy) methyltrimethylacetate (260mg,0.35mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 30min, and the solvent was removed to give 230mg of a white solid in yield: 96 percent.

Compound 271:¹H NMR(400MHz,CD₃OD):δppm 7.80(d,J＝1.8Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.59(dd,J₁＝14.8Hz,J₂＝8.4Hz,1H),7.34(d,J＝8.3Hz,1H),7.02–7.10(m,2H),6.92(t,J_F-H＝75.1Hz,1H),6.07(s,1H),5.95(dd,J₁＝5.7Hz,J₂＝1.8Hz,1H),5.75(dd,J₁＝5.7Hz,J₂＝1.5Hz,1H),5.15–5.22(m,1H),4.05(d,J＝6.9Hz,2H),1.76(dd,J₁＝6.9Hz,J₂＝1.1Hz,3H),1.31–1.38(m,1H),1.15(s,9H),0.67–0.72(m,2H),0.41–0.46(m,2H)；

MS-ESI:m/z 652.10[M+H-HCl]⁺。

example 99: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Yl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride and (S) -5- (1-aminoethyl) -2- (3- (cyclo)Propyl methoxy Synthesis of yl) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (300mg,0.64mmol), HOAT (130.8mg,0.961mmol) and EDCI (183.7mg,0.961mmol) were dissolved in DCM (25mL) and, after stirring for 30min at room temperature, 2, 4-difluorobenzylamine (109.9mg,0.769mmol) was added thereto, DIPEA (0.35mL,1.923mmol) was slowly added dropwise under ice bath, then stirring was continued overnight at room temperature, water (25mL) was added, and then, DIPEA (0.35mL,1.923mmol) was added thereto₂Cl₂Extraction (25 mL. times.3), combining the organic phases and then applying anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (Petroleum ether/EtOAc (v/v) ═ 5/1) afforded 316.4mg of a white solid, yield: 83.2 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.57(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.53(d,J＝1.8Hz,1H),7.39-7.44(d,1H),7.23(d,J＝8.3Hz,1H),6.82-6.89(m,2H),6.70(t,J＝75.0Hz,1H),5.27-5.30(m,1H),4.65(brs,2H),3.97(d,J＝6.9Hz,2H),1.53(d,J＝7.0Hz,3H),1.43(s,9H),1.28-1.29(m,1H),0.66-0.71(m,2H),0.39-0.42(m,2H)；

MS-ESI:m/z 494.0[M-100+H]⁺。

The compound tert-butyl (S) - (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (316.4mg,0.533mmol) was dissolved in CH₂Cl₂(2mL), HCl was added^.EA(4M,3mL), reacted at room temperature for 2h, after removal of the solvent, CH was added₂Cl₂The crude product was just dissolved, a large amount of ethyl acetate was added to precipitate a large amount of white solid, which was filtered and drained to give 250mg of white solid, yield: 88.6 percent.

Compound 7:¹H NMR(600MHz,CD₃OD):δppm 7.70(s,1H),7.63(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.37-7.41(m,1H),7.24(d,J＝8.3Hz,1H),6.86-6.92(m,2H),6.82(t,J＝75.0Hz,1H),5.07(q,J＝7.0Hz,1H),4.55(s,2H),3.94(d,J＝7.0Hz,2H),1.68(d,J＝7.0Hz,3H),1.24-1.28(m,1H),0.58-0.61(m,2H),0.32-0.34(m,2H)；

MS-ESI:m/z 494.0[M-HCl+H]⁺。

And step 3: synthesis of compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide

The compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride (150mg,0.28mmol) was dissolved in water (10mL), the pH was adjusted to 9 with aqueous NaOH (1.0M), extracted with ethyl acetate (10 mL. times.3), and the organic phase was extracted with anhydrous Na₂SO₄Drying and removal of the solvent gave 130mg of a white solid in yield: 94 percent.

Compound 313:¹H NMR(600MHz,CD₃OD):δppm 7.66(d,J＝1.9Hz,1H),7.58(dd,J₁＝8.3Hz,J₂＝2.0Hz,1H),7.33–7.37(m,1H),7.18(d,J＝8.3Hz,1H),6.83–6.89(m,2H),6.78(t,J_F-H＝75.0Hz,1H),4.65(q,J＝6.9Hz,1H),4.50(s,2H),3.91(d,J＝6.9Hz,2H),1.44(d,J＝6.9Hz,3H),1.21–1.27(m,1H),0.55–0.59(m,2H),0.29–0.33(m,2H)；

MS-ESI:m/z 494.30[M+H]⁺。

Example 100: the compound N- ((S) -2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1- Synthesis of aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide

The compound N- ((S) -2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride (150mg,0.28mmol) was dissolved in water (10mL), pH was adjusted to 9 with aqueous NaOH (1.0M), dichloromethane was extracted (10mL × 3), and the organic phase was extracted with anhydrous Na₂SO₄Drying and removal of the solvent gave 110mg of a white solid in yield: 79 percent.

Compound 322:¹H NMR(400MHz,CD₃OD):δppm 7.57–7.69(m,2H),7.41–7.52(m,1H),7.17–7.24(m,1H),6.87–6.97(m,2H),6.81(t,J_F-H＝75.0Hz,1H),5.82(s,1H),4.85–4.90(m,1H),3.88–3.93(m,2H),1.58(d,J＝6.6Hz,3H),1.17–1.30(m,1H),0.54–0.63(m,2H),0.28–0.37(m,2H)；

MS-ESI:m/z 536.95[M+H]⁺。

Example 101: the compound (S) -5- (1-aminoethyl) -2- (3, 4-diethoxyphenyl) -N- (2, 4-difluorobenzyl Synthesis of Yl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (1- (2- (3, 4-diethoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxylic acid (176mg,0.41mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (118.8mg,0.62mmol) and N-hydroxy-7-azabenzotriazole (83.8mg,0.62mmol) were dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.06mL,0.49mmol) and N, N-diisopropylethylamine (0.22mL,1.23mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, after adding water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 149mg of a white solid in yield: 67%.

¹H NMR(400MHz,CDCl₃):δppm 7.52(d,J＝8.4Hz,1H),7.46(s,1H),7.41-7.35(m,1H),6.89(d,J＝8.4Hz,1H),6.86-6.78(m,2H),5.29-5.25(m,1H),4.63-4.60(m,2H),4.16-4.10(m,4H),1.52(d,J＝7.0Hz,3H),1.48-1.44(m,6H),1.42(s,9H)；

MS-ESI:m/z 546.2[M+H]⁺。

Step 2: synthesis of compound (S) -5- (1-aminoethyl) -2- (3, 4-diethoxyphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (S) - (1- (2- (3, 4-diethoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (100mg,0.18mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,5mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 75mg of a white solid, yield: 92 percent.

Compound 3:¹H NMR(400MHz,CD₃OD):δppm 7.67(d,J＝8.4Hz,1H),7.63(s,1H),7.48-7.42(m,1H),7.07(d,J＝8.4Hz,1H),6.98-6.91(m,2H),5.12-5.09(m,1H),4.62(s,2H),4.17-4.11(m,4H),1.74(d,J＝6.6Hz,3H),1.46-1.42(m,6H)；

MS-ESI:m/z 446.2[M+H-HCl]⁺。

Example 102: the compound (S) -5- (1-aminoethyl) -2- (3- (benzyloxy) -4-methoxyphenyl) -N- (2,4- Synthesis of difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound methyl 3-benzyloxy-4-methoxybenzoate

Methyl 3-hydroxy-4-methoxybenzoate (10.00g,54.93mmol), potassium carbonate (15.66g,113.30mmol) and benzyl bromide (7.8mL,66.07mmol) were dissolved in N, N-dimethylformamide (60mL) and reacted at 60 ℃ for 4.5h, water (40mL) was added, extraction was performed with ethyl acetate (50 mL. times.3), organic phases were combined and anhydrous Na was used₂SO₄Drying, removing solvent, and separating the concentrated solution with column (petroleum ether/ethyl acetate)ester (v/v) ═ 5/1), yielding 11.2g of a white solid, yield: 75 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.69(d,J＝8.4Hz,1H),7.62(s,1H),7.46(d,J＝7.3Hz,2H),7.40-7.31(m,3H),6.91(d,J＝8.4Hz,1H),5.18(s,2H),3.93(s,3H),3.85(s,3H)；

MS-ESI:m/z 273.1[M+H]⁺。

Step 2: synthesis of compound 3-benzyloxy-4-methoxybenzoic acid

The compound methyl 3-benzyloxy-4-methoxybenzoate (11.2g,41.18mmol) and sodium hydroxide (8.89g,222.3mmol) were dissolved in a mixed solvent of ethanol (150mL) and water (50mL), reacted at 60 ℃ for 1.5h, ethanol was removed, pH was adjusted to 1 with hydrochloric acid (1M), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and extracted with anhydrous Na₂SO₄Drying and removal of the solvent gave 8.51g of a white solid, yield: 80 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.69(d,J＝8.4Hz,1H),7.62(s,1H),7.46(d,J＝7.3Hz,2H),7.40-7.31(m,3H),6.91(d,J＝8.4Hz,1H),5.18(s,2H),3.85(s,3H)；

MS-ESI:m/z 259.2[M+H]⁺。

And step 3: synthesis of Compound methyl 2- (3- (benzyloxy) -4-methoxybenzoylamino) acetate

the compounds 3-benzyloxy-4-methoxybenzoic acid (8.51g,33.0mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (9.62g,50.2mmol), 1-hydroxybenzotriazole (6.69g,49.5mmol) were dissolved in dichloromethane (80mL), stirred at room temperature for 0.5h, glycine methyl ester hydrochloride (4.97g,39.6mmol) and N, N-diisopropylethylamine (17.8mL,102.3mmol) were added at 0 deg.C, stirred at room temperature for 12h, washed with water (40 mL. times.3), and the organic phase was washed with Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 9.88g of a white solid, yield: 91 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.47-7.44(m,3H),7.38-7.35(m,3H),7.32-7.28(m,1H),6.89(d,J＝8.4Hz,1H),6.57(br.s,1H),5.16(s,2H),4.20(d,J＝5.0Hz,2H),3.91(s,3H),3.80(s,3H)；

MS-ESI:m/z 330.2[M+H]⁺。

And 4, step 4: synthesis of Compound methyl 2- (3- (benzyloxy) -4-methoxyphenyl thioamide) acetate

The compound methyl 2- (3- (benzyloxy) -4-methoxybenzoylamino) acetate (2.5g,7.59mmol) and Lawson's reagent (3.07g,7.59mmol) were dissolved in tetrahydrofuran (40mL), stirred at 75 ℃ under reflux for 2h, a saturated sodium bicarbonate solution (40mL) was added, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 2.55g of a yellow solid, yield: 97 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.02(br.s,1H),7.59(s,1H),7.47-7.45(m,2H),7.39-7.28(m,4H),6.84(d,J＝8.4Hz,1H),5.17(s,2H),4.54(m,J＝4.6Hz,2H),3.90(s,3H),3.83(s,3H)；

MS-ESI:m/z 346.2[M+H]⁺。

And 5: synthesis of Compound methyl 2- (((3- (benzyloxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate

A solution of the compound methyl 2- (3- (benzyloxy) -4-methoxyphenyl thioamide) acetate (2.55g,7.39mmol) in dichloromethane (30mL) was slowly added dropwise at-78 ℃ to a solution of trimethyloxonium tetrafluoroborate (1.31g,8.87mmol) in dichloromethane (20mL), stirring was continued at 0 ℃ for 3h, then a saturated sodium bicarbonate solution was added and the organic phase was washed (25 mL. times.3) with anhydrous Na₂SO₄drying and removal of the solvent gave 2.1g of a yellow oil, yield: 80 percent.

MS-ESI:m/z 360.1[M+H]⁺。

Step 6: synthesis of Compound (S) -methyl 2- (3- (benzyloxy) -4-methoxyphenyl) -5- (1- (tert-butoxycarbonylamino) ethyl) oxazole-4-carboxylate

The compound methyl 2- (((3- (benzyloxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate (2.47g,8.31mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (2.38g,12.46mmol) were dissolved in anhydrous tetrahydrofuran (20mL) and hexamethyldisilazane was added dropwise at-78 deg.CPotassium in tetrahydrofuran (20.78mL,20.78mmol), reacted at-78 deg.C for 1h, quenched with ice water (20mL), extracted with ethyl acetate (15 mL. times.3), combined organic phases and dried over anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 1g of a yellow solid, yield: 28 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.68-7.64(m,2H),7.50-7.48(m,2H),7.41-7.30(m,3H),6.95(d,J＝8.4Hz,1H),5.69(br.s,1H),5.47-5.43(m,1H),5.20(s,2H),3.97(s,3H),3.93(s,3H),1.53(d,J＝7.0Hz,3H),1.39(s,9H)；

MS-ESI:m/z 483.1[M+H]⁺。

And 7: synthesis of the Compound (S) -2- (3- (benzyloxy) -4-methoxyphenyl) -5- (1- (tert-butoxycarbonylamino) ethyl) oxazole-4-carboxylic acid

The compound methyl (S) -2- (3- (benzyloxy) -4-methoxyphenyl) -5- (1- (tert-butoxycarbonylamino) ethyl) oxazole-4-carboxylate (390mg,0.81mmol) and lithium hydroxide monohydrate (172mg,4.1mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added and extracted (30 mL. times.3), and the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 352mg of white solid, yield: 93 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.69-7.66(m,2H),7.51(d,J＝7.2Hz,1H),7.42-7.34(m,3H),6.97(d,J＝8.3Hz,1H),5.72(br.s,1H),5.43-5.41(m,1H),5.22(s,2H),3.95(s,3H),1.58(d,J＝7.0Hz,3H), 1.45(s,9H)；

MS-ESI:m/z 467.2[M-H]^-。

And 8: synthesis of Compound (S) - (1- (2- (3- (benzyloxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -2- (3- (benzyloxy) -4-methoxyphenyl) -5- (1- (tert-butoxycarbonylamino) ethyl) oxazole-4-carboxylic acid (352mg,0.75mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (215.7mg,1.13mmol) and N-hydroxy-7-azabenzotriazole (152.7 mg)1.13mmol) in dichloromethane (10mL), stirring at room temperature for 0.5h, adding dropwise 2, 4-difluorobenzylamine (0.10mL,0.90mmol) and N, N-diisopropylethylamine (0.40mL,2.25mmol) at 0 deg.C, stirring at room temperature for 12h, adding water (20mL), extracting with dichloromethane (20 mL. times.3), combining the organic phases, and adding Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 320mg of a white solid, yield: 72 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60-7.54(m,2H),7.48(d,J＝7.2Hz,2H),7.44-7.36(m,3H),7.32(d,J＝7.2Hz,1H),6.94(d,J＝8.5Hz,1H),6.90-6.82(m,2H),5.28-5.26(m,1H),5.25(s,2H),4.66-4.63(m,2H),3.93(s,3H),1.52(d,J＝7.0Hz,3H),1.25(s,9H)；

MS-ESI:m/z 594.0[M+H]⁺。

And step 9: synthesis of compound (S) -5- (1-aminoethyl) -2- (3- (benzyloxy) -4-methoxyphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (S) - (1- (2- (3- (benzyloxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (300mg,0.51mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,5mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 230mg of a white solid, yield: 92 percent.

Compound 6:¹H NMR(400MHz,CD₃OD):δppm 7.73-7.71(m,2H),7.48-7.44(m,3H),7.39-7.31(m,3H),7.13(d,J＝8.1Hz,1H),6.99-6.92(m,2H),5.17(s,2H),5.13-5.08(m,1H),4.62(s,2H),3.92(s,3H),1.73(d,J＝7.0Hz,3H)。

example 103: the compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (3-nitro-4-methoxy Synthesis of phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound methyl 2- (3-nitro-4-methoxybenzoylamino) acetate

3-Nitro-4-methoxybenzoic acid (5.0g,25.4mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (7.3g,38.1mmol) and 1-hydroxybenzotriazole (5.15g,38.1mmol) were dissolved in dichloromethane (30mL), stirred at room temperature for 0.5h, glycine methyl ester hydrochloride (3.83g,30.5mmol) and N, N-diisopropylethylamine (13.3mL,76.2mmol) were added at 0 deg.C, stirred at room temperature for 12h, water (30mL) was added, extraction was performed with dichloromethane (40 mL. times.3), the organic phases were combined and Na was used₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 6.34g of a white solid in yield: 95 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.28(s,1H),8.04-8.00(m,1H),7.14-6.99(m,1H),6.88(br.s,1H),4.24-4.21(m,2H),4.00(s,3H),3.80(s,3H)；

MS-ESI:m/z 269.0[M+H]⁺。

Step 2: synthesis of compound methyl 2- (3-nitro-4-methoxyphenyl thioamide) acetate

The compound methyl 2- (3-nitro-4-methoxybenzamido) acetate (2.0g,7.46mmol) and Lawson's reagent (3.02g,7.46mmol) were dissolved in tetrahydrofuran (20mL), stirred at 75 ℃ under reflux for 2h, after addition of saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 2.1g of a yellow solid, yield: 98 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.33(s,1H),8.10(d,J＝8.9Hz,1H),7.11(d,J＝8.9Hz,1H),4.57(d,J＝4.6Hz,2H),4.02(s,3H),3.86(s,3H)；

MS-ESI:m/z 285.1[M+H]⁺。

And step 3: synthesis of compound methyl 2- (((3-nitro-4-methoxyphenyl) (methylthio) methylene) amino) acetate

A solution of the compound methyl 2- (3-nitro-4-methoxyphenylthioamide) acetate (0.5g,1.76mmol) in dichloromethane (20mL) was slowly added dropwise at-78 ℃ to a solution of trimethyloxonium tetrafluoroborate (0.39g,2.64mmol) in dichloromethane (20mL), stirring was continued at 0 ℃ for 3h, and then addedWashed with saturated sodium bicarbonate solution (25 mL. times.3) and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 0.495g of a yellow oil, yield: 95 percent.

MS-ESI:m/z 299.0[M+H]⁺。

and 4, step 4: synthesis of Compound (S) -methyl 5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3-nitro-4-methoxyphenyl) oxazole-4-carboxylate

Dissolving the compound methyl 2- (((3-nitro-4-methoxyphenyl) (methylthio) methylene) amino) acetate (0.495g,1.66mmol), the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (0.476g,2.49mmol) in anhydrous tetrahydrofuran (20mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (6.6mL,6.6mmol) at-78 deg.C, reacting at-78 deg.C for 1h, quenching the reaction with ice water (20mL), extracting with ethyl acetate (15 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 0.213g of a yellow solid, yield: 32 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.51(s,1H),8.27(d,J＝8.9Hz,1H),7.18(d,J＝8.9Hz,1H),5.59(br.s,1H),5.49-5.45(m,1H),4.04(s,3H),3.98(s,3H),1.55(d,J＝7.0Hz,3H),1.42(s,9H)；

MS-ESI:m/z 422.1[M+H]⁺。

And 5: synthesis of Compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3-nitro-4-methoxyphenyl) oxazole-4-carboxylic acid

The compound methyl (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3-nitro-4-methoxyphenyl) oxazole-4-carboxylate (0.24g,0.57mmol) and lithium hydroxide monohydrate (0.068g,2.85mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added and extracted (30 mL. times.3), the organic phases were combined and Na was added thereto₂SO₄Drying and removal of the solvent gave 0.211mg of a white solid, yield: 91 percent.

Step 6: synthesis of Compound (S) - (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (3-nitro-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

the compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3-nitro-4-methoxyphenyl) oxazole-4-carboxylic acid (211mg,0.52mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (149.5mg,0.78mmol) and N-hydroxy-7-azabenzotriazole (105.4mg,0.78mmol) were dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.08mL,0.63mmol) and N, N-diisopropylethylamine (0.27mL,1.56mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, water (15mL) was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 190mg of a white solid in yield: 70 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.48(s,1H),8.14(d,J＝8.8Hz,1H),7.44-7.38(m,1H),7.17(d,J＝8.9Hz,1H),6.89-6.82(m,2H),6.74(br.s,1H),5.30(t,J＝7.0Hz,1H),4.64(d,J＝4.2Hz,2H),4.03(s,3H),1.53(d,J＝7.0Hz,3H),1.42(s,9H)；

MS-ESI:m/z 533.0[M+H]⁺。

And 7: synthesis of compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (3-nitro-4-methoxyphenyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (S) - (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (3-nitro-4-methoxyphenyl) oxazol-5-yl) ethyl) carbamate (190mg,0.36mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 144mg of a white solid, yield: 93 percent.

Compound 10:¹H NMR(400MHz,CDCl₃):δppm 8.49(s,1H),8.16(d,J＝8.7Hz,1H),7.62-7.58(m,1H),7.41-7.39(m,1H),7.19(d,J＝8.9Hz,1H),6.90-6.87(m,1H),4.99-4.96(m,1H),4.63(d,J＝6.0Hz,2H),4.05(s,3H),1.74(d,J＝7.0Hz,3H)；

MS-ESI:m/z 433.2[M+H-HCl]⁺。

Example 104: compound 5- (aminomethyl) -2- (3- (cyclopropylmethoxy)Yl) -4-methoxyphenyl) -N- (2,4- Synthesis of difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (2-fluoro-2-oxoethyl) carbamic acid tert-butyl ester

Dissolving N-Boc-glycine (2.5g,14.29mmol) and triethylamine (2.15mL,15.72mmol) in dichloromethane (20mL), slowly adding dropwise cyanuric fluoride (2.7mL,28.58mmol) at-40 deg.C, reacting at-10 deg.C for 1h, washing with ice water (20mL × 3), and reacting the organic phase with anhydrous Na₂SO₄Drying and removal of the solvent gave 2.12g of a white solid, yield: 84 percent.

¹H NMR(400MHz,d₆-DMSO):δppm 7.54-7.51(m,1H),4.03-4.00(m,2H),1.39(s,9H)。

Step 2: synthesis of compound methyl 5- ((tert-butoxycarbonylamino) methyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate

Dissolving compound methyl 2- (((3- (cyclopropylmethoxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate (1.99g,6.16mmol), compound tert-butyl 2-fluoro-2-oxoethyl) carbamate (2.18g,12.32mmol) in anhydrous tetrahydrofuran (30mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (18.48mL,18.48mmol) at-78 deg.C, reacting at-78 deg.C for 1h, quenching with ice water (20mL), extracting with ethyl acetate (15 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 0.57g of a yellow solid, yield: 25 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.66(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.55(d,J＝2.0Hz,1H),6.92(d,J＝8.5Hz,1H),5.28(br.s,1H),4.72(d,J＝5.7Hz,2H),3.97(s,3H),3.93(s,3H),3.92(d,J＝6.0Hz,2H),1.46(s,9H),1.39-1.35(m,1H),0.69-0.64(m,2H),0.40-0.36(m,2H)；

MS-ESI:m/z 433.3[M+H]⁺。

And step 3: synthesis of compound 5- ((tert-butoxycarbonylamino) methyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid

the compound methyl 5- ((tert-butoxycarbonylamino) methyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate (0.57g,1.32mmol) and lithium hydroxide monohydrate (0.28g,6.60mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added and extraction was carried out (30 mL. times.3), and the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 0.54g of a white solid, yield: 99 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.64(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.56(s,1H),6.93(d,J＝8.5Hz,1H),5.36(br.s,1H),4.71-4.64(m,2H),3.94(s,3H),3.93(d,J＝7.1Hz,2H),1.47(s,9H),1.37-1.35(m,1H),0.69-0.65(m,2H),0.40-0.38(m,2H)；

MS-ESI:m/z 419.1[M+H]⁺。

And 4, step 4: synthesis of the Compound tert-butyl ((2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) methyl) carbamate

The compounds 5- ((t-butoxycarbonylamino) methyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid (0.21g,0.48mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.14g,0.72mmol) and N-hydroxy-7-azabenzotriazole (0.10g,0.72mmol) were dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.06mL,0.58mmol) and N, N-diisopropylethylamine (0.25mL,1.44mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, after adding water (15mL), extracted with dichloromethane (20 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 0.26g of a white solid in yield: 97 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.46(d,J＝2.0Hz,1H),7.43-7.37(m,1H),6.92(d,J＝8.5Hz,1H),6.89-6.81(m,2H),4.70(d,J＝6.2Hz,2H),4.63(d,J＝6.2Hz,2H),3.93(s,3H),3.92(d,J＝6.9Hz,2H),1.46(s,9H),1.38-1.35(m,1H),0.70-0.65(m,2H),0.41-0.38(m,2H)；

MS-ESI:m/z 544.2[M+H]⁺。

And 5: synthesis of compound 5- (aminomethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl ((2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) methyl) carbamate (0.26g,0.48mmol) in dichloromethane (3mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 210mg of a white solid, yield: 91 percent.

Compound 15:¹H NMR(400MHz,CD₃OD):δppm 7.69(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.61(d,J＝2.0Hz,1H),7.48-7.42(m,1H),7.09(d,J＝8.5Hz,1H),6.98-6.90(m,2H),4.61(s,2H),4.58(s,2H),3.91(d,J＝6.9Hz,2H),3.91(s,3H),1.34-1.26(m,1H),0.65-0.61(m,2H),0.38-0.34(m,2H)；

MS-ESI:m/z 444.1[M+H-HCl]⁺。

Example 105: the compound (R) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- Synthesis of (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (R) - (1-fluoro-1-oxopropan-2-yl) carbamic acid tert-butyl ester

Dissolving N-Boc-R-alanine (1.0g,5.29mmol) and triethylamine (0.8mL,5.82mmol) in dichloromethane (20mL), slowly adding dropwise cyanuric fluoride (1.0mL,10.58mmol) at-40 deg.C, reacting at-10 deg.C for 1h, washing with ice water (20mL × 3), and mixing the organic phase with anhydrous Na₂SO₄Drying and removal of the solvent gave 0.82g of a white solid, yield: 81 percent.

¹H NMR(400MHz,d₆-DMSO):δppm 4.33-4.26(m,1H),1.39(s,9H),1.35(d,J＝7.2Hz,3H)。

Step 2: synthesis of Compound (R) -methyl 5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate

Dissolving the compound methyl 2- (((3- (cyclopropylmethoxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate (0.5g,1.55mmol), the compound tert-butyl (R) - (1-fluoro-1-oxopropan-2-yl) carbamate (0.59g,3.1mmol) in anhydrous tetrahydrofuran (20mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (6.2mL,6.2mmol) at-78 deg.C, reacting at-78 deg.C for 1h, adding ice water (20mL), quenching the reaction, extracting with ethyl acetate (15 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 0.34g of a yellow solid, yield: 50 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.63(d,J＝8.4Hz,1H),7.54(s,1H),6.92(d,J＝8.4Hz,1H),5.46-5.42(m,1H),3.97(s,3H),3.94(s,3H),3.93(d,J＝7.0Hz,2H),1.53(d,J＝7.0Hz,3H),1.42(s,9H),1.27-1.24(m,1H),0.69-0.65(m,2H),0.40-0.37(m,2H)；

MS-ESI:m/z 447.3[M+H]⁺。

And step 3: synthesis of Compound (R) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid

The compound (R) -methyl 5- (1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate (0.34g,0.76mmol) and lithium hydroxide monohydrate (0.16g,3.8mmol) were dissolved in a mixed solvent of tetrahydrofuran (20mL) and water (10mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, the pH was adjusted to 1 with hydrochloric acid (1M), ethyl acetate was added and extracted (30 mL. times.3), and the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 310mg of a white solid, yield: 94 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.62(d,J＝8.4Hz,1H),7.54(s,1H),6.93(d,J＝8.4Hz,1H),5.40-5.36(m,1H),3.94(s,3H),3.93(d,J＝7.0Hz,2H),1.57(d,J＝7.1Hz,3H),1.44(s,9H),1.27-1.25(m,1H),0.68-0.66(m,2H),0.40-0.38(m,2H)；

MS-ESI:m/z 433.3[M+H]⁺。

And 4, step 4: synthesis of Compound (R) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (R) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid (0.31g,0.72mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.21g,1.08mmol) and N-hydroxy-7-azabenzotriazole (0.15g,1.08mmol) were dissolved in dichloromethane (10mL), stirred at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.10mL,0.86mmol) and N, N-diisopropylethylamine (0.38mL,2.16mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, water (15mL) was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 0.29g of a white solid, yield: 73 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.57(d,J＝8.4Hz,1H),7.54(br.s,1H),7.45-7.38(m,2H),6.93-6.80(m,2H),5.29-5.27(m,1H),4.65-4.62(m,2H),3.93(s,3H),3.92(d,J＝6.9Hz,2H),1.52(d,J＝7.0Hz,3H),1.43(s,9H),1.25-1.23(m,1H),0.69-0.66(m,2H),0.42-0.38(m,2H)；

MS-ESI:m/z 558.2[M+H]⁺。

And 5: synthesis of Compound (R) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (R) - (1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.29g,0.52mmol) in dichloromethane (3mL) was added an ethyl acetate solution of HCl (4M,5mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 184mg of a white solid, yield: 78 percent.

Compound 16:¹H NMR(400MHz,CD₃OD):δppm 7.69(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.61(d,J＝2.0Hz,1H),7.48-7.42(m,1H),7.10(d,J＝8.5Hz,1H),6.99-6.91(m,2H),5.14-5.09(m,1H),4.61(s,2H),3.91(s,3H),3.91(d,J＝6.9Hz,2H),1.73(d,J＝7.0Hz,3H),1.32-1.28(m,1H),0.66-0.61(m,2H),0.38-0.34(m,2H)；

MS-ESI:m/z 458.1[M+H-HCl]⁺。

Example 106: the compound (S) -5- (1-amino-2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4-methoxy Synthesis of phenylphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (1-fluoro-3-methyl-1-oxobutan-2-yl) carbamic acid tert-butyl ester

Dissolving N-Boc-L-valine (3.1g,14.29mmol) and triethylamine (2.2mL,15.72mmol) in dichloromethane (20mL), slowly adding dropwise cyanuric fluoride (2.7mL,28.58mmol) at-40 deg.C, reacting at-10 deg.C for 1h, washing with ice water (20mL × 3), and mixing the organic phase with anhydrous Na₂SO₄Drying and removal of the solvent gave 3.01g of a white solid, yield: 96 percent.

¹H NMR(400MHz,d₆-DMSO):δppm 4.10-4.06(m,1H),2.12-2.03(m,1H),1.45(s,9H),0.97-0.94(m,6H)。

Step 2: synthesis of compound (S) -methyl 5- (1- (tert-butoxycarbonylamino) -2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate

Dissolving the compound methyl 2- (((3- (cyclopropylmethoxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate (2.2g,6.80mmol) and the compound tert-butyl (S) - (1-fluoro-3-methyl-1-oxobutan-2-yl) carbamate (2.98g,13.60mmol) in anhydrous tetrahydrofuran (40mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (20.4mL,20.40mmol) at-78 deg.C, reacting for 1h at-78 deg.C, adding ice water (20mL) to quench the reaction, and extracting with ethyl acetate (15 mL.)3) Combining the organic phases and then using anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 6/1) afforded 1.13g of a yellow solid, yield: 38 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.63(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.54(d,J＝2.0Hz,1H),6.93(d,J＝8.5Hz,1H),5.11-5.07(m,1H),3.94(d,J＝6.9Hz,2H),3.93(s,3H),3.89(s,3H),1.44(s,9H),1.36-1.33(m,1H),1.04(d,J＝6.6Hz,3H),0.89(d,J＝6.7Hz,3H),0.68-0.63(m,2H),0.40-0.35(m,2H)；

MS-ESI:m/z 475.3[M+H]⁺。

And step 3: synthesis of the Compound (S) -5- (1- (tert-butoxycarbonylamino) -2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid

The compound methyl (S) -5- (1- (tert-butoxycarbonylamino) -2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate (1.13g,2.38mmol) and lithium hydroxide monohydrate (0.50g,11.92mmol) were dissolved in a mixed solvent of tetrahydrofuran (40mL) and water (20mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, the pH was adjusted to 1 by adding hydrochloric acid (1M), extraction was performed with ethyl acetate (30 mL. times.3), and the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 0.47g of a white solid, yield: and 43 percent.

MS-ESI:m/z 461.3[M+H]⁺。

And 4, step 4: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) -2-methylpropyl) carbamate

The compound (S) -5- (1- (t-butoxycarbonylamino) -2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid (0.20g,0.43mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.12g,0.65mmol) and N-hydroxy-7-azabenzotriazole (0.09g,0.65mmol) were dissolved in methylene chloride (10mL), stirred at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.06mL,0.52mmol) and N, N-diisopropylethylamine (0.23mL,1.30mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, and after adding water (15mL), extraction was carried out with methylene chloride (20mL)X 3), the organic phases are combined and washed with Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 0.23g of a white solid, yield: 93 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.57(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.45(d,J＝2.0Hz,1H),7.42-7.38(m,1H),6.92(d,J＝8.5Hz,1H),6.89-6.82(m,2H),4.90-4.85(m,1H),4.66-4.64(m,2H),3.93(s,3H),3.94(d,J＝5.3Hz,2H),2.20-2.11(m,1H),1.44(s,9H),1.36-1.35(m,1H),1.02(d,J＝6.7Hz,3H),0.86(d,J＝6.7Hz,3H),0.71-0.66(m,2H),0.43-0.39(m,2H)；

MS-ESI:m/z 586.2[M+H]⁺。

And 5: synthesis of Compound (S) -5- (1-amino-2-methylpropyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound (S) - (1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) -2-methylpropyl) carbamic acid tert-butyl ester (0.29g,0.50mmol) in dichloromethane (2mL) was added an ethyl acetate solution of HCl (4M,8mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 246mg of a white solid, yield: 94 percent.

Compound 17:¹H NMR(400MHz,CDCl₃):δppm 7.74-7.71(m,1H),7.59(d,J＝8.4Hz,1H),7.46(s,1H),7.44-7.40(m,1H),6.94-6.91(m,1H),6.89-6.84(m,1H),4.80-4.75(m,1H),4.66-4.63(m,2H),3.95(s,3H),3.94(d,J＝7.0Hz,2H),2.70-2.68(m,1H),1.41–1.34(m,1H),1.13(d,J＝5.7Hz,3H),1.00(d,J＝5.6Hz,3H),0.72-0.67(m,2H),0.44–0.41(m,2H)；

MS-ESI:m/z 486.1[M+H-HCl]⁺。

Example 107: the compound (S) -5- (1-amino-2-phenylethyl) -2- (3- (cyclopropylmethoxy) -4-methoxy Synthesis of phenylphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (1-fluoro-1-oxo-3-phenylpropan-2-yl) carbamic acid tert-butyl ester

Dissolving N-Boc-L-phenylalanine (3.6g,14.29mmol) and triethylamine (2.2mL,15.72mmol) in dichloromethane (20mL), slowly adding dropwise cyanuric fluoride (2.7mL,28.58mmol) at-40 deg.C, reacting at-10 deg.C for 1h, washing with ice water (20mL × 3), and adding anhydrous Na to organic phase₂SO₄Drying and removal of the solvent gave 3.07g of a white solid, yield: 85 percent.

¹H NMR(400MHz,d₆-DMSO):δppm 7.32-7.22(m,5H),4.50-4.44(m,1H),3.11-2.98(m,2H),1.35(s,9H)；

MS-ESI:m/z 266.0[M-H]^-。

Step 2: synthesis of compound (S) -methyl 5- (1- (tert-butoxycarbonylamino) -2-phenylethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate

Dissolving the compound methyl 2- (((3- (cyclopropylmethoxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate (2.1g,6.50mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxo-3-phenylpropan-2-yl) carbamate (3.47g,13.00mmol) in anhydrous tetrahydrofuran (40mL), adding dropwise a solution of potassium hexamethyldisilazide in tetrahydrofuran (19.5mL,19.50mmol) at-78 deg.C, reacting at-78 deg.C for 1h, quenching the reaction with ice water (20mL), extracting with ethyl acetate (15 mL. times.3), combining the organic phases, and adding anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 0.95g of a yellow solid, yield: 28 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.51(d,J＝6.7Hz,1H),7.42(s,1H),7.23-7.11(m,5H),6.90(d,J ＝8.5Hz,1H),5.63-5.57(m,1H),3.94(s,3H),3.92(s,3H),3.90(d,J＝7.0Hz,2H),3.15-3.10(m,2H),1.40(s,9H),1.34-1.31(m,1H),0.70-0.64(m,2H),0.40-0.36(m,2H)；

MS-ESI:m/z 523.3[M+H]⁺。

And step 3: synthesis of the Compound (S) -5- (1- (tert-butoxycarbonylamino) -2-phenylethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid

The compound methyl (S) -5- (1- (tert-butoxycarbonylamino) -2-phenylethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate (0.95g,1.82mmol) and lithium hydroxide monohydrate (0.38g,9.10mmol) were dissolved in a mixed solvent of tetrahydrofuran (40mL) and water (20mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, the pH was adjusted to 1 by adding hydrochloric acid (1M), extraction was performed with ethyl acetate (30 mL. times.3), and the organic phases were combined and Na was added₂SO₄Drying and removal of the solvent gave 0.90g of a white solid, yield: 97 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.25-7.14(m,7H),6.90(d,J＝8.5Hz,1H),5.94(br.s,1H),5.57-5.55(m,1H),3.93(s,3H),3.91(d,J＝7.1Hz,2H),3.21-3.18(m,2H),1.39(s,9H),1.34-1.31(m,1H),0.70-0.65(m,2H),0.41-0.37(m,2H)；

MS-ESI:m/z 509.2[M+H]⁺。

And 4, step 4: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) -2-phenylethyl) carbamate

The compound (S) -5- (1- (tert-butoxycarbonylamino) -2-phenylethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid (0.20g,0.40mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.14g,0.72mmol) and N-hydroxy-7-azabenzotriazole (0.10g,0.72mmol) were dissolved in dichloromethane (10mL), after stirring at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.06mL,0.48mmol) and N, N-diisopropylethylamine (0.25mL,1.44mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, water (15mL) was added, followed by extraction with dichloromethane (20 mL. times.3), and the organic phases were combined and then Na was added.₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 0.24g of a white solid, yield: 94 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.53-7.48(m,1H),7.43-7.37(m,2H),7.22-7.18(m,2H),7.15-7.11(m,3H),6.91-6.83(m,3H),5.43-5.37(m,1H),4.71-4.60(m,2H),3.92(s,3H),3.89(d,J＝7.0Hz,2H),3.23-3.10(m,2H),1.40(s,9H),1.36-1.34(m,1H),0.71-0.66(m,2H),0.42-0.38(m,2H)；

MS-ESI:m/z 534.1[M+H-100]⁺。

and 5: synthesis of Compound (S) -5- (1-amino-2-phenylethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl (S) - (1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) -2-phenylethyl) carbamate (0.24g,0.38mmol) in dichloromethane (3mL) was added an ethyl acetate solution of HCl (4M,4mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 150mg of a white solid, yield: 70 percent.

compound 19:¹H NMR(400MHz,CD₃OD)δppm 7.58(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.48(d,J＝2.0Hz,1H),7.39–7.33(m,1H),7.26–7.20(m,3H),7.15–7.13(m,2H),7.07(d,J＝8.5Hz,1H),6.99–6.91(m,2H),5.32–5.29(m,1H),4.56(s,2H),3.90(s,3H),3.88(d,J＝7.0Hz,2H),3.44-3.34(m,2H),1.33–1.25(m,1H),0.66–0.61(m,2H),0.38–0.34(m,2H)；

MS-ESI:m/z 534.1[M+H-HCl]⁺。

Example 108: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- synthesis of (3, 5-dichloropyridin-4-yl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid (0.30g,0.70mmol) and triethylamine (0.10mL,0.77mmol) were dissolved in methylene chloride (10mL), and to this solution was slowly added dropwise melamine (0.20mL,1.40mmol) at-40 ℃ to react at-10 ℃ for 1h, washed with ice water (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 282mg of a white solid, yield: 93 percent.

¹H NMR(400MHz,d₆-DMSO):δppm 7.59(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.45(d,J＝2.0Hz,1H),7.17(d,J＝8.6Hz,1H),5.22–5.18(m,1H),3.90(d,J＝7.0Hz,2H),3.87(s,3H),1.47(d,J＝7.0Hz,3H),1.37(s,9H),1.27–1.25(m,1H),0.62–0.58(m,2H),0.38–0.35(m,2H)；

MS-ESI:m/z 435.2[M+H]⁺。

Step 2: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((3, 5-dichloropyridin-4-yl) carbamoyl) oxazol-5-yl) ethyl) carbamate

3, 5-dichloro-4-aminopyridine (162mg,1.00mmol) and sodium hydride (60%, 80mg,2.00mmol) were dissolved in tetrahydrofuran (5mL), stirred at room temperature for 1h, a solution of compound (S) - (1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester (282mg,0.65mmol) in tetrahydrofuran (9mL) was added dropwise at 0 deg.C, stirred at room temperature for 12h, a saturated ammonium chloride solution (20mL) was added, extracted with ethyl acetate (20 mL. times.3), the combined organic phases were Na over Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 40mg of a white solid, yield: 11 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.78(s,2H),7.74–7.65(m,2H),7.21(d,J＝8.4Hz,1H),5.18– 4.95(m,1H),3.93–3.88(m,5H),1.65(d,J＝7.0Hz,3H),1.37(s,9H),1.24–1.22(s,1H),0.65–0.54(m,2H),0.41–0.30(m,2H)；

MS-ESI:m/z 577.1[M+H]⁺。

And step 3: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- (3, 5-dichloropyridin-4-yl) oxazole-4-carboxamide dihydrochloride

To a solution of the compound tert-butyl (S) - (1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((3, 5-dichloropyridin-4-yl) carbamoyl) oxazol-5-yl) ethyl) carbamate (316mg,0.55mmol) in dichloromethane (2mL) was added an ethyl acetate solution of HCl (4M,6mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 135mg of a white solid, yield: 52 percent.

Compound 41:¹H NMR(400MHz,d₆-DMSO):δppm 8.78(s,2H),7.73(d,J＝8.5Hz,1H),7.66(s,1H),7.21(d,J＝8.6Hz,1H),5.11–5.07(m,1H),3.92(d,J＝7.0Hz,2H),3.88(s,3H),1.65(d,J＝7.0Hz,3H),1.30–1.26(m,1H),0.63–0.58(m,2H),0.38–0.35(m,2H)；

MS-ESI:m/z 477.0[M+H-2HCl]⁺。

Example 109: the compound (S) -5- (1-aminoethyl) -N- (3, 5-dichloropyridin-4-yl) -2- (3, 4-diethoxy) Synthesis of phenylphenyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (1- (2- (3, 4-diethoxyphenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxylic acid (1.02g,2.42mmol) and triethylamine (0.37mL,2.66mmol) were dissolved in dichloromethane (20mL), and then melamine (0.46mL,4.84mmol) was slowly added dropwise at-40 ℃ to continue the reaction at-10 ℃ for 1h, washed with ice water (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 1.00g of a white solid, yield: 97 percent.

¹H NMR(400MHz,d₆-DMSO):δppm 7.57(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.48(d,J＝2.0Hz,1H),7.16(d,J＝8.5Hz,1H),5.21–5.19(m,1H),4.28–3.97(m,4H),1.47(d,J＝7.0Hz,3H),1.39–1.23(m,15H)；

MS-ESI:m/z 423.3[M+H]⁺。

step 2: synthesis of the Compound (S) - (1- (4- ((3, 5-dichloropyridin-4-yl) carbamoyl) -2- (3, 4-diethoxyphenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

Mixing 3, 5-dichloro-4-aminopyridine (469mg,2.84 mmo)l) with sodium hydride (60%, 114mg,2.84mmol) in tetrahydrofuran (5mL), stirring at room temperature for 1h, adding dropwise a solution of the compound tert-butyl (S) - (1- (2- (3, 4-diethoxyphenyl) -4- (fluorocarbonyl) oxazol-5-yl) ethyl) carbamate (1.00g,2.37mmol) in tetrahydrofuran (10mL) at 0 deg.C, stirring at room temperature for 12h, washing with a saturated ammonium chloride solution (20 mL. times.3), and subjecting the organic phase to Na₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 264mg of a white solid, yield: 20 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.63(s,2H),7.65(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.57(d,J＝2.0Hz,1H),6.97(d,J＝8.5Hz,1H),5.40–5.27(m,1H),4.26–4.18(m,4H),1.60(d,J＝7.0Hz,3H),1.55–1.51(m,6H),1.44(s,9H)；

MS-ESI:m/z 565.1[M+H]⁺。

And step 3: synthesis of compound (S) -5- (1-aminoethyl) -N- (3, 5-dichloropyridin-4-yl) -2- (3, 4-diethoxyphenyl) oxazole-4-carboxamide dihydrochloride

To a solution of the compound tert-butyl (S) - (1- (4- ((3, 5-dichloropyridin-4-yl) carbamoyl) -2- (3, 4-diethoxyphenyl) oxazol-5-yl) ethyl) carbamate (264mg,0.47mmol) in dichloromethane (2mL) was added an ethyl acetate solution of HCl (4M,6mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 161mg of a white solid, yield: 74 percent.

Compound 45:¹H NMR(400MHz,d₆-DMSO):δppm 8.77(s,2H),7.71(s,1H),7.72(d,J＝6.9Hz,1H),7.19(d,J＝9.0Hz,1H),5.14–5.04(m,1H),4.20–4.06(m,4H),1.65(d,J＝7.0Hz,3H),1.40–1.35(m,6H)；

MS-ESI:m/z 465.2[M+H-2HCl]⁺。

Example 110: the compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (3-hydroxy-4-methoxy Synthesis of phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound methyl 4-methoxy-3- (4-methoxybenzyloxy) benzoate

Methyl 3-hydroxy-4-methoxybenzoate (10.00g,54.95mmol), potassium carbonate (32.80g,238.00mmol) and benzyl p-methoxybenzoate (23.70g,166.00mmol) were dissolved in N, N-dimethylformamide (60mL) and reacted at 60 ℃ for 4.5h, water (40mL) was added and extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and anhydrous Na was used₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 16.2g of a pale yellow solid, yield: 97 percent.

MS-ESI:m/z 303.3[M+H]⁺。

Step 2: synthesis of compound 4-methoxy-3- (4-methoxybenzyloxy) benzoic acid

The compound methyl 4-methoxy-3- (4-methoxybenzyloxy) benzoate (16.20g,53.64mmol), lithium hydroxide monohydrate (6.80g,162.00mmol) were dissolved in a mixed solvent of tetrahydrofuran (60mL) and water (30mL) and reacted at 40 ℃ for 1.5h, the tetrahydrofuran was removed, the pH was adjusted to 1 with hydrochloric acid (1M), extraction was performed with ethyl acetate (50 mL. times.3), the organic phases were combined and then dried over anhydrous Na₂SO₄Drying and removal of the solvent gave 15.01g of a white solid in yield: 97 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.78(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.69(d,J＝1.9Hz,1H),7.42(d,J＝8.7Hz,2H),6.95–6.92(m,3H),5.14(s,2H),3.83(s,6H)；

MS-ESI:m/z 287.3[M-H]^-。

And step 3: synthesis of Compound methyl 2- (4-methoxy-3- (4-methoxybenzyloxy) benzoylamino) acetate

The compounds 4-methoxy-3- (4-methoxybenzyloxy) benzoic acid (13.0g,45.10mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13.0g,67.65mmol) and 1-hydroxybenzotriazole (9.13g,67.65mmol) were dissolved in dichloromethane (80mL), stirred at ambient temperature for 0.5h, glycine methyl ester hydrochloride (6.83g,54.20mmol) and N, N-diisopropylethylamine (24.3mL,135.30mmol) were added at 0 deg.C, stirred at room temperature for 12h, washed with water (40 mL. times.3), the organic phase was Na₂SO₄Drying, removal of solvent, column separation of the concentrate (dichloromethane/methanol (v/v) ═ 50/1) afforded 9.5g of a white solid, yield: 62 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.47(s,1H),7.38-7.34(m,3H),6.90-6.86(m,3H),6.60(br.s,1H),5.08(s,2H),4.21(d,J＝5.0Hz,2H),3.89(s,3H),3.80(s,3H),3.79(s,3H)；

MS-ESI:m/z 360.2[M+H]⁺。

and 4, step 4: synthesis of compound methyl 2- (4-methoxy-3- (4-methoxybenzyloxy) phenylthioamide) acetate

The compound methyl 2- (4-methoxy-3- (4-methoxybenzyloxy) benzoylamino) acetate (2.0g,5.57mmol) and Lawson's reagent (2.25g,5.57mmol) were dissolved in tetrahydrofuran (40mL), stirred at 75 ℃ under reflux for 2h, saturated sodium bicarbonate solution (40mL) was added, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and Na was used₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 2.05g of a yellow viscous liquid, yield: 98 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.63(s,1H),7.43-7.39(m,3H),6.92(d,J＝8.7Hz,2H),6.87(d,J＝8.4Hz,1H),5.13(s,2H),4.58(d,J＝4.5Hz,2H),3.92(s,3H),3.87(s,3H),3.82(s,3H)；

MS-ESI:m/z 376.2[M+H]⁺。

And 5: synthesis of Compound methyl 2- (((4-methoxy-3- (4-methoxybenzyloxy) phenyl) (methylthio) methylene) amino) acetate

A solution of the compound methyl 2- (4-methoxy-3- (4-methoxybenzyloxy) phenylthioamide) acetate (2.05g,5.47mmol) in dichloromethane (30mL) was slowly added dropwise at-78 ℃ to a solution of trimethyloxonium tetrafluoroborate (1.62g,10.94mmol) in dichloromethane (20mL), stirring was continued at 0 ℃ for 3h, then a saturated sodium bicarbonate solution was added and the organic phase was washed (25 mL. times.3) with anhydrous Na₂SO₄Drying and removal of the solvent gave 2.24g of a yellow oil, yield: 99 percent.

MS-ESI:m/z 390.1[M+H]⁺。

Step 6: synthesis of Compound (S) -methyl 5- (1- (tert-butoxycarbonylamino) ethyl) -2- (4-methoxy-3- (4-methoxybenzyloxy) phenyl) oxazole-4-carboxylate

The compound methyl 2- (((4-methoxy-3- (4-methoxybenzyloxy) phenyl) (methylthio) methylene) amino) acetate (2.24g,5.47mmol) and the compound tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (2.34g,12.25mmol) were dissolved in anhydrous tetrahydrofuran (20mL), a solution of potassium hexamethyldisilazide in tetrahydrofuran (16.4mL,16.4mmol) was added dropwise at-78 deg.C, the reaction was quenched with ice water (20mL) at-78 deg.C for 1h, extracted with ethyl acetate (15 mL. times.3), the organic phases were combined and then quenched with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 347mg of a yellow solid in yield: 14 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.69-7.67(m,2H),7.42(d,J＝8.6Hz,2H),6.96-6.90(m,3H),5.49-5.45(m,1H),5.14(s,2H),3.99(s,3H),3.93(s,3H),3.83(s,3H),1.55(d,J＝7.0Hz,3H),1.45(s,9H)；

MS-ESI:m/z 513.3[M+H]⁺。

And 7: synthesis of Compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (4-methoxy-3- (4-methoxybenzyloxy) phenyl) oxazole-4-carboxylic acid

The compound methyl (S) -5- (1- (tert-butoxycarbonylamino) ethyl) -2- (4-methoxy-3- (4-methoxybenzyloxy) phenyl) oxazole-4-carboxylate (374mg,0.73mmol) and lithium hydroxide monohydrate (153mg,0.95mmol) were dissolved in a mixed solvent of tetrahydrofuran (30mL) and water (15mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, the pH was adjusted to 1 with hydrochloric acid (1M), ethyl acetate was added and extracted (30 mL. times.3), and the organic phases were combined and Na was added thereto₂SO₄Drying and removal of the solvent gave 230mg of a white solid, yield: and 64 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.68-7.66(m,2H),7.43(d,J＝8.7Hz,2H),7.00-6.89(m,3H),5.44-5.40(m,1H),5.15(s,2H),3.94(s,3H),3.83(s,3H),1.59(d,J＝7.0Hz,3H),1.45(s,9H)；

MS-ESI:m/z 499.3[M+H]⁺。

And 8: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4-methoxy-3- (4-methoxybenzyloxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (4-methoxy-3- (4-methoxybenzyloxy) phenyl) oxazole-4-carboxylic acid (230mg,0.46mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (133mg,0.69mmol) and N-hydroxy-7-azabenzotriazole (93mg,0.69mmol) were dissolved in dichloromethane (15mL), stirred at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.07mL,0.55mmol) and N, N-diisopropylethylamine (0.25mL,1.38mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, water (15mL) was added, and then extracted with dichloromethane (20 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of the solvent, and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) gave 154mg of a white solid in yield: and 55 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60(dd,J₁＝8.3Hz,J₂＝2.0Hz,1H),7.58(d,J＝1.8Hz,1H),7.44-7.41(m,3H),6.96-6.84(m,5H),5.32–5.28(m,1H),5.15(s,2H),4.68-4.65(m,2H),3.94(s,3H),3.83(s, 3H),1.55(d,J＝7.0Hz,3H),1.46(s,9H)；

MS-ESI:m/z 624.3[M+H]⁺。

And step 9: synthesis of compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (3-hydroxy-4-methoxyphenyl) oxazole-4-carboxamide hydrochloride

to a solution of the compound tert-butyl (S) - (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4-methoxy-3- (4-methoxybenzyloxy) phenyl) oxazol-5-yl) ethyl) carbamate (154mg,0.25mmol) in dichloromethane (2mL) was added an ethyl acetate solution of HCl (4M,8mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 81mg of a white solid, yield: 62 percent.

compound 47:¹H NMR(400MHz,CDCl₃):δppm 7.74-7.70(m,1H),7.55(s,1H),7.47(d,J＝8.0Hz,1H),7.43-7.38(m,1H),6.90-6.81(m,2H),5.03(br.s,1H),4.60(d,J＝5.3Hz,2H),3.89(s,3H),1.89(d,J＝5.2Hz,3H)；

MS-ESI:m/z 404.1[M+H-HCl]⁺。

Example 111: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopentyloxy) -4-methoxyphenyl) -N- ((3, Synthesis of 5-dichloropyridin-4-yl) methyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (1- (2- (3- (cyclopentyloxy) -4-methoxyphenyl) -4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- (t-butoxycarbonylamino) ethyl) -2- (3- (cyclopentyloxy) -4-methoxyphenyl) oxazole-4-carboxylic acid (0.30g,0.67mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.19g,1.00mmol) and N-hydroxy-7-azabenzotriazole (0.14g,1.00mmol) were dissolved in dichloromethane (15mL), after stirring at room temperature for 0.5h, the compound (3, 5-dichloropyridin-4-yl) methylamine (0.14g,0.81mmol) and N, N-diisopropylethylamine (0.18mL,2.01mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, water (15mL) was added, extraction was performed with dichloromethane (20 mL. times.3), and the organic phases were combined and then Na was added.₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 330mg of a white solid, yield: 82 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.54(s,2H),7.56(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.47(d,J＝2.0Hz,1H),6.92(d,J＝8.5Hz,1H),5.30–5.28(m,1H),4.95(d,J＝5.8Hz,2H),4.91–4.82(m,1H),3.91(s,3H),1.99–1.84(m,6H),1.70–1.60(m,2H),1.55(d,J＝7.0Hz,3H),1.44(s,9H)；

MS-ESI:m/z 605.2[M+H]⁺。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopentyloxy) -4-methoxyphenyl) -N- ((3, 5-dichloropyridin-4-yl) methyl) oxazole-4-carboxamide dihydrochloride

To a solution of the compound tert-butyl (S) - (1- (2- (3- (cyclopentyloxy) -4-methoxyphenyl) -4- (((3, 5-dichloropyridin-4-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (330mg,0.55mmol) in dichloromethane (2mL) was added an ethyl acetate solution of HCl (4M,8mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 242mg of a white solid, yield: 88 percent.

Compound 70:¹H NMR(400MHz,CD₃OD):δppm 8.71(s,2H),7.70(d,J＝8.4Hz,1H),7.61(s,1H),7.11(d,J＝8.5Hz,1H),5.19–5.14(m,1H),4.94(s,2H),4.93–4.90(m,1H),3.91(s,3H),2.04–1.80(m,6H),1.77(d,J＝7.0Hz,3H),1.69–1.65(s,2H)；

MS-ESI:m/z 505.1[M+H-2HCl]⁺。

Example 112: the compound 5- (2-aminopropyl-2-yl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) - synthesis of N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (1-fluoro-2-methyl-1-oxopropan-2-yl) carbamic acid tert-butyl ester

N-Boc-2-aminoisobutyric acid (3.5g,14.97mmol) and triethylamine (2.3mL,16.50mmol) were dissolved in dichloromethane (30mL), and the mixture was slowly added dropwise with cyanuric acid (2.5mL,29.94mmol) at-40 deg.C, reacted further at-10 deg.C for 1h, washed with ice water (20 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 2.80g of a white solid, yield: 91 percent.

¹H NMR(400MHz,d₆-DMSO):δppm 1.40(s,6H),1.39(s,9H)。

Step 2: synthesis of Compound methyl 5- (2- (t-butoxycarbonylamino) propan-2-yl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate

The compound methyl 2- (((3- (cyclopropylmethoxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate (1.85g,5.73mmol) and the compound tert-butyl (1-fluoro-2-methyl-1-oxopropan-2-yl) carbamate (2.80g,13.66mmol) were dissolved in anhydrous tetrahydrofuran (30mL) and hexamethyl chloride was added dropwise thereto at-78 deg.CReacting tetrahydrofuran solution (20.00mL,20.00mmol) of potassium silyl amino at-78 deg.C for 1h, adding ice water (20mL) to quench the reaction, extracting with ethyl acetate (15mL × 3), combining organic phases, and adding anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 323mg of a yellow solid, yield: 15 percent.

MS-ESI:m/z 461.3[M+H]⁺。

And step 3: synthesis of Compound 5- (2- (t-butoxycarbonylamino) propan-2-yl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid

The compound methyl 5- (2- (tert-butoxycarbonylamino) propan-2-yl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylate (323mg,0.70mmol) and lithium hydroxide monohydrate (147mg,3.5mmol) were dissolved in a mixed solvent of tetrahydrofuran (30mL) and water (15mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, hydrochloric acid (1M) was added to adjust the pH to 1, ethyl acetate was added and extraction was carried out (30 mL. times.3), the organic phases were combined and Na was added thereto₂SO₄Drying and removal of the solvent gave 309mg of a white solid, yield: 99 percent.

MS-ESI:m/z 445.3[M-H]^-。

And 4, step 4: synthesis of the Compound tert-butyl (2- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) propan-2-yl) carbamate

The compounds 5- (2- (tert-butoxycarbonylamino) propan-2-yl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) oxazole-4-carboxylic acid (309mg,0.70mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (203mg,1.05mmol) and N-hydroxy-7-azabenzotriazole (142mg,1.05mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.10mL,0.84mmol) and N, N-diisopropylethylamine (0.38mL,2.10mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, water (15mL) was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 30mg of a white solid, yield: 7.5 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.51(d,J＝1.9Hz,1H),7.47–7.40(m,1H),6.94(d,J＝8.5Hz,1H),6.90–6.82(m,2H),4.65(d,J＝6.2Hz,2H),3.96(d,J＝6.9Hz,2H),3.96(s,3H),1.83(s,6H),1.43–1.38(m,1H),1.35(s,9H),0.72–0.68(m,2H),0.44–0.40(m,2H)；

MS-ESI:m/z 572.2[M+H]⁺。

And 5: synthesis of Compound 5- (2-aminopropyl-2-yl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl 2- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) propan-2-yl) carbamate (36mg,0.06mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,3mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 18.5mg of a white solid, yield: 66 percent.

Compound 71:¹H NMR(400MHz,CD₃OD):δppm 7.70(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.63(d,J＝2.0Hz,1H),7.51–7.45(m,1H),7.13(d,J＝8.5Hz,1H),7.02–6.94(m,2H),4.67(s,2H),3.94(s,3H),3.94(d,J＝6.9Hz,2H),1.85(s,6H),1.35–1.32(m,1H),0.71–0.62(m,2H),0.43–0.32(m,2H)；

MS-ESI:m/z 472.2[M+H-HCl]⁺。

Example 113: the compound 5- ((S) -1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) - Synthesis of 3- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound methyl 4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) benzoate

Methyl 3-hydroxy-4- (difluoromethoxy) benzoate (2.0g,9.18mmol), potassium carbonate (2.54g,18.38mmol) and 3-bromotetrahydrofuran (2.1g,13.9mmol) were dissolved in N, N-bisMethyl formamide (50mL), reaction at 60 ℃ for 4.5h, addition of water (40mL), extraction with ethyl acetate (50 mL. times.3), combination of the organic phases and anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 2.48g of a white solid in yield: 94 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.68(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.60(d,J＝1.9Hz,1H),7.23(d,J＝8.4Hz,1H),6.63(t,J_F-H＝74.4Hz,1H),5.08-5.04(m,1H),4.06-3.99(m,3H),3.97-3.95(m,1H),3.93(s,3H),2.33-2.17(m,2H)；

MS-ESI:289.2[M+H]⁺。

Step 2: synthesis of Compound 4- (Difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) benzoic acid

the compound methyl 4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) benzoate (2.48g,8.62mmol) and sodium hydroxide (0.83g,20.65mmol) were dissolved in a mixed solvent of ethanol (40mL) and water (20mL), reacted at 60 ℃ for 1.5h, ethanol was removed, pH was adjusted to 1 with hydrochloric acid (1M), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and then treated with anhydrous Na₂SO₄Drying and removal of the solvent gave 2.24g of a white solid in yield: 95 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.76(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.65(d,J＝1.9Hz,1H),7.26(d,J＝8.4Hz,1H),6.65(t,J_F-H＝74.2Hz,1H),5.10-5.07(m,1H),4.08–4.02(m,3H),4.01-3.97(m,1H),2.33-2.20(m,2H)；

MS-ESI:273.0[M-H]^-。

And step 3: synthesis of the compound methyl 2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) benzoylamino) acetate

The compounds 4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) benzoic acid (2.24g,8.20mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.37g,12.30mmol) and 1-hydroxybenzotriazole (1.67g,12.30mmol) were dissolved in dichloromethane (40mL), stirred at ambient temperature for 0.5h, glycine methyl ester hydrochloride (1.33g,9.84mmol) and N, N-diiso-phenyl at 0 deg.CPropylethylamine (4.4mL,24.60mmol), stirred at room temperature for 12h, washed with water (20 mL. times.3), and the organic phase Na₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 2.56g of a colorless liquid, yield: 91 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.48(d,J＝1.9Hz,1H),7.33(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.20(d,J＝8.3Hz,1H),6.85(br.s,1H),6.60(t,J_F-H＝74.4Hz,1H),5.07-5.04(m,1H),4.23(d,J＝4.9Hz,2H),4.01-3.97(m,3H),3.95-3.90(m,1H),3.81(s,3H),2.30-2.14(m,2H)；

MS-ESI:m/z 346.0[M+H]⁺。

and 4, step 4: synthesis of the compound methyl 2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenylthioamide) acetate

The compound methyl 2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) benzoylamino) acetate (2.56g,7.42mmol) and lawson's reagent (2.98g,7.42mmol) were dissolved in tetrahydrofuran (40mL), stirred at 75 ℃ under reflux for 2h, saturated sodium bicarbonate solution (30mL) was added, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and Na was used₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 2.45g of a yellow solid, yield: 92 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59(d,J＝2.0Hz,1H),7.29(dd,J₁＝8.3Hz,J₂＝2.1Hz,1H),7.20(d,J＝8.3Hz,1H),6.60(t,J_F-H＝74.6Hz,1H),5.09-5.07(m,1H),4.58(d,J＝4.4Hz,2H),4.05-3.99(m,3H),3.97-3.94(m,1H),3.88(s,3H),2.33-2.17(m,2H)；

MS-ESI:m/z 362.0[M+H]⁺。

And 5: synthesis of the compound methyl 2- (((4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenyl) (methylthio) methylene) amino) acetate

A solution of the compound methyl 2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenylthioamide) acetate (2.45g,6.79mmol) in dichloromethane (30mL) was slowly added dropwise to trimethyloxonium salt at-78 deg.CTetrafluoroboric acid (2.00g,13.58mmol) in dichloromethane (20mL) was stirred at 0 ℃ for 3h, washed with saturated sodium bicarbonate solution (25 mL. times.3) and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 2.53g of a yellow oil, yield: 99 percent.

Compound 77-5: MS-ESI: M/z 376.2[ M + H ]]⁺。

Step 6: synthesis of compound methyl 5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazole-4-carboxylate

Methyl 2- (((4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenyl) (methylthio) methylene) amino) acetate (2.53g,6.75mmol), tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (2.60g,13.5mmol) were dissolved in anhydrous tetrahydrofuran (30mL), a solution of potassium hexamethyldisilazide in tetrahydrofuran (27.0mL,27.0mmol) was added dropwise at-78 deg.C, the reaction was quenched with ice water (20mL), ethyl acetate was extracted (15 mL. times.3), the organic phases were combined and then quenched with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 1.45g of a yellow solid, yield: 45 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.68(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.65(s,1H),7.27(d,J＝8.3Hz,1H),6.62(t,J_F-H＝74.5Hz,1H),5.50-5.46(m,1H),5.15-5.13(m,1H),4.06–4.03(m,3H),4.01(s,3H),3.98-3.94(m,1H),2.34-2.20(m,2H),1.57(d,J＝7.0Hz,3H),1.45(s,9H)；

MS-ESI:m/z 499.3[M+H]⁺。

And 7: synthesis of compound 5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazole-4-carboxylic acid

The compound methyl 5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazole-4-carboxylate (1.45g,2.92mmol) and lithium hydroxide monohydrate (0.62g,14.6mmol) were dissolved in a mixed solvent of tetrahydrofuran (50mL) and water (25mL) to give a solution, 4%Reacting at 0 deg.C for 3h, removing tetrahydrofuran, adding hydrochloric acid (1M) to adjust pH to 1, extracting with ethyl acetate (30 mL. times.3), combining organic phases, and adding Na₂SO₄Drying and removal of the solvent gave 1.29g of a white solid, yield: 92 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.68-7.66(m,2H),7.28(d,J＝8.7Hz,1H),6.62(t,J_F-H＝74.6Hz,1H),5.63(br.s,1H),5.47-5.44(m,1H),5.16-5.18(m,1H),4.06-3.94(m,4H),2.36-2.20(m,2H),1.61(d,J＝4.8Hz,3H),1.45(s,9H)。

And 8: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound 5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazole-4-carboxylic acid (0.20g,0.42mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.12g,0.63mmol) and N-hydroxy-7-azabenzotriazole (0.09g,0.63mmol) were dissolved in dichloromethane (15mL), after stirring at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.06mL,0.51mmol) and N, N-diisopropylethylamine (0.23mL,1.26mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, water (15mL) was added, followed by extraction with dichloromethane (20 mL. times.3), and the organic phases were combined and then Na was added.₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 183.0mg of white solid, yield: 72 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.63(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.55(br.s,1H),7.49-7.42(m,1H),7.27(d,J＝8.4Hz,1H),6.92-6.84(m,2H),6.62(t,J_F-H＝74.5Hz,1H),5.32(br.s,1H),5.14-5.11(m,1H),4.73-4.63(m,2H),4.10-3.95(m,4H),2.34-2.20(m,2H),1.56(d,J＝7.0Hz,3H),1.45(s,9H)；

MS-ESI:m/z 610.2[M+H]⁺。

And step 9: synthesis of the Compound 5- ((S) -1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl ((1S) -1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate (183mg,0.30mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,3mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 160mg of a white solid, yield: 95 percent.

Compound 77:¹H NMR(400MHz,CD₃OD):δppm 7.79-7.75(m,2H),7.52-7.46(m,1H),7.36(d,J＝8.3Hz,1H),6.99-6.94(m,2H),6.88(t,J_F-H＝74.3Hz,1H),5.24-5.22(m,1H),5.19-5.14(m,1H),4.66(s,2H),4.07-3.99(m,3H),3.97-3.92(m,1H),2.38-2.30(m,1H),2.23-2.17(m,1H),1.78(d,J＝7.0Hz,3H)；

MS-ESI:m/z 510.1[M+H-HCl]⁺。

Example 114: the compound (S) -5- (5- (5- (1-aminoethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxa Synthesis of (2-methoxy) ethyl oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate hydrochloride

Step 1: synthesis of (2-methoxy) ethyl 5- (5- (5- (1- (tert-butoxycarbonylamino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate, compound

Dissolving compound (S) -5- (5- (5- (1- (t-butoxycarbonylamino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (253mg,0.40mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (116mg,0.60mmol) and N-hydroxy-7-azabenzotriazole (82mg,0.60mmol) in dichloromethane (10mL), stirring at room temperature for 0.5h, dropwise adding ethylene glycol monomethyl ether (0.05mL,0.60mmol) and N, N-diisopropylethylamine (0.22mL,1.20mmol) at 0 deg.C, stirring at room temperature for 12h, adding water (15mL), extracting with dichloromethane (20 mL. times.3), the organic phases were combined and washed with Na₂SO₄Drying, removing solvent, separating the concentrated solution with column (3/1 petroleum ether/ethyl acetate (v/v)),190mg of white solid are obtained, yield: 68 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60–7.57(m,1H),7.57(s,1H),7.47–7.41(m,1H),7.24(d,J＝8.2Hz,1H),6.91–6.84(m,2H),6.64(t,J_F-H＝74.6Hz,1H),5.33–5.28(m,1H),4.68–4.66(m,2H),4.27–4.24(m,2H),4.16–4.13(m,2H),3.62–3.60(m,2H),3.40(s,3H),2.49(t,J＝6.9Hz,2H),1.95–1.87(m,4H),1.56(d,J＝7.0Hz,3H),1.44(s,9H)；

MS-ESI:m/z 698.3[M+H]⁺。

Step 2: synthesis of (2-methoxy) ethyl 5- (5- (5- (1-aminoethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate hydrochloride

To a solution of the compound (S) -5- (5- (5- (1- (tert-butoxycarbonylamino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (2-methoxy) ethyl ester (190mg,0.27mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,3mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 139mg of a white solid, yield: 82 percent.

Compound 97:¹H NMR(400MHz,CD₃OD):δppm 7.81(d,J＝1.9Hz,1H),7.73(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.52–7.46(m,1H),7.34(d,J＝8.4Hz,1H),7.02–6.94(m,2H),6.88(t,J_F-H＝74.4Hz,1H),5.20–5.14(m,1H),4.65(s,2H),4.24–4.18(m,4H),3.62–3.60(m,2H),3.37(s,3H),2.49(t,J＝7.0Hz,2H),1.95–1.85(m,4H),1.78(d,J＝7.0Hz,3H)；

MS-ESI:m/z 598.2[M+H-HCl]⁺。

Example 115: the compound (S) -5- (5- (5- (1-aminoethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxa Synthesis of oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid methyl ester hydrochloride

to a solution of the compound methyl (S) -5- (5- (5- (1- (tert-butoxycarbonylamino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate (90mg,0.14mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,3mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 70mg of a white solid, yield: 92 percent.

compound 99:¹H NMR(400MHz,CD₃OD):δppm 7.79(s,1H),7.71(d,J＝8.2Hz,1H),7.50–7.44(m,1H),7.31(d,J＝8.3Hz,1H),7.01–6.89(m,2H),6.86(t,J_F-H＝74.5Hz,1H),5.17–5.15(m,1H),4.63(s,2H),4.25–4.11(m,2H),3.66(s,3H),2.45(t,J＝7.1Hz,2H),1.94–1.79(m,4H),1.76(d,J＝7.0Hz,3H)；

MS-ESI:m/z 554.1[M+H-HCl]⁺。

Example 116: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-) Synthesis of (yl) oxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound methyl 3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) benzoate

Methyl 3-cyclopropylmethoxy-4-hydroxybenzoate (2.0g,9.00mmol), potassium carbonate (3.73g,27.00mmol) and 3-bromotetrahydrofuran (2.72g,18.00mmol) were dissolved in N, N-dimethylformamide (40mL) and reacted at 60 ℃ for 4.5h, water (40mL) was added and extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and anhydrous Na was used₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 2.87g of a white solid in yield: 100 percent.

¹H NMR(400MHz,CDCl₃)δppm 7.63(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.56(d,J＝1.9Hz,1H),6.85(d,J＝8.4Hz,1H),5.05–5.02(m,1H),4.06–4.00(m,3H),3.95–3.91(m,1H),3.89(s,3H),3.88(d,J＝6.7Hz,2H),2.23–2.19(m,2H),1.34–1.28(m,1H),0.66–0.61(m,2H),0.38–0.34(m,2H)；

MS-ESI:293.3[M+H]⁺。

Step 2: synthesis of compound 3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) benzoic acid

The compound methyl 3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) benzoate (2.87g,9.83mmol) and sodium hydroxide (0.98g,24.5mmol) were dissolved in a mixed solvent of ethanol (40mL) and water (20mL), reacted at 60 ℃ for 1.5h, ethanol was removed, pH was adjusted to 1 with hydrochloric acid (1M), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and then extracted with anhydrous Na₂SO₄Drying and removal of the solvent gave 2.66g of a white solid, yield: 97 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.74(d,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.63(d,J＝2.0Hz,1H),6.89(d,J＝8.5Hz,1H),5.09–5.05(m,1H),4.09–4.03(m,3H),3.98–3.93(m,1H),3.91(d,J＝6.8Hz,2H),2.27–2.22(m,2H),1.36–1.29(m,1H),0.68–0.63(m,2H),0.40–0.37(m,2H)；

MS-ESI:279.0[M+H]⁺。

And step 3: synthesis of compound methyl 2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) benzoylamino) acetate

The compounds 3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) benzoic acid (2.66g,9.57mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.77g,14.36mmol) and 1-hydroxybenzotriazole (1.94g,14.36mmol) were dissolved in dichloromethane (40mL), stirred at ambient temperature for 0.5h, glycine methyl ester hydrochloride (1.44g,11.48mmol) and N, N-diisopropylethylamine (5.15mL,28.72mmol) were added at 0 deg.C, stirred at room temperature for 12h, washed with water (20 mL. times.3), and the organic phase was Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 2.87g of a white solid in yield: 86 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.43(d,J＝2.0Hz,1H),7.34(dd,J₁＝8.3Hz,J₂＝2.1Hz,1H),6.86(d,J＝8.3Hz,1H),6.68(br.s,1H),5.04–5.01(m,1H),4.23(d,J＝5.1Hz,2H),4.07–4.00(m,3H),3.96–3.93(m,1H),3.89(d,J＝6.8Hz,2H),3.81(s,3H),2.23–2.18(m,2H),1.34–1.27(m,1H),0.66–0.61(m,2H),0.37–0.34(m,2H)；

MS-ESI:m/z 350.1[M+H]⁺。

and 4, step 4: synthesis of compound methyl 2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenylthioamide) acetate

The compound methyl 2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) benzoylamino) acetate (2.87g,8.22mmol) and Lawson's reagent (3.32g,8.22mmol) were dissolved in tetrahydrofuran (40mL), stirred at 75 ℃ under reflux for 2h, saturated sodium bicarbonate solution (30mL) was added, extracted with ethyl acetate (50 mL. times.3), the organic phases combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) afforded 2.22g of a yellow solid, yield: 74 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.11(br.s,1H),7.53(d,J＝2.2Hz,1H),7.34(dd,J₁＝8.4Hz,J₂＝2.2Hz,1H),6.82(d,J＝8.4Hz,1H),5.04–5.00(m,1H),4.58(d,J＝4.6Hz,2H),4.06–3.99(m,3H),3.95–3.92(m,1H),3.90(d,J＝6.9Hz,2H),3.85(s,3H),2.22–2.17(m,2H),1.34–1.28(m,1H),0.66–0.61(m,2H),0.38–0.35(m,2H)；

MS-ESI:m/z 366.2[M+H]⁺。

And 5: synthesis of the compound methyl 2- (((3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenyl) (methylthio) methylene) amino) acetate

A solution of the compound methyl 2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenylthioamide) acetate (2.22g,6.08mmol) in dichloromethane (30mL) was slowly added dropwise at-78 ℃ to a solution of trimethyloxonium tetrafluoroborate (1.80g,12.20mmol) in dichloromethane (20mL), stirring was continued at 0 ℃ for 3h, washing was carried out with saturated sodium bicarbonate solution (25 mL. times.3), and the organic phase was washed with anhydrous Na₂SO₄Drying and removal of the solvent gave 2.31g of a yellow oil, yield: 93 percent.

MS-ESI:m/z 380.1[M+H]⁺。

Step 6: synthesis of compound methyl 5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazole-4-carboxylate

Methyl 2- (((3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenyl) (methylthio) methylene) amino) acetate (2.31g,6.09mmol) and tert-butyl (S) - (1-fluoro-1-oxopropan-2-yl) carbamate (2.85g,12.20mmol) were dissolved in anhydrous tetrahydrofuran (30mL), a solution of potassium hexamethyldisilazide in tetrahydrofuran (25.0mL,25.00mmol) was added dropwise at-78 deg.C, the reaction was quenched with ice water (20mL), ethyl acetate was extracted (15 mL. times.3), the organic phases were combined and then quenched with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 1.39g of a yellow solid, yield: 45 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.62(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.59(d,J＝2.2Hz,1H),6.90(d,J＝8.3Hz,1H),5.50-5.42(m,1H),5.06-5.02(m,1H),4.06-4.04(m,3H),3.99(s,3H),3.95-3.92(m,1H),3.93(d,J＝6.8Hz,2H),2.24-2.19(m,2H),1.55(d,J＝7.0Hz,3H),1.44(s,9H),1.32–1.29(m,1H),0.68-0.63(m,2H),0.40-0.36(m,2H)；

MS-ESI:m/z 503.2[M+H]⁺。

And 7: synthesis of compound 5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazole-4-carboxylic acid

The compound methyl 5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazole-4-carboxylate (1.39g,2.77mmol) and lithium hydroxide monohydrate (0.59g,13.80mmol) were dissolved in a mixed solvent of tetrahydrofuran (30mL) and water (15mL) and reacted at 40 ℃ for 3 hours to remove tetrahydrofuran, the pH was adjusted to 1 with hydrochloric acid (1M), ethyl acetate was added and extracted (30 mL. times.3), the organic phases were combined and Na was added₂SO₄drying and removal of the solvent gave 1.35g of a white solid, yield: 96 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.64–7.61(m,2H),6.91(d,J＝8.2Hz,1H),5.46–5.44(m,1H),5.06–5.03(m,1H),4.10–4.00(m,3H),3.99–3.90(m,1H),3.89(d,J＝6.8Hz,2H),2.32–2.15(m,2H),1.58(d,J＝7.0Hz,3H),1.44(s,9H),1.34–1.32(m,1H),0.67–0.64(m,2H),0.40–0.37(m,2H)；

MS-ESI:m/z 487.3[M-H]^-。

And 8: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 5- ((S) -1- (tert-butoxycarbonylamino) ethyl) -2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenyl) oxazole-4-carboxylic acid (0.32g,0.65mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.19g,0.99mmol) and N-hydroxy-7-azabenzotriazole (0.14g,1.02mmol) were dissolved in dichloromethane (15mL), after stirring at room temperature for 0.5h, 2, 4-difluorobenzylamine (0.10mL,0.90mmol) and N, N-diisopropylethylamine (0.40mL,2.25mmol) were added dropwise at 0 ℃ and stirred at room temperature for 12h, water (15mL) was added, followed by extraction with dichloromethane (20 mL. times.3), and the organic phases were combined and then Na was added.₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 302mg of a white solid, yield: 75 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.57(d,J＝8.4Hz,1H),7.51(s,1H),7.46–7.40(m,1H),7.01–6.77(m,3H),5.30–5.28(m,1H),5.06–5.02(m,1H),4.72–4.58(m,2H),4.10–4.00(m,3H),3.98–3.92(m,1H),3.89(d,J＝6.8Hz,2H),2.25–2.20(m,2H),1.54(d,J＝7.0Hz,3H),1.44(s,9H),0.93–0.82(m,1H),0.70–0.60(m,2H),0.41–0.37(m,2H)；

MS-ESI:m/z 614.3[M+H]⁺。

And step 9: synthesis of compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl ((1S) -1- (2- (3- (cyclopropylmethoxy) -4- ((tetrahydrofuran-3-yl) oxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (302mg,0.49mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,3mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 235mg of a white solid, yield: 87 percent.

Compound 104:¹H NMR(400MHz,CD₃OD):δppm 7.82–7.59(m,2H),7.51–7.46(m,1H),7.10(d,J＝8.4Hz,1H),7.00–6.94(m,2H),5.20–5.12(m,2H),4.64(s,2H),4.08–3.81(m,6H),2.38–2.09(m,2H),1.78(d,J＝7.0Hz,3H),1.34–1.28(m,1H),0.72–0.51(m,2H),0.41–0.36(m,2H)；

MS-ESI:m/z 514.3[M+H-HCl]⁺。

Example 117: the compound 5- ((S) -1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) - Synthesis of 3- (4- ((2-oxotetrahydrofuran-3-yl) amino) butoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the compound (S) -butyl 4- (5- (5- (1- (tert-butoxycarbonylamino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) acetate

The compound tert-butyl (S) - (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate (1.30g,2.4mmol), potassium carbonate (0.65g,4.7mmol) and 4-bromobutyl acetate (0.40mL,3.0mmol) were dissolved in N, N-dimethylformamide (20mL), reacted at 60 ℃ for 4.5h, after addition of water (30mL), extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and dried over anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 1.50g of a white solid in yield: 95 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59–7.56(m,2H),7.45–7.39(m,1H),7.23(d,J＝8.1Hz,1H),6.89–6.84(m,2H),6.61(t,J_F-H＝74.5Hz,1H),5.34–5.29(m,1H),4.70–4.60(m,2H),4.18–4.13(m,6H),2.05(s,3H),1.96–1.93(m,2H),1.89–1.83(m,2H),1.53(t,J＝7.0Hz,3H),1.43(s,9H)；

MS-ESI:654.2[M+H]⁺。

Step 2: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- (4-hydroxybutoxy) phenyl) oxazol-5-yl) ethyl) carbamate

the compound (S) -butyl 4- (5- (5- (1- (tert-butoxycarbonylamino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) acetate (1.50g,2.29mmol) and lithium hydroxide monohydrate (0.6g,14.29mmol) were dissolved in a mixed solvent of tetrahydrofuran (40mL) and water (20mL) and reacted at 40 ℃ for 6 hours to remove tetrahydrofuran, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined and Na was added₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 1.34g of a white solid in yield: 95 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60–7.57(m,2H),7.46–7.40(m,1H),7.24(d,J＝8.8Hz,1H),6.90–6.86(m,2H),6.63(t,J_F-H＝74.5Hz,1H),5.33–5.31(m,1H),4.71–4.62(m,2H),4.18(t,J＝6.2Hz,2H),3.77(t,J＝6.3Hz,2H),2.02–1.95(m,2H),1.87–1.77(m,2H),1.55(d,J＝7.0Hz,3H),1.44(s,9H)；

MS-ESI:610.1[M-H]^-。

And step 3: synthesis of the compound (S) -butyl 4- (5- (5- (1- (tert-butoxycarbonylamino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) 4-methylbenzenesulfonate

the compound tert-butyl (S) - (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- (4-hydroxybutoxy) phenyl) oxazol-5-yl) ethyl) carbamate (1.32g,2.16mmol) and 4-methylbenzenesulfonyl chloride (1.20g,6.29mmol) were dissolved in dichloromethane (40mL), triethylamine (0.9mL,6.5mmol) was added dropwise at 0 ℃ and reacted at 0 ℃ for 6h, dichloromethane was added and extracted (30 mL. times.3), the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 1.60g of a white solid, yield: 96 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.80(d,J＝8.3Hz,2H),7.59(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.56(d,J＝1.8Hz,1H),7.46–7.40(m,1H),7.35(d,J＝8.0Hz,2H),7.23(d,J＝8.3Hz,1H),6.90–6.84(m,2H),6.56(t,J_F-H＝74.3Hz,1H),5.34–5.30(m,1H),4.71–4.61(m,2H),4.17–4.10(m,4H),2.45(s,3H),1.95–1.89(m,4H),1.55(d,J＝7.0Hz,3H),1.44(s,9H)；

MS-ESI:766.2[M+H]⁺。

And 4, step 4: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (4-azidobutoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -butyl 4- (5- (5- (1- (tert-butoxycarbonylamino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) 4-methylbenzenesulfonate (1.60g,2.09mmol) and sodium azide (0.7g,10.0mmol) were dissolved in a mixed solvent of acetone (30mL) and water (10mL) and reacted at 80 ℃ for 6 hours to remove acetone, ethyl acetate was added and extracted (30 mL. times.3), and the organic phases were combined and Na was added₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 1.30g of a white solid in yield: 97 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60(dd,J₁＝8.3Hz,J₂＝1.8Hz,1H),7.58(d,J＝1.7Hz,1H),7.47–7.41(m,1H),7.25(d,J＝8.2Hz,1H),6.92–6.84(m,2H),6.61(t,J_F-H＝74.4Hz,1H),5.33–5.28(m,1H),4.72–4.62(m,2H),4.17(t,J＝6.0Hz,2H),3.43(t,J＝6.6Hz,2H),2.02–1.95(m,2H),1.89–1.82(m,2H),1.56(d,J＝7.0Hz,3H),1.45(s,9H)；

MS-ESI:637.3[M+H]⁺。

And 5: synthesis of the Compound (S) - (tert-butyl 1- (2- (3- (4-aminobutoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl (S) - (1- (2- (3- (4-azidobutoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (1.298g,2.039mmol) was reacted withTriphenylphosphine (0.85g,3.2mmol) was dissolved in a mixed solvent of ethyl acetate (25mL) and water (5mL), reacted at room temperature for 6h, extracted with ethyl acetate (30 mL. times.3), the organic phases combined and Na was added₂SO₄Drying, solvent removal, and column separation of the concentrated solution (methanol/dichloromethane (v/v) ═ 10/1) gave 1.177g of a white solid in yield: 94 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.58–7.53(m,2H),7.44–7.39(m,1H),7.20(d,J＝8.3Hz,1H),6.88–6.83(m,2H),6.67(t,J＝74.1Hz,1H),5.31–5.22(m,1H),4.66–4.64(m,2H),4.17–4.12(m,2H), 3.11–3.06(m,2H),1.98–1.89(m,4H),1.55(d,J＝7.0Hz,3H),1.43(s,9H)；

MS-ESI:611.3[M+H]⁺。

Step 6: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- (4- ((2-oxotetrahydrofuran-3-yl) amino) butoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -tert-butyl (1- (2- (3- (4-aminobutoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (500mg,0.82mmol), 2-bromo-gamma-butyrolactone (201.6mg,1.23mmol) and potassium carbonate (250mg,1.81mmol) were added to anhydrous N, N-dimethylformamide (10mL), reacted at 90 ℃ for 1h, water (20mL) was added, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined and Na was used₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) afforded 216mg of a white solid, yield: 38 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59–7.57(m,2H),7.46–7.41(m,1H),7.25–7.22(m,1H),6.89–6.84(m,2H),6.64(t,J_F-H＝74.6Hz,1H),5.39–5.25(m,1H),4.71–4.63(m,2H),4.50–4.46(m,1H),4.29–4.23(m,1H),4.18–4.10(m,2H),3.84–3.76(m,1H),3.13–3.05(m,1H),2.98–2.86(m,1H),2.66–2.58(m,1H),2.42–2.35(m,1H),2.00–1.89(m,4H),1.56(d,J＝7.0Hz,3H),1.44(s,9H)；

MS-ESI:695.9[M+H]⁺。

And 7: synthesis of the compound 5- ((S) -1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) -3- (4- ((2-oxotetrahydrofuran-3-yl) amino) butoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of the compound tert-butyl ((1S) -1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- (4- ((2-oxotetrahydrofuran-3-yl) amino) butoxy) phenyl) oxazol-5-yl) ethyl) carbamate (206mg,0.29mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 116mg of a white solid in yield: 62 percent.

Compound 105:¹H NMR(400MHz,CD₃OD):δppm 7.58–7.55(m,2H),7.46–7.41(m,1H),7.25–7.22(m,1H),6.89–6.84(m,2H),6.64(t,J_F-H＝74.6Hz,1H),5.42–5.22(m,1H),4.75–4.58(m,2H),4.50–4.46(m,1H),4.33–4.08(m,3H),3.84–3.76(m,1H),3.15–3.00(m,1H),2.92–2.86(m,1H),2.66–2.58(m,1H),2.42–2.35(m,1H),2.01–1.83(m,4H),1.56(d,J＝7.0Hz,3H)；

MS-ESI:595.1[M+H-HCl]⁺。

Example 118: the compound (S) -5- (5- (5- (1-aminoethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxa Synthesis of oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid hydrochloride

To a solution of the compound (S) -5- (5- (5- (1- (tert-butoxycarbonylamino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (194mg,0.30mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,3mL), stirred at room temperature for 0.5h, after removal of the solvent, recrystallized from methanol/ethyl acetate (v/v ═ 1/20) to give 70mg of a white solid, yield: 92 percent.

Compound 113:¹H NMR(600MHz,CD₃OD):δppm 7.82(d,J＝1.8Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.50–7.47(m,1H),7.33(d,J＝8.3Hz,1H),7.00–6.96(m,2H),6.88(t,J_F-H＝74.4Hz,1H),5.20–5.17(m,1H),4.65(s,2H),4.20(t,J＝6.1Hz,2H),2.43(t,J＝7.2Hz,2H),1.94–1.90(m,2H),1.87–1.83(m,2H),1.78(d,J＝7.0Hz,3H)；

MS-ESI:m/z 540.9[M+H-HCl]⁺。

Example 119: the compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) - Synthesis of 3- ((5- (methylamino) -5-oxopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5- (methylamino) -5-oxopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (300mg,0.496mmol), methylamine hydrochloride (38mg,0.563mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (134mg,0.704mmol) and N-hydroxy-7-azabenzotriazole (96mg,0.704mmol) were dissolved in dichloromethane (20mL) and stirred at room temperature for 30min, to this solution was added dropwise N, N-diisopropylethylamine (0.33mL,1.876 mmol) at 0 ℃ and stirred at room temperature for 10 hours, followed by addition of water (25mL) and extraction with dichloromethane (25 mL. times.3). Combining the organic phases, using anhydrous Na for the organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) afforded 255mg of white solid, yield: 83.3 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.58-7.60(m,2H),7.42-7.46(m,1H),7.24(d,J＝8.4Hz,1H),6.85-6.91(m,2H),6.63(t,J_F-H＝74.4Hz,1H),5.65(br.s,1H),5.31-5.32(m,1H),4.66-4.69(m,2H),4.12-4.17(m,2H),2.83(s,3H),2.30-2.35(m,2H),1.86-1.99(m,4H),1.56(d,J＝6.8Hz,3H),1.45(s,9H)；

MS-ESI:m/z 653.20[M+H]⁺。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) -3- ((5- (methylamino) -5-oxopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5- (methylamino) -5-oxopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate (250mg,0.383mmol) 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 give 225.6mg of a white solid, yield: 100 percent.

Compound 162:¹H NMR(600MHz,CD₃OD):δppm 7.82(s,1H),7.72(d,J＝7.8Hz,1H),7.47-7.49(m,1H),7.31(d,J＝7.8Hz,1H),6.95-7.0(m,2H),6.87(t,J_F-H＝74.4Hz,1H),5.15-5.19(m,1H),4.63(s,2H),4.19(m,2H),2.77(s,3H),2.37(m,2H),1.86-1.99(m,4H),1.78(d,J＝7.0Hz,3H)；

MS-ESI:m/z 553.20[M+H-HCl]⁺。

Example 120: the compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) - Synthesis of 3- ((5- (dimethylamino) -5-oxopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5- (dimethylamino) -5-oxopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate

dissolving compound (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (334mg,0.5222mmol), dimethylamine hydrochloride (52mg,0.6266mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (151mg,0.7833mmol) and N-hydroxy-7-azabenzotriazole (107mg,0.7833mmol) in dichloromethane (20mL), stirring at room temperature for 30min, adding N, N-diisopropylethylamine (0.36mL,2.089mmol) dropwise to the solution at 0 deg.C, and stirring at room temperature for 1.20mmolAfter 0h, water (25mL) was added, extracted with dichloromethane (25 mL. times.3), and the organic phases combined. Anhydrous Na for organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) afforded 252mg of a white solid in yield: 72.38 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.58-7.59(m,2H),7.42-7.46(m,1H),7.24(d,J＝8.7Hz,1H),6.85-6.91(m,2H),6.64(t,J_F-H＝74.6Hz,1H),5.29-5.34(m,1H),4.67-4.69(m,2H),4.15-4.18(m,2H),3.04(s,3H),2.97(s,3H),2.44-2.47(m,2H),1.93-1.98(m,2H),1.86-1.91(m,2H),1.56(d,J＝7.0Hz,3H),1.45(s,9H)；

MS-ESI:m/z 667.2[M+H]⁺。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) -3- ((5- (dimethylamino) -5-oxopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5- (dimethylamino) -5-oxopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate (252mg,0.378mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, the solvent was removed to give 233mg of a white solid, yield: 102.2 percent.

Compound 176:¹H NMR(600MHz,CD₃OD):δppm 7.81(d,J＝1.8Hz,1H),7.72(dd,J₁＝8.3Hz,J₂＝1.8Hz,1H),7.46-7.50(m,1H),7.33(d,J＝8.3Hz,1H),6.95-7.0(m,2H),6.89(t,J_F-H＝74.4Hz,1H),5.15-5.19(m,1H),4.65(s,2H),4.19-4.21(m,1H),3.01(s,3H),2.94(s,3H),2.51-2.53(m,1H),1.91-1.96(m,2H),1.81-1.86(m,2H),1.77(d,J＝7.0Hz,3H)；

MS-ESI:m/z 567.20[M+H-HCl]⁺。

Example 121: the compound (S) -5- (1-aminoethyl) -2- (3- ((5- ((cyclopropylmethyl) amino) -5-oxopentane synthesis of (yl) oxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- ((5- ((cyclopropylmethyl) amino) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

Dissolving compound (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (300mg,0.469mmol), cyclopropylmethylamine (40mg,0.563mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (135mg,0.7036mmol) and N-hydroxy-7-azabenzotriazole (96mg,0.7036mmol) in dichloromethane (20mL), stirring at room temperature for 30min, dropwise adding N, N-diisopropylethylamine (0.25mL,1.407mmol) to the solution at 0 ℃, stirring at room temperature for 10h, adding water (25mL), extracting with dichloromethane (25 mL. times.3), the organic phases were combined. Anhydrous Na for organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) afforded 322mg of a white solid, yield: 99.11 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.58-7.60(m,2H),7.43-7.46(m,1H),7.25(d,J＝6.0Hz,1H),6.85-6.91(m,2H),6.64(t,J_F-H＝74.4Hz,1H),5.67(br.s,1H),5.28-5.32(m,1H),4.64-4.71(m,2H),4.13-4.18(m,2H),3.13-3.15(m,2H),2.33(t,J＝6.6Hz,2H),1.90-1.96(m,4H),1.56(d,J＝7.0Hz,3H),1.45(s,9H),0.94-0.99(m,1H),0.51-0.54(m,2H),0.20-0.23(m,2H)；

MS-ESI:m/z 693.2[M+H]⁺。

Step 2: synthesis of the compound (S) -5- (1-aminoethyl) -2- (3- ((5- ((cyclopropylmethyl) amino) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound (S) - (1- (2- (3- ((5- ((cyclopropylmethyl) amino) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (322mg,0.4648mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, the solvent was removed to give 285mg of a white solid, yield: 97.47 percent.

Compound 177:¹H NMR(400MHz,CD₃OD):δppm 7.82(d,J＝1.8Hz,1H),7.72(dd,J₁＝1.8Hz,J₂＝8.4Hz,1H),7.46-7.52(m,1H),7.33(d,J＝8.4Hz,1H),6.94-7.01(m,2H),6.88(t,J_F-H＝74.5Hz,1H),5.15-5.20(m,1H),4.65(s,2H),4.19-4.22(m,2H),3.06(d,J＝7.0Hz,2H),2.33-2.36(m,2H),1.86-1.92(m,4H),1.78(d,J＝7.2Hz,3H),0.94-1.02(m,1H),0.47-0.52(m,2H),0.19-0.23(m,2H)；

MS-ESI:m/z 593.20[M+H-HCl]⁺。

Example 122: the compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) - Synthesis of 3- ((5-oxo-5- (4- (pyrimidin-2-yl) piperazin-1-yl) pentyl) oxy) phenyl) oxazole-4-carboxamide dihydrochloride Become into

Step 1: synthesis of the Compound tert-butyl (S) - (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5-oxo-5- (4- (pyrimidin-2-yl) piperazin-1-yl) pentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate

Dissolving compound (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (300mg,0.469mmol), 1- (2-pyrimidinyl) piperazine (93mg,0.469mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (135mg,0.7036mmol) and N-hydroxy-7-azabenzotriazole (96mg,0.7036mmol) in dichloromethane (20mL), stirring at room temperature for 30min, dropwise adding N, N-diisopropylethylamine (0.25mL,1.407mmol) to the solution at 0 ℃, stirring at room temperature for 10h, adding water (25mL), extraction was carried out with dichloromethane (25 mL. times.3) and the organic phases were combined. Anhydrous Na for organic phase₂SO₄Drying, removal of the solvent, and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) gave 284mg of a white solid in yield: 77.05 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.35(d,J＝4.8Hz,2H),7.58-7.60(m,2H),7.41-7.45(m,1H),7.24(d,J＝8.8Hz,1H),6.84-6.92(m,2H),6.64(t,J_F-H＝74.8Hz,1H),6.56(t,J＝4.8Hz,1H),5.30-5.35(m,1H),4.66-4.69(m,2H),4.17-4.20(m,2H),3.83-3.89(m,4H),3.71-3.74(m,2H),3.57-3.60(m,2H),2.51-2.55(m,2H),1.90-1.98(m,4H),1.56(d,J＝7.2Hz,3H),1.45(s,9H)；

MS-ESI:m/z 786.20[M+H]⁺。

step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) -3- ((5-oxo-5- (4- (pyrimidin-2-yl) piperazin-1-yl) pentyl) oxy) phenyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5-oxo-5- (4- (pyrimidin-2-yl) piperazin-1-yl) pentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate (284mg,0.3614mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, the solvent was removed to give 271.1mg of a white solid, yield: 99 percent.

Compound 178:¹H NMR(400MHz,CD₃OD):δppm 8.65(d,J＝5.2Hz,2H),7.84(d,J＝2.0Hz,1H),7.73(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.46-7.52(m,1H),7.33(d,J＝8.4Hz,1H),7.05(t,J＝5.2Hz,1H),6.94-7.01(m,2H),6.90(t,J_F-H＝74.4Hz,1H),5.15-5.21(m,1H),4.65(s,2H),4.22-4.25(m,2H),4.02-4.05(m, 2H),3.93-3.96(m,2H),3.81-3.86(m,4H),2.61-2.64(m,2H),1.87-1.99(m,4H),1.78(d,J＝7.2Hz,3H)；

MS-ESI:m/z 343.70[M+2H-2HCl]²⁺。

Example 123: the compound (S) -5- (1-aminoethyl) -2- (3- ((5- (4- (cyclopropylformyl) piperazin-1-yl) - Synthesis of 5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride Become into

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- ((5- (4- (cyclopropylformyl) piperazin-1-yl) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

Dissolving compound (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (300mg,0.469mmol), N-cyclopropylcarbonylpiperazine hydrochloride (107mg,0.5690mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (135mg,0.7036mmol) and N-hydroxy-7-azabenzotriazole (96mg,0.7036mmol) in dichloromethane (20mL), stirring at room temperature for 30min, dropwise adding N, N-diisopropylethylamine (0.25mL,1.407mmol) to the solution at 0 ℃, stirring at room temperature for 10h, adding water (25mL), the layers were separated, the aqueous layer was extracted with dichloromethane (25 mL. times.3), and the organic layers were combined. Anhydrous Na for organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) afforded 251mg of a white solid, yield: 69.0 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59-7.61(m,2H),7.42-7.47(m,1H),7.24(d,J＝8.0Hz,1H),6.84-6.92(m,2H),6.63(t,J_F-H＝74.8Hz,1H),5.28-5.33(m,1H),4.66-4.69(m,2H),4.18(t,J＝6.0Hz,2H),3.51-3.70(m,8H),2.50(t,J＝6.4Hz,2H),1.91-1.97(m,4H),1.56(d,J＝7.2Hz,3H),1.45(s,9H),1.30-1.35(m,1H),1.02-1.05(m,2H),0.80-0.85(m,2H)；

MS-ESI:m/z 776.25[M+H]⁺。

Step 2: synthesis of the compound (S) -5- (1-aminoethyl) -2- (3- ((5- (4- (cyclopropylformyl) piperazin-1-yl) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound (S) - (1- (2- (3- ((5- (4- (cyclopropylformyl) piperazin-1-yl) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (251mg,0.3235mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, and the solvent was removed to give 225mg of a white solid, yield: 97.66 percent.

Compound 179:¹H NMR(400MHz,CD₃OD):δppm 7.83(d,J＝2.0Hz,1H),7.73(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.46-7.52(m,1H),7.33(d,J＝8.4Hz,1H),6.94-7.02(m,2H),6.90(t,J_F-H＝74.4Hz,1H),5.15-5.20(m,1H),4.65(s,2H),4.22(t,J＝6.0Hz,2H),3.59-3.83(m,8H),2.58(t,J＝7.2Hz,2H),1.92-2.04(m,2H),1.85-1.90(m,2H),1.78(d,J＝6.8Hz,3H),1.34-1.36(m,1H),0.89-0.92(m,2H),0.84-0.88(m,2H)；

MS-ESI:m/z 676.20[M+H-HCl]⁺。

Example 124: the compound 5- ((S) -1-aminoethyl) -2- (3- ((5- (4- (cyclopropylformyl) piperazin-1-yl) - 5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -N- (2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorobenzene Synthesis of yl) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -4- ((cyano (2, 4-difluorophenyl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) oxazole-4-carboxylic acid (940mg,1.9mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (540mg,2.8mmol) and N-hydroxy-7-azabenzotriazole (380mg,2.8mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, 2-amino-2- (2, 4-difluorophenyl) acetonitrile hydrochloride (460mg,2.2mmol) was added, to this solution was added dropwise N, N-diisopropylethylamine (1.3mL,7.5mmol) at 0 ℃, stirred at room temperature for 10h, washed with water (25 mL. times.3), the aqueous phase was back-extracted with dichloromethane (15 mL. times.3), the organic phases were combined and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of the solvent, and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 7/1) gave 645mg of a white solid in yield: 53 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.69-7.70(m,1H),7.66-7.68(m,1H),7.62(dd,J₁＝8.4Hz,J₂＝1.5Hz,1H),7.38-7.51(m,5H),7.29(d,J＝7.6Hz,1H),6.96-7.03(m,2H),6.66(t,J_F-H＝74.4Hz,1H),6.39(d,J＝8.8Hz,1H),5.30-5.34(m,1H),5.25-5.37(d,J＝2.0Hz,1H),1.54-1.58(m,3H),1.46(s,9H)；

MS-ESI:m/z 677.15[M+Na]⁺。

Step 2: synthesis of the compound 2- (2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid

The compound tert-butyl ((1S) -1- (2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -4- ((cyano (2, 4-difluorophenyl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.645g,0.985mmol) and sodium hydroxide (2.244g,56.1mmol) were dissolved in water (10mL) and ethanol (10mL), stirred at 75 ℃ for 4h, ethanol was spun dry, pH was adjusted to 1 with hydrochloric acid (1M), ethyl acetate was extracted (20 mL. times.3), the organic phases were combined, and the organic phase was washed with anhydrous Na₂SO₄drying and removal of the solvent gave 0.452g of a pale red solid, yield: 68.1 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.71(d,J＝2.0Hz,1H),7.62-7.66(m,1H),7.35-7.52(m,6H),7.27(d,J＝7.6Hz,1H),6.88-6.96(m,2H),6.66(t,J_F-H＝74.4Hz,1H),5.98-6.01(m,1H),5.32-5.37(m,1H),5.25(s,2H),1.47-1.53(m,3H),1.39-1.40(m,9H)；

MS-ESI:m/z 696.15[M+Na]⁺。

And step 3: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

2- (2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) oxazole-4-carboxamido) -2- (2, 4-difluorophenyl) acetic acid (452mg,0.671mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (193mg,1.01mmol) and N-hydroxy-7-azabenzotriazole (137mg,1.01mmol) were dissolved in dichloromethane (20mL) and stirred at room temperature for 30min, cyclopropylmethylamine (71.6mg,1.01mmol) was addedTo this solution was added dropwise N, N-diisopropylethylamine (0.47mL,2.68mmol) at 0 ℃ and stirred at room temperature for 10 hours, then washed with water (25 mL. times.3), the aqueous phase was extracted with dichloromethane (25 mL. times.3), the organic phases were combined and the organic phase was extracted with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 287mg of white solid, yield: 58.9 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.76(d,J＝2.0Hz,1H),7.65-7.67(m,1H),7.52-7.54(m,3H),7.43-7.47(m,2H),7.38-7.74(m,1H),7.29(d,J＝7.6Hz,1H),6.90-6.94(m,2H),6.67(t,J_F-H＝74.8Hz,1H),5.86-5.89(m,1H),5.30-5.32(m,1H),5.28(s,2H),3.15-3.20(m,2H),1.47-1.53(m,3H),1.39-1.40(m,9H),1.33-1.34(m,1H),0.52-0.54(m,2H),0.18-0.23(m,2H)；

MS-ESI:m/z 727.25[M+H]⁺。

And 4, step 4: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (4- (difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (287mg,0.395mmol) and nickel chloride (51.2mg,0.395mmol) were dissolved in ethanol (10mL), stirred at room temperature, a solution of sodium borohydride (75mg,1.97mmol) in ethanol (20mL) was slowly added dropwise in an ice bath, stirred at room temperature for 1.5h, adjusted to pH 1 by adding hydrochloric acid (1M), stirred at room temperature until the reaction solution was clear, adjusted to pH 14 by adding sodium hydroxide solution (1M), extracted with ethyl acetate (25 mL. times.3), the organic phases were combined, anhydrous Na₂SO₄Drying and removal of the solvent gave a reddish-brown solid 0.246g, yield: 97.8 percent.

MS-ESI:m/z 637.30[M+H]⁺。

And 5: synthesis of the compound methyl 5- (5- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate

The compound tert-butyl ((1S) -1- (4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (4- (difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate (246mg,0.386mmol), methyl 5-bromovalerate (113mg,0.58mmol) and potassium carbonate (107mg,0.773mmol) were added to DMF (15mL), the reaction was blocked at 60 ℃ for 5 hours, suction filtered, potassium carbonate was removed, the filtrate was concentrated, column separation was performed (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give 232mg of a white solid, yield: 80 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.63-7.65(m,2H),7.48-7.55(m,1H),7.26(d,J＝8.8Hz,1H),6.84-6.95(m,2H),6.65(t,J_F-H＝74.8Hz,1H),5.86-5.89(m,1H),5.28-5.36(m,1H),4.18-4.21(m,2H),3.70(s,3H),3.13-3.23(m,2H),2.45-2.49(m,2H),1.89-1.97(m,4H),1.47-1.48(m,3H),1.40-1.44(m,9H),1.30-1.31(m,1H),0.51-0.53(m,2H),0.18-0.22(m,2H)；

MS-ESI:m/z 751.20[M+H]⁺。

Step 6: synthesis of the compound 5- (5- (5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) -4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid

The compound methyl 5- (5- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate (232mg,0.309mmol) and sodium hydroxide solid (61mg,1.55mmol) were dissolved in a mixed solvent of water (10mL) and ethanol (20mL), reacted at 60 ℃ for 2h, rotary evaporated to remove ethanol, adjusted to pH 1 with hydrochloric acid (1M), extracted with ethyl acetate (25 mL. times.3), the organic phases were combined, anhydrous Na₂SO₄Drying and removal of the solvent gave 210mg of a pale yellow oil, yield: 92.2 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.82-7.85(m,1H),7.50-7.59(m,2H),7.26(d,J＝8.0Hz,1H),6.87-6.95(m,2H),6.64(t,J_F-H＝74.7Hz,1H),5.86(m,1H),5.35-5.37(m,1H),4.26-4.29(m,2H),3.13-3.21(m,2H),2.49(m,2H),1.81-1.90(m,4H),1.49-1.54(m,3H),1.39-1.49(m,9H),1.31-1.36(m,1H),0.51-0.53(m,2H),0.20-0.22(m,2H)；

MS-ESI:m/z 737.20[M+H]⁺。

And 7: synthesis of the Compound tert-butyl ((1S) -1- (2- (3- ((5- (4- (cyclopropylformyl) piperazin-1-yl) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound 5- (5- (5- ((S) -1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (210mg,0.28mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (80mg,0.42mmol) and N-hydroxy-7-azabenzotriazole (57mg,0.42mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, N-cyclopropylcarbonylpiperazinate (80mg,0.42mmol) was added, N was added dropwise to the solution at 0 ℃, n-diisopropylethylamine (0.20mL,1.12mmol), stirred at room temperature for 10h, washed with water (25 mL. times.3), the aqueous phase extracted with dichloromethane (15 mL. times.3), the organic phases combined and the organic phase over anhydrous Na₂SO₄Drying, removal of the solvent, and column separation of the concentrated solution (petroleum ether/ethyl acetate (v/v) ═ 1/2) gave 211mg of a white solid in yield: 86.4 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.63-7.65(m,2H),7.48-7.53(m,1H),7.24(d,J＝8.4Hz,1H),6.89-6.95(m,2H),6.64(t,J_F-H＝74.8Hz,1H),5.86-5.87(m,1H),5.28-5.34(m,1H),4.22(t,J＝5.6Hz,2H),3.53-3.70(m,8H),3.13-3.24(m,2H),2.52(t,J＝6.8Hz,2H),1.93-2.01(m,4H),1.48-1.53(m,3H),1.40-1.43(m,9H),1.32-1.35(m,1H),1.27-1.30(m,1H),1.02-1.05(m,2H),0.80-0.85(m,2H),0.51-0.55(m,2H),0.19-0.20(m,2H)；

MS-ESI:m/z 873.30[M+H]⁺。

And 8: synthesis of the compound 5- ((S) -1-aminoethyl) -2- (3- ((5- (4- (cyclopropylformyl) piperazin-1-yl) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -N- (2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (2- (3- ((5- (4- (cyclopropylformyl) piperazin-1-yl) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -4- ((2- ((cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (211mg,0.242mmol) in dichloromethane (2mL) was added an ethyl acetate solution of HCl (4M,2mL), stirred at room temperature for 30min, the solvent was removed to give 195mg of a white solid, yield: 99.7 percent.

Compound 196:¹H NMR(400MHz,CD₃OD):δppm 7.83(s,1H),7.73(d,J＝8.4Hz,1H),7.58(m,1H),7.34(d,J＝8.4Hz,1H),7.04-7.09(m,2H),6.90(t,J_F-H＝74.4Hz,1H),5.92(d,J＝1.4Hz,1H),5.16-5.20(m,1H),4.23(t,J＝6.0Hz,2H),3.59-3.84(m,8H),3.01-3.18(m,2H),2.57-2.60(t,J＝7.2Hz,2H),1.87-2.01(m,4H),1.76(d,J＝6.8Hz,3H),1.30-1.35(m,2H),0.83-0.93(m,4H),0.45-0.50(m,2H),0.19-0.22(m,2H)；

MS-ESI:m/z 773.25[M+H-HCl]⁺。

Example 125: the compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) - Synthesis of 3- ((5- (methylsulfonylamino) -5-oxopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5- (methylsulfonylamino) -5-oxopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compounds (S) -5- (5- (5- (1- ((tert-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (200mg,0.313mmol) and N, N' -carbonyldiimidazole (152mg,0.938mmol) were dissolved in anhydrous tetrahydrofuran (20mL), stirred at 60 ℃ for 20min, cooled to room temperature, and after adding methylsulfonamide (119mg,1.25mmol) and 1, 8-diazabicyclo [5.4.0 ]]undec-7-ene (71.4mg,0.469mmol), stirred at 60 ℃ for 3.5h, washed with saturated ammonium chloride solution (25 mL. times.3), the aqueous phase extracted with ethyl acetate (25mL),Combining the organic phases, using anhydrous Na for the organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) afforded 112mg of a white solid, yield: 50 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.58-7.62(m,2H),7.40-7.46(m,1H),7.24(d,J＝8.4Hz,1H),6.83-6.91(m,2H),6.64(t,J_F-H＝74.0Hz,1H),5.31-5.33(m,1H),4.66-4.68(m,2H),4.12-4.17(m,2H),3.31(s,3H),2.51-2.54(m,2H),1.94-1.96(m,4H),1.56(d,J＝6.8Hz,2H),1.45-1.47(m,9H)；

MS-ESI:m/z 717.30[M+H]⁺。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) -3- ((5- (methylsulfonylamino) -5-oxopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5- (methylsulfonylamino) -5-oxopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate (133mg,0.188mmol) in dichloromethane (1mL) was added HCl in isopropanol (7M,2mL), stirred at room temperature for 40min, the solvent was removed to give 121mg of a white solid, yield: 100 percent.

Compound 228:¹H NMR(600MHz,CD₃OD):δppm 7.82(s,1H),7.73(d,J＝8.4Hz,1H),7.47-7.51(m,1H),7.33(d,J＝8.4Hz,1H),6.97-7.01(m,2H),6.89(t,J_F-H＝74.4Hz,1H),5.16-5.19(m,1H),4.65(s,2H),4.19-4.21(m,2H),3.24(s,3H),2.45-2.47(m,2H),1.87-1.95(m,4H),1.78(d,J＝7.2Hz,3H)；

MS-ESI:m/z 617.15[M+H-HCl]⁺。

Example 126: the compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) - Synthesis of 3- ((5-morpholinyl-5-oxopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound (S) - (tert-butyl 1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5-morpholinyl-5-oxopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate

Dissolving compound (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (150mg,0.235mmol), morpholine (31mg,0.352mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (67mg,0.352mmol) and N-hydroxy-7-azabenzotriazole (48mg,0.352mmol) in dichloromethane (20mL), stirring at room temperature for 30min, dropwise adding N, N-diisopropylethylamine (0.12mL,0.704mmol) to the solution at 0 deg.C, stirring at room temperature for 10h, washing with water (25 mL. times.3), extracting the aqueous phase with dichloromethane (25 mL. times.3), combining the organic phases, using anhydrous Na for the organic phase₂SO₄Drying, removal of the solvent, and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) gave 133mg of a white solid in yield: 80 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.58-7.61(m,2H),7.41-7.47(m,1H),7.23(d,J＝8.0Hz,1H),6.84-6.92(m,2H),6.62(t,J_F-H＝74.8Hz,1H),5.31-5.33(m,1H),4.66-4.71(m,2H),4.18(d,J＝6.0Hz,1H),3.68-3.71(m,4H),3.63-3.65(m,2H),3.49-3.52(m,2H),2.46(t,J＝6.8Hz,2H),1.88-2.01(m,4H),1.56(d,J＝6.8Hz,2H),1.45(s,9H)；

MS-ESI:m/z 709.30[M+H]⁺。

Step 2: synthesis of compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) -3- ((5-morpholinyl-5-oxopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5-morpholinyl-5-oxopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate (133mg,0.188mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (7M,2mL), stirred at room temperature for 40min, the solvent was removed to give 121mg of a white solid, yield: 100 percent.

Compound 235:¹H NMR(400MHz,CD₃OD):δppm 7.83(s,1H),7.73(d,J＝8.4Hz,1H),7.46-7.52(m,1H),7.33(d,J＝8.4Hz,1H),6.95-7.01(m,2H),6.90(t,J_F-H＝74.4Hz,1H),5.16-5.21(m,1H),4.65(s,2H),4.20-4.23(m,2H),3.64-3.68(m,4H),3.57-3.59(m,4H),2.53(t,J＝6.8Hz,2H),1.83-1.99(m,4H),1.78(d,J＝6.8Hz,3H)；

MS-ESI:m/z 609.25[M+H-HCl]⁺。

Example 127: the compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) - Synthesis of 3- ((5-oxo-5-ureidopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5-oxo-5-ureidopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compounds (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (300mg,0.469mmol) and N, N' -carbonyldiimidazole (228mg,1.41mmol) were dissolved in anhydrous tetrahydrofuran (20mL), stirred at 60 ℃ for 20min, cooled to room temperature, and then urea (214mg,3.563mmol) and 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (0.305mL,0.315mmol), stirring at 80 deg.C for 18h, washing with saturated ammonium chloride solution (25 mL. times.3), extracting the aqueous phase with ethyl acetate (25mL), combining the organic phases, and extracting the organic phase with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 100mg of a white solid, yield: 31.3 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.72-7.77(m,1H),7.66-7.67(m,1H),7.45-7.51(m,1H),7.29(d,J＝8.4Hz,1H),6.94-6.99(m,2H),6.86(t,J_F-H＝74.8Hz,1H),5.41-5.45(m,1H),4.62(s,2H),4.18-4.20(m,2H),2.45-2.49(m,2H),1.86-1.92(m,4H),1.53(d,J＝7.2Hz,3H),1.42(s,9H)；

MS-ESI:m/z 682.20[M+H]⁺。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -N- (2, 4-difluorobenzyl) -2- (4- (difluoromethoxy) -3- ((5-oxo-5-ureidopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((2, 4-difluorobenzyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5-oxo-5-ureidopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate (100mg,0.147mmol) in dichloromethane (1mL) was added a solution of HCl in isopropanol (7M,2mL), stirred at room temperature for 40min, the solvent was removed to give 91mg of a white solid, yield: 100 percent.

Compound 240:¹H NMR(600MHz,CD₃OD):δppm 7.82(s,1H),7.72-7.76(m,2H),7.62-7.65(m,1H),7.47-7.51(m,1H),7.33(d,J＝8.4Hz,1H),6.95-7.01(m,2H),6.89(t,J_F-H＝74.4Hz,1H),5.16-5.19(m,1H),4.65(s,2H),4.19-4.21(m,2H),2.46-2.48(m,2H),1.87-1.94(m,4H),1.78(d,J＝6.6Hz,3H)；

MS-ESI:m/z 582.30[M+H-HCl]⁺。

Example 128: the compound N- (2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl Process for preparation of phenyl) -2- (4- (difluoromethoxy) -3- ((5-morpholinyl-5-oxopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride Synthesis of

Step 1: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

the compound (S) -2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -5- (1- ((t-butoxycarbonyl) amino) ethyl) oxazole-4-carboxylic acid (0.30g,0.595mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.170g,0.892mmol) and N-hydroxy-7-azabenzotriazole (0.125g,0.892mmol) were dissolved in methylene chloride (20mL), stirred at room temperature for 30min, 2-amino-2- (2, 4-difluorophenyl) acetamide (0.159g,0.714mmol) was added, N-diisopropylethylamine (0.45mL,2.38mmol) was added dropwise to the solution at 0 ℃, stirred at room temperature for 10h, washed with water (25 mL. times.3), aqueous phaseExtraction with dichloromethane (25 mL. times.3), combining the organic phases, and application of anhydrous Na to the organic phase₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 0.333g of a white solid in yield: 81.9 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.75(s,1H),7.65(d,J＝8.4Hz,1H),7.36-7.55(m,6H),7.29(d,J＝8.4Hz,1H),6.90-6.96(m,2H),6.67(t,J_F-H＝74.4Hz,1H),5.94(d,J＝7.2Hz,1H),5.31-5.35(m,1H),5.27(s,2H),1.48-1.53(m,3H),1.41-1.48(m,9H)；

MS-ESI:m/z 673.20[M+H]⁺。

Step 2: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoylamino) -2- (4- (difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (0.333g,0.495mmol) and nickel chloride (0.068g,0.495mmol) were dissolved in ethanol (5mL), a solution of sodium borohydride (0.098g,2.48mmol) in ethanol (20mL) was added dropwise to this solution at 0 ℃, stirred at room temperature for 10h, hydrochloric acid (1M) was added to adjust pH 1, stirred to clarify, sodium hydroxide solution (1M) was added to adjust pH 14, ethyl acetate extraction (25mL × 3), the organic phases were combined, and the organic phase was taken up with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 221mg of a white solid in yield: 76.6 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.63(d,J＝2.0Hz,1H),7.48(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H), 7.25(d,J＝8.4Hz,1H),7.00-7.06(m,2H),6.89(t,J_F-H＝74.8Hz,1H),5.88(d,J＝12.4Hz,1H),5.35-5.40(m,1H),1.50(d,J＝7.2Hz,3H),1.39(s,9H)；

MS-ESI:m/z 583.20[M+H]⁺。

And step 3: synthesis of the compound methyl 5- (5- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate

The compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoylamino) -2- (4- (difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate (442mg,0.818mmol), methyl 5-bromovalerate (239mg,1.23mmol) and potassium carbonate (226mg,1.64mmol) were dissolved in DMF (15mL), a tube-sealing reaction was performed at 60 ℃ for 4 hours, the potassium carbonate was removed by suction filtration, the filtrate was concentrated, and column separation was performed (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give 454mg of a colorless oil, yield: 84.8 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.63-7.65(m,2H),7.50-7.56(m,1H),7.26(d,J＝8.4Hz,1H),6.90-6.96(m,2H),6.65(t,J_F-H＝74.4Hz,1H),5.94(d,J＝6.8Hz,1H),5.29-5.37(m,1H),4.17-4.20(m,2H),3.71(s,3H),2.45-2.49(m,2H),1.89-1.97(m,4H),1.48-1.53(m,3H),1.40-1.45(m,9H)；

MS-ESI:m/z 697.25[M+H]⁺。

And 4, step 4: synthesis of the compound 5- (5- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid

The compound methyl 5- (5- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate (220mg,0.316mmol) and sodium hydroxide (64mg,1.58mmol) were dissolved in a mixed solvent of water (10mL) and ethanol (20mL), reacted at 60 ℃ for 90min, ethanol was removed by rotary evaporation, pH was adjusted to 1 by adding hydrochloric acid (1M), ethyl acetate was extracted (25 mL. times.3), the organic phases were combined, anhydrous Na was added₂SO₄Drying and removal of the solvent gave 179mg of a pale yellow oil, yield: 83.0 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.44-7.77(m,1H),7.67(dd,J₁＝8.0Hz,J₂＝2.0Hz,1H),7.57-7.61(m,1H),7.29(d,J＝8.0Hz,1H),6.99-7.05(m,2H),6.86(t,J_F-H＝74.4Hz,1H),5.89-5.91(m,1H),5.41-5.44(m,1H),4.17-4.20(m,2H),2.41-2.45(m,2H),1.82-1.94(m,4H),1.51(d,J＝7.2Hz,3H),1.40(s,9H)；

MS-ESI:m/z 683.20[M+H]⁺。

And 5: synthesis of the Compound tert-butyl ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5-morpholinyl-5-oxopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound 5- (5- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -5- ((S) -1- ((tert-butoxycarbonyl) amino) ethyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (0.179g,0.262mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.076g,0.393mmol) and N-hydroxy-7-azabenzotriazole (0.054g,0.393mmol) were dissolved in dichloromethane (20mL), stirred at room temperature for 30min, morpholine (0.027g,0.315mmol) was added, N-diisopropylethylamine (0.15 mL), 0.787mmol), stirred at room temperature for 10h, washed with water (25 mL. times.3), the aqueous phase extracted with dichloromethane (25 mL. times.3), the organic phases combined and the organic phase extracted with anhydrous Na₂SO₄Drying, removal of the solvent, column separation of the concentrated solution (methanol/dichloromethane (v/v) ═ 1/20), preliminary purification, preparative silica gel plate separation (developing solvent: methanol/dichloromethane (v/v) ═ 1/10) to give 81mg of white solid, yield: 41 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.77(s,1H),7.66(d,J＝8.4Hz,1H),7.55-7.58(m,1H),7.29(d,J＝8.4Hz,1H),6.98-7.04(m,2H),6.87(t,J_F-H＝74.4Hz,1H),5.90(d,J＝11.6Hz,1H),5.41-5.44(m,1H),4.16-4.20(m,2H),3.64-3.69(m,4H),3.56-3.60(m,4H),2.51-2.54(m,2H),1.88-1.93(m,2H),1.92-1.86(m,2H),1.52(d,J＝6.8Hz,3H),1.40(s,9H)；

MS-ESI:m/z 752.10[M+H]⁺。

Step 6: synthesis of the compound N- (2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) -5- ((S) -1-aminoethyl) -2- (4- (difluoromethoxy) -3- ((5-morpholinyl-5-oxopentyl) oxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound ((1S) -1- (4- ((2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (4- (difluoromethoxy) -3- ((5-morpholinyl-5-oxopentyl) oxy) phenyl) oxazol-5-yl) ethyl) carbamate (81mg,0.108mmol) in dichloromethane (2mL) was added an ethyl acetate solution of HCl (4M,3mL), stirred at room temperature for 40min, the solvent was removed to give 74mg of a white solid, yield: 100 percent.

Compound 256:¹H NMR(600MHz,CD₃OD):δppm 7.82(s,1H),7.73(d,J＝7.8Hz,1H),7.58-7.62(m,1H),7.34(d,J＝8.4Hz,1H),7.02-7.07(m,2H),6.90(t,J_F-H＝74.4Hz,1H),5.92(s,1H),5.16-5.19(m,1H),4.21-4.23(m,2H),3.65-3.70(m,4H),3.59(m,4H),2.53-2.55(m,2H),1.92-1.97(m,2H),1.83-1.88(m,2H),1.77(d,J＝7.2Hz,3H)；

MS-ESI:m/z 652.20[M+H-HCl]⁺。

Example 129: the compound (S) -2- (4- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethyl) synthesis of oxy) phenyl) oxazole-4-carboxamide) phenyl) ethyl acetate hydrochloride

Step 1: synthesis of ethyl p-aminophenylacetate

To a solution of ethyl p-nitroanilinoate (500mg,2.39mmol) in methanol (10mL) was added Pd/C (64mg), reduced by hydrogen, stirred at room temperature for 1.5h, filtered over celite, and the filtrate was spin-dried to give ethyl p-aminophenylacetate: light red liquid 420mg, yield: 97 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.03(d,J＝8.4Hz,2H),6.71(d,J＝8.4Hz,2H),4.13(q,J＝7.1Hz,1H),3.49(s,2H),1.24(t,J＝7.1Hz,3H)；

MS-ESI:m/z 180.2[M+H]⁺。

Step 2: synthesis of ethyl 2- (4- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide) phenyl) acetate, compound

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), ethyl p-aminophenylacetate (11)5mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise to the solution at 0 deg.C, stirred at room temperature for 2.5h, water (10 mL. times.2) was added, and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 5/1) afforded 256mg of a white solid, yield: 76 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.68(d,J＝8.4Hz,2H),7.63(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.59(s,1H),7.32(d,J＝8.4Hz,2H),7.27(d,J＝6.2Hz,1H),6.72(t,J_F-H＝75.0Hz,1H),5.35–5.30(m,1H),4.16(q,J＝7.1Hz,2H),4.01(d,J＝6.9Hz,2H),3.61(s,2H),1.57(d,J＝7.0Hz,3H),1.43(s,9H),1.37–1.33(m,1H),1.26(t,J＝7.1Hz,3H),0.73–0.68(m,2H),0.44–0.41(m,2H)；

MS-ESI:m/z 574.2[M-55]⁺。

And step 3: synthesis of Compound ethyl 2- (4- (5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide) phenyl) acetate hydrochloride

To a solution of the compound (S) -ethyl 2- (4- (5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide) phenyl) acetate (249mg,0.40mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,5mL), stirred at room temperature for 1.5h, the solvent was removed to give 220mg of a white solid in yield: 98 percent.

Compound 370:¹H NMR(600MHz,CD₃OD):δppm 7.86(s,1H),7.77(d,J＝8.8Hz,1H),7.75(d,J＝8.5Hz,2H),7.34(d,J＝8.3Hz,1H),7.32(d,J＝8.1Hz,2H),6.93(t,J_F-H＝74.7Hz,1H),5.28–5.25(m,1H),4.16(q,J＝7.1Hz,2H),4.07(d,J＝6.9Hz,2H),3.65(s,2H),1.82(d,J＝6.9Hz,3H),1.38–1.35(m,1H),1.26(t,J＝7.1Hz,3H),0.71–0.68(m,2H),0.46–0.44(m,2H)；

MS-ESI:m/z 530.8[M+H-HCl]⁺。

Example 130: the compound (S) -N- (4-(2-amino-2-oxoethyl) phenyl) -5- (1-aminoethyl) -2- (3- Synthesis of (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of p-aminophenylacetamide

Ethyl p-nitroacetoacetate (500mg,2.39mmol) and a methanol solution of ammonia (7M,12mL) were added to a sealed tube, reacted at 75 ℃ for 24h, after the reaction was stopped, the solvent was removed, washed with dichloromethane (10mL), and filtered to give p-nitroacetoamide: light red solid 340mg, yield: 78 percent.

¹H NMR(400MHz,CD₃OD):δppm 8.22(d,J＝8.7Hz,2H),7.58(d,J＝8.7Hz,2H),3.69(s,2H)；

MS-ESI:m/z 181.0[M+H]⁺。

To a solution of p-nitroanilide (340mg,1.89mmol) in methanol (10mL) was added Pd/C (34mg), reduced with hydrogen, stirred at room temperature for 3h, filtered through celite, and the filtrate was spin-dried to give p-aminophenylacetamide: pale red solid 280mg, yield: 98 percent.

¹H NMR(400MHz,CD₃OD):δppm 7.06(d,J＝8.3Hz,2H),6.71(d,J＝8.4Hz,2H),3.38(s,2H)；

MS-ESI:m/z 151.2[M+H]⁺。

Step 2: synthesis of the Compound (S) - (tert-butyl 1- (4- ((4- (2-amino-2-oxoethyl) phenyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), p-aminophenylacetamide (96mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (154mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), and N, N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise to the solution at 0 deg.C, followed by stirring at room temperature for 3 hours, followed by addition of water(10 mL. times.2), and anhydrous Na as an organic phase₂SO₄Drying, removal of the solvent, column separation of the concentrate (dichloromethane/methanol (v/v) ═ 40/1) afforded 220mg of a white solid in yield: 68 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.72(d,J＝8.2Hz,2H),7.63(d,J＝8.3Hz,1H),7.59(s,1H),7.31(d,J＝8.2Hz,2H),7.26(d,J＝8.2Hz,1H),6.72(t,J_F-H＝75.0Hz,1H),5.52–5.44(m,2H),5.37–5.33(m,1H),4.00(d,J＝6.9Hz,2H),3.59(s,2H),1.57(d,J＝7.0Hz,3H),1.43(s,9H),1.37–1.33(m,1H),0.72–0.68(m,2H),0.43–0.41(m,2H)；

MS-ESI:m/z 545.7[M-55]⁺.

And step 3: synthesis of Compound (S) -N- (4- (2-amino-2-oxoethyl) phenyl) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((4- (2-amino-2-oxoethyl) phenyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (220mg,0.37mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1.5h, the solvent was removed to give 196mg of a white solid in yield: 99 percent.

Compound 361:¹H NMR(600MHz,CD₃OD):δppm 7.86(s,1H),7.77(d,J＝9.8Hz,1H),7.75(d,J＝8.4Hz,2H),7.37(s,1H),7.34(d,J＝7.9Hz,2H),6.93(t,J_F-H＝74.7Hz,1H),5.27–5.24(m,1H),4.07(d,J＝6.9Hz,2H),3.55(s,2H),1.81(d,J＝6.9Hz,3H),1.38–1.36(m,1H),0.71–0.68(m,2H),0.46–0.44(m,2H)；

MS-ESI:m/z 501.3[M+H-HCl]⁺。

Example 131: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of yl) -N- (1H-pyrazol-4-yl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of the Compound (S) - (1- (4- ((1H-pyrazol-4-yl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), 4-aminopyrazole (53mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 10h, water (10 mL. times.2) was added, and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 138mg of a white solid, yield: and 47 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.96(s,2H),7.62–7.59(m,1H),7.58(s,1H),7.24(d,J＝8.4Hz,1H),6.70(t,J_F-H＝75.0Hz,1H),5.36–5.32(m,1H),3.98(d,J＝6.9Hz,2H),1.56(d,J＝7.0Hz,3H),1.43(s,9H),1.35–1.32(m,1H),0.71–0.66(m,2H),0.43–0.39(m,2H)；

MS-ESI:m/z 478.8[M-55]⁺.

step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1H-pyrazol-4-yl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((1H-pyrazol-4-yl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (117mg,0.22mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1.5H, the solvent was removed to give 87mg of a white solid, yield: 78 percent.

Compound 380:¹H NMR(600MHz,CD₃OD):δppm 8.30(s,2H),7.85(d,J＝1.6Hz,1H),7.78(dd,J₁＝8.3Hz,J₂＝1.6Hz,1H),7.35(d,J＝8.3Hz,1H),6.93(t,J_F-H＝74.7Hz,1H),5.29–5.26(m,1H),4.07(d,J＝6.9Hz,2H),1.82(d,J＝7.0Hz,3H),1.39–1.35(m,1H),0.72–0.69(m,2H),0.44–0.42(m,2H)；

MS-ESI:m/z 434.9[M+H-2HCl]⁺。

Example 132: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (pyridin-4-ylmethyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((pyridin-4-ylmethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), 4-pyridylmethylamine hydrochloride (93mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), to this solution was added dropwise N, N-diisopropylethylamine (0.37mL,2.14mmol) at 0 ℃ and stirred at room temperature for 3.5h, water was added (10 mL. times.2), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) afforded 194mg of a white solid in yield: 65 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.55(d,J＝4.7Hz,2H),7.53(dd,J₁＝8.3Hz,J₂＝1.8Hz,1H),7.49(d,J＝1.7Hz,1H),7.25(d,J＝5.6Hz,2H),7.19(d,J＝8.3Hz,1H),6.66(t,J_F-H＝75.0Hz,1H),5.29–5.25(m,1H),4.63(d,J＝6.3Hz,2H),3.92(d,J＝6.9Hz,2H),1.50(d,J＝7.0Hz,3H),1.38(s,9H),1.30–1.26(m,1H),0.66–0.62(m,2H),0.37–0.33(m,2H)；

MS-ESI:m/z 559.3[M+H]⁺。

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (pyridin-4-ylmethyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((pyridin-4-ylmethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (188mg,0.34mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1h, the solvent was removed to give 178mg of a white solid in yield: 99 percent.

Compound 383:¹H NMR(600MHz,CD₃OD):δppm 8.86(d,J＝6.1Hz,2H),8.13(d,J＝6.1Hz,2H),7.84(d,J＝1.4Hz,1H),7.76(dd,J₁＝8.3Hz,J₂＝1.4Hz,1H),7.34(d,J＝8.3Hz,1H),6.93(t,J_F-H＝74.7Hz,1H),5.23–5.20(m,1H),4.95(s,2H),4.05(d,J＝6.9Hz,2H),1.80(d,J＝6.9Hz,3H),1.38–1.35(m,1H),0.70–0.67(m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 457.8[M-H-2HCl]^-。

Example 133: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of yl) -N- (pyridin-2-ylmethyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((pyridin-2-ylmethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), 2-aminomethylpyridine (69mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), to this solution was added dropwise N, N-diisopropylethylamine (0.37mL,2.14mmol) at 0 ℃ and stirred at room temperature for 12h, water-washed (10 mL. times.2) and the organic phase was washed with anhydrous Na₂SO₄drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 223mg of white solid, yield: 74 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.61(d,J＝4.4Hz,1H),8.11(br.s,1H),7.70(td,J₁＝7.7Hz,J₂＝1.7Hz,1H),7.60(dd,J₁＝8.3Hz,J₂＝1.8Hz,1H),7.57(s,1H),7.36(d,J＝7.8Hz,1H),7.25–7.23(m,2H),6.70(t,J_F-H＝75.1Hz,1H),5.31–5.28(m,1H),4.76(d,J＝5.5Hz,2H),3.98(d,J＝7.0Hz,2H),1.53(d,J＝7.0Hz,3H),1.43(s,9H),1.35–1.30(m,1H),0.71–0.66(m,2H),0.43–0.39(m,2H)；

MS-ESI:m/z 559.8[M+H]⁺。

step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (pyridin-2-ylmethyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((pyridin-2-ylmethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (216mg,0.39mmol) in dichloromethane (6mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1h, the solvent was removed to give 205mg of a white solid in yield: 99 percent.

Compound 384:¹H NMR(600MHz,CD₃OD):δppm 8.85(d,J＝5.6Hz,1H),8.65(t,J＝7.7Hz,1H),8.15(d,J＝8.0Hz,1H),8.05(t,J＝6.6Hz,1H),7.84(s,1H),7.76(d,J＝8.3Hz,1H),7.34(d,J＝8.3Hz,1H),6.93(t,J_F-H＝74.7Hz,1H),5.24–5.20(m,1H),5.03(s,2H),4.05(d,J＝6.8Hz,2H),1.79(d,J＝6.9Hz,3H),1.37–1.34(m,1H),0.70–0.66(m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 459.9[M+H-2HCl]⁺。

Example 134: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene synthesis of phenyl-N- ((5-fluoropyridin-2-yl) methyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of compound (5-fluoropyridin-2-yl) methylamine

Adding hydroxylamine hydrochloride (333mg,4.80mmol) to a solution of 5-fluoropyridine-2-aldehyde (300mg,2.40mmol) in acetonitrile (15mL), stirring at room temperature, dropwise adding triethylamine (1.33mL,9.60mmol), reacting at 80 ℃ for 3 hours, removing the solvent, adding ethyl acetate (15mL), washing with water (10 mL. times.2), and reacting the organic phase with anhydrous Na₂SO₄drying and concentrating to obtain 5-fluoropyridine-2-formaldehyde oxime: 336mg of white solid, yield: 98 percent.

¹H NMR(400MHz,CD₃OD):δppm 8.38(s,1H),8.14(s,1H),7.82–7.75(m,1H),7.48–7.36(m,1H)；

MS-ESI:m/z 141.1[M+H]⁺。

Adding sodium borohydride (476mg,11.88mmol) into a solution of 5-fluoropyridine-2-formaldoxime (333mg,2.38mmol) and nickel chloride (308mg,2.38mmol) in absolute ethyl alcohol (18mL) under ice bath conditions, releasing heat violently, continuing to react for 40min under ice bath, stirring for 20min at room temperature, adding hydrochloric acid solution to adjust the pH value to be about 1, stirring until the solution becomes clear, adding sodium hydroxide to adjust the pH value to be about 14, precipitating white solid, sucking supernatant, removing solvent, adding dichloromethane (25mL), filtering, and adding Na to filtrate₂SO₄drying and removal of the solvent gave 150mg of brown liquid, yield: 50 percent.

¹H NMR(600MHz,CD₃OD):δppm 8.51(d,J＝2.7Hz,1H),7.66(td,J₁＝8.5Hz,J₂＝2.8Hz,1H),7.51(dd,J₁＝8.6Hz,J₂＝4.2Hz,1H),4.27(s,2H)；

MS-ESI:m/z 127.2[M+H]⁺。

Step 2: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((5-fluoropyridin-2-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), (5-fluoropyridin-2-yl) methylamine (81mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (20mL) and added to this solution at 0 deg.CN, N-diisopropylethylamine (0.37mL,2.14mmol) was added dropwise, stirred at room temperature for 7.5h, washed with water (10 mL. times.2) and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 130mg of a white solid, yield: 41 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.48(d,J＝2.4Hz,1H),8.05(br.s,1H),7.62(dd,J₁＝8.3Hz,J₂＝1.8Hz,1H),7.59(d,J＝1.7Hz,1H),7.44–7.40(m,2H),7.26(d,J＝8.3Hz,1H),6.72(t,J_F-H＝75.0Hz,1H),5.34–5.30(m,1H),4.76(d,J＝5.5Hz,2H),4.00(d,J＝7.0Hz,2H),1.55(d,J＝7.0Hz,3H),1.45(s,9H),1.36–1.32(m,1H),0.74–0.69(m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 577.3[M+H]⁺。

And step 3: synthesis of the Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((5-fluoropyridin-2-yl) methyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) -tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((5-fluoropyridin-2-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (128mg,0.22mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1.5h and the solvent removed to give 118mg of a white solid in yield: 96 percent.

compound 385:¹H NMR(600MHz,CD₃OD):δppm 8.83(br.s,1H),8.27(t,J＝8.1Hz,1H),8.00–7.99(m,1H),7.82(s,1H),7.75(d,J＝8.2Hz,1H),7.35–7.33(m,1H),7.05–6.80(m,1H),5.21–5.20(m,1H),4.93(s,2H),4.05–4.04(m,2H),1.80–1.79(m,3H),1.37–1.34(m,1H),0.69–0.68(m,2H),0.44–0.42(m,2H)；

MS-ESI:m/z 477.8[M+H-2HCl]⁺。

example 135: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of yl) -N- (pyridin-3-ylmethyl) oxazole-4-carboxamide dihydrochloride

step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((pyridin-3-ylmethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), 3-aminomethylpyridine (69mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), to this solution was added dropwise N, N-diisopropylethylamine (0.37mL,2.14mmol) at 0 ℃ and stirred at room temperature for 5h, water was added (10 mL. times.2), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of the solvent, and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/2) gave 254mg of a white solid in yield: 85 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.65(br.s,1H),8.56(d,J＝4.3Hz,1H),7.73(d,J＝7.8Hz,1H),7.57–7.55(m,1H),7.52(s,1H),7.32–7.29(m,1H),7.22(d,J＝8.3Hz,1H),6.69(t,J_F-H＝75.0Hz,1H),5.32–5.30(m,1H),4.68–4.65(m,2H),3.96(d,J＝6.9Hz,2H),1.54(d,J＝7.0Hz,3H),1.43(s,9H),1.34–1.30(m,1H),0.70–0.65(m,2H),0.41–0.37(m,2H)；

MS-ESI:m/z 559.3[M+H]⁺。

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (pyridin-3-ylmethyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((pyridin-3-ylmethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (250mg,0.45mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 2h, the solvent was removed to give 220mg of a white solid in yield: 92 percent.

compound 406:¹H NMR(600MHz,CD₃OD):δppm 8.97(s,1H),8.84(d,J＝5.5Hz,1H),8.72(d,J＝8.1Hz,1H),8.15–8.13(m,1H),7.81(d,J＝1.7Hz,1H),7.74(dd,J₁＝8.4Hz,J₂＝1.7Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,J_F-H＝74.7Hz,1H),5.23–5.19(m,1H),4.86–4.85(m,2H),4.04(d,J＝6.9Hz,2H),1.78(d,J＝7.0Hz,3H),1.37–1.34(m,1H),0.70–0.67(m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 459.3[M+H-2HCl]⁺。

Example 136: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of yl) -N- (1-methyl-1H-pyrazol-3-yl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1-methyl-1H-pyrazol-3-yl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), N-methyl-3-aminopyrazole (62mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), to this solution was added dropwise N, N-diisopropylethylamine (0.37mL,2.14mmol) at 0 ℃, the mixture was stirred at room temperature for 3.5h, water (10 mL. times.2) was added, and the organic phase was washed with anhydrous Na₂SO₄drying, removal of the solvent, and column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 260mg of a white solid in yield: 85 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59(s,1H),7.58–7.55(m,1H),7.31(d,J＝2.1Hz,1H),7.25(d,J＝8.8Hz,1H),6.79(d,J＝2.2Hz,1H),6.71(t,J_F-H＝75.1Hz,1H),5.36–5.32(m,1H),4.00(d,J＝7.0Hz,2H),3.86(s,3H),1.56(d,J＝7.0Hz,3H),1.43(s,9H),1.37–1.32(m,1H),0.73–0.68(m,2H),0.46–0.42(m,2H)；

MS-ESI:m/z 548.8[M+H]⁺。

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1-methyl-1H-pyrazol-3-yl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1-methyl-1H-pyrazol-3-yl) carbamoyl) oxazol-5-yl) ethyl) carbamate (265mg,0.48mmol) in dichloromethane (4mL) was added an ethyl acetate solution of HCl (4M,4mL), stirred at room temperature for 1H, and the solvent was removed to give 231mg of a white solid in yield: 98 percent.

compound 411:¹H NMR(400MHz,CD₃OD):δppm 7.84(d,J＝1.6Hz,1H),7.77(dd,J₁＝8.4Hz,J₂＝1.6Hz,1H),7.73(s,1H),7.35(d,J＝8.3Hz,1H),6.93(t,J_F-H＝74.7Hz,1H),6.66(d,J＝2.2Hz,1H),5.31–5.28(m,1H),4.07(d,J＝6.9Hz,2H),3.94(s,3H),1.83(d,J＝6.9Hz,3H),1.39–1.34(m,1H),0.72–0.68(m,2H),0.47–0.43(m,2H)；

MS-ESI:m/z 448.3[M+H-HCl]⁺。

Example 137: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of yl) -N- (pyrimidin-2-ylmethyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((pyrimidin-2-ylmethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250mg,0.53mmol), 2-aminomethylpyrimidine hydrochloride (93mg,0.64mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (153mg,0.80mmol) and N-hydroxy-7-azabenzotriazole (182mg,1.33mmol) were dissolved in dichloromethane (15mL), and N, N-diisopropylethylamine (0.0 mmol) was added dropwise to the solution at 0 deg.C37mL,2.14mmol) was stirred at room temperature for 17h, water was added (10 mL. times.2), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 225mg of a white solid, yield: 73 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.77(d,J＝4.9Hz,2H),8.24(br.s,1H),7.64(dd,J₁＝8.3Hz,J₂＝1.9Hz,1H),7.59(d,J＝1.7Hz,1H),7.25–7.24(m,1H),6.71(t,J_F-H＝75.0Hz,1H),5.32–5.28(m,1H),4.91(d,J＝5.2Hz,2H),3.99(d,J＝6.9Hz,2H),1.54(d,J＝7.0Hz,3H),1.43(s,9H),1.36–1.31(m,1H),0.72–0.67(m,2H),0.43–0.39(m,2H)；

MS-ESI:m/z 560.8[M+H]⁺。

Step 2: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (pyrimidin-2-ylmethyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((pyrimidin-2-ylmethyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (218mg,0.39mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 1h, the solvent was removed to give 207mg of a white solid in yield: 99 percent.

Compound 412:¹H NMR(600MHz,CD₃OD):δppm 9.01(d,J＝4.9Hz,2H),7.82(s,1H),7.76(d,J＝8.3Hz,1H),7.71–7.69(m,1H),7.34(d,J＝8.3Hz,1H),6.93(t,J_F-H＝74.7Hz,1H),5.20–5.17(m,1H),4.96–4.95(m,2H),4.04(d,J＝6.8Hz,2H),1.79(d,J＝6.7Hz,3H),1.37–1.35(m,1H),0.70–0.67(m,2H),0.45 –0.42(m,2H)；

MS-ESI:m/z 460.2[M+H-2HCl]⁺。

Example 138: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene synthesis of yl) -N- ((5-methylpyridin-2-yl) methyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((5-methylpyridin-2-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (220mg,0.47mmol), 2-methylamino-5-methylpyridine (69mg,0.56mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (135mg,0.70mmol) and N-hydroxy-7-azabenzotriazole (160mg,1.17mmol) were dissolved in dichloromethane (16mL), N-diisopropylethylamine (0.33mL,1.88mmol) was added dropwise to the solution at 0 ℃ and the solution was stirred at room temperature for 14 hours, followed by addition of water (10 mL. times.2), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) afforded 202mg of a white solid, yield: 75 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.44(s,1H),8.06(br.s,1H),7.62(dd,J₁＝8.3Hz,J₂＝1.8Hz,1H),7.59(d,J＝1.7Hz,1H),7.52(dd,J₁＝7.9Hz,J₂＝1.7Hz,1H),7.27(s,1H),7.23(d,J＝8.7Hz,1H),6.70(t,J_F-H＝75.0Hz,1H),5.31–5.27(m,1H),4.72(d,J＝5.5Hz,2H),3.98(d,J＝6.9Hz,2H),2.34(s,3H),1.53(d,J＝7.0Hz,3H),1.43(s,9H),1.35–1.31(m,1H),0.71–0.67(m,2H),0.44–0.40(m,2H)；

MS-ESI:m/z 573.3[M+H]⁺。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((5-methylpyridin-2-yl) methyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) -tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- (((5-methylpyridin-2-yl) methyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (200mg,0.35mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 2h and the solvent removed to give 190mg of a white solid in yield: 99 percent.

Compound (I)429：¹H NMR(600MHz,CD₃OD):δppm 8.69(s,1H),8.46(d,J＝5.5Hz,1H),7.99(d,J＝5.5Hz,1H),7.82(d,J＝1.8Hz,1H),7.75(dd,J₁＝8.4Hz,J₂＝1.9Hz,1H),7.35(d,J＝8.3Hz,1H),6.93(t,J_F-H ＝74.7Hz,1H),5.23–5.19(m,1H),4.95(d,J＝6.4Hz,2H),4.04(d,J＝7.0Hz,2H),2.58(s,3H),1.77(d,J＝7.0Hz,3H),1.37–1.34(m,1H),0.71–0.68(m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 473.3[M+H-2HCl]⁺。

Example 139: the compound (S) -5- (1-aminoethyl) -N- ((5-chloropyridin-2-yl) methyl) -2- (3- (cyclopropyl) Synthesis of methoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of Compound (S) - (1- (4- (((5-chloropyridin-2-yl) methyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamic acid tert-butyl ester

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (220mg,0.47mmol), 2-aminomethyl-5-chloropyridine hydrochloride (101mg,0.56mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (135mg,0.70mmol) and N-hydroxy-7-azabenzotriazole (160mg,1.17mmol) were dissolved in dichloromethane (16mL), N-diisopropylethylamine (0.33mL,1.88mmol) was added dropwise to the solution at 0 ℃ and stirred at room temperature for 10 hours, water was added (10 mL. times.2), and the organic phase was washed with anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 3/1) afforded 223mg of white solid, yield: 80 percent.

¹H NMR(400MHz,CDCl₃):δppm 8.56(d,J＝2.3Hz,1H),8.01(br.s,1H),7.67(dd,J₁＝8.3Hz,J₂＝2.4Hz,1H),7.60(dd,J₁＝8.3Hz,J₂＝1.8Hz,1H),7.56(d,J＝1.7Hz,1H),7.33(d,J＝8.3Hz,1H),7.24(d,J＝8.4Hz,1H),6.70(t,J_F-H＝75.0Hz,1H),5.32–5.27(m,1H),4.74–4.73(m,2H),3.98(d,J＝7.0Hz,2H),1.53(d,J＝7.0Hz,3H),1.43(s,9H),1.34–1.31(m,1H),0.72–0.67(m,2H),0.43–0.40(m,2H)；

MS-ESI:m/z 594.3[M+H]⁺。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -N- ((5-chloropyridin-2-yl) methyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (4- (((5-chloropyridin-2-yl) methyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate (219mg,0.37mmol) in dichloromethane (4mL) was added a solution of HCl in ethyl acetate (4M,4mL), stirred at room temperature for 3h and the solvent removed to afford 207mg of a white solid in yield: 99 percent.

Compound 436:¹H NMR(600MHz,CD₃OD):δppm 8.82(s,1H),8.32(d,J＝8.4Hz,1H),7.83(d,J＝8.6 Hz,1H),7.82(s,1H),7.75(d,J＝8.3Hz,1H),7.34(d,J＝8.3Hz,1H),6.93(t,J_F-H＝74.7Hz,1H),5.22–5.18(m,1H),4.87(s,2H),4.04(d,J＝6.9Hz,2H),1.78(d,J＝6.9Hz,3H),1.36–1.34(m,1H),0.70–0.68(m,2H),0.45–0.42(m,2H)；

MS-ESI:m/z 493.3[M+H-2HCl]⁺。

example 140: the compound 2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- (2, 4-difluorobenzyl) -5- Synthesis of phenylthiazole-4-carboxamide

Step 1: synthesis of thiobenzoic acid ethyl ester compound

Concentrated hydrochloric acid (3mL) was added to a solution of benzoic acid (5.73g,46.97mmol) in ethanol (60mL), stirred at 86 ℃ for 3h, concentrated to give the crude product, which was added saturated NaHCO₃the solution was adjusted to pH 7, DCM extracted (100 mL. times.3), the combined organic phases washed with water (50 mL. times.2), Na₂SO₄Drying and concentration gave 5.2g of a colourless oil (ethyl benzoate), yield: 74 percent.

Lawson's reagent (8.08g,20mmol) was added to a solution of ethyl benzoate (3g,20mmol) in anhydrous xylene (25mL), stirred at 140 ℃ for 10h, Et was added₂O (25mL), filtration, concentration of the filtrate, and isolation and purification of the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20/1), to give 2.85g of a pale yellow oil, yield: 86 percent.

Step 2: synthesis of compound methyl 2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -5-phenylthiazole-4-carboxylate

The compound methyl 2- (((3- (cyclopropylmethoxy) -4-methoxyphenyl) (methylthio) methylene) amino) acetate (1.183g,3.663mmol) was dissolved in anhydrous tetrahydrofuran (40mL), ethyl thiobenzoate (2.8g,16.87mmol) and DBU (2.784g,18.32mmol) were added, stirring was carried out at 80 ℃ for 15.5 hours, water (40mL) was added, ethyl acetate was extracted (20 mL. times.3), the organic phases were combined and washed with saturated brine (40 mL. times.3), Na₂SO₄drying, concentration, and separation and purification of the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give 347mg of a yellow solid, yield: 24 percent.

MS-ESI(pos.ion)m/z:396.1[M+H]⁺。

and step 3: synthesis of compound 2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -5-phenylthiazole-4-carboxylic acid

The compound methyl 2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -5-phenylthiazole-4-carboxylate (160mg,0.4046mmol) was dissolved in THF/H₂to O (v/v ═ 2/1,6mL), a solution of LiOH (48.4mg,2.023mmol) in water (0.5mL) was added, stirred at 40 ℃ for 3h, hydrochloric acid (1.2M,2mL) was added to adjust the pH to 1-2, ethyl acetate was extracted (10mL × 3), the organic phases were combined and washed with saturated brine (10mL × 3), Na₂SO₄Drying and concentration gave 120mg of a yellow solid, yield: 78 percent.

MS-ESI(pos.ion)m/z:382.0[M+H]⁺。

And 4, step 4: synthesis of compound 2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- (2, 4-difluorobenzyl) -5-phenylthiazole-4-carboxamide

the compound 2- (3- (cyclopropyl methoxy) -4-methoxyphenyl) -5-phenylthiazole-4-Carboxylic acid (90mg,0.2344mmol) was dissolved in anhydrous DCM (15mL), EDCI (67.5mg,0.3516mmol) and HOBT (47.5mg,0.3516mmol) were added, stirring was carried out at room temperature for 30min, then the compound 2, 4-difluorobenzylamine (40.2mg,0.2812mmol) and DIPEA (126. mu.L, 0.7032mmol) were added, stirring was carried out at 25 ℃ for 16h, water (15mL) was added, DCM extraction (10 mL. times.3) was carried out, the organic phases were combined and washed with saturated brine (15 mL. times.3), Na₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to give 92mg of a pale yellow solid, yield: 77.5 percent.

compound 44:¹HNMR(400MHz,CDCl₃):δ(ppm)7.97(br.s,1H),7.68-7.60(m,2H),7.51-7.35(m,6H),6.93(d,J＝8.8Hz,1H),6.87-6.77(m,2H),4.62(d,J＝5.6Hz,2H),3.98-3.91(m,5H),1.43-1.31(m,1H),0.72-0.65(m,2H),0.43-0.37(m,2H)；

MS-ESI(pos.ion)m/z:507.1[M+H]⁺。

Example 141: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- Synthesis of (2, 4-difluorobenzyl) thiazole-4-carboxamide hydrochloride

Step 1: synthesis of compound (S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propionic acid

Mixing Na₂CO₃(29.8g,280.9mmol) and 9-fluorenylmethyl-N-succinimidyl carbonate (28.4g,84.27mmol) were added to a solution of L-alanine (5g,56.18mmol) in water/dioxane (v/v. 1/1,400mL), stirred at room temperature for 18h, filtered, Et₂O extraction (100 mL. times.3), acidification of the aqueous phase with concentrated hydrochloric acid, extraction with ethyl acetate (150 mL. times.3), combination of the organic phases and Na₂SO₄Drying and concentration gave 17.3g of a white solid, yield: 99 percent.

MS-ESI(pos.ion)m/z:334.2[M+Na]⁺。

Step 2: synthesis of Compound (S) - (9H-fluoren-9-yl) methyl (1-fluoro-1-oxopropan-2-yl) Carbamate

The compound(S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propionic acid (5g,14.38mmol) was dissolved in anhydrous DCM (100mL), triethylamine (2.2mL,15.82mmol) and cyanuric acid (2.4mL,28.76mmol) were added, stirred at 40 ℃ for 2H, washed with ice water (50 mL. times.5), and the organic phase was washed with Na₂SO₄Drying and concentration gave 4.2g of a white solid, yield: 93 percent.

MS-ESI(pos.ion)m/z:326.2[M-F+OCH₃]⁺。

And step 3: synthesis of Compound (4S) -4- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-amino-3-oxopentanoic acid ethyl ester hydrochloride

KHMDS (1M,13.7mL) was added to diphenylmethyleneglycine ethyl ester (3.67g,13.72mmol) in dry THF (80mL) at-78 deg.C, stirred for 1H at-78 deg.C, then the compound (S) - (9H-fluoren-9-yl) methyl (1-fluoro-1-oxopropan-2-yl) carbamate (4.3g,13.72mmol) in dry THF (20mL) at-78 deg.C, after stirring for 1H at 78 deg.C, then hydrochloric acid (3M,34.3mL) was added at-78 deg.C, stirred for 20min at 25 deg.C, concentrated, and concentrated with Et₂o wash (100 mL. times.2) and coevaporation with toluene at 40 ℃ below gave 4.75g of a white solid, yield: 79 percent.

MS-ESI(pos.ion)m/z:397.3[M+H]⁺。

And 4, step 4: synthesis of compound 3- (cyclopropylmethoxy) -4-methoxybenzoyl chloride

Oxalyl chloride (1.41mL,14.85mmol) and DMF (104 μ L,1.35mmol) were added to compound 3- (cyclopropylmethoxy) -4-methoxybenzoic acid (3g,13.50mmol) in anhydrous DCM (100mL) at 0 ℃, stirred for 15.5h at 25 ℃, concentrated, and distilled under reduced pressure to give 3.25g of a white solid (crude product), yield: 100.3 percent.

MS-ESI(pos.ion)m/z:237.2[M-Cl+OCH₃]⁺。

And 5: synthesis of Compound (4S) -4- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2- (3- (cyclopropylmethoxy) -4-methoxybenzamido) -3-oxopentanoic acid ethyl ester

The compound 3- (cyclopropylmethoxy) -4-methoxybenzoyl chloride (3.17g,13.17mmol) was dissolved in anhydrous THF (100mL) and the compound (4S) -4- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-ethyl amino-3-oxopentanoate hydrochloride (4.75g,10.97mmol) in anhydrous DMF (50mL) and triethylamine (3.04mL,21.94mmol), stirred at 25 ℃ for 3.5h, concentrated and the residue dissolved in EtOAc/Et₂O (v/v-1/1,100 mL), washed with hydrochloric acid (1M), NaHCO₃Solution wash (10%, 70 mL. times.2) and saturated brine wash (70 mL. times.2), Na₂SO₄drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to obtain 3.4g of a white powder, yield: and 43 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)7.79-7.72(m,2H),7.64-7.56(m,2H),7.45-7.35(m,3H),7.35-7.27(m,2H),7.19(d,J＝6.0Hz,1H),6.93(d,J＝8.4Hz,1H),5.89(d,J＝7.6Hz,1H),5.66-5.57(m,1H),5.02-4.90(m,1H),4.48-4.18(m,4H),3.97-3.86(m,5H),1.56(d,J＝7.6Hz,3H),1.37-1.23(m,4H),0.70-0.60(m,2H),0.40-0.30(m,2H)；

MS(ESI,pos.ion)m/z:601.2[M+H]⁺。

Step 6: synthesis of Compound (S) -ethyl 5- (1- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) thiazole-4-carboxylate

The compound (4S) -4- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2- (3- (cyclopropylmethoxy) -4-methoxybenzamido) -3-oxopentanoic acid ethyl ester (2.7g,4.5mmol) was dissolved in anhydrous THF (100mL), Lawson' S reagent (3.64g,9mmol) was added, stirring was carried out at 80 ℃ for 10.5H, water (100mL) was added, ethyl acetate was extracted (100 mL. times.3), the organic phases were combined and washed with saturated brine (100mL), Na₂SO₄Drying, concentrating, and separating and purifying the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1.5/1), to obtain 2.6g of a pale yellow solid.

MS-ESI(pos.ion)m/z:599.2[M+H]⁺。

And 7: synthesis of the compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) thiazole-4-carboxylic acid

The compound ethyl (S) -5- (1- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) thiazole-4-carboxylate (2.1g,3.5mmol) was dissolved in THF/H₂To O (v/v ═ 1/1,210mL) was added a sodium hydroxide solution (1M,15.4mL), and the mixture was stirred at 80 ℃ for 3.5 hours, followed by di-tert-butyl dicarbonate (916.7mg,4.2mmol), and at 33 ℃ for 4 hours, hydrochloric acid (1M) was added to adjust the pH to 2-3, followed by extraction with ethyl acetate (150mL × 3), and the organic phases were combined, washed with saturated brine (30mL × 2), and Na₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 1.08g of a yellow solid, yield: 68 percent.

MS-ESI(pos.ion)m/z:449.3[M+H]⁺。

And 8: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) thiazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) thiazole-4-carboxylic acid (200mg,0.4464mmol) was dissolved in DCM (15mL), EDCI (128mg,0.6696mmol) and HOBT (90.4mg,0.6696mmol) were added, stirring was carried out at 25 ℃ for 0.5h, 2, 4-difluorobenzylamine (76.6mg,0.5357mmol) and DIPEA (240. mu.L, 1.339mmol) were then added, stirring was carried out at 25 ℃ for 15h, after addition of water (20mL), extraction was carried out with DCM (15 mL. times.2), the organic phases were combined and then saturated Na was used₂CO₃Solution washing (30 mL. times.2) and saturated brine washing (30 mL. times.2), Na₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to obtain 131mg of a white solid, yield: 43.6 percent.

MS-ESI(pos.ion)m/z:574.2[M+H]⁺。

And step 9: synthesis of compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -N- (2, 4-difluorobenzyl) thiazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) thiazol-5-yl) ethyl) carbamate (131mg,0.1947mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 30min, filtered, the filter cake was washed with ethyl acetate (0.5mL × 6), dissolved in methanol (5mL), and concentrated to give 83mg of a white solid, yield: 74 percent.

Compound 63:¹HNMR(400MHz,CD₃OD):δ(ppm)7.65(d,J＝2.4Hz,1H),7.56(dd,J＝8.4Hz,1H),7.50-7.42(m,1H),7.05(d,J＝8.4Hz,1H),7.00-6.90(m,2H),5.35-5.27(m,1H),4.66(s,2H),3.93(d,J＝6.8Hz,2H),3.90(s,3H),1.75(d,J＝6.4Hz,3H),1.35-1.24(m,1H),0.66-0.60(m,2H),0.39-0.33(m,2H)；

MS-ESI(pos.ion)m/z:474.1[M+H-HCl]⁺。

Example 142: the compound (S) -6- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxybenzene) Synthesis of yl) thiazole-4-carboxamido) methyl) picolinic acid dihydrochloride

Step 1: synthesis of compound ethyl (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) thiazole-4-carboxamido) methyl) picolinate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) thiazole-4-carboxylic acid (250mg,0.5580mmol) was dissolved in DCM (20mL), EDCI (214mg,1.117mmol) and HOBT (151mg,1.117mmol) were added, stirring was carried out at 25 ℃ for 0.5h, then ethyl 6-aminomethyl-2-pyridinecarboxylate (121mg,0.6696mmol) and DIPEA (300. mu.L, 1.675mmol) were added, stirring was carried out at 25 ℃ for 18h, and after addition of water (30mL), extraction was carried out with DCM (20 mL. times.2). The organic phases were combined and saturated with Na₂CO₃Solution washing (30 mL. times.2) and saturated brine washing (30 mL. times.2), Na₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give 200mg of a white foamy solid, yield: 58.7 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)8.46(br.s,1H),8.04(d,J＝7.2Hz,1H),7.87-7.80(m,1H),7.65(d,J＝7.6Hz,1H),7.44-7.39(m,2H),6.89(d,J＝8.8Hz,1H),6.27(br.s,1H),5.65-5.40(m,1H),4.91-4.83(m,2H),4.54-4.42(m,2H),3.98(d,J＝7.6Hz,2H),3.92(s,3H),1.98-1.76(m,3H),1.58(d,J＝6.8Hz,3H),1.37-1.32(m,1H),0.70-0.62(m,2H),0.43-0.38(m,2H),0.06(s,9H)；

MS-ESI(pos.ion)m/z:611.2[M+H]⁺。

Step 2: synthesis of compound (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) thiazole-4-carboxamido) methyl) picolinic acid

The compound ethyl (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) thiazole-4-carboxamido) methyl) picolinate (200mg,0.3275mmol) was dissolved in THF/H₂O (v/v ═ 2/1,9mL), lithium hydroxide monohydrate (69mg,1.637mmol) was added, stirring was carried out at 40 ℃ for 3.5h, hydrochloric acid (1.2M) was added to adjust pH to 2-3, ethyl acetate extraction (15mL × 3) was carried out, the organic phases were combined, and then washed with saturated brine (15mL × 2), Na₂SO₄Drying and concentration gave 174mg of a white solid, yield: 91.2 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)8.44(br.s,1H),8.15(d,J＝7.6Hz,1H),7.98-7.91(m,1H),7.68(d,J＝7.2Hz,1H),7.46-7.38(m,2H),6.90(d,J＝8.4Hz,1H),6.07(br.s,1H),5.65-5.50(m,1H),4.89-4.83(m,2H),3.98-3.87(m,5H),1.58(d,J＝7.2Hz,3H),1.37-1.30(m,1H),0.70-0.63(m,2H),0.43-0.36(m,2H),0.07(s,9H)；

MS-ESI(pos.ion)m/z:583.2[M+H]⁺。

And step 3: synthesis of compound (S) -6- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) thiazole-4-carboxamido) methyl) picolinic acid dihydrochloride

To a solution of compound (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-methoxyphenyl) thiazole-4-carboxamido) methyl) picolinic acid (174mg,0.2918mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, filtered, the filter cake was washed with ethyl acetate (0.5mL × 6), dissolved in methanol (5mL), and concentrated to give 128mg of a yellow solid, yield: 91 percent.

Compound 64:¹HNMR(400MHz,CD₃OD):δ(ppm)8.47–8.42(m,1H),8.35(d,J＝7.6Hz,1H),8.07(d,J＝7.6Hz,1H),7.67(d,J＝2.0Hz,1H),7.59(dd,J＝4.4Hz,1H),7.07(d,J＝8.4Hz,1H),5.43-5.35(m,1H),5.00(d,J＝3.2Hz,2H),3.94(d,J＝6.8Hz,2H),3.91(s,3H),1.77(d,J＝7.6Hz,3H),1.35-1.24(m,1H),0.66-059(m,2H),0.40-0.34(m,2H)；

MS-ESI(pos.ion)m/z:483.2[M+H-2HCl]⁺。

Example 143: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) -N- Synthesis of (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of compound 3- (cyclopropylmethoxy) -4-ethoxybenzoic acid methyl ester

The compound methyl 3- (cyclopropylmethoxy) -4-hydroxybenzoate (5g,22.50mmol) was dissolved in DMF (100mL) and K was added₂CO₃(7.77g,56.25mmol) and bromoethane (2.02mL,27mmol), stirring at 60 ℃ for 10.5h, filtering, concentrating the filtrate, adding water (50mL), DCM extracting (100 mL. times.3), combining the organic phases and washing with saturated brine (100 mL. times.2), Na₂SO₄Drying and concentration gave 5.5g of a pale red liquid, yield: 97.7 percent.

MS-ESI(pos.ion)m/z:251.2[M+H]⁺。

Step 2: synthesis of compound 3- (cyclopropylmethoxy) -4-ethoxybenzoic acid

The compound methyl 3- (cyclopropylmethoxy) -4-ethoxybenzoate (5.5g,21.97mmol) was dissolved in THF/H₂To O (v/v ═ 2/1,150mL), a solution of sodium hydroxide (2.2g,54.93mmol) in water (15mL) was added, stirred at 60 ℃ for 2h, concentrated, adjusted to pH 2-3 with concentrated hydrochloric acid, extracted with DCM (100mL × 3), the organic phases combined and washed with saturated brine (100mL × 2), Na₂SO₄Drying and concentration gave 5.02g of white solid, yield: 96.3 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)7.78-7.70(m,1H),7.60(d,J＝2.0Hz,1H),6.90(d,J＝8.4Hz,1H),4.22-4.14(m,2H),3.91(d,J＝6.8Hz,2H),1.53-1.45(m,3H),1.39-1.28(m,1H),0.69-0.61(m,2H), 0.41-0.34(m,2H)；

MS-ESI(pos.ion)m/z:237.3[M+H]⁺。

And step 3: synthesis of compound methyl 2- (3- (cyclopropylmethoxy) -4-ethoxyphenylamido) acetate

The compound 3- (cyclopropylmethoxy) -4-ethoxybenzoic acid (5g,21.16mmol) was dissolved in anhydrous DCM (150mL), EDCI (6.094g,31.74mmol) and HOBT (4.285g,31.74mmol) were added, stirring was continued at room temperature for 30min, glycine methyl ester hydrochloride (3.188g,25.40mmol) was added, DIPEA (11.4mL,63.48mmol) was slowly added dropwise in an ice bath, and after 16.5h at room temperature, water (100mL) was added and the mixture was stirred with CH₂Cl₂extraction (100 mL. times.2), combination of organic phases, washing with saturated brine (100 mL. times.2), Na₂SO₄Drying, removal of the solvent, and separation of the concentrated solution by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) gave 3.93g of a white solid in yield: 61.6 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)7.41(d,J＝2.0Hz,1H),7.33(dd,J＝8.2Hz,1H),6.85(d,J＝8.4Hz,1H),6.61(br.s,1H),4.22(d,J＝5.2Hz,2H),4.17–4.09(m,2H),3.89(d,J＝6.8Hz,2H),3.79(s,3H),1.50-1.43(m,3H),1.36-1.26(m,1H),0.65-0.58(m,2H),0.38-0.31(m,2H)；

MS-ESI(pos.ion)m/z:308.1[M+H]⁺。

And 4, step 4: synthesis of compound methyl 2- (3- (cyclopropylmethoxy) -4-ethoxyphenylthioamido) acetate

The compound methyl 2- (3- (cyclopropylmethoxy) -4-ethoxyphenylamido) acetate (3.93g,12.8mmol) was dissolved in anhydrous tetrahydrofuran (130mL), Lawson's reagent (5.18g,12.8mmol) was added, the reaction was carried out at 75 ℃ for 2 hours, water (100mL) was added, extraction was carried out with ethyl acetate (100 mL. times.3), the organic phases were combined and then each was treated with saturated Na₂CO₃Washing with a solution (100mL × 3) and a saturated brine (100mL × 2), drying over anhydrous sodium sulfate, and subjecting the concentrate to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 3.704g of a yellow solid, yield: 89.5 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)8.03(br.s,1H),7.54(d,J＝2.0Hz,1H),7.35(dd,J＝8.4Hz,1H),6.84(d,J＝8.4Hz,1H),4.57(d,J＝4.4Hz,2H),4.18–4.10(m,2H),3.91(d,J＝6.8Hz,2H),3.84(s,3H),1.50-1.43(m,3H),1.38-1.23(m,1H),0.66-0.60(m,2H),0.39-0.33(m,2H)；

MS-ESI(pos.ion)m/z:324.2[M+H]⁺。

And 5: synthesis of compound methyl 2- (((3- (cyclopropylmethoxy) -4-ethoxyphenyl) (methylthio) methylene) amino) acetate

To a suspension of trimethyloxonium tetrafluoroborate (3.39g,22.90mmol) in dry dichloromethane (50mL) at-78 deg.C was added dropwise a solution of the compound methyl 2- (3- (cyclopropylmethoxy) -4-ethoxyphenylthioamido) acetate (3.704g,11.45mmol) in dry dichloromethane (100mL), after stirring at 0 deg.C for 2h, a saturated solution of sodium bicarbonate (100mL) was added, DCM was extracted (100 mL. times.2), the organic phases were combined and washed with ice water (100 mL. times.3), Na₂SO₄Drying and removal of the solvent gave 3.86g of a pale red liquid, yield: 100 percent.

MS-ESI(pos.ion)m/z:338.2[M+H]⁺。

Step 6: synthesis of compound (S) -methyl 5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) oxazole-4-carboxylate

A solution of the compound methyl 2- (((3- (cyclopropylmethoxy) -4-ethoxyphenyl) (methylthio) methylene) amino) acetate (3.86g,11.45mmol) in anhydrous tetrahydrofuran (50mL) and a solution of potassium hexamethyldisilazide in tetrahydrofuran (1M,45.8mL) were added to a solution of the compound tert-butyl (4.38g,22.9mmol) of the compound (S) - (1-fluoro-1-oxopropan-2-yl) carbamate in anhydrous tetrahydrofuran (50mL) at-78 deg.C for 1.5h, water (70mL) was added, after stirring at 25 deg.C for 10min, extraction was performed with ethyl acetate (100 mL. times.3), the organic phases were combined and washed with brine (10%, 100 mL. times.2), Na₂SO₄Drying, removal of the solvent, and silica gel column chromatography of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 2.69g of a pale yellow solid, yield: 51 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)7.57(dd,J＝8.4Hz,1H),7.51(d,J＝2.0Hz,1H),6.87(d,J＝8.4Hz,1H),5.75-5.57(m,1H),4.14-4.07(m,2H),3.92(s,3H),3.88(d,J＝7.2Hz,2H),1.55(d,J＝6.8Hz,3H),1.52-1.49(m,3H),1.28-1.22(m,1H),0.67-0.60(m,2H),0.40-0.34(m,2H),0.06(s,9H)；

MS-ESI(pos.ion)m/z:461.2[M+H]⁺。

And 7: synthesis of the compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) oxazole-4-carboxylic acid

The compound methyl (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) oxazole-4-carboxylate (1.344g,2.918mmol) was dissolved in THF/H₂O (v/v ═ 2/1,60mL), lithium hydroxide monohydrate (0.613g,14.59mmol) was added, reaction was carried out at 40 ℃ for 4.5h, pH was adjusted to 2-3 with hydrochloric acid (1M), ethyl acetate was added for extraction (100mL × 3), the organic phases were combined and washed with saturated brine (100mL × 2), Na₂SO₄Drying and removal of the solvent gave 1.1g of a white solid, yield: 84.5 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)7.61(dd,J＝8.4Hz,1H),7.56(s,1H),6.91(d,J＝8.4Hz,1H),5.50-5.35(m,1H),4.19-4.09(m,2H),3.92(d,J＝7.2Hz,2H),1.55(d,J＝6.8Hz,3H),1.52-1.49(m,3H),1.28-1.22(m,1H),0.67-0.60(m,2H),0.40-0.34(m,2H),0.06(s,9H)；

MS-ESI(pos.ion)m/z:447.1[M+H]⁺。

And 8: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

the compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) oxazole-4-carboxylic acid (300mg,0.6721mmol) was dissolved in DCM (20mL), EDCI (193.6mg,1.008mmol) and HOBT (136.1mg,1.117mmol) were added, stirring was carried out at 25 ℃ for 0.5h, 2, 4-difluorobenzylamine (115.3mg,0.8065mmol) and DIPEA (361. mu.L, 2.016mmol) were then added, stirring was carried out at 25 ℃ for 3h, water (20mL) was added, DCM extraction (20 mL. times.2) was carried out, the organic phases were combined and washed with saturated common salt (30 mL. times.2), Na₂SO₄Drying, concentrating, and separating and purifying the concentrated solution with silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to obtain 144mg of colorless colloidal solutionBody, yield: 37.5 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)7.68(br.s,1H),7.58(d,J＝8.4Hz,1H),7.51(s,1H),7.46-7.37(m,1H),6.92(d,J＝8.0Hz,1H),6.90-6.82(m,2H),5.22-5.04(m,1H),4.67-4.62(m,2H),4.20-4.12(m,2H),3.94(d,J＝6.8Hz,2H),1.53(d,J＝6.8Hz,3H),1.51-1.46(m,3H),1.36-1.32(m,1H),0.69-0.62(m,2H), 0.42-0.37(m,2H),0.07(s,9H)。

and step 9: synthesis of compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (140mg,0.2449mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, concentrated, the residue was added ethyl acetate and filtered, the filter cake was washed with ethyl acetate (20mL × 5), dissolved in methanol (5mL), concentrated to give 100mg of a white solid, yield: 80.4 percent.

Compound 76:¹HNMR(400MHz,CD₃OD):δ(ppm)7.67(dd,J＝8.4Hz,1H),7.62(d,J＝2.4Hz,1H),7.49-7.41(m,1H),7.08(d,J＝8.8Hz,1H),7.00-6.90(m,2H),5.15-5.07(m,1H),4.61(s,2H),4.19-4.11(m,2H),3.92(d,J＝6.8Hz,2H),1.73(d,J＝6.4Hz,3H),1.58(d,J＝7.2Hz,3H),1.47-1.41(m,3H),1.35-1.25(m,1H),0.66-0.60(m,2H),0.39-0.33(m,2H)；

MS-ESI(pos.ion)m/z:472.2[M+H-HCl]⁺。

Example 144: the compound (S) -6- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxybenzene Synthesis of yl) oxazole-4-carboxamido) methyl) picolinic acid dihydrochloride

Step 1: synthesis of Compound ethyl (S) -6- ((5- (1- ((t-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) oxazole-4-carboxamido) methyl) picolinate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) oxazole-4-carboxylic acid (560mg,1.255mmol) was dissolved in DCM (30mL), EDCI (361mg,1.883mmol) and HOBT (256mg,1.883mmol) were added, stirring was performed at 25 ℃ for 0.5h, then ethyl 6-aminomethyl-2-pyridinecarboxylate (271mg,1.506mmol) and DIPEA (675. mu.L, 3.765mmol) were added, stirring was performed at 25 ℃ for 3h, water (30mL) was added, DCM extraction (30 mL. times.2) was performed, the organic phases were combined and brine (30 mL. times.2) and Na were washed with saturated water₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give 319mg of a white solid, yield: 99 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)8.50(br.s,1H),8.17(d,J＝6.4Hz,1H),8.11–8.03(m,1H),7.94-7.84(m,1H),7.60(d,J＝8.4Hz,1H),7.55(s,1H),6.92(d,J＝8.4Hz,1H),5.35-5.25(m,1H),5.15-5.08 (m,2H),4.60-4.50(m,2H),4.20-4.13(m,2H),3.96(d,J＝6.8Hz,2H),1.60(d,J＝7.2Hz,3H),1.52-1.43(m,6H),1.39-1.33(m,1H),0.69-0.61(m,2H),0.45-0.37(m,2H),0.07(s,9H)；

MS-ESI(pos.ion)m/z:609.4[M+H]⁺。

Step 2: synthesis of compound (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid

The compound ethyl (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) oxazole-4-carboxamido) methyl) picolinate (319mg,0.5241mmol) was dissolved in THF/H₂O (v/v ═ 2/1,9mL), lithium hydroxide monohydrate (110mg,2.620mmol) was added, stirring was performed at 40 ℃ for 4.5h, hydrochloric acid (1M) was added to adjust pH 2-3, ethyl acetate extraction (15mL × 3) was performed, the organic phases were combined, and then washing with saturated brine (20mL × 2), Na₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to obtain 102mg of a white solid, yield: 33.5 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)8.30(br.s,1H),8.18(d,J＝6.8Hz,1H),8.02–7.93(m,1H),7.72-7.65(m,1H),7.62(d,J＝7.6Hz,1H),7.56(s,1H),6.94(d,J＝8.0Hz,1H),6.66(br.s,1H),5.40-5.25(m,1H),4.97-4.75(m,2H),4.22-4.12(m,2H),4.00-3.90(m,2H),1.54(d,J＝6.8Hz,3H),1.52-1.46(m,3H),1.39-1.30(m,1H),0.70-0.60(m,2H),0.45-0.36(m,2H),0.07(s,9H)；

MS-ESI(pos.ion)m/z:581.1[M+H]⁺。

And step 3: synthesis of Compound (S) -6- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid dihydrochloride

To a solution of compound (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-ethoxyphenyl) oxazole-4-carboxamido) methyl) picolinic acid (102mg,0.1756mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, concentrated, to the residue was added ethyl acetate, filtered, the filter cake was washed with ethyl acetate (2mL × 5), dissolved in methanol (5mL), concentrated to give 59mg of a yellow solid, yield: 65 percent.

Compound 82:¹HNMR(400MHz,CD₃OD):δ(ppm)8.22-8.07(m,2H),7.85-7.75(m,1H),7.69(dd,J＝8.0Hz,1H),7.65(d,J＝2.0Hz,1H),7.10(d,J＝8.4Hz,1H),5.18-5.09(m,1H),4.94-4.85(m,2H),4.20-4.12(m,2H),3.93(d,J＝6.8Hz,2H),1.74(d,J＝6.8Hz,3H),1.49-1.41(m,3H),1.39-1.23(m,1H),0.67-0.60(m,2H),0.40-0.34(m,2H)；

MS-ESI(pos.ion)m/z:481.1[M+H-2HCl]⁺。

example 145: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of phenyl-N- (2, 4-difluorobenzyl) thiazole-4-carboxamide hydrochloride

Step 1: synthesis of compound 3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzoyl chloride

Oxalyl chloride (1.55mL,16.27mmol) and DMF (114 μ L,1.48mmol) were added to a solution of the compound 3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzoic acid (3.82g,14.79mmol) in anhydrous DCM (100mL) at 0 ℃, stirred for 3h at 25 ℃ and distilled under reduced pressure to give 4.09g of a white solid, yield: 100 percent.

MS-ESI(pos.ion)m/z:273.1[M-Cl+OCH₃]⁺。

Step 2: synthesis of Compound ethyl (4S) -4- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzamido) -3-oxopentanoate

The compound 3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzoyl chloride (4.09g,14.79mmol) was dissolved in anhydrous THF (100mL), a solution of the compound (4S) -4- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-amino-3-oxopentanoic acid ethyl ester hydrochloride (5.31g,13.40mmol) in anhydrous DMF (50mL) and triethylamine (3.72mL,26.80mmol) was added at-78 deg.C, the mixture was stirred for 3H at 25 deg.C, concentrated, and the residue was dissolved in Et/Et₂O (v/v-1/1,100 mL), washed with hydrochloric acid (1M), NaHCO₃Solution wash (10%, 70 mL. times.2) and saturated brine wash (70 mL. times.2), Na₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to obtain 3.24g of a white solid, yield: 38 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)7.79-7.73(m,2H),7.63-7.52(m,2H),7.48(s,1H),7.44-7.34(m,3H),7.34-7.27(m,2H),7.22(d,J＝8.4Hz,1H),6.88-6.51(m,1H),5.74(d,J＝8.4Hz,1H),5.61(d,J＝6.4Hz,1H),5.02-4.90(m,1H),4.49-4.16(m,4H),3.96-3.85(m,2H),1.55(d,J＝7.2Hz,3H),1.36-1.24(m,4H),0.69-0.56(m,2H),0.38-0.28(m,2H)。

And step 3: synthesis of Compound (S) -ethyl 5- (1- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxylate

The compound (4S) -4- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzamido) -3-oxopentanoic acid ethyl ester (2.6g,4.084mmol) was dissolved in anhydrous THF (100mL), the Lawson' S reagent (3.3g,8.168mmol) was added and stirred at 80 ℃ for 21H, after addition of water (100mL), ethyl acetate was extracted (100 mL. times.3), the organic phases were combined and washed with saturated brine (100mL), Na₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 1.86g of a pale blue solid.

¹HNMR(400MHz,CD₃OD):δ(ppm)7.79-7.53(m,5H),7.40-7.15(m,5H),7.13-6.97(m,1H),6.96-6.50(m,1H),5.70-5.55(m,1H),4.52-4.37(m,2H),4.37-4.24(m,1H),4.23-4.12(m,1H),3.98(d,J＝6.8Hz,2H),3.88-3.76(m,2H),1.55(d,J＝6.0Hz,2H),1.47-1.36(m,3H),1.36-1.24(m,4H),0.70-0.56(m,2H),0.45-0.30(m,2H)。

And 4, step 4: synthesis of the compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxylic acid

The compound ethyl (S) -5- (1- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxylate (1.86g,2.931mmol) was dissolved in THF/H₂To O (v/v ═ 1/1,210mL) was added a sodium hydroxide solution (1M,12.89mL), and the mixture was stirred at 80 ℃ for 3 hours, followed by di-tert-butyl dicarbonate (768mg,3.517mmol), at 33 ℃ for 4 hours, hydrochloric acid (1M) was added to adjust the pH to 2-3, ethyl acetate was extracted (150mL × 3), the organic phases were combined and washed with saturated brine (30mL × 2), Na₂SO₄drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to obtain 1.145g of a white solid, yield: 80.6 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)7.50(s,1H),7.39(d,J＝8.0Hz,1H),7.22(d,J＝8.4Hz,1H),6.90-6.49(m,1H),5.65-5.55(m,1H),3.97(d,J＝6.8Hz,2H),1.60(d,J＝6.4Hz,3H),1.36-1.28(m,1H),0.72-0.65(m,2H),0.43-0.36(m,2H),0.07(s,9H)；

MS-ESI(pos.ion)m/z:485.1[M+H]⁺。

and 5: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) thiazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxylic acid (300mg,0.6192mmol) was dissolved in DCM (20mL)EDCI (178mg,0.9288mmol) and HOBT (126mg,0.9288mmol) were added and stirred at 25 ℃ for 0.5h, followed by 2, 4-difluorobenzylamine (106mg,0.7430mmol) and DIPEA (333. mu.L, 1.858mmol), stirring at 25 ℃ for 3h, addition of water (20mL), extraction with DCM (15 mL. times.2), combination of the organic phases and then addition of saturated Na₂CO₃Solution washing (30 mL. times.2) and saturated brine washing (30 mL. times.2), Na₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to obtain 285mg of a white solid, yield: 75.5 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)8.56(br.s,1H),8.06(d,J＝7.6Hz,1H),7.90-7.83(m,1H),7.67(d,J＝7.6Hz,1H),7.53(d,J＝2Hz,1H),7.41(dd,J＝8.4Hz,1H),7.20(d,J＝8.8Hz,1H),6.89-6.49(m,1H),6.16(br.s,1H),5.65-5.45(m,1H),4.55-4.45(m,2H),4.01(d,J＝6.8Hz,2H),1.59(d,J＝6.8Hz,3H),1.35-1.27(m,1H),0.71-0.62(m,2H),0.46-0.39(m,2H),0.07(s,9H)。

Step 6: synthesis of compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) thiazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) thiazol-5-yl) ethyl) carbamate (285mg,0.4680mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, concentrated, to the residue was added ethyl acetate, filtered, the filter cake was washed with ethyl acetate (1mL × 6), dissolved in methanol (5mL), concentrated to give 230mg of a white solid, yield: 90 percent.

Compound 83:¹HNMR(400MHz,CD₃OD):δ(ppm)7.81(d,J＝1.6Hz,1H),7.59(dd,J＝8.4Hz,1H),7.51-7.43(m,1H),7.25(d,J＝8.4Hz,1H),7.07-6.67(m,1H),7.00-6.90(m,1H),5.38-5.30(m,1H),4.72-4.62(m,2H),4.02(d,J＝6.8Hz,2H),1.77(d,J＝6.8Hz,3H),1.38-1.26(m,1H),0.69-0.62(m,2H),0.43-0.37(m,2H)；

MS-ESI(pos.ion)m/z:510.1[M+H-HCl]⁺。

Example 146: the compound (S) -6- ((5- (1-aminoethyl) -2- (3- (cyclopropyl)Methoxy) -4- (difluoromethoxy) Synthesis of bi-hydrochloride of phenyl) thiazole-4-formamido) methyl) picolinic acid

Step 1: synthesis of the compound ethyl (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxamido) methyl) picolinate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxylic acid (300mg,0.6192mmol) was dissolved in DCM (20mL), EDCI (178mg,0.9288mmol) and HOBT (126mg,0.9288mmol) were added, stirring was carried out at 25 ℃ for 0.5h, then ethyl 6-aminomethyl-2-pyridinecarboxylate (134mg,0.7430mmol) and DIPEA (333. mu.L, 1.858mmol) were added, stirring was carried out at 25 ℃ for 3h, after addition of water (20mL), extraction was carried out with DCM (15 mL. times.2), the organic phases were combined and then extracted with saturated Na₂CO₃Solution washing (30 mL. times.2) and saturated brine washing (30 mL. times.2), Na₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to obtain 332mg of a white solid, yield: 82.9 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)8.59(br.s,1H),8.08(d,J＝7.6Hz,1H),7.93-7.85(m,1H),7.70(d,J＝8.0Hz,1H),7.56(d,J＝2.4Hz,1H),7.43(dd,J＝8.6Hz,1H),7.22(d,J＝8.4Hz,1H),6.87-6.50(m,1H),6.18(br.s,1H),5.66-5.50(m,1H),4.98-4.84(m,2H),4.56-4.46(m,2H),4.04(d,J＝7.2Hz,2H),1.61(d,J＝7.2Hz,3H),1.49-1.43(m,3H),1.38-1.30(m,1H),0.75-0.66(m,2H),0.48-0.42(m,2H),0.09(s,9H)；

MS-ESI(pos.ion)m/z:647.3[M+H]⁺。

Step 2: synthesis of compound (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxamido) methyl) picolinic acid

The compound (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxamido) methyl) picolinic acid ethyl ester (320mg,0.4949mmol) in THF/H₂O (v/v ═ 2/1,9mL), lithium hydroxide monohydrate (104mg,2.474mmol) was added, stirring was performed at 40 ℃ for 4.5h, hydrochloric acid (1M) was added to adjust pH 2-3, ethyl acetate extraction (15mL × 3) was performed, the organic phases were combined, and then washing with saturated brine (15mL × 2), Na₂SO₄Drying, concentration, and isolation and purification of the concentrate by silica gel column chromatography (petroleum ether) gave 230mg of a white solid, yield: 75 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)8.55(br.s,1H),8.19(d,J＝6.4Hz,1H),8.07-8.00(m,1H),7.77(d,J＝7.6Hz,1H),7.53(s,1H),7.42(dd,J＝8.2Hz,1H),7.23(d,J＝8.4Hz,1H),6.92-6.50(m,1H),5.97(br.s,1H),5.70-5.55(m,1H),4.94(d,J＝5.2Hz,2H),4.01(d,J＝7.2Hz,2H),1.61(d,J＝6.4Hz,3H),1.38-1.30(m,1H),0.72-0.64(m,2H),0.47-0.39(m,2H),0.09(s,9H)；

MS-ESI(pos.ion)m/z:619.3[M+H]⁺。

And step 3: synthesis of compound (S) -6- ((5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxamido) methyl) picolinic acid dihydrochloride

To a solution of compound (S) -6- ((5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxamido) methyl) picolinic acid (220mg,0.3557mmol) in dichloromethane (1mL) was added an ethyl acetate solution of HCl (4M,3mL), stirred at room temperature for 40min, ethyl acetate was added, filtered, the filter cake was washed with ethyl acetate (1mL × 6), dissolved in methanol (5mL), and concentrated to give 150mg of a light yellow solid, yield: 87.8 percent.

Compound 85:¹HNMR(400MHz,CD₃OD):δ(ppm)8.36-8.25(m,2H),8.03-7.92(m,1H),7.86(d,J＝2.4Hz,1H),7.63(dd,J＝8.4Hz,1H),7.30(d,J＝8.4Hz,1H),7.09-6.70(m,1H),5.45-5.38(m,1H),4.97(s,2H),4.06(d,J＝7.2Hz,2H),1.81(d,J＝5.6Hz,3H),1.41-1.30(m,1H),0.72-0.65(m,2H),0.46-0.42(m,2H)；

MS-ESI(pos.ion)m/z:519.3[M+H-2HCl]⁺。

Example 147: the compound (S) -5- (1-aminoethyl) -N- (benzofuran-3-yl)Methyl) -2- (3- (cyclopropylmethyl) methyl ester Synthesis of oxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxamide hydrochloride

Step 1: synthesis of the Compound (S) - (tert-butyl 1- (4- ((benzofuran-3-ylmethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxylic acid (200mg,0.4129mmol) was dissolved in DCM (20mL), EDCI (119mg,0.6194mmol) and HOBT (85mg,0.6194mmol) were added, stirring was carried out at 25 ℃ for 0.5h, then benzofuran-3-ylmethylamine hydrochloride (91mg,0.4953mmol) and DIPEA (259. mu.L, 1.445mmol) were added, stirring was carried out at 25 ℃ for 3h, and after addition of water (20mL), extraction was carried out with DCM (15 mL. times.2). The organic phases were combined and saturated with Na₂CO₃Solution washing (30 mL. times.2) and saturated brine washing (30 mL. times.2), Na₂SO₄Drying, concentration, and separation and purification of the concentrated solution by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 5/1) to obtain 147mg of a white solid, yield: 58 percent.

¹HNMR(400MHz,CDCl₃):δ(ppm)7.72-7.66(m,2H),7.50(d,J＝8.4Hz,1H),7.42(s,1H),7.38-7.30(m,2H),7.29-7.23(m,1H),7.18(d,J＝8.4Hz,1H),6.86-6.46(m,1H),5.67-5.47(m,1H),4.78(d,J＝6.0Hz,2H),3.91(d,J＝6.4Hz,2H),1.63(d,J＝7.2Hz,3H),1.33-1.27(m,1H),0.68-0.62(m,2H),0.39-0.33(m,2H),0.07(s,9H)；

MS-ESI(pos.ion)m/z:614.3[M+H]⁺。

Step 2: synthesis of the compound (S) -5- (1-aminoethyl) -N- (benzofuran-3-ylmethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazole-4-carboxamide hydrochloride

To a solution of compound (S) tert-butyl (1- (4- ((benzofuran-3-ylmethyl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) thiazol-5-yl) ethyl) carbamate (147mg,0.2395mmol) in dichloromethane (1mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 40min, ethyl acetate was added, filtered, the filter cake was washed with ethyl acetate (1mL × 6), dissolved in methanol (5mL), concentrated to give 125mg of a white solid, yield: 95 percent.

Compound 86:¹HNMR(400MHz,CD₃OD):δ(ppm)7.83-7.77(m,3H),7.58(dd,J＝8.4Hz,1H),7.49(d,J＝8.4Hz,1H),7.35-7.23(m,3H),7.08-6.69(m,1H),5.43-5.35(m,1H),4.81-4.77(m,2H),4.02(d,J＝6.8Hz,2H),1.82(d,J＝7.2Hz,3H),1.38-1.28(m,1H),0.71-0.63(m,2H),0.45-0.38(m,2H)；

MS-ESI(pos.ion)m/z:514.3[M+H-HCl]⁺。

example 148: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Yl) -N- ((S) -1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyridin-4-ylmethyl) piperazin-1-yl) ethyl) oxazole-4- Carboxamide trihydrochloride and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyridin-4-ylmethyl) piperazin-1-yl) ethyl) oxazole-4-carboxamide Synthesis of trihydrochloride

Resolution of the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyridin-4-ylmethyl) piperazin-1-yl) ethyl) oxazole-4-carboxamide trihydrochloride of example 60 gave the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) -1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyridin-4-ylmethyl) piperazine-1-carboxamide trihydrochloride -yl) ethyl) oxazole-4-carboxamide trihydrochloride (white solid) and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) -1- (2, 4-difluorophenyl) -2-oxo-2- (4- (pyridin-4-ylmethyl) piperazin-1-yl) ethyl) oxazole-4-carboxamide trihydrochloride (white solid).

example 149: the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Yl) -N- ((S) - (2, 4-difluorophenyl) (2H-tetrazol-5-yl) methyl) oxazole-4-carboxamide dihydrochloride and 5- ((S) -1- Aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) - (2, 4-difluorophenyl) (2H-tetrakis Synthesis of oxazol-5-yl) methyl) oxazole-4-carboxamide dihydrochloride

Resolution of the compound 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((2, 4-difluorophenyl) (2H-tetrazol-5-yl) methyl) oxazole-4-carboxamide dihydrochloride from example 59 gave the compounds 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- ((S) - (2, 4-difluorophenyl) (2H-tetrazol-5-yl) methyl) oxazole-4-carboxamide dihydrochloride (white solid) and 5- ((S) -1-aminoethyl) -2- (3- (cyclopropylmethoxy) methyl) Methoxymethoxy) -4- (difluoromethoxy) phenyl) -N- ((R) - (2, 4-difluorophenyl) (2H-tetrazol-5-yl) methyl) oxazole-4-carboxamide dihydrochloride (white solid).

Example 150: the compound (S) -5- (1-aminoethyl) -2- (3- ((5- (cyclopentylamino) -5-oxopentyl) oxy) Synthesis of yl) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) - (tert-butyl 1- (2- (3- ((5- (cyclopentylamino) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (5- (5- (1- ((t-butoxycarbonyl) amino) ethyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoic acid (0.25g,0.39mmol), cyclopropylamine (40mg,0.47mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (112mg,0.59mmol) and N-hydroxy-7-azabenzotriazole (80mg,0.59mmol) were dissolved in dichloromethane (15mL) and N, N-diisopropylamine was added dropwise to the solution at 0 deg.CYlethylamine (0.27mL,1.56mmol), stirred at room temperature for 5h, washed with water (10 mL. times.3), and the organic phase over anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 1/1) afforded 240mg of a white solid, yield: 86 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.60–7.58(m,2H),7.47–7.41(m,1H),7.24(d,J＝8.0Hz,1H),6.91–6.86(m,2H),6.63(t,J_F-H＝74.5Hz,1H),5.53–5.51(m,1H),5.32–5.30(m,1H),4.68–4.67(m,2H),4.25–4.19(m,1H),4.17–4.14(m,2H),2.28(t,J＝7.0Hz,2H),2.03–1.96(m,2H),1.92–1.86(m,4H),1.68–1.58(m,4H),1.56(d,J＝7.0Hz,3H),1.45(s,9H),1.38–1.35(m,1H)；

MS-ESI:m/z 707.2[M+H]⁺。

Step 2: synthesis of the Compound (S) -5- (1-aminoethyl) -2- (3- ((5- (cyclopentylamino) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

To a solution of tert-butyl compound (S) - (1- (2- (3- ((5- (cyclopentylamino) -5-oxopentyl) oxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (0.23g,0.33mmol) in dichloromethane (3mL) was added an ethyl acetate solution of HCl (4M,2mL), stirred at room temperature for 1.5h, the solvent was removed to give 209mg of a white solid, yield: 99 percent.

Compound 193:¹H NMR(400MHz,CD₃OD):δppm 7.82(s,1H),7.73(d,J＝8.4Hz,1H),7.52–7.46(m,1H),7.33(d,J＝8.3Hz,1H),7.01–6.94(m,2H),6.88(t,J_F-H＝74.5Hz,1H),5.18–5.17(m,1H),4.65(s,2H),4.19(t,J＝5.6Hz,2H),4.13–4.09(m,1H),2.31(t,J＝6.8Hz,2H),1.95–1.84(m,6H),1.78(d,J＝6.9Hz,3H),1.74–1.68(m,2H),1.64–1.59(m,2H),1.50–1.40(m,2H)；

MS-ESI:m/z 607.2[M+H-HCl]⁺。

Example 151: the compound (S) -2- (3- (4-aminobutoxy) -4- (difluoromethoxy) phenyl) -5- (1-aminoethylethanol) Synthesis of phenyl-N- (2, 4-difluorobenzyl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (4-aminobutoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) carbamate (160mg,0.26mmol) in dichloromethane (2mL) was added a solution of HCl in ethyl acetate (4M,3mL), stirred at room temperature for 1h, the solvent was removed to give 140mg of a white solid which was worked up to 53mg of a white solid in yield: 36 percent.

Compound 128:¹H NMR(600MHz,CD₃OD):δppm 7.86(d,J＝1.8Hz,1H),7.76(dd,J₁＝8.4Hz,J₂＝1.8Hz,1H),7.52–7.48(m,1H),7.35(d,J＝8.4Hz,1H),7.01–6.85(m,2H),6.91(t,J_F-H＝74.1Hz,1H),5.20–5.16(m,1H),4.65(s,2H),4.25(t,J＝5.7Hz,2H),3.09(t,J＝7.5Hz,2H),2.03–1.93(m,4H),1.78(d,J＝7.0Hz,3H)；

MS-ESI:511.0[M+H-2HCl]⁺。

Example 152: the compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) benzene Synthesis of yl) -N- (1-methyl-1H-pyrazol-4-yl) oxazole-4-carboxamide dihydrochloride

Step 1: synthesis of 1-methyl-1H-pyrazol-4-amine

1-methyl-4-nitro-1H-pyrazole (500mg,3.93mmol) and Pd/C (10%, 50mg) were added to methanol (10mL), reduced with hydrogen at room temperature under normal pressure, reacted for 6H, stopped, filtered with suction, and the filtrate was concentrated to give 305mg of a red liquid, yield: 80 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.18(s,1H),7.14(s,1H),3.78(s,3H)；

MS-ESI:m/z 98.20[M+H]⁺。

Step 2: synthesis of Compound (S) - (tert-butyl 1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1-methyl-1H-pyrazol-4-yl) carbamoyl) oxazol-5-yl) ethyl) carbamate

The compound (S) -5- (1- ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (300mg,0.64mmol), 1-methyl-1H-pyrazol-4-amine (75mg,0.77mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (245mg,1.28mmol) and N-hydroxy-7-azabenzotriazole (130mg,0.96mmol) were dissolved in dichloromethane (10mL), to this solution was added dropwise N, N-diisopropylethylamine (0.33mL,1.92mmol) at 0 deg.C, stirred at room temperature for 5h, washed with water (10 mL. times.3), and the organic phase was washed with anhydrous Na.₂SO₄Drying, removal of the solvent, column separation of the concentrate (petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 232mg of a pale yellow solid in yield: 66 percent.

¹H NMR(600MHz,CDCl₃):δppm 7.89(br.s,1H),8.05(s,1H),7.61(dd,J₁＝8.3Hz,J₂＝1.8Hz,1H),7.57(d,J＝12.2Hz,2H),7.25(d,J＝8.3Hz,1H),6.71(t,J_F-H＝75.1Hz,1H),5.32–5.35(m,1H),3.99(d,J＝6.9Hz,2H),3.91(s,3H),1.56(d,J＝7.0Hz,3H),1.44(s,9H),1.31–1.36(m,1H),0.68–0.71(m,2H),0.40–0.43(m,2H)；

MS-ESI:m/z 546.70[M-H]^-。

And step 3: synthesis of Compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (1-methyl-1H-pyrazol-4-yl) oxazole-4-carboxamide dihydrochloride

To a solution of compound (S) tert-butyl (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((1-methyl-1H-pyrazol-4-yl) carbamoyl) oxazol-5-yl) ethyl) carbamate (225mg,0.41mmol) in dichloromethane (4mL) was added an ethyl acetate solution of HCl (4M,4mL), stirred at room temperature for 30min, and the solvent was removed to give 212mg of a white solid, yield: 97 percent.

Compound 402:¹H NMR(600MHz,CD₃OD):δppm 8.20–8.23(m,1H),7.95–7.99(m,1H),7.81(s,1H),7.73(dd,J₁＝8.3Hz,J₂＝1.7Hz,1H),7.31(d,J＝8.3Hz,1H),6.89(t,J_F-H＝75.1Hz,1H),5.20–5.24(m,1H),4.03(d,J＝6.9Hz,2H),3.97(s,3H),1.78(d,J＝7.0Hz,3H),1.31–1.37(m,1H),0.65–0.68(m,2H),0.40–0.43(m,2H)；

MS-ESI:m/z 448.10[M+H-2HCl]⁺。

Example 153: the compound (S) -5- (1- (4- (aminomethyl) -1H-1,2, 3-triazole-1-yl) ethyl) -2- (3- Synthesis of (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

Step 1: synthesis of Compound (S) -5- (1-azidoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide

The compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride (312.4mg,0.59mmol), copper sulfate pentahydrate (1.476mg,0.059mmol) and potassium carbonate (244.5mg,1.77mmol) were added to methanol (25mL), a solution of 1H-imidazole-1-sulfonyl azide (204.3mg,1.18mmol) in methanol (5mL) was added slowly and dropwise to the solution, the reaction was continued at room temperature for 12H, methanol was removed, saturated NH was added₄Cl solution (20mL), extraction with ethyl acetate (25 mL. times.3), combining the organic phases, and addition of anhydrous Na₂SO₄Dry for 1h, remove solvent, concentrate for column separation (Petroleum ether/EtOAc (v/v) ═ 3/1) to give 274mg of a white solid, yield: 89.4 percent.

Step 2: synthesis of tert-butyl (S) - ((1- (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) carbamate, a compound

The compound N-Boc-aminopropyne (98.2mg,0.633mmol), anhydrous copper sulfate (13mg,0.05mmol) and sodium ascorbate (20.9mg,0.105mmol) were added to a 25mL two-necked round bottom flask, evacuated and protected with nitrogen, a solution of the compound (S) -5- (1-azidoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide (274mg,0.528mmol) in THF (16mL) was added, distilled water (4mL) was added, the reaction was allowed to proceed for 1h at 60 ℃ and the mixture was cooledTHF is removed and saturated NH is added₄Cl solution (25mL), extraction with dichloroethane (25 mL. times.3), combining the organic phases and then applying anhydrous Na₂SO₄Drying, removal of solvent, column separation of the concentrate (Petroleum ether/EtOAc (v/v) ═ 1/1) afforded 320mg of a white solid, yield: 89.9 percent.

And step 3: synthesis of compound (S) -5- (1- (4- (aminomethyl) -1H-1,2, 3-triazol-1-yl) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride

The compound tert-butyl (S) - ((1- (1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) carbamate (385mg,0.571mmol) was dissolved in CH₂Cl₂(2mL), HCl was added^.EtOAc (4M,5mL), stirred at rt overnight, and the solvent removed to give 328.4mg of a white solid, yield: 94.2 percent.

Compound 72:¹H NMR(400MHz,CD₃OD):δppm 8.93–8.96(m,1H),8.32(s,1H),7.77(d,J＝1.6Hz,1H),7.69(dd,J₁＝8.4Hz,J₂＝1.7Hz,1H),7.43–7.49(m,1H),7.32(d,J＝8.1Hz,1H),6.94–7.01(m,2H), 6.91(t,J_F-H＝74.8Hz,1H),6.82–6.87(m,1H),4.60–4.63(m,2H),4.27(s,2H),4.03(d,J＝6.9Hz,2H),2.12(d,J＝7.2Hz,3H),1.31–1.37(m,1H),0.67–0.71(m,2H),0.41–0.45(m,2H)；

MS-ESI:m/z 575.45[M+H-HCl]⁺。

Example 154: the compound (S) -4- ((1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4-) Synthesis of ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) amino) -4-oxobutanoic acid

Step 1: synthesis of methyl 4- ((1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) amino) -4-oxobutanoate, compound (S)

The compound (S) -5- (1-aminoethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -N- (2, 4-difluorobenzyl) oxazole-4-carboxamide hydrochloride (250mg,0.47mmol), monomethyl succinate (74mg,0.56mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (135mg,0.71mmol) and N-hydroxy-7-azabenzotriazole (96mg,0.71mmol) were added to dichloromethane (15mL), stirred at room temperature for 30min, N-diisopropylethylamine (0.33mL,1.88mmol) was added dropwise to the solution at 0 deg.C, stirred at room temperature for 15h, the solvent was removed, and the concentrate was subjected to column separation (petroleum ether/ethyl acetate (v/v) ═ 1/1), 204mg of a white solid are obtained, yield: 71 percent.

¹H NMR(400MHz,CDCl₃):δppm 7.59(dd,J₁＝8.4Hz,J₂＝2.0Hz,1H),7.54(s,1H),7.41-7.46(m,1H),7.25(d,J＝8.3Hz,1H),6.85-6.93(m,2H),6.72(t,J_F-H＝74.9Hz,1H),5.57-5.61(m,1H),4.67(d,J＝6.2Hz,2H),3.99(d,J＝7.0Hz,2H),3.69(s,3H),2.66-2.70(m,2H),2.52-2.63(m,2H),1.54(d,J＝7.0Hz,3H),1.31-1.37(m,1H),0.68-0.73(m,2H),0.40-0.44(m,2H)；

MS-ESI:m/z 608.2[M+H]⁺。

Step 2: synthesis of compound (S) -4- ((1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) amino) -4-oxobutanoic acid

Methyl 4- ((1- (2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4- ((2, 4-difluorobenzyl) carbamoyl) oxazol-5-yl) ethyl) amino) -4-oxobutanoate (150mg,10.63mmol) and sodium hydroxide (50mg,1.23mmol) were dissolved in a mixed solvent of ethanol (20mL) and water (10mL), reacted at 60 ℃ for 2h, ethanol was removed, pH was adjusted to about 1 with hydrochloric acid (1M), ethyl acetate was added for extraction (10 mL. times.3), the organic phases were combined and then anhydrous Na was used₂SO₄Drying and removal of the solvent gave 146mg of a white solid, yield: 99 percent.

Compound 437:¹H NMR(600MHz,CD₃OD):δppm 7.69(s,1H),7.61(dd,J₁＝8.3Hz,J₂＝1.7Hz,1H),7.42-7.46(m,1H),7.25(d,J＝8.3Hz,1H),6.90-6.93(m,2H),6.87(t,J_F-H＝74.9Hz,1H),5.68-5.71(m,1H),4.55-4.63(m,2H),3.95(d,J＝7.0Hz,2H),2.58-2.61(m,2H),2.51-2.55(m,2H),1.56(d,J＝7.0Hz,3H),1.29-1.35(m,1H),0.63-0.66(m,2H),0.37-0.39(m,2H)；

MS-ESI:m/z 594.1[M+H]⁺。

the compound numbers in tables 2 to 20 correspond one-to-one to the compound numbers in the specific structures of the description part of the compounds of the present invention in the detailed description of the present invention.

By a similar synthetic method to example 102, using appropriate starting materials, the compounds shown in table 2 can be obtained:

Table 2 Compounds and characterization data thereof

By a similar synthetic procedure to example 108, using the appropriate starting materials, the compounds shown in table 3 can be obtained:

Table 3 Compounds and characterization data thereof

By a similar synthetic procedure to example 1, using appropriate starting materials, the compounds shown in table 4 can be obtained:

Table 4 Compounds and characterization data thereof

By a similar synthetic procedure to example 124, using the appropriate starting materials, the compounds shown in table 5 can be obtained:

Table 5 Compounds and characterization data thereof

By a similar synthetic procedure to example 125, using the appropriate starting materials, the compounds shown in table 6 can be obtained:

Table 6 Compounds and characterization data thereof

By a similar synthetic procedure to example 39, using the appropriate starting materials, the compounds shown in table 7 can be obtained:

Table 7 compounds and characterization data thereof

examples	Compound numbering	Characterization data
			175	120	Compound 120: MS-ESI: M/z 587.15[ M + H-2HCl ]]⁺.
176	121	Compound 121: MS-ESI: M/z 587.15[ M + H-2HCl ]]⁺.
			177	122	Compound 122: MS-ESI: M/z 587.15[ M + H-2HCl ]]⁺.

By a similar synthetic method to example 40, using appropriate starting materials, the compounds shown in table 8 can be obtained:

Table 8 Compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			178	108	Compound 108: MS-ESI: M/z 484.20[ M + H-HCl ]]⁺.

By a similar synthetic procedure to example 65, using the appropriate starting materials, the compounds shown in table 9 can be obtained:

Table 9 Compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			179	169	Chemical combinationSubstance 169: MS-ESI: M/z 552.18[ M + H-2HCl ]]⁺.

By a similar synthetic method to example 74, using appropriate starting materials, the compounds shown in table 10 can be obtained:

table 10 Compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			180	189	Compound 189: MS-ESI: M/z 619.25[ M + H-HCl ]]⁺.
181	190	Compound 190: MS-ESI: M/z 619.25[ M + H-HCl ]]⁺.

By a similar synthetic method to example 76, using appropriate starting materials, the compounds shown in table 11 can be obtained:

Table 11 Compounds and characterization data thereof

Examples

Compound numbering

Characterization data

Examples	Compound numbering	Characterization data
			182	200	Compound 200: MS-ESI: M/z 608.21[ M + H-HCl ]]⁺.

By a similar synthetic method to example 79 using appropriate starting materials, the compounds shown in table 12 can be obtained:

Table 12 Compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			183	197	Compound 197: MS-ESI: M/z 580.20[ M + H-HCl ]]⁺.

By a similar synthetic method to example 99, using appropriate starting materials, the compounds shown in table 13 can be obtained:

Table 13 compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			184	40	Compound 40: MS-ESI: M/z 513.08[ M + H-2HCl ]]⁺.
185	84	Compound 84: MS-ESI: M/z 508.18[ M + H-HCl ]]⁺.
			186	111	Compound 111: MS-ESI: M/z 536.17[ M + H-HCl ]]⁺.
187	124	Compound 124: MS-ESI: M/z 508.18[ M + H-HCl ]]⁺.
			188	126	Compound 126: MS-ESI of m/z 512.15[M+H-HCl]⁺.
189	127	Compound 127: MS-ESI: M/z 510.16[ M + H-HCl ]]⁺.
			190	130	Compound 130: MS-ESI: M/z 511.15[ M + H-HCl ]]⁺.
191	131	Compound 131: MS-ESI: M/z 519.16[ M + H-HCl ]]⁺.
			192	142	Compound 142: MS-ESI: M/z 523.19[ M + H-2HCl ]]⁺.
193	143	Compound 143: MS-ESI: M/z 523.19[ M + H-2HCl ]]⁺.
			194	362	Compound 362: MS-ESI: M/z 487.17[ M + H-HCl ]]⁺.
195	363	compound 363: MS-ESI: M/z 519.18[ M + H-HCl ]]⁺.
			196	381	Compound 381: MS-ESI: M/z 474.19[ M + H-HCl ]]⁺.
197	397	Compound 397: MS-ESI: M/z 459.18[ M + H-2HCl ]]⁺.

By a similar synthetic method to example 119 using appropriate starting materials, the compounds shown in table 14 can be obtained:

Table 14 compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			198	118	Compound 118: MS-ESI: M/z 653.25[ M + H-HCl ]]⁺.
199	119	Compound 119: MS-ESI: M/z 652.27[ M + H-2HCl ]]⁺.
			200	259	Compound 259: MS-ESI: M/z 628.29[ M + H-HCl ]]⁺.

By a similar synthetic method to example 120 using appropriate starting materials, the compounds shown in table 15 can be obtained:

Table 15 Compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			201	191	Compound 191: MS-ESI: M/z 539.18[ M + H-HCl ]]⁺.
202	204	Compound 204: MS-ESI: M/z 554.19[ M + H-2HCl ]]⁺.
			203	205	Compound 205: MS-ESI: M/z 610.22[ M + H-HCl ]]⁺.

By a similar synthetic method to example 59, using appropriate starting materials, the compounds shown in table 16 can be obtained:

Table 16 compounds and characterization data thereof

Examples	compound numbering	Characterization data
			204	163	Compound 163: MS-ESI: M/z 563.17[ M + H-3HCl ]]⁺.

By using the appropriate starting materials, and following the sixteen synthetic routes, the compounds shown in table 17 can be obtained:

Table 17 compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			205	18	Compound 18: MS-ESI: M/z 474.18[ M + H-HCl ]]⁺.
206	116	Compound 116: MS-ESI: M/z 510.16[ M + H-HCl ]]⁺.

By following the route of synthetic method seventeen, using appropriate starting materials, the compounds shown in table 18 can be obtained:

Table 18 Compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			207	117	Compound 117: MS-ESI: M/z 495.15[ M + H ]]⁺.
208	125	Compound 125: MS-ESI: M/z 493.13[ M + H ]]⁺.

The compounds shown in table 19 can be obtained by the eighteen routes of the synthetic method using appropriate starting materials:

Table 19 compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			209	123	Compound 123: MS-ESI: M/z 493.18[ M + H-HCl ]]⁺.

The compounds shown in table 20 can be obtained by a route to nineteen synthetic methods using appropriate starting materials:

TABLE 20 Compounds and characterization data thereof

Examples	Compound numbering	Characterization data
			210	129	Compound 129: MS-ESI: M/z 677.25[ M + H-2HCl ]]⁺.

Biological assay

The present invention provides a biological assay for a compound of formula (I), formula (I') or formula (II) using the following method:

1. Compounds were tested for PDE4B2 enzyme inhibition using the BPS manufacturing kit (BPS, 603343) using fluorescence polarization methods according to the manufacturer's instructions.

2. The concentration of PDE4B2 enzyme was prepared to be 83.33pg/μ L, and the final concentration was 27.78pg/μ L; the concentration of a substrate FAM-Cyclic-3 ', 5' -AMP is prepared to be 300nM, the final reaction concentration is 100nM, and enzyme and substrate diluent are both prepared by using a PDE Assay buffer with a kit; the Binding Agent utilizes the Binding Agent Diluent carried by the kit to dilute 100 times for later use. The reaction system is shown in Table 21.

TABLE 21 Compound on PDE4B2 enzyme IC₅₀Detecting bodyIs a system

3. The detection is carried out by adopting a 384-well plate, a test sample well, a positive control well, a negative control well and a blank well are arranged in the experiment, each sample utilizes the inhibition effect of double-well detection on the PDE4B2 enzyme concentration under 10 concentrations, a PDE4B2 enzyme and FAM-Cyclic-3 ', 5' -AMP substrate reaction well is used as a positive control, a FAM-Cyclic-3 ', 5' -AMP substrate reaction well is used as a negative control, and a buffer well is used as a blank control. After adding corresponding samples, enzymes, substrates and buffer solutions into each well in sequence according to the table 21, incubating for 1h in a constant temperature box at 25 ℃, adding 15 mu L of prepared Binding Agent into each well, shaking for 1h in a constant temperature oscillator at 25 ℃, and detecting at the wavelength of FP485/525 by using a PHER Astar FS multifunctional enzyme-linked immunosorbent assay (BMG). The inhibition of PDE4B2 enzyme at various concentrations of compound was plotted using Graph Padprism 5 software to calculate IC₅₀。

The results of the measurement of the inhibitory effect on PDE4B2 enzyme by the compounds provided in the examples of the present invention according to the above-mentioned method are shown in Table 22, and Table 22 shows the results of the measurement of the inhibitory effect on PDE4B2 enzyme by the examples of the present invention. The compound numbers in Table 22 correspond one-to-one to the compound numbers in the specific structures of the description part of the compounds of the present invention in the detailed description of the present invention.

TABLE 22 results of the measurement of the inhibitory effect of the compounds of the present invention on PDE4B2 enzyme

Compound numbering	IC₅₀(nM)	Compound numbering	IC₅₀(nM)	Compound numbering	IC₅₀(nM)
						Roflumilast	0.60	Compound 2	0.50	Compound 3	2.40
Compound 4	1.58	Compound 5	4.70	Compound 6	19.50
						Compound 7	6.50	Compound 9	101.68	Compound 10	29.74
Compound 13	4.25	Compound 15	39.50	Compound 16	33.89
						Compound 17	3.31	Compound 21	19.87	Compound 22	3.51
Compound 23	1.86	Compound 24	0.64	Compound 28	101.88
						Compound 29	0.40	Compound 30	3.41	Compound 31	2.66

Compound numbering	IC₅₀(nM)	Compound numbering	IC₅₀(nM)	Compound numbering	IC₅₀(nM)
						Compound 32	38.12	Compound 33	15.42	Compound 34	3.22
Compound 35	7.20	Compound 36	5.66	Compound 37	1.68
						compound 38	3.78	Compound 39	18.28	Compound 41	7.30
Compound 43	146.85	Compound 46	70.74	Compound 49	36.66
						Compound 51	3.05	Compound 52	28.83	Compound 54	3.25
Compound 57	4.26	Compound 70	1.75	Compound 73	13.85
						Compound 74	4.28	Compound 75	1.60	Compound 76	0.69
compound 77	0.57	Compound 78	4.01	Compound 79	3.03
						Compound 80	6.90	Compound 81	1.39	compound 82	104.90
compound 84	6.70	Compound 87	1.66	Compound 88	9.59
						Compound 89	0.86	Compound 92	5.00	Compound 95	5.54
Compound 96	34.10	Compound 97	5.52	Compound 98	28.99
						Compound 99	4.54	Compound 100	3.55	Compound 101	0.16
Compound 102	1.50	Compound 106	0.29	Compound 113	8.04
						Compound 114	10.05	Compound 132	2.98	Compound 133	2.28
Compound 134	8.02	Compound 135	0.32	Compound 137	1.09
						compound 138	2.20	Compound 139	2.51	Compound 140	1.49
Compound 141	4.53	Compound 144	6.21	Compound 146	14.44
						Compound 147	52.22	Compound 148	0.36	Compound 150	3.49
compound 151	12.66	Compound 152	3.47	Compound 154	1.09
						compound 155	0.34	Compound 156	3.75	Compound 158	1.54
Compound 159	5.40	Compound 160	2.24	Compound 161	15.6
						Compound 162	3.51	Compound 164	15.97	Compound 165	15.9
Compound 166	1.57	Compound 167	9.59	Compound 168	13.68
						Compound 170	31.48	Compound 171	4.09	Compound 172	4.98
Compound 173	15.22	Compound 174	15.41	Compound 176	10.72
						Compound 177	6.71	Compound 178	3.15	Compound 179	1.21
Compound 180	5.45	Compound 182	6.10	Compound 183	7.13
						compound 184	17.47	Compound 187	1.77	Compound 188	11.35
Compound 193	34.29	Compound 194	24.64	Compound 196	7.39
						compound 198	8.03	Compound 199	25.74	Compound 200	1.84
compound 201	11.82	Compound 202	0.60	Compound 207	13.32
						Compound 208	1.38	Compound 209	6.16	compound 211	5.83

Compound numbering	IC₅₀(nM)	Compound numbering	IC₅₀(nM)	Compound numbering	IC₅₀(nM)
						compound 212	7.32	Compound 214	0.48	Compound 217	29.81
Compound 219	0.51	Compound 220	0.53	Compound 221	2.29
						Compound 222	17.54	Compound 223	6.71	Compound 224	10.48
Compound 225	18.82	Compound 226	0.51	Compound 227	1.32
						Compound 228	15.00	Compound (I)229	5.39	Compound 231	88.73
Compound 232	4.65	Compound 233	33.45	Compound 234	12.37
						compound 235	6.78	Compound 236	26.88	Compound 238	15.41
Compound 239	35.50	Compound 240	73.84	compound 244	6.61
						Compound 256	23.92	Compound 257 (Novak)	13.29	compound 271	27.13
Compound 313	14.97	compound 325	8.91	Compound 380	5.32
						Compound 383	3.28	Compound 384	0.81	Compound 385	1.73
Compound 402	54.32	Compound 406	0.76	Compound 411	30.56
						Compound 412	0.22	compound 429	0.65	Compound 436	1.39

The data in table 22 show that the compounds of the present invention generally exhibit high inhibitory activity in vitro screening assays for PDE4B2 enzyme inhibition.

It will be evident 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 the essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing embodiments, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation to the description of the present invention, and modifications made within the scope of the present invention or equivalents added to the claims are possible. All publications or patents cited herein are incorporated by reference.

Claims

1. A compound which is a compound of formula (i ') or a stereoisomer or a pharmaceutically acceptable salt of a compound of formula (i'):

Wherein:

p is 0 or 1;

X is-O-or-S-;

R¹Is C_1-4Alkyl or halo C_1-4An alkyl group;

Each R²Independently H, D, F, Cl, Br, I, CN, NO₂，OH，NH₂，HOC(＝O)-C_1-4alkoxy-C_1-4alkoxy- (CH)₂)_e-C(＝O)-C_1-4alkoxy-C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-4alkoxy-C_1-4alkyl-NH-C (═ O) -C_1-4Alkoxy-, R^eR^fN-C(＝O)-C_1-4alkoxy-C_1-5heteroaryl-C_2-6heterocyclyl-C (═ O) -C_1-4alkoxy-C_3-6cycloalkyl-C (═ O) -C_2-6heterocyclyl-C (═ O) -C_1-4Alkoxy-, NH₂-C(＝O)-C_1-4alkoxy-C_1-4alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-4Alkoxy-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-4alkoxy-C_1-4alkyl-S (═ O)₂-NH-C(＝O)-C_1-4alkoxy-C_1-4alkyl-O-C (═ O) -C_1-4Alkoxy-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-4alkoxy-C_2-6heterocyclyl-C (═ O) -C_1-4alkoxy-C_1-4Alkoxy, amino-substituted C_1-4Alkoxy, halo C_1-4Alkoxy radical, C_2-6Heterocyclyloxy, C_6-10Aryl radical C_1-4Alkoxy radical, C_3-6Cycloalkyloxy or C_3-6cycloalkyl radical C_1-4Alkoxy, said aryl group is phenyl or naphthyl, said heterocyclyl group is pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl or thiaxanyl, said heteroaryl group is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; each R²Independently optionally substituted by one or more R¹²Substitution;

Each e is independently 0,1 or 2;

Each f is independently 0, 1 or 2;

Each R⁵And R⁶Independently H, D, F, Cl, Br, I, CN, NO₂，NH₂OH, COOH or C_1-4An alkyl group;

R⁴is C_6-10Aryl radical, C_6-10aryl-S (═ O)₂-，C_1-9Heteroaryl or C_6-10Aryl radical C_1-4Alkyl, aryl is phenyl or naphthyl, heteroaryl is thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrid-2-yl N-oxidopyridin-4-yl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, furo [3,2-c ] o]pyridyl, furo [3,2-b ] compounds]pyridyl, furo [2,3-b ] compounds]Pyridyl, furo [2,3-c ]]Pyridyl, benzoxadiazolyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzopyrazinyl, benzofuranyl, pyridopyrazinyl, 3, 4-dihydro-pyridine [3,2-b ]][1,4]Oxazinyl, 1, 3-benzodioxolyl, 2, 3-dihydrobenzofuranyl, thieno [3,2-b ]]Pyridyl, thieno [2,3-c ]]Pyridyl, thieno [2,3-b ]]Pyridyl, 1, 4-benzodioxanyl or 1,2,3, 4-tetrahydroquinolin-2-yl; r⁴Optionally substituted by one or more R¹⁴Substitution;

Each R⁷Independently is H, D or C_1-4An alkyl group;

Each R^aAnd R^bIndependently H, D, F, Cl, Br, I, CN, OH, NO₂，NH₂，-COOR^9c，C_1-4Alkyl, -C (═ O) -NR⁹R^9a，-C_1-4alkyl-C (═ O) -NR⁹R^9a，-C(＝S)-NH₂Amino-substituted C_1-4Alkyl, -NH-C (═ O) -R^9b，-C_1-4alkyl-NH-C (═ O) -R^9b，-NH-S(＝O)₂-C_1-4Alkyl radical, -C_1-4alkyl-NH-S (═ O)₂-C_1-4Alkyl, -NH-S (═ O)₂-C_3-6Cycloalkyl, -C_1-4alkyl-NH-S (═ O)₂-C_3-6Cycloalkyl, -S (═ O)₂-C_1-4Alkyl radical, -C_1-4alkyl-S (═ O)₂-C_1-4Alkyl radical, C_6-10Aryl or C_1-5Heteroaryl, said aryl is phenyl or naphthyl, said heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolylOxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;

Each R^cAnd R^dIndependently is H, OH, CN, F, Cl, Br, I or C_1-4An alkyl group;

Each R^eAnd R^fIndependently is H, OH or C_1-4An alkyl group;

Each R⁹，R^9aAnd R^9bIndependently is H, D, OH, NH₂，-S(＝O)₂-NH₂，-C(＝O)-NH₂，-C_1-4alkyl-C (═ O) -NH₂，-C_1-4alkyl-C (═ O) O-C_1-4Alkyl radical, -C_1-4alkyl-O-C (═ O) -C_1-4Alkyl radical, C_1-4Alkyl, -S (═ O)₂-C_1-4Alkyl, -S (═ O)₂-C_3-6Cycloalkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_3-6cycloalkyl radical, C_3-6Cycloalkyl radical C_1-4Alkylamino radical, C_3-6Cycloalkyl radical C_1-4Alkyl radical, C_3-6Cycloalkyloxy or C_3-6A cycloalkylamino group; or R⁹，R^9aTogether with the nitrogen atom to which they are attached form a ring of 3 to 6 atoms; said ring of 3 to 6 atoms, R⁹、R^9aAnd R^9bEach independently optionally substituted with one or more R¹⁵Substitution;

Each R^9cIndependently of one another, are H, D, -C_1-4alkyl-C (═ O) O-C_1-4Alkyl radical, -C_1-4alkyl-O-C (═ O) -C_1-4Alkyl radical, C_1-4Alkyl or C_6-10Aryl radical C_1-4An alkyl group, the aryl group being a phenyl group or a naphthyl group;

Each R¹²independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-4Alkyl or C_1-4An alkoxy group;

each R¹⁴Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂COOH or C_1-4An alkyl group;

Each R¹⁵Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-4Alkyl radical, C_6-10Aryl radical, C_1-5heteroaryl group, C_1-5Heteroaryl C_1-4Alkyl or C_3-6A cycloalkylcarbonyl, the aryl group being phenyl or naphthyl, the heteroaryl group being pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; and

R¹¹Is H or C_1-4An alkyl group.

2. The compound of claim 1, which is a compound of formula (ii) or a stereoisomer or a pharmaceutically acceptable salt of a compound of formula (ii):

Wherein:

m is 0;

R¹⁰Is H, HOC (═ O) -C_1-4Alkyl-, C_1-4Alkoxy- (CH)₂)_e-C(＝O)-C_1-4alkyl-, C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-4Alkyl-, C_1-4alkyl-NH-C (═ O) -C_1-4Alkyl-, R^eR^fN-C(＝O)-C_1-4Alkyl-, C_1-5heteroaryl-C_2-6heterocyclyl-C (═ O) -C_1-4Alkyl-, C_3-6cycloalkyl-C (═ O) -C_2-6heterocyclyl-C (═ O) -C_1-4Alkyl-, NH₂-C(＝O)-C_1-4Alkyl-, C_1-4alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-4Alkyl-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-4Alkyl-, C_1-4alkyl-S (═ O)₂-NH-C(＝O)-C_1-4Alkyl-, C_1-4alkyl-O-C (═ O) -C_1-4Alkyl-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-4Alkyl-, C_2-6heterocyclyl-C (═ O) -C_1-4Alkyl-, amino-substituted C_1-4An alkyl group, a carboxyl group,Halogen substituted C_1-4Alkyl radical, C_1-4Alkyl radical, C_2-6heterocyclic radical, C_6-10Aryl radical C_1-4Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-4An alkyl group, the aryl group being phenyl or naphthyl, the heterocyclyl group being pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl or thiaxanyl, the heteroaryl group being pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; r¹⁰Optionally substituted by one or more R¹²Substitution; and

R¹¹Is H or C_1-4An alkyl group.

3. The compound of claim 1 or 2, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate or a combination thereof.

4. The compound of claim 1 or 2, wherein R¹Is methyl, ethyl, propyl, isopropyl, halomethyl, haloethyl or halopropyl.

5. The compound of claim 1, wherein each R²independently H, D, F, Cl, Br, I, CN, NO₂，OH，NH₂Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butyloxy, cyclopropyloxy, cyclobutyloxyPentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy, cyclohexylmethoxy, cyclohexylethoxy, oxetanyloxy, tetrahydrofuryloxy, benzyloxy, phenylethoxy, HOC (═ O) -C_1-4alkoxy-C_1-3Alkoxy- (CH)₂)_e-C(＝O)-C_1-4alkoxy-C_1-4alkyl-O-C (═ O) -C_1-4alkoxy-C_2-4heterocyclyl-C (═ O) -C_1-4alkoxy-C_1-4heteroaryl-C_2-4heterocyclyl-C (═ O) -C_1-4alkoxy-C_3-6cycloalkyl-C (═ O) -C_2-4heterocyclyl-C (═ O) -C_1-4Alkoxy-, NH₂-C(＝O)-C_1-4Alkoxy-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-4Alkoxy-, R^eR^fN-C(＝O)-C_1-4alkoxy-C_1-4alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-4Alkoxy-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-4alkoxy-C_1-3alkyl-S (═ O)₂-NH-C(＝O)-C_1-4alkoxy-C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-4Alkoxy-or amino-substituted C_1-4Alkoxy, said heterocyclyl is pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl or thiaxanyl, and said heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; each R²Independently optionally substituted by one or more R¹²Substitution;

Each R^cAnd R^dIndependently is H, OH, CN, F, Cl, Br, I or C_1-3An alkyl group;

Each R^eAnd R^fIndependently is H, OH or C_1-3An alkyl group; and

Each R¹²Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂COOH, methyl, ethyl, propyl, methoxy, ethoxy or propoxy.

6. The compound of claim 1 or 2, wherein each R⁵And R⁶Independently H, D, F, Cl, Br, I, NH₂Methyl, ethyl, propyl or isopropyl.

7. The compound of claim 1, wherein R⁴Is phenyl, naphthyl, thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrid-2-yl, pyrid-4-yl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl, naphthyridinyl, furo [3,2-c ] group]Pyridyl, furo [3,2-b ] compounds]Pyridyl, furo [2,3-b ] compounds]Pyridyl, furo [2,3-c ]]Pyridyl, benzoxadiazolyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzopyrazinyl, benzofuranyl, pyridopyrazinyl, 3, 4-dihydro-pyridine [3,2-b ]][1,4]Oxazinyl, 1, 3-benzodioxolyl, 2, 3-dihydrobenzofuranyl, thieno [3,2-b ]]Pyridyl, thieno [2,3-c ]]Pyridyl, thieno [2,3-b ]]Pyridyl, 1, 4-benzodioxanyl, 1,2,3, 4-tetrahydroquinolin-2-yl or benzenesulfonyl; r⁴Optionally substituted by one or more R¹⁴Substitution; and

Each R¹⁴Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂COOH methyl, ethyl, propyl or isopropyl.

8. The compound of claim 1 or 2, wherein each R^aAnd R^bIndependently H, D, F, Cl, Br, I, CN, OH, NO₂，NH₂，-COOR^9cMethyl, ethyl, propyl, isopropyl, -C (═ O) -NR⁹R^9a，-C(＝S)-NH₂Aminomethyl, aminoethyl, -C_1-3alkyl-NH-C (═ O) -R^9b，-C_1-3alkyl-NH-S (═ O)₂-C_3-6Cycloalkyl, -C_1-3alkyl-S (═ O)₂-C_1-3Alkyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, phenyl, pyridyl or pyrimidinyl;

Each R⁹，R^9aAnd R^9bIndependently is H, D, OH, NH₂，-S(＝O)₂-NH₂，-C(＝O)-NH₂，-C_1-3alkyl-C (═ O) -NH₂，-C_1-4alkyl-C (═ O) O-C_1-4Alkyl radical, -C_1-3alkyl-O-C (═ O) -C_1-3Alkyl, methyl, ethyl, propyl, isopropyl, -S (═ O)₂-C_1-3Alkyl, -S (═ O)₂-cyclopropyl, -S (═ O)₂-cyclobutyl, -S (═ O)₂-cyclopentyl, -S (═ O)₂-cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R⁹，R^9aAnd the nitrogen atom to which it is attached form a 3-6 atom ring, said 3-6 atom ring being azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1-oxo-thiomorpholine or 1, 1-dioxo-thiomorpholine; said ring of 3 to 6 atoms, R⁹、R^9aand R^9beach independently optionally substituted with one or more R¹⁵Substitution;

Each R^9cIndependently of one another, are H, D, -C_1-3alkyl-C (═ O) O-C_1-3Alkyl radical, -C_1-3alkyl-O-C (═ O) -C_1-4Alkyl, methyl, ethyl, propyl, isopropyl, benzyl, phenethyl; and

Each R¹⁵Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂COOH, methyl, ethyl, propyl, phenyl, pyridylPyrimidinyl, thiazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, pyridylmethyl, pyrimidinylmethyl, pyridylethyl, pyrimidylethyl, benzoyl, cyclopropylcarbonyl, cyclobutylcarbonyl or cyclopentylcarbonyl.

9. The compound of claim 2, wherein R¹⁰Is H, HOC (═ O) -C_1-4Alkyl-, C_1-4Alkoxy- (CH)₂)_e-C(＝O)-C_1-4Alkyl-, C_3-6Cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-4Alkyl-, C_1-4alkyl-NH-C (═ O) -C_1-4Alkyl-, R^eR^fN-C(＝O)-C_1-4Alkyl-, C_1-5heteroaryl-C_2-6heterocyclyl-C (═ O) -C_1-4Alkyl-, C_3-6cycloalkyl-C (═ O) -C_2-6heterocyclyl-C (═ O) -C_1-4Alkyl-, NH₂-C(＝O)-C_1-4Alkyl-, C_1-4alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-4Alkyl-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-4Alkyl-, C_1-4alkyl-S (═ O)₂-NH-C(＝O)-C_1-4Alkyl-, C_1-4alkyl-O-C (═ O) -C_1-4Alkyl-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-4Alkyl-, C_2-6heterocyclyl-C (═ O) -C_1-4Alkyl-, amino-substituted C_1-4Alkyl, halo C_1-4Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C_2-6Heterocyclic radical, C_6-10Aryl radical C_1-4Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-4Alkyl, aryl is phenyl or naphthyl, heterocyclyl is pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl or thioxanthyl, said heteroAryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; r¹⁰Optionally substituted by one or more R¹²Substitution;

Each R^cAnd R^dindependently is H, OH, CN, F, Cl, Br, I or C_1-3An alkyl group;

Each R^eAnd R^findependently is H, OH or C_1-3An alkyl group; and

Each R¹²Independently is D, F, Cl, Br, I, CN, NO₂，OH，NH₂，COOH，C_1-3Alkyl or C_1-3An alkoxy group.

10. The compound of claim 9, wherein R¹⁰Is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, oxetanyl, tetrahydrofuranyl, benzyl, phenethyl, HOC (═ O) -C_1-4Alkyl-, C_1-3Alkoxy- (CH)₂)_e-C(＝O)-C_1-4Alkyl-, C_1-4alkyl-O-C (═ O) -C_1-4Alkyl-, C_2-4heterocyclyl-C (═ O) -C_1-4Alkyl-, C_1-4heteroaryl-C_2-4heterocyclyl-C (═ O) -C_1-4Alkyl-, C_3-6cycloalkyl-C (═ O) -C_2-4heterocyclyl-C (═ O) -C_1-4Alkyl-, NH₂-C(＝O)-C_1-4Alkyl-, NH₂-C(＝O)-(CR^cR^d)_f-NH-C(＝O)-C_1-4Alkyl-, R^eR^fN-C(＝O)-C_1-4Alkyl-, C_1-4alkyl-OC (═ O) - (CR)^cR^d)_f-NH-C(＝O)-C_1-4Alkyl-, NH₂-S(＝O)₂-NH-C(＝O)-C_1-4Alkyl-, C_1-3alkyl-S (═ O)₂-NH-C(＝O)-C_1-4alkyl-, C_3-6cycloalkyl- (CH)₂)_e-NH-C(＝O)-C_1-4Alkyl-or amino-substituted C_1-4An alkyl group, the heterocyclyl group being a pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, 1, 3-dioxolanyl group, dithiocyclopentyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, dioxanyl group, dithianyl group or thiaxanyl group, the heteroaryl group being a pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, oxadiazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group or pyridazinyl group; r¹⁰Optionally substituted by one or more R¹²Substitution;

each R^cAnd R^dIndependently H, OH, CN, F, Cl, Br, I, methyl, ethyl or propyl;

Each R^eAnd R^findependently H, OH, methyl, ethyl or propyl; and

11. A compound which is a compound having one of the following structures or a stereoisomer or a pharmaceutically acceptable salt of a compound having one of the following structures:

12. A pharmaceutical composition comprising a compound of any one of claims 1-11.

13. The pharmaceutical composition of claim 12, further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.

14. Use of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to any one of claims 12 to 13 for the preparation of a medicament for the prevention, treatment or alleviation of a disease or a condition associated with the phosphodiesterase type 4 PDE 4.

15. The use according to claim 14, wherein the diseases associated with phosphodiesterase type 4 PDE4 are respiratory diseases, allergies and inflammation, diseases of the CNS, pulmonary fibrosis or non-insulin dependent diabetes mellitus.

16. The use according to claim 15, wherein the respiratory disorder is: chronic respiratory obstruction COPD, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome ARDS or respiratory inflammation.

17. The use of claim 16, wherein the respiratory inflammation is bronchitis.

18. The use according to claim 17, wherein the bronchitis is chronic bronchitis, allergic bronchitis, diffuse bronchiolitis or bronchiolitis obliterans.

19. The use according to claim 15, wherein the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis.