TW202146384A - Substituted aza five-membered ring compound and its application in medicine - Google Patents

Abstract

The invention belongs to the field of medicine, and relates to a class of substituted aza five-membered ring compounds and their application in medicine. Specifically, the present invention relates to compounds represented by formula (I), or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, Metabolites, esters, pharmaceutically acceptable salts or prodrugs; also related to pharmaceutical compositions comprising the compounds and methods of use and use thereof. In particular, the compounds described in the present invention are PDE4 inhibitors for the treatment of PDE4-related diseases such as atopic dermatitis (AD) or chronic obstructive pulmonary disease (COPD).

Description

Substituted aza five-membered ring compounds and their application in medicine

The invention belongs to the field of medicine, and particularly relates to substituted aza five-membered ring compounds, pharmaceutical compositions containing the compounds, and their uses and methods in medicine. In particular, the compounds described in the present invention are PDE4 inhibitors for the treatment of PDE4-related diseases such as atopic dermatitis (AD) or chronic obstructive pulmonary disease (COPD).

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are two important second messengers in cells, mainly involved in energy metabolism, memory, immunity by initiating protein kinase A (PKA) and protein kinase G (PKG) pathways. The regulation of intracellular concentration of physiological activities such as reaction, vision and smell formation is mainly determined by the balance between the synthesis of adenosine (guanylate) cyclase and the hydrolysis of phosphodiesterases (PDEs). PDEs can specifically use 3,5-cyclic nucleotides as substrates to catalyze the hydrolysis of cGMP and cAMP in cells to generate the corresponding inactive adenosine 5-phosphate, thereby affecting various metabolic functions of organisms. Therefore, inhibition of PDEs is a very effective way to induce many cellular activities, which can affect the activation of inflammatory cells and immune cells and the contractile response of smooth muscle cells.

Phosphodiesterases (PDEs) have been reported to date with 11 gene families, each of which includes multiple subfamilies. PDEs are distributed in multiple tissues, and their inhibitors have a wide range of physiological effects. Among them, PDE4, PDE7 and PDE8 mainly specifically hydrolyze cAMP, PDE5, PDE6 and PDE9 specifically hydrolyze cGMP, while PDE1, PDE2, PDE3, PDE10 and PDE11 specifically hydrolyze cGMP. Works on both cAMP and cGMP. Among them, PDE4 is mainly distributed in various inflammatory cells. Its tissue distribution shows that it is closely related to the central nervous system and immune system. Its inhibitors can be used to treat various diseases, including allergic and inflammatory diseases, diabetes, central nervous system diseases and pain. .

At present, the research on PDE4 mainly focuses on immune and inflammation-related diseases, and many famous pharmaceutical companies in the world have used PDE4 as the target of chronic inflammation-related diseases. The anti-inflammatory effect of PDE4 inhibitors is mainly through the following ways: (1) inhibiting the activity of various inflammatory mediators; (2) inhibiting the up-regulation and expression of cell adhesion factors; (3) inhibiting the activation of blood leukocytes; (4) inducing cells Apoptosis; (5) induce the production of cytokines with inhibitory activity (such as interleukin-6); (6) induce the release of catecholamines and endogenous hormones. The first-generation PDE4 inhibitors mainly include theophylline, rolipram and Piclamilast, etc. Rolipram has certain effects on neurological diseases such as Parkinson's disease, depression and anxiety. Therapeutic effect. However, the clinical application of the first-generation PDE4 inhibitors has been limited due to serious side effects such as nausea and vomiting; the second-generation PDE4 inhibitors include Roflumilast and Cilomilast, among which Roflumilast is used in the treatment of COPD and also has a certain therapeutic effect on other inflammatory diseases, such as ulcerative colitis and Crohn's disease. Apremilast, a third-generation PDE4 inhibitor, has been used in the treatment of autoimmune diseases such as psoriasis with fewer side effects and better tolerance by patients. WO/2000/064260 discloses that the PDE4 inhibitor Ro 20-1724 1% cream is effective in the treatment of psoriasis. WO 2000/009504 discloses another PDE4 inhibitor, CP-80633 (0.5% ointment), which significantly improved clinical scores (erythema, induration and exfoliation) of atopic dermatitis. However, there is still a need for more PDE4 inhibitors that can effectively treat atopic dermatitis.

The following only outlines some aspects of the present invention, and is not limited thereto. These and other sections are described more fully later. All references in this specification are hereby incorporated by reference in their entirety. When there is a discrepancy between the disclosure content of this specification and the cited documents, the disclosure content of this specification shall prevail.

The present invention provides a class of compounds with phosphodiesterase-4 (Phosphodiesterase-4, PDE4) inhibitory activity, which are used to prepare, prevent, treat or alleviate PDE4-related respiratory diseases, allergies, inflammations, central nervous system diseases or non-insulin Medications dependent on diabetes, such as chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, cystic fibrosis, acute respiratory distress syndrome, or airway inflammation ; Bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis, obliterative bronchiolitis, allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis , interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis, etc.; the compounds of the present invention can well inhibit PDE4 and have excellent physical and chemical properties and pharmacokinetic properties.

The present invention also provides methods for the preparation of these compounds and pharmaceutical compositions comprising these compounds and methods of using these compounds or compositions to treat the above-mentioned diseases in mammals, especially humans.

Specifically:

(I)；In one aspect, the present invention relates to a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of the compound represented by formula (I), pharmaceutically acceptable salts or their prodrugs,

(I);

in:

R ¹ and R ² are each independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl , Heterocyclic group composed of 3-10 atoms, C _6-10 aryl group, Heteroaryl group composed of 5-10 atoms, C _3-8 cycloalkyl-C _1-4 alkylene group, C _1-6 Alkyl-C(=O)-, C _3-8 Cycloalkyl-C(=O)-, Heterocyclyl consisting of 3-10 atoms-C _1-4 Alkylene, C _6-10 Aryl -C _1-4 alkylene or heteroaryl-C _1-4 alkylene composed of 5-10 atoms;

X and X ¹ are each independently a bond, -O-, -S-, -N(R ^c )-, -C(=O)- or -S(=O) _t -;

R ³ is hydrogen, deuterium, carboxyl, C _1-6 alkyl, C _{1-6 haloalkyl} , C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, C _{6- 10} aryl, 3-10 atoms heterocyclyl, 5-10 atoms heteroaryl, C _3-8 cycloalkyl-C _1-4 alkylene, C _6-10 aryl-C heteroaryl -C _1-4 alkylene group, 3 to 10 atoms consisting of heterocyclyl -C _1-4 alkylene, composed of 5-10 atoms _1-4 alkylene group, C _1-6 alkoxy base-C(=O)-, C _1-6 alkyl-S(=O) _t- , C _1-6 alkoxy-C(=O)-, C _3-8 cycloalkyl-C(= O)-, C _3-8 cycloalkyl-S(=O) _t- , heterocyclyl-C(=O)- composed of 3-10 atoms, heterocyclyl-S composed of 3-10 atoms _{(= O) t -, -} C (= O) -NR d R e, -S (= O) t -NR d R e, C 6-10 aryl group -C (= O) -, 5-10 months Heteroaryl-C(=O)-, C _6-10 aryl-S(=O) _t- or heteroaryl-S(=O) _t- consisting of 5-10 atoms, wherein R ³ is unsubstituted or substituted by 1, 2, 3 or 4 R ⁶ ;

Each R ⁶ is independently deuterium, -F, -Cl, -Br, -I , hydroxy, amino, cyano, oxo, C _1-4 alkyl, C _{1-4 haloalkyl,} C _1-4 alkoxy, C _1-4 alkylamino or C _1-4 alkyl-C(=O)-N(R ^c )-;

R ⁴ is -(CH ₂ ) _m -L-(CH ₂ ) _n -G;

L is a bond, -O-, -S-, -NR ^x -, -NR ^x -C(=O)-, -NR ^x -S(=O) _t -, -NR ^x -C(=O)- NR ^y -, -NR ^x -C(=O)-O-, -S(=O) _t -, -C(=O)- or -C(=O)-O-;

Preferably, L is -O -, - S -, - NR x -, - NR x -C (= O) -, - NR x -S (= O) t -, - NR x -C (= O) -NR ^y -, -NR ^x -C(=O)-O-, -S(=O) _t -, -C(=O)- or -C(=O)-O-, where -NR ^x The left ends of -C(=O)-, -NR ^x -S(=O) _t -, -NR ^x -C(=O)-NR ^y - and -NR ^x -C(=O)-O- are respectively (CH ₂ ) _{m is} connected, the right ends are respectively connected with (CH ₂ ) _n , the right end of -C(=O)-O- is connected with (CH ₂ ) _m , and the left end is connected with (CH ₂ ) _n ;

Wherein, each R ^x and R ^{y is} independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _3-8 cycloalkyl, C _6-10 aryl, 3-10 Heterocyclic group composed of atoms, heteroaryl group composed of 5-10 atoms, C _3-8 cycloalkyl-C _1-6 alkylene group, C _6-10 aryl group-C _1-6 alkylene group, 3 -Heterocyclyl-C _1-6 alkylene composed of 10 atoms, heteroaryl-C _1-6 alkylene composed of 5-10 atoms, C _1-6 alkyl-S(=O) _t -, C _1-6 alkyl-C(=O)- or C _1-6 alkoxy-C(=O)-C _1-6 alkylene;

G is a C _3-8 cycloalkyl group, a C _6-10 aryl group, a heterocyclic group consisting of 3-10 atoms or a heteroaryl group consisting of 5-10 atoms; wherein, G is unsubstituted or replaced by 1, 2 , 3 or 4 R ⁷ substituted;

Each R ^{7 is} independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, carboxyl, C _1-6 alkyl, C _{1-6 haloalkyl} , C _{1 -6} alkoxy, C _1-6 alkylamino, -C(=O)-NR ^a R ^b , -S(=O) _t -NR ^a R ^b , C _1-6 alkyl-C(=O) -N(R ^c )-, C _1-6 alkyl-S(=O) _t -N(R ^c )-, C _1-6 alkoxy-C(=O)-N(R ^c )-, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O) _t- , C _1-6 alkoxy-C(=O)-, C _1-6 alkyl -C(=O)-O-, C _3-8 cycloalkyl, C _6-10 aryl, heterocyclic group consisting of 3-10 atoms or heteroaryl group consisting of 5-10 atoms;

Each of R ^a and R ^{b is} independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _3-8 cycloalkyl, C _6-10 aryl, and consists of 3-10 atoms The heterocyclic group, the heteroaryl group composed of 5-10 atoms, the C _3-8 cycloalkyl-C _1-6 alkylene group, the C _6-10 aryl group-C _1-6 alkylene group, the 3-10 Heterocyclyl-C _1-6 alkylene consisting of 5-10 atoms, heteroaryl-C _1-6 alkylene consisting of 5-10 atoms, C _1-6 alkyl-S(=O) _t - or C _1-6 alkyl-C(=O)-, wherein each R ^a and R ^{b are} independently unsubstituted or by 1, 2 or 3 selected from deuterium, -F, -Cl, -Br, -I, Hydroxyl, amino, cyano, oxo, -C(=O)-NH ₂ , C _1-6 alkoxy C(=O)-, C _1-6 alkyl-C(=O)-N(R ^c )-, C _1-6 alkyl-S(=O) _t -N(R ^c )-, C _1-4 alkyl, C _{1-4 haloalkyl} , C _1-4 alkoxy or C _1-4 alkylamino groups are substituted;

Each R ^d and R ^{e is} independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _3-8 cycloalkyl, C _6-10 aryl, 3-10 atoms. The heterocyclic group, the heteroaryl group composed of 5-10 atoms, the C _3-8 cycloalkyl-C _1-6 alkylene group, the C _6-10 aryl group-C _1-6 alkylene group, the 3-10 Heterocyclyl-C _1-6 alkylene consisting of 5-10 atoms, heteroaryl-C _1-6 alkylene consisting of 5-10 atoms, C _1-6 alkyl-S(=O) _t - or C _1-6 alkyl -C (= O) -, wherein each R ^d and R ^e are independently unsubstituted or substituted with 1, 2 or 3 substituents selected from deuterium, -F, -Cl, -Br, -I , Hydroxyl, amino, cyano, oxo, -C(=O)-NH ₂ , C _1-6 alkoxy C(=O)-, C _1-6 alkyl-C(=O)-N(R ^c )-, C _1-6 alkyl-S(=O) _t -N(R ^c )-, C _1-4 alkyl, C _{1-4 haloalkyl} , C _1-4 alkoxy or C _1-4 alkylamino groups are substituted;

each R ^{c is} independently hydrogen, deuterium, C _1-3 alkyl or C _{1-3 haloalkyl} ;

R is hydrogen, deuterium, -F, -Cl, -Br, -I , hydroxy, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _{1-3 haloalkoxy} or C _{1 -3 haloalkyl} ;

R ^5a , R ^5b , R ^6a and R ^6b are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, C _1-3 alkyl, C _1-3 alkane alkoxy, C _{1-3 haloalkoxy} group or a C _{1-3 haloalkyl;}

t is 1 or 2;

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

m is 1, 2, 3 or 4.

(II)，In some embodiments, the compound of the present invention is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, their prodrugs:

(II),

Wherein, each of R ¹ , R ² , R ³ , R ^5a , R ^5b , R ^6a , R ^6b , R, G, L and n has the meaning as described in the present invention.

(III)，In some embodiments, the compound of the present invention is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, their prodrugs:

(III),

Wherein, each of R ¹ , R ² , R ³ , R ^5a , R ^5b , R ^6a , R ^6b , R, G, L and n has the meaning as described in the present invention.

In some embodiments, R ¹ and R ² are each independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, isobutyl, -CH ₂ F, -CHF ₂ , -CF ₃ , _{-CH 2 CH 2 F, -CH 2} CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 Cl, - CHCl ₂ , -CH=CH ₂ , -CH ₂ CH=CH ₂ , -C≡CH, -CH ₂ C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethylene , cyclopropylethylene, cyclobutylmethylene, cyclobutylethylene, cyclopentylmethylene, cyclopentylethylene, cyclohexylmethylene, cyclohexylethylene, CH ₃ C (= O) -, CH 3 CH 2 C (= O) -, CH 3 CH 2 CH 2 C (= O) -, (CH 3) 2 CHC (= O) -, cyclopropyl -C (= O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl , thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, oxazinyl, pyridinyl, morpholinyl, thiomorpholinyl, tetrahydropyran base, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, pyridyl-C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, Furyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, pyrazolyl-C _1-3 alkylene, thiazolyl-C _{1 -3} alkylene, oxazolyl-C _1-3 alkylene, triazolyl-C _1-3 alkylene, tetrazolyl-C _1-3 alkylene, oxazinyl-C _{1 -3} alkylene, pyridinyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene, thiomorpholinyl-C _1-3 alkylene, tetrahydropyranyl- C _1-3 alkylene or pyrrolidinyl-C _1-3 alkylene;

R ³ is hydrogen, deuterium, carboxyl, C _1-3 alkyl, C _{1-3 haloalkyl} , C _2-4 alkenyl, C _2-4 alkynyl, CH ₃ -C(=O)-, CH ₃ CH ₂ -C(=O)-, CH ₃ CH ₂ CH ₂ -C(=O)-, (CH ₃ ) ₂ CH-C(=O)-, CH ₃ -S(=O) ₂ -, CH ₃ CH ₂ -S(=O) ₂ -, CH ₃ CH ₂ CH ₂ -S(=O) ₂ -, (CH ₃ ) ₂ CH-S(=O) ₂ -, CH ₃ -OC(=O )-, CH ₃ CH ₂ -OC(=O)-, CH ₃ CH ₂ CH ₂ -OC(=O)-, (CH ₃ ) ₂ CH-OC(=O)-, -S(=O) ₂ -NH ₂ or -C (= O) -NH _2, wherein R ³ is unsubstituted or substituted with 1,2, 3, or 4 R ^6;

Each R ⁶ is independently deuterium, -F, -Cl, -Br, -I , hydroxy, amino, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, -CH ₂ F, - CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -CH ₂ Cl, -CHCl _2, methoxy, ethoxy, n-propyl group, methylamino, ethylamino, or n-propylamino.

Some embodiments are wherein each R ^x and R ^y are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C _{1-4 haloalkyl,} cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cyclopropyl-C _1-3 alkylene, cyclobutyl-C _1-3 alkylene, cyclopentyl-C _1-3 alkylene, cyclohexyl-C _1-3 Alkylene, phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, oxazinyl, Piridinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, pyridyl-C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene , pyrazolyl-C _1-3 alkylene, thiazolyl-C _1-3 alkylene, oxazolyl-C _1-3 alkylene, triazolyl-C _1-3 alkylene, four Azazolyl-C _1-3 alkylene, oxazinyl-C _1-3 alkylene, oxidyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene, thio Morpholinyl-C _1-3 alkylene, tetrahydropyranyl-C _1-3 alkylene, pyrrolidinyl-C _1-3 alkylene, C _1-3 alkyl-S(=O) _2- , C _1-3 alkyl-C(=O)- or C _1-3 alkoxy-C(=O)-C _1-3 alkylene.

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；其中G未被取代或被1、2、3或4個R⁷ 所取代；In some embodiments, G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

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; wherein G is unsubstituted or substituted by 1, 2, 3 or 4 R ⁷ ;

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；其中各R^a 和R^b 具有如本發明所述的含義。Each R ^{7 is} independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, carboxyl, C _1-4 alkyl, C _{1-4 haloalkyl} , C _{1 -4} alkoxy, C _1-4 alkylamino, -C(=O)-NR ^a R ^b , -S(=O) ₂ -NR ^a R ^b , C _1-4 alkyl-C(=O) -NH-, C _1-4 alkyl-S(=O) ₂ -NH-, C _1-4 alkoxy-C(=O)-NH-, CH ₃ -C(=O)-, CH ₃ CH ₂ -C(=O)-, CH ₃ CH ₂ CH ₂ -C(=O)-, (CH ₃ ) ₂ CH-C(=O)-, CH ₃ CH ₂ CH ₂ CH ₂ -C(= O)-, CH ₃ -S(=O) ₂ -, CH ₃ CH ₂ -S(=O) ₂ -, CH ₃ CH ₂ CH ₂ -S(=O) ₂ -, (CH ₃ ) ₂ CH- S(=O) ₂ -, CH ₃ OC(=O)-, CH ₃ CH ₂ OC(=O)-, CH ₃ CH ₂ CH ₂ OC(=O)-, (CH ₃ ) ₂ CHO-C( =O)-, CH ₃ CH ₂ CH ₂ CH ₂ OC(=O)-, CH ₃ -C(=O)-O-, CH ₃ CH ₂ -C(=O)-O-, CH ₃ CH ₂ CH ₂ -C(=O)-O-, (CH ₃ ) ₂ CH-C(=O)-O-, CH ₃ CH ₂ CH ₂ CH ₂ -C(=O)-O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

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or

; wherein each of R ^a and R ^b has the meaning as described in the present invention.

Some embodiments are wherein, R ^a and R ^{b are} each independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, _{n-butyl, -CH 2 F, -CHF 2,} -CF 3, _{-CH 2 CH 2 F, -CH 2} CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 Cl, - CHCl ₂ , phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, oxazinyl, oxazolyl Peridyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, pyridyl-C _{1 -3} alkylene, pyrimidinyl-C _1-3 alkylene, furyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, Pyazolyl-C _1-3 alkylene, thiazolyl-C _1-3 alkylene, oxazolyl-C _1-3 alkylene, triazolyl-C _1-3 alkylene, tetrazolium azolyl-C _1-3 alkylene, oxazinyl-C _1-3 alkylene, oxidyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene, thiomorpho Linyl-C _1-3 alkylene, tetrahydropyranyl-C _1-3 alkylene, pyrrolidinyl-C _1-3 alkylene, C _1-3 alkyl-S(=O) ₂ - or C _1-3 alkyl-C(=O)-; wherein each R ^a and R ^{b are} independently unsubstituted or by 1, 2 or 3 selected from deuterium, -F, -Cl, -Br, - I, hydroxyl, amino, cyano, oxo, -C(=O)-NH ₂ , C _1-3 alkoxy C(=O)-, C _1-3 alkyl-C(=O)-NH -, C _1-3 alkyl-S(=O) _t -NH-, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ F, -CHF ₂ , -CF ₃ , _{-CH 2 CH 2 F, -CH 2} CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 Cl, - CHCl ₂ , methoxy, ethoxy, n-propyloxy, isopropyloxy, N -methylamino, N -ethylamino, N'N -dimethylamino, N'N -diethyl substituted with amino or N'N -methylethylamino groups.

In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.

Some of these embodiments are the pharmaceutical composition of the present invention, which further comprises at least one of pharmaceutically acceptable carriers, excipients, additives, adjuvants and vehicles.

Some of the embodiments are that the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, telukast , theophylline, formoterol, salmeterol, fluticasone propionate, rolipram, piramister, cilomilast, indacaterol, odaterol, midestane, qifluu , salbutamol, camoxirol, budesonide, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, roflunomide, ciclesonide, ipratropium bromide Ammonium, oxtropium, tiotropium, glycopyrronium, umeclidinium, vilanterol, aclidinium, benralizumab, Tralokinumab, revatropate, cresabor, fluocinolone acetate , Desoxymetasone, Mometasone, Triamcinolone, Betamethasone, Aclometasone, Desonide, Hydrocortisone, Clobetasol, Halobetasol, Diflurasone, Meprolac Lays, Tacrolimus, Pimecrolimus, Tazarotene, Cyclosporine, Apremilast, E-6005, OPA-15406, LEO-29102, DRM02, Roflumilast, Ibudilast, Tofacitinib, JTE-052, baricitinib, upadacitinib, WBI-1001, MRX-6, GSK2981278, duruzumab, lekinizumab, nimolizumab, trelogis Noumumab, Etanercept, Adalimumab, Infliximab, Utecalumab, Sekuginu, Omalizumab, CIM-331, Golimumab, and Pegylated Serum, Tutu Zizumab, Calcipotriol, Calcitriol, Aliretinoin, VTP-38543, ZPL-389, Aprepitant, Tripitant, Faviprant, OC-459, SUN 13834, SB -011, VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02 or a combination thereof.

In another aspect, the present invention provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used for preventing, treating or alleviating a disease related to phosphodiesterase type 4 .

Some of these embodiments are the use of the present invention, wherein the disease associated with phosphodiesterase type 4 is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin-dependent diabetes mellitus;

Wherein, the respiratory diseases are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, pulmonary tuberculosis fibrosis, cystic fibrosis, acute respiratory distress syndrome Or respiratory tract inflammation; among them, bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;

Wherein, the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatism Arthritis or psoriatic arthritis.

In another aspect, the present invention provides a method of preventing, treating or alleviating a disease associated with phosphodiesterase type 4, comprising administering to a patient a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition of the present invention.

Some of these embodiments are the methods of the present invention, wherein the disease associated with phosphodiesterase type 4 is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis, or non-insulin-dependent diabetes mellitus;

Wherein, the respiratory diseases are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, pulmonary tuberculosis fibrosis, cystic fibrosis, acute respiratory distress syndrome Or respiratory tract inflammation; among them, bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;

Wherein, the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatism Arthritis or psoriatic arthritis.

In another aspect, the present invention provides the compounds of the present invention or the pharmaceutical compositions of the present invention for preventing, treating or alleviating phosphodiesterase type 4-related diseases in patients.

Some of the embodiments are that the compounds or pharmaceutical compositions of the present invention are used to prevent, treat or alleviate a phosphodiesterase type 4-related disease in a patient, wherein the phosphodiesterase type 4-related disease is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin dependent diabetes;

Wherein, the respiratory diseases are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, pulmonary tuberculosis fibrosis, cystic fibrosis, acute respiratory distress syndrome Or inflammation of the respiratory tract; wherein bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;

Wherein, the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatism Arthritis or psoriatic arthritis.

Another aspect of the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (II) or (III).

The foregoing has outlined only certain aspects of the invention, but is not limited to these aspects. These and other aspects are described in more detail below.

Definitions and General Terms

Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein could 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 literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can 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, can also be provided separately or in any suitable subcombination.

Unless otherwise defined, 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.

Unless otherwise stated, the following definitions used herein shall apply. For the purposes of the present invention, chemical elements are in accordance with the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 description, the entire contents of which are incorporated herein by reference.

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

The term "subject" as used herein refers to animals. Typically the animal is a mammal. Test objects, for example, also refer to primates (eg, humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human. The term "patient" as used herein refers to humans (including adults and children or other animals). In some embodiments, "patient" refers to a human.

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

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

The term "chirality" refers to a molecule that has the property of being non-superimposable with its mirror image; whereas "achiral" refers to a molecule that is superimposable with its mirror image.

The term "enantiomer" refers to two nonsuperimposable, but mirror-image isomers of a compound.

The term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

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

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

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

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

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

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

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

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. Unless otherwise indicated, a substituted group may have a substituent 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.

The term "optionally substituted with" means that the structure is unsubstituted or substituted with one or more substituents described herein. The substituents described in the present invention include, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, carboxyl, azido, aryl, heteroaryl, alkoxy, alkylamino, Alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, haloalkyl, haloalkoxy, hydroxy substituted alkyl , hydroxy-substituted alkoxy, amino-substituted alkyl, cyano-substituted alkyl, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-OC(= O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) ₂ -, carboxyalkoxy, NH ₂ -C(=O)-, NH ₂ -S(=O) ₂ -, aryl-alkylene, heteroaryl-alkylene, heterocyclyl-alkylene , cycloalkyl-alkylene, etc.

In addition, it should be noted that, unless clearly stated otherwise, the description modes "each independently" and "...independently" and "...independently" used in the present invention can be interchanged, and should be In a broad sense, it can either mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols are one of the do not affect each other. For example, specific options for _{R p} between the structural formula "-C(=O)-N(R _p R _q )" and the structural formula "-C _1-6 alkylene-N(R _p R _{q )"} are not affected by each other.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term "C ₁ -C ₆ alkyl" or "C _1-6 alkyl" refers particularly to the disclosure independently methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl base.

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

The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be is substituted by one or more of the substituents described herein, wherein the substituents are, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, carboxyl, azido, aryl, hetero Aryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, haloalkyl , haloalkoxy, hydroxy substituted alkyl, hydroxy substituted alkoxy, amino substituted alkyl, cyano substituted alkyl, hydroxy substituted alkyl-C(=O)-, alkyl-C(= O)-, alkyl-OC(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) ₂ -, carboxyalkoxy, NH ₂ -C(=O)-, NH ₂ -S(=O) ₂ -, aryl-alkylene, heteroaryl-idene Alkyl, heterocyclyl-alkylene, cycloalkyl-alkylene, and the like. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in still other embodiments, the alkyl group contains 1 -4 carbon atoms; also in some embodiments, the alkyl group contains 1-3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH _3), ethyl _{(Et, -CH 2 CH 3)} , n-propyl _{(n -Pr, -CH 2 CH 2} CH 3 ), isopropyl _{(i -Pr, -CH (CH 3} ) 2), n-butyl _{(n -Bu, -CH 2 CH 2} CH 2 CH 3), isobutyl (i -Bu, -CH ₂ CH (CH ₃ ) ₂ ), sec-butyl ( s- Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl ( t -Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH _{2 CH 2 CH 2 CH 2 CH} 3), 2- pentyl _{(-CH (CH 3) CH 2} CH 2 CH 3), 3- pentyl _{(-CH (CH 2 CH 3)} 2), 2- methyl 2-butyl _{(-C (CH 3) 2 CH} 2 CH 3), 3- methyl-2-butyl _{(-CH (CH 3) CH (} CH 3) 2), 3- methyl-1- butyl _{(-CH 2 CH 2 CH (CH} 3) 2), 2- methyl-1-butyl _{(-CH 2 CH (CH 3)} CH 2 CH 3), n-hexyl (-CH ₂ CH ₂ CH _{2 CH 2 CH 2 CH 3),} 2- hexyl _{(-CH (CH 3) CH 2} CH 2 CH 2 CH 3), 3- hexyl _{(-CH (CH 2 CH 3)} (CH 2 CH 2 CH 3)), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, and the like.

The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group A group contains 1-3 carbon atoms; also in some embodiments, an alkylene group contains 1-2 carbon atoms. Examples of such include methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene _{(-CH 2 CH 2 CH 2 -} ), isopropylene (-CH (CH ₃ )CH ₂ -) and so on.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp ² double bond, wherein the alkenyl group A group can be optionally substituted with one or more substituents described herein, including the "cis" and "tans" positions, or the " E " and " Z " positions. In some embodiments, alkenyl groups contain 2-8 carbon atoms; in other embodiments, alkenyl groups contain 2-6 carbon atoms; in yet other embodiments, alkenyl groups contain 2 -4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH _2), allyl (-CH ₂ CH = CH ₂₎ and the like.

The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more of the substituents described herein. In some embodiments, the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in still other embodiments, the alkynyl group contains 2 -4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1- propynyl (-C≡C-CH _3), etc. .

The term "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -CO ₂ H or -COOH.

The term "deuterium" refers to a single deuterium atom. For example, one deuterium atom replaces one hydrogen atom in a methyl group to form a mono-deuterated methyl group (-CDH ₂ ), and two deuterium atoms replace two hydrogen atoms in a methyl group to form a bis-deuterated methyl group (- CD ₂ H), a deuterium atom and three three hydrogen atoms in the methyl group, form a three - deuterated methyl (-CD _3).

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

The term "heteroatom" refers to O, S, N, P, B, and Si, including N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or a nitrogen atom in a heterocyclic ring the hydrogen substituted form, e.g., N (as 3,4-dihydro -2 H - N-pyrrolyl), NH (as in pyrrolidinyl NH) or NR (as in N- substituted pyrrolidine NR in the base).

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

The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups 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 2 CH 3)} , 1- propoxy (n -PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy ( i- PrO, i -propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propoxy ( i- BuO, i -butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy ( t- BuO, t -butoxy, -OC(CH _{3) 3),} 1-pentyl group (N- pentyloxy _{group, -OCH 2 CH 2 CH 2 CH} 2 CH 3), 2- pentyloxy group _{(-OCH (CH 3) CH 2} CH 2 CH 3), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy group (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), etc.

The term "alkylamino" represents two hydrogen atoms on an amino group (-NH ₂₎ is independently optionally substituted by the same or different alkyl group, comprising N - alkylamino or N'N - dialkylamino, where the alkyl group has the meaning as defined in the present invention. Unless otherwise specified, the alkylamino group contains 1-12 carbon atoms. In some embodiments, the alkylamino group contains 1-6 carbon atoms; in other embodiments, the alkylamino group contains 1-4 carbon atoms; in still other embodiments, the alkylamino group contains 1 -3 carbon atoms. The alkylamino group may be optionally substituted with one or more substituents described herein.

)，N’N -甲基異丙基氨基(

)，等等。Examples of alkylamino groups include, but are not limited to, N - methylamino (-NHCH _3), N - ethylamino _{(-NHCH 2 CH 3), N'N} - dimethylamino (-N (CH _{3) 2),} N'N - diethylamino group _{(-N (CH 2 CH 3)} 2), N'N - methyl amino ethyl (

), N'N -methylisopropylamino (

),etc.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group is substituted with one or more halogen atoms, such examples include, but are not limited _{to, -CH 2 F, -CHF 2,} - _{CF 3, -CH 2 CH 2 F} , -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 cl, -CHCl _2, and the like.

The term "consisting of j-k atoms", wherein each of j and k is independently any non-zero natural number, and k>j; said "j-k" includes j, k and any natural number in between. The number of ring-forming atoms in a molecule is typically described, where the number of ring-forming atoms in the molecule is j-k, and the atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3-6 carbon atoms carbon atom. The cycloalkyl groups can be independently optionally substituted with one or more substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The terms "cycloalkylalkyl" or "cycloalkyl-alkylene" are used interchangeably, and both refer to the substitution of an alkyl group by one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group are The radical group has the meaning as described herein, such examples include, but are not limited to, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-methylene Ethyl, cyclopentyl-methylene, cyclopentyl-ethylene, cyclohexyl-methylene, cyclohexyl-ethylene, and the like.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein, and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, wherein a monocyclic, bicyclic or tricyclic ring No aromatic rings are included in the ring, and at least one ring atom is selected from nitrogen, phosphorus, sulfur, boron and oxygen atoms. Unless otherwise indicated, heterocyclyl groups may be carbon or nitrogen-based groups, and -CH ₂ - groups may be optionally substituted with -C (= O) - instead. Ring sulfur atoms can optionally be oxidized to S -oxides. The nitrogen atoms of the rings can optionally be oxidized to N -oxygen compounds. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, imidazolinyl , Imidazolidinyl, Tetrahydrofuranyl, Dihydrofuranyl, Tetrahydrothienyl, Dihydrothienyl, 1,3-Dioxopentyl, Dithiocyclopentyl, Tetrahydropyranyl, Dihydropyranyl , tetrahydrothiopyranyl, pyridyl, tetrahydropyridyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl , oxazinyl, dioxanyl, dithianyl, thioxanyl, homooxazinyl, homoxiridinyl, oxepenyl. Heterocyclyl group -CH ₂ - group is -C (= O) - Examples of substituents include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto and 3,5-dioxoguaridinyl. Examples of the oxidized sulfur atom in the heterocyclyl group include, but are not limited to, cyclobutanyl, 1,1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents described herein.

The terms "heterocyclylalkyl" or "heterocyclyl-alkylene" are used interchangeably, and both refer to a heterocyclyl-substituted alkyl group; wherein the heterocyclyl and alkyl groups have the meanings as described herein . Such examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-ylmethyl, pyrrolidin-2-ylmethyl, olin-4-ylmethyl, etc.

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic A family of rings in which each ring system contains a ring of 3-7 atoms with one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl groups can be independently optionally substituted with one or more substituents described herein.

The terms "arylalkyl" or "aryl-alkylene" are used interchangeably, and both refer to one or more aryl-substituted alkyl groups, wherein the aryl and alkyl groups have the properties described herein. meaning. In some embodiments, an arylalkyl group refers to a "lower arylalkyl" group, ie, an aryl group attached to a _C1-6 alkyl or alkylene group. In other embodiments, an arylalkyl group refers to a "phenylalkyl" _{containing a C1-4 alkyl group.} Specific examples thereof include diphenylmethyl, phenylmethylene, and phenylethylene. The aryl group on the arylalkyl or arylalkylene group may be further substituted with the substituents described in the present invention.

The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-7 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 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic", "aromatic heterocycle" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In some of these embodiments, a heteroaryl group of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S, N or B.

、

、

、

、

、

、

或

等等。Examples of heteroaryl groups include, but are not limited to, furyl (eg, 2-furyl, 3-furyl), imidazolyl (eg, N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- imidazolyl), isoxazolyl (such as 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (such as 2-oxazolyl, 4-oxazolyl, 5-isoxazolyl) -oxazolyl), pyrrolyl (eg N -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (such as 3-pyridazinyl), thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazole base (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), thienyl (such as 2-thienyl, 3-thienyl), pyrazolyl (such as 2-thienyl) pyrazolyl), isothiazolyl, pyrimidinonyl, pyridinone; also including, but in no way limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothienyl, Indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl),

,

,

,

,

,

,

or

etc.

The terms "heteroarylalkyl" or "heteroarylalkylene" are used interchangeably, and both refer to an alkyl group substituted with one or more heteroaryl groups, wherein the heteroaryl and alkyl groups have the present Within the meaning of the invention, such examples include, but are not limited to, imidazol-2-ylmethylene, furan-2-ylethylene, indol-3-ylmethylene, and the like.

As described in the present invention, the substituent group is attached to the central ring by a bond to form a ring system (as shown in formula c), which means that the substituent group can be substituted at any substitutable position on the ring. For example, formula c represents that the substituent R can be mono- or poly-substituted at any possible substituted position on the C ring, as shown in formula c1 to formula c19.

As described herein, a linker attached to a ring system (as shown in formula d) means that the linker can be attached to the rest of the molecule at any linkable position on the ring system. Formula d represents that any possible linking position on the ring can be connected to the rest of the molecule, as shown in formula d1 to formula d5.

In the present invention, R ⁴ is -(CH ₂ ) _m -L-(CH ₂ ) _n -G, wherein the left and right linkages of the L group are interchangeably connected to (CH ₂ ) _m and (CH ₂ ) _n ; for example, when L is -NR ^x -C(=O)-, -NR ^x -S(=O) _t -, -NR ^x -C(=O)-NR ^y - or -NR ^x -C(= When O)-O-, -(CH ₂ ) _m -L-(CH ₂ ) _n -G is defined as the left end of L is connected to (CH ₂ ) _m while the right end of L is connected to (CH ₂ ) _n , and the left end of L is connected (CH ₂ ) _n at the same time the right end of L is connected to (CH ₂ ) _{m in} two cases, wherein the preferred solution is: when L is -NR ^x -C(=O)-, -NR ^x -S(=O) _t - , -NR ^x -C(=O)-NR ^y - or -NR ^x -C(=O)-O-, the left end of L is connected to (CH ₂ ) _m while the right end of L is connected to (CH ₂ ) _n ; When L is -C(=O)-O-, -(CH ₂ ) _m -L-(CH ₂ ) _n -G is defined as -(CH ₂ ) _m -C(=O)-OG and -(CH ₂ ) _m -OC(=O)-(CH ₂ ) _n -G in two cases, wherein, the preferred solution is, when L is -C(=O)-O-, -(CH ₂ ) _m -L - (CH _{2) n} -G is defined as _{- (CH 2) m -OC (} = O) -G.

As used in the present invention, the term "prodrug" refers to the conversion of a compound into a compound of formula (I) or formula (II) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters can be used as prodrugs such as phenyl esters, aliphatic (C _1-24 ) esters, hydroxymethyl esters, carbonates, Carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in the form of a prodrug. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design , American Pharmaceutical Association and Pergamon Press, 1987 , J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery , 2008 , 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008 , 51, 2328-2345.

"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, 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 described in: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977 . Pharmaceutically acceptable nontoxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and Organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods described in books such as ion exchange . Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate , camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate , Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malic Acid salt, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-benzene propionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate halides include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1- 8} Sulfonates and aromatic sulfonates.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

The term "nitroxide" means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N -oxides. N - Specific examples of oxides are tertiary amine N - oxide or a nitrogen-containing heterocyclic nitrogen atom of N - oxide. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (eg, peroxycarboxylic acids) to form N -oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N -oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), in which, for example, an amine compound is mixed with m-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane. ) reaction.

The term "carrier" includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial, antifungal), isotonic agents, salts, pharmaceutical stabilizers, binders, excipients Agents, dispersing agents, lubricants, sweeteners, flavoring agents, coloring agents, or combinations thereof, these carriers are known to those skilled in the art (eg Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in the event that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

The term "treating" any disease or disorder, as used herein, in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, "treating" refers to modulating a disease or disorder, physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.

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

Additionally, the compounds disclosed herein, including their salts, may also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization. Compounds of the present disclosure may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to encompass both solvated and unsolvated forms.

Any structural formula given herein is also intended to represent both isotopically unenriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. It can be incorporated into compounds of the invention Exemplary isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ^{2 H, 3 H, 11 C} , 13 C, 14 C, 15 N, 17 O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those in which radioactive isotopes, such as ³ H, ¹⁴ C and ¹⁸ F are present, or in which non-radioactive isotopes, such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetic studies (using eg ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single-photon emission computed tomography (SPECT) for substrate tissue distribution measurement, or may be used in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) or formula (II) can be replaced by a suitable isotopically labeled reagent by conventional techniques familiar to those skilled in the art or as described in the examples and preparation procedures of the present invention. prepared by labeling reagents.

Furthermore, substitution of heavier isotopes, particularly deuterium (ie, ² H or D), may offer certain therapeutic advantages that result from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound represented by formula (I) or formula (II). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has for each designated deuterium atom at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated) Deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). The present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D ₂ O, acetone - d _6, DMSO- d ₆ solvate of those.

Description of Compounds of the Invention

The present invention relates to novel substituted aza five-membered ring compounds and the use of said compounds in medicine. As a PDE4 inhibitor, the compound of the present invention or the pharmaceutical composition comprising the compound has a good therapeutic effect on atopic dermatitis.

(I)；In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of the compound represented by formula (I) , pharmaceutically acceptable salts or their prodrugs:

(I);

Wherein, each of R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ^6a , R ^6b , X, X ¹ and R has the meaning described in the present invention.

In some embodiments, R ¹ and R ² are each independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, heterocyclyl consisting of 3-10 atoms, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _3-8 cycloalkyl-C _1-4 alkylene base, C _1-6 alkyl-C(=O)-, C _3-8 cycloalkyl-C(=O)-, heterocyclyl-C _1-4 alkylene composed of 3-10 atoms, C _6-10 aryl-C _1-4 alkylene or heteroaryl-C _1-4 alkylene composed of 5-10 atoms;

X and X ¹ are each independently a bond, -O-, -S-, -N(R ^c )-, -C(=O)- or -S(=O) _t -;

R ³ is hydrogen, deuterium, carboxyl, C _1-6 alkyl, C _{1-6 haloalkyl} , C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, C _{6- 10} aryl, 3-10 atoms heterocyclyl, 5-10 atoms heteroaryl, C _3-8 cycloalkyl-C _1-4 alkylene, C _6-10 aryl-C heteroaryl -C _1-4 alkylene group, 3 to 10 atoms consisting of heterocyclyl -C _1-4 alkylene, composed of 5-10 atoms _1-4 alkylene group, C _1-6 alkoxy base-C(=O)-, C _1-6 alkyl-S(=O) _t- , C _1-6 alkoxy-C(=O)-, C _3-8 cycloalkyl-C(= O)-, C _3-8 cycloalkyl-S(=O) _t- , heterocyclyl-C(=O)- composed of 3-10 atoms, heterocyclyl-S composed of 3-10 atoms _{(= O) t -, -} C (= O) -NR d R e, -S (= O) t -NR d R e, C 6-10 aryl group -C (= O) -, 5-10 months Heteroaryl-C(=O)-, C _6-10 aryl-S(=O) _t- or heteroaryl-S(=O) _t- consisting of 5-10 atoms, wherein R ³ is unsubstituted or substituted by 1, 2, 3 or 4 R ⁶ ;

Each R ⁶ is independently deuterium, -F, -Cl, -Br, -I , hydroxy, amino, cyano, oxo, C _1-4 alkyl, C _{1-4 haloalkyl,} C _1-4 alkoxy, C _1-4 alkylamino or C _1-4 alkyl-C(=O)-N(R ^c )-;

R ⁴ is -(CH ₂ ) _m -L-(CH ₂ ) _n -G;

L is a bond, -O-, -S-, -NR ^x -, -NR ^x -C(=O)-, -NR ^x -S(=O) _t -, -NR ^x -C(=O)- NR ^y -, -NR ^x -C(=O)-O-, -S(=O) _t -, -C(=O)-, -OC(=O)- or -C(=O)-O -;

Preferably, L is -O -, - S -, - NR x -, - NR x -C (= O) -, - NR x -S (= O) t -, - NR x -C (= O) -NR ^y -, -NR ^x -C(=O)-O-, -S(=O) _t -, -C(=O)- or -C(=O)-O-, where -NR ^x The left ends of -C(=O)-, -NR ^x -S(=O) _t -, -NR ^x -C(=O)-NR ^y - and -NR ^x -C(=O)-O- are respectively (CH ₂ ) _{m is} connected, the right ends are respectively connected with (CH ₂ ) _n , the right end of -C(=O)-O- is connected with (CH ₂ ) _m , and the left end is connected with (CH ₂ ) _n ;

Wherein, each R ^x and R ^{y is} independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _3-8 cycloalkyl, C _6-10 aryl, 3-10 Heterocyclic group composed of atoms, heteroaryl group composed of 5-10 atoms, C _3-8 cycloalkyl-C _1-6 alkylene group, C _6-10 aryl group-C _1-6 alkylene group, 3 -Heterocyclyl-C _1-6 alkylene composed of 10 atoms, heteroaryl-C _1-6 alkylene composed of 5-10 atoms, C _1-6 alkyl-S(=O) _t -, C _1-6 alkyl-C(=O)- or C _1-6 alkoxy-C(=O)-C _1-6 alkylene; G is C _3-8 cycloalkyl, C _{6 -10} aryl, 3-10 atom heterocyclyl or 5-10 atom heteroaryl; wherein G is unsubstituted or substituted by 1, 2, 3 or 4 R ⁷ ;

Each R ^{7 is} independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, carboxyl, C _1-6 alkyl, C _{1-6 haloalkyl} , C _{1 -6} alkoxy, C _1-6 alkylamino, -C(=O)-NR ^a R ^b , -S(=O) _t -NR ^a R ^b , C _1-6 alkyl-C(=O) -N(R ^c )-, C _1-6 alkyl-S(=O) _t -N(R ^c )-, C _1-6 alkoxy-C(=O)-N(R ^c )-, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O) _t- , C _1-6 alkoxy-C(=O)-, C _1-6 alkyl -C(=O)-O-, C _3-8 cycloalkyl, C _6-10 aryl, heterocyclic group consisting of 3-10 atoms or heteroaryl group consisting of 5-10 atoms;

Each of R ^a and R ^{b is} independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _3-8 cycloalkyl, C _6-10 aryl, and consists of 3-10 atoms The heterocyclic group, the heteroaryl group composed of 5-10 atoms, the C _3-8 cycloalkyl-C _1-6 alkylene group, the C _6-10 aryl group-C _1-6 alkylene group, the 3-10 Heterocyclyl-C _1-6 alkylene consisting of 5-10 atoms, heteroaryl-C _1-6 alkylene consisting of 5-10 atoms, C _1-6 alkyl-S(=O) _t - or C _1-6 alkyl-C(=O)-, wherein each R ^a and R ^{b are} independently unsubstituted or by 1, 2 or 3 selected from deuterium, -F, -Cl, -Br, -I, Hydroxyl, amino, cyano, oxo, -C(=O)-NH ₂ , C _1-6 alkoxy C(=O)-, C _1-6 alkyl-C(=O)-N(R ^c )-, C _1-6 alkyl-S(=O) _t -N(R ^c )-, C _1-4 alkyl, C _{1-4 haloalkyl} , C _1-4 alkoxy or C _1-4 alkylamino groups are substituted;

Each R ^d and R ^{e is} independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _3-8 cycloalkyl, C _6-10 aryl, 3-10 atoms. The heterocyclic group, the heteroaryl group composed of 5-10 atoms, the C _3-8 cycloalkyl-C _1-6 alkylene group, the C _6-10 aryl group-C _1-6 alkylene group, the 3-10 Heterocyclyl-C _1-6 alkylene consisting of 5-10 atoms, heteroaryl-C _1-6 alkylene consisting of 5-10 atoms, C _1-6 alkyl-S(=O) _t - or C _1-6 alkyl -C (= O) -, wherein each R ^d and R ^e are independently unsubstituted or substituted with 1, 2 or 3 substituents selected from deuterium, -F, -Cl, -Br, -I , Hydroxyl, amino, cyano, oxo, -C(=O)-NH ₂ , C _1-6 alkoxy C(=O)-, C _1-6 alkyl-C(=O)-N(R ^c )-, C _1-6 alkyl-S(=O) _t -N(R ^c )-, C _1-4 alkyl, C _{1-4 haloalkyl} , C _1-4 alkoxy or C _1-4 alkylamino groups are substituted;

each R ^{c is} independently hydrogen, deuterium, C _1-3 alkyl or C _{1-3 haloalkyl} ;

R is hydrogen, deuterium, -F, -Cl, -Br, -I , hydroxy, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _{1-3 haloalkoxy} or C _{1 -3 haloalkyl} ;

R ^5a , R ^5b , R ^6a and R ^6b are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, C _1-3 alkyl, C _1-3 alkane alkoxy, C _{1-3 haloalkoxy} group or a C _{1-3 haloalkyl;}

t is 1 or 2;

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

m is 1, 2, 3 or 4.

(II)；In some embodiments, the present invention relates to a compound that is a compound of formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate of a compound of formula (II) , metabolites, pharmaceutically acceptable salts or their prodrugs:

(II);

Among them, each of R ¹ , R ² , R ³ , R ^5a , R ^5b , R ^6a , R ^6b , R, L, n and G has the meaning described in the present invention.

(III)；In some embodiments, the present invention relates to a compound which is a compound of formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate of the compound of formula (III) , metabolites, pharmaceutically acceptable salts or their prodrugs:

(III);

Wherein, each of R ¹ , R ² , R ³ , R ^5a , R ^5b , R ^6a , R ^6b , R, G, L and n has the meaning as described in the present invention.

(IV)；In some embodiments, the present invention relates to a compound that is a compound of formula (IV) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate of a compound of formula (IV) , metabolites, pharmaceutically acceptable salts or their prodrugs:

(IV);

Among them, each of R ¹ , R ² , R ³ , R ^5a , R ^5b , R ^6a , R ^6b , R, L, n and G has the meaning described in the present invention.

(V)；In some embodiments, the present invention relates to a compound that is a compound of formula (V) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate of a compound of formula (V) , metabolites, pharmaceutically acceptable salts or their prodrugs:

(V);

Wherein, each of R ¹ , R ² , R ³ , R ^5a , R ^5b , R ^6a , R ^6b , R, G, L and n has the meaning as described in the present invention.

(VI)；In some embodiments, the present invention relates to a compound that is a compound of formula (VI) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate of a compound of formula (VI) , metabolites, pharmaceutically acceptable salts or their prodrugs:

(VI);

Wherein, each of R ¹ , R ² , R ³ , R ^5a , R ^5b , R ^6a , R ^6b , R, G, L and n has the meaning as described in the present invention.

(VII)；In some embodiments, the present invention relates to a compound that is a compound of formula (VII) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate of a compound of formula (VII) , metabolites, pharmaceutically acceptable salts or their prodrugs:

(VII);

Wherein, each of R ¹ , R ² , R ³ , R ^5a , R ^5b , R ^6a , R ^6b , R, G, L and n has the meaning as described in the present invention.

Some embodiments are wherein, R ¹ is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, _{isobutyl, -CH 2 F, -CHF 2,} -CF 3, -CH 2 CH 2 F _{, -CH 2 CHF 2, -CH 2} CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 Cl, -CHCl 2, -CH = CH ₂ , -CH ₂ CH=CH ₂ , -C≡CH, -CH ₂ C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, cyclopropylethylene , cyclobutylmethylene, cyclobutylethylene, cyclopentylmethylene, cyclopentylethylene, cyclohexylmethylene, cyclohexylethylene, CH ₃ C(=O)- , CH ₃ CH ₂ C(=O)-, CH ₃ CH ₂ CH ₂ C(=O)-, (CH ₃ ) ₂ CHC(=O)-, cyclopropyl-C(=O)-, cyclobutyl base-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl , pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, oxazinyl, oxidyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, Phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, pyridyl-C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furyl-C _{1- 3} alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, pyrazolyl-C _1-3 alkylene, thiazolyl-C _1-3 alkylene, Oxazolyl-C _1-3 alkylene, triazolyl-C _1-3 alkylene, tetrazolyl-C _1-3 alkylene, oxazinyl-C _1-3 alkylene, Ciridinyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene, thiomorpholinyl-C _1-3 alkylene, tetrahydropyranyl-C _1-3 alkylene or pyrrolidinyl-C _1-3 alkylene.

Some embodiments are wherein, R ² is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, _{isobutyl, -CH 2 F, -CHF 2,} -CF 3, -CH 2 CH 2 F _{, -CH 2 CHF 2, -CH 2} CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 Cl, -CHCl 2, -CH = CH ₂ , -CH ₂ CH=CH ₂ , -C≡CH, -CH ₂ C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, cyclopropylethylene , cyclobutylmethylene, cyclobutylethylene, cyclopentylmethylene, cyclopentylethylene, cyclohexylmethylene, cyclohexylethylene, CH ₃ C(=O)- , CH ₃ CH ₂ C(=O)-, CH ₃ CH ₂ CH ₂ C(=O)-, (CH ₃ ) ₂ CHC(=O)-, cyclopropyl-C(=O)-, cyclobutyl base-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl , pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, oxazinyl, oxidyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, Phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, pyridyl-C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furyl-C _{1- 3} alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, pyrazolyl-C _1-3 alkylene, thiazolyl-C _1-3 alkylene, Oxazolyl-C _1-3 alkylene, triazolyl-C _1-3 alkylene, tetrazolyl-C _1-3 alkylene, oxazinyl-C _1-3 alkylene, Ciridinyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene, thiomorpholinyl-C _1-3 alkylene, tetrahydropyranyl-C _1-3 alkylene or pyrrolidinyl-C _1-3 alkylene.

In some embodiments, R ³ is hydrogen, deuterium, carboxyl, C _1-3 alkyl, C _{1-3 haloalkyl} , C _2-4 alkenyl, C _2-4 alkynyl, CH ₃ -C( =O)-, CH ₃ CH ₂ -C(=O)-, CH ₃ CH ₂ CH ₂ -C(=O)-, (CH ₃ ) ₂ CH-C(=O)-, CH ₃ -S( =O) ₂ -, CH ₃ CH ₂ -S(=O) ₂ -, CH ₃ CH ₂ CH ₂ -S(=O) ₂ -, (CH ₃ ) ₂ CH-S(=O) ₂ -, CH _{3 -OC (= O) -,} CH 3 CH 2 -OC (= O) -, CH 3 CH 2 CH 2 -OC (= O) -, (CH 3) 2 CH-OC (= O) -, - S(=O) ₂ -NH ₂ or -C(=O)-NH ₂ , wherein R ³ is unsubstituted or substituted with 1 ^{, 2, 3 or 4 R 6} .

Some embodiments are wherein each R ⁶ is independently deuterium, -F, -Cl, -Br, -I , hydroxy, amino, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, _{-CH 2 F, -CHF 2, -CF} 3, -CH 2 CH 2 F, -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, - _{CH 2 CH 2 CF 3, -CH} 2 Cl, -CHCl 2, methoxy, ethoxy, n-propyl group, methylamino, ethylamino, or n-propylamino.

Some embodiments are wherein each R ^x is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C _{1-4 haloalkyl,} cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cyclopropyl-C _1-3 alkylene, cyclobutyl-C _1-3 alkylene, cyclopentyl-C _1-3 alkylene, cyclohexyl-C _1-3 alkylene , phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, oxazinyl, oxidyl , morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, pyridyl-C _1-3 Alkylene, pyrimidinyl-C _1-3 alkylene, furyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, pyrazole base-C _1-3 alkylene, thiazolyl-C _1-3 alkylene, oxazolyl-C _1-3 alkylene, triazolyl-C _1-3 alkylene, tetrazolyl -C _1-3 alkylene, oxazinyl-C _1-3 alkylene, oxidyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene, thiomorpholinyl -C _1-3 alkylene, tetrahydropyranyl-C _1-3 alkylene, pyrrolidinyl-C _1-3 alkylene, C _1-3 alkyl-S(=O) ₂ -, C _1-3 alkyl-C(=O)- or C _1-3 alkoxy-C(=O)-C _1-3 alkylene.

Some embodiments are wherein each R ^y is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C _{1-4 haloalkyl,} cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cyclopropyl-C _1-3 alkylene, cyclobutyl-C _1-3 alkylene, cyclopentyl-C _1-3 alkylene, cyclohexyl-C _1-3 alkylene , phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, oxazinyl, oxidyl , morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, pyridyl-C _1-3 Alkylene, pyrimidinyl-C _1-3 alkylene, furyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, pyrazole base-C _1-3 alkylene, thiazolyl-C _1-3 alkylene, oxazolyl-C _1-3 alkylene, triazolyl-C _1-3 alkylene, tetrazolyl -C _1-3 alkylene, oxazinyl-C _1-3 alkylene, oxidyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene, thiomorpholinyl -C _1-3 alkylene, tetrahydropyranyl-C _1-3 alkylene, pyrrolidinyl-C _1-3 alkylene, C _1-3 alkyl-S(=O) ₂ -, C _1-3 alkyl-C(=O)- or C _1-3 alkoxy-C(=O)-C _1-3 alkylene.

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或

；其中G未被取代或被1、2、3或4個R⁷ 所取代；其中，各R⁷ 具有本發明所述的含義。In some embodiments, G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

; wherein G is unsubstituted or substituted by 1, 2, 3 or 4 R ⁷ ; wherein each R ⁷ has the meaning described in the present invention.

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或

；其中，各R^a 和R^b 具有本發明所述的含義。Some embodiments are wherein each R ⁷ is independently deuterium, -F, -Cl, -Br, -I , hydroxy, amino, cyano, oxo, carboxy, C _1-4 alkyl, C _{1-4 halo Substituted} alkyl, C _1-4 alkoxy, C _1-4 alkylamino, -C(=O)-NR ^a R ^b , -S(=O) ₂ -NR ^a R ^b , C _1-4 alkyl -C(=O)-NH-, C _1-4 alkyl-S(=O) ₂ -NH-, C _1-4 alkoxy-C(=O)-NH-, CH ₃ -C(= O)-, CH ₃ CH ₂ -C(=O)-, CH ₃ CH ₂ CH ₂ -C(=O)-, (CH ₃ ) ₂ CH-C(=O)-, CH ₃ CH ₂ CH ₂ CH ₂ -C(=O)-, CH ₃ -S(=O) ₂ -, CH ₃ CH ₂ -S(=O) ₂ -, CH ₃ CH ₂ CH ₂ -S(=O) ₂ -, ( CH ₃ ) ₂ CH-S(=O) ₂ -, CH ₃ OC(=O)-, CH ₃ CH ₂ OC(=O)-, CH ₃ CH ₂ CH ₂ OC(=O)-, (CH ₃ ) ₂ CHO-C(=O)-, CH ₃ CH ₂ CH ₂ CH ₂ OC(=O)-, CH ₃ -C(=O)-O-, CH ₃ CH ₂ -C(=O)-O -, CH ₃ CH ₂ CH ₂ -C(=O)-O-, (CH ₃ ) ₂ CH-C(=O)-O-, CH ₃ CH ₂ CH ₂ CH ₂ -C(=O)-O -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

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,

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,

or

; Wherein, each R ^a and R ^b have the meanings described in the present invention.

Some embodiments are wherein, R ^a and R ^{b are} each independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, _{n-butyl, -CH 2 F, -CHF 2,} -CF 3, _{-CH 2 CH 2 F, -CH 2} CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH 2 Cl, - CHCl ₂ , phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, oxazinyl, oxazolyl Peridyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, pyridyl-C _{1 -3} alkylene, pyrimidinyl-C _1-3 alkylene, furyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, Pyazolyl-C _1-3 alkylene, thiazolyl-C _1-3 alkylene, oxazolyl-C _1-3 alkylene, triazolyl-C _1-3 alkylene, tetrazolium azolyl-C _1-3 alkylene, oxazinyl-C _1-3 alkylene, oxidyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene, thiomorpho Linyl-C _1-3 alkylene, tetrahydropyranyl-C _1-3 alkylene, pyrrolidinyl-C _1-3 alkylene, C _1-3 alkyl-S(=O) ₂ - or C _1-3 alkyl-C(=O)-; wherein each R ^a and R ^{b are} independently unsubstituted or by 1, 2 or 3 selected from deuterium, -F, -Cl, -Br, - I, hydroxyl, amino, cyano, oxo(=O), -C(=O)-NH ₂ , C _1-3 alkoxy C(=O)-, C _1-3 alkyl-C(= O)-NH-, C _1-3 alkyl-S(=O) _t -NH-, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ F, -CHF ₂ , _{-CF 3, -CH 2 CH 2 F} , -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CH ₂ Cl, -CHCl ₂ , methoxy, ethoxy, n-propyloxy, isopropyloxy, N -methylamino, N -ethylamino, N'N -dimethylamino, N' N -diethylamino or N'N -methylethylamino groups are substituted.

In some embodiments, each R ^{c is} independently hydrogen, deuterium, C _1-3 alkyl, or C _{1-3 haloalkyl} .

In some embodiments, R is hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethyl oxy, n-propoxy, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ Cl or -CHCl ₂ .

In some embodiments, R ^5a , R ^5b , R ^6a and R ^6b are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, _{n-propoxy, -CH 2 F, -CHF 2,} -CF 3, -CH 2 Cl , or -CHCl _2.

(1)、

(2)、

(3)、

(4)、

(5)、

(6)、

(7)、

(8)、

(9)、

(10)、

(11)、

(12)、

(13)、

(14)、

(15)、

(16)、

(17)、

(18)、

(19)、

(20)、

(21)、

(22)、

(23)、

(24)、

(25)、

(26)、

(27)、

(28)、

(29)、

(30)、

(31)、

(32)、

(33)、

(34)、

(35)、

(36)、

(37)、

(38)、

(39)、

(40)、

(41)、

(42)、

(43)、

(44)、

(45)、

(46)、

(47)、

(48)、

(49)、

(50)、

(51)、

(52)、

(53)、

(54)、

(55)、

(56)、

(57)、

(58)、

(59)、

(60)、

(61)、

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(63)、

(64)、

(65)、

(66)、

(67)、

(68)、

(69)、

(70)、

(71)、

(72) 或

(73)。In some embodiments, the present invention includes, but is in no way limited to, compounds having one of the following structures or stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites of compounds having one of the following structures , pharmaceutically acceptable salts or their prodrugs:

(1),

(2),

(3),

(4),

(5),

(6),

(7),

(8),

(9),

(10),

(11),

(12),

(13),

(14),

(15),

(16),

(17),

(18),

(19),

(20),

(twenty one),

(twenty two),

(twenty three),

(twenty four),

(25),

(26),

(27),

(28),

(29),

(30),

(31),

(32),

(33),

(34),

(35),

(36),

(37),

(38),

(39),

(40),

(41),

(42),

(43),

(44),

(45),

(46),

(47),

(48),

(49),

(50),

(51),

(52),

(53),

(54),

(55),

(56),

(57),

(58),

(59),

(60),

(61),

(62),

(63),

(64),

(65),

(66),

(67),

(68),

(69),

(70),

(71),

(72) or

(73).

Some of these embodiments are that the pharmaceutically acceptable salts of the compounds represented by formulae (I), (II), (III), (IV), (V), (VI) and (VII) of the present invention are salts Acid, Hydrobromide, Sulfate, Nitrate, Phosphate, Acetate, Maleate, Succinate, Mandelate, Fumarate, Malonate, Malate, 2-Hydroxy Propionate, pyruvate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate , benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, mesylate, ethanesulfonate, triflate, or a combination thereof.

In one aspect, the present invention relates to a pharmaceutical composition comprising formula (I), (II), (III), (IV), (V), (VI) or (VII) disclosed in the present invention the compound described.

Some of these embodiments are the pharmaceutical composition of the present invention, which further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, adjuvant, vehicle or any combination thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, telukast, Theophylline, formoterol, salmeterol, fluticasone propionate, rolipram, piramister, cilomilast, indacaterol, olodaterol, midestane, qitong, salbutamol, camoxirol, budesonide, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, roflunomide, ciclesonide, ipratropium bromide , oxtropium bromide, tiotropium bromide, glycopyrronium bromide, umeclidinium bromide, vilanterol, aclidinium bromide, benralizumab, Tralokinumab, revatropate, cresabor, fluocinolone acetate, Desoxymetasone, mometasone, triamcinolone, betamethasone, aclomethasone, desonide, hydrocortisone, clobetasol (clobatsol), halobetasol, diflurasone, Praklide, tacrolimus, pimecrolimus, tazarotene, cyclosporine, apremilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, ibuprofen Tetra, Tofacitinib, JTE-052, Baricitinib, Upadatinib, WBI-1001, MRX-6, GSK2981278, Duvolumab, Lekinizumab, Nimolizumab, Tris loginumab, etanercept, adalimumab, infliximab, ustekinumab, sekuginu, omalizumab, CIM-331, golimumab, and pegylated , Tocilizumab, Calcipotriol, Calcitriol, Aliretinoin, VTP-38543, ZPL-389, Aprepitant, Tripitant, Faviprand, OC-459, SUN 13834, SB-011, VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02 or any combination thereof.

On the other hand, the present invention relates to the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) disclosed in the present invention or their pharmaceutical compositions in the preparation of medicines. Use in , wherein the medicament is for preventing, treating or alleviating a disease associated with phosphodiesterase type 4 (PDE4).

In some embodiments, the disease associated with phosphodiesterase type 4 (PDE4) is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis, or non-insulin dependent diabetes mellitus.

In other embodiments, the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, pulmonary tuberculosis fibrosis, cystic fibrosis, acute Respiratory distress syndrome or inflammation of the airways; where bronchitis includes acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis, or bronchiolitis obliterans;

The inflammations described are: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis inflammation or psoriatic arthritis.

Another aspect of the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII).

PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND ADMINISTRATION OF THE COMPOUNDS OF THE INVENTION

The present invention provides a pharmaceutical composition comprising a compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) or its individual stereoisomer, isomeric Racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof. In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adsorbent, adjuvant or vehicle, and optionally, other therapeutic and/or prophylactic Element.

Suitable carriers, excipients or adsorbents are well known to those skilled in the art and are described in detail in, for example, Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro AR et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

"Pharmaceutically acceptable excipient" as used in the present invention means a pharmaceutically acceptable material, admixture or vehicle that is relevant to the consistency of the administered dosage form or pharmaceutical composition. Each excipient must, when mixed, be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would greatly reduce the efficacy of the disclosed compounds when administered to a patient and would result in a pharmaceutical composition that is not pharmaceutically acceptable Interaction. In addition, each excipient must be pharmaceutically acceptable, eg, of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their particular function in the composition. For example, certain pharmaceutically acceptable excipients can be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected which aid in carrying or transporting the compounds of the present invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected to enhance patient compliance.

Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, Polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: vehicles, propellants, solubilizers, solubilizers, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, lubricants, etc. Wetting agent, osmotic pressure regulator, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adherent, antioxidant, chelating agent, penetration enhancer, pH adjuster , plasticizers, surfactants, foaming agents, defoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants and filter aids. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may serve more than one function, and provide alternative functions, depending on how much of that excipient is present in the formulation and what other excipients are present in the formulation. . The compounds of the present invention can be formulated by methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.

The skilled artisan possesses the knowledge and skills in the art to enable them to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in the present invention. In addition, there are numerous resources available to the skilled artisan describing pharmaceutically acceptable excipients and for use in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New Various carriers for formulating pharmaceutically acceptable compositions, and well-known techniques for their preparation, are disclosed in York, the contents of each of which are incorporated herein by reference. except for any undesired biological effects, such as

With the exception of any common carrier that interacts in a deleterious manner with any other ingredient of the pharmaceutically acceptable composition and is incompatible with the compounds of the present invention, it is within the scope of the present invention to focus on its use.

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

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

Non-limiting examples for pharmaceutically acceptable carriers include those having components selected from the group consisting of lactose, gelatin, sugar alcohols (eg, starch, mannitol, cornstarch, etc.), vegetable oils, talc, magnesium stearate, Colloidal silica, carboxymethyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, aqueous buffer solutions, copovidone, polysorbate, ethanol, propylene glycol, polyethylene glycol (preferably polyethylene glycol, such as PEG400), Tween® 80 (i.e. PEG(20), sorbitan monooleate), DMSO, mixtures of water and cosolvents, for example aqueous solutions including alcohols such as ethanol and/or polyglycols such as polyethylene glycol, Polyols such as glycerol and/or polyethylene glycol esters with fatty acids, surfactants such as anionic, cationic, nonionic and amphoteric surfactants, complexing agents such as cyclodextrins, for example alpha-cyclodextrin (alpha-CD) or hydroxypropyl-beta-cyclodextrin (HP-beta-CD), bile acids or lipids, such as salts of animal or vegetable phospholipids, micelle-forming agents, and oils such as corn oil, or both or Mixtures of more components.

Further non-limiting examples of suitable pharmaceutically acceptable carriers and suitable additives that can be used in the pharmaceutical compositions of the present invention are mentioned below.

In one embodiment, the present invention relates to a pharmaceutical composition of the present invention that forms a lipid-based drug delivery system (DDS) in an aqueous medium. The pharmaceutical composition, in addition to at least one compound or a salt thereof among the compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII), also At least one surfactant is included. Non-limiting examples of suitable surfactants are described above. In various embodiments, lipid-based drug delivery systems form the following structures: (1) liposomes (ie, dispersed closed bilayer assemblies of lamellar phases in water); (2) non-lamellar phases (eg, cubic, hexagonal) , sponge) nanoparticles; or (3) micelles, emulsions, microemulsions (ie simple self-assembled structures of lipids and surfactants).

In some embodiments, lipid-based drug delivery systems that form micelles, emulsions, or microemulsions are preferred. Suitable surfactants or surfactant mixtures for forming micelles, emulsions, or microemulsions generally have a hydrophilic-lipophilic balance (HLB-value) of about 8-18, about 10-18, or about 12-16. Lipid-based drug delivery systems form self-emulsifying drug delivery systems (SEDDS) or self-microemulsifying drug delivery systems (SMEDDS). SEDDS and SMEDDS are mixtures of oils (ie lipids, such as compounds of formula (I) or salts thereof), at least one surfactant, optionally at least one co-solvent and optionally at least one co-surfactant, ideally each Isotropic, it spontaneously emulsifies to form oil-in-water emulsifiers when introduced into the aqueous phase with gentle agitation. Gentle agitation may be provided, for example, by gastric motility.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some commonly used methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

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

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

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

Various topical dosage forms can be used to administer the compounds of this invention, such as lotions, ointments, tinctures, liniments, elixirs, powders, creams, oils, pastes, plasters, films and aerosols. Topical administration may also include transdermal administration by means of, for example, transdermal patches. The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents and excipients known in the art, including but not limited to solvents, oily solvents, diluents, stabilizers, absorption delays Agents, disintegrating agents, emulsifiers, antioxidants, binders, binding agents, tackifiers, solubilizers, dispersants, suspoemulsifying agents, lubricants, hygroscopic agents, liposomes, microemulsions and β-cyclodextrin, etc. .

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

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

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

Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane may contain a compound of the present invention in solution or dispersed form. The propellant-driven formulation may also contain other ingredients such as co-solvents, stabilizers, and optionally other excipients.

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

The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or reduce symptoms of a disease is administered or brought into balance in the body. The effective amount required for a particular treatment regimen will depend on a variety of factors, including the disease being treated, the severity of the disease, the activity of the particular drug used, the mode of administration, the clearance of the particular drug, the duration of treatment, concomitant medications, age, Weight, gender, diet and patient's health, etc. Additional considerations in the art regarding a "therapeutically effective amount" can be found in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8 ^th ed., Pergamon Press, 1990; Remington's Pharmaceutical Sciences, 17 ^th ed., Mack Publishing Company, Easton, Pa., 1990.

The dosage of a compound of the present invention will depend on a variety of factors, including the specific disease to be treated, the severity of the symptoms, the route of administration, the frequency of dosage intervals, the specific compound used, the potency of the compound, its toxicological profile and its pharmacokinetics. feature.

The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. For example, formulations intended for smeared administration to humans may conveniently contain from about 5 mg to about 250 mg/kg body weight/day of the active agent in combination with a suitable and convenient amount of carrier material (which may range from about 5% to about 5% of the total composition to about 250 mg/kg body weight/day). about 95%) are compounded. A unit dosage form will generally contain from about 1 mg to about 500 mg of active ingredient.

Advantageously, they are administered at a dose of 5-250 mg/kg body weight/day, preferably 25-150 mg/kg body weight/day.

The term "administration" refers to the provision of a therapeutically effective amount of a drug to an individual by means of oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, Inhalation, rectal, vaginal, etc. Dosage forms include ointments, lotions, tablets, capsules, pills, powders, granules, suppositories, pills, lozenges, injections, sterile solutions or non-aqueous solutions, suspensions, emulsions, patches Wait. The active ingredient is combined with a non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, Dextran, etc.) complex.

The preferred route of administration will vary with clinical characteristics, dosage changes must depend on the condition of the patient being treated, and the appropriate dosage will be determined by the physician on a case-by-case basis. The therapeutically effective amount per unit dose depends on body weight, physiology and the chosen vaccination regimen. Compound per unit dose refers to the weight of the compound per administration, excluding the weight of the carrier (which is contained in the drug).

Any suitable route of administration can be used to provide mammals, particularly humans, with effective doses of the compounds of the present invention. For example, oral, rectal, parenteral, topical, ocular, nasal, pulmonary, and the like may be employed. Dosage forms include tablets, troches, capsules, creams, ointments, suspensions, dispersions, solutions, aerosols, and the like. Preferably, the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered by inhalation or topically.

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

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

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

In some embodiments, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered at one time, or several times at different time intervals over a specified period of time, depending on the dosing regimen. For example, it is administered once, twice, three times or four times a day. In some embodiments, the administration is once a day. In yet other embodiments, the administration is twice daily. Administration may be performed until the desired therapeutic effect is achieved or maintained indefinitely. A suitable dosing regimen for a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled artisan. In addition, a suitable dosing regimen for a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, including the duration for which the regimen is carried out, depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated , the medical history of the patient being treated, the nature of concomitant therapy, the desired therapeutic effect, etc., factors within the knowledge and experience of the technician. Such skilled artisans will also appreciate that adjustments to appropriate dosing regimens may be required as individual patient responses to dosing regimens or as individual patient needs change over time.

The compounds of the present invention may be administered concurrently with, before or after one or more other therapeutic agents. The compounds of the present invention can be administered separately with other therapeutic agents by the same or different route of administration, or in the same pharmaceutical composition. This is selected by those skilled in the art according to the actual conditions of the patient's health, age, weight and other physical conditions. If formulated as a fixed dose, such a combination product employs a compound of the invention (within the dosage range described herein) and the other pharmaceutically active agent (within its dosage range).

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

The compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) can be used for prevention, treatment or alleviation of formula (I), (II), The compound of (III), (IV), (V), (VI) or (VII) is suitable for use in combination with other drugs for diseases or symptoms. These other drugs can be administered simultaneously or sequentially with the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) by their usual routes and amounts. When the compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) is used concomitantly with one or more other drugs, such other drugs and formula Pharmaceutical unit dosage forms of the compounds shown in (I), (II), (III), (IV), (V), (VI) or (VII) are preferred.

In various embodiments, the compounds described in this invention are combined with other drugs to provide combination therapy for chronic obstructive pulmonary disease (COPD), atopic dermatitis (AD), psoriasis or other conditions. The pharmaceutical composition of the present invention includes at least one of the PDE4 inhibitors described in the present invention and an additional therapeutic agent. Examples of the additional therapeutic agent include, but are not limited to:

2-agonists, such as salbutamol, formoterol, salmeterol, and camoxirol;

Corticosteroids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, flunisolide, mometasone furoate, roflunomide, ciclesonide, fluocinolone acetonide, didometasone, momethasone Metathasone, Triamcinolone, Betamethasone, Aclometasone, Desonide, Hydrocortisone, Meproclair;

anticholinergic or antimuscarinic drugs, such as ipratropium, oxytropium, tiotropium, glycopyrronium, revatropate;

topical calcineurin inhibitors, such as tacrolimus, pimecrolimus, cyclosporine;

Topical formulations of PDE4 inhibitors, such as apremilast, ibudilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, cresabor;

Topical formulations of JAK kinase inhibitors, such as tofacitinib, JTE-052, baricitinib, upatinib;

Topical NSAIDs, such as WBI-1001, MRX-6;

Topical ROR agents, such as GSK2981278;

Injectable anti-IL4, IL-31, IL-22, IL-33, IL-12, IL-23, IL-17, IgE, IL-4 therapeutics such as Dupilumab, Lekinizumab Antiviral, Nemolizumab, Tralogikinumab, Etanercept, Adalimumab, Infliximab, Utecalumab, Secukinumab, Omalizumab (Omazumilab), CIM-331;

Vitamin D analogs such as calcipotriol, calcitriol;

Oral retinoic acid derivatives, such as alveretin;

Oral liver X receptor (LXR) selective agonists, such as VTP-38543;

Oral H4 receptor antagonists, such as ZPL-389;

Oral NK1 receptor antagonists, such as aprepitant, tripipitant;

Oral CRTH2 receptor antagonists, such as Fevipiprant, and OC-459;

Oral chymotrypsin inhibitors such as SUN 13834.

Preferably, a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered alone or in combination with other active ingredients for prophylaxis and /or for the treatment of respiratory or skin inflammatory diseases such as chronic obstructive pulmonary disease (COPD), atopic dermatitis (AD) or psoriasis.

A method of treatment comprising the administration of a compound or pharmaceutical composition of the present invention, further comprising administering to the patient other anti-chronic obstructive pulmonary disease (COPD) or atopic dermatitis drugs (combination therapy), wherein the other anti-chronic obstructive pulmonary disease (COPD) The drug for COPD) or atopic dermatitis is one of the above-mentioned additional therapeutic agents or a combination thereof.

The present invention provides methods of treating pulmonary disease (eg, COPD, asthma or fibrocysts) or inflammation (eg, atopic dermatitis or psoriasis) in a patient in need of such treatment comprising administering to said patient in combination a therapeutically effective Amount of at least one compound represented by formula (I) or formula (II), or a pharmaceutically acceptable salt or solvate thereof, and at least one compound selected from the group consisting of steroids (such as glucocorticoids), calcineurin Enzyme Inhibitors, PDE4 Inhibitors, JAK Kinase Inhibitors, Cysteinyl Leukotriene Antagonists, Non-Steroidal Anti-Inflammatory Drugs, Topical ROR Agents, Anti-IL4 Antibodies, IL-31 Antibodies, IL-22 Antibodies, IL -33 antibody, IL-12 antibody, IL-23 antibody, IL-17 antibody, IgE antibody, IL-4 antibody, vitamin D analog, liver X receptor (LXR) selective agonist, histamine H1 antagonist, Histamine H3 antagonists, H4 receptor antagonists, NK1 receptor antagonists, CRTH2 receptor antagonists, chymotrypsin inhibitors, 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists , α-adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, bronchodilators, PDE inhibitors.

Use of the Compounds and Pharmaceutical Compositions of the Invention

The amount of the compound of the invention or the compound in the composition of the invention is effective to detectably antagonize PDE4 to treat the following conditions: pain (eg, acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain), acute inflammation , chronic inflammation, psoriatic arthritis, rheumatoid arthritis, psoriasis, proliferative and inflammatory skin diseases (eg, atopic dermatitis, seborrheic dermatitis, contact dermatitis), asthma, chronic obstructive pulmonary disease (COPD) ), arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram-negative sepsis, glomerulonephritis, Parkinson's disease, Alzheimer's disease Zheimer's Disease, Mild Cognitive Impairment (MCI), Depression, Anxiety, Acute Respiratory Distress Syndrome, Osteoarthritis, Ankylosing Spondylitis, Multiple Sclerosis, Gingivitis, Periodontitis, Pruritus, Blisters Rash, CNS tumor, interstitial pneumonia, allergy, crystal-induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, acute respiratory distress syndrome, pulmonary hypertension , gout, alcoholic liver disease, lupus, cancer, allergic rhinitis, non-allergic rhinitis, autoimmune hemolytic syndrome, autoimmune hepatitis, autoimmune neuropathy, liver cirrhosis, fibrotic diseases, gastritis, Goodpasture's syndrome symptoms, Graves' disease, Gullin-Barre disease, Hashimoto's thyroiditis, HIV-related autoimmune syndromes and blood disorders, lichen planus, myocarditis (including viral myocarditis), neuropathy (including, for example, IgA neuropathy, cell membrane neuropathy and idiopathic neuropathy), nephritic syndrome, Reiter's syndrome, Sjogren's syndrome, systemic lupus erythematosus, the method comprising administering to the patient an effective amount of at least one of A compound represented by formula (I), (II) or (III) or a pharmaceutically acceptable salt or solvate thereof.

General synthetic steps

In general, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are as defined in formula (I), (II), (III), (IV), (V) , (VI) or (VII). The following reaction schemes and examples serve to further illustrate the content of the present invention.

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

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

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N , N -dimethylacetamide and N , N -dimethylformamide were dried over anhydrous sodium sulfate before use.

The following reactions are generally carried out under positive nitrogen or argon pressure or a drying tube is set over anhydrous solvent (unless otherwise indicated), the reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. The test conditions for NMR spectroscopy are: Bruker 400 MHz or 600 MHz NMR instrument at room temperature, with CDC1 ₃ , DMSO- d ₆ , CD ₃ OD or acetone- d ₆ as solvent (reported in ppm units), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet, multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constant, expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data were measured using an Agilent 6120 Quadrupole HPLC-MS (column type: Zorbax SB-C18, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate 0.6 mL/min, mobile phase: 5 ratio of 95% (0.1% formic acid in CH ₃ CN) in (H containing 0.1% formic acid ₂ O) in)), with UV detection at 210/254 nm, electrospray ionization mode (ESI).

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

The stereoconfiguration of each chiral compound described in the present invention is resolved by one of the following analytical methods:

Analytical method:

1. Use an OD-H column (manufacturer: Daicel, size: 4.6 × 250 mm, 5 μm), mobile phase conditions: column temperature 30 °C, flow rate 1 mL/min, 20% ethanol, 80% n-hexane;

2. Use IA column (manufacturer: Daicel, size: 4.6 × 250 mm, 5 μm) mobile phase conditions: column temperature 40 °C, flow rate 1.0 mL/min, 40% ethanol, 60% n-hexane. The following abbreviations are used throughout this disclosure: g gram EtOH Ethanol KOAc Potassium Acetate, Potassium Acetate mg mg CDCl ₃ deuterated chloroform PE Petroleum ether mol Moore DCM Dichloromethane MsCl Methylsulfonyl chloride h Hour DMF N , N -Dimethylformamide TEA triethylamine min minute DMSO dimethyl sulfite HOAc Acetic acid L Rise THF tetrahydrofuran CD ₃ OD Deuterated methanol mL, ml ml B _n OH Benzyl alcohol CH ₃ CN Acetonitrile M, mol/L moles/liter EtOAc, EA Ethyl acetate Pd/C Palladium on carbon DPPA Diphenylphosphonium azide DIPEA N , N -diisopropylethylamine Tf ₂ O Trifluoromethanesulfonic anhydride Pd(dppf)Cl ₂ [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride CDI N , N '-Carbonyldiimidazole HOAT N -Hydroxy-7-azabenzotriazole

Synthetic scheme of compound (IA):

Compound (IA) can be prepared by the above synthetic route, wherein R ¹ , R ² , R ³ , X, X ¹ , R ^5a , R ^5b , R ^6a , R ^6b , R, n and G are as defined in the present invention . Compound (IA-1) is _{esterified with HOOC(CH 2} )nG under basic or acidic conditions to obtain compound (IA).

Synthetic scheme of compound (IB):

Compound (IB) can be prepared by the above synthetic route, wherein R ¹ , R ² , R ³ , X, X ¹ , R ^5a , R ^5b , R ^6a , R ^6b , R, n and G are as defined in the present invention . Compound (IB-1) or its salt (such as hydrochloride, etc.) _{is subjected to condensation reaction with HOOC(CH 2} )nG under suitable conditions to obtain compound (IB).

Synthetic scheme of intermediate N and intermediate N':

Intermediate N can be prepared by synthetic methods of intermediates, wherein, unless otherwise stated, R ¹ and R ² have the meanings as described herein. The starting material N1 reacts with the material BnOH and diphenylphosphoryl azide under alkaline conditions to form an amino protecting group to obtain intermediate N2, which undergoes catalytic hydrogenation reduction to obtain intermediate N3, and intermediate N3 undergoes diazotization the reaction, then a substitution reaction occurs with potassium iodide to give the intermediate N; N intermediate removed under acidic conditions, the corresponding radicals R ¹ to give intermediate N4, N4 intermediate substitution reaction with benzyl bromide to give the intermediate N '.

The specific synthetic method of intermediate N and intermediate N':

The following specific synthetic methods of intermediate N and intermediate N' are only examples of specific synthetic methods, and the synthetic methods of intermediate N and intermediate N' referred to in the present invention should include, but are not limited to, the following specific examples.

Intermediate N2: Synthesis of benzyl (3-cyclopropylmethoxy-4-difluoromethoxy)phenyl)carbamate

3-Cyclopropylmethoxy-4-difluoromethoxybenzoic acid (5.0 g, 19.4 mmol) was dissolved in toluene (25 ml), DPPA (5.0 mL, 23.0 mmol), triethylamine (4.3 mL) were added , 31.0 mmol), reacted at room temperature for 1 h, added benzyl alcohol (3.0 mL, 29.0 mmol), heated to 90 ℃ and heated for 3 h. Concentrate under reduced pressure to remove the solvent, add water (100 ml) to the residue, and then extract with ethyl acetate (25 mL×3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent). : PE/EtOAc (v/v) = 4/1) to give a white solid 5.01 g with a yield of 71%.

¹ H NMR (600 MHz, CDCl ₃ ): δ (ppm) δ 7.35-7.43 (m, 5H), 7.09 (d, J =8.6 Hz, 1H), 6.65-6.69 (m, 1H), 6.58 (t, J _FH =75.8 Hz, 1H), 5.22 (s, 3H), 3.88 (s, 3H), 1.27-1.34 (m, 1H), 0.58-0.73 (m, 2H), 0.29-0.44 (m, 2H);

MS (ESI, pos.ion) m/z: 364.10 [M+H] ⁺ .

Intermediate N3: Synthesis of (3-cyclopropylmethoxy-4-difluoromethoxy)aniline

(3-Cyclopropylmethoxy-4-difluoromethoxy)phenyl)carbamate (145 mg, 0.45 mmol) was dissolved in anhydrous methanol (6 mL), and palladium on carbon (50 mg) was added. ), the air was removed, hydrogen was introduced, and the reaction was carried out at room temperature for 2 h. The catalyst was removed by suction filtration with celite, and the filtrate was concentrated to obtain 102 mg of a light red liquid with a yield of 98%.

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 6.94 (d, J =8.4 Hz, 1H), 6.47 (t, J _FH =76.3 Hz, 1H), 6.26 (d, J =2.2 Hz, 1H), 6.20 (dd, J =8.4, 2.4 Hz, 1H), 3.80 (d, J =6.8 Hz, 2H), 1.25-1.31 (m, 1H), 0.58-0.65 (m, 2H), 0.30-0.35 (m, 2H);

MS (ESI, pos.ion) m/z: 230.10 [M+H] ⁺ .

Intermediate N: Synthesis of 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene

Compound (3-cyclopropylmethoxy-4-difluoromethoxy)aniline hydrochloride (17 g, 64.0 mmol) was dissolved in 1,4-dioxane (85 mL) and water (30 mL) ), stirred evenly, cooled to below 0 °C, added concentrated hydrochloric acid (17 mL), cooled to -15 °C, and added dropwise a solution of sodium nitrite (5.3 g, 77.0 mmol) and water (15 mL) , continue the reaction for 40 min, add a solution of potassium iodide (13.8 g, 83.1 mmol) and water (15 mL), after the dropwise addition, the temperature is raised to 0 °C to continue the reaction for 2 h, water (200 mL) is added, and the mixture is stirred evenly. The reaction was stopped, and extracted with EA (200 mL×2) after returning to room temperature. The organic phase was washed with saturated sodium sulfite, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 21 g of the target product as a light brown liquid with a yield of 96%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.21-7.27 (m, 2H), 6.89 (d, J = 8.1 Hz, 1H), 6.59 (t, J _FH = 75.2 Hz, 1H), 3.84 (d, J = 6.9 Hz, 2H), 1.23-1.29 (m, 1H), 0.61-0.69 (m, 2H), 0.32-0.40 (m, 2H);

GC-MS: m/z 340.0.

Intermediate N4: Synthesis of 2-(difluoromethoxy)-5-iodophenol

Compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (4.9 g, 14.0 mmol) was dissolved in acetonitrile (8 mL), water (10 mL) and Concentrated hydrochloric acid (10 mL) was reacted at 80 °C for 4 h, sodium hydroxide solution was added to adjust pH=5, extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the concentrated solution Silica gel column chromatography was performed (eluent: PE/EA (v/v)=5/1) to obtain 1.8 g of pale yellow liquid with a yield of 44%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 10.30 (s, 1H), 7.28 (d, J =2.0 Hz, 1H)), 7.15 (dd, J =8.4, 2.0 Hz, 1H) , 7.02 (t, J _FH =74.7 Hz, 1H), 6.90 (d, J =8.4 Hz, 1H).

MS (ESI, pos.ion) m/z: 286.00 [M].

Intermediate N': Synthesis of 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene

The compound 2-(difluoromethoxy)-5-iodophenol (3.8 g, 13.0 mmol) and potassium carbonate (5.8 g, 42.0 mmol) were added to N , N -dimethylformamide (30 mL), Add benzyl bromide (2.5 mL, 21.0 mmol), react at 100 °C for 16 h, remove the solid by filtration, concentrate the filtrate, add water (50 mL), extract with EA (25 mL × 3), and dry the organic phase with anhydrous sodium sulfate, The solvent was removed under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: PE/EA (v/v)=4/1) to obtain 4.8 g of pale yellow liquid with a yield of 96%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.57 (d, J =1.9 Hz, 1H), 7.45-7.47 (m, 2H), 7.41 (s, 1H), 7.39 (d, J =3.4 Hz, 1H), 7.33-7.37 (m, 2H), 7.09 (t, J _FH =74.2 Hz, 1H), 7.00 (d, J =8.4 Hz, 1H), 5.18 (s, 2H).

Synthetic scheme of intermediate M:

Intermediate M can be prepared by the above two synthetic routes, wherein, X is halogen, and R ¹ , R ² and R ³ have the meanings described in the present invention.

The starting material M1 is subjected to enolization under alkaline conditions (such as lithium hydroxide, potassium hydroxide, etc.) and then undergoes a substitution reaction to obtain intermediate M2. Intermediate M2 and biboronic acid pinacol ester are passed through boron Compound M3 is obtained by the radicalization reaction, and M3 and intermediate N' (route 1) or intermediate N (route 2) are coupled through suzuki to obtain intermediates M4-1 and M4-6, respectively, wherein route 1 is intermediate M4 -1 First, the intermediate M4-2 is obtained by deprotection and salification reaction, and then the intermediate M4-2 is obtained by substitution reaction under basic conditions (such as triethylamine, N,N-diisopropylethylamine, etc.) 3, then carry out catalytic hydrogenation reduction to obtain intermediate M4-4, and finally a substitution reaction occurs under alkaline conditions to obtain intermediate M4-5; and route 2 is that intermediate M4-6 is first catalytically hydrogenated and reduced under the action of palladium carbon The intermediate M4-7 is obtained, and then the intermediate M4-8 is obtained through deprotection. Finally, the intermediate M4-9 is obtained by the substitution reaction under basic conditions (such as triethylamine, N , N-diisopropylethylamine, etc.). ; M4-5 or M4-9 finally obtains intermediate M through reduction reaction, halogenation reaction, azide reaction, hydrogenation reduction, etc.

The specific synthetic method of intermediate M:

The synthetic method of intermediate M is only an example of a specific synthetic method, and the synthetic method of intermediate M referred to in the present invention should include, but not be limited to, the following specific examples. The intermediate M described in the present invention is not limited to a specific compound, and within the scope allowed by the substituents described in the present invention, each specific embodiment will optionally prepare the same or different intermediate M.

Intermediate M2: (R) -1-tert-Butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro- 1H -pyrrole-1,2 - Synthesis of dicarboxylates

Compound (R) -1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (0.98 g, 4.0 mmol) was dissolved in dichloromethane (15 mL) solution,- DIPEA (3.4 mL, 20.5 mmol) and trifluoromethanesulfonic anhydride (1.3 mL, 7.7 mmol) were added at 15 °C, and after stirring for 10 min, the temperature was returned to room temperature, and the reaction was continued for 18 h. The reaction was stopped, and water (50 mL) was added. Extracted with dichloromethane (5 mL×3), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=6/1) to obtain 1.3 g of yellow oil, Yield 86%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 5.71 (dd, J=18.8, 1.6 Hz, 1H), 4.99-5.06 (m, 1H), 4.24-4.41 (m, 2H), 3.76 (s , 3H), 1.42–1.47 (m, 9H).

MS-ESI: m/z 398.10 [M+Na] ⁺ .

Intermediate M3: (R) -1-tert-Butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) Synthesis of -2,5-dihydro- 1H -pyrrole-1,2dicarboxylate

(R) -1-tert-Butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro- 1H -pyrrole-1,2-dicarboxylate Acetate (1.3 g, 3.5 mmol), pinacol diboronate (1.3 g, 5.1 mmol), KOAc (1.1 g, 11.2 mmol) and Pd(dppf)Cl ₂ (130 mg, 0.2 mmol) were added to dry 1 ,4-dioxane (30 mL), reacted at 100 °C for 13 h under nitrogen protection, cooled to room temperature, filtered, water (50 mL) was added to the filtrate, extracted with EtOAc (5 mL×3), the organic phases were used in combination Dry over anhydrous sodium sulfate, remove the solvent, concentrate, and conduct silica gel column chromatography separation (eluent: PE/EtOAc (v/v)=6/1) to obtain 1.05 g of a light red liquid with a yield of 85%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.33 (dd, J =23.4, 1.9 Hz, 1H), 5.01-5.12 (m, 1H), 4.26-4.40 (m, 2H), 3.71-3.73 (m, 3H), 1.42–1.47 (m, 9H), 1.26 (s, 12H).

MS-ESI: m/z 376.15 [M+Na] ⁺ .

Route one:

Compound 1-1: (R) -1-tert-Butyl 2-methyl 4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1 Synthesis of H -pyrrole-1,2-dicarboxylate

(R) -1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2, 5-Dihydro-1 H -pyrrole-1,2-dicarboxylate (2.1 g, 5.9 mmol), 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene (5.8 g, 2.2 mmol), potassium phosphate (5.0 g, 24.0 mmol) and Pd(dppf)Cl ₂ (88 mg, 0.12 mmol) were mixed in a dry solution of 1,4-dioxane (20 mL) under nitrogen protection at 100 °C for 5 h, the reaction solution was suction filtered, water (20 mL) was added to the filtrate, extracted with EtOAc (15 mL×3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, concentrated, and a silica gel column layer was performed. Separation (eluent: PE/EtOAc (v/v)=4/1) gave 2.1 g of a yellow-brown liquid with a yield of 74%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.37–7.44 (m, 5H), 7.18–7.20 (m, 1H), 7.04 (s, 1H), 6.95–7.01 (m, 1H), 6.60 (t, J _FH =75.0 Hz, 1H), 6.00–6.03 (m, 1H), 5.13–5.21 (m, 3H), 4.54–4.67 (m, 2H), 3.78–3.79 (m, 3H), 1.48 – 1.55 (m, 9H).

MS-ESI: m/z 498.20 [M+Na] ⁺ .

Compound 1-2: (R) -4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2-carboxylate Synthesis of Ester Hydrochloride

Compound (R) -1-tert-butyl-2-methyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H - Pyrrole-1,2-dicarboxylate (2.3 g, 4.8 mmol) was dissolved in dichloromethane (5 mL), HCl in ethyl acetate solution (4 mol/L, 15 mL) was added, and the reaction was carried out at room temperature for 1 h, the solvent was removed to obtain 2.02 g of pale yellow liquid with a yield of 100%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.48–7.50 (m, 2H), 7.33–7.43 (m, 4H), 7.23 (d, J =8.3 Hz, 1H), 7.12 (dd, J =8.3, 1.9 Hz, 1H), 6.81 (t, J _FH =74.8 Hz, 1H), 6.45–6.46 (m, 1H), 5.40–5.43 (m, 1H), 5.24 (s, 2H), 4.53– 4.62 (m, 2H), 3.93 (s, 3H).

MS-ESI: m/z 376.05 [M+H-HCl] ⁺ .

Compound 1-3: (R) -1-Acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole Synthesis of -2-carboxylate methyl ester

Compound (R) -4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2-carboxylate methyl ester hydrochloride The salt (2.0 g, 4.9 mmol) was dissolved in dichloromethane (10 mL), DIPEA (4.0 mL, 24 mmol) was added, cooled to 0 °C, acetyl chloride (1.1 g, 14 mmol) was added, and the mixture was stirred at room temperature for 3 After h, the reaction was stopped, water (20 mL×3) was added, stirred, extracted with dichloromethane (20 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated, and separated by silica gel column chromatography (eluent: PE/ EtOAc (v/v)=1/2) to obtain light yellow liquid 1.8 g, yield 89%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.36–7.47 (m, 5H), 7.20 (d, J =8.2 Hz, 1H), 7.05–7.06 (m, 1H), 6.95 (dd, J =8.3, 1.9 Hz, 1H), 6.61 (t, J _FH =74.8 Hz, 1H), 6.07–6.10 (m, 1H), 5.27–5.35 (m, 1H), 5.17 (s, 2H), 5.16 (s , 1H), 4.73–4.80 (m, 1H), 4.58–4.66 (m, 1H), 3.83 (s, 1H), 3.79 (s, 2H), 2.22 (s, 2H), 2.11 (s, 1H).

MS-ESI: m/z 418.60 [M+H] ⁺ .

Compound 1-4: Synthesis of (2R )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylate methyl ester

Compound (R) -1-Acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2- Methyl carboxylate (4.5 g, 11 mmol) was dissolved in methanol (30 mL), 10% Pd/C (450 mg) was added, hydrogen was passed through, the reaction was carried out at room temperature for 5 h, filtered, and the filtrate was concentrated to obtain 3.1 g of a light brown liquid , the yield is 87%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J =8.3 Hz, 1H), 6.96 (d, J =1.9 Hz, 1H), 6.79 (dd, J =8.3, 2.0 Hz, 1H), 6.56 (t, J _FH =73.7 Hz, 1H), 4.48–4.53 (m, 1H), 3.94–3.98 (m, 1H), 3.78 (s, 3H), 3.63 (t, J =10.5 Hz, 1H), 3.38–3.47 (m, 1H), 2.65–2.71 (m, 1H), 2.14 (s, 3H), 2.05–2.11 (m, 1H).

MS-ESI: m/z 330.00 [M+H] ⁺ .

Compound 1-5: Synthesis of (2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylate methyl ester

Compound (2R) -methyl 1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylate (1.3 g, 3.9 mmol) was dissolved in anhydrous DMF (10 mL), potassium carbonate (1.8 g, 13 mmol) and 2-iodopropane (1.5 g, 8.8 mmol) were added, the reaction was heated at 80 °C for 4 h, the solvent was removed under reduced pressure, water (50 mL) was added, and extracted with EtOAc (20 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=50/1) to obtain a light brown liquid 1.5 g, 100% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14 (d, J =8.1 Hz, 1H), 6.87 (s, 1H), 6.83 (dd, J =8.0, 1.9 Hz, 1H), 6.56 ( t, J _FH =75.5 Hz, 1H), 4.56–4.61 (m, 1H), 4.48–4.55 (m, 1H), 3.94–3.98 (m, 1H), 3.79 (s, 3H), 3.63 (t, J =10.5 Hz, 1H), 3.40–3.48 (m, 1H), 2.65–2.72 (m, 1H), 2.14 (s, 3H), 2.02–2.11 (m, 1H), 1.37 (d, J =6.0 Hz, 6H).

MS-ESI: m/z 372.30 [M+H] ⁺ .

Compound 1-6: 1-(( 2R )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethyl Synthesis of Ketones

Compound (2R) -methyl 1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylate (560 mg, 1.51 mmol) was dissolved in In anhydrous THF (8 mL), lithium borohydride (320 mg, 15.0 mmol) was added in an ice bath, the reaction was stopped after 1 h at room temperature, saturated aqueous sodium chloride solution (20 mL) was added, and extracted with EtOAc (20 mL× 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 502 mg of a colorless liquid with a yield of 96%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14 (d, J =8.2 Hz, 1H), 6.85 (s, 1H), 6.81 (dd, J =8.2, 1.8 Hz, 1H), 6.56 (t, J _FH =75.5 Hz, 1H), 4.55–4.61 (m, 1H), 4.23–4.29 (m, 1H), 3.91–3.94 (m, 1H), 3.76–3.82 (m, 1H), 3.67– 3.72 (m, 1H), 3.44 (t, J =10.8 Hz, 1H), 2.44–2.51 (m, 1H), 2.16 (s, 3H), 1.65–1.74 (m, 1H), 1.38 (d, J = 6.1 Hz, 6H).

MS-ESI: m/z 344.10 [M+H] ⁺ .

Compound 1-7: 1-(( 2R )-2-(bromomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethane Synthesis of Ketones

Compound 1-(( 2R )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (493 mg, 1.44 mmol) was dissolved in EtOAc (20 mL), triethylamine (442 mg, 4.37 mmol) was added, MsCl (333 mg, 2.91 mmol) was added in an ice bath, and after reacting at room temperature for 1 h, lithium bromide (1.26 mmol) was added. g, 14.56 mmol), reacted at room temperature for 8 h, water (30 mL) was added to stop the reaction, the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 376 mg of light yellow liquid with a yield of 64%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm): 7.15 (d, J =8.2 Hz, 1H), 6.94 (d, J =1.4 Hz, 1H), 6.87 (dd, J =8.1, 1.5 Hz, 1H), 6.57 (t, J _FH =75.5 Hz, 1H), 4.56–4.62 (m, 1H), 4.36–4.43 (m, 1H), 4.18–4.23 (m, 1H), 3.88–3.93 (m , 1H), 3.68–3.71 (m, 1H), 3.52 (d, J =10.7 Hz, 1H), 3.26–3.36 (m, 1H), 2.51–2.62 (m, 1H), 2.13–2.22 (m, 1H) ), 2.13 (s, 3H), 1.39 (d, J =6.0 Hz, 6H).

MS-ESI: m/z 408.15 [M+H] ⁺ .

Compound 1-8: 1-(( 2R )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl) Synthesis of ethyl ketone

Compound 1-(( 2R )-2-(bromomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (320 mg, 0.79 mmol) was dissolved in DMF (5 mL), sodium azide (512 mg, 7.9 mmol) was added, the reaction was heated at 80 °C for 6 h, cooled to room temperature, added water (30 mL), and extracted with EtOAc (10 mL). ×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=60/1) to obtain 223 mg of light brown liquid, Yield 76%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.15 (d, J =8.2 Hz, 1H), 6.91 (d, J =1.5 Hz, 1H), 6.86 (dd, J =8.2, 1.7 Hz, 1H), 6.57 (t, J _FH =75.5 Hz, 1H), 4.56–4.62 (m, 1H), 4.28–4.34 (m, 1H), 4.13–4.19 (m, 1H), 3.91–3.95 (m, 1H) ), 3.39–3.48 (m, 2H), 3.38–3.41 (m, 1H), 3.26–3.33 (m, 1H), 2.43–2.49 (m, 1H), 2.09–2.18 (m, 1H), 2.13 (s , 3H), 1.39 (d, J =6.1 Hz, 6H).

MS-ESI: m/z 369.20 [M+H] ⁺ .

Compound 1-9: 1-(( 2R )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethane Synthesis of Ketones

Compound 1-(( 2R )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone ( 220 mg, 0.60 mmol) was dissolved in methanol (8 mL), 10% Pd/C (23 mg) was added, hydrogen was passed through, the reaction was carried out at room temperature for 3 h, the catalyst was removed by filtration, and the filtrate was concentrated to obtain 176 mg of a colorless liquid with a yield of 86 %.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.08–7.12 (m, 2H), 6.95 (dd, J =8.2, 1.7 Hz, 1H), 6.69 (t, J _FH =75.6 Hz, 1H) ), 4.64–4.72 (m, 1H), 4.07–4.14 (m, 1H), 4.01–4.05 (m, 1H), 3.46 (d, J =10.8 Hz, 1H), 2.97–3.05 (m, 2H), 2.62–2.67 (m, 1H), 2.48–2.55 (m, 1H), 2.13 (s, 3H), 1.92–2.01 (m, 1H), 1.36 (d, J =6.0 Hz, 6H).

MS-ESI: m/z 343.10 [M+H] ⁺ .

Route two :

Compound 2-1: (R) -1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-di Synthesis of Hydrogen- 1H -pyrrole-1,2-dicarboxylate

(R) -1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2, 5-Dihydro- 1H -pyrrole-1,2-dicarboxylate (1.15 g, 3.3 mmol), 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodo benzene (1.1 g, 3.2 mmol), potassium phosphate (2.1 g, 9.9 mmol) and _{Pd (dppf) Cl 2 (120} mg, 0.16 mmol) was dissolved in dry 1,4-dioxane (15 mL), The reaction was carried out at 100 °C for 3 h under nitrogen protection, the reaction solution was suction filtered, water (50 mL) was added to the filtrate, and EtOAc (5 mL×3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column layer Separation was carried out (eluent: PE/EtOAc (v/v)=8/1) to obtain 1.13 g of a light red liquid with a yield of 80%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14 (d, J =8.2 Hz, 1H), 6.90-6.97 (m, 2H), 6.63 (t, J _FH =75.4 Hz, 1H), 6.00 -6.03 (m, 1H), 5.11-5.19 (m, 1H), 4.47-4.66 (m, 2H), 3.86-3.90 (m, 2H), 3.76 (d, J =4.0 Hz, 3H), 1.46–1.52 (m, 9H), 1.26-1.31 (m, 1H), 0.61-0.70 (m, 2H), 0.33-0.38 (m, 2H).

MS-ESI: m/z 462.20 [M+Na] ⁺ .

Compound 2-2: ( 2R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1, Synthesis of 2-dicarboxylate

(R) -1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -Pyrrole-1,2-dicarboxylate (1.1 g, 2.5 mmol) was dissolved in methanol (15 mL), Pd/C (260 mg) was added, hydrogen was passed through, and the reaction was carried out at room temperature for 7 h, and then the reaction solution was pumped Filtration, the filtrate was concentrated to obtain 990 mg of yellow liquid, the yield was 90%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J =8.0 Hz, 1H), 6.77-6.81 (m, 2H), 6.60 (t, J _FH =74.2 Hz, 1H), 4.30 -4.40 (m, 1H), 3.91-3.95 (m, 0.5H), 4.02-4.06 (m, 0.5H), 3.84-3.87 (m, 2H), 3.76 (d, J =6.7 Hz, 3H), 3.30 -3.45 (m, 2H), 2.62-2.68 (m, 1H), 1.99-2.07 (m, 1H), 1.43–1.47 (m, 9H), 1.28-1.31 (m, 1H), 0.62-0.67 (m, 2H), 0.33-0.37 (m, 2H).

MS-ESI: m/z 464.25 [M+Na] ⁺ .

Compound 2-3: Synthesis of (2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride

The compound ( 2R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-di Carboxylic acid ester (990 mg, 2.2 mmol) was dissolved in dichloromethane (6 mL), HCl ethyl acetate solution (4 mol/L, 8 mL) was added, stirred at room temperature for 50 min, and the solvent was removed to obtain a white solid 751 mg, the yield is 98%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14 (d, J =8.2 Hz, 1H), 7.07 (s, 1H), 6.91-6.94 (m, 1H), 6.76 (t, J _FH =75.5 Hz, 2H), 4.60-4.64 (m, 1H), 3.94 (d, J =6.9 Hz, 2H), 3.90 (s, 3H), 3.78-3.83 (m, 1H), 3.65-3.72 (m, 1H), 3.33-3.39 (m, 1H), 2.82-2.89 (m, 1H), 2.20-2.29 (m, 1H), 1.28-1.36 (m, 1H), 0.63-0.66 (m, 2H), 0.37- 0.41 (m, 2H).

MS-ESI: m/z 342.20 [M+H-HCl] ⁺ .

Compound 2-4: (2R) -1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester Synthesis

Compound (2R) -4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride (203 mg, 0.6 mmol ) was dissolved in dichloromethane (5 mL), DIPEA (0.2 mL, 1.0 mmol) and acetyl chloride (0.1 mL, 1.0 mmol) were added dropwise at 0 °C, and the reaction was stopped after stirring at room temperature for 5 h. mL×3) washed, dried over anhydrous Na ₂ SO ₄ , and the concentrated solution was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=1/1) to obtain light yellow liquid 186 mg, yield 82 %.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.11 (d, J =8.2 Hz, 1H), 7.04 (s, 1H), 6.90-6.94 (m, 1H), 6.74 (t, J _FH =75.6 Hz, 1H), 4.45-4.49 (m, 1H), 4.08-4.12 (m, 1H), 3.93 (d, J =6.8 Hz, 2H), 3.75 (s, 3H), 3.50-3.64 (m, 2H), 2.67-2.74 (m, 1H), 2.13 (s, 3H), 1.99-2.06 (m, 1H), 1.27-1.33 (m, 1H), 0.62-0.67 (m, 2H), 0.36-0.40 ( m, 2H).

MS-ESI: m/z 384.20 [M+H] ⁺ .

Compound 2-5: 1-(( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine- Synthesis of 1-yl)ethanone

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester (800 mg, 2.09 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL), lithium borohydride (445 mg, 20.9 mmol) was added to the ice bath, and the reaction was carried out at room temperature for 4 h, and then ice water (15 mL) was added, and then water (15 mL) was added after concentration. 30 mL), extracted with EtOAc (20 mL×3), the organic phase was washed with dilute hydrochloric acid (15 mL×1, 1M), washed with saturated aqueous sodium chloride solution (15 mL×1), and the organic phase was dried with anhydrous sodium sulfate , the solvent was removed to obtain 655 mg of a colorless liquid with a yield of 88%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14 (d, J =8.7 Hz, 1H), 6.81 (s, 2H), 6.62 (t, J _FH =75.5 Hz, 1H), 5.57–5.59 (m, 1H), 4.22–4.28 (m, 1H), 3.90–3.95 (m, 1H), 3.89 (d, J =6.9 Hz, 2H), 3.76–3.82 (m, 1H), 3.66–3.71 (m , 1H), 3.44 (t, J =10.8 Hz, 1H), 3.26–3.36 (m, 1H), 2.43–2.50 (m, 1H), 2.15 (s, 3H), 1.65–1.74 (m, 1H), 1.27–1.35 (m, 1H), 0.65–0.70 (m, 2H), 0.36–0.40 (m, 2H).

MS-ESI: m/z 356.25 [M+H] ⁺ .

Compound 2-6: 1-(( 2R )-2-(bromomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- Synthesis of 1-yl)ethanone

Compound 1-(( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl ) ethyl ketone (520 mg, 1.46 mmol) was dissolved in EtOAc (20 mL), triethylamine (525 mg, 5.19 mmol) was added, MsCl (301 mg, 2.63 mmol) was added in an ice bath, and the reaction was carried out at room temperature for 2 h and then added Lithium bromide (636 mg, 7.32 mmol) was continued at room temperature for 12 h, water (30 mL) was added to stop the reaction, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH). (v/v)=50/1), 146 mg of light yellow liquid was obtained, and the yield was 23%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.15 (d, J =8.1 Hz, 1H), 6.90 (s, 1H), 6.88 (d, J =8.2 Hz, 1H), 6.63 (t, J _FH =75.6 Hz, 1H), 4.36–4.42 (m, 1H), 4.17–4.21 (m, 1H), 4.05–4.10 (m, 1H), 3.90 (d, J =6.9 Hz, 2H), 3.69– 3.72 (m, 1H), 3.52 (d, J =10.7 Hz, 1H), 3.26–3.36 (m, 1H), 3.51–3.57 (m, 1H), 2.15–2.24 (m, 1H), 2.13 (s, 3H), 1.28–1.38 (m, 1H), 0.66–0.70 (m, 2H), 0.36–0.41 (m, 2H).

MS-ESI: m/z 419.15 [M+H] ⁺ .

Compound 2-7: 1-(( 2R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine Synthesis of -1-yl)ethanone

Compound 1-(( 2R )-2-(bromomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) ethyl ketone (250 mg, 0.60 mmol) was dissolved in DMF (3 mL), sodium azide (388 mg, 5.97 mmol) was added, the reaction was heated at 90 °C for 2.5 h, cooled to room temperature, added water (30 mL), EtOAc extraction (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=60/1), 163 mg of light brown liquid was obtained with a yield of 71%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.16 (d, J =8.4 Hz, 1H), 6.87 (s, 1H), 6.85 (d, J =8.2 Hz, 1H), 6.63 (t, J _FH =75.6 Hz, 1H), 4.27–4.33 (m, 1H), 4.14–4.18 (m, 1H), 3.88–3.94 (m, 1H), 3.91 (d, J =6.9 Hz, 2H), 3.39– 3.47 (m, 2H), 3.25–3.33 (m, 1H), 2.42–2.48 (m, 1H), 2.07–2.18 (m, 1H), 2.13 (s, 3H), 1.28–1.36 (m, 1H), 0.66–0.71 (m, 2H), 0.38–0.41 (m, 2H).

MS-ESI: m/z 381.20 [M+H] ⁺ .

Compound 2-8: 1-(( 2R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- Synthesis of 1-yl)ethanone

Compound 1-(( 2R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1- (2.7 g, 7.1 mmol) and triphenylphosphine (2.4 g, 9.2 mmol) were dissolved in a mixed solvent of tetrahydrofuran/water ((v/v)=3/1, 40 mL), and reacted at 50 °C for 4 h, concentrated under reduced pressure, extracted with EtOAc (10 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 15/1) to obtain 1.8 g of a light brown liquid with a yield of 71%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.10 (d, J =8.2 Hz, 1H), 7.08 (s, 1H), 6.93–6.95 (m, 1H), 6.74 (t, J _FH =75.8 Hz, 1H), 4.06–4.13 (m, 1H), 4.00–4.04 (m, 1H), 3.94 (d, J =6.9 Hz, 2H), 3.46 (d, J =10.8 Hz, 1H), 3.30 –3.36 (m, 1H), 2.95–3.05 (m, 2H), 2.47–2.54 (m, 1H), 2.13 (s, 3H), 1.93–2.01 (m, 1H), 1.29–1.35 (m, 1H) , 0.63–0.67 (m, 2H), 0.37–0.41 (m, 2H).

MS-ESI: m/z 355.00 [M+H] ⁺ .

Example:

Example 1: 3-(((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl ) carbamoyl) methyl benzoate

Compound 1-(( 2R )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (40 mg, 0.12 mmol), monomethyl isophthalate (27 mg, 0.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg, 0.59 mmol) ) and HOAT (30 mg, 0.22 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 °C, DIPEA (90 mg, 0.70 mmol) was added, the reaction was carried out at room temperature for 12 h, water (10 mL) was added, and Dichloromethane extraction (10 mL×3), combined organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=50/1), 23 mg of white viscous material was obtained with a yield of 39% and a purity of 92.31%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.94 (br.s, 1H), 8.59 (s, 1H), 8.17 (d, J =7.6 Hz, 1H), 8.07 (d, J =7.7 Hz, 1H), 7.55 (t, J =7.7 Hz, 1H), 7.15 (d, J =8.2 Hz, 1H), 6.86 (s, 1H), 6.83 (d, J =8.3 Hz, 1H), 6.57 ( t, J _FH =75.5 Hz, 1H), 4.55–4.61 (m, 1H), 4.37–4.43 (m, 1H), 3.96–4.12 (m, 2H), 3.96 (s, 3H), 3.48 (t, J =10.9 Hz, 1H), 3.25–3.39 (m, 2H), 2.65–2.71 (m, 1H), 2.20 (s, 3H), 1.82–1.91 (m, 1H), 1.38 (d, J =5.9 Hz, 6H).

MS-ESI: m/z 505.15 [M+H] ⁺ .

Example 2: 3-((((2R)-1-Acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl) carbamoyl)benzoic acid

The compound 3-(((( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)amino Methyl carboxyl)benzoate (23 mg, 0.045 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL), lithium hydroxide monohydrate (10 mg, 0.24 mmol) was added, and the reaction was carried out at 50 °C It was stopped after 1.5 h, diluted hydrochloric acid (1M) was added to adjust the pH of the solution to 1, THF was removed under reduced pressure, the residue was extracted with EtOAc (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 18 mg of light yellow solid , the yield is 80%.

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm): 8.53 (s, 1H), 8.22 (d, J =7.5 Hz, 1H), 8.07 (d, J =7.7 Hz, 1H), 7.62 ( t, J =7.8 Hz, 1H), 7.08 (d, J =8.2 Hz, 1H), 6.99 (s, 1H), 6.89–6.94 (m, 1H), 6.66 (t, J _FH =75.6 Hz, 1H) , 4.49–4.58 (m, 1H), 4.36–4.44 (m, 1H), 4.05–4.09 (m, 1H), 3.72–3.90 (m, 2H), 3.46 (t, J =10.9 Hz, 1H), 3.32 –3.41 (m, 1H), 2.53–2.60 (m, 1H), 2.17 (s, 3H), 1.98–2.06 (m, 1H), 1.26 (d, J =6.0 Hz, 6H).

MS-ESI: m/z 491.30 [M+H] ⁺ .

Example 3: N -((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl) -2-Ethoxybenzamide

Compound 1-(( 2R )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (50 mg, 0.15 mmol), 2-ethoxybenzoic acid (37 mg, 0.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (142 mg, 0.74 mmol) ) and HOAT (40 mg, 0.29 mmol) were dissolved in dichloromethane (10 mL), cooled to 0 °C, DIPEA (116 mg, 0.90 mmol) was added, the reaction was carried out at room temperature for 6 h, water (10 mL) was added, and Dichloromethane extraction (10 mL×3), combined organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=50/1), 30 mg of white viscous substance was obtained with a yield of 41% and a purity of 97.18%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.48 (br.s, 1H), 8.20 (d, J =7.8 Hz, 1H), 7.42–7.46 (m, 1H), 7.07–7.10 (m , 2H), 6.98 (d, J =8.2 Hz, 1H), 6.81 (s, 1H), 6.77 (d, J =8.3 Hz, 1H), 6.53 (t, J _FH =75.6 Hz, 1H), 4.41– 4.48 (m, 1H), 4.20–4.35 (m, 3H), 3.95–4.03 (m, 1H), 3.86–3.94 (m, 2H), 3.39 (t, J =10.7 Hz, 1H), 3.17–3.26 ( m, 1H), 2.53–2.59 (m, 1H), 2.14 (s, 3H), 1.99–2.02 (m, 1H), 1.52 (t, J =6.9 Hz, 3 H), 1.27–1.31 (m, 6H) ).

MS-ESI: m/z 491.30 [M+H] ⁺ .

Example 4: 4-(((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl ) carbamoyl) methyl benzoate

Compound 1-(( 2R )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (40 mg, 0.12 mmol), monomethyl terephthalate (27 mg, 0.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg, 0.59 mmol) ) and HOAT (30 mg, 0.22 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 °C, DIPEA (90 mg, 0.70 mmol) was added, the reaction was carried out at room temperature for 12 h, water (10 mL) was added, and the Dichloromethane extraction (10 mL×3), combined organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=50/1), 26 mg of white viscous substance was obtained, the yield was 44%, and the purity was 94.77%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.05 (br.s, 1H), 8.13 (d, J =8.4 Hz, 2H), 7.97 (d, J =8.4 Hz, 2H), 7.16 ( d, J =8.1 Hz, 1H), 6.86 (s, 1H), 6.83 (d, J =8.2 Hz, 1H), 6.57 (t, J _FH =75.4 Hz, 1H), 4.55–4.61 (m, 1H) , 4.37–4.43 (m, 1H), 3.97–4.13 (m, 2H), 3.96 (s, 3H), 3.48 (t, J =10.9 Hz, 1H), 3.26–3.36 (m, 2H), 2.64–2.72 (m, 1H), 2.20 (s, 3H), 1.81–1.89 (m, 1H), 1.39 (d, J =6.0 Hz, 6H).

MS-ESI: m/z 505.30 [M+H] ⁺ .

Example 5: 4-(((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl ) carbamoyl) benzoic acid

Compound 4-((((2 R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)amino Methyl carboxyl)benzoate (20 mg, 0.039 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL), and lithium hydroxide monohydrate (8 mg, 0.19 mmol) was added, and the reaction was carried out at 50 °C It was stopped after 1.5 h, diluted hydrochloric acid (1M) was added to adjust the pH of the solution to 1, tetrahydrofuran was removed under reduced pressure, the residue was extracted with EtOAc (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 15 mg of light yellow solid , the yield is 77%, and the purity is 91.92%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.13 (d, J =8.2 Hz, 2H), 7.94 (d, J =8.1 Hz, 2H), 7.08 (d, J =8.2 Hz, 1H) ), 7.00 (s, 1H), 6.86–6.94 (m, 1H), 6.67 (t, J _FH =75.6 Hz, 1H), 4.50–4.56 (m, 1H), 4.36–4.44 (m, 1H), 4.05 –4.09 (m, 1H), 3.70–3.88 (m, 2H), 3.47 (t, J =10.9 Hz, 1H), 3.32–3.40 (m, 1H), 2.54–2.61 (m, 1H), 2.18 (s , 3H), 1.96–2.07 (m, 1H), 1.27 (d, J =6.0 Hz, 6H).

MS-ESI: m/z 491.05 [M+H] ⁺ .

Example 6: 4-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -yl)methyl)carbamoyl)methyl benzoate

Compound 1-(( 2R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) ethyl ketone (60 mg, 0.17 mmol), monomethyl terephthalate (45 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 113 mg, 0.59 mmol) and HOAT (46 mg, 0.36 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 °C, added DIPEA (131 mg, 1.01 mmol), and then returned to room temperature for 12 h , then added dichloromethane (15 mL), added water (10 mL), extracted with dichloromethane (10 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography ( Eluent: DCM/MeOH (v/v)=30/1) to obtain 58 mg of white solid, yield 66%, purity 92.69%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.05 (br.s, 1H), 8.13 (d, J =8.4 Hz, 2H), 7.97 (d, J =8.4 Hz, 2H), 7.16 ( d, J =8.1 Hz, 1H), 6.83 (s, 2H), 6.63 (t, J _FH =75.5 Hz, 1H), 4.37–4.43 (m, 1H), 3.97–4.04 (m, 2H), 3.96 ( s, 3H), 3.90 (d, J =6.9 Hz, 2H), 3.48 (t, J =10.9 Hz, 1H), 3.25–3.36 (m, 2H), 2.65–2.71 (m, 1H), 2.20 (s , 3H), 1.81–1.90 (m, 1H), 1.28–1.37 (m, 1H), 0.66–0.71 (m, 2H), 0.37–0.41 (m, 2H).

MS-ESI: m/z 517.30 [M+H] ⁺ .

Example 7: 4-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -yl)methyl)carbamoyl)benzoic acid

Compound 4-((((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-difluoromethoxy)phenyl)pyrrolidin-2-yl) Methyl)carbamoyl)benzoate (50 mg, 0.097 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL), and lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added , the reaction was stopped after 2 h at 50 °C, diluted hydrochloric acid (1 M) was added to adjust the pH of the solution to 1, THF was removed under reduced pressure, the residue was extracted with EtOAc (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, and removed under reduced pressure solvent to obtain 48 mg of white solid with a yield of 98% and a purity of 94.39%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.13 (d, J =8.3 Hz, 2H), 7.93 (d, J =8.3 Hz, 2 H), 7.08 (d, J =8.2 Hz, 1H), 6.98 (s, 1H), 6.89–6.91 (m, 1H), 6.72 (t, J _FH =75.6 Hz, 1H), 4.36–4.43 (m, 1H), 4.04–4.10 (m, 1H), 3.82–3.88 (m, 1H), 3.82 (d, J =6.9 Hz, 2H), 3.69–3.74 (m, 1H), 3.48 (t, J =10.8 Hz, 1H), 3.32–3.40 (m, 1H) , 2.54–2.61 (m, 1H), 2.17 (s, 3H), 1.96–2.05 (m, 1H), 1.31–1.35 (m, 1H), 0.59–0.63 (m, 2H), 0.31–0.35 (m, 2H).

MS-ESI: m/z 503.20 [M+H] ⁺ .

Example ^{8: N 1 - (((} 2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁴ - ethyl - N ⁴ - methyl terephthalamide Amides

Compound 4-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl)benzoic acid (40 mg, 0.08 mmol), N -ethylmethylamine (14 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (76 mg, 0.40 mmol) and HOAT (21 mg, 0.15 mmol) were dissolved in dichloromethane (5 mL), and after cooling to 0 °C, DIPEA (62 mg, 0.48 mmol) was added, Return to room temperature and continue the reaction for 12 h, add water (5 mL), stir, extract with dichloromethane (10 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and conduct silica gel column chromatography separation (eluting Reagent: DCM/MeOH (v/v)=25/1) to obtain 16 mg of white solid, yield 37%, purity 97.79%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.96 (br.s, 1H), 7.94 (d, J =7.4 Hz, 2H), 7.74 (d, J =7.4 Hz, 1H), 7.15 ( d, J =8.0 Hz, 1H), 6.83 (s, 2H), 6.62 (t, J _FH =75.6 Hz, 1H), 4.36–4.43 (m, 1H), 3.94–4.03 (m, 2H), 3.89 ( d, J =6.4 Hz, 2H), 3.55–3.65 (m, 1H), 3.47 (t, J =10.8 Hz, 1H), 3.22–3.35 (m, 3H), 3.09 (s, 2H), 2.92 (s , 1H), 2.62–2.70 (m, 1H), 2.18 (s, 3H), 1.77–1.90 (m, 1H), 1.22–1.35 (m, 1H), 1.22–1.31 (m, 3H), 0.65–0.70 (m, 2H), 0.35–0.40 (m, 2H).

MS-ESI: m/z 544.40 [M+H] ⁺ .

Example 9: 6-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -yl)methyl)carbamoyl))methyl nicotinate

Compound 1-(( 2R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) ethyl ketone (40 mg, 0.11 mmol), methyl 5-(methoxycarbonyl)-2-pyridinecarboxylate (30 mg, 0.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride (108 mg, 0.56 mmol) and HOAT (30 mg, 0.22 mmol) were dissolved in dichloromethane (5 mL), and after cooling to 0 °C, DIPEA (87 mg, 0.67 mmol) was added, Return to room temperature and continue the reaction for 10 h, add dichloromethane (15 mL), wash the organic phase with water (10 mL×3), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and conduct silica gel column chromatography separation (eluting Reagent: DCM/MeOH (v/v)=50/1) to obtain 40 mg of pale yellow solid, yield 68%, purity 98.29%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.24 (s, 1H), 9.17 (br.s, 1H), 8.46 (d, J =8.1 Hz, 1H), 8.27 (d, J =8.1 Hz, 1H), 7.11 (d, J =8.1 Hz, 1H), 6.80 (s, 2H), 6.61 (t, J _FH =75.6 Hz, 1H), 4.29–4.37 (m, 1H), 3.92–4.08 ( m, 2H), 4.00 (s, 3H), 3.84 (d, J =6.9 Hz, 2H), 3.60–3.67 (m, 1H), 3.44 (t, J =10.9 Hz, 1H), 3.23–3.32 (m , 1H), 2.57–2.64 (m, 1H), 2.18 (s, 3H), 1.92–2.03 (m, 1H), 1.27–1.34 (m, 1H), 0.62–0.67 (m, 2H), 0.31–0.38 (m, 2H).

MS-ESI: m/z 518.30 [M+H] ⁺ .

Example 10: 6-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -yl)methyl)carbamoyl))nicotinate hydrochloride

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl))methylnicotinate (36 mg, 0.070 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL), and lithium hydroxide monohydrate (14 mg, 0.33 mL) was added. mmol), the reaction was stopped after 2 h at 50 °C, diluted hydrochloric acid (1 M) was added to adjust the pH of the solution to 4, THF was removed under reduced pressure, the residue was extracted with EtOAc (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed. 35 mg of white solid was obtained with a yield of 97% and a purity of 97.13%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 9.22 (s, 1H), 8.52 (dd, J =8.1, 1.9 Hz, 1H), 8.20 (d, J =8.1 Hz, 1 H), 7.06 (d, J =8.2 Hz, 1H), 6.98 (s, 1H), 6.87–6.90 (m, 1H), 6.71 (t, J _FH =75.6 Hz, 1H), 4.34–4.40 (m, 1H), 4.02–4.06 (m, 1H), 3.91–3.95 (m, 1H), 3.82 (d, J =6.9 Hz, 2H), 3.69–3.74 (m, 1H), 3.47 (t, J =10.8 Hz, 1H) , 3.32–3.39 (m, 1H), 2.53–2.59 (m, 1H), 2.17 (s, 3H), 1.97–2.05 (m, 1H), 1.30–1.34 (m, 1H), 0.59–0.63 (m, 2H), 0.32–0.35 (m, 2H).

MS-ESI: m/z 504.20 [M-HCl +H] ⁺ .

Example ^{11: N 2 - (((} 2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-Amides

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl))nicotinic acid hydrochloride (30 mg, 0.06 mmol), N -ethylmethylamine (10 mg, 0.17 mmol), 1-ethyl-3-(3-dimethylamine) Aminopropyl)carbodiimide hydrochloride (57 mg, 0.30 mmol) and HOAT (16 mg, 0.12 mmol) were dissolved in dichloromethane (5 mL), and after cooling to 0 °C, DIPEA (46 mg, 0.12 mmol) was added. 0.36 mmol), reacted at room temperature for 6 h, added water (50 mL), stirred, extracted with dichloromethane (10 mL×3), dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent). : DCM/MeOH (v/v)=24/1) to obtain 18 mg of white solid, yield 55%, purity 98.84%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.11 (s, 1H), 8.67 (s, 1H), 8.23 (d, J =7.9 Hz, 1H), 7.89 (br.s, 1H), 7.11 (d, J =7.9 Hz, 1H), 6.81 (s, 2H), 6.60 (t, J _FH =75.6 Hz, 1H), 4.26–4.36 (m, 1H), 4.00–4.08 (m, 1H), 3.92–3.96 (m, 1H), 3.86 (d, J =6.8 Hz, 2H), 3.59–3.67 (m, 2H), 3.44 (t, J =10.7 Hz, 1H), 3.22–3.33 (m, 2H) , 3.12 (s, 1.7H), 2.97 (s, 1.3H), 2.57–2.63 (m, 1H), 2.18 (s, 3H), 1.92–2.01 (m, 1H), 1.22–1.30 (m, 4H) , 0.63–0.69 (m, 2H), 0.35–0.38 (m, 2H).

MS-ESI: m/z 545.30 [M+H] ⁺ .

Example 12: 6-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -yl)methyl)carbamoyl))methyl picolinate

Compound 1-(( 2R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) ethyl ketone (40 mg, 0.11 mmol), 2,6-pyridinedicarboxylate monomethyl ester (30 mg, 0.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide The hydrochloride salt (108 mg, 0.56 mmol) and HOAT (30 mg, 0.22 mmol) were dissolved in dichloromethane (5 mL), and after cooling to 0 °C, DIPEA (87 mg, 0.67 mmol) was added and returned to room temperature The reaction was continued at temperature for 7 h, dichloromethane (15 mL) was added, the organic phase was washed with water (10 mL×3), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=50/1) to obtain 34 mg of light brown solid, yield 58%, purity 97.59%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.00 (br.s, 1H), 8.38 (d, J =7.7 Hz, 1H), 8.25 (d, J =7.7 Hz, 1H), 8.03 ( t J =7.8 Hz, 1H), 7.09 (d, J =8.7 Hz, 1H), 6.80 (s, 2H), 6.60 (t, J _FH =75.6 Hz, 1H), 4.33–4.40 (m, 1H), 4.04 (s, 3H), 4.00–4.04 (m, 1H), 3.93–3.97 (m, 1H), 3.82 (d, J =6.9 Hz, 2H), 3.72–3.78 (m, 1H), 3.48 (t, J =10.8 Hz, 1H), 3.19–3.32 (m, 1H), 2.54–2.61 (m, 1H), 2.20 (s, 3H), 1.96–2.05 (m, 1H), 1.23–1.30 (m, 1H) , 0.63–0.67 (m, 2H), 0.33–0.36 (m, 2H).

MS-ESI: m/z 518.20 [M+H] ⁺ .

Example 13: 6-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -yl)methyl)carbamoyl))picolinate hydrochloride

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl))methyl picolinate (30 mg, 0.058 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL), and lithium hydroxide monohydrate (12 mg, 0.29 mL) was added. mmol), reacted at 50 °C for 1 h, cooled to room temperature, added dilute hydrochloric acid (1 M) to adjust the pH of the solution to 4, removed THF under reduced pressure, the residue was extracted with EtOAc (10 mL×2), and the organic phase was dried over anhydrous sodium sulfate , the solvent was removed under reduced pressure to obtain 29 mg of white solid with a yield of 92% and a purity of 97.01%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.35 (d, J =7.4 Hz, 2H), 8.19–8.23 (m, 1H), 7.03 (d, J =8.2 Hz, 1H), 6.94 (s, 1H), 6.85–6.88 (m, 1H), 6.69 (t, J _FH =75.7 Hz, 1H), 4.38–4.45 (m, 1H), 4.01–4.05 (m, 1H), 3.83–3.95 ( m, 2H), 3.79 (d, J =6.8 Hz, 2H), 3.44 (t, J =10.8 Hz, 1H), 3.32–3.39 (m, 1H), 2.52–2.59 (m, 1H), 2.29 (s , 0.5H), 2.17 (s, 2.5H), 2.01–2.09 (m, 1H), 1.20–1.26 (m, 1H), 0.59–0.62 (m, 2H), 0.30–0.35 (m, 2H).

MS-ESI: m/z 504.20 [M+H] ⁺ .

Example ^{14: N 2 - (((} 2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁶ - ethyl - N ⁶ - methyl 2,6-dimethyl Amides

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl))picolinate hydrochloride (30 mg, 0.06 mmol) was dissolved in dry THF (4 mL), CDI (39 mg, 0.24 mmol) was added, and reacted at 60 °C for 1 h, N -ethylmethylamine (14 mg, 0.24 mmol) was added, the reaction was continued for 6 h, water (15 mL) was added, stirred, extracted with EtOAc (5 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the Silica gel column chromatography (eluent: DCM/MeOH (v/v)=30/1) gave 14 mg of pale yellow solid, yield 43%, purity 98.99%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.22–8.25 (m, 1H), 7.95–7.99 (m, 1H), 7.71–7.79 (m, 1H), 7.09–7.12 (m, 1H) , 6.79 (s, 2H), 6.60 (t, J _FH =75.6 Hz, 1H), 4.27–4.35 (m, 1H), 3.90–4.03 (m, 2H), 3.83–3.86 (m, 2H), 3.62– 3.72 (m, 2H), 3.35–3.44 (m, 2H), 3.20–3.30 (m, 1H), 3.16 (s, 1.5H), 3.011 (s, 1.5H), 2.52–2.60 (m, 1H), 2.14 (s, 3H), 1.94–2.05 (m, 1H), 1.20 (t, J =7.1 Hz, 3H), 1.13–1.17 (m, 1H), 0.62–0.67 (m, 2H), 0.33–0.38 ( m, 2H).

MS-ESI: m/z 545.20 [M+H] ⁺ .

Example 15: N -((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- yl)methyl)-2-ethoxybenzamide

Dissolve 2-ethoxybenzoic acid (46 mg, 0.28 mmol) in dry tetrahydrofuran (4 mL), add CDI (49 mg, 0.30 mmol), react at room temperature for 1 h, add 1-((2 R ) -2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (60 mg, 0.17 mmol ), reacted at 60 °C for 6 h, cooled to room temperature, added water (15 mL), the organic phase was extracted with EtOAc (15 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column Chromatographic separation (eluent: DCM/MeOH (v/v)=30/1) gave 35 mg of light brown solid, yield 41%, purity 94.40%.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.60 (br.s, 1H), 7.38 (t, J =7.7 Hz, 1H), 7.09 (d, J =7.1 Hz, 1H), 7.02 ( t, J =7.3 Hz, 1H), 6.93 (d, J =8.2 Hz, 1H), 6.74 (s, 1H), 6.73 (d, J =8.4 Hz, 1H), 6.59 (t, J _FH =75.6 Hz , 1H), 4.50–4.54 (m, 1H), 4.10–4.14 (m, 2H), 3.84–3.90 (m, 1H), 3.85 (d, J =6.9 Hz, 2H), 3.56–3.65 (m, 1H) ), 3.34–3.47 (m, 2H), 3.15–3.23 (m, 1H), 2.63–2.70 (m, 1H), 2.03 (s, 3H), 1.81–1.87 (m, 1H), 1.43 (t, J =6.9 Hz, 3H), 1.29–1.36 (m, 1H), 0.65–0.68 (m, 2H), 0.35–0.37 (m, 2H).

MS-ESI: m/z 503.25 [M+H] ⁺ .

Example 16: N -((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- yl)methyl)-2-ethoxy-3-fluorobenzamide

Compound 1-(( 2R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) ethyl ketone (50 mg, 0.14 mmol), 2-ethoxy-3-fluorobenzoic acid (41 mg, 0.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (105 mg, 0.55 mmol) and HOAT (29 mg, 0.21 mmol) were dissolved in dichloromethane (10 mL), cooled to 0 °C, added DIPEA (85 mg, 0.66 mmol), and returned to room temperature The reaction was continued for 8 h, dichloromethane (15 mL) was added, the organic phase was washed with water (20 mL×2), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=30/1) to obtain 53 mg of light brown solid, yield 72%, purity 93.25%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.64 (br.s, 1H), 7.08–7.18 (m, 4H), 6.73–6.78 (m, 2H), 6.59 (t, J _FH =75.6 Hz, 1H), 4.48–4.55 (m, 1H), 4.17–4.32 (m, 2H), 3.82–3.91 (m, 1H), 3.86 (d, J =6.9 Hz, 2H), 3.53–3.64 (m, 1H), 3.37–3.47 (m, 2H), 3.15–3.25 (m, 1H), 2.65–2.70 (m, 1H), 2.03 (s, 3H), 1.81–1.94 (m, 1H), 1.37 (t, J =6.9 Hz, 3H), 1.29–1.36 (m, 1H), 0.64–0.69 (m, 2H), 0.35–0.38 (m, 2H).

MS-ESI: m/z 521.30 [M+H] ⁺ .

Example ^{17: N 2 - (((} 2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁵ - isopropyl - N ⁵ - methyl-pyridine-2,5-Amides

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl))nicotinate hydrochloride (60 mg, 0.12 mmol), N -isopropylmethylamine (43 mg, 0.59 mmol), 1-ethyl-3-(3-di Methylaminopropyl)carbodiimide hydrochloride (114 mg, 0.59 mmol) and HOAT (32 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 °C, and DIPEA (77 mg) was added , 0.60 mmol), reacted at room temperature for 12 h, added water (30 mL), extracted with dichloromethane (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: DCM /MeOH(v/v)=66/1), 42 mg of white solid was obtained, the yield was 63%, and the purity was 98.25%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.10 (br.s, 1H), 8.62 (s, 1H), 8.21 (d, J =7.9 Hz, 1H), 7.80–7.87 (m, 1H) ), 7.09 (d, J =7.9 Hz, 1H), 6.79 (s, 1H), 6.76 (d, J =8.2 Hz, 1H), 6.58 (t, J _FH =75.6 Hz, 1H), 4.88–5.00 ( m, 0.4H), 4.26–4.33 (m, 1H), 3.97–4.06 (m, 1H), 3.90–3.94 (m, 1H), 3.80–3.87 (m, 0.6H), 3.84 (d, J =6.8 Hz, 2H), 3.55–3.65 (m, 1H), 3.42 (t, J =10.8 Hz, 1H), 3.20–3.29 (m, 1H), 2.97 (s, 1.8H), 2.79 (s, 1.2H) , 2.53–2.61 (m, 1H), 2.16 (s, 3H), 1.90–2.02 (m, 1H), 1.27–1.34 (m, 1H), 1.16–1.24 (m, 6H), 0.62–0.66 (m, 2H), 0.33–0.36 (m, 2H).

MS-ESI: m/z 559.20 [M+H] ⁺ .

Example ^{18: N 2 - (((} 2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁵ - (4- fluorophenyl) - N ⁵ - methyl-pyridine-2,5-Amides

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl))nicotinic acid hydrochloride (60 mg, 0.12 mmol), 4-fluoro- N -methylaniline (74 mg, 0.59 mmol), 1-ethyl-3-(3- Dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.59 mmol) and HOAT (32 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 °C, and added DIPEA (78 mg, 0.60 mmol), reacted at room temperature for 12 h, added water (30 mL), extracted with dichloromethane (10 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography ( Eluent: EtOAc (v)=100%) to give 48 mg of white solid, yield 66%, purity 96.39%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.99 (br.s, 1H), 8.50 (s, 1H), 7.99 (d, J =7.8 Hz, 1H), 7.68 (d, J =7.4 Hz, 1H), 6.92–7.09 (m, 5H), 6.77 (s, 1H), 6.76 (d, J =8.2 Hz, 1H), 6.58 (t, J _FH =75.6 Hz, 1H), 4.20–4.27 ( m, 1H), 3.86–3.99 (m, 2H), 3.83 (d, J =6.8 Hz, 2H), 3.49–3.56 (m, 1H), 3.48 (s, 3H), 3.38 (t, J =10.7 Hz , 1H), 3.17–3.27 (m, 1H), 2.51–2.58 (m, 1H), 2.13 (s, 3H), 1.86–1.94 (m, 1H), 1.23–1.32 (m, 1H), 0.60–0.65 (m, 2H), 0.32–0.35 (m, 2H).

MS-ESI: m/z 611.15 [M+H] ⁺ .

Example ^{19: N 2 - (((} 2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁵ - (2- (dimethylamino) ethyl) - N ⁵ - methyl-pyridine-2,5-Amides

Compound 6-((((2R)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl) methyl) carbamoyl acyl)) nicotinic acid hydrochloride (60 mg, 0.12 mmol), N 1, N 1, N 2 - trimethylethylenediamine (60 mg, 0.60 mmol), 1- ethyl - 3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.59 mmol) and HOAT (32 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 °C , added DIPEA (77 mg, 0.60 mmol), reacted at room temperature for 12 h, added water (30 mL), extracted with dichloromethane (10 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and carried out Separation by silica gel column chromatography (eluent: DCM/MeOH (v/v)=18/1) gave 42 mg of white solid with a yield of 60% and a purity of 97.07%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.08 (br.s, 1H), 8.67 (s, 1H), 8.20 (d, J =8.0 Hz, 1H), 7.87–7.94 (m, 1H) ), 7.09 (d, J =8.0 Hz, 1H), 6.78 (s, 1H), 6.77 (d, J =5.4 Hz, 1H), 6.58 (t, J _FH =73.2 Hz, 1H), 4.26–4.34 ( m, 1H), 3.98–4.04 (m, 1H), 3.89–3.93 (m, 1H), 3.84 (d, J =6.9 Hz, 2H), 3.66–3.74 (m, 1H), 3.57–3.65 (m, 1H), 3.41 (t, J =10.8 Hz, 1H), 3.19–3.34 (m, 2H), 3.01–3.10 (m, 3H), 2.61–2.70 (m, 1H), 2.54–2.61 (m, 1H) , 2.37 (s, 3H), 2.15 (s, 3H), 1.90–2.07 (m, 2H), 2.04 (s, 3H), 1.23–1.34 (m, 1H), 0.61–0.66 (m, 2H), 0.32 –0.36 (m, 2H).

MS-ESI: m/z 588.50 [M+H] ⁺ .

Example ^{20: N 2 - (((} 2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁵ - methyl - N ⁵ - (2,2,2- trifluoro-ethyl) pyridine-2,5-Amides

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl))nicotinic acid hydrochloride (60 mg, 0.12 mmol), N -methyl-2,2,2-trifluoroethylamine hydrochloride (71 mg, 0.47 mmol) and HOAT (33 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol) and DIPEA (142 mg, 1.10 mmol), react at room temperature for 4 h, add water (30 mL), extract the aqueous phase with dichloromethane (10 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and reduce the pressure. Concentrated, and the concentrated solution was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=54/1) to obtain 32 mg of white solid with a yield of 44% and a purity of 97.31%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.66 (br.s, 1H), 7.91 (s, 2H), 7.33 (s, 1H), 7.09 (d, J =8.2 Hz, 1H), 6.75 (d, J =7.4 Hz, 1H), 6.76 (s, 1H), 6.58 (t, J _FH =75.6 Hz, 1H), 4.49–4.53 (m, 1H), 4.16–4.29 (m, 1H), 4.02–4.05 (m, 2H), 3.84–3.91 (m, 1H), 3.85 (d, J =6.8 Hz, 2H), 3.72 (t, J =11.6 Hz, 1H), 3.43–3.49 (m, 1H) , 3.10–3.23 (m, 4H), 2.57–2.63 (m, 1H), 2.01 (s, 3H), 1.86–1.95 (m, 1H), 1.25–1.36 (m, 1H), 0.62–0.66 (m, 2H), 0.33–0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 599.10 [M+H] ⁺ .

Example ^{21: N 2 - (((} 2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁵ - (cyanomethyl) - N ⁵ - methyl-pyridine-2,5-Amides

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl))nicotinic hydrochloride (80 mg, 0.16 mmol), 2-(methylamino)acetonitrile hydrochloride (71 mg, 0.84 mmol) and HOAT (43 mg, 0.32 mmol) Dissolve in dichloromethane (10 mL), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (155 mg, 0.81 mmol) and DIPEA (186 mg) in an ice bath , 1.44 mmol), reacted at room temperature for 15 h, added water (30 mL), the aqueous phase was extracted with dichloromethane (10 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to silica gel column Chromatographic separation (eluent: DCM/MeOH (v/v)=54/1) gave 18 mg of white solid, yield 20%, purity 93.44%.

MS (ESI, pos.ion) m/z: 556.40 [M+H] ⁺ .

Example ^{22: N 2 - (((} 2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁵ - (2- amino-2-oxoethyl) - N ⁵ - methyl-pyridine-2,5-Amides

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl))nicotinic hydrochloride (60 mg, 0.12 mmol), 2-(methylamino)acetamide hydrochloride (50 mg, 0.40 mmol) and HOAT (33 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol) and DIPEA ( 146 mg, 1.13 mmol), react at room temperature for 3 h, cool to room temperature, add water (30 mL) and stir, extract the aqueous phase with dichloromethane (10 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, reduce It was concentrated under pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=30/1) to obtain 34 mg of white solid with a yield of 49% and a purity of 93.49%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.16 (br.s, 1H), 8.74 (s, 1H), 8.24 (d, J =7.5 Hz, 1H), 7.96 (d, J =7.4 Hz, 1H), 7.09 (d, J =8.0 Hz, 1H), 6.79 (s, 1H), 6.77 (d, J =3.9 Hz, 1H), 6.59 (t, J _FH =75.6 Hz, 1H), 4.25 –4.34 (m, 1H), 4.15–4.24 (m, 1H), 3.90–3.94 (m, 1H), 3.84 (d, J =6.9 Hz, 2H), 3.55–3.62 (m, 1H), 3.42 (t , J =10.8 Hz, 1H), 3.22–3.29 (m, 1H), 3.11 (m, 3H), 2.55–2.62 (m, 1H), 2.15 (s, 3H), 1.89–1.98 (m, 1H), 1.62–1.67 (m, 2H), 1.25–1.33 (m, 1H), 0.62–0.66 (m, 2H), 0.32–0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 574.05 [M+H] ⁺ .

Example 23: 4-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -yl)methyl)amino)o-methoxybenzamide

Step 1: Synthesis of methyl o-methoxybenzoate

To compound methyl salicylate (1.02 g, 6.68 mmol) was added anhydrous DMF (10 mL), stirred at room temperature until completely dissolved, then added potassium carbonate (2.79 g, 19.98 mmol) and iodomethane (2.86 g, 20.1 mmol), heated to 60 °C, stirred for 2 h, stopped the reaction, concentrated, added water (15 mL), extracted with EtOAc (20 mL×3), dried over anhydrous Na ₂ SO ₄ , concentrated, and separated by silica gel column chromatography (eluent). PE/EtOAc (v/v)=19:1) to obtain 1.12 g of yellow oil, yield 100.51%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.84-7.78 (m, 1H), 7.52-7.46 (m, 1H), 7.03-6.96 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H).

MS-ESI: m/z 167.20 [M+H] ⁺ .

Step 2: Synthesis of o-methoxybenzoic acid

To the compound methyl o-methoxybenzoate (1.11 g, 6.68 mmol) was added THF (12 mL) and water (10 mL), and lithium hydroxide monohydrate (0.86 g, 20.45 mmol) was added at room temperature, and the Warm stirring for 3 h to stop the reaction, add dilute hydrochloric acid (1M) under ice bath, adjust pH to 5-6, concentrate, add water (10 mL), extract with EtOAc (15 mL×3), dry over anhydrous Na ₂ SO ₄ , concentrated, and separated by silica gel column chromatography (gradient elution, eluent DCM/MeOH (v/v)=1/0 to 19/1 to 18/1 to 17/1) to obtain 153.6 mg of light cyan solid, which was collected The rate is 15.12%.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 7.89-7.82 (m, 1H), 7.60-7.52 (m, 1H), 7.16 (d, J =8.1 Hz, 1H), 7.04 (t , J =8.1 Hz, 1H), 3.93 (s, 3H).

MS-ESI: m/z 153.20 [M+H] ⁺ .

Step 3: 4-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of base)methyl)amino)o-methoxybenzamide

To the compound o-methoxybenzoic acid (73.9 mg, 0.49 mmol) was added anhydrous THF (8 mL), stirred at room temperature until dissolved, and then added carbodiimidazole (86.5 mg, 0.52 mmol), stirred at room temperature for 1 h, Add 1-(( 2R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) ethyl ketone (93.2 mg, 0.26 mmol), heated to 60 °C, stirred for 5 h, stopped the reaction, concentrated, added water (15 mL), extracted with EtOAc (30 mL×3), dried over anhydrous Na ₂ SO ₄ , concentrated, silica gel Column chromatography separation (eluent PE/EtOAc (v/v)=1:3) gave 91.1 mg of light brown oil, yield 70.9%, purity 91.93%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.24-8.14 (m, 1H), 7.53-7.42 (m, 1H), 7.12 (s, 4H), 7.05-6.96 (m, 1H), 6.60 (t, J _FH =75.5 Hz, 1H), 4.00 (s, 3H), 3.98–3.87 (m, 3H), 3.86-3.76 (m, 3H), 3.46-3.34 (m, 1H), 2.16 (s , 2H), 2.12–1.96 (m, 2H), 1.38–1.18 (m, 4H), 0.70–0.55 (m, 2H), 0.40–0.28 (m, 2H).

MS-ESI: m/z 489.25 [M+H] ⁺ .

Example 24: 4-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -yl)methyl)amino)o-methylaminobenzamide

Step 1: Synthesis of methyl o-methylaminobenzoate

Anhydrous DMF (10 mL) was added to the compound anthranilate methyl ester (1.03 g, 6.81 mmol), stirred at room temperature until completely dissolved, potassium carbonate (2.94 g, 21.08 mmol) and iodomethane (0.87 g, 6.1 mmol) were added. ), heated to 60 °C, stirred for 6 h, stopped the reaction, concentrated, added water (15 mL), extracted with EtOAc (20 mL×3), dried over anhydrous Na ₂ SO ₄ , concentrated, and separated by silica gel column chromatography (eluent PE ) to obtain 483 mg of bright yellow oil, yield 43%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.96-7.88 (m, 1H), 7.45-7.35 (m, 1H), 6.72-6.56 (m, 2H), 3.87 (s, 3H), 2.98-2.87 (m, 3H).

MS-ESI: m/z 166.25 [M+H] ⁺ .

Step 2: Synthesis of o-methylaminobenzoic acid

To compound o-methylaminobenzoic acid methyl ester (247.1 mg, 1.50 mmol) were added THF (4 mL) and water (4 mL), then potassium hydroxide (142 mg, 2.53 mmol) was added, heated to 60 °C and stirred for 22 h , stop the reaction, add dilute hydrochloric acid (1 M) under ice bath to adjust pH to 2-3, concentrate, add water (10 mL), extract with EtOAc (15 mL×3), dry over anhydrous Na ₂ SO ₄ , and concentrate to obtain a white solid 213.1 mg, yield 94.24%.

¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 7.94-7.82 (m, 1H), 7.45-7.32 (m, 1H), 6.77-6.66 (m, 1H), 6.62-6.51 (m, 1H), 2.90 (s, 3H).

MS-ESI: m/z 152.20 [M+H] ⁺ .

Step 3: 4-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of base) methyl) amino) o-methylaminobenzamide

To the compound o-methylaminobenzoic acid (72.1 mg, 0.48 mmol) was added anhydrous THF (8 mL), stirred at room temperature until completely dissolved, then added carbodiimidazole (86.9 mg, 0.53 mmol), stirred at room temperature for 2 h, Then 1-(( 2R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl was added ) ethyl ketone (106.6 mg, 0.30 mmol), heated to 60 °C, stirred for 6 h, stopped the reaction, concentrated, added water (15 mL), extracted with EtOAc (30 mL×3), dried over anhydrous Na ₂ SO ₄ , concentrated, silica gel Column chromatography separation (eluent PE: EtOAc (v/v)=1:3) gave 59.3 mg of light brown oil, yield 40.4%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.54-7.48 (m, 1H), 7.37–7.30 (m, 1H), 7.17–7.12 (m, 1H), 6.85–6.80 (m, 2H) ), 6.69–6.64(m, 2H), 6.63 (t, J _FH =75.5 Hz, 1H), 4.42–4.32 (m, 1H), 4.00–3.92 (m, 2H), 3.90–3.86 (m, 2H) , 3.50–3.40 (m, 1H), 3.38–3.22 (m, 2H), 2.88(s, 3H), 2.70–2.60 (m, 1H), 2.18 (s, 3H), 2.08–1.98 (m, 2H) , 0.95–0.85 (m, 2H), 0.72–0.64 (m, 2H), 0.43–0.34 (m, 2H).

MS-ESI: m/z 488.25 [M+H] ⁺ .

Example 25: 1-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -yl)methyl)carbamoyl)pyridine-4-carboxylic acid

Step 1: 1-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Methyl)methyl)carbamoyl)pyridine-4-carboxylate

Compound 1-(( 2R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) ethyl ketone (100 mg, 0.28 mmol) was dissolved in dry tetrahydrofuran (10 mL), DIPEA (44 mg, 0.34 mmol) and phenyl 4-nitrochloroformate (62 mg, 0.31 mmol) were added, and the reaction was carried out at room temperature 1.5 h, methyl pyridine-4-carboxylate (47 mg, 0.32 mmol) was added, the reaction was carried out at room temperature for 14 h, water (10 mL) was added, extracted with EtOAc (5 mL×3), and the organic phase was dried over anhydrous sodium sulfate , concentrated, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=30/1) to obtain 132 mg of white solid with a yield of 49%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14 (d, J =8.7 Hz, 1H), 7.10 (d, J =5.6 Hz, 1H), 6.81 (s, 2H), 6.62 (t, J _FH =75.5 Hz, 1H), 4.24–4.30 (m, 1H), 3.91–3.99 (m, 3H), 3.89 (d, J =7.0 Hz, 2H), 3.70–3.75 (m, 1H), 3.70 ( s, 3H), 3.42 (t, J =11.0 Hz, 1H), 3.13–3.28 (m, 2H), 2.85–2.92 (m, 2H), 2.58–2.64 (m, 1H), 2.46–2.51 (m, 1H), 2.15 (s, 3H), 1.92–1.94 (m, 2H), 1.66–1.81 (m, 3H), 1.26–1.34 (m, 1H), 0.65–0.70 (m, 2H), 0.37–0.40 ( m, 2H).

MS (ESI, pos.ion) m/z: 524.20 [M+H] ⁺ .

Step 2: 1-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- yl)methyl)carbamoyl)pyridine-4-carboxylic acid

Compound 1-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl)pyridine-4-carboxylic acid methyl ester (130 mg, 0.25 mmol) was dissolved in a mixed solvent of THF (3 mL) and water (2 mL), and then lithium hydroxide monohydrate ( 52 mg, 1.24 mmol), the reaction was stopped after 1.5 h at 50 °C, dilute hydrochloric acid (1 M) was added to adjust the pH of the solution to 1, THF was removed under reduced pressure, the residue was extracted with dichloromethane (10 mL×3), and the organic phase was washed with anhydrous It was dried over sodium sulfate, and the solvent was removed to obtain 126 mg of a white solid with a yield of 99% and a purity of 96.66%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.11 (d, J =8.2 Hz, 1H), 7.02–7.03 (m, 1 H), 6.90–6.92 (m, 1H), 6.74 (t , J _FH =75.7 Hz, 1H), 4.59–4.68 (m, 2H), 4.22–4.29 (m, 1H), 4.02–4.06 (m, 1H), 3.93–3.98 (m, 2H), 3.93 (d, J =6.8 Hz, 2H), 3.54–3.59 (m, 1H), 3.41–3.48 (m, 1H), 2.92–2.98 (m, 2H), 2.48–2.64 (m, 2H), 2.21 (s, 0.8H ), 2.15 (s, 2.2H), 1.89–1.94 (m, 3H), 1.54–1.63 (m, 2H), 1.29–1.37 (m, 1H), 0.63–0.67 (m, 2H), 0.37–0.41 ( m, 2H).

MS-ESI: m/z 510.20 [M+H] ⁺ .

Example ^{26: N 1 - (((} 2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁴ - ethyl - N ⁴ - methyl-piperidine-1,4-dicarboxylic Amides

Compound 1-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)carbamoyl)pyridine-4-carboxylic acid (90 mg, 0.18 mmol), N -ethylmethylamine (68 mg, 1.15 mmol), 1-ethyl-3-(3-dimethylamine) Aminopropyl)carbodiimide hydrochloride (170 mg, 0.89 mmol) and HOAT (48 mg, 0.35 mmol) were dissolved in dichloromethane (5 mL), and after cooling to 0 °C, DIPEA (114 mg, 0.35 mmol) was added. 0.88 mmol), reacted at room temperature for 5.5 h, added water (20 mL), extracted with dichloromethane (5 mL×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=20/1) to obtain 71 mg of white viscous substance, yield 73%, purity 98.69%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.13 (d, J =8.0 Hz, 1H), 7.07 (br.s, 1H), 6.81 (s, 2H), 6.62 (t, J _FH = 75.6 Hz, 1H), 4.25–4.32 (m, 1H), 4.05–4.12 (m, 2H), 3.88–3.94 (m, 1H), 3.89 (d, J =6.9 Hz, 2H), 3.67–3.75 (m , 1H), 3.36–3.45 (m, 3H), 3.14–3.28 (m, 2H), 3.04 (s, 1.5H), 2.92 (s, 1.5H), 2.77–2.87 (m, 2H), 2.57–2.69 (m, 2H), 2.14 (s, 3H), 1.68–1.82 (m, 5H), 1.26–1.34 (m, 1H), 1.22 (t, J =6.6 Hz, 1.5H), 1.10 (t, J = 6.6 Hz, 1.5H), 0.63–0.70 (m, 2H), 0.34–0.41 (m, 2H).

MS-ESI: m/z 551.10 [M+H] ⁺ .

Example 27: 1-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- yl)methyl)-3-(1-hydroxy-1,3-dihydrobenzo[ c ][1,2]oxaboran-5-yl)urea

Compound 2-hydroxymethyl-5-aminophenylboronic acid half ester (47 mg, 0.32 mmol) was dissolved in dry tetrahydrofuran (5 mL), DIPEA (44 mg, 0.34 mmol) and 4-nitrochloroformate benzene were added Ester (62 mg, 0.31 mmol), react at room temperature for 3.5 h, add 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(bis) Fluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (100 mg, 0.28 mmol), react at room temperature for 5.5 h, add water (10 mL), extract with EtOAc (5 mL×3), the organic phase It was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=30/1) to obtain 43 mg of white solid, yield 28%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.58–7.69 (m, 2H), 7.05–7.14 (m, 3H), 6.93 (d, J =6.4 Hz, 1H), 6.74 (t, J _FH =75.6 Hz, 1H), 5.06 (s, 2H), 4.25–4.33 (m, 1H), 4.04–4.08 (m, 1H), 3.89 (d, J =6.7 Hz, 2H), 3.65–3.70 ( m, 1H), 3.43–3.56 (m, 2H), 3.29–3.40 (m, 1H), 2.51–2.59 (m, 1H), 2.14 (s, 3H), 2.00–2.10 (m, 1H), 1.23– 1.34 (m, 1H), 0.57–0.62 (m, 2H), 0.30–0.34 (m, 2H).

MS (ESI, pos.ion) m/z: 530.30 [M+H] ⁺ .

Example 28: 1-Hydroxy-1,3-dihydrobenzo[ c ][1,2]oxaboran-5-yl((( 2R )-1-acetyl-4-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamate

Compound 2-hydroxymethyl-5-hydroxybenzeneboronic acid half ester (47 mg, 0.31 mmol) was dissolved in dry tetrahydrofuran (5 mL), DIPEA (44 mg, 0.34 mmol) and 4-nitrochloroformate benzene were added Ester (62 mg, 0.31 mmol), react at room temperature for 3 h, add 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(bis) Fluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (100 mg, 0.28 mmol), react at room temperature for 5 h, add water (10 mL), extract with EtOAc (5 mL×3), the organic phase It was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v)=40/1) to obtain 28 mg of white solid, yield 18%, and purity 99.05%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.57–7.73 (m, 2H), 7.05–7.14 (m, 3H), 6.93 (d, J =6.4 Hz, 1H), 6.74 (t, J _FH =75.6 Hz, 1H), 5.06 (s, 2H), 4.25–4.33 (m, 1H), 4.03–4.08 (m, 1H), 3.89 (d, J =6.7 Hz, 2H), 3.66–3.71 ( m, 1H), 3.44–3.56 (m, 2H), 3.33–3.40 (m, 1H), 2.53–2.58 (m, 1H), 2.14–2.23 (m, 3H), 1.99–2.11 (m, 1H), 1.22–1.31 (m, 1H), 0.57–0.62 (m, 2H), 0.30–0.34 (m, 2H).

MS (ESI, pos.ion) m/z: 531.30 [M+H] ⁺ .

Example 37: N -((( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- yl)methyl)-2-ethoxybenzamide

Step 1: Compound ( S) -1-tert-butyl 2-methyl 4-((trifluoromethyl)sulfonyl)oxy- 1H -pyrrole-1,2( 2H , 5H )-di Synthesis of Carboxylic Acid Esters

Compound ( 2S )-1-tert-butyloxycarbonyl-4-oxoproline methyl ester (7.75 g, 31.9 mmol) and N , N -diisopropylethylamine (15.0 mL, 88.9 mmol) were dissolved In dichloromethane (50 mL), a dichloromethane solution (20 mL) of trifluoromethanesulfonic anhydride (10.5 mL, 59.3 mmol) was added dropwise at -15 °C, and the mixture was stirred at room temperature for 2 h. Dichloromethane (100 mL) was added to dilute, the organic phase was washed with saturated brine (100 mL × 3), adjusted to pH = 1 with hydrochloric acid (2 mol/L), and washed with saturated sodium bicarbonate solution (100 mL), Dry over anhydrous sodium sulfate, and concentrate the solution under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: 60-90 petroleum ether/ethyl acetate (v/v) = 10/1)) to obtain a yellow liquid (11.1 g, yield 93%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 5.79–5.66 (m, 1H), 5.09–4.97 (m, 1H), 4.44–4.33 (m, 1H), 4.33–4.22 (m, 1H) , 3.76 (s, 3H), 1.47 (s, 4H), 1.42 (s, 5H).

MS-ESI: m/z 320.40 [M-55] ⁺ .

Step 2: Compound ( S) -1-tert-Butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1 Synthesis of H -pyrrole-1,2( 2H , 5H)-dicarboxylate

Compound ( S) -1-tert-butyl 2-methyl 4-((trifluoromethyl)sulfonyl)oxy- 1H -pyrrole-1,2(2H,5H)-dicarboxylate ( 11.0 g, 29.3 mmol), pinacol diboronate (8.92 g, 35.1 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium dichloromethane complex (1.23 g, 1.47 mmol) and potassium acetate (3.47 g, 35.4 mmol) were dissolved in anhydrous 1,4-dioxane (95 mL), and stirred at 100 °C for 3 h under nitrogen protection. Concentrated under reduced pressure, added ethyl acetate (200 mL), washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: 60-90 petroleum Ether/ethyl acetate (v/v) = 4/1) gave a yellow clear liquid (10.0 g, 97% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.37–6.24 (m, 1H), 5.14 – 4.94 (m, 1H), 4.36 – 4.22 (m, 2H), 3.70 (d, J = 4.7 Hz , 3H), 1.44 (s, 5H), 1.39 (s, 4H), 1.24 (s, 12H).

MS-ESI: m/z 216.10 [M-137] ⁺ .

Step 3: Compound (S) - 1- tert-butyl-2-methyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -1 H - pyrrole -1 Synthesis of ,2( 2H , 5H)-dicarboxylate

The compound (S) - 1- tert-butyl-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H - Pyrrole-1,2( 2H , 5H )-dicarboxylate (8.51 g, 21.7 mmol), 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-iodobenzene (8.40 g, 24.7 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium dichloromethane complex (850 mg, 1.02 mmol) and potassium phosphate (13.0 g, 61.2 mmol) It was dissolved in anhydrous 1,4-dioxane (80 mL) and stirred at 100 °C for 3 h under nitrogen protection. Concentrated under reduced pressure, added ethyl acetate (200 mL), washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: 60-90 petroleum Ether/ethyl acetate (v/v) = 8/1) gave a yellow liquid (8.23 g, 86% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.13 (d, J = 8.2 Hz, 1H), 6.99 – 6.86 (m, 2H), 6.62 (t, J = 75.4 Hz, 1H), 6.04 – 5.97 (m, 1H), 5.19 – 5.08 (m, 1H), 4.66 – 4.43 (m, 2H), 3.89 – 3.84 (m, 2H), 3.75 (s, 3H), 1.51 (s, 3H), 1.44 ( s, 6H), 1.28 – 1.24 (m, 1H), 0.70 – 0.60 (m, 2H), 0.39 – 0.31 (m, 2H).

MS-ESI: m/z 384.10 [M- t- Bu+2H] ⁺ .

Step 4: Compound ( 2S) -1-tert-Butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrole-1,2 - Synthesis of dicarboxylates

The compound (S) - 1- tert-butyl-2-methyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -1 H - pyrrole-1,2 ( 2H , 5H )-dicarboxylate (3.72 g, 8.47 mmol) and 10% palladium on carbon (405 mg) were added to methanol (250 mL), and stirred for 12 h under a hydrogen atmosphere. The solid was filtered off through celite and concentrated under reduced pressure to give a yellow liquid (3.49 g, 93% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.09 (d, J = 8.0 Hz, 1H), 6.83 – 6.75 (m, 2H), 6.59 (t, J = 75.6 Hz, 1H), 4.42 – 4.26 (m, 1H), 4.07 – 3.89 (m, 1H), 3.88 – 3.81 (m, 2H), 3.79 – 3.67 (m, 3H), 3.46 – 3.37 (m, 1H), 3.37 – 3.24 (m, 1H) ), 2.71 – 2.57 (m, 1H), 2.09 – 1.92 (m, 1H), 1.46 (s, 3H), 1.42 (s, 6H), 1.31 – 1.21 (m, 1H), 0.68 – 0.59 (m, 2H) ), 0.39 – 0.29 (m, 2H).

MS-ESI: m/z 386.50 [M- t- Bu+2H] ⁺ .

Step 5: Compound ( 2S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxymethylpyrrolidine-1-carboxylate Synthesis of acid esters

The compound ( 2S) -1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-1,2- Dicarboxylate (1.70 g, 3.85 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), a solution of lithium borohydride (140 mg, 5.78 mmol) was added in portions, and the mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure, saturated brine (20 mL) was added to the residue, the aqueous phase was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was subjected to silica gel extraction. Column chromatography separation (eluent: 60-90 petroleum ether/ethyl acetate (v/v) = 2/1) gave a colorless transparent liquid (1.10 g, yield 69%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.09 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 2H), 6.58 (t, J = 76.5 Hz, 1H) , 5.16 (s, 1H), 4.15 – 3.99 (m, 1H), 3.94 (s, 1H), 3.85 (d, J = 6.9 Hz, 2H), 3.80 – 3.72 (m, 1H), 3.73 – 3.60 (m , 1H), 3.29 – 3.10 (m, 2H), 2.47 – 2.29 (m, 1H), 1.72 – 1.55 (m, 1H), 1.47 (s, 9H), 1.27 – 1.20 (m, 1H), 0.67 – 0.55 (m, 2H), 0.35 – 0.26 (m, 2H).

MS-ESI: m/z 358.10 [M- ^t Bu+2H] ⁺ .

Step 6: Compound ( 2S )-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1 -Synthesis of carboxylate

The compound ( 2S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxymethylpyrrolidine-1-carboxylate (1.11 g, 2.68 mmol) and triethylamine (750 uL, 5.35 mmol) were dissolved in ethyl acetate (20 mL), and a solution of methanesulfonic acid chloride in ethyl acetate (7.3 mL, 3.48 mL) was slowly added dropwise at 0 °C. mmol, 0.48 mol/L) solution, stirred at room temperature for 3 h. The solid was filtered off, washed with ethyl acetate (10 mL), and the solvent was removed under reduced pressure to give a yellow liquid ( 2S )-2-methanesulfonyloxymethyl-1-tert-butyloxycarbonyl-4-(3 -(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine (1.31 g, 99% yield).

The compound ( 2S )-2-methanesulfonyloxymethyl-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene yl)-pyrrolidine (1.19 g, 2.42 mmol) and sodium azide (490 mg, 7.31 mmol) were dissolved in anhydrous N , N -dimethylformamide (12 mL) and stirred at 80 °C for 3 h. N , N -dimethylformamide was removed under reduced pressure, diluted with ethyl acetate (50 mL), the organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was Silica gel column chromatography was performed (eluent: 60-90 petroleum ether/ethyl acetate (v/v) = 8/1) to obtain a yellow liquid (1.05 g, yield 99%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.11 (d, J = 7.9 Hz, 1H), 6.86 – 6.80 (m, 2H), 6.60 (t, J = 75.7 Hz, 1H), 4.17 – 3.93 (m, 3H), 3.87 (d, J = 6.4 Hz, 2H), 3.50 – 3.30 (m, 1H), 3.29 – 3.12 (m, 2H), 2.52 – 2.31 (m, 1H), 2.10 – 1.95 ( m, 1H), 1.48 (s, 9H), 1.35 – 1.23 (m, 1H), 0.67 – 0.55 (m, 2H), 0.35 – 0.26 (m, 2H).

MS-ESI: m/z 383.20 [M- t- Bu+2H] ⁺ .

Step 7: Synthesis of Compound (2S )-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (11162-4)

The compound ( 2S )-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-1- Carboxylic acid ester (1.03 g, 2.35 mmol) was dissolved in DCM (7 mL), injected into a solution of hydrogen chloride in dioxane (10.0 mL, 40.0 mmol, 4 mol/L), and stirred at room temperature for 3 h. The solvent was removed under reduced pressure to give a brown viscous liquid (889 mg, 99% yield).

MS-ESI: m/z 339.20 [M-HCl+H] ⁺ .

Step 8: Compound 1-(( 2S )-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1 Synthesis of -yl) ethyl ketone

Compound ( 2S )-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (880 mg, 2.35 mmol), triethylamine (992 uL, 7.05 mmol) was dissolved in dichloromethane (23 mL), and acetyl chloride (251 uL, 3.52 mmol) was slowly added dropwise at 0 °C, and stirred at room temperature for 3 h. Saturated brine (20 mL) was added, the aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent). : dichloromethane/methanol (v/v) = 70/1) to give a yellow viscous liquid (702 mg, 79% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.12 (d, J = 7.9 Hz, 1H), 6.88 – 6.79 (m, 2H), 6.60 (t, J = 75.6 Hz, 1H), 4.32 – 4.23 (m, 1H), 4.16 – 4.08 (m, 1H), 3.92 – 3.84 (m, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.46 – 3.34 (m, 2H), 3.31 – 3.20 ( m, 1H), 2.48 – 2.37 (m, 1H), 2.16 – 2.06 (m, 1H), 2.09 (s, 3H), 1.30 – 1.24 (m, 1H), 0.67 – 0.55 (m, 2H), 0.35 – 0.26 (m, 2H).

MS-ESI: m/z 381.20 [M+H] ⁺ .

Step 9: Compound 1-(( 2S )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) Synthesis of ethyl ketone hydrochloride

Compound 1-(( 2S )-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) ethyl ketone (399 mg, 1.05 mmol), triphenylphosphine (3413 mg, 1.58 mmol) was dissolved in tetrahydrofuran/water (8 mL, (v/v) = 3/1 ), placed at 50 °C and stirred for 3 h. The tetrahydrofuran was removed under reduced pressure, saturated brine (10 mL) was added, the aqueous phase was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography Separation (eluent: dichloromethane/methanol (v/v) = 8/1) to obtain a yellow viscous liquid, add hydrogen chloride in dioxane solution (1 mL, 4 mol/L), stir well, remove the solvent under reduced pressure A yellow viscous liquid was obtained (119 mg, 29% yield).

MS-ESI: m/z 355.15 [M-HCl+H] ⁺ .

Step 10: Compound N -((( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2 Synthesis of -yl)methyl)-2-ethoxybenzamide

Compound 1-(( 2S )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethyl Ketone hydrochloride (40 mg, 0.10 mmol), o-ethoxybenzoic acid (18 uL, 0.12 mmol) and N -hydroxy-7-azabenzotriazole (29 mg, 0.21 mmol) were dissolved in two Chloromethane (5 mL), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59 mg, 0.31 mmol) and N , N -diiso Propylethylamine (67 uL, 0.41 mmol), stirred at room temperature for 5 h. Saturated brine (20 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v) = 50/1) to give a yellow liquid (19 mg, 37% yield).

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.45 (t, J = 5.6 Hz, 1H), 8.15 (dd, J = 7.8, 1.7 Hz, 1H), 7.46 – 7.37 (m, 1H), 7.09 – 7.01 (m, 2H), 6.95 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 1.6 Hz, 1H), 6.76 – 6.72 (m, 1H), 6.56 (t, J = 75.7 Hz , 1H), 4.32 – 4.15 (m, 3H), 4.03 – 3.91 (m, 1H), 3.91 – 3.81 (m, 2H), 3.77 (q, J = 6.1 Hz, 2H), 3.36 (t, J = 10.8 Hz, 1H), 3.26 – 3.15 (m, 1H), 2.55 – 2.48 (m, 1H), 2.22 (s, 0.7H), 2.10 (s, 2.3H), 2.06 (td, J = 12.6, 9.6 Hz, 1H), 1.48 (t, J = 7.0 Hz, 3H), 1.26 – 1.22 (m, 1H), 0.67 – 0.55 (m, 2H), 0.35 – 0.26 (m, 2H).

MS-ESI: m/z 503.20 [M+H] ⁺ .

Example 38: Synthesis of ^{N 2 - (((2 S} ) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidin - 2- yl) methyl) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-Amides

Step 1: Compound 6-(((( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 Synthesis of Methyl -yl)methyl)carbamoyl)nicotinate

Compound 1-(( 2S )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethyl ketone hydrochloride (105 mg, 0.27 mmol, see Example 37, step 9), 2,5-pyridinedicarboxylate-5-methyl ester (56 mg, 0.30 mmol) and N -hydroxy-7-azabenzene Triazole (70 mg, 0.51 mmol) was dissolved in dichloromethane (10 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added in an ice bath (148 mg, 0.77 mmol) and N , N -diisopropylethylamine (169 uL, 1.02 mmol), stirred at room temperature for 5 h. Saturated brine (20 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v) = 70/1) to give a red liquid (75 mg, 54% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.19 – 9.08 (m, 1H), 8.43 (dd, J = 8.1, 2.0 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.58 – 7.42 (m, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.82 – 6.74 (m, 2H), 6.58 (t, J = 75.6 Hz, 1H), 4.35 – 4.25 (m, 1H) , 4.08 – 4.00 (m, 1H), 3.97 (s, 3H), 3.95 – 3.88 (m, 1H), 3.82 (d, J = 6.9 Hz, 2H), 3.68 – 3.57 (m, 1H), 3.42 (t , J = 10.8 Hz, 1H), 3.31 – 3.19 (m, 1H), 2.78 – 2.52 (m, 1H), 2.16 (s, 3H), 2.04 – 1.89 (m, 1H), 1.31 – 1.21 (m, 1H) ), 0.67 – 0.55 (m, 2H), 0.35 – 0.26 (m, 2H).

MS-ESI: m/z 518.35 [M+H] ⁺ .

Step 2: Compound 6-(((( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 Synthesis of -yl)methyl)aminocarbamoyl)nicotinic acid

Compound 6-(((( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)aminocarbamoyl)nicotinic acid methyl ester (70 mg, 0.14 mmol), lithium hydroxide monohydrate (11 mg, 0.26 mmol) in tetrahydrofuran/water (6 mL, (v/v) = 5 /1), stirred at room temperature for 3 h. The tetrahydrofuran was removed under reduced pressure, ethyl acetate (50 mL) was added to the residue to dilute, pH=1 was adjusted with hydrochloric acid (2 mol/L), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, reduced The solvent was removed under pressure to give a white solid (68 mg, 99% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.77 (s, 1H), 9.50 (s, 1H), 8.48 (d, J = 7.5 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.57 – 7.42 (m, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.84 – 6.77 (m, 2H), 6.61 (t, J = 75.5 Hz, 1H), 4.56 – 4.46 (m , 1H), 4.05 – 3.95 (m, 2H), 3.88 (d, J = 6.8 Hz, 2H), 3.55 – 3.41 (m, 2H), 3.31 (s, 1H), 2.76 – 2.61 (m, 1H), 2.37 (s, 3H), 1.95 – 1.81 (m, 1H), 1.34 – 1.22 (m, 1H), 0.67 – 0.55 (m, 2H), 0.35 – 0.26 (m, 2H).

MS-ESI: m/z 504.20 [M+H] ⁺ .

Step 3: Compound ^{N 2 - (((2 S} ) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidin - yl) methyl) - N ⁵ - ethyl - N ⁵ - synthesis of 2,5-lutidine Amides of

Compound 6-(((( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl )methyl)aminocarbamoyl)nicotinic acid (60 mg, 0.12 mmol), N -methylethylamine (20 uL, 0.23 mmol) and N -hydroxy-7-azabenzotriazole (32 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added in an ice bath. N , N -diisopropylethylamine (78 uL, 0.42 mmol) was stirred at room temperature for 5 h. Saturated brine (20 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v) = 20/1) to give a yellow liquid (20 mg, 31% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.08 (s, 1H), 8.64 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.86 (t, J = 7.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.81 – 6.75 (m, 2H), 6.58 (t, J = 75.5 Hz, 1H), 4.33 – 4.23 (m, 1H), 4.06 – 3.97 (m , 1H), 3.91 (t, J = 10.3, 7.0 Hz, 1H), 3.83 (d, J = 6.9 Hz, 2H), 3.65 – 3.55 (m, 2H), 3.41 (t, J = 10.8 Hz, 1H) , 3.31 – 3.19 (m, 2H), 3.09 (s, 1.6H), 2.94 (s, 1.4H), 2.62 – 2.52 (m, 1H), 2.15 (s, 3H), 2.01 – 1.90 (m, 1H) , 1.25 (t, J = 6.2 Hz, 1.5H), 1.27 – 1.21 (m, 1H), 1.15 (t, J = 6.2 Hz, 1.5H), 0.67 – 0.55 (m, 2H), 0.35 – 0.26 (m , 2H).

MS-ESI: m/z 545.20 [M+H] ⁺ .

Embodiment 39 ^{cases: N 2 - (((2} R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrole 2-yl) methyl) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-Amides

Step 1: Compound 2-(3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-di Synthesis of Oxaborane

Compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (11.0 g, 29.43 mmol), pinacol biboronate (8.96 g, 35.3 mmol), acetic acid potassium (8.6 g, 87.6 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride dichloromethane complex _{(Pd (dppf) Cl 2 .CH} 2 Cl 2) ( 2.40 g, 2.94 mmol) was dissolved in dry N , N -dimethylformamide (80 mL) solution, and reacted at 100 °C for 2 h under nitrogen protection. mL of ethyl acetate, washed with saturated brine (50 ml × 2), combined the organic phases, dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v ) = 10/1) to obtain a green liquid product (10.01 g, 99.97% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.39 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.67 (t, J = 75.6 Hz, 1H), 3.91 (d, J = 7.0 Hz, 2H), 1.34 (s, 12H), 1.26 – 1.32 (m, 1H), 0.69 – 0.61 (m, 2H), 0.40 – 0.32 (m , 2H).

MS-ESI: m/z 341.15 [M+H] ⁺ .

Step 2 :( R) -1- tert-butyl 2-methyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -1 H - pyrrole-1, Synthesis of 2( 2H , 5H)-dicarboxylate

The compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa dioxaborolane (5 g, 14.7 mmol), (R) -1- tert-butyl 2-methyl 4 - (((trifluoromethyl) sulfonyl acyl) oxy) -1 H - pyrrole-1, 2-( 2H , 5H )-dicarboxylate (5.00 g, 13.3 mmol, Intermediate M), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex (Pd(dppf)Cl ₂ .CH ₂ Cl ₂ ) (550 mg, 0.67 mmol), potassium phosphate (K ₃ PO ₄ ) (7.60 g, 35.8 mmol ), dissolved in toluene (50 mL) solution, Under nitrogen protection, the reaction was stirred in an oil bath at 50 °C for 8 h. After the reaction solution was filtered through celite, the filter cake was washed with ethyl acetate solution (50 ml), and the organic phase was washed with saturated brine (50 ml×2). The organic phases were combined and dried with anhydrous sodium sulfate for 30 min. It was concentrated under pressure and purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give a pale yellow viscous liquid (4.60 g, yield 78.60%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14 (d, J = 8.2 Hz, 1H), 6.97 – 6.90 (m, 2H), 6.63 (t, J = 75.4 Hz, 1H), 6.05 – 5.98 (m, 1H), 5.21 – 5.09 (m, 1H), 4.67 – 4.45 (m, 2H), 3.88 (dd, J = 11.6, 6.9 Hz, 2H), 3.76 (d, J = 4.3 Hz, 3H) , 1.52 (s, 3H), 1.46 (s, 6H), 1.33 – 1.25 (m, 1H), 0.69 – 0.63 (m, 2H), 0.34 – 0.39 (m, 2H).

MS-ESI: m/z 384.10 [M-55] ⁺ .

Step 3: ( 2R , 4S )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1 , Synthesis of 2-dicarboxylate

The compound (R) -1- tert-butyl 2-methyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -1 H - pyrrole-1, 2 - ( 2H , 5H )-dicarboxylate (4.60 g, 10.5 mmol), dissolved in methanol solution (70 mL), then added 10% Pd/C reducing agent (140 mg), replaced with hydrogen three times , the reaction was stirred for 3 h under hydrogen protection and room temperature, the reaction solution was filtered with celite, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to obtain light yellow Viscous liquid product (4.60 g, 99.50 % yield). Synthetic reference: Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2. J. Med. Chem. 2014, 57, 9042 - 9064 .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J = 8.0 Hz, 1H), 6.81 – 6.78 (m, 2H), 6.60 (t, J = 76.4 Hz, 1H), 4.44 – 4.26 (m, 1H), 4.07 – 3.90 (m, 1H), 3.90 – 3.82 (m, 2H), 3.76 (d, J = 6.5 Hz, 3H), 3.47 – 3.37 (m, 1H), 3.38 – 3.25 ( m, 1H), 2.68 – 2.58 (m, 1H), 2.10 – 1.95 (m, 1H), 1.45 (d, J = 14.1 Hz, 9H), 1.24 – 1.31 (m, 1H), 0.71 – 0.59 (m, 2H), 0.41 – 0.29 (m, 2H).

MS-ESI: m/z 386.10 [M-55] ⁺ :

Step 4: ( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1- Synthesis of tert-butyl formate

The compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1, 2-Dicarboxylate (1.90 g, 4.301 mmol) was dissolved in dry tetrahydrofuran (15 mL) solution, lithium borohydride (332 mg, 15.6 mmol) was added under ice bath conditions, and the starting materials were transferred to room temperature for reaction 1 h. Saturated aqueous sodium chloride solution (30 mL) was added, extracted with ethyl acetate (30 ml×2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless liquid (1.80 g, 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J = 8.7 Hz, 1H), 6.84 – 6.78 (m, 2H), 6.59 (t, J _FH = 75.6 Hz, 1H), 5.19 (d, J = 8.7 Hz, 1H), 4.10 – 4.02 (m, 1H), 4.00 – 3.91 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.82 – 3.71 (m, 1H), 3.70 – 3.65 (m, 1H), 3.27 – 3.17 (m, 2H), 2.44 – 2.33 (m, 1H), 1.68 – 1.58 (m, 1H), 1.48 (s, 9H), 1.34 – 1.24 (m, 1H) ), 0.67 – 0.62 (m, 2H), 0.37 – 0.33 (m, 2H).

MS-ESI: m/z 358.55 [M-55] ⁺ .

Step 5: Compound ( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy Synthesis of tert-butyl)methyl)pyrrolidine-1-carboxylate

The compound ( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-Butyl acid (1.8 g, 4.40 mmol) was dissolved in dichloromethane (20 mL), triethylamine (880 mg, 8.70 mmol) was added, methanesulfonic acid chloride (702 mg, 6.13 mmol) was added in an ice bath, The reaction was carried out at room temperature for 3.5 h, water (30 mL) was added to stop the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane (30 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pale yellow liquid (2.1 g, 98% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.12 (d, J = 8.7 Hz, 1H), 6.85 – 6.81 (m, 2H), 6.62 (t, J _FH = 75.7 Hz, 1H), 4.72 – 4.64 (m, 0.5H), 4.50 – 4.32 (m, 1.5H), 4.25 – 3.13 (m, 1H), 4.00 – 3.93 (m, 0.5H), 3.89 (d, J = 6.9 Hz, 2H), 3.82 – 3.75 (m, 0.5H), 3.34 – 3.15 (m, 2H), 3.05 – 3.03 (m, 3H), 2.60 – 2.30 (m, 1H), 2.21 – 2.04 (m, 1H), 1.50 (s, 9H), 1.35 – 1.24 (m, 1H), 0.68 – 0.64 (m, 2H), 0.40 – 0.35 (m, 2H).

MS-ESI: m/z 436.10[M- t- Bu+2H] ⁺ . ^.

Step 6: Compound ( 2R , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- Synthesis of tert-butyl 1-carboxylate

Compound (2 R ,4 S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methane (base) pyrrolidine-1-carboxylate tert-butyl ester (2.1 g, 4.30 mmol) was dissolved in DMF (11 mL), sodium azide (1.1 g, 17.0 mmol) was added, the reaction was heated at 80 °C for 3.5 h, and cooled to room temperature Warm, add water (30 mL), extract with ethyl acetate (10 mL×3), dry the organic phase with anhydrous Na ₂ SO ₄ , concentrate, and conduct silica gel column separation (eluent: PE/EtOAc (v/v) = 8 /1) A colorless liquid (1.6 g, 88% yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.11 (d, J = 7.9 Hz, 1H), 6.88 – 6.79 (m, 2H), 6.60 (t, J _FH = 75.7 Hz, 1H), 4.14 – 3.97 (m, 3H), 3.87 (d, J = 6.4 Hz, 2H), 3.44 – 3.33 (m, 1H), 3.26 – 3.16 (m, 2H), 2.50 – 2.32 (m, 1H), 2.06 – 1.98 (m, 1H), 1.48 (s, 9H), 1.33 – 1.22 (m, 1H), 0.67 – 0.62 (m, 2H), 0.38 – 0.34 (m, 2H).

MS-ESI: m/z 383.60 [M-55] ⁺ .

Step 7: Compound ( 2R , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine salt Synthesis of acid salts

Compound ( 2R , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1- tert-Butyl carboxylate (1.66 g, 3.79 mmol) was dissolved in dichloromethane (20 mL) solution, added 3 mol/L HCl in 1,4-dioxane solution (6 mL), stirred at room temperature for 2 h , concentrated under reduced pressure to give a colorless liquid (1.40 g, 99% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.15 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.94 (dd, J = 8.2, 1.9 Hz) , 1H), 6.76 (t, J = 75.5 Hz, 1H), 4.01 – 3.98 (m, 1H), 3.96 (d, J = 6.9 Hz, 2H), 3.94 – 3.91 (m, 1H), 3.81 – 3.78 ( m, 1H), 3.76 – 3.73 (m, 1H), 3.65 – 3.59 (m, 1H), 3.28 (t, J = 11.2 Hz, 1H), 2.57 – 2.53 (m, 1H), 1.99 – 1.94 (m, 1H), 1.34 – 1.29 (m, 1H), 0.67 – 0.64 (m, 2H), 0.41 – 0.38 (m, 2H).

MS-ESI: m/z 339.15 [M-HCl+H] ⁺ .

Step 8: Compound 1-(( 2R , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Synthesis of Pyrrolidin-1-yl)ethanone

Compound ( 2R , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (1.42 g, 3.79 mmol) was dissolved in dichloromethane (20 mL), cooled in an ice bath, and added with N , N -diisopropylethylamine (1.9 g, 15.0 mmol) and acetyl chloride (653 mg, 8.32 mmol), the reaction was stopped after stirring at room temperature for 1.5 h, water (20 mL) was added and stirred for 2 min, the organic phase was separated, the organic phase was dried with anhydrous Na ₂ SO ₄ , and the concentrated solution was separated by silica gel column chromatography (eluent: PE /EtOAc (v/v)=1/1) to give a light brown liquid (1.29 g, 90% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.13 (d, J = 8.1 Hz, 1H), 6.85 (s, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.61 (t, J = 75.6 Hz, 1H), 4.31 – 4.25 (m, 1H), 4.13 (dd, J = 12.4, 4.7 Hz, 1H), 3.93 – 3.85 (m, 1H), 3.89 (d, J = 6.9 Hz, 2H) ), 3.45 – 3.36 (m, 2H), 3.30 – 3.21 (m, 1H), 2.46 – 2.39 (m, 1H), 2.15 – 2.06 (m, 1H), 2.10 (s, 3H), 1.34 – 1.24 (m , 1H), 0.68 – 0.64 (m, 2H), 0.38 – 0.35 (m, 2H).

MS-ESI: m/z 381.20 [M+H] ⁺ .

Step 9: Compound 1-(( 2R , 4S )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrole Synthesis of Alk-1-yl)ethanone hydrochloride

Compound 1-(( 2R , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine -1-yl)ethanone (1.2 g, 3.20 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) were dissolved in a mixed solvent of tetrahydrofuran/water (v/v= 3/1, 40 mL) at 50 °C The reaction was carried out for 1 h, concentrated under reduced pressure, extracted with ethyl acetate (15 mL × 3), the organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: DCM/MeOH ( v/v)=10/1) to obtain light brown liquid, add HCl in 1,4-dioxane solution (2 mL, 4 mol/L), adjust pH=1, and concentrate under reduced pressure to obtain light yellow solid (1.14 g, 92% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.12 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H) ), 6.75 (t, J _FH = 75.7 Hz, 1H), 4.31 – 4.24 (m, 1H), 4.10 – 4.06 (m, 1H), 3.95 (d, J = 6.9 Hz, 2H), 3.56 (d, J = 10.8 Hz, 1H), 3.46 – 3.37 (m, 1H), 3.29 – 3.19 (m, 2H), 2.64 – 2.57 (m, 1H), 2.18 (s, 3H), 1.98 – 1.90 (m, 1H), 1.35 – 1.27 (m, 1H), 0.67 – 0.63 (m, 2H), 0.41 – 0.37 (m, 2H).

MS-ESI: m/z 355.10 [M-HCl+H] ⁺ .

Step ^{10: N 2 - (((} 2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine 2-yl) methyl) - N ⁵ - ethyl - N ⁵ - synthesis of 2,5-lutidine Amides of

Compound 1-(( 2R , 4S )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 1-yl)ethanone hydrochloride (660 mg, 1.69 mmol), 5-(ethyl(methyl)carbamoyl)picolinic acid (452 mg, 2.17 mmol) and 1-hydroxybenzotriazole (342 mg, 2.53 mmol) was dissolved in dry N , N -dimethylformamide (15 ml) solution, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) was added (649 mg, 3.39 mmol), after cooling at 0 °C, N -methylmorpholine (553 mg, 5.47 mmol) was added, and the reaction was stirred at room temperature for 4 h. Water (150 mL) was added to stop the reaction, the organic phase was extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH (v/v) = 23 /1) to give a white solid (632 mg, 69% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.11 (s, 1H), 6.87 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.89 (br.s, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.81 (s, 2H), 6.60 (t, J _FH = 75.6 Hz, 1H), 4.26 – 4.36 (m, 1H), 4.00 – 4.08 (m, 1H), 3.92 – 3.96 (m, 1H), 3.86 (d, J = 6.8 Hz, 2H), 3.59 – 3.67 (m, 2H), 3.44 (t, J = 10.7 Hz, 1H), 3.23 – 3.33 (m, 2H) , 3.12 (s, 1.7H), 2.97 (s, 1.3H), 2.57 – 2.63 (m, 1H), 2.18 (s, 3H), 1.92 – 2.01 (m, 1H), 1.13 – 1.36 (m, 4H) , 0.63 – 0.69 (m, 2H), 0.35 – 0.38 (m, 2H).

MS-ESI: m/z 545.20 [M+H] ⁺ .

Embodiment 40 ^{cases: N 2 - (((2} R, 4 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrole 2-yl) methyl) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-Amides

Step 1: Compound ( R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)-2,5-dihydro- Synthesis of 1 H -pyrrole-1-carboxylate tert-butyl ester

The compound (R) -1- tert-butyl 2-methyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -1 H - pyrrole-1,2 ( 2H , 5H )-dicarboxylate (4.6 g, 10.0 mmol, Example 39, step 2) was dissolved in 50 mL of anhydrous tetrahydrofuran solution, and lithium borohydride (507 mg, 13.4 mmol) was added under ice bath conditions. ), reacted at room temperature for 3 h, the raw materials reacted completely, and the reaction was stopped. An ice-water mixture was added to quench the reaction, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: PE/EtOAc (v/v) = 5/1) to give a white foamy solid (3.78 g, 88% yield,).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.13 (d, J = 8.2 Hz, 1H), 6.93 – 7.00 (m, 1.25H), 6.87 – 6.89 (m, 0.75H), 6.63 (t , J = 75.4 Hz, 1H), 6.03 (s, 0.3H), 5.93 (s, 0.7H), 4.89 (s, 0.8H), 4.74 (s, 0.2H), 4.59 – 4.66 (m, 1H), 4.40 – 4.52 (m, 2H), 3.89 (d, J = 6.9 Hz, 2H), 3.81 – 3.86 (m, 1H), 3.73 – 3.79 (m, 0.3H), 3.64 – 3.68 (m, 0.7H), 1.53 (s, 9H), 1.29 – 1.32 (m, 1H), 0.63 – 0.68 (m, 2H), 0.35 – 0.38 (m, 2H).

MS-ESI: m/z 356.20 [M-55] ⁺ .

Step 2: Compound ( 2R , 4R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1 -Synthesis of tert-butyl carboxylate

Compound ( R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)-2,5-dihydro- 1H - tert-butyl pyrrole-1-carboxylate (2.2 g, 5.3 mmol), hexafluorophosphate (tricyclohexylphosphine) (1,5-cyclooctadiene) (pyridine) iridium (Crabtrees catalyst) (0.66 g, 0.80 mmol) was dissolved in 90 mL of anhydrous dichloromethane solution and reacted at room temperature for 72 h under 0.5 Mpa hydrogen atmosphere. The reaction of the raw materials was complete and the reaction was stopped. 300 mL of saturated brine was added, extracted with dichloromethane (50 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: PE/EtOAc (v/v) = 10/1) gave a yellow liquid (1.75 g, 76% yield). Synthetic reference: Azacyclic FTY720 Analogues that Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in Vivo. ACS Chem. Biol. 2016, 11, 2, 409-414 .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.09 (d, J = 7.9 Hz, 1H), 6.76 – 6.81 (m, 1.75H), 6.75 (s, 0.5H), 6.59 (t, J = 75.7 Hz, 0.75H), 4.15 – 4.23 (m, 1H), 3.85 (d, J = 6.9 Hz, 2H), 3.70 – 3.75 (m, 3H), 3.30 – 3.46 (m, 2H), 2.08 – 2.16 ( m, 1H), 1.96 – 2.03 (m, 1H), 1.47 (s, 9H), 1.27 – 1.30 (m, 1H), 0.61 – 0.66 (m, 2H), 0.32 – 0.36 (m, 2H).

MS-ESI: m/z 358.20 [M-55] ⁺ .

Step 3: Compound ( 2R , 4R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl) Synthesis of tert-butyl oxy)methyl)pyrrolidine-1-carboxylate

Compound (2 R , 4 R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate Acid tert-butyl ester (1.7 g, 3.9 mmol) was dissolved in 30 mL of anhydrous dichloromethane solution, under ice bath condition, added methylsulfonyl chloride (MsCl) (1.8 mL, 13.0 mmol), and reacted at room temperature for 2 h , the reaction of the raw materials is complete, and the reaction is stopped. The reaction was quenched by adding ice-water mixture, extracted with dichloromethane (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: PE/EtOAc (v/v) = 5/1) to give a pale yellow oil (1.95 g, 98% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J = 7.9 Hz, 1H), 6.77 – 6.79 (m, 2H), 6.59 (t, J = 75.7 Hz, 1H), 4.30 – 4.37 (m, 1H), 4.17 – 4.26 (m, 1H), 3.86 (d, J = 6.6 Hz, 2H), 3.74 – 3.79 (m, 1H), 3.40 – 3.50 (m, 1H), 3.14 – 3.08 ( m, 2H), 3.03 (s, 3H), 2.29 – 2.38 (m, 1H), 2.14 – 2.19 (m, 1H), 1.49 (s, 4H), 1.46 (s, 5H), 1.27 – 1.34 (m, 1H), 0.62 – 0.66 (m, 2H), 0.33 – 0.37 (m, 2H).

MS-ESI: m/z 436.10 [M- t- Bu+2H] ⁺ .

Step 4: Compound ( 2R , 4R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- Synthesis of tert-butyl 1-carboxylate

Compound (2 R , 4 R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy )methyl)pyrrolidine-1-carboxylate tert-butyl ester (1.8 g, 3.7 mmol), sodium azide (716 mg, 11.0 mmol) was dissolved in 15 mL of N , N -dimethylformamide solution, The reaction was heated at 80 °C for 4 h, the reaction of the starting materials was complete, and the reaction was stopped. 100 mL of water was added, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: PE/EtOAc (v/v) = 5/ 1) A colorless oil (1.3 g, 81% yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.10 (d, J = 7.9 Hz, 1H), 6.77 – 6.79 (m, 2H), 6.59 (t, J = 75.7 Hz, 1H), 4.08 – 4.16 (m, 0.6H), 3.98 – 4.05 (m, 0.4H), 3.86 (d, J = 6.2 Hz, 2H), 3.76 – 3.81 (m, 1H), 3.64 – 3.71 (m, 0.5H), 3.47 – 3.59 (m , 1H), 3.38 – 3.46 (m, 2H), 3.27 – 3.32 (m, 0.5H), 2.17 – 2.27 (m, 1H), 2.07 – 2.15 (m, 1H), 1.50 (s, 4H), 1.47 ( s, 5H), 1.26 – 1.32 (m, 1H), 0.62 – 0.67 (m, 2H), 0.33 – 0.37 (m, 2H).

MS-ESI: m/z 383.40 [M-55] ⁺ .

Step 5: Compound ( 2R , 4R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine salt Synthesis of acid salts

Compound (2 R , 4 R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1- Carboxylic acid tert-butyl ester (1.3 g, 2.9 mmol) was dissolved in 30 mL of dichloromethane solution, then hydrochloric acid 1,4-dioxane solution (5 mL) was added, and the reaction was carried out at room temperature for 1 h. The reaction of the raw materials was completed and stopped. reaction. The solvent was removed by distillation under reduced pressure, and the concentrated solution gave a yellow liquid (1.1 g, yield 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.07 (d, J = 8.0 Hz, 1H), 6.84 (s, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.57 (t, J = 75.5 Hz, 1H), 4.02 – 4.11 (m, 1H), 3.94 – 3.99 (m, 1H), 3.85 (d, J = 6.9 Hz, 2H), 3.78 – 3.82 (m, 1H), 3.65 (s , 3H), 3.25 – 3.36 (m, 1H), 2.22 – 2.24 (m, 2H), 1.22 – 1.29 (m, 1H), 0.58 – 0.62 (m, 2H), 0.30 – 0.34 (m, 2H).

MS-ESI: m/z 339.10 [M-HCl+H] ⁺ .

Step 6: Compound 1-(( 2R , 4R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Synthesis of Pyrrolidin-1-yl)ethanone

(2 R , 4 R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride ( 4.6 g, 10.0 mmol) was dissolved in 20 mL of dichloromethane solution, and under ice bath conditions, triethylamine (0.8 mL, 6.0 mmol), acetyl chloride (0.1 mL, 3 mmol) were added, and the reaction was carried out at room temperature for 1 h , the reaction of the raw materials is complete, and the reaction is stopped. Saturated brine was added to quench the reaction, extracted with dichloromethane (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: PE/EA (v/v) = 2/1) to give a yellow liquid (1.04 g, 93% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.12 (d, J = 7.9 Hz, 1H), 6.78 – 6.80 (m, 2H), 6.60 (t, J = 75.6 Hz, 1H), 4.38 – 4.41 (m, 1H), 3.89 – 3.94 (m, 1H), 3.87 (d, J = 6.9 Hz, 2H), 3.76 (dd, J = 12.3, 6.0 Hz, 1H), 3.63 – 3.72 (m, 1H) , 3.47 (dd, J = 12.2, 2.8 Hz, 1H), 3.40 (t, J = 9.8 Hz, 1H), 2.22 – 2.27 (m, 1H), 2.13 – 2.18 (m, 1H), 2.07 (s, 3H) ), 1.29 – 1.35 (m, 1H), 0.63 – 0.68 (m, 2H), 0.34 – 0.38 (m, 2H).

MS-ESI: m/z 380.90 [M+H] ⁺ .

Step 7: Compound 1-(( 2R , 4R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrole Synthesis of Alkyl-1-yl)ethanone

Compound 1-((2 R , 4 R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine yl-1-yl)ethanone (1.0 g, 2.63 mmol) was dissolved in a mixed solvent of 30 mL of tetrahydrofuran and 10 mL of water, then triphenylphosphine (1.04 g, 4.0 mmol) was added, and the reaction was carried out at 50 °C for 2 h, The reaction of the raw materials was completed, and the reaction was stopped. 30 mL of saturated brine was added, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: DCM/MeOH (v/v) = 20/1) gave a light brown sticky substance (0.89 g, 95% yield).

MS-ESI: m/z 355.10 [M+H] ⁺ .

Step 8: Compound 1-(( 2R , 4R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrole Synthesis of Alk-1-yl)ethanone hydrochloride

Compound 1-((2 R , 4 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidinyl -1-yl)ethanone (0.88 g, 2.5 mmol) was dissolved in 30 mL of dichloromethane solution, then hydrochloric acid 1,4-dioxane solution (2 mL) was added, and the reaction was carried out at room temperature for 1 h, and the reaction of the raw materials was complete. , stop the reaction. The solvent was removed by distillation under reduced pressure, and the concentrated solution gave a tan solid (0.95 g, yield 98%).

Step 9: Compound N ² -((((2 R , 4 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) pyrrolidin-2-yl) methyl) - N ⁵ - ethyl - N ⁵ - methyl-2, 5 - synthesis of Amides of dimethyl

Compound 1-(( 2R , 4R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 1-yl)ethanone hydrochloride (950 mg, 2.43 mmol), 5-(ethyl(methyl)carbamoyl)picolinic acid (603 mg, 2.89 mmol) and 1-hydroxy-7-azobenzene Triazole (1.12 g, 7.82 mmol) was dissolved in dichloromethane (40 mL) solution, cooled in an ice bath, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiidene Amine hydrochloride (1.56 g, 7.72 mmol) and N , N -diisopropylethylamine (1.8 mL, 10.0 mmol) were reacted at room temperature for 1 h, the raw materials reacted completely, the reaction was stopped, and saturated brine (100 mmol) was added. mL), extracted with dichloromethane (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) for separation and purification , a dark red solid (900 mg, 68% yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.76 (s, 1H), 8.64 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.87 (br.s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.49 (d, J = 9.5 Hz, 1H), 6.59 (t, J = 75.6 Hz, 1H), 4.49 – 4.54 (m, 1H) ), 3.90 – 3.95 (m, 1H), 3.86 (d, J = 6.8 Hz, 2H), 3.76 – 3.82 (m, 1H), 3.55 – 3.72 (m, 4H), 3.42 (t, J = 9.9 Hz, 1H), 3.10 (s, 2H), 2.95 (s, 1H), 2.20 – 2.26 (m, 1H), 2.09 – 2.17 (m, 1H), 2.09 (s, 3H), 1.30 – 1.34 (m, 1H) , 1.11 – 1.21 (m, 3H), 0.63 – 0.66 (m, 2H), 0.33 – 0.37 (m, 2H).

MS-ESI: m/z 545.25 [M+H] ⁺ .

Example ^{41: N 2 - (((} 2 S, 4 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrole 2-yl) methyl) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-Amides

Step 1: Compound ( 2S , 4R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxy Synthesis of Pyrrolidine-1,2-Dicarboxylate

Compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (10.410 g, 26.73 mmol) was dissolved in anhydrous tetrahydrofuran (62 mL), cooled to -20 °C, dropwise Add isopropylmagnesium chloride-lithium chloride (22 mL, 29.00 mmol, 1.3 mol/L in THF), stir at room temperature for 2 h, place at -78 °C and stir for 0.5 h, add dropwise ( 2S )-1-tert-butyl Oxycarbonyl-4-oxoproline methyl ester (5.00 g, 20.60 mmol) in anhydrous tetrahydrofuran (20 mL), stirred at -70 °C for 2 h. Saturated ammonium chloride solution (5 mL) was added to quench the reaction, ethyl acetate (100 mL) was added to dilute, the organic phase was washed with saturated brine (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3), The organic phases were combined, dried over anhydrous anhydrous sodium sulfate, concentrated to give a yellow liquid, and purified by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 4/1) to give a yellow transparent liquid (5.21 g, yield rate 55.40%). Synthesis reference: Synthesis of 4- cis- Phenyl-L-proline via Hydrogenolysis J. Org. Chem. 2001, 66, 3593-3596 .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.19 (d, J = 14.9 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H) , 6.62 (t, J = 75.6 Hz, 1H), 4.57 – 4.42 (m, 1H), 3.95 – 3.84 (m, 3H), 3.82 (d, J = 6.0 Hz, 3H), 3.76 – 3.62 (m, 1H) ), 2.68 – 2.58 (m, 1H), 2.33 – 2.21 (m, 1H), 1.45 (d, J = 8.5 Hz, 9H), 1.28 – 1.24 (m, 1H), 0.69 – 0.60 (m, 2H), 0.38 – 0.29 (m, 2H).

MS-ESI: m/z 340.10 [MH ₂ O-Boc+2H] ⁺ .

Step 2: Compound ( 2S , 4R )-1-tert-butoxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine -2-Carboxylic acid synthesis

The compound ( 2S , 4R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine -1,2-carboxylate (5.21 g, 11.38 mmol), lithium hydroxide monohydrate (560 mg, 22.91 mmol) was dissolved in tetrahydrofuran/water (13 mL, (v/v) = 5/1), Stir at room temperature for 4 h. Place in an ice bath to cool for 10 min, add dilute hydrochloric acid (4 mol/L) dropwise to adjust pH = 4, add saturated brine (50 mL), extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with anhydrous Dry over sodium sulfate and concentrate under reduced pressure to give a light brown solid (5.15 g, yield 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14 – 7.05 (m, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.61 (t, J = 75.6 Hz, 1H), 4.58 – 4.46 (m, 2H), 3.91 – 3.82 (m, 2H), 3.82 – 3.70 (m, 1H), 3.67 – 3.50 (m, 1H), 2.64 – 2.52 (m, 1H), 2.47 (d, J = 13.6 Hz, 1H), 1.41 (s, 9H), 1.27 – 1.22 (m, 1H), 0.66 – 0.54 (m, 2H), 0.39 – 0.25 (m, 2H).

MS-ESI: m/z 370.10 [MH ₂ O-tBu+2H] ⁺ .

Step 3: Compound ( 1R , 4S )-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa Synthesis of -5-azabicyclo[2.2.1]heptane-5-carboxylate

The compound ( 2S , 4R )-1-tert-butoxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine-2 -Carboxylic acid (5.10 g, 11.50 mmol) and N , N -diisopropylethylamine (5.6 mL, 34.00 mmol) were dissolved in dichloromethane (45 mL), and methanesulfonyl chloride was slowly added dropwise at 0 °C (1.3 mL, 17.00 mmol), and stirred at room temperature for 2 h. Dichloromethane (100 mL) was added to dilute, the organic phase was washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow liquid, which was subjected to silica gel column chromatography (eluent: PE/AcOEt (v/v) = 5/1) was purified to give a yellow liquid (3.19 g, yield 65.20%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.19 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.93 (dd, J = 8.3, 2.0 Hz, 1H), 6.64 (t, J = 75.2 Hz, 1H), 4.69 (br.s, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.70 – 3.58 (m, 2H), 2.42 (d, J = 11.9 Hz , 1H), 2.27 (d, J = 10.6 Hz, 1H), 1.47 (s, 9H), 1.29 – 1.24 (m, 1H), 0.67 – 0.61 (m, 2H), 0.38 – 0.32 (m, 2H).

MS-ESI: m/z370.10 [M-tBu+2H] ⁺ .

Step 4: Compound ( 2S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro Synthesis of -1 H -pyrrole-2-carboxylic acid

The compound ( 1R , 4S )-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa-5 - Azabicyclo[2.2.1]heptane-5-carboxylate (3.15 g, 7.40 mmol) was dissolved in dichloromethane (85 mL), and trifluoroacetic acid (5.6 mL, 34.00 mmol) in dichloromethane was added dropwise Methane solution (20 mL), stirred at room temperature for 2.5 h. The organic phase was washed with water (80 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow liquid, which was purified by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 5/1) to obtain a yellow solid (1.53 g, 48.50%).

MS-ESI: m/z 370.10 [M-tBu+2H] ⁺ .

Step 5: Compound ( 2S , 4R )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2 -Synthesis of carboxylic acids

The compound ( 2S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1 H -pyrrole-2-carboxylic acid (640 mg, 1.50 mmol) was dissolved in ethanol (31 mL) and added with Pd/C (520 mg, 10% Pd, 55% H ₂ O) and triethylamine (319 uL, 2.29 mmol), remove the air, and stir at room temperature for 17 h under a hydrogen atmosphere. The reaction solution was filtered through celite to remove solids, and the filtrate was removed under reduced pressure to obtain a colorless transparent liquid (645 mg, yield 100%). Reference synthesis: Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2. J. Med. Chem. 2014, 57, 9042 - 9064 .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.03 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 9.1 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H) , 6.55 (t, J = 75.8 Hz, 1H), 4.25 – 4.19 (m, 1H), 4.04 – 3.85 (m, 1H), 3.88 – 3.80 (m, 2H), 3.38 (t, J = 10.7 Hz, 1H) ), 3.27 – 3.15 (m, 1H), 2.72 – 2.55 (m, 1H), 2.07 – 1.92 (m, 1H), 1.41 (s, 9H), 1.28 – 1.20 (m, 1H), 0.63 – 0.56 (m , 2H), 0.34 – 0.28 (m, 2H).

MS-ESI: m/z 372.05 [M- t- Bu+2H] ⁺ .

Step 6: Compound ( 2S , 4R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- Synthesis of 1,2-Dicarboxylate

The compound ( 2S , 4R )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylate Acid (920 mg, 2.15 mmol), methanol (175 uL, 4.32 mmol) and 1-hydroxybenzotriazole (445 mg, 3.23 mmol) were dissolved in N , N -dimethylformamide (15 mL), Add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (622 mg, 3.23 mmol) and N -methylmorpholine (480 uL, 4.30 mmol) in an ice bath, Stir at room temperature for 12 h. Water (50 mL) was added to dilute, the reaction solution was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE /AcOEt (v/v) = 5/1) to give a colorless transparent liquid (764 mg, 80.39% yield).

MS-ESI: m/z 386.05 [M- t- Bu+2H] ⁺ .

Step 7: Compound ( 2S , 4R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrole Synthesis of Alkane-1-Carboxylic Acid Esters

The compound ( 2S , 4R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1, 2-Dicarboxylate (212-1) (760 mg, 1.72 mmol) was dissolved in anhydrous tetrahydrofuran (7 mL), lithium borohydride (68 mg, 2.81 mmol) was added under ice bath, and the mixture was stirred at room temperature for 3.5 h. Saturated ammonium chloride (20 mL) was added to quench lithium borohydride, extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (Eluent: PE/AcOEt (v/v) = 4/1) A colorless transparent liquid (518 mg, 1.25 mmol, 72.77% yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.08 (d, J = 8.1 Hz, 1H), 6.79 (s, 1H), 6.78 (d, J = 6.7 Hz, 1H), 6.58 (t, J = 75.7 Hz, 1H), 5.18 (d, J = 8.2 Hz, 1H), 4.07 – 4.00 (m, 1H), 3.99 – 3.89 (m, 1H), 3.85 (d, J = 6.9 Hz, 2H), 3.80 – 3.70 (m, 1H), 3.70 – 3.62 (m, 1H), 3.28 – 3.12 (m, 2H), 2.46 – 2.30 (m, 1H), 1.69 – 1.57 (m, 1H), 1.47 (s, 9H) ), 1.28 – 1.23 (m, 1H), 0.67 – 0.59 (m, 2H), 0.38 – 0.30 (m, 2H).

MS-ESI: m/z 358.20 [M- t- Bu+2H] ⁺ .

Step 8: Compound ( 2S , 4R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl Synthesis of Acyl)oxy)methyl)pyrrolidine-1-carboxylate

The compound ( 2S , 4R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine- 1-Carboxylic acid ester (212-2) (510 mg, 1.23 mmol) and N,N-diisopropylethylamine (612 uL, 3.70 mmol) were dissolved in dichloromethane (5 mL) at 0 °C Methanesulfonyl chloride (114 uL, 1.85 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: PE/AcOEt (v/v) = 4/1) to obtain a yellow liquid (606 mg, yield 99.97%).

MS-ESI: m/z 436.10 [M- t- Bu+2H] ⁺ .

Step 9: Compound ( 2S , 4R )-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrole Synthesis of Alkane-1-Carboxylic Acid Esters

The compound ( 2S , 4R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl )oxy)methyl)pyrrolidine-1-carboxylate (590 mg, 1.20 mmol) and sodium azide (241 mg, 3.60 mmol) were dissolved in dry N , N -dimethylformamide (6 mL) ) and stirred at 80 °C for 2 h. N , N -dimethylformamide was removed under reduced pressure, ethyl acetate (50 mL) was added to the residue to dilute, the organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and removed under reduced pressure solvent, and the residue was separated by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 5/1) to obtain a yellow liquid (308 mg, 58.51%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J = 7.9 Hz, 1H), 6.86 – 6.79 (m, 2H), 6.59 (t, J = 75.7 Hz, 1H), 4.18 – 3.93 (m, 2.6H), 3.87 (d, J = 6.4 Hz, 2H), 3.73 – 3.63 (m, 0.4H), 3.48 – 3.31 (m, 1H), 3.29 – 3.15 (m, 2H), 2.50 – 2.31 (m, 1H), 2.08 – 1.95 (m, 1H), 1.47 (s, 9H), 1.31 – 1.24 (m, 1H), 0.67 – 0.62 (m, 2H), 0.37 – 0.33 (m, 2H).

MS-ESI: m/z 383.10 [M- t- Bu+2H] ⁺ .

Step 10: Compound ( 2S , 4R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine Synthesis of hydrochloride

The compound ( 2S , 4R )-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 1-Carboxylic acid ester (270 mg, 0.62 mmol) was dissolved in DCM (6 mL), injected into a solution of hydrogen chloride in dioxane (1.5 mL, 6.00 mmol, 4 mol/L), and stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give a yellow viscous solid (230 mg, 99.66% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.11 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.59 (t, J = 75.5 Hz, 1H), 4.05 – 3.93 (m, 2H), 3.87 (d, J = 6.9 Hz, 2H), 3.82 – 3.72 (m, 2H), 3.59 – 3.47 (m, 1H), 3.45 – 3.32 (m, 1H), 2.53 – 2.43 (m, 1H), 2.06 – 1.91 (m, 1H), 1.32 – 1.22 (m, 1H), 0.69 – 0.57 (m, 2H), 0.41 – 0.31 (m, 2H) .

MS-ESI: m/z 339.15 [M-HCl+H] ⁺ .

Step 11: Compound 1-( 2S , 4R )-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine Synthesis of -1-yl)ethanone

Compound ( 2S , 4R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride The salt (220 mg, 0.59 mmol) was dissolved in dichloromethane (6 mL), triethylamine (248 uL, 1.76 mmol) and acetyl chloride (62 uL, 0.87 mmol) were slowly added dropwise at 0 °C, room temperature Stir for 2 h. Saturated brine (20 mL) was added to the reaction solution, extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluting) Agent: PE/AcOEt (v/v) = 1/1) to give a yellow liquid (180 mg, 80.61% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.11 (d, J = 7.9 Hz, 1H), 6.84 (s, 1H), 6.83 – 6.80 (m, 1H), 6.60 (t, J = 75.6 Hz, 1H), 4.30 – 4.21 (m, 1H), 4.15 – 4.08 (m, 1H), 3.92 – 3.88 (m, 1H), 3.87 (d, J = 6.9 Hz, 2H), 3.45 – 3.34 (m, 2H), 3.30 – 3.20 (m, 1H), 2.46 – 2.37 (m, 1H), 2.09 (s, 3H), 2.08 – 2.02 (m, 1H), 1.31 – 1.25 (m, 1H), 0.68 – 0.61 ( m, 2H), 0.38 – 0.32 (m, 2H).

MS-ESI: m/z 381.15 [M+H] ⁺ .

Step 12: Compound 1-( 2S , 4R )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1 Synthesis of -yl) ethyl ketone hydrochloride

Compound 1-( 2S , 4S )-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1 -yl)ethanone (180 mg, 0.47 mmol), methanol (5 mL), added palladium carbon (18 mg, 10% Pd, 55% H ₂ O), and stirred at room temperature for 2 h. A solution of hydrogen chloride in dioxane (0.5 mL, 2.00 mmol, 4 mol/L) was injected, the reaction solution was filtered through celite to remove palladium carbon, and the solvent was removed under reduced pressure to obtain a yellow viscous liquid (185 mg, yield 100%). ).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.15 – 7.04 (m, 2H), 6.94 – 6.90 (m, 1H), 6.73 (t, J = 75.7 Hz, 1H), 4.36 – 4.21 (m , 1H), 4.12 – 4.00 (m, 1H), 3.93 (d, J = 6.2 Hz, 2H), 3.77 – 3.66 (m, 1H), 3.67 – 3.52 (m, 2H), 3.46 – 3.32 (m, 1H) ), 2.65 – 2.52 (m, 1H), 2.16 (s, 3H), 2.00 – 1.87 (m, 1H), 1.32 – 1.24 (m, 1H), 0.67 – 0.58 (m, 2H), 0.42 – 0.33 (m , 2H).

MS-ESI: m/z 355.10 [M-HCl+H] ⁺ .

Step 13: Compound ^{N 2 - (((2 S} , 4 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrole 2-yl) methyl) - N ⁵ - methyl - N ⁵ - synthesis of ethyl pyridine-2,5-Amides of

Compound 1-( 2S , 4R )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) ethyl ketone hydrochloride (150 mg, 0.38 mmol), 5-(ethyl(methyl)carbamoyl)picolinic acid (88 mg, 0.42 mmol) and 1-hydroxybenzotriazole (79 mg, 0.57 mmol) was dissolved in N , N -dimethylformamide (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (111) was added in an ice bath mg, 0.58 mmol) and N -methylmorpholine (86 uL, 0.77 mmol), stirred at room temperature for 15 h. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 3/2) gave a white solid (118 mg, 56.45% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.08 (s, 1H), 8.64 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.86 (t, J = 7.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.81 – 6.76 (m, 2H), 6.58 (t, J = 75.6 Hz, 1H), 4.34 – 4.24 (m, 1H), 4.05 – 3.97 (m , 1H), 3.95 – 3.87 (m, 1H), 3.83 (d, J = 6.9 Hz, 2H), 3.66 – 3.46 (m, 2H), 3.41 (t, J = 10.8 Hz, 1H), 3.27 – 3.20 ( m, 2H), 3.09 (s, 1.7H), 2.94 (s, 1.3H), 2.64 – 2.52 (m, 1H), 2.15 (s, 3H), 2.00 – 1.92 (m, 1H), 1.27 – 1.23 ( m, 2.5H), 1.18 – 1.10 (m, 1.5H), 0.68 – 0.58 (m, 2H), 0.39 – 0.30 (m, 2H).

MS-ESI: m/z 545.20 [M+H] ⁺ .

Example ^{42: N 2 - (((2} S, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrole 2-yl) methyl) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-Amides

Step 1: Compound ( 2 S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxy acid synthesis

The compound ( 2S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1 H -pyrrole-2-carboxylic acid (1.04 g, 2.45 mmol, Example 41 step 4), tris(triphenylphosphine)rhodium chloride (295 mg, 0.32 mmol), triethylamine (490 uL, 3.52 mmol) , anhydrous tetrahydrofuran (2 mL) was dissolved in anhydrous ethanol (18 mL), the air was removed, and the mixture was stirred at room temperature for 4 days under a hydrogen (0.8 MPa) atmosphere. The solvent was concentrated, ethyl acetate (50 mL) was added to the residue to dilute, the pH was adjusted to 1 with dilute hydrochloric acid (1 mol/L), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic The phase was dried over anhydrous sodium sulfate and concentrated to obtain a yellow liquid, which was purified by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 5:1) to obtain a white viscous solid (843 mg, yield 80.45%). Synthetic reference: Carboxylate-Directed Highly Stereoselective Homogeneous Hydrogenation of Cyclic Olefins with Wilkinson's Catalyst. Organic Letters. 2003 Vol. 5, No. 9 1587 - 1589 .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.15 – 7.06 (m, 1H), 6.85 – 6.73 (m, 2H), 6.59 (t, J = 75.6 Hz, 1H), 4.56 – 4.30 (m , 1H), 4.09 – 3.92 (m, 1H), 3.92 – 3.79 (m, 2H), 3.56 – 3.38 (m, 1H), 3.39 – 3.23 (m, 1H), 2.77 – 2.54 (m, 1H), 2.50 – 2.14 (m, 1H), 1.49 – 1.44 (m, 9H), 1.33 – 1.18 (m, 1H), 0.68 – 0.55 (m, 2H), 0.41 – 0.27 (m, 2H).

MS-ESI: m/z 372.05 [M- t- Bu+2H] ⁺ .

Step 2: Compound ( 2S )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2 - Synthesis of dicarboxylates

The compound ( 2S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid (810 mg, 1.90 mmol), methanol (154 uL, 3.80 mmol) and 1-hydroxybenzotriazole (392 mg, 2.84 mmol) were dissolved in N , N -dimethylformamide (12 mL) in an ice bath 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (548 mg, 2.84 mmol) and N -methylmorpholine (430 uL, 3.80 mmol) were added to it, and the mixture was stirred at room temperature 13h. Water (50 mL) was added to dilute, the reaction solution was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE /AcOEt (v/v) = 5/1) to give a colorless transparent liquid (571 mg, 68.24 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.08 (d, J = 8.0 Hz, 1H), 6.80 – 6.75 (m, 2H), 6.58 (t, J = 75.6 Hz, 1H), 4.53 – 4.43 (m, 0.3H), 4.40 – 4.35 (m, 0.7H), 4.04 – 3.91 (m, 1H), 3.87 – 3.81 (m, 2H), 3.75 (s, 3H), 3.54 – 3.44 (m, 1H) ), 3.43 – 3.36 (m, 0.5H), 3.35 – 3.25 (m, 0.5H), 2.70 – 2.56 (m, 0.3H), 2.35 – 2.24 (m, 1.4H), 2.07 – 1.93 (m, 0.3H) ), 1.45 – 1.42 (m, 9H), 1.29 – 1.22 (m, 1H), 0.67 – 0.58 (m, 2H), 0.36 – 0.29 (m, 2H).

MS-ESI: m/z 386.10 [M- t- Bu+2H] ⁺ .

Step 3: Compound ( 2S , 4S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrole Synthesis of Alkane-1-Carboxylic Acid Esters

The compound ( 2S )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-di The carboxylate (540 mg, 1.22 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), lithium borohydride (48 mg, 1.98 mmol) was added under ice bath, and the mixture was stirred at room temperature for 2 h. Saturated ammonium chloride (20 mL) was added to quench lithium borohydride, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (Eluent: PE/AcOEt (v/v) = 4/1) to obtain a colorless transparent liquid (311 mg, yield 61.49%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.09 (d, J = 7.9 Hz, 1H), 6.78 (s, 2H), 6.58 (t, J = 75.7 Hz, 1H), 4.25 – 4.12 ( m, 1H), 3.85 (d, J = 6.9 Hz, 2H), 3.79 – 3.63 (m, 3H), 3.49 – 3.30 (m, 2H), 2.20 – 2.06 (m, 1H), 2.06 – 1.96 (m, 1H), 1.47 (s, 9H), 1.33 – 1.23 (m, 1H), 0.69 – 0.59 (m, 2H), 0.39 – 0.31 (m, 2H).

MS-ESI: m/z358.10 [M- t- Bu+2H] ⁺ .

Step 4: Compound ( 2S , 4S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl Synthesis of Acyl)oxy)methyl)pyrrolidine-1-carboxylate

The compound ( 2S , 4S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine- 1-Carboxylic acid ester (260 mg, 0.63 mmol) and N , N -diisopropylethylamine (324 uL, 1.96 mmol) were dissolved in dichloromethane (5 mL), and methanesulfonic acid was slowly added dropwise at 0 °C Acyl chloride (76 uL, 0.98 mmol), stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: PE/AcOEt (v/v) = 4/1) to obtain a yellow liquid (309 mg, yield 99.99%).

MS-ESI: m/z 436.10 [M- t- Bu+2H] ⁺ .

Step 5: Compound ( 2S , 4S )-tert-butyl 2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl ) Synthesis of pyrrolidine-1-carboxylate

The compound ( 2S , 4S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl )oxy)methyl)pyrrolidine-1-carboxylate (320 mg, 0.65 mmol) and sodium azide (131 mg, 1.95 mmol) were dissolved in dry N , N -dimethylformamide (5 mL) ) and stirred at 80 °C for 2 h. The N , N -dimethylformamide was removed by rotary evaporation under reduced pressure, ethyl acetate (50 mL) was added to the residue to dilute, the organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, reduced The solvent was removed under pressure, and the residue was separated by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 5/1) to obtain a yellow liquid (189 mg, yield 66.20%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J = 7.9 Hz, 1H), 6.79 (s, 2H), 6.60 (t, J = 75.5 Hz, 1H), 4.17 – 3.97 ( m, 1H), 3.86 (d, J = 6.2 Hz, 2H), 3.79 (t, J = 9.1 Hz, 1H), 3.71 – 3.62 (m, 0.5H), 3.57 – 3.38 (m, 3H), 3.38 – 3.27 (m, 0.5H), 2.27 – 2.16 (m, 1H), 2.15 – 2.06 (m, 1H), 1.50 – 1.47 (m, 9H), 1.30 – 1.24 (m, 1H), 0.69 – 0.61 (m, 2H), 0.40 – 0.30 (m, 2H).

MS-ESI: m/z 383.15 [M- t- Bu+2H] ⁺ .

Step 6: Compound ( 2S , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine Synthesis of hydrochloride (11213-5)

The compound ( 2S , 4S )-tert-butyl 2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrole Alkane-1-carboxylate (270 mg, 0.62 mmol) was dissolved in DCM (6 mL), injected into a solution of hydrogen chloride in dioxane (1.5 mL, 6.00 mmol, 4 mol/L), and stirred at room temperature for 2 h . The solvent was removed under reduced pressure to give a yellow solid (270 mg, 99.66% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.12 (d, J = 8.1 Hz, 1H), 6.86 (s, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.60 (t, J = 75.5 Hz, 1H), 4.13 – 4.02 (m, 1H), 4.02 – 3.94 (m, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.86 – 3.81 (m, 1H), 3.80 – 3.73 (m, 1H), 3.68 – 3.60 (m, 1H), 3.39 – 3.27 (m, 1H), 2.29 – 2.23 (m, 1H), 2.11 – 2.02 (m, 1H), 1.29 – 1.23 (m, 1H) , 0.70 – 0.59 (m, 2H), 0.42 – 0.32 (m, 2H).

MS-ESI: m/z 339.20 [M-HCl+H] ⁺ .

Step 7: Compound 1-( 2S , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) Synthesis of Pyrrolidin-1-yl)ethanone (213-6)

Compound ( 2S , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride Salt (220 mg, 0.59 mmol), triethylamine (248 uL, 1.76 mmol) was dissolved in dichloromethane (6 mL), and acetyl chloride (62 uL, 0.87 mmol) was slowly added dropwise at 0 °C, room temperature Stir for 2 h. Saturated brine (20 mL) was added to the reaction solution, extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluting) Agent: PE/AcOEt (v/v) = 1/1) to give a yellow liquid (171 mg, 76.58% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.13 (d, J = 7.9 Hz, 1H), 6.81 (s, 2H), 6.62 (t, J = 75.6 Hz, 1H), 4.44 – 4.37 ( m, 1H), 3.97 – 3.90 (m, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.79 – 3.74 (m, 1H), 3.70 – 3.62 (m, 1H), 3.52 – 3.46 (m, 1H), 3.41 (t, J = 9.7 Hz, 1H), 2.29 – 2.22 (m, 1H), 2.18 – 2.13 (m, 1H), 2.08 (s, 3H), 1.33 – 1.26 (m, 1H), 0.70 – 0.63 (m, 2H), 0.40 – 0.34 (m, 2H).

MS-ESI: m/z 381.20 [M+H] ⁺ .

Step 8: Compound 1-( 2S , 4S )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1 Synthesis of -yl) ethyl ketone hydrochloride

Compound 1-( 2S , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine -1-yl)ethanone (165 mg, 0.43 mmol), methanol (5 mL), palladium carbon (34 mg, 10% Pd, 55% H ₂ O) was added, and the mixture was stirred at room temperature for 2 h. A solution of hydrogen chloride in dioxane (0.5 mL, 2.00 mmol, 4 mol/L) was injected, the reaction solution was filtered through celite to remove palladium carbon, and concentrated under reduced pressure to obtain a yellow viscous liquid (169 mg, yield 100%) .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.15 – 7.03 (m, 2H), 6.96 – 6.88 (m, 1H), 6.72 (t, J = 75.7 Hz, 1H), 4.54 – 4.44 (m , 1H), 4.09 – 3.97 (m, 1H), 3.95 – 3.90 (m, 2H), 3.77 – 3.72 (m, 1H), 3.69 – 3.64 (m, 2H), 3.59 – 3.53 (m, 1H), 2.35 – 2.22 (m, 1H), 2.23 – 2.15 (m, 1H), 2.12 (s, 2.2H), 2.04 (s, 0.8H), 1.31 – 1.26 (m, 1H), 0.66 – 0.59 (m, 2H) , 0.40 – 0.34 (m, 2H).

MS-ESI: m/z 355.25 [M-HCl+H] ⁺ .

Step 9: Compound ^{N 2 - (((2 S} , 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrole 2-yl) methyl) - N ⁵ - synthesis of ethyl pyridine-2,5-Amides - methyl - N ⁵

Compound 1-( 2S , 4S )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl ) ethyl ketone hydrochloride (163 mg, 0.42 mmol), 5-(ethyl(methyl)carbamoyl)picolinic acid (94 mg, 0.45 mmol) and 1-hydroxybenzotriazole (85 mg, 0.62 mmol) was dissolved in N , N -dimethylformamide (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118) was added in an ice bath mg, 0.62 mmol) and N -methylmorpholine (92 uL, 0.82 mmol), stirred at room temperature for 15 h. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 3/2) gave a white solid (110 mg, 48.43% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.81 – 8.71 (m, 1H), 8.65 – 8.56 (m, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.85 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.82 – 6.76 (m, 2H), 6.58 (t, J = 75.6 Hz, 1H), 4.55 – 4.46 (m, 1H), 3.95 – 3.87 (m, 1H), 3.85 (d, J = 6.8 Hz, 2H), 3.82 – 3.74 (m, 1H), 3.72 – 3.50 (m, 3H), 3.41 (t, J = 9.9 Hz, 1H), 3.33 – 3.21 (m, 1H), 3.09 (s, 1.6H), 2.94 (s, 1.4H), 2.25 – 2.17 (m, 1H), 2.19 – 2.11 (m, 1H), 2.08 (s, 3H), 1.32 – 1.22 (m, 1H), 1.24 – 1.21 (m, 1.5H), 1.18 – 1.11 (m, 1.5H), 0.67 – 0.59 (m, 2H), 0.39 – 0.29 (m, 2H).

MS-ESI: m/z 545.30[M+H] ⁺ .

Embodiment 43 ^{cases: N 2 - (((2} R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrole Alk-2-yl)methyl)pyridine-2,5-dimethylamide

Step 1: 6 - (((( 2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine Synthesis of -2-yl)methyl)carbamoyl)nicotinate

Compound 1-(( 2R , 4S )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 1-yl)ethanone hydrochloride (1.19 g, 3.05 mmol, Example 39, step 9) was dissolved in dichloromethane (24 mL) solvent and 5-(methoxycarbonyl)picolinic acid (853 mg, 4.57 g) was added. mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (630 mg, 4.63 mmol), cooled at 0 °C, and then added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI) (1.75 g, 9.13 mmol), N , N -diisopropylethylamine (DIPEA) (2.09 g, 16.20 mmol), transfer to room temperature and stir the reaction for 2 h, add water (20 mL) to stop the reaction, extracted with dichloromethane (20 mL×3), dried with anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: methanol/dichloromethane (v/v ) = 1/10) to give a white foam (1.01 g, 65.90 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.22 (s, 1H), 9.13 (br.s, 1H), 8.44 (dd, J = 8.1, 1.7 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.59 (t, J = 75.4 Hz, 1H), 4.35 – 4.27 (m, 1H), 4.07 – 4.00 (m, 1H), 3.98 (s, 3H), 3.96 – 3.89 (m, 1H), 3.82 (d, J = 6.9 Hz, 2H), 3.67 – 3.58 ( m, 1H), 3.43 (t, J = 10.8 Hz, 1H), 3.31 – 3.20 (m, 1H), 2.63 – 2.54 (m, 1H), 2.16 (s, 3H), 2.00 – 1.90 (m, 1H) , 1.23 – 1.32 (m, 1H), 0.67 – 0.62 (m, 2H), 0.37 – 0.33 (m, 2H).

MS-ESI: m/z 518.15 [M+H] ⁺ .

Step 2: 6 - (((( 2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine Synthesis of -2-yl)methyl)carbamoyl)nicotinic acid

Compound 6 - ((((2 R , 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidin - 2-yl)methyl)carbamoyl)nicotinate (1.01 g, 1.96 mmol) was dissolved in tetrahydrofuran (20 mL) solvent, and then lithium hydroxide monohydrate (440 mg, 10.49 mmol) and aqueous solution ( 10 mL), transferred to 50 °C and stirred for 2 h, cooled at 0 °C, added dropwise with 1 mol/L hydrochloric acid to make it acidic (pH=3), washed with ethyl acetate (20 mL×2) After extraction, the organic phase was dried over anhydrous sodium sulfate for 30 min and concentrated under reduced pressure. A white solid was obtained (943 mg, 95.80% yield).

¹ H NMR (400 MHz, Chloroform- d ) δ (ppm): 9.77 (br.s, 1H), 9.51 (s, 1H), 8.48 (dd, J = 8.1, 2.0 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 6.86 – 6.79 (m, 2H), 6.62 (t, J = 75.5 Hz, 1H), 4.54 – 4.47 (m, 1H), 4.06 – 3.96 (m, 2H), 3.88 (d, J = 6.9 Hz, 2H), 3.56 – 3.42 (m, 2H), 3.36 – 3.25 (m, 1H), 2.75 – 2.65 (m, 1H), 2.37 ( s, 3H), 1.93 – 1.83 (m, 1H), 1.35 – 1.23 (m, 1H), 0.69 – 0.65 (m, 2H), 0.39 – 0.35 (m, 2H).

MS-ESI: m/z 504.20 [M+H] ⁺ .

Step ^{3: N 2 - (((} (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrole Synthesis of Alk-2-yl)methyl)pyridine-2,5-dimethylamide

Compound 6-((((2R, 4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- yl)methyl)carbamoyl)nicotinic acid (300 mg, 0.60 mmol), ethylamine (286 mg, 3.51 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (123 mg, 0.90 mmol) was dissolved in dry tetrahydrofuran (20 mL) solvent, cooled at 0 °C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (440 mg, 2.30 mmol), N , N -diisopropylethylamine (DIPEA) (740 mg, 5.73 mmol), transferred to room temperature and stirred for 6 h, stopped the reaction, concentrated the reaction solution under reduced pressure, added water (20 mL) , extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: methanol/dichloromethane (v/v) = 1/10) to give a white solid (300 mg, 90.45 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.16 (br.s, 1H), 9.05 (s, 1H), 8.34 – 8.20 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H ), 6.79 (s, 1H), 6.78 (d, J = 9.1 Hz, 1H), 6.59 (t, J = 75.5 Hz, 1H), 4.37 – 4.26 (m, 1H), 4.05 – 3.96 (m, 1H) , 3.93 (t, J = 8.8 Hz, 1H), 3.84 (d, J = 6.9 Hz, 2H), 3.64 – 3.56 (m, 1H), 3.43 (t, J = 10.8 Hz, 1H), 3.31 – 3.21 ( m, 1H), 2.64 – 2.55 (m, 1H), 2.16 (s, 3H), 1.98 – 1.89 (m, 1H), 1.33 – 1.21 (m, 1H), 0.67 – 0.62 (m, 2H), 0.37 – 0.33 (m, 2H).

MS-ESI: m/z 503.30 [M+H] ⁺ .

Embodiment 44 ^{cases: N 2 - (((2} R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrole 2-yl) methyl) - N ⁵ - methyl-pyridine-2,5-Amides

Compound 6 - ((((2 R , 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidin - 2--2-yl)methyl)carbamoyl)nicotinic acid (300 mg, 0.60 mmol), methylammonium hydrochloride (270 mg, 4.00 mmol), 1-hydroxy-7-azabenzotriazepine Azole (HOAT) (123 mg, 0.90 mmol) was dissolved in dry tetrahydrofuran (20 mL) solvent, transferred to 0 °C, and then 1-(3-dimethylaminopropyl)-3-ethylcarbobis was added Imine (EDCI) (360 mg, 1.88 mmol), N , N -diisopropylethylamine (DIPEA) (769 mg, 5.59 mmol), transferred to room temperature and stirred for 6 h. The reaction was stopped, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and passed through silica gel column chromatography Purification (eluent: methanol/dichloromethane (v/v = 1/10) gave the product as a white solid (300 mg, 94.15 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.11 (br.s, 1H), 8.98 (s, 1H), 8.22 (s, 2H), 7.09 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 8.5 Hz, 2H), 6.59 (t, J = 75.5 Hz, 1H), 6.41 (br.s, 1H), 4.34 – 4.26 (m, 1H), 4.05 – 3.97 (m, 1H) , 3.96 – 3.89 (m, 1H), 3.83 (d, J = 6.9 Hz, 2H), 3.64 – 3.56 (m, 1H), 3.43 (t, J = 10.8 Hz, 1H), 3.31 – 3.20 (m, 1H) ), 3.05 (d, J = 4.8 Hz, 3H), 2.63 – 2.54 (m, 1H), 2.16 (s, 3H), 1.98 – 1.90 (m, 1H), 1.31 – 1.22 (m, 1H), 0.67 – 0.62 (m, 2H), 0.36 – 0.32 (m, 2H).

MS-ESI: m/z 517.53 [M+H] ⁺ .

Example ^{45: N 2 - (((} 2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy-l-4- (difluoromethoxy) phenyl) pyrrole 2-yl) methyl) - N ⁵ - ethyl pyridine-2,5-Amides

Compound 6 - ((((2 R , 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidin - 2-yl)methyl)carbamoyl)nicotinic acid (300 mg, 0.60 mmol), ethylamine (286 mg, 3.51 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (123 mg, 0.90 mmol) was dissolved in dry DMF (20 mL) solvent, transferred to 0 medium temperature, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) was added ( 440 mg, 2.30 mmol), N , N -diisopropylethylamine (DIPEA) (740 mg, 5.73 mmol), transferred to room temperature and stirred for 6 h. The reaction was stopped, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography ( Eluent: methanol/dichloromethane (v/v) = 1/10) to give the product as a white solid (300 mg, 90.45 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.11 (br.s, 1H), 8.98 (s, 1H), 8.21 (s, 2H), 7.09 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.5 Hz, 2H), 6.59 (t, J = 75.6 Hz, 1H), 6.35 (br.s, 1H), 4.35 – 4.27 (m, 1H), 4.05 – 3.96 (m, 1H) , 3.96 – 3.89 (m, 1H), 3.83 (d, J = 6.9 Hz, 2H), 3.64 – 3.57 (m, 1H), 3.57 – 3.49 (m, 2H), 3.43 (t, J = 10.8 Hz, 1H) ), 3.31 – 3.20 (m, 1H), 2.63 – 2.54 (m, 1H), 2.16 (s, 3H), 1.98 – 1.90 (m, 1H), 1.31 – 1.22 (m, 1H), 1.28 (d, J = 7.3 Hz, 3H), 0.67 – 0.58 (m, 2H), 0.40 – 0.32 (m, 2H).

MS-ESI: m/z 531.30 [M+H] ⁺ .

Embodiment 46 ^{cases: N 2 - (((2} R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-hydroxyphenyl) pyrrolidin-2-yl) methyl yl) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-Amides

Compound N ² -((((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine 2-yl) methyl) - N ⁵ - ^-N-ethyl-5 - methyl-2, 5 - dimethyl Amides (125 mg, 0.23 mmol, Example 39) was dissolved in acetonitrile (3 mL) solvent , then concentrated hydrochloric acid (1.2 g, 32.91 mmol) was added dropwise, and the reaction was stirred at 80 °C for 6 h. Cooled to room temperature, water was added to dissolve the precipitate, and extracted with ethyl acetate (300 mL×3). The phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: dichloromethane/methanol=16:1) to obtain a white solid (74 mg, yield 63.30%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.11 (s, 1H), 8.64 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.87 (br.s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.88 (s, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.53 (t, J = 70.3 Hz, 1H), 4.34 – 4.26 (m, 1H) ), 4.06 – 3.98 (m, 1H), 3.95 – 3.88 (m, 1H), 3.66 – 3.56 (m, 2H), 3.41 (t, J = 10.7 Hz, 1H), 3.31 – 3.19 (m, 2H), 3.11 (s, 1.7H), 2.95 (s, 1.3H), 2.60 – 2.51 (m, 1H), 2.16 (s, 3H), 1.88 – 1.83 (m, 1H), 1.16 (t, J = 7.1 Hz, 3H).

MS-ESI: m/z 491.15 [M+H] ⁺ .

Example ^{47: N 2 - (((} 2 R, 4 S) -1- -4- (4- ( difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) methyl yl) -N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dimethylamide

Step 1: Compound ^{N 2 - ((((2} R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-hydroxyphenyl) pyrrolidin-2-yl) methyl) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-Amides (1245-1) synthesis of

Compound N ² -((((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidinyl) 2-yl) methyl) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-acyl amine (400 mg, 0.73 mmol) was dissolved in acetonitrile (6 mL), followed by addition of concentrated hydrochloric acid (3 mL, 36.5%), placed under heating at 80 °C and reacted for 12 h. After the reaction was completed, 30 mL of water was added, extracted with dichloromethane (20 mL × 3), the organic phase was dried by adding anhydrous sodium sulfate, and distilled under reduced pressure , removed the solvent, and separated and purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to obtain a white solid (180 mg, yield 51%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.13 – 9.09 (m, 1H), 8.64 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.90 – 7.83 (m, 1H) ), 7.04 (d, J = 8.3 Hz, 1H), 6.89 – 6.87 (m, 1H), 6.72 – 6.70 (m, 1H), 6.53 (t, J = 78.3 Hz, 1H), 6.39 (s, 1H) , 4.29 (s, 1H), 4.06 – 4.00 (m, 1H), 3.93 – 3.89 (m, 1H), 3.66 – 3.54 (m, 2H), 3.41 (t, J = 10.7 Hz, 1H), 3.28 – 3.20 (m, 2H), 3.10 (s, 1.5H), 2.95 (s, 1.5H), 2.59 – 2.53 (m, 1H), 2.15 (s, 3H), 1.96 – 1.87 (m, 1H), 1.26 (t , J = 7.1 Hz, 3H).

MS-ESI: m/z 491.20 [M+H] ⁺ .

Step ^{2: N 2 - (((} (2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidine-2- yl) methyl) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-Amides (DLR011245) synthesis of

Compound N ² -((((2 R , 4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl ) - N ⁵ - ethyl - N ⁵ - methyl-pyridine-2,5-acyl amine (180 mg, 0.37 mmol) and 2-iodopropane (94 mg, 0.55 mmol) was dissolved in DMF (10 mL) in , then potassium carbonate (150 mg, 1.11 mmol) was added, and the reaction was carried out under heating at 80 °C for 4 h. After the reaction was completed, 50 mL of water was added, extracted with ethyl acetate (30 mL×3), and anhydrous sodium sulfate was added to the organic phase. Dry, evaporate under reduced pressure, remove the solvent, and separate and purify by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to obtain 130 mg of white solid, with a yield of 66%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.10 (s, 1H), 8.65 (s, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.87 (s, 1H), 7.09 ( d, J = 8.1 Hz, 1H), 6.81 (s, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.52 (t, J = 75.5 Hz, 1H), 4.57 – 4.44 (m, 1H), 4.35 – 4.25 (m, 1H), 4.07 – 4.00 (m, 1H), 3.95 – 3.91 (m, 1H), 3.61 (d, J = 7.7 Hz, 2H), 3.42 (t, J = 10.7 Hz, 1H) , 3.30 – 3.21 (m, 2H), 3.10 (s, 2H), 2.95 (s, 1H), 2.62 – 2.55 (m, 1H), 2.16 (s, 3H), 1.94 (dd, J = 22.3, 12.0 Hz , 1H), 1.33 (dd, J = 5.8, 2.5 Hz, 6H), 1.29 – 1.22 (m, 1H), 1.10 – 1.20 (m, 2H).

MS-ESI: m/z 533.20 [M+H] ⁺ .

Embodiment 48 ^{cases: N 2 - (((2} R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidine-2- yl) methyl) - N ⁵ - ethyl pyridine-2,5-Amides

Step ^{1: N 2 - (((} 2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-hydroxyphenyl) pyrrolidin-2-yl) methyl ) - Synthesis of N ⁵ -ethylpyridine-2,5-dimethylamide

Compound N ² -(((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidinyl) 2-yl) methyl) -N ⁵ - ethyl-2, 5-dimethyl Amides (150 mg, 0.28 mmol, Example 45) was dissolved in acetonitrile (5 mL) solvent was added dropwise concentrated hydrochloric acid (1 mL), transferred to 80 °C and stirred for 8 h. The reaction was stopped, cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (10 mL×2), the organic phases were combined and dried over anhydrous sodium sulfate for 30 min. Concentration under reduced pressure gave a white solid (114 mg, 85.45% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 9.05 (s, 1H), 8.35 – 8.32 (m, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.90 – 6.89 (m, 1H), 6.80 – 6.78 (m, 1H), 6.71 (t, J = 75.2 Hz, 1H), 4.44 – 4.31 (m, 2H), 4.06 – 4.01 (m , 1H), 3.92 – 3.88 (m, 1H), 3.75 – 3.68 (m, 1H), 3.49 – 3.42 (m, 3H), 3.28 – 3.07 (m, 1H), 2.60 – 2.53 (m, 1H), 2.26 (s, 1H), 2.17 (s, 2H), 1.97 – 1.92 (m, 1H), 1.26 (t, J = 7.3 Hz, 3H).

MS-ESI: m/z 477.20 [M+H] ⁺ .

Step ^{2: N 2 - (((} 2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3- (isopropoxyphenyl) pyrrolidine-2- yl) methyl) - N ⁵ - ethyl-2, 5 - synthesis of Amides of dimethyl

Compound N ² -(((2 R , 4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl) - N ⁵ - ethyl-2, 5-dimethyl Amides (108 mg, 0.23 mmol) was dissolved in N, N - dimethylformamide solvent (10 mL), and then was added anhydrous potassium carbonate (95 mg , 0.69 mmol) and 2-iodopropane (59 mg, 0.35 mmol), were transferred to 80 °C and stirred for 4.5 h. Stop the reaction, cool to room temperature, add water (50 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate for 30 min, and purify by silica gel column chromatography (eluting solvent: methanol/dichloromethane (v/v) = 25 %) to give a light brown solid (100 mg, 80.69 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.14 (s, 1H), 8.98 (s, 1H), 8.22 (s, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.81 ( s, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.53 (t, J = 75.6 Hz, 1H), 6.50 (br.s, 1H), 4.58 – 4.43 (m, 1H), 4.37 – 4.25 (m, 1H), 4.06 – 3.97 (m, 1H), 3.97 – 3.87 (m, 1H), 3.65 – 3.47 (m, 3H), 3.43 (t, J = 10.8 Hz, 1H), 3.31 – 3.19 (m , 1H), 2.64 – 2.54 (m, 1H), 2.16 (s, 3H), 2.02 – 1.88 (m, 1H), 1.40 – 1.29 (m, 6H), 1.27 (d, J = 7.0 Hz, 3H).

MS-ESI: m/z 519.20 [M+H] ⁺ .

Example ^{49: N 2 - (((} 2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidine-2- yl) methyl) - N ⁵ - methyl-pyridine-2,5-Amides

Step ^{1: N 2 - (((} 2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-hydroxyphenyl) pyrrolidin-2-yl) methyl Synthesis of ) -N ⁵ -picoline-2,5-dimethylamide

Compound N ² -(((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 2- yl) methyl) - N ⁵ - methyl-2, 5-dimethyl Amides (450 mg, 0.87 mmol, was dissolved in acetonitrile solvent (10 mL) in Example 44), was added dropwise concentrated hydrochloric acid ( 1 mL), and the reaction was stirred at 80 °C for 6.5 h. Stop the reaction. Cool to room temperature, add 50 mL of water, extract with ethyl acetate (10 mL × 2), combine the organic phases, and dry with anhydrous sodium sulfate for 30 min. The crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane (v/v)=1/10) to obtain a white solid (285 mg, yield 70.84%).

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 9.06 (s, 1H), 8.34 (dd, J = 8.1, 1.8 Hz, 1H), 8.18 (d, J= 8.1 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.90 (s, 1H), 6.79 (d, J= 8.2 Hz, 1H), 6.72 (t, J = 75.0 Hz, 1H), 4.45 – 4.34 (m, 2H) , 4.06 – 4.02 (m, 1H), 3.93 – 3.88 (m, 1H), 3.77 – 3.68 (m, 1H), 3.45 (t, J = 10.9 Hz, 1H), 2.98 (s, 3H), 2.61 – 2.54 (m, 1H), 2.17 (s, 3H), 2.01 – 1.93 (m, 1H).

MS-ESI: m/z 463.20 [M+H] ⁺ .

Step ^{2: N 2 - (((} 2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) Synthesis of methyl) -N ⁵ -methylpyridine-2,5-dimethylamide

Compound N ² -(((2 R ,4 S )-1-acetoxy-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl) - N ⁵ - methyl-pyridine-2,5-acyl amine (140 mg, 0.3 mmol) was dissolved cultured in 10 mL of N, N - dimethyl acyl amine solvent, was added anhydrous potassium carbonate (120 mg, 0.9 mmol ) and 2-iodopropane (76 mg, 0.45 mmol), transfer to 80 °C and stir the reaction for 4 h, stop the reaction, cool to room temperature, add water (50 mL), extract with ethyl acetate (50 mL×3) , the organic phases were combined, the organic phase was dried with anhydrous sodium sulfate for 30 min, and subjected to silica gel column chromatography (eluent: methanol/dichloromethane (v/v)=25%) to obtain a light brown solid (91 mg, yield 59.86%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.13 (s, 1H), 8.98 (s, 1H), 8.22 (s, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.81 – 6.70 (m, 2H), 6.70 (s, 1H), 6.53 (t, J = 75.5 Hz, 1H), 4.58 – 4.41 (m, 1H), 4.36 – 4.24 (m, 1H), 4.07 – 3.86 (m, 2H), 3.67 – 3.52 (m, 1H), 3.43 (t, J = 10.3 Hz, 1H), 3.32 – 3.19 (m, 1H), 3.04 (s, 3H), 2.64 – 2.53 (m, 1H), 2.16 (s, 3H), 2.03 – 1.84 (m, 1H), 1.37 – 1.26 (m, 6H).

MS-ESI: m/z 505.20 [M+H] ⁺ .

Embodiment 50 ^{cases: N 2 - (((2} R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidine-2- yl)methyl)pyridine-2,5-dimethylamide

Compound 1-(( 2R , 4S )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl) Ethanone hydrochloride (100 mg, 0.26 mmol, Example 58 step 11), 5-carbamoylpicolinic acid (45 mg, 0.26 mmol) and 1-hydroxy-7-azabenzotriazole (71 mg , 0.52 mmol) was dissolved in N , N -dimethylformamide (10 mL) solution, under ice bath conditions, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added in turn Hydrochloride (100 mg, 0.52 mmol) and N , N -diisopropylethylamine (100 mg, 0.78 mmol) were reacted at room temperature for 10 h, the reaction of the raw materials was complete, the reaction was stopped, and saturated brine (50 mL) was added. ), extracted with ethyl acetate (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1), A white solid (78 mg, 61% yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.17 (s, 1H), 9.07 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.81 (s, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.52 (t, J = 75.5 Hz, 1H), 6.18 (s, 1H), 4.54 – 4.46 (m, 1H) ), 4.31 (s, 1H), 4.03 – 3.91 (m, 2H), 3.66 – 3.56 (m, 1H), 3.43 (t, J = 10.4 Hz, 1H), 3.33 – 3.19 (m, 1H), 2.65 – 2.55 (m, 1H), 2.15 (s, 3H), 1.97 – 1.87 (m, 1H), 1.32 (d, J = 3.9 Hz, 6H).

MS-ESI: m/z 491.20 [M+H] ⁺ .

Embodiment 51 cases: ((2 R, 4 S ) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2 yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate

Step 1: (( 2R , 4S )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidinyl-2 Synthesis of -yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate

The compound ( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl The ester (380 mg, 0.92 mmol, Example 39, step 4) was dissolved in N , N -dimethylformamide (10 mL) solvent and 5-(ethyl(methyl)carbamoyl)pyridine was added Formic acid (211 mg, 1.01 mmol), 1-hydroxybenzotriazole (HOBT) (249 mg, 1.84 mmol), cooled at 0 °C, and 1-(3-dimethylaminopropyl)-3-ethyl was added carbodiimide hydrochloride (EDCI) (353 g, 1.84 mmol), N -methylmorpholine (NMM) (279 mg, 2.76 mmol), transfer to room temperature and stir the reaction for 16 h, add water (20 mL) ) to stop the reaction, after extraction with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA (v/v ) = 1/3 ) to give the product as a colorless oil (287 mg, 51.68% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.77 (s, 1H), 8.19 – 8.10 (m, 1H), 7.93 – 7.84 (m, 1H), 7.12 – 7.05 (m, 1H), 6.89 – 6.80 (m, 2H), 6.58 (t, J = 75.7 Hz, 1H), 4.77 – 4.53 (m, 2H), 4.42 – 4.21 (m, 1H), 4.20 – 3.92 (m, 1H), 3.84 (d , J = 6.9 Hz, 2H), 3.69 – 3.55 (m, 1H), 3.35 – 3.16 (m, 3H), 3.10 (s, 1.7H), 2.95 (s, 1.3H), 2.64 - 2.52 (m, 1H) ), 2.17 – 1.93 (m, 1H), 1.62 (s, 3H), 1.56 – 1.36 (m, 9H), 1.17 – 1.14 (m, 1H), 0.67 – 0.58 (m, 2H), 0.37 – 0.29 (m , 2H).

MS-ESI: m/z 604.30 [M+H] ⁺ .

Step 2: (( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl) Synthesis of (Methyl)carbamoyl)picolinate hydrochloride

Compound (( 2R , 4S )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidinyl-2- yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate (290 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL) solvent, and 1,4-dichlorohydrochloric acid was added The oxane solution (2.4 mL, 9.60 mmol) was stirred at room temperature for 2 h to stop the reaction, concentrated under reduced pressure for one time, then added dichloromethane (20 mL) to dissolve, and concentrated under reduced pressure again to obtain a white solid Product (241 mg, 92.97 %).

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.86 – 8.79 (m, 1H), 8.43 – 8.34 (m, 1H), 8.26 – 8.13 (m, 1H), 7.19 – 7.09 (m, 2H) ), 7.03 – 6.95 (m, 1H), 6.75 (t, J = 75.6 Hz, 1H), 4.85 – 4.77 (m, 1H), 4.74 – 4.63 (m, 1H), 4.31 – 4.20 (m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.86 – 3.78 (m, 1H), 3.77 – 3.57 (m, 3H), 3.50 – 3.39 (m, 1H), 3.13 (s, 2H), 3.01 (s, 2H), 2.69 – 2.59 (m, 1H), 2.18 – 2.04 (m, 1H), 1.41 – 1.22 (m, 3H), 1.21 – 1.16 (m, 1H), 0.68 – 0.59 (m, 2H), 0.41 – 0.33 (m, 2H).

MS-ESI: m/z 504.30 [M-HCl+H] ⁺ .

Step 3: (( 2R , 4S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl Synthesis of 5-(ethyl(methyl)carbamoyl)picolinate

Compound (( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl( Methyl)carbamoyl)picolinate hydrochloride (241 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL) solvent, cooled at 0 °C, and N , N -diisopropyl was added Ethylamine (DIPEA) (248 mg, 1.92 mmol), acetyl chloride (75 mg, 0.96 mmol), transferred to room temperature and stirred for 1 h, the reaction solution was washed with water (20 mL×2), and dried over anhydrous sodium sulfate , concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give the product as a pale yellow solid (108 mg, yield 41.24%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.77 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.92 – 7.83 (m, 1H), 7.14 – 7.05 (m, 1H) ), 6.94 – 6.82 (m, 2H), 6.59 (t, J = 75.6 Hz, 1H), 4.82 – 4.74 (m, 1H), 4.73 – 4.64 (m, 1H), 4.63 – 4.51 (m, 1H), 3.94 – 3.88 (m, 1H), 3.88 – 3.80 (m, 2H), 3.66 – 3.56 (m, 1H), 3.51 (t, J = 10.8 Hz, 1H), 3.33 – 3.22 (m, 2H), 3.11 ( s, 1.7H), 2.96 (s, 1.3H), 2.64 – 2.54 (m, 1H), 2.24 (s, 0.6H), 2.15 – 2.02 (m, 3.4H), 1.34 – 1.21 (m, 3H), 1.18 – 1.13 (m, 1H), 0.68 – 0.56 (m, 2H), 0.38 – 0.28 (m, 2H).

MS-ESI: m/z 546.20 [M+H] ⁺ .

Embodiment 52 cases: ((2 R, 4 S ) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2-pyrrolidinyl -yl)methyl 5-(ethylcarboxamido)picolinate

Step 1: Synthesis of 6-(methoxycarbonyl)nicotinic acid

Pyridine-2,5-dicarboxylic acid (500 mg, 2.99 mmol) was added to methanol (10 mL), concentrated sulfuric acid (0.16 mL, 2.99 mmol) was added slowly, the reaction was refluxed at 70 °C for 1 h, and cooled to room temperature , add ice water (20 mL), stir until the white solid is completely precipitated and then suction filtration, the solid is dissolved in tetrahydrofuran (20 mL), the organic phase is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a white solid product (400 mg, yield 73.85 %).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.20 – 9.11 (m, 1H), 8.49 – 8.39 (m, 1H), 8.22 – 8.09 (m, 1H), 3.91 (s, 3H) .

MS-ESI: m/z 182.10 [M+H] ⁺ .

Step 2: Synthesis of methyl 5-(ethylcarbamoyl)picolinate

Compound 6-(methoxycarbonyl)nicotinic acid (2.50 g, 13.80 mmol), ethylamine hydrochloride (1.35 g, 16.56 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) ( 3.76 g, 27.60 mmol) was dissolved in dry N , N -dimethylformamide (30 mL) solvent, cooled at 0 °C, and 1-(3-dimethylaminopropyl)-3-ethyl was added. carbodiimide hydrochloride (EDCI) (5.29 g, 27.60 mmol), N , N -diisopropylethylamine (DIPEA) (5.35 g, 41.40 mmol), transferred to room temperature and stirred for 27 h, The reaction was stopped, the solvent was concentrated under reduced pressure, water (30 mL) was added to dissolve the concentrate, extracted with dichloromethane (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give a white solid (1.78 g, 61.95% yield).

¹ H NMR (400 MHz, MeOH- d ₄ ) δ (ppm): 9.07 – 9.02 (m, 1H), 8.39 – 8.32 (m, 1H), 8.25 – 8.19 (m, 1H), 4.00 (s, 3H) , 3.51 – 3.42 (m, 2H), 1.25 (t, J = 7.3 Hz, 3H).

MS-ESI: m/z 209.10 [M+H] ⁺ .

Step 3: Lithium 5-(Ethylcarbamoyl)picolinate

The compound methyl 5-(ethylcarbamoyl)picolinate (1.77 g, 8.50 mmol) was dissolved in tetrahydrofuran (16 mL) solvent, and then lithium hydroxide monohydrate (0.37 g, 8.93 mmol) and aqueous solution were added. (2.5 mL), transferred to 50 °C and stirred for 23 h, cooled to room temperature, filtered with suction, and the filter cake was vacuum-dried at 50 °C for 8 h to obtain a white solid product (1.55 g, yield 91.12%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.89 – 8.84 (m, 1H), 8.33 – 8.23 (m, 1H), 8.02 (d, J = 8.1 Hz, 1H), 3.34 – 3.26 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H).

MS-ESI: m/z 195.20 [M-Li+2H] ⁺ .

Step 4: Synthesis of ((2R ,2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methanol hydrochloride

The compound ( 2R , 2S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl The ester (1.7 g, 4.11 mmol, Example 39, step 4) was dissolved in dichloromethane (15 mL) solvent, and a solution of hydrochloric acid in 1,4-dioxane (10.3 mL, 41.1 mmol) was added at room temperature The reaction was stirred at a temperature for 2 h, the reaction was stopped, and after concentration under reduced pressure once, dichloromethane (20 mL) was added to dissolve, and concentrated under reduced pressure again to obtain a light brown oily product (1.44 g, yield 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.11 (d, J = 8.1 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.60 (t, J = 75.5 Hz, 1H), 4.74 (br.s, 1H), 4.11 – 4.03 (m, 1H), 4.02 – 3.91 (m, 2H), 3.89 – 3.81 (m, 2H), 3.76 (s, 1H) , 3.62 – 3.48 (m, 1H), 3.40 – 3.24 (m, 1H), 2.44 – 2.32 (m, 1H), 2.17 (br.s, 1H), 2.08 – 1.96 (m, 1H), 1.32 – 1.25 ( m, 1H), 0.67 – 0.59 (m, 2H), 0.40 – 0.31 (m, 2H).

MS-ESI: m/z 314.20 [M+H] ⁺ .

Step 5: (( 2R , 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetic acid Synthesis of methyl esters

Compound (( 2R , 2S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methanol hydrochloride (1.44 g, 4.12 mmol) was dissolved in dichloromethane (20 mL) solvent, cooled at 0 °C, and then added with N , N -diisopropylethylamine (DIPEA) (2.66 g, 20.6 mmol), acetyl chloride (0.97 g) , 12.36 mmol), transferred to room temperature and stirred for 1 h, the reaction solution was washed with water (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EA/PE (v/v ) = 9/1) to give a yellow liquid product (1.15 g, 70.24% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.16 – 7.08 (m, 1H), 6.87 – 6.76 (m, 2H), 6.80 – 6.39 (m, 1H), 4.39 (s, 2H), 4.29 – 4.18 (m, 1H), 3.96 – 3.78 (m, 3H), 3.45 – 3.33 (m, 1H), 3.33 – 3.13 (m, 1H), 2.55 – 2.45 (m, 1H), 2.17 (s, 1H) , 2.13 – 2.05 (m, 5H), 2.01 – 1.87 (m, 1H), 1.33 – 1.26 (m, 1H), 0.73 – 0.60 (m, 2H), 0.43 – 0.29 (m, 2H).

MS-ESI: m/z 398.20 [M+H] ⁺ .

Step 6: 1-(( 2R , 2S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1 Synthesis of -yl)ethyl-1-one

The compound (( 2R , 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetic acid methyl The ester (1.15 g, 2.89 mmol) was dissolved in tetrahydrofuran (20 mL) solvent, then lithium hydroxide monohydrate (0.30 g, 7.23 mmol) and aqueous solution (10 mL) were added, and the reaction was transferred to 50 °C and stirred for 2 After h, it was cooled at 0 °C, 1 M hydrochloric acid was added dropwise to make it acidic (pH = 2), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 2). , the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was obtained as a brown oil (1.00 g, 97.37 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14 – 7.09 (m, 1H), 6.81 – 6.78 (m, 2H), 6.60 (t, J = 73.8 Hz, 1H), 4.27 – 4.18 (m , 1H), 3.95 – 3.89 (m, 1H), 3.89 – 3.83 (m, 2H), 3.82 – 3.74 (m, 1H), 3.70 – 3.63 (m, 1H), 3.47 – 3.37 (m, 1H), 3.34 – 3.23 (m, 1H), 2.48 – 2.40 (m, 1H), 2.16 – 2.10 (m, 3H), 1.74 – 1.60 (m, 1H), 1.34 – 1.27 (m, 1H), 0.69 – 0.62 (m, 2H), 0.39 – 0.32 (m, 2H).

MS-ESI: m/z 356.15 [M+H] ⁺ .

Step 7: (( 2R , 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)5 Synthesis of Methyl-(Ethylcarbamoyl)picolinate

A solution of lithium 5-(ethylcarbamoyl)picolinate (168 mg, 0.84 mmol) and hydrochloric acid in 1,4-dioxane (0.28 mL, 1 mmol) was dissolved in N , N -dimethylformaldehyde 1-(( 2R , 2S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -2-(Hydroxymethyl)pyrrolidin-1-yl)ethyl-1-one (11250-3) (200 mg, 0.56 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (114 mg, 0.84 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (268 mg, 1.40 mmol), N, N-diisopropylethylamine (DIPEA) (325 mg, 2.52 mmol), transferred to room temperature, stirred for 9 h, added water (20 mL), extracted with ethyl acetate (20 mL×2), combined organic phase was washed with saturated brine (20 mL×2), the organic phase was dried with anhydrous sodium sulfate, concentrated and mixed with the sample and passed through column chromatography (DCM/MeOH (v/v) = 15/1) to obtain a white solid product (151 mg) , yield 50.73%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.05 (s, 1H), 8.28 – 8.19 (m, 1H), 8.19 – 8.11 (m, 1H), 7.14 – 7.05 (m, 1H), 6.91 – 6.82 (m, 2H), 6.80 – 6.35 (m, 1H), 6.40 (s, 1H), 4.82 – 4.72 (m, 1H), 4.71 – 4.62 (m, 1H), 4.62 – 4.53 (m, 1H) , 3.94 – 3.87 (m, 1H), 3.85 – 3.74 (m, 2H), 3.61 – 3.45 (m, 3H), 3.36 – 3.22 (m, 1H), 2.65 – 2.52 (m, 1H), 2.23 (s, 0.6H), 2.15 – 2.01 (m, 3.4H), 1.34 – 1.21 (m, 4H), 0.69 – 0.53 (m, 2H), 0.39 – 0.21 (m, 2H).

MS-ESI: m/z 532.20 [M+H] ⁺ .

Example 53: ((2 R, 4 S ) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2 yl)methyl 5-(methylcarbamoyl)picolinate

Step 1: Synthesis of methyl 5-(methylcarbamoyl)picolinate

Compound 6-(methoxycarbonyl)nicotinic acid (2.35 g, 12.97 mmol, Example 52 step 1), methylamine hydrochloride (1.05 g, 15.56 mmol), 1-hydroxy-7-azabenzotri Azole (HOAT) (3.76 g, 27.60 mmol) was dissolved in dry N , N -dimethylformamide (30 mL) solvent, cooled at 0 °C, and 1-(3-dimethylaminopropyl) was added. yl)-3-ethylcarbodiimide hydrochloride (EDCI) (4.97 g, 25.94 mmol), N , N -diisopropylethylamine (DIPEA) (5.03 g, 38.91 mmol), transferred to room temperature The reaction was stirred for 17 h, the reaction was stopped, the solvent was concentrated under reduced pressure, water (30 mL) was added to dissolve the concentrate, extracted with dichloromethane (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) gave a white solid (1.50 g, 59.56 % yield).

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 9.10 – 9.00 (m, 1H), 8.42 – 8.32 (m, 1H), 8.28 – 8.19 (m, 1H), 4.00 (s, 3H), 2.96 (s, 3H).

MS-ESI: m/z 195.10 [M+H] ⁺ .

Step 2: Synthesis of lithium 5-(methylcarbamoyl)picolinate

Compound 5-(ethylcarbamoyl)picolinate methyl ester (250-1) (1.40 g, 7.21 mmol) was dissolved in tetrahydrofuran (16 mL) solvent, and lithium hydroxide monohydrate (0.36 g, 8.65 mmol) and aqueous solution (2.5 mL), transferred to 50 °C and stirred for 23 h, the reaction solution was concentrated, and vacuum dried at 50 °C for 8 h to obtain a white solid product (1.40 g, yield 100%).

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.99 – 8.94 (m, 1H), 8.28 – 8.22 (m, 1H), 8.12 – 8.06 (m, 1H), 2.95 (s, 3H).

MS-ESI: m/z 181.20 [M-Li+2H] ⁺ .

Step 3: (( 2R , 4S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)5 Synthesis of -(methylcarbamoyl)picolinate

A solution of lithium 5-(methylcarbamoyl)picolinate (248 mg, 1.33 mmol) and hydrochloric acid in 1,4-dioxane (0.45 mL, 1.78 mmol) was dissolved in N , N -dimethylformaldehyde 1-(( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -2-(Hydroxymethyl)pyrrolidin-1-yl)ethyl-1-one (315 mg, 0.89 mmol, Example 52, step 6), 1-hydroxy-7-azabenzotriazole (HOAT ) (182 mg, 1.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (426 mg, 2.23 mmol) was added successively under ice bath, N , N -diisopropylethylamine (DIPEA) (517 mg, 4.00 mmol), transfer to room temperature and stir the reaction for 24 h, add water (20 mL), extract with ethyl acetate (20 mL×2), combine The organic phase was washed with saturated brine (20 mL × 2), the organic phase was dried with anhydrous sodium sulfate, concentrated and mixed with sample, and then passed through column chromatography (DCM/MeOH (v/v) = 15/1) to obtain a white solid product ( 206 mg, yield 44.72 %)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.06 (s, 1H), 8.30 – 8.21 (m, 1H), 8.20 – 8.10 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H ), 6.91 – 6.80 (m, 2H), 6.67 – 6.61 (m, 1H), 6.59 (t, J = 75.6 Hz, 1H), 4.78 – 4.73 (m, 1H), 4.70 – 4.63 (m, 1H), 4.62 – 4.54 (m, 1H), 3.94 – 3.87 (m, 1H), 3.81 (d, J = 6.9 Hz, 2H), 3.51 (t, J = 10.8 Hz, 1H), 3.35 – 3.24 (m, 1H) , 3.05 (d, J = 4.7 Hz, 3H), 2.63 – 2.53 (m, 1H), 2.22 (s, 0.6H), 2.14 – 2.02 (m, 1H), 2.09 (s, 2.4H), 1.27 – 1.22 (m, 1H), 0.67 – 0.57 (m, 2H), 0.38 – 0.26 (m, 2H).

MS-ESI: m/z 518.20 [M+H] ⁺ .

Embodiment 54 cases: ((2 R, 4 S ) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2 yl) methyl 5-carbamoyl picolinate

Step 1: Synthesis of methyl 5-carbamoylpicolinate

Compound 6-(methoxycarbonyl)nicotinic acid (2.50 g, 13.80 mmol, Example 52 step 1), ammonium chloride (1.11 g, 20.70 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (3.76 g, 27.60 mmol) was dissolved in N , N -dimethylformamide (30 mL) solvent, cooled at 0 °C, and 1-(3-dimethylaminopropyl)-3 was added -Ethylcarbodiimide (EDCI) (5.29 g, 27.60 mmol), N , N -diisopropylethylamine (DIPEA) (5.35 g, 41.40 mmol), transfer to room temperature and stir the reaction for 27 h, stop After reaction, the solvent was concentrated under reduced pressure, water (30 mL) was added to dissolve the concentrate, extracted with dichloromethane (30 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography ( DCM/MeOH (v/v) = 20/1) to give a colorless liquid (1.26 g, 50.68 % yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.14 – 9.07 (m, 1H), 8.43 – 8.35 (m, 1H), 8.33 (s, 1H), 8.13 (d, J = 8.1 Hz , 1H), 7.78 (s, 1H), 3.90 (s, 3H).

MS-ESI: m/z 181.15 [M+H] ⁺ .

Step 2: Synthesis of lithium 5-carbamoylpicolinate

Compound 5-(ethyl(methyl)carbamoyl)picolinate methyl ester (249-1) (1.24 g, 6.88 mmol) was dissolved in tetrahydrofuran (20 mL) solvent, and lithium hydroxide monohydrate was added (0.32 g, 7.57 mmol) and an aqueous solution (10 mL) were transferred to 50 °C and stirred for 3.5 h, then concentrated under reduced pressure to remove the solvent, and vacuum dried at 50 °C for 8 h to obtain a white solid product (1.18 g, yield rate 99.68%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.94 – 8.87 (m, 1H), 8.34 – 8.27 (m, 1H), 8.24 (s, 1H), 8.01 (d, J = 8.1 Hz , 1H), 7.63 (s, 1H).

MS-ESI: m/z 167.25 [M-Li+2H] ⁺ .

Step 3: (( 2R , 4S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl Synthesis of 5-carbamoylpicolinic acid

A solution of lithium 5-carbamoylpicolinate (248 mg, 1.44 mmol) and hydrochloric acid in 1,4-dioxane (0.48 mL, 1.92 mmol) was dissolved in DMF (5 mL) and stirred until clear 1-(( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1- yl)ethyl-1-one (342 mg, 0.96 mmol, Example 52, step 6), 1-hydroxy-7-azabenzotriazole (HOAT) (196 mg, 1.44 mmol) under ice bath 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (460 mg, 2.40 mmol), N , N -diisopropylethylamine (DIPEA) ( 558 mg, 4.32 mmol), transfer to room temperature and stir the reaction for 24 h, add water (20 mL), extract with ethyl acetate (20 mL×2), combine the organic phases, add saturated brine (20 mL×2) After washing, the organic phase was dried with anhydrous sodium sulfate, and the mixed sample was concentrated and subjected to silica gel column chromatography (DCM/MeOH (v/v) = 15/1) to obtain a white solid product (180 mg, yield 37.24 %)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.14 (s, 1H), 8.39 – 8.28 (m, 1H), 8.24 – 8.12 (m, 1H), 7.21 – 7.01 (m, 1H), 6.96 – 6.81 (m, 2H), 6.76 – 6.63 (m, 1H), 6.59 (t, J = 75.6 Hz, 1H), 6.23 – 5.98 (m, 1H), 4.82 – 4.73 (m, 1H), 4.71 – 4.63 (m, 1H), 4.62 – 4.46 (m, 1H), 3.98 – 3.86 (m, 1H), 3.86 – 3.75 (m, 2H), 3.52 (t, J = 10.7 Hz, 1H), 3.37 – 3.21 (m , 1H), 2.65 – 2.51 (m, 1H), 2.23 (s, 1H), 2.15 – 2.02 (m, 3H), 1.27 – 1.22 (m, 1H), 0.69 – 0.56 (m, 2H), 0.39 – 0.25 (m, 2H).

MS-ESI: m/z 504.20 [M+H] ⁺ .

Example 55: ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) methyl 5-(Ethyl(methyl)carbamoyl)picolinate

Step 1: Synthesis of 2-(difluoromethoxy)-5-iodophenol

2-(Cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (20.00 g, 58.80 mmol) was added to a 250 mL two-necked round-bottomed flask, acetonitrile (80 mL) was dissolved, Concentrated hydrochloric acid (40 mL) was slowly added dropwise, and the reaction was stopped in an oil bath at 80 °C for 12 h under nitrogen protection. Cool to room temperature, add water (100 mL), then add ethyl acetate (100 mL × 2) for extraction, combine the organic phases, and dry with anhydrous sodium sulfate for 30 min. The crude product was purified by silica gel column chromatography (eluent: PE=100%) to give a pale yellow oily product (13.4 g, yield 79.68 %)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.37 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.5, 2.1 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.51 (t, J = 73.1 Hz, 1H), 5.61 (s, 1H).

GC-MS: m/z 285.9 [M] ⁺ .

Step 2: Synthesis of 1-(difluoromethoxy)-4-iodo-2-isopropoxybenzene

2-(difluoromethoxy)-5-iodophenol (11.4 g, 39.86 mmol) was added to a 250 mL one-neck flask, N , N -dimethylformamide (55 mL) was dissolved, and potassium carbonate ( 16.53 g, 119.58 mmol) and 2-iodopropane (10.16 g, 59.79 mmol), and the reaction was stirred at 80 °C for 2 h to stop the reaction. Cool to room temperature, add water (150 mL), extract with ethyl acetate (50 mL × 2), wash the organic phase with saturated brine (100 mL) once, dry over anhydrous sodium sulfate for 30 min, and concentrate under reduced pressure. The product was obtained as light yellow oil (12.51 g, 95.66 % yield)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.26 – 7.23 (m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 6.52 (t, J = 75.2 Hz, 1H), 4.56 - 4.50 (m, 1H), 1.36 (d, J = 6.1 Hz, 6H).

GC-MS: m/z 328 [M] ⁺ .

Step 3: Compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane Synthesis of Borane

Compound 1-(difluoromethoxy)-4-iodo-2-isopropoxybenzene (13.7 g, 41.76 mmol), pinacol biboronate (11.13 g, 43.85 mmol), potassium acetate (6.15 g, 62.64 mmol), 2-dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) (1.52 g, 4.18 mmol) and palladium acetate (470 mg, 2.09 mmol) were dissolved in dry N , N -dimethylene In the solution of methylformamide (82 mL), under nitrogen protection, react at 80 °C for 2 h. After the reaction solution was cooled, water (700 mL) was added to mix, extracted with ethyl acetate (40 mL × 3), and anhydrous sulfuric acid was used. Dry over sodium, concentrate under reduced pressure, and purify by silica gel column chromatography (EtOAc/PE (v/v) = 1/10) to give the product as a brown liquid (11.4 g, 83.19 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.40 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.60 (t, J _FH = 75.5 Hz, 1H), 4.69 – 4.62 (m, 1H), 1.36 (d, J = 6.1 Hz, 6H), 1.34 (s, 12H).

GC-MS: m/z 286.10 [M-(i-Pr)+H].

Step 4 :( R) -1- tert-butyl 2-methyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) -1 H - pyrrole -1, 2 (2 H Synthesis of , 5 H )-dicarboxylate

The compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (10.58 g, 32.24 mmol), (R) -1- tert-butyl 2-methyl 4 - (((trifluoromethyl) sulfonyl acyl) oxy) -1 H - pyrrole-1, 2- (2 H , 5H )-dicarboxylate (11.0 g, 29.31 mmol, intermediate M2), palladium acetate (160 mg, 0.73 mmol), 2-dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) ( 530 mg, 1.47 mmol), N -methylmorpholine (NMM) (6.52 g, 64.48 mmol), dissolved in a solution of toluene (55 mL) and water (27 mL), under nitrogen protection, in an oil bath at 80 °C The reaction was carried out for 40 min. After the reaction solution was cooled, water (200 mL × 2) was added to wash the organic phase, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v) = 8/1) to obtain Brown liquid (12.4 g, 98.98% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.40 (s, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.60 (t, J _FH = 75.5 Hz, 1H), 6.02 – 6.59 (m, 1H), 4.69 – 4.62 (m, 1H), 4.66 – 4.46 (m, 3H), 3.76 (d, J = 4.4 Hz, 3H), 1.52 ( s, 3H), 1.45 (s, 6H), 1.37 – 1.33 (m, 6H).

MS-ESI: m/z 372.10 [M- t- Bu+2H] ⁺ .

Step 5: ( 2R , 4S )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1,2-di Synthesis of Carboxylic Acid Esters

The compound (R) -1- tert-butyl 2-methyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) -1 H - pyrrole -1,2 (2 H, 5H )-dicarboxylate (4.60 g, 10.5 mmol) was dissolved in methanol solution (70 mL), then 10% Pd/C reducing agent (140 mg) was added, and after replacing with hydrogen three times, under hydrogen protection, The reaction was stirred at room temperature for 3 h, the reaction solution was filtered through celite, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to obtain a light yellow viscous liquid product ( 4.60 g, 99.50% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J = 8.0 Hz, 1H), 6.81 – 6.78 (m, 2H), 6.60 (t, J = 76.4 Hz, 1H), 4.44 – 4.26 (m, 1H), 4.07 – 3.90 (m, 1H), 3.90 – 3.82 (m, 2H), 3.76 (d, J = 6.5 Hz, 3H), 3.47 – 3.37 (m, 1H), 3.38 – 3.25 ( m, 1H), 2.68 – 2.58 (m, 1H), 2.10 – 1.95 (m, 1H), 1.45 (d, J = 14.1 Hz, 9H), 1.24 – 1.31 (m, 1H), 0.71 – 0.59 (m, 2H), 0.41 – 0.29 (m, 2H).

MS-ESI: m/z 374.20 [M- t- Bu+2H] ⁺ .

Step 6: (2 R, 4 S ) - 4- (4- ( difluoromethoxy) -3-isopropoxyphenyl) -2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl Synthesis of Esters

The compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1,2-dicarboxylate The acid ester (4.40 g, 10.25 mmol) was dissolved in dry tetrahydrofuran (22 mL) solution, cooled at -5 °C, and 2 mol/L lithium borohydride tetrahydrofuran solution (5.13 mL) was added. After adding the raw materials, transfer to room temperature React for 4 hours. Saturated aqueous sodium chloride solution (30 mL) was added, extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give a colorless liquid (4.10 g, 99.64 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.09 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.53 (t, J _FH = 75.6 Hz, 1H), 5.18 (d, J = 8.6 Hz, 1H), 4.57 – 4.51 (m, 1H), 4.11 – 4.02 (m, 1H), 4.00 – 3.90 (m, 1H), 3.81 – 3.64 (m, 2H), 3.27 – 3.17 (m, 2H), 2.43 – 2.34 (m, 1H), 1.67 – 1.57 (m, 1H), 1.48(s, 9H), 1.35 (d, J = 6.1 Hz, 6H).

MS-ESI: m/z 346.10 [M- t- Bu+2H] ⁺ .

Step 7: Synthesis of Compound ((2R , 4S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methanol hydrochloride

The compound ( 2R , 4S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl ester (4.10 g, 10.21 mmol) was dissolved in dichloromethane (20 mL) solution, added 4.02 mol/L HCl in 1,4-dioxane solution (15.2 mL), stirred at room temperature for 3 h, concentrated under reduced pressure, A light brown liquid was obtained (3.40 g, 98.57% yield).

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.16 – 7.12 (m, 2H), 6.97 (dd, J = 8.3, 1.8 Hz, 1H), 6.70 (t, J _FH = 75.3 Hz, 1H) ), 4.73 – 4.66 (m, 1H), 3.98 – 3.88 (m, 2H), 3.84 – 3.78 (m, 1H), 3.77 – 3.70 (m, 1H), 3.67 – 3.59 (m, 1H), 3.30 – 3.24 (m, 1H), 2.54 – 2.47 (m, 1H), 2.03 – 1.95 (m, 1H), 1.35 (d, J = 6.1 Hz, 6H).

MS-ESI: m/z 302.20 [M-HCl+H] ⁺ .

Step 8: Compound ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) methyl Synthesis of Acetate

Compound (( 2R , 4S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methanol hydrochloride (3.40 g, 10.06 mmol ) was dissolved in dichloromethane (35 mL), cooled at -10 °C, added N , N -diisopropylethylamine (6.50 g, 50.3 mmol) and acetyl chloride (2.21 g, 28.17 mmol), transferred The reaction was stopped after reaching room temperature for 1 h, water (50 mL) was added to wash the organic phase, the organic phase was separated, the organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE /EtOAc (v/v) = 5/3) to give a brown liquid (3.80 g, 98.01% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.13 – 7.10 (m, 1H), 6.84 – 6.78 (m, 2H), 6.54 (t, J _FH = 74.9 Hz, 1H), 4.58 – 4.51 ( m, 1H), 4.44 – 4.35 (m, 2H), 4.27 – 4.10 (m, 1H), 3.92 – 3.88 (m, 1H), 3.41 – 3.35 (m, 1H), 3.31 – 3.15 (m, 1H), 2.52 – 2.47 (m, 1H), 2.10 – 2.04 (m, 6H), 1.98 – 1.88 (m, 1H), 1.37 – 1.34 (m, 6H).

MS-ESI: m/z 386.30 [M+H] ⁺ .

Step 9: Compound 1-(( 2R , 4S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1- Synthesis of ethyl) ethyl ketone

Compound ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) methyl acetate Ester (3.80 g, 9.86 mmol) and lithium hydroxide monohydrate (830 mg, 19.72 mmol) were dissolved in a mixed solvent of tetrahydrofuran/water (v/v) = 2/1 (45 mL), and reacted at 50 °C for 1 h , tetrahydrofuran was removed under reduced pressure, extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a brown liquid (3.30 g, yield 97.47%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.12 – 7.09 (m, 2H), 6.98 (t, J _FH = 74.9 Hz, 1H), 6.91 – 6.86 (m, 1H), 5.04 – 4.93 (m, 1H), 4.71 – 4.61 (m, 1H), 4.02 – 3.94 (m, 1H), 3.65 – 3.51 (m, 2H), 3.33 – 3.20 (m, 2H), 2.39 – 2.33 (m, 1H) ), 2.02 – 2.04 (m, 3H), 1.96 – 1.84 (m, 1H), 1.28 (d, J = 6.0 Hz, 6H).

MS-ESI: m/z 344.20 [M+H] ⁺ .

Step 10: ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) methyl-5 Synthesis of -(ethyl(methyl)carbamoyl)picolinate

Compound 5-(ethyl(methyl)carbamoyl)picolinate lithium salt (280 mg, 1.32 mmol) was added to dry N,N-dimethylformamide (6 ml) solution, added 4.02 mol/L HCl in 1,4-dioxane solution (0.44 mL), add 1-((2 R ,4 S )-4-(4-(difluoromethoxy)-3-isopropoxy phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (302 mg, 0.88 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (180 mg, 1.32 mmol) ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (420 mg, 2.20 mmol), after cooling in an ice bath, N , N -diisopropyl was added Ethylamine (DIPEA) (510 mg, 3.96 mmol), transferred to room temperature and stirred for 13 h. Water (50 ml) was added to quench the reaction, the organic phase was extracted with ethyl acetate (15 ml × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH (v/v)= 50/1) to give a pale yellow solid (165 mg, 31.87% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.76 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.91 – 7.84 (m, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.89 – 6.86 (m, 2H), 6.52 (t, J _FH = 75.5 Hz, 1H), 4.81 – 4.65 (m, 2H), 4.62 – 4.43 (m, 3H), 3.93 – 4.89 (m , 1H), 3.65 – 3.57 (m, 1H), 3.51 (t, J = 10.8 Hz, 1H), 3.34 – 3.20 (m, 2H), 3.10 (s, 1.7H), 2.95 (s, 1.3H), 2.63 – 2.53 (m, 1H), 2.10 (s, 3H), 1.32 – 1.28 (m, 6H), 1.27 – 1.14 (m, 3H).

MS-ESI: m/z 534.20 [M+H] ⁺ .

Example 56: ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) methyl 5-(Methylcarbamoyl)picolinate

The compound 5-(methylaminocarbamoyl)picolinate lithium salt (250 mg, 1.32 mmol) was added to dry N , N -dimethylformamide (6 ml) solution, and 4.02 mol/L was added HCl in 1,4-dioxane (0.44 mL), add 1-(( 2R , 4S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl) -2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (301 mg, 0.88 mmol, Example 55, step 9), 1-hydroxy-7-azabenzotriazole (HOAT) (180 mg, 1.32 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (420 mg, 2.20 mmol), after cooling in an ice bath, N , N -diisopropyl was added Diethylamine (DIPEA) (510 mg, 3.96 mmol), transferred to room temperature and stirred for 14 h. Water (50 mL) was added to quench the reaction, the organic phase was extracted with ethyl acetate (15 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH (v/v)= 25/1) to give a pale yellow solid (157 mg, 34.98% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.07 (s, 1H), 8.25 (dd, J = 8.1, 2.0 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.08 ( d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 6.87 – 6.83 (m, 1H), 6.78 – 6.67 (m, 1H), 6.52 (t, J _FH = 75.5 Hz, 1H), 4.78 – 4.41 (m, 4H), 3.94 – 4.88 (m, 1H), 3.51 (t, J = 10.8 Hz, 1H), 3.35 – 3.14 (m, 1H), 3.04 (d, J = 4.7 Hz, 3H), 2.79 – 2.55 (m, 1H), 2.14 – 2.00 (m, 1H), 2.09 (s, 3H), 1.33 – 1.30 (m, 6H).

MS-ESI: m/z 506.20 [M+H] ⁺ ..

Example 57: ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) methyl 5-Carboxylic picolinate

The compound 5-aminocarbamoylpicolinate lithium salt (220 mg, 1.30 mmol) was added to a dry solution of N , N -dimethylformamide (6 mL), and 4.02 mol/L HCl in 1,000 was added. 4-dioxane solution (0.43 mL), add 1-((2 R ,4 S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-( Hydroxymethyl)pyrrolidin-1-yl)ethanone (299 mg, 0.87 mmol, Example 55, step 9), 1-hydroxy-7-azabenzotriazole (HOAT) (180 mg, 1.30 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (420 mg, 2.17 mmol), after cooling in an ice bath, N , N -diisopropylethylamine ( DIPEA) (510 mg, 3.92 mmol), transferred to room temperature and stirred for 14 h. Water (50 mL) was added to quench the reaction, and the organic phase was extracted with ethyl acetate (15 mL of ethyl ester 10), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH (v/v) = 15/1) to give a pale yellow solid (163 mg, 36.50% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.22 (s, 1H), 8.38 (d, J = 7.0 Hz, 1H), 8.19 (d, J = 6.2 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 6.87 (d, J = 9.9 Hz, 1H), 6.52 (t, J _FH = 75.5 Hz, 1H), 4.75 – 4.50 (m, 4H), 3.97 – 3.88 (m, 1H), 3.56 – 3.47 (m, 1H), 2.66 – 2.39 (m, 3H), 2.10 (s, 3H), 1.31 (d, J = 5.8 Hz, 6H).

MS-ESI: m/z 492.20 [M+H] ⁺ .

Example 58: N - (((2 R , 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl )methyl)pyridamide

Step 1: Synthesis of compound 2-(difluoromethoxy)-5-iodophenol

Compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (20 g, 58.8 mmol) was dissolved in acetonitrile (80 mL), and concentrated hydrochloric acid (48 g) was added , 480.5 mmol, 36.5%), placed under heating at 80 °C for 12 h. After the reaction was completed, 150 mL of water was added, extracted with dichloromethane (50 mL × 3), the organic phase was dried by adding anhydrous sodium sulfate, distilled under reduced pressure, removed the solvent, and separated and purified by silica gel column chromatography (PE/EtOAc (v/v) =100/1) to give a colorless liquid (13.6 g, 81% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.37 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.5, 1.9 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.51 (t, J = 73.2 Hz, 1H), 5.74 (s, 1H).

GC-MS(EI): m/z 285.93 [M] ⁺ .

Step 2: Synthesis of compound 1-(difluoromethoxy)-4-iodo-2-isopropoxybenzene

Compound 2-(difluoromethoxy)-5-iodophenol (13.6 g, 47.6 mmol) and 2-iodopropane (12.1 g, 71.3 mmol) were dissolved in DMF (70 mL) and potassium carbonate (19.7 mmol) was added g, 142.7 mmol), placed under heating at 80 °C for 4 h. After the reaction was completed, 150 mL of water was added, extracted with ethyl acetate (50 mL × 3), the organic phase was dried by adding anhydrous sodium sulfate, distilled under reduced pressure, the solvent was removed, and the silica gel column chromatography was used for separation and purification (PE/EtOAc (v/v) =100/1) to give a pale yellow liquid (14.4 g, 92% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.26 (s, 1H), 7.23 (dd, J = 8.4, 1.6 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.52 ( t, J = 75.2 Hz, 1H), 4.56 – 4.50 (m, 1H), 1.35 (d, J = 6.1 Hz, 6H).

GC-MS(EI): m/z 327.9 [M] ⁺ .

Step 3: Compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane Synthesis of Borane

Compound 1-(difluoromethoxy)-4-iodo-2-isopropoxybenzene (14 g, 42.7 mmol), pinacol biboronate (10.8 g, 42.7 mmol), potassium acetate (6.3 g , 64.0 mmol), dicyclohexyl-[2-(2-methylphenyl)phenyl]phosphine (1.6 g, 4.27 mmol) and palladium acetate (0.48 g, 2.13 mmol) in DMF (70 mL) solution, The reaction was carried out at 80 °C for 6 h under nitrogen protection, the reaction was stopped, and the reaction was cooled to room temperature. Water (250 mL) was added to the reaction solution, extracted with petroleum ether (50 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: PE/EtOAc (v /v ) = 100/1) to give a brownish-yellow liquid (12.6 g, 90% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.40 (s, 1H), 7.39 (d, J = 9.7 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.60 (t, J = 75.6 Hz, 1H), 4.68 – 4.62 (m, 1H), 1.36 (d, J = 6.1 Hz, 6H), 1.34 (s, 12H).

Step 4: Compound (R) -1- tert-butyl 2-methyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) -1 H - pyrrole-1,2 (2 Synthesis of H , 5H)-dicarboxylate

The compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (12 g, 32 mmol), ( R )-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy) 1H -pyrrole-1,2( 2H , 5H )-dicarboxylate (13 g, 32 mmol), N -methylmorpholine (7.1 g, 70.3 mmol), dicyclohexyl-[2-(2-methylphenyl)phenyl]phosphine ( 0.58 g, 1.6 mmol) and palladium acetate (0.18 g, 0.8 mmol) were mixed in a mixed solution of toluene (60 mL) and water (30 mL), reacted at 80 °C for 1 h under nitrogen protection, stopped the reaction, and cooled to room temperature. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: PE/EtOAc ( v/v ) = 5/1) to give a yellow liquid (12.6 g, 90% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.13 – 7.11 (m, 1H), 6.98 – 6.89 (m, 2H), 6.56 (t, J = 75.3 Hz, 1H), 6.00 (dd, J = 12.6, 1.8 Hz, 1H), 5.19 – 5.10 (m, 1H), 4.66 – 4.60 (m, 1H), 4.56 – 4.59 (m, 1H), 4.54 – 4.46 (m, 1H), 3.76 (s, 1H) ), 3.75 (s, 2H), 1.51 (s, 3H), 1.45 (s, 6H), 1.36 (s, 3H), 1.34 (s, 3H).

MS-ESI: m/z 328.20 [M-Boc+H] ⁺ .

Step 5: Compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1,2- Synthesis of Dicarboxylates

The compound (R) -1- tert-butyl 2-methyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) -1 H - pyrrole -1,2 (2 H, 5H )-dicarboxylate (12.5 g, 29.2 mmol), 10% palladium/carbon (2.84 g, 2.92 mmol) was dissolved in 190 mL of methanol, under a hydrogen atmosphere, reacted at room temperature for 6 h, the reaction of the raw materials was complete, Stop the reaction. The palladium carbon was filtered through celite, and the organic phase was concentrated under reduced pressure to obtain a yellow liquid (10 g, yield 81%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.08 (d, J = 8.2 Hz, 1H), 6.86 – 6.74 (m, 2H), 6.52 (t, J = 75.6 Hz, 1H), 4.57 – 4.49 (m, 1H), 4.40 – 4.30 (m, 1H), 4.06 – 3.91 (m, 1H), 3.76 (s, 1H), 3.74 (s, 2H), 4.43 – 4.38 (m, 1H), 3.35 – 3.26 (m, 1H), 2.68 – 2.60 (m, 1H), 2.06 – 1.95 (m, 1H), 1.46 (s, 3H), 1.42 (s, 6H), 1.34 (s, 3H), 1.33 (s, 3H).

MS-ESI: m/z 330.20 [M-Boc+2H] ⁺ .

Step 6: Compound (2 R , 4 S ) tert-butyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate Synthesis

The compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1,2-dicarboxylate The acid ester (10 g, 13.3 mmol) was dissolved in 50 mL of anhydrous tetrahydrofuran solution, and under ice bath conditions, lithium borohydride solution (11.6 mL, 2 mol/L) was added, and the reaction was carried out at room temperature for 3 h. The reaction of the raw materials was completed and stopped. reaction. The reaction was quenched by adding ice-water mixture, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: PE/EtOAc (v/v) = 5/1) to give a colorless liquid (8.8 g, 94% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.09 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.52 (t, J = 75.6 Hz, 1H), 4.58 – 4.50 (m, 1H), 4.05 – 3.95 (m, 2H), 3.77 (d, J = 11.2 Hz, 1H), 3.69 – 3.65 (m, 1H), 3.26 – 3.16 (m, 2H), 2.42 – 2.36 (m, 1H), 1.60 – 1.74 (m, 1H), 1.48 (s, 9H), 1.35 (d, J = 6.1 Hz, 6H).

MS-ESI: m/z 346.15 [M- ^t Bu+2H] ⁺ .

Step 7: Compound (2 R , 4 S ) 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-((((methylsulfonyl)oxy)methan Synthesis of tert-butyl)pyrrolidine-1-carboxylate

Compound (2 R , 4 S ) 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (7.0 g, 14.7 mmol) and N , N -diisopropylethylamine (3.6 g, 27.9 mmol) were dissolved in 50 mL of dichloromethane solution, under ice bath conditions, added methylsulfonyl chloride (MsCl) (2.6 g, 22.7 mmol), reacted at room temperature for 2 h, the reaction of the raw materials was complete, and the reaction was stopped. An ice-water mixture was added to quench the reaction, extracted with dichloromethane (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain a yellow liquid (8.0 g, yield 96%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.09 (d, J = 8.2 Hz, 1H), 6.86 (s, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.53 (t, J = 75.6 Hz, 1H), 4.71 – 4.63 (m, 0.5H), 4.60 – 4.51 (m, 1H), 4.48 – 4.31 (m, 1.5H), 4.19 – 4.06 (m, 1.5H), 4.00 – 3.91 (m, 0.5H), 3.30 – 3.12 (m, 2H), 3.01 (s, 3H), 2.58 – 2.43 (m, 1H), 2.12 – 2.03 (m, 1H), 1.52 – 1.47 (m, 9H), 1.35 (d, J = 6.0 Hz, 6H).

MS-ESI: m/z 380.20 [M- Boc +2H] ⁺ .

Step 8: Compound (2 R , 4 S ) 2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl Synthesis of Esters

Compound (2 R , 4 S ) 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-((((methylsulfonyl)oxy)methyl) Pyrrolidine-1-carboxylate tert-butyl ester (8.0 g, 16.7 mmol), sodium azide (1.6 g, 25.0 mmol) were dissolved in 40 mL of N , N -dimethylformamide solution and heated at 80 °C The reaction was carried out for 6 h under the conditions, and the reaction of the raw materials was complete, and the reaction was stopped. 100 mL of water was added, extracted with ethyl acetate (20 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (elution). Agent: PE/EA (v/v) = 10/1) to give a colorless oil (5.0 g, 71% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J = 8.2 Hz, 1H), 6.86 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.53 (t, J = 75.6 Hz, 1H), 4.60 – 4.51 (m, 1H), 4.14 – 3.90 (m, 3H), 3.46 – 3.30 (m, 1H), 3.26 – 3.17 (m, 2H), 2.41 (s, 1H) , 2.06 – 1.98 (m, 1H), 1.49 (s, 9H), 1.36 (d, J = 6.0 Hz, 6H).

MS-ESI: m/z 327.20 [M-Boc+2H] ⁺ .

Step 9: Synthesis of Compound (2R , 4S )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine hydrochloride

The compound (2 R , 4 S ) 2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester ( 4.8 g, 11.3 mmol) was dissolved in 10 mL of dichloromethane solution, then 1,4-dioxane hydrochloric acid solution (14 mL, 4.01 mol/L) was added, and the reaction was carried out at room temperature for 1.5 h. The reaction of the raw materials was complete, and the reaction was stopped. . The solvent was removed by distillation under reduced pressure, and the concentrated solution gave a yellow liquid (4.4 g, yield 100%).

MS-ESI: m/z 327.20 [M+H-HCl] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.11 (d, J = 8.2 Hz, 1H), 6.92 (s, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.53 (t, J = 75.5 Hz, 1H), 4.63 – 4.53 (m, 1H), 4.05 – 3.97(m, 3H), 3.82 – 3.73 (m, 1H), 3.63 – 3.50 (m, 1H), 3.45 – 3.33 (m, 1H), 2.53 – 2.42 (m, 1H), 2.05 – 1.95 (m, 1H), 1.34 (d, J = 5.9 Hz, 6H).

MS-ESI: m/z 327.20 [M+H-HCl] ⁺ .

Step 10: Compound 1-(( 2R , 4S )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1 -Synthesis of ethyl) ethyl ketone

Compound (2 R , 4 S )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine hydrochloride (4.4 g, 12.1 mmol) was dissolved in 20 mL of dichloromethane solution, under ice bath conditions, added N , N -diisopropylethylamine (6.3 g, 48.5 mmol), acetyl chloride (1.9 g, 24.3 mmol), room After 1 h of warm reaction, the reaction of the raw materials was completed, and the reaction was stopped. Saturated brine was added to quench the reaction, extracted with dichloromethane (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: PE/EA (v/v) = 1/1) to give a yellow liquid (4.2 g, 94% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.12 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 1.5 Hz, 1H), 6.83 (dd, J = 8.2, 1.7 Hz, 1H), 6.54 (t, J = 75.5 Hz, 1H), 4.56 (dt, J = 12.1, 6.1 Hz, 1H), 4.31 – 4.25 (m, 1H), 4.13 (dd, J = 12.4, 4.4 Hz, 1H) ), 3.90 (dd, J = 9.6, 7.7 Hz, 1H), 3.45 – 3.36 (m, 2H), 3.31 – 3.21 (m, 1H), 2.47 – 2.37 (m, 1H), 2.10 (s, 3H), 2.07 – 2.04 (m, 1H), 1.36 (d, J = 6.1 Hz, 6H).

MS-ESI: m/z 369.20 [M+H] ⁺ .

Step 11: Compound 1-(( 2R , 4S )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1- Synthesis of base) ethyl ketone hydrochloride

Compound 1-((2 R , 4 S )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl ) ethyl ketone (4.1 g, 11.1 mmol) was dissolved in 40 mL methanol, palladium carbon (0.82 g, 2.23 mmol) and hydrochloric acid (3.6 mL, 4.01 mol/L) were added, and the reaction was carried out at room temperature for 2.5 h under 1 Mpa hydrogen atmosphere. The reaction of the raw materials was completed, and the reaction was stopped. The reaction solution was filtered through celite, the organic phase was concentrated under reduced pressure, and the solvent was removed to obtain a yellow solid (4.3 g, yield 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.68 (s, 2H), 7.08 (s, 1H), 6.97 – 6.77 (m, 2H), 6.53 (t, J = 75.5 Hz, 1H), 4.61 – 4.51 (m, 2H), 4.07 – 3.81 (m, 1H), 3.70 – 3.04 (m, 3H), 2.82 – 2.55 (m, 1H), 2.23 (s, 3H), 2.05 – 1.84 (m, 1H) ), 1.34 (s, 6H).

MS-ESI: m/z 343.20 [M+H-HCl] ⁺ .

Step 12: N - (((( 2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) Synthesis of Methyl)pyridamide

Compound 1-(( 2R , 4S )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl) Ethanone hydrochloride (200 mg, 0.53 mmol), 2-picolinic acid (78 mg, 0.64 mmol) and 1-hydroxy-7-azabenzotriazole (140 mg, 1.1 mmol) were dissolved in dichloromethane ( 10 mL) solution, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (200 mg, 1.1 mmol) and N , N -diiso Propylethylamine (210 mg, 1.6 mmol) was reacted at room temperature for 10 h, the reaction of the raw materials was complete, the reaction was stopped, saturated brine (50 mL) was added, extracted with dichloromethane (30 mL×3), and the organic phase was Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) to obtain a white solid (128 mg, yield 52%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.99 (s, 1H), 8.62 (d, J = 4.4 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.43 (dd, J = 6.9, 5.2 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.79 (s, 1H), 6.77 – 6.75 (m, 1H), 6.51 (t, J = 75.6 Hz, 1H), 4.51 – 4.40 (m, 1H), 4.35 – 4.28 (m, 1H), 4.05 – 3.98 (m, 1H), 3.94 – 3.90 (m, 1H), 3.70 – 3.61 (m, 1H), 3.42 (t, J = 10.8 Hz, 1H), 3.29 – 3.21 (m, 1H), 2.60 – 2.53 (m, 1H), 2.16 (s, 3H), 2.01 – 1.92 (m, 1H), 1.32 – 1.29 (m, 6H).

MS-ESI: m/z 448.20 [M+H] ⁺ .

Example 59: N - (((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl )methyl)-2-ethoxybenzamide

Compound 1-(( 2R , 4S )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl) Ethanone hydrochloride (150 mg, 0.40 mmol, Example 58, step 11), o-ethoxybenzoic acid (80 mg, 0.48 mmol) and 1-hydroxy-7-azabenzotriazole (110 mg, 0.80 mmol) was dissolved in dichloromethane (10 mL) solution, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150 mg, 0.8 mmol) was added successively under ice bath conditions. ) and N , N -diisopropylethylamine (160 mg, 1.2 mmol), reacted at room temperature for 10 h, the reaction of the raw materials was complete, the reaction was stopped, saturated brine (50 mL) was added, and extracted with dichloromethane (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) for separation and purification to obtain a white solid (76 mg, yield 39%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.46 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.06 – 7.04 ( m, 2H), 6.96 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.50 (t, J = 75.6 Hz, 1H), 4.47 – 4.37 (m, 1H), 4.34 – 4.27 (m, 1H), 4.25 – 4.17 (m, 2H), 4.05 – 3.95 (m, 1H), 3.92 – 3.84 (m, 2H), 3.37 (t, J = 10.5 Hz, 1H), 3.27 – 3.18 (m, 1H), 2.57 – 2.50 (m, 1H), 2.12 (s, 3H), 2.08 – 2.00 (m, 1H), 1.50 (t, J = 6.9 Hz, 3H) , 1.27 (dd, J = 11.4, 5.9 Hz, 6H).

MS-ESI: m/z 491.25 [M+H] ⁺ .

Example 60: ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) methyl 5-(Ethylcarbamoyl)picolinate

Step 1: 2-(3-(Benzyloxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane Synthesis of Borane

Compound 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene (10.0 g, 26.59 mmol), pinacol biboronate (7.43 g, 29.25 mmol), potassium acetate (5.22 g g, 53.18 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (Pd(dppf)Cl ₂ .CH ₂ Cl ₂ ) (2.17 g, 2.66 mmol) was dissolved in N , N -dimethylformamide (100 mL) solution, reacted at 80 °C for 8 h under nitrogen protection, the reaction solution was diluted with 100 mL of water, extracted with ethyl acetate (100 mL × 3), the combined organic phases were washed with water (100 mL × 3), dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) , a yellow solid product (8.90 g, 88.97% yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.53 – 7.49 (m, 1H), 7.48 – 7.31 (m, 6H), 7.23 – 7.15 (m, 1H), 6.61 (t, J = 75.3 Hz , 1H), 5.16 (s, 2H), 1.35 (s, 12H).

Step 2: 1-(tert-Butyl)2-methyl( R )-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1 Synthesis of H -pyrrole-1,2-dicarboxylate

The compound 2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane ( 739 mg, 1.96 mmol), ( R) -1- tert-butyl 2-methyl 4 - ((((trifluoromethyl) sulfonyl acyl) methoxy) -1 H - pyrrole-1, 2 (2 H , 5H )-dicarboxylate (700 mg, 1.87 mmol, intermediate M2), palladium acetate (21 mg, 0.09 mmol), 2-dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) ( 68 mg, 0.19 mmol), N -methylmorpholine (NMM) (416 mg, 4.11 mmol) was dissolved in a mixed solution of toluene (10 mL) and water (5 mL), under nitrogen protection, 80 ℃ oil bath The reaction was stirred at low temperature for 1 h, the reaction solution was diluted with ethyl acetate (20 mL), the organic phase was washed with water (20 mL×2), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/ EtOAc=5:1) to give the product as a yellow oil (823 mg, yield 92.56%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.46 – 7.37 (m, 4H), 7.37 – 7.30 (m, 1H), 7.20 – 7.11 (m, 1H), 7.06 – 7.00 (m, 1H) , 7.00 – 6.91 (m, 1H), 6.58 (t, J = 75.0 Hz, 1H), 6.03 – 5.99 (m, 0.4H), 5.99 – 5.95 (m, 0.6H), 5.20 – 5.07 (m, 3H) , 4.66 – 4.41 (m, 2H), 3.80 – 3.72 (m, 3H), 1.53 (s, 3H), 1.46 (s, 6H).

MS-ESI: m/z 420.10 [M- t- Bu+2H] ⁺ .

Step 3: 1-(tert-Butyl)2-methyl( 2R , 4S )-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine 1,2-dicarboxylic acid Synthesis of Esters

Compound 1-(tert-butyl)2-methyl( R )-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H - Pyrrole-1,2-dicarboxylate (823 mg, 1.73 mmol) was dissolved in methanol (20 mL) solvent, then Pd/C (201 mg, 0.83 mmol) was added, and after hydrogen replacement three times, under hydrogen protection, The reaction was stirred at room temperature for 2 h, the reaction was stopped, filtered through celite, and concentrated under reduced pressure to obtain a white oily product (670 mg, yield 99.98%).

¹ H NMR (400 MHz, CDCl3) δ (ppm): 7.05 (d, J = 8.3 Hz, 1H), 6.95 – 6.87 (m, 1H), 6.78 – 6.71 (m, 1H), 6.52 (t, J = 73.9 Hz, 1H), 4.42 – 4.29 (m, 1H), 4.06 – 3.88 (m, 1H), 3.75 (s, 3H), 3.45 – 3.35 (m, 1H), 3.36 – 3.20 (m, 1H), 2.67 – 2.57 (m, 1H), 2.09 – 1.94 (m, 1H), 1.51 – 1.36 (m, 9H).

MS-ESI: m/z 288.20 [M-Boc+2H] ⁺ .

Step 4: 1-(tert-Butyl)2-methyl( 2R , 4S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)pyrrolidine-1,2 - Synthesis of Diformate

Compound 1-(tert-butyl) 2-methyl( 2R , 4S )-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine 1,2-dicarboxylate (617 mg, 1.59 mmol), potassium carbonate (659 mg, 4.77 mmol), bromoisobutane (327 mg, 2.39 mmol) were dissolved in N , N -dimethylformamide (10 mL) solvent, in The reaction was stirred at 80 °C for 3.5 h. The reaction was stopped and cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with water (20 mL × 2). Column chromatography (PE/EtOAc (v/v) = 3/1 ) gave the product as a colorless liquid (600 mg, 85.09 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.09 (d, J = 8.1 Hz, 1H), 6.85 – 6.74 (m, 2H), 6.52 (t, J = 75.5 Hz, 1H), 4.44 – 4.29 (m, 1H), 4.07 – 3.86 (m, 1H), 3.79 – 3.69 (m, 5H), 3.49 – 3.38 (m, 1H), 3.38 – 3.24 (m, 1H), 2.70 – 2.58 (m, 1H) ), 2.19 – 2.06 (m, 1H), 2.06 – 1.97 (m, 1H), 1.50 – 1.38 (m, 9H), 1.04 (d, J = 6.7 Hz, 6H).

MS-ESI: m/z 344.70 [M- Boc +2H] ⁺ .

Step 5: ( 2R , 4S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester Synthesis

The compound 1-(tert-butyl)2-methyl( 2R , 4S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)pyrrolidine-1,2- Diformate (561 mg, 1.26 mmol) was dissolved in tetrahydrofuran (10 mL) solvent, lithium borohydride solution in tetrahydrofuran (1.26 mL, 2 M) was added under ice bath, and the reaction was stirred at room temperature for 1.5 h. It was slowly added to ice water (20 mL), adjusted to acidity (pH = 2) with dilute hydrochloric acid (1 M), the aqueous phase was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined with saturated brine (25 mL). × 2) Washed, the organic phase was dried with anhydrous sodium sulfate, concentrated and the mixed sample was purified by column chromatography (PE/EtOAc (v/v) = 4/1) to obtain a colorless liquid product (480 mg, yield 91.69%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J = 7.9 Hz, 1H), 6.84 – 6.74 (m, 2H), 6.52 (t, J = 75.6 Hz, 1H), 4.08 – 3.89 (m, 2H), 3.82 – 3.72 (m, 3H), 3.72 – 3.64 (m, 1H), 3.30 – 3.14 (m, 2H), 2.44 – 2.33 (m, 1H), 2.19 – 2.07 (m, 1H) ), 1.81 – 1.60 (m, 1H), 1.48 (s, 9H), 1.04 (d, J = 6.7 Hz, 6H).

MS-ESI: m/z 360.15 [M- t- Bu+2H] ⁺ .

Step 6: Synthesis of ((2R , 4S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)pyrrolidin-2-yl)methanol hydrochloride

The compound ( 2R , 4S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester ( 480 mg, 1.16 mmol) was dissolved in dichloromethane (10 mL) solvent, and then a solution of hydrochloric acid in 1,4-dioxane (2.9 mL, 4 M) was added, and the reaction was stirred at room temperature for 1.5 h and stopped. After the reaction was concentrated once under reduced pressure, dichloromethane (20 mL) was added to dissolve, and concentrated under reduced pressure again to obtain a white solid product (364 mg, yield 89.18%).

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.16 – 7.10 (m, 1H), 7.10 – 7.06 (m, 1H), 6.97 – 6.89 (m, 1H), 6.68 (t, J = 75.3 Hz, 1H), 3.98 – 3.86 (m, 2H), 3.84 (d, J = 6.4 Hz, 2H), 3.81 – 3.55 (m, 3H), 3.25 (t, J = 10.8 Hz, 1H), 2.52 – 2.40 (m, 1H), 2.16 – 2.05 (m, 1H), 2.05 – 1.93 (m, 1H), 1.06 (d, J = 6.7 Hz, 6H).

MS-ESI: m/z l316.10 [M-HCl+H] ⁺ .

Step 7: ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isobutoxy-phenyl) pyrrolidin-2-yl) methyl acetate acid ester

Compound (( 2R , 4S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)pyrrolidin-2-yl)methanol hydrochloride (364 mg, 1.03 mmol ) was dissolved in dichloromethane (10 mL) solvent, cooled at 0 °C, and added with N , N -diisopropylethylamine (DIPEA) (666 mg, 5.15 mmol), acetyl chloride (243 mg, 3.09 mmol), transferred to room temperature and stirred for 1 h. The reaction solution was washed with water (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/PE (v/v) = 9/1) to obtain a yellow liquid product (312 mg, 75.84% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.17 – 7.06 (m, 1H), 6.86 – 6.75 (m, 2H), 6.54 (t, J = 75.5 Hz, 1H), 4.45 – 4.34 (m , 2H), 4.28 – 4.08 (m, 1H), 3.95 – 3.84 (m, 1H), 3.81 – 3.73 (m, 2H), 3.45 – 3.34 (m, 1H), 3.34 – 3.19 (m, 1H), 2.58 – 2.45 (m, 1H), 2.20 – 2.05 (m, 7H), 2.00 – 1.86 (m, 1H), 1.05 (d, J = 6.7 Hz, 6H).

MS-ESI: m/z 400.15 [M+H] ⁺ .

Step 8: 1-(( 2R , 4S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl ) Synthesis of Ethan-1-one

Compound ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isobutoxy-phenyl) pyrrolidin-2-yl) methyl acetate (312 mg, 0.78 mmol) was dissolved in tetrahydrofuran (6 mL) solvent, then lithium hydroxide monohydrate (82 mg, 1.95 mmol) and water (3 mL) were added, and the reaction was stirred at 50 °C for 2 h. After cooling at 0 °C, 1 M hydrochloric acid was added dropwise to make it acidic (pH = 2), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 2). The phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was obtained as a yellow oil (280 mg, 100 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.12 (d, J = 8.0 Hz, 1H), 6.83 – 6.74 (m, 2H), 6.53 (t, J = 75.4 Hz, 1H), 4.29 – 4.15 (m, 1H), 3.95 – 3.85 (m, 1H), 3.84 – 3.73 (m, 3H), 3.72 – 3.62 (m, 1H), 3.49 – 3.38 (m, 1H), 3.36 – 3.21 (m, 1H) ), 2.49 – 2.40 (m, 1H), 2.17 – 2.10 (m, 4H), 1.75 – 1.62 (m, 1H), 1.05 (d, J = 6.7 Hz, 6H).

MS-ESI: m/z 358.20 [M+H] ⁺ .

Step 9: ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isobutoxy-phenyl) pyrrolidin-2-yl) methyl-5 Synthesis of -(ethylcarbamoyl)picolinate

A solution of lithium 5-(ethylcarbamoyl)picolinate (147 mg, 0.73 mmol) and hydrochloric acid in 1,4-dioxane (0.24 mL, 4 M) was dissolved in N , N -dimethylformaldehyde ethylformamide (5 mL) solvent, stir until clear, add 1-((2 R ,4 S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)- 2-(Hydroxymethyl)pyrrolidin-1-yl)ethan-1-one (175 mg, 0.49 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (100 mg, 0.73 mmol) , 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (235 mg, 1.40 mmol), N , N -diisopropylethyl acetate were added successively under an ice bath. Amine (DIPEA) (285 mg, 2.21 mmol) was transferred to room temperature and stirred for 18 h, water (20 mL) was added to dilute the reaction solution, extracted with ethyl acetate (20 mL×2), the organic phases were combined and saturated with Washed with brine (20 mL × 2), the organic phase was dried with anhydrous sodium sulfate, concentrated and the mixed sample was subjected to column chromatography (DCM/MeOH (v/v) = 15/1) to obtain a white solid product (150 mg, yield 57.37 %,).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.13 – 9.03 (m, 1H), 8.30 – 8.22 (m, 1H), 8.20 – 8.11 (m, 1H), 7.09 (d, J = 8.1 Hz , 1H), 6.91 – 6.78 (m, 2H), 6.72 – 6.29 (m, 1H), 6.51 – 6.39 (m, 1H), 4.82 – 4.63 (m, 2H), 4.62 – 4.51 (m, 1H), 3.95 – 3.86 (m, 1H), 3.75 – 3.67 (m, 2H), 3.60 – 3.44 (m, 3H), 3.38 – 3.22 (m, 1H), 2.66 – 2.51 (m, 1H), 2.15 – 2.03 (m, 4H), 1.34 – 1.20 (m, 4H), 1.07 – 0.94 (m, 6H).

MS-ESI: m/z 534.10 [M+H] ⁺ .

Example 61: 5 - ((3 S , 5 R) -1- acetyl-5 - ((5- (acyl-ethylcarbamoyl) pyridine carboxylic acyl) methyl) -3- pyrrolidinyl yl)-2-(difluoromethoxy)phenylcyclopropylcarboxylate

Compound N ² -((((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl ) - N ⁵ - ethyl pyridine-2,5-acyl amine (200 mg, 0.42 mmol, 48 the procedure of Example 1) was dissolved in was dissolved in N, N - dimethylformamide (10 mL) solvent , stirred until clear, and then added cyclopropylcarboxylic acid (54 mg, 0.63 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (114 mg, 0.84 mmol), followed by adding 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (161 mg, 0.84 mmol), N , N -diisopropylethylamine (DIPEA) (217 mg, 1.68 mmol), transfer to room temperature and stir the reaction for 18 h, add water (20 mL) to dilute the reaction solution, extract with ethyl acetate (20 mL × 2), combine the organic phases, and wash with saturated brine (20 mL × 2) , the organic phase was dried with anhydrous sodium sulfate, and the mixed sample was concentrated and subjected to column chromatography (DCM/MeOH (v/v) = 20/1) to obtain a white solid product (150 mg, yield 65.58%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.08 (s, 1H), 8.96 (s, 1H), 8.21 (s, 2H), 7.20 – 7.13 (m, 1H), 7.11 – 7.04 (m , 1H), 7.02 – 6.96 (m, 1H), 6.51 – 6.42 (m, 1H), 6.36 (t, J = 73.8 Hz, 1H), 4.35 – 4.24 (m, 1H), 4.04 – 3.97 (m, 1H) ), 3.97 – 3.89 (m, 1H), 3.64 – 3.56 (m, 1H), 3.56 – 3.46 (m, 2H), 3.41 (t, J = 10.7 Hz, 1H), 3.33 – 3.21 (m, 1H), 2.65 – 2.53 (m, 1H), 2.23 (s, 0.3H), 2.14 (s, 2.7H), 1.97 – 1.89 (m, 1H), 1.86 – 1.82 (m, 1H), 1.29 – 1.24 (m, 3H) ), 1.21 – 1.14 (m, 2H), 1.09 – 1.01 (m, 2H).

MS-ESI: m/z 545.05 [M+H] ⁺ .

Example 62: ((2 R, 4 S) -1- acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl 5- (ethyl (Methyl)carbamoyl)picolinate

Compound 1-((2 R , 4 S )-4-(3-ethoxy-4-methoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (100 mg , 0.34 mmol, Example 64 step 11), 5-(ethyl(methyl)carbamoyl)pyridine-2-carboxylic acid (71 mg, 0.34 mmol) and 1-hydroxy-7-azabenzotri Azole (93 mg, 0.68 mmol) was dissolved in dichloromethane (10 mL) solution, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added sequentially under ice bath conditions (130 mg, 0.68 mmol) and N , N -diisopropylethylamine (130 mg, 1.02 mmol), react at room temperature for 2 h, the reaction of the raw materials is complete, stop the reaction, add saturated brine (50 mL), use Dichloromethane extraction (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) to obtain a white solid (32 mg, 19% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.76 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.89 – 7.84 (m, 1H), 6.83 – 6.80 (m, 2H) ), 6.79 – 6.77 (m, 1H), 4.77 – 4.67 (m, 2H), 4.59 – 4.54 (m, 1H), 4.06 – 4.01 (m, 2H), 3.93 – 3.85 (m, 1H), 3.83 (s , 3H), 3.63 – 3.55 (m, 1H), 3.48 (t, J = 10.8 Hz, 1H), 3.29 – 3.22 (m, 2H), 3.09 (s, 2H), 2.94 (s, 1H), 2.59 – 2.52 (m, 1H), 2.09 (s, 3H), 2.07 – 2.03 (m, 1H), 1.42 (t, J = 6.9 Hz, 3H), 1.27 – 1.24 (m, 1.5H), 1.16 – 1.13 (m , 1.5H).

MS-ESI: m/z 484.10 [M+H] ⁺ .

Embodiment 63 cases: ((2 R, 4 S ) -1- acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl 5- (ethylamino carboxyl)picolinate

The compound lithium 5-(ethylcarbamoyl)picolinate (68 mg, 0.34 mmol) was dissolved in DMF (10 mL), and a solution of hydrochloric acid in 1,4-dioxane (0.17 mL, 4.01 mmol/ L), after 10 min of reaction, 1-((2 R , 4 S )-4-(3-ethoxy-4-methoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1- yl) ethyl ketone (100 mg, 0.34 mmol, Example 64, step 11) and 1-hydroxy-7-azabenzotriazole (93 mg, 0.68 mmol), under ice bath conditions, then add 1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg, 0.68 mmol) and N , N -diisopropylethylamine (130 mg, 1.02 mmol), react at room temperature for 2 h, the reaction of the raw materials was completed, the reaction was stopped, saturated brine (50 mL) was added, extracted with ethyl acetate (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure for silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) was separated and purified to obtain a white solid (68 mg, yield 40%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.09 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 6.82 – 6.80 ( m, 2H), 6.78 – 6.76 (m, 1H), 6.76 – 6.66 (m, 2H), 4.57 – 4.53 (m, 1H), 4.05 – 3.99 (m, 2H), 3.92 – 3.86 (m, 1H), 3.83 (s, 3H), 3.54 – 3.49 (m, 3H), 3.30 – 3.21 (m, 1H), 2.59 – 2.53 (m, 1H), 2.08 (s, 3H), 2.05 – 2.02 (m, 1H), 1.41 (t, J = 6.8 Hz, 3H), 1.26 (t, J = 7.3 Hz, 3H).

MS-ESI: m/z 470.10 [M+H] ⁺ .

Example ^{64: N 2 - (((} 2 R, 4 S) -1- acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl) - N ⁵ -Ethylpyridine-2,5-dimethylamide

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

Compound 3-hydroxy-4-methoxybenzoic acid methyl ester (5.00 g, 27.45 mmol), bromoethane (4.49 g, 41.17 mmol) and potassium carbonate (11.83 g, 82.35 mmol) were mixed in acetone (25 mL) was placed at 60 °C to react for 10 h, diluted with dichloromethane (100 mL), the organic phase was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to obtain a yellow solid ( 5.23 g, yield 90.63%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm): 7.66 (dd, J = 8.4, 1.7 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 6.88 (d, J = 8.4 Hz , 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H).

MS-ESI: m/z 211.10 [M+H] ⁺ .

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

The compound 3-ethoxy-4-methoxybenzoic acid methyl ester (10.46 g, 49.76 mmol), sodium hydroxide (3.98 g, 99.52 mmol, ethanol (30 mL), water (10 mL) were mixed uniformly, and set aside. Stir for 2 h at 50 ° C. Dilute hydrochloric acid (4 mol/L) was added dropwise to adjust pH = 1, water (100 mL) was added, stirred (a large amount of solid was precipitated), filtered, and the obtained filter cake was washed with water (50 mL × 3), Dry under vacuum at 60 °C for 12 h to obtain a white solid (9.76 g, yield 97%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm): 7.77 (dd, J = 8.4, 1.9 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.5 Hz , 1H), 4.17 (q, J = 7.0 Hz, 2H), 3.95 (s, 3H), 1.50 (t, J = 7.0 Hz, 3H).

MS-ESI: m/z 197.15 [M+H] ⁺ .

Step 3: Synthesis of compound benzyl(3-ethoxy-4-methoxyphenyl)carbamate

Step 1: At room temperature, add 3-ethoxy-4-methoxybenzoic acid (9.40 g, 47.91 mmol), triethylamine (6.30 g, 62.28 mmol) to a two-necked flask (100 mL) (A bottle) , toluene (50 mL), stirred in an ice bath, slowly added dropwise diphenylphosphoryl azide (14.50 g, 52.70 mmol), and stirred at room temperature for 2 h.

Step 2: Add toluene (50 mL) and benzyl alcohol (5.70 g, 52.70 mmol) to another single-necked bottle (250 mL) (B bottle), heat to 110 °C, drop the material from A bottle into B bottle, and finish dropping Keep stirring for 2 h. The heating and stirring were stopped, cooled to room temperature, the reaction solution was washed with water (100 mL), then washed with 5% aqueous sodium hydroxide solution (100 mL × 3), dried over anhydrous Na ₂ SO ₄ , and concentrated by rotary evaporation under reduced pressure to obtain a yellow solid . Petroleum ether/ethyl acetate (50 mL, v/v=10/1) was added to the crude product, stirred for 3 h, and filtered to obtain a white solid (11.55 g, yield 80.00%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.44 – 7.31 (m, 5H), 6.85 – 6.72 (m, 2H), 6.59 (s, 1H), 5.19 (s, 2H), 4.08 (d , J = 6.3 Hz, 2H), 3.84 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H).

MS-ESI: m/z 302.10 [M+H] ⁺ .

Step 4: Synthesis of compound 3-ethoxy-4-methoxyaniline

To the autoclave (1 L) was added (3-ethoxy-4-methoxyphenyl)carbamate (11.50 g, 38.16 mmol), 10% palladium on carbon (0.61 g, 0.57 mmol), methanol ( 40 mL), remove the air, pass hydrogen (0.5 MPa), and stir at room temperature for 2 h. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a brown solid (6.38 g, yield 100%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.71 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 6.23 (dd, J = 8.4, 2.6 Hz, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.79 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H).

MS-ESI: m/z 168.20 [M+H] ⁺ .

Step 5: Synthesis of compound 3-ethoxy-4-methoxyiodobenzene

Compound 3-ethoxy-4-methoxyaniline) (6.40 g, 38.28 mmol) was dissolved in 1,4-dioxane (30 mL) and water (11 mL), cooled to 0 °C, Concentrated hydrochloric acid (9.7 mL, 36% aq) was added, stirred well, cooled to -15 °C, and a solution of sodium nitrite (2.91 g, 42.11 mmol) and water (7 mL) was added dropwise, and the dropwise temperature was controlled at -15 Between ℃ and -5 ℃, return to -5 ℃ and stir for 30 min after dropping, add a solution of potassium iodide (8.26 g, 49.76 mmol) and water (12 mL), and control the dropwise temperature at -15 ℃ to -5 ℃. After dropping, the temperature was returned to 0 °C and stirred for 2 h. Sodium bisulfite (1.99 g, 19.14 mmol) was added and stirred for 1 h to quench the reaction. Petroleum ether (200 mL) was added to the reaction solution, and the organic phase was washed with water (100 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a yellow viscous liquid. Silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) was purified to give a white solid (6.24 g, yield 58.62%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.21 (dd, J = 8.4, 1.9 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.84 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H).

GC-MS: m/z 278.00 [M] ⁺ .

Step 6: Synthesis of compound 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxazolidine

3-Ethoxy-4-methoxyiodobenzene (1277-6) (6.24 g, 22.44 mmol), pinacol diboronate (5.70 g, 22.44 mmol), potassium acetate (3.30 g, 33.66 mmol) , palladium acetate (0.25 g, 1.12 mmol), 2-dicyclohexylphosphonium-2'-methylbiphenyl (Mephos) (0.82 g, 2.24 mmol) were mixed in N , N -dimethylformamide (36 mL) ), stirred at 80 °C for 6 h under nitrogen protection. Cooled to room temperature, water (100 mL) was added to the reaction solution, the reaction solution was extracted with petroleum ether (100 mL × 3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to obtain a brown liquid. Chromatography (petroleum ether/ethyl acetate (v/v)=10/1) was purified to give a yellow solid (4.85 g, yield: 77.70%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.41 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.89 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H), 1.33 (s, 12H).

MS-ESI: m/z 279.35 [M+H] ⁺ .

Step 7: Compound (R) -1- tert-butyl 2-methyl-4- (3-ethoxy-4-methoxyphenyl) -1 H - pyrrole -1,2 (2 H, 5 H) - Synthesis of Diformate

Compound 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.0 g, 7.19 mmol) , ( R )-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy) 1H -pyrrole- 1,2(2H , 5H )-dicarboxylic acid ester (2.7 g, 7.19 mmol), N -methylmorpholine (1.6 g, 15.82 mmol), dicyclohexyl-[2-(2-methylphenyl)phenyl]phosphine (0.13 g, 0.36 mmol) and Palladium acetate (0.04 g, 0.18 mmol) was mixed with a mixed solution of toluene (10 mL) and water (5 mL), reacted at 80 °C for 1 h under nitrogen protection, stopped the reaction, and cooled to room temperature. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: PE/EtOAc ( v/v ) = 5/1) to give a yellow liquid (1.1 g, 44% yield).

MS-ESI: m/z 278.18 [M- Boc +H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.93 – 6.88 (m, 2H), 6.85 – 6.81 (m, 1H), 5.94 – 5.89 (m, 1H), 5.18 – 5.08 (m, 1H) , 4.66 – 4.47 (m, 2H), 4.14 – 4.07 (m, 2H), 3.88 (s, 3H), 3.75 (d, J = 4.8 Hz, 3H), 1.52 (s, 3H), 1.50 – 1.43 (m , 9H).

Step 8: Compound ( 2R , 4S )-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate synthesis

The compound (R) -1- tert-butyl 2-methyl-4- (3-ethoxy-4-methoxyphenyl) -1 H - pyrrole -1,2 (2 H, 5 H) - two Formate (2.0 g, 5.30 mmol) and palladium on carbon (0.45 g, 5.30 mmol) were dissolved in 35 mL of methanol, and reacted at room temperature for 12 h under a hydrogen atmosphere. The reaction of the raw materials was completed and the reaction was stopped. The palladium carbon was filtered through celite, and the organic phase was concentrated under reduced pressure to obtain a yellow liquid (1.26 g, yield 63%).

MS-ESI: m/z 279.20 [M- Boc +H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.82 – 6.74 (m, 3H), 4.39 – 4.29 (m, 1H), 4.11 – 4.05 (m, 2H), 4.02 – 4.00 (m, 0.5H) ), 3.95 – 3.89 (m, 0.5H), 3.85 (s, 3H), 3.76 (d, J = 7.0 Hz, 3H), 3.44 – 3.37 (m, 1H), 3.33 – 3.24 (m, 1H), 2.66 – 2.57 (m, 1H), 2.07 – 1.96 (m, 1H), 1.50 – 1.44 (m, 6H), 1.43 (s, 6H).

Step 9: Synthesis of Compound (2R , 4S )-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

Compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (1.2 g , 3.16 mmol) was dissolved in 10 mL of dichloromethane solution, and then hydrochloric acid 1,4-dioxane solution (3.94 mL, 4.01 mol/L) was added, and the reaction was carried out at room temperature for 1.5 h. The reaction of the raw materials was completed and the reaction was stopped. The solvent was removed by distillation under reduced pressure, and the concentrated solution gave a yellow liquid (1.02 g, yield 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.86 (s, 1H), 6.79 (s, 2H), 4.67 – 4.57 (m, 1H), 4.09 (q, J = 6.9 Hz, 2H), 3.90 – 3.78 ( m, 1H), 3.83 (s, 6H), 3.64 – 3.52 (m, 2H), 2.82 – 2.70 (m, 1H), 2.28 – 2.17 (m, 1H), 1.44 (t, J = 6.9 Hz, 3H) .

MS-ESI: m/z 280.30 [M+H-HCl] ⁺ .

Step 10: Compound (2 R, 4 S) -1- acetyl-yl Synthesis of 4- (3-ethoxy-4-methoxyphenyl) pyrrolidine-2-carboxylate

Compound ( 2R , 4S )-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0 g, 3.17 mmol) was dissolved in 20 mL of bismuth In the methyl chloride solution, under ice bath conditions, N , N -diisopropylethylamine (1.64 g, 12.68 mmol), acetyl chloride (0.50 g, 6.34 mmol) were added, and the reaction was carried out at room temperature for 1 h, and the reaction of the raw materials was complete. , stop the reaction. Saturated brine was added to quench the reaction, extracted with dichloromethane (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: DCM/MeOH (v/v) = 20/1) to give a yellow liquid (0.95 g, 93% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.84 – 6.80 (m, 1H), 6.79 – 6.77 (m, 1H), 6.76 – 6.74 (m, 1H), 4.46 (dd, J = 9.7, 7.5 Hz, 1H), 4.08 (q, J = 6.9 Hz, 2H), 3.93 – 3.89 (m, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.59 (t, J = 10.5 Hz, 1H), 3.42 – 3.33 (m, 1H), 2.66 – 2.60 (m, 1H), 2.10 (s, 3H), 2.05 – 2.00 (m, 1H), 1.46 (t, J = 7.0 Hz, 3H).

MS-ESI: m/z 322.20 [M+H] ⁺ .

Step 11: Compound 1-(( 2R , 4S )-4-(3-ethoxy-4-methoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone synthesis

Compound (2 R, 4 S) -1- Acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidine-2-carboxylate (0.50 g, 1.56 mmol) was dissolved in In 15 mL of tetrahydrofuran solution, lithium borohydride solution (1.17 mL, 2 mol/L) was added under ice bath conditions, and the reaction was carried out at room temperature for 3 h. The reaction of the raw materials was completed and the reaction was stopped. The reaction was quenched by adding ice-water mixture, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: PE/EtOAc (v/v) = 5/1) to give a colorless liquid (0.42 g, 92% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.84 – 6.82 (m, 1H), 6.77 – 6.73 (m, 2H), 4.22 (dd, J = 17.3, 7.2 Hz, 1H), 4.14 – 4.05 (m, 3H), 3.91 – 3.87 (m, 1H), 3.85 (s, 3H), 3.77 – 3.74 (m, 1H), 3.66 (dd, J = 11.8, 7.5 Hz, 1H), 3.41 (t, J = 10.8 Hz, 1H), 3.30 – 3.23 (m, 1H), 2.42 (dt, J = 12.8, 6.5 Hz, 1H), 2.13 (s, 2.5H), 2.03 (s, 0.5H), 1.46 (t, J = 7.0 Hz, 3H).

MS-ESI: m/z 294.50 [M+H] ⁺ .

Step 12: compound ((2 R, 4 S) -1- acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl methanesulfonate synthesis

Compound 1-((2 R , 4 S )-4-(3-ethoxy-4-methoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (1.35 g , 4.60 mmol) and N , N -diisopropylethylamine (0.95 g, 7.36 mmol) were dissolved in 15 mL of dichloromethane solution, under ice bath conditions, was added methylsulfonyl chloride (MsCl) (0.69 g , 5.98 mmol), reacted at room temperature for 2 h, the raw materials reacted completely, and the reaction was stopped. An ice-water mixture was added to quench the reaction, extracted with dichloromethane (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain a yellow liquid (1.55 g, 91% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.82 – 6.79 (m, 3H), 4.43 – 4.38 (m, 1H), 4.22 (dd, J = 10.9, 5.0 Hz, 1H), 4.11 – 4.07 (m, 2H), 3.85 (s, 3H), 3.76 (dd, J = 10.9, 1.8 Hz, 1H), 3.67 (s, 3H), 3.45 (t, J = 10.7 Hz, 1H), 3.27 – 3.21 ( m, 1H), 3.12 – 3.06 (m, 1H), 2.52 – 2.43 (m, 1H), 2.21 – 2.15 (m, 1H), 2.12 (s, 3H), 1.41 – 1.39 (m, 3H).

MS-ESI: m/z 372.14 [M+H] ⁺ .

Step 13: Compound 1-(( 2R , 4S )-2-(azidomethyl)-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone Synthesis

Compound ((2 R, 4 S) -1- acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl methanesulfonate (1.5 g , 4.04 mmol), sodium azide (0.39 g, 6.06 mmol) was dissolved in 10 mL of N , N -dimethylformamide solution, and the reaction was heated at 80 °C for 3 h. The reaction of the raw materials was completed and the reaction was stopped. 100 mL of water was added, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: PE/EtOAc (v/v) = 10/ 1) A colorless oil was obtained (0.95 g, 74% yield).

MS-ESI: m/z 319.20 [M+H] ⁺ .

Step 14: Compound 1-(( 2R , 4S )-2-(aminomethyl)-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone salt Synthesis of acid salts

Compound 1-((2 R , 4 S )-2-(azidomethyl)-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone (0.94 g, 2.95 mmol) was dissolved in 40 mL of methanol, palladium carbon (94.0 mg, 0.30 mmol) and hydrochloric acid (0.96 mL, 4.01 mol/L) were added, and the reaction was carried out at room temperature for 5 h under 1 Mpa hydrogen atmosphere. The reaction of the raw materials was complete and stopped. reaction. The reaction solution was filtered through celite, the organic phase was concentrated under reduced pressure, and the solvent was removed to obtain a yellow liquid (0.78 g, yield 80%).

MS-ESI: m/z 293.20 [M-HCl+H] ⁺ .

Step ^{15 N 2 - ((((} 2 R, 4 S) -1- Acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl) - N ⁵ -Ethylpyridine-2,5-dimethylamide

Compound 1-(( 2R , 4S )-2-(aminomethyl)-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone hydrochloride (100 mg, 0.34 mmol), lithium 5-(ethylcarbamoyl)pyridine-2-carboxylate (68 mg, 0.34 mmol) was dissolved in N , N -dimethylformamide (10 mL) , hydrochloric acid (0.17 mL, 0.68 mmol) was added, and after 30 min of reaction, 1-hydroxy-7-azabenzotriazole (93 mg, 0.68 mmol) was added, and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg, 0.68 mmol) and N , N -diisopropylethylamine (130 mg, 1.02 mmol) were reacted at room temperature for 4 h , the reaction of the raw materials was completed, the reaction was stopped, saturated brine (50 mL) was added, extracted with ethyl acetate (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure for silica gel column chromatography (eluent: DCM /MeOH (v/v) = 20/1) was separated and purified to obtain a white solid (68 mg, yield 40%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.14 (s, 1H), 8.97 (s, 1H), 8.24 – 8.20 (m, 1H), 8.15 – 8.11 (m, 1H), 7.08 – 7.02 (m, 1H), 6.79 – 6.77 (m, 1H), 6.73 – 6.69 (m, 2H), 4.30 – 4.23 (m, 1H), 4.01 (dd, J = 13.9, 7.0 Hz, 2H), 3.97 – 3.92 (m, 1H), 3.90 – 3.86 (m, 1H), 3.81 (s, 3H), 3.58 – 3.52 (m, 1H), 3.50 – 3.45 (m, 2H), 3.40 (t, J = 10.8 Hz, 1H ), 3.25 – 3.16 (m, 1H), 2.57 – 2.51 (m, 1H), 2.13 (s, 3H), 1.93 – 1.84 (m, 1H), 1.40 (t, J = 6.9 Hz, 3H), 1.24 ( t, J = 7.2 Hz, 3H).

MS-ESI: m/z 469.60 [M+H] ⁺ .

Example 65: ((2 R, 4 S) -1- acetyl-4- (3-isopropoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl 5- (ethyl carbamate) picolinate

Step 1: Synthesis of compound 3-isopropoxy-4-methoxybenzoic acid methyl ester

Compound 3-hydroxy-4-methoxybenzoic acid methyl ester (5.00 g, 27.45 mmol), isopropyl iodide (7.00 g, 41.17 mmol) and potassium carbonate (11.83 g, 82.35 mmol) were mixed in N , N - dimethylformamide (25 mL), and stirred at 80 °C for 10 h. Ethyl acetate (100 mL) was added for dilution, the organic phase was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow liquid (5.48 g, yield 89.02 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.62 (dd, J = 8.5, 1.8 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 4.60 – 4.54 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 1.35 (d, J = 6.1 Hz, 6H).

MS-ESI: m/z 225.20 [M+H] ⁺ .

Step 2: Synthesis of compound 3-isopropoxy-4-methoxybenzoic acid

Compound 3-isopropoxy-4-methoxybenzoic acid methyl ester (11.05 g, 49.28 mmol), sodium hydroxide (3.94 g, 98.56 mmol), ethanol (30 mL), water (10 mL) were mixed uniformly , and stirred at 50 °C for 2 h. Dilute hydrochloric acid (4 mol/L) was added dropwise to adjust pH=1, water (100 mL) was added, stirred (a large amount of solid was precipitated), filtered, and the obtained filter cake was washed with water (50 mL×3), dried in vacuum at 60 °C for 12 h, A white solid (10.36 g, 100 % yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 (dd, J = 8.5, 1.9 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.66 – 4.60 (m, 1H), 3.93 (s, 3H), 1.40 (d, J = 6.1 Hz, 6H).

MS-ESI: m/z 211.15 [M+H] ⁺ .

Step 3: Synthesis of compound benzyl(3-isopropoxy-4-methoxyphenyl)carbamate

The first step : at room temperature, add 3-isopropoxy-4-methoxybenzoic acid (10.30 g, 48.99 mmol), triethylamine (6.44 g, 663.69 mmol) to the two-necked flask (A bottle), Toluene (50 ml) was stirred in an ice bath, diphenylphosphoryl azide (DPPA) (14.83 g, 53.89 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 h.

The second step: add toluene (50 mL) and benzyl alcohol (5.83 g, 53.89 mmol) to another three-necked bottle (B bottle), heat to 110 ℃, drop the material from A bottle into B bottle, and stir at constant temperature for 2 h. The heating and stirring were stopped, cooled to room temperature, the reaction solution was washed with water (100 mL), then washed with 5% aqueous sodium hydroxide solution (100 mL×3), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain a yellow solid. Petroleum ether/ethyl acetate (50 mL, v/v = 10:1) was added to the crude product, stirred for 3 h, and filtered to obtain a white solid (11.34 g, yield 73.40 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.47 – 7.30 (m, 5H), 7.16 (s, 1H), 6.86 – 6.72 (m, 2H), 6.56 (s, 1H), 5.19 (s , 2H), 4.53 (s, 1H), 3.82 (s, 3H), 1.36 (d, J = 5.9 Hz, 6H).

MS-ESI: m/z 316.20 [M+H] ⁺ .

Step 4: Synthesis of compound 3-isopropoxy-4-methoxyaniline

To the autoclave was added (3-isopropoxy-4-methoxyphenyl)carbamate (11.34 g, 35.96 mmol), 10% palladium on carbon (0.51 g, 0.54 mmol), methanol (40 mL) , replaced hydrogen (0.5 MPa), and stirred at room temperature for 2 h. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a brown solid (6.52 g, yield 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.71 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 6.24 (dd, J = 8.4, 2.5 Hz, 1H), 4.49 – 4.43 (p, J = 6.1 Hz, 1H), 3.77 (s, 3H), 1.34 (d, J = 6.1 Hz, 6H).

MS-ESI: m/z 182.20 [M+H] ⁺ .

Step 5: Synthesis of compound 3-isopropoxy-4-methoxyiodobenzene

Compound 3-isopropoxy-4-methoxyaniline (6.90 g, 38.07 mmol) was dissolved in 1,4-dioxane (30 mL) and water (11 mL), cooled to 0 °C, Add concentrated hydrochloric acid (9.6 mL, 36% aq), stir well, cool to -15 °C, add a solution of sodium nitrite (2.89 g, 41.88 mmol) and water (7 mL) dropwise, control the dropwise temperature at -15 Between ℃ and -5 ℃, return to -5 ℃ and stir for 30 min after dripping, then add a solution of potassium iodide (8.22 g, 49.49 mmol) and water (12 mL), and control the dropwise temperature at -15 ℃ to -5 ℃. After dropping, the temperature was returned to 0 °C and stirred for 2 h. Sodium bisulfite (1.98 g, 19.04 mmol) was added and stirred for 1 h to quench the reaction. Petroleum ether (200 mL) was added to the reaction solution, and the organic phase was washed with water (100 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a yellow viscous liquid. Silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=10/1) to obtain a white solid (7.83 g, yield 70.41 %)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.21 (dd, J = 8.5, 1.9 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 4.53 – 4.44 (m, 1H), 3.82 (s, 3H), 1.36 (d, J = 6.1 Hz, 6H).

GC-MS: m/z 292.0 [M] ⁺ .

Step 6: Synthesis of compound 2-(3-isopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

3-Isopropoxy-4-methoxyiodobenzene (8.64 g, 26.63 mmol), pinacol diboronate (6.76 g, 26.63 mmol), potassium acetate (39.2 g, 39.95 mmol), palladium acetate ( 0.30 g, 1.33 mmol), 2-dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) (0.97 g, 2.66 mmol) was mixed in N , N -dimethylformamide (48 mL) under nitrogen Stir at 80 °C for 6 h under protection. Cool to room temperature, add water (100 mL) to the reaction solution, extract the reaction solution with petroleum ether (100 mL×3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a brown liquid, which is passed through a silica gel column layer. It was purified by analysis (eluent: petroleum ether/ethyl acetate=10:1) to obtain a yellow solid (5.04 g, yield 64.78%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 77.41 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.67 – 4.56 ( m, 1H), 3.87 (s, 3H), 1.37 (d, J = 6.1 Hz, 6H), 1.33 (s, 12H).

MS-ESI: m/z 293.25 [M+H] ⁺ .

Step 7: Compound (R) -1- tert-butyl 2-methyl-4- (3-isopropoxy-4-methoxy-phenyl) -1 H - pyrrole -1, 2 (2 H, 5 H )-Diformate Synthesis

The compound (R) -1- tert-butyl 2-methyl 4 - ((((trifluoromethyl) sulfonyl acyl) methoxy) -1 H - pyrrole -1, 2 (2 H, 5 H) - Dicarboxylate (5.50 g, 14.65 mmol, Intermediate M ₂ ), 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4,4,5 , 5-tetramethyl-1,3,2-dioxaborolane (4.49 g, 15.38 mmol), palladium acetate (82.23 mg, 0.37 mmol), dicyclohexyl-[2-(2-methyl) phenyl)phenyl] phosphine (267.00 mg, 0.73 mmol), dissolved in toluene (30 mL) solvent, then added 4-methylmorpholine (3.25 g, 32.08 mmol), water (15 mL), under nitrogen atmosphere The mixture was transferred to 80 °C and stirred for 2 h, cooled to room temperature, added with water (100 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was dried with anhydrous sodium sulfate for 30 min, and passed through a silica gel column layer. Purification (eluent: ethyl acetate/petroleum ether (v/v) = 3/20) gave a brown sticky (5 g, 87.19 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.96 – 6.90 (m, 2H), 6.85 – 6.82 (m, 1H), 5.93 – 5.87 (m, 1H), 5.17 – 5.08 (m, 1H) , 4.66 – 4.46 (m, 3H), 3.85 (s, 3H), 3.74 (d, J = 5.0 Hz, 3H), 1.52 (s, 3H), 1.45 (s, 6H), 1.36 (d, J = 6.1 Hz, 6H).

MS-ESI: m / z 336.05 [M- t -Bu + 2H] +..

Step 8: Compound ( 2R , 4S )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate Synthesis

Compound ( R )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)-1H-pyrrole-1,2( 2H , 5H )-di The carboxylate (5.55 g, 14.18 mmol) was dissolved in methanol (90 mL) solvent, then palladium carbon (0.56 mg, 1.42 mmol) was added, and the reaction was stirred at room temperature for 4 h under a hydrogen atmosphere. The reaction was stopped, filtered through celite, and concentrated under reduced pressure to obtain a colorless sticky substance (4.45 g, yield 79.76%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.83 – 6.76 (m, 3H), 4.53 – 4.46 (m, 1H), 4.39 – 4.29 (m, 1H), 4.04 – 3.89 (m, 1H) , 3.82 (s, 3H), 3.75 (s, 3H), 3.42 – 3.35 (m, 1H), 3.32 – 3.23 (m, 1H), 2.65 – 2.57 (m, 1H), 2.06 – 1.95 (m, 1H) , 1.44 (s, 9H), 1.34 (d, J= 6.0 Hz, 6H).

MS-ESI: m / z 337.40 [M- t -Bu + H] +..

Step 9: Synthesis of compound (2R , 4S )-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

The compound ( 2R , 4S )-1-tert-butyl 2-methyl 4-(4-methoxy-3-(propoxy)phenyl)pyrrolidine-1,2-dicarboxylate ( 1.70g, 4.32mmol) was dissolved in dichloromethane (3 mL) solvent, and then hydrogen chloride/1,4-dioxane (9 mL) solution was added. After adding the raw materials, the reaction was stirred at room temperature for 2 h. The reaction was stopped and concentrated under reduced pressure once, then dichloromethane (20 mL) was added to dissolve, and concentrated under reduced pressure again to obtain a pale yellow viscous substance (1.27 g, yield 100%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.84 (s, 1H), 6.80 (s, 2H), 4.66 – 4.58 (m, 1H), 4.56 – 4.50 (m, 1H), 3.83 (s , 3H), 3.81 (s, 3H), 3.64 – 3.61 (m, 1H), 3.55 – 3.47 (m, 1H), 2.82 – 2.73 (m, 1H), 2.25 – 2.10 (m, 2H), 1.34 (d , J = 4.9 Hz, 6H).

MS-ESI: m/z 294.36[M+H-HCl] ⁺ .

Step 10: Compound (2 R, 4 S) -1- acetyl-4- (3-isopropoxy-4-methoxyphenyl) pyrrolidine-2-carboxylic acid methyl ester Synthesis of

Compound ( 2R , 4S )-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride (1.7 g, 5.79 mmol) was dissolved in two In methyl chloride (10 mL) solvent, at 0 °C, slowly add ethyldiisopropylamine (DIPEA) (2.99 g, 23.16 mmol) and acetyl chloride (0.91 g, 11.58 mmol) in sequence, and turn to room temperature The reaction was stirred for 2 h. The reaction was stopped, the reaction solution was washed with water (50 mL×1), the organic phase was extracted once with dichloromethane (20 mL), the organic phases were combined, washed once with saturated brine (50 mL), the organic phase was separated, and anhydrous sulfuric acid was added to the organic phase. It was dried over sodium for 30 min, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=80%) to obtain a light brown viscous (1.386 g, yield 71.37%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.84 – 6.75 (m, 3H), 4.54 – 4.43 (m, 2H), 3.93 – 3.88 (m, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.58 (t, J = 10.5 Hz, 1H), 3.41 – 3.31 (m, 1H), 2.66 – 2.59 (m, 1H), 2.10 (s, 3H), 2.07 – 2.00 (m, 1H) ), 1.34 (d, J = 6.1 Hz, 6H).

MS-ESI: m/z 336.35 [M+H] ⁺ .

Step 11: Synthesis of compound (2R , 4S )-2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-ethanone

Compound (2 R, 4 S) -1- acetyl-4- (3-isopropoxy-4-methoxyphenyl) pyrrolidine-2-carboxylic acid methyl ester (0.74 g, 2.20 mmol) was dissolved In tetrahydrofuran (8 mL) solvent, 2 mol/L lithium hydroxide in tetrahydrofuran (95.83 mg, 4.4 mmol) solvent was added dropwise at -5 °C,

After the dropwise addition, the reaction was stirred at room temperature for 2 h. The reaction solution was slowly poured into an ice-water mixture (50 mL) and stirred continuously to generate hydrogen gas, then ethyl acetate (30 mL) was added and stirred, the organic phase was separated, concentrated under reduced pressure, and the aqueous phase was washed with ethyl acetate (20 mL). ) extraction, separate the organic phase, dissolve and concentrate the obtained liquid, add ethyl acetate (20 mL) to dissolve completely, adjust pH=3 with saturated sodium chloride (30 mL) and dilute hydrochloric acid, dry with anhydrous sodium sulfate and concentrate under reduced pressure , a colorless viscous liquid (560 mg, 82.81 % yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.83 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.3 Hz, 2H), 4.55 – 4.46 (m, 1H), 4.24 – 4.08 (m, 1H), 3.90 – 3.85 (m, 1H), 3.82 (s, 3H), 3.77 – 3.74 (m, 1H), 3.67 – 3.63 (m, 1H), 3.39 (t, J = 10.8 Hz, 1H), 3.29 – 3.20 (m, 1H), 2.45 – 2.39 (m, 1H), 2.12 (s, 3H), 1.69 – 1.61 (m, 1H), 1.35 (d, J = 6.1 Hz, 6H).

MS-ESI: m/z 308.10 [M+H] ⁺ .

Step 12: compound ((2 R, 4 S) -1- acetyl-4- (3-isopropoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl 5- (ethyl Synthesis of amide)picolinate

The compound 6-(acetamide)pyridine-3-carboxylate lithium (130 mg, 0.65 mmol) was dissolved in N , N -dimethylformamide (2 mL) solvent, and a solution of hydrogen chloride in dioxane was added ( 36 mg, 0.98 mmol), stirred for 2 min, and after the solution was clear, (2 R , 4 S )-2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl) was added ) pyrrolidine-1-ethanone (200 mg, 0.65 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (130 mg, 0.98 mmol), cooled at 0 °C, added 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (250 mg, 1.30 mmol), N , N -diisopropylethylamine (DIPEA) (420 mg, 3.25 mmol), in The reaction was stirred at room temperature for 12 h. Stop the reaction, stop the reaction, add water (20 mL), extract with ethyl acetate (10 mL×2), wash the organic phase with saturated brine (20 mL) once, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, Silica gel column chromatography (eluent: methanol/dichloromethane (v/v) = 1/20) gave a pale yellow solid (83 mg, yield 26.10 %)

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.11 (s, 1H), 8.86 (s, 1H), 8.35 (dd, J = 8.1, 2.2 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 6.89 – 6.85 (m, 3H), 4.63 – 4.52 (m, 2H), 4.49 – 4.33 (m, 2H), 3.96 (t, J = 8.5 Hz, 1H), 3.71 (s, 3H), 3.48 - 3.24 (m, 3H), 3.24 – 3.02 (m, 1H), 2.67 – 2.41 (m, 2H), 2.10 (s, 0.5 H), 2.00 (s, 2.5 H), 1.17 – 1.12 ( m, 9H).

MS-ESI: m/z 484.10 [M+H] ⁺ .

Example ^{66: N 2 - (((} 2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isobutoxy-phenyl) pyrrolidin-2 yl) methyl) - N ⁵ - ethyl pyridine-2,5-Amides

Compound N ² -((((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl) - N ⁵ - ethyl pyridine-2,5-acyl amine (250 mg, 0.52 mmol, Example 48, step 1) was dissolved in was dissolved in N, N - dimethylformamide (10 mL) solvent, After stirring until clear, potassium carbonate (216 mg, 1.56 mmol) and bromoisobutane (107 mg, 0.78 mmol) were added successively, and the mixture was transferred to an oil bath at 80 °C and stirred for 3 h. Water (20 mL) was added to dilute the reaction solution. Extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 2), dry the organic phase with anhydrous sodium sulfate, concentrate the mixed sample and pass through column chromatography (DCM/MeOH (v/ v)=20/1) to give the product as a white solid (212 mg, 76.55 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.25 – 9.08 (m, 1H), 8.98 (s, 1H), 8.21 (s, 2H), 7.12 – 7.01 (m, 1H), 6.84 – 6.72 (m, 2H), 6.52 (t, J = 75.5 Hz, 1H), 6.49 – 6.37 (m, 1H), 4.37 – 4.24 (m, 1H), 4.07 – 3.97 (m, 1H), 3.97 – 3.86 (m , 1H), 3.79 – 3.69 (m, 2H), 3.65 – 3.56 (m, 1H), 3.56 – 3.48 (m, 2H), 3.47 – 3.38 (m, 1H), 3.34 – 3.19 (m, 1H), 2.63 – 2.52 (m, 1H), 2.24 (s, 0.4H), 2.16 (s, 2.6H), 2.13 – 2.06 (m, 1H), 2.03 – 1.87 (m, 1H), 1.27 (t, J = 7.2 Hz , 3H), 1.03 (d, J = 6.6 Hz, 6H).

MS-ESI: m/z 533.10 [M+H] ⁺ .

Example 67: ((2 R, 4 S) -1- acetyl-4- (3-4-methoxyphenyl) pyrrolidin-2-yl) methyl-5-methyl pyridine carboxylic acyl acid ester

The compound lithium 6-amide pyridine-3-carboxylate (390 mg, 2.28 mmol) was dissolved in N , N -dimethylformamide (2 mL) solvent, and a solution of hydrogen chloride in dioxane (62 mg, 2 mL) was added. 1.71 mmol), stirred for 2 min, and after the solution was clear, (2R, 4S)-2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1 was added -Ethanone (350 mg, 1.14 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (230 mg, 1.17 mmol), cooled at 0 °C, added 1-(3-dimethylamino) propyl)-3-ethylcarbodiimide (EDCI) (440 mg, 2.28 mmol), N , N -diisopropylethylamine (DIPEA) (740 mg, 5.7 mmol), the reaction was stirred at room temperature 13h. The reaction was stopped, water (20 mL) was added, extracted with ethyl acetate (10 mL × 2), the organic phase was washed with saturated brine (20 mL) once, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used. Separation (eluent: methanol/dichloromethane (v/v)=1/20) gave a light red solid (113 mg, yield 20.54%,)

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.15 (s, 1H), 8.39 – 8.28 (m, 2H), 8.14 (d, J = 8.3 Hz, 1H), 7.79 (s, 1H) ), 6.88 (s, 3H), 4.58 (s, 2H), 4.53 – 4.25 (m, 2H), 4.04 – 3.86 (m, 1H), 3.71 (s, 3H), 3.30 – 3.02 (m, 2H), 2.69 – 2.43 (m, 1H), 2.11 – 1.90 (m, 1H), 2.01 (s, 3H), 1.22 – 1.09 (m, 6H).

MS-ESI: m/z 456.20 [M+H] ⁺ .

Example 68: ((2 R, 4 S) -1- acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl 5 carbamoyltetrazole picolinate

The compound lithium 5-carbamoyl picolinate (180 mg, 1.02 mmol) was dissolved in DMF (10 mL), and a solution of hydrochloric acid in 1,4-dioxane (0.34 mL, 4.01 mmol/L) was added to react. After 10 min, add 1-((2 R , 4 S )-4-(3-ethoxy-4-methoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (200 mg, 0.68 mmol, Example 64, step 11) and 1-hydroxy-7-azabenzotriazole (190 mg, 1.36 mmol), under ice bath conditions, followed by adding 1-(3-dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride (260 mg, 1.36 mmol) and N , N -diisopropylethylamine (260 mg, 2.04 mmol), reacted at room temperature for 2 h, the raw materials were reacted Complete, stop the reaction, add saturated brine (50 mL), extract with ethyl acetate (30 mL × 3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure for silica gel column chromatography (eluent: DCM/MeOH ( v/v) = 20/1) was separated and purified to obtain a white solid (162 mg, yield 51%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.17 (s, 1H), 8.32 (dd, J = 8.0, 1.8 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 6.83 – 6.80 (m, 2H), 6.79 – 6.77 (m, 1H), 4.76 – 4.67 (m, 1.5H), 4.60 – 4.43 (m, 1.5H), 4.03 (q, J = 7.0 Hz, 2H), 3.92 – 3.88 (m, 1H), 3.84 (s, 3H), 3.50 (t, J = 10.8 Hz, 1H), 3.32 – 3.22 (m, 1H), 2.61 – 2.54 (m, 1H), 2.24 (s, 0.5H ), 2.10 (s, 2.5H), 2.08 – 2.02 (m, 1H), 1.42 (t, J = 7.0 Hz, 3H).

MS-ESI: m/z 442.10 [M+H] ⁺ .

Example 69: ((2 R, 4 S) -1- acetyl-4- (3-isopropoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl-5- (methylsulfonyl carbamate) picolinate

The compound 5-(methylaminocarbamoyl)lithium picolinate was dissolved in N,N -dimethylformamide (4 mL) solvent, hydrogen chloride dioxane solution (130 mg, 3.50 mmol) was added, and the mixture was stirred. After 2 min, the solution was clear, then (2 R , 4 S )-2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-ethanone was added (715 mg, 2.33 mmol, Example 65, step 11), 1-hydroxy-7-azabenzotriazole (HOAT) (480 mg, 3.50 mmol), cooled at 0 °C, added 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (890 mg, 4.66 mmol), N,N -diisopropylethylamine (DIPEA) (1.51 g, 1.93 mmol), and N , N -dimethylformamide (6 mL) solvent, and the reaction was stirred at 30 °C for 4 h. The reaction was stopped, water (20 mL) was added, extracted with ethyl acetate (10 mL × 2), the organic phase was washed with saturated brine (20 mL) once, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used. Separation (eluent: methanol/dichloromethane (v/v)=1/20) gave a light yellow solid (297 mg, yield 25.98%)

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.11 (s, 1H), 8.82 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 6.87 (s, 3H) ), 4.58 (s, 2H), 4.52 – 4.23 (m, 2H), 4.07 – 3.87 (m, 1H), 3.71 (s, 3H), 3.32 – 2.97 (m, 2H), 2.83 (s, 3H), 2.68 – 2.45 (m, 1H), 2.19 – 1.92 (m, 1H), 2.01 (s, 3H), 1.30 – 1.03 (m, 6H).

MS-ESI: m/z 470.10 [M+H] ⁺ .

Example 70: ((2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) pyrrolidin-2-yl) methyl 5-(Ethylcarbamoyl)picolinate

Compound 5-(ethylaminocarbamoyl)picolinate lithium salt (260 mg, 1.30 mmol) was added to dry N , N -dimethylformamide (6 ml) solution, and 4.02 mol/L was added HCl in 1,4-dioxane (0.43 mL), add 1-(( 2R , 4S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl) -2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (298 mg, 0.87 mmol, Example 55, step 9), 1-hydroxy-7-azabenzotriazole (HOAT) (180 mg, 1.30 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (420 mg, 2.17 mmol), after cooling in an ice bath, N , N -diisopropyl was added Ethylethylamine (DIPEA) (510 mg, 3.92 mmol), transferred to room temperature and stirred for 16 h. Water (50 ml) was added to quench the reaction, the organic phase was extracted with ethyl acetate (15 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH (v/v)= 25/1) to give a pale yellow solid (319 mg, 69.59% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.07 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 6.88 – 6.83 (m, 1H), 6.65 – 6.55 (m, 1H), 6.52 (t, J FH = 75.5 Hz, 1H), 4.81 – 4.39 ( m, 4H), 3.94 – 4.87 (m, 1H), 3.57 – 3.47 (m, 3H), 3.35 – 3.14 (m, 1H), 2.80 – 2.54 (m, 1H), 2.14 – 1.99 (m, 1H), 2.22 (s, 3H), 1.33 – 1.26 (m, 3H), 1.30 (d, J = 6.3 Hz, 6H).

MS-ESI: m/z 520.30 [M+H] ⁺ .

Example ^{71: N 2 - (((} 2 R, 4 S) -1- acetyl-4- (3-isopropoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl ) -N ⁵ -ethylpyridine-2,5-dimethylamide

Step 1: Synthesis of compound 3-isopropoxy-4-methoxybenzoic acid methyl ester

The compound methyl 3-hydroxy-4-methoxybenzoate (5.00 g, 27.45 mmol), isopropyl iodide (7.00 g, 41.17 mmol) and potassium carbonate (11.83 g, 82.35 mmol) were mixed in N , N - dimethylformamide (25 mL), and stirred at 80 °C for 10 h. Ethyl acetate (100 mL) was added for dilution, the organic phase was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow liquid (5.48 g, yield 89.02 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.62 (dd, J = 8.5, 1.8 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 4.60 – 4.54 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 1.35 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 225.20 [M+H] ⁺ .

Step 2: Synthesis of compound 3-isopropoxy-4-methoxybenzoic acid

Compound 3-isopropoxy-4-methoxybenzoic acid methyl ester (11.05 g, 49.28 mmol), sodium hydroxide (3.94 g, 98.56 mmol), ethanol (30 mL), water (10 mL) were mixed uniformly , and stirred at 50 °C for 2 h. Dilute hydrochloric acid (4 mol/L) was added dropwise to adjust pH=1, water (100 mL) was added, stirred (a large amount of solid was precipitated), filtered, and the obtained filter cake was washed with water (50 mL×3), dried in vacuum at 60 °C for 12 h, A white solid (10.36 g, 100 % yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 (dd, J = 8.5, 1.9 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.66 – 4.60 (m, 1H), 3.93 (s, 3H), 1.40 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 211.15 [M+H] ⁺ .

Step 3: Synthesis of compound benzyl(3-isopropoxy-4-methoxyphenyl)carbamate

Step 1: at room temperature, add 3-isopropoxy-4-methoxybenzoic acid (10.30 g, 48.99 mmol), triethylamine (6.44 g, 663.69 mmol), toluene (50 ml), placed in an ice bath and stirred, slowly added dropwise diphenylphosphoryl azide (DPPA) (14.83 g, 53.89 mmol), and stirred at room temperature for 2 h.

Step 2: Add toluene (50 ml) and benzyl alcohol (5.83 g, 53.89 mmol) to another three-necked bottle (B bottle), heat to 110 °C, drop the material from bottle A into bottle B, and stir at constant temperature for 2 h after dropping . The heating and stirring were stopped, cooled to room temperature, the reaction solution was washed with water (100 mL), then washed with 5% aqueous sodium hydroxide solution (100 mL×3), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain a yellow solid. Petroleum ether/ethyl acetate (50 mL, v/v = 10:1) was added to the crude product, stirred for 3 h, and filtered to obtain a white solid (11.34 g, yield 73.40 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.47 – 7.30 (m, 5H), 7.20 – 7.11 (m, 1H), 6.86 – 6.72 (m, 2H), 6.56 (s, 1H), 5.19 (s, 2H), 3.82 (s, 3H), 1.36 (d, J = 5.9 Hz, 6H).

MS (ESI, pos.ion) m/z: 316.20 [M+H] ⁺ .

Step 4: Synthesis of compound 3-isopropoxy-4-methoxyaniline

To the autoclave was added (3-isopropoxy-4-methoxyphenyl)carbamate (11.34 g, 35.96 mmol), 10% palladium on carbon (0.51 g, 0.54 mmol), methanol (40 mL) , replaced hydrogen (0.5 MPa), and stirred at room temperature for 2 h. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a brown solid (6.52 g, yield 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.71 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 6.24 (dd, J = 8.4, 2.5 Hz, 1H), 4.49 – 4.43 (p, J = 6.1 Hz, 1H), 3.77 (s, 3H), 1.34 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 182.20 [M+H] ⁺ .

Step 5: Synthesis of compound 3-isopropoxy-4-methoxyiodobenzene

Compound 3-isopropoxy-4-methoxyaniline (6.90 g, 38.07 mmol) was dissolved in 1,4-dioxane (30 mL) and water (11 mL), cooled to 0 °C, Add concentrated hydrochloric acid (9.6 mL, 36% aq), stir well, cool to -15 °C, add a solution of sodium nitrite (2.89 g, 41.88 mmol) and water (7 mL) dropwise, control the dropwise temperature at -15 Between ℃ and -5 ℃, return to -5 ℃ and stir for 30 min after dripping, then add a solution of potassium iodide (8.22 g, 49.49 mmol) and water (12 mL), and control the dropwise temperature at -15 ℃ to -5 ℃. After dropping, the temperature was returned to 0 °C and stirred for 2 h. Sodium bisulfite (1.98 g, 19.04 mmol) was added and stirred for 1 h to quench the reaction. Petroleum ether (200 mL) was added to the reaction solution, and the organic phase was washed with water (100 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a yellow viscous liquid. Silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=10/1) to obtain a white solid (7.83 g, yield 70.41 %)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.21 (dd, J = 8.5, 1.9 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 4.53 – 4.44 (m, 1H), 3.82 (s, 3H), 1.36 (d, J = 6.1 Hz, 6H).

GC-MS: m/z 292.0 [M] ⁺ .

Step 6: Synthesis of compound 2-(3-isopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

3-Isopropoxy-4-methoxyiodobenzene (8.64 g, 26.63 mmol), pinacol diboronate (6.76 g, 26.63 mmol), potassium acetate (39.2 g, 39.95 mmol), palladium acetate ( 0.30 g, 1.33 mmol), 2-dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) (0.97 g, 2.66 mmol) was mixed in N , N -dimethylformamide (48 mL) under nitrogen Stir at 80 °C for 6 h under protection. Cool to room temperature, add water (100 mL) to the reaction solution, extract the reaction solution with petroleum ether (100 mL×3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a brown liquid, which is passed through a silica gel column layer. It was purified by separation (eluent: petroleum ether/ethyl acetate (v/v) = 10/1) to give a yellow solid (5.04 g, yield 64.78%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 77.41 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.67 – 4.56 ( m, 1H), 3.87 (s, 3H), 1.37 (d, J = 6.1 Hz, 6H), 1.33 (s, 12H).

MS (ESI, pos.ion) m/z: 293.25 [M+H] ⁺ .

Step 7: Compound (R) -1- tert-butyl 2-methyl-4- (3-isopropoxy-4-methoxy-phenyl) -1 H - pyrrole -1, 2 (2 H, 5 H )-Diformate Synthesis

The compound (R) -1- tert-butyl 2-methyl 4 - ((((trifluoromethyl) sulfonyl acyl) methoxy) -1 H - pyrrole -1,2 (2 H, 5 H) - Dicarboxylate (5.50 g, 14.65 mmol, Intermediate M ₂ ), 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4,4,5 , 5-tetramethyl-1,3,2-dioxaborolane (4.49 g, 15.38 mmol), palladium acetate (82.23 mg, 0.37 mmol), dicyclohexyl-[2-(2-methyl) phenyl)phenyl] phosphine (267.00 mg, 0.73 mmol), dissolved in toluene (30 mL) solvent, then added 4-methylmorpholine (3.25 g, 32.08 mmol), water (15 mL), under nitrogen atmosphere The mixture was transferred to 80 °C and stirred for 2 h, cooled to room temperature, added with water (100 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was dried with anhydrous sodium sulfate for 30 min, and passed through a silica gel column layer. Purification (eluent: ethyl acetate/petroleum ether (v/v) = 3/20) gave a brown sticky (5 g, 87.19 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.96 – 6.90 (m, 2H), 6.85 – 6.82 (m, 1H), 5.93 – 5.87 (m, 1H), 5.17 – 5.08 (m, 1H) , 4.66 – 4.46 (m, 3H), 3.85 (s, 3H), 3.74 (d, J = 5.0 Hz, 3H), 1.52 (s, 3H), 1.45 (s, 6H), 1.36 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 336.05 [M- t- Bu+2H] ⁺ .

Step 8: Compound ( 2R , 4S )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate Synthesis

Compound ( R )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)-1H-pyrrole-1,2( 2H , 5H )-di The carboxylate (5.55 g, 14.18 mmol) was dissolved in methanol (90 mL) solvent, then palladium carbon (0.56 mg, 1.42 mmol) was added, and the reaction was stirred at room temperature for 4 h under a hydrogen atmosphere. The reaction was stopped, filtered through celite, and concentrated under reduced pressure to obtain a colorless sticky substance (4.45 g, yield 79.76%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.83 – 6.76 (m, 3H), 4.53 – 4.46 (m, 1H), 4.39 – 4.29 (m, 1H), 4.04 – 3.89 (m, 1H) , 3.82 (s, 3H), 3.75 (s, 3H), 3.42 – 3.35 (m, 1H), 3.32 – 3.23 (m, 1H), 2.65 – 2.57 (m, 1H), 2.06 – 1.95 (m, 1H) , 1.44 (s, 9H), 1.34 (d, J= 6.0 Hz, 6H).

MS (ESI, pos.ion) m/z: 337.40 [M -t- Bu+H] ⁺ .

Step 9: Compound ( 2R , 4S )-tert-butyl 2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-carboxylate synthesis

The compound (2R,4S)-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (3.00 g, 7.62 mmol) was dissolved in tetrahydrofuran (10 mL), at 0 °C, lithium borohydride in tetrahydrofuran solvent (2 mol/L, 0.33 g, 15.24 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction solution was slowly poured into ice-water (50 mL) and stirred continuously to generate hydrogen gas, then ethyl acetate (30 mL) was added and stirred, the organic phase was separated, concentrated under reduced pressure, and the aqueous phase was extracted with ethyl acetate (20 mL). , separate the organic phase, dissolve and concentrate the obtained liquid, add ethyl acetate (20 mL) to dissolve completely, adjust pH=3 with saturated sodium chloride solution (30 mL) and dilute hydrochloric acid, dry with anhydrous sodium sulfate, and concentrate under reduced pressure , a colorless viscous liquid (2.95 g, 100 % yield) was obtained

¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 6.83 – 6.81 (m, 1H), 6.77 (d, J = 7.1 Hz, 2H), 4.53 – 4.47 (m, 1H), 4.06 – 3.93 (m, 2H), 3.82 (s, 3H), 3.78 – 3.72 (m, 1H), 3.69 – 3.64(m, 1H), 3.23 – 3.13 (m, 2H), 2.40 – 2.31 (m, 1H), 1.63 – 1.59 ( m, 1H), 1.47 (s, 9H), 1.35 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 310.55 [M -t- Bu+2H] ⁺ .

Step 10: Compound ( 2R , 4S )-tert-butyl 4-(3-isopropoxy-4-methoxyphenyl)-2-(((methylsulfonyl)oxy)methyl ) Synthesis of pyrrolidine-1-carboxylate

The compound ( 2R , 4S )-tert-butyl 2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-carboxylate (2.78 g , 7.61 mmol) was dissolved in dichloromethane solvent (15 mL), then N , N -diisopropylethylamine (DIPEA) (1.57 g, 12.18 mmol) was added, and the temperature was changed to 0 °C and slowly added dropwise methanesulfonic acid Acyl chloride (1.13 g, 9.89 mmol), after 5 minutes, methanesulfonyl chloride was added dropwise, and the reaction was stirred at room temperature for 1 h. Wash the reaction solution with water (50 mL) once, add saturated brine (50 mL), wash with dilute hydrochloric acid to adjust pH=3, separate the organic phase, adjust pH=8 with saturated sodium bicarbonate, dry with anhydrous sodium sulfate, reduce Concentrated under pressure to obtain a brown viscous liquid (3.4 g, 100 % yield)

¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 6.85 – 6.76 (m, 3H), 4.71 – 4.48 (m, 2H), 4.47 – 4.32 (m, 1H), 4.17 – 4.08 (m, 1H), 4.01 – 3.89 (m, 1H), 3.83 (s, 3H), 3.27 – 3.12 (m, 2H), 3.01 (s, 3H), 2.58 – 2.42 (m, 1H), 2.12 – 2.02 (m, 1H), 1.48 (s, 9H), 1.36 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 388.10 [M -t- Bu+2H] ⁺ .

Step 11: Synthesis of compound (2R, 4S)-tert-butyl 2-(azidomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-carboxylate

Compound (2 R , 4 S )-tert-butyl 4-(3-isopropoxy-4-methoxyphenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrole Alkane-1-carboxylate (3.3 g, 7.44 mmol) was dissolved in N , N -dimethylformamide solvent (15 mL), then sodium azide (0.63 g, 9.67 mmol) was added and transferred to 80 The reaction was stirred at °C for 3 h. Stop the reaction, slowly pour the reaction solution into water (150 mL) and keep stirring, add ethyl acetate (100 mL × 3) for extraction, combine the organic phases, wash with saturated brine (200 mL × 3), and dry with anhydrous sodium sulfate , concentrated under reduced pressure, separated and purified by column chromatography (eluent: ethyl acetate/petroleum ether (v/v)=1/10) to obtain a colorless oily liquid (1.83 g, yield 62.99%)

¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 6.85 (s, 1 H), 6.82 (d, J = 5.5 Hz, 2H), 4.53 – 4.50 (m, 1H), 4.12 (s, 1H), 4.01 – 3.90 (m, 2H), 3.83 (s, 3H), 3.45 – 3.34 (m, 1H), 3.26 – 3.13 (m, 2H), 2.39 (s, 1H), 2.05 – 1.97 (m, 1H), 1.48 (s, 9H), 1.36 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 335.20 [M -t- Bu+2H] ⁺ .

Step 12: Synthesis of Compound (2R , 4S )-2-(azidomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine hydrochloride

The compound (2 R , 4 S )-tert-butyl 2-(azidomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-carboxylate (1.83 g, 4.69 mmol) was dissolved in dichloromethane (5 mL), and 1,4-dioxane hydrochloric acid solution (0.85 g, 23.45 mmol, 5.85 mL) was added, and the reaction was stirred at room temperature for 2 h. The reaction was stopped, the reaction solution was concentrated under reduced pressure, then dichloromethane (20 mL) was added to dissolve, and then concentrated under reduced pressure to obtain a light yellow viscous (1.53 g, yield 100%)

¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 6.88 – 6.78 (m, 3H), 4.57 – 4.50 (m, 1H), 4.06 – 3.91 (m, 3H), 3.82 (s, 3H), 3.80 – 3.71 (m, 1H), 3.57 – 3.45 (m, 1H), 3.41 – 3.30 (m, 1H), 2.51 – 2.42 (m, 1H), 2.03 – 1.91 (m, 1H), 1.35 (d, J = 6.0 Hz, 6H).

MS (ESI, pos.ion) m/z: 291.10 [M-HCl+H] ⁺ .

Step 13: Compound 1-(( 2R , 4S )-2-(azidomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethyl Synthesis of Ketones

Compound ( 2R , 4S )-2-(azidomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine hydrochloride (1.53 g, 4.68 mmol) was dissolved in In dichloromethane (8 mL) solvent, at 0 °C, N , N -diisopropylethylamine (DIPEA) (2.42 g, 18.72 mmol), acetyl chloride (0.73 g, 9.36 mmol) were sequentially added , and the reaction was stirred at room temperature for 2 h. The reaction solution was washed once with water (100 mL), the organic phase was extracted once with dichloromethane (50 mL), the organic phases were combined and washed once with saturated brine (100 mL), the organic phase was separated, and the organic phase was dried over anhydrous sodium sulfate. , concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v) = 4/5) to obtain light yellow oil (1.5 g, yield 96.42%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.88 – 6.77 (m, 3H), 4.58 – 4.49 (m, 1H), 4.30 – 4.24 (m, 1H), 4.14 – 4.10 (m, 1H) , 3.90 – 3.86 (m, 1H), 3.85 (s, 3H), 3.44 – 3.37 (m, 2H), 3.28 – 3.18 (m, 1H), 2.45 – 2.38 (m, 1H), 2.10 (s, 3H) , 2.16 – 2.04 (m, 1H), 1.37 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 333.20 [M+H] ⁺ .

Step 14: Compound 1-(( 2R , 4S )-2-(aminomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone Synthesis of hydrochloride

Compound 1-(( 2R , 4S )-2-(azidomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone ( 1.5 g, 4.51 mmol) was dissolved in methanol (15 mL) solvent, and then reducing agent palladium carbon (0.15 g, 0.41 mmol) and hydrochloric acid 1,4-dioxane (0.21 g, 5.86 mmol, 1.46 mL) were added, In a 1 Mpa hydrogen atmosphere, the reaction was stirred at room temperature for 3 h. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a yellow foamy solid (1.47 g, 95.05%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.89 – 6.71 (m, 3H), 4.63 – 4.20 (m, 3H), 3.95 – 3.81 (m, 1H), 3.82 (s, 3H), 3.56 – 3.12 (m, 3H), 2.73 – 2.46 (m, 1H), 2.26 – 2.09 (m, 3H), 1.94 – 1.77 (m, 1H), 1.36 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 307.20 [M+H-HCl] ⁺ .

Step 15: Compound ^{N 2 - (((2 R} , 4 S) -1- acetyl-4- (3-isopropoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl Synthesis of ) -N ⁵ -ethylpyridine-2,5-dimethylamide

The compound 6-(acetamide)pyridine-3-carboxylate lithium (220 mg, 1.09 mmol) was dissolved in N , N -dimethylformamide (5 mL) solvent, transferred to 0 °C, and hydrogen chloride was added 1,4-dioxane solution (40 mg, 1.09 mmol) was stirred for 2 min. After the solution was clear, it was brought to room temperature, and 1-((2 R , 4 S )-2-(aminomethyl ) was added. )-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone hydrochloride (250 mg, 0.73 mmol), 1-hydroxy-7-azabenzone Triazole (HOAT) (150 mg, 1.09 mmol), cooled at 0 °C, added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (420 mg, 2.19 mmol) ), N , N -diisopropylethylamine (DIPEA) (570 mg, 4.38 mmol), and the reaction was stirred at room temperature for 15 h. Stop the reaction, stop the reaction, add water (20 mL), extract with ethyl acetate (10 mL × 2), wash the organic phase with saturated brine (20 mL) once, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, Silica gel column chromatography (eluent: methanol/dichloromethane (v/v)=1/20) gave a white solid (219 mg, yield: 58.79 %)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.18 (s, 1H), 8.98 – 8.92 (m, 1H), 8.20 (s, 2H), 6.82 – 6.68 (m, 3H), 6.59 (s , 1H), 4.56 – 4.37 (m, 1H), 4.36 – 4.20 (m, 1H), 4.09 – 3.85 (m, 2H), 3.81 (s, 3H), 3.66 – 3.44 (m, 3H), 3.43 – 3.32 (m, 1H), 3.28 – 3.10 (m, 1H), 2.15 (s, 3H), 2.00 – 1.75 (m, 2H), 1.31 (d, J = 6.1 Hz, 6H), 1.25 (d, J = 7.5 Hz, 3H).

MS (ESI, pos.ion) m/z: 483.25 [M+H] ⁺ .

Example 72: ((2 R, 4 S) -1- acetyl-4- (3-isopropoxy-4-methoxyphenyl) pyrrolidin-2-yl) methyl 5- (ethyl carbamate) picolinate

Step 1: Synthesis of compound 3-isobutoxy-4-methoxybenzoic acid methyl ester

Compound 3-hydroxy-4-methoxybenzoic acid methyl ester (10.00 g, 54.89 mmol), bromoisobutane (11.28 g, 82.34 mmol) and potassium carbonate (22.76 g, 164.67 mmol) were mixed in N , N -Dimethylformamide (50 mL), placed at 80 ℃ and stirred for 10 h. Add ethyl acetate (200 mL) to dilute, the organic phase was washed with saturated brine (100 mL × 3), and anhydrous sodium sulfate It was dried and concentrated under reduced pressure to obtain a yellow liquid (11.06 g, yield 84.56%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.64 (dd, J = 8.4, 1.8 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.80 (d, J = 6.8 Hz, 2H), 2.20 – 2.12 (m, 1H), 1.03 (d, J = 6.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 239.50 [M+H] ⁺ .

Step 2: Synthesis of compound 3-isobutoxy-4-methoxybenzoic acid

Compound 3-isobutoxy-4-methoxybenzoic acid methyl ester (11.00 g, 46.16 mmol), sodium hydroxide (3.69 g, 92.32 mmol), ethanol (30 mL), water (10 mL) were mixed uniformly , and stirred at 50 °C for 2 h. Dilute hydrochloric acid (4 mol/L) was added dropwise to adjust pH=1, water (100 mL) was added, a large amount of solid was precipitated by stirring, and filtered. Solid (10.35 g, 100% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 (dd, J = 8.4, 1.9 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 3.94 (s, 3H), 3.83 (d, J = 6.8 Hz, 2H), 2.24 – 2.14 (m, 1H), 1.05 (d, J = 6.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 225.50 [M+H] ⁺ .

Step 3: Synthesis of compound benzyl(3-isobutoxy-4-methoxyphenyl)carbamate

Step 1: at room temperature, add 3-isobutoxy-4-methoxybenzoic acid (10.35 g, 46.15 mmol), triethylamine (6.07 g, 59.99 mmol) to a two-necked flask (100 mL) (A bottle) ), toluene (50 ml), stirred in an ice bath, slowly added dropwise diphenylphosphoryl azide (13.97 g, 50.77 mmol), and stirred at room temperature for 2 h.

Step 2: Add toluene (50 mL) and benzyl alcohol (5.49 g, 50.77 mmol) to another single-necked bottle (250 mL) (bottle B), heat to 110 °C, drop the material from bottle A into bottle B, and finish dropping Keep stirring for 2 h. Heating and stirring were stopped, cooled to room temperature, the reaction solution was washed with water (100 mL), then washed with 5% aqueous sodium hydroxide solution (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid. Petroleum ether/ethyl acetate (50 mL, v/v = 10/1) was added to the crude product, stirred for 3 h, and filtered to obtain a white solid (10.98 g, yield 72.23%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.46 – 7.37 (m, 5H), 7.24 – 7.12 (m, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.61 (br.s, 1H), 5.22 (s, 2H), 3.85 (s, 3H), 3.78 (d, J = 6.4 Hz, 2H), 2.23 – 2.11 (m, 1H) , 1.05 (d, J = 6.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 330.20 [M+H] ⁺ .

Step 4: Synthesis of compound 3-isobutoxy-4-methoxyaniline

To the autoclave (250 mL) was added (3-isobutoxy-4-methoxyphenyl)carbamate (10.90 g, 33.09 mmol), 10% palladium on carbon (0.53 g, 0.50 mmol), methanol (50 mL), the air was removed, hydrogen (0.5 MPa) was introduced, and the mixture was stirred at room temperature for 2 h. The reaction solution was filtered through celite, the filtrate was collected and concentrated under reduced pressure to obtain a brown solid (4.05 g, yield 62.68%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.71 (d, J = 8.4 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H), 6.23 (dd, J = 8.4, 2.6 Hz, 1H), 3.78 (s, 3H), 3.70 (d, J = 6.8 Hz, 2H), 2.17 – 2.09 (m, 1H), 1.01 (d, J = 6.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 196.45 [M+H] ⁺ .

Step 5: Synthesis of compound 3-isobutoxy-4-methoxyiodobenzene

Compound 3-isobutoxy-4-methoxyaniline (4.05 g, 20.74 mmol) was dissolved in 1,4-dioxane (30 mL) and water (11 mL), cooled to 0 °C, Add concentrated hydrochloric acid (5.3 mL, 36% concentration), stir evenly, cool to -15 ℃, add a solution of sodium nitrite (1.57 g, 22.81 mmol) and water (7 mL) dropwise, control the dropwise temperature at -15 Between ℃ and -5 ℃, after the dropwise addition, the temperature was raised to -5 ℃ and stirred for 30 min, then a solution of potassium iodide (4.48 g, 26.96 mmol) and water (12 mL) was added, and the dropwise temperature was controlled at -15 ℃ to Between -5 °C, after the dropwise addition, the temperature was raised to 0 °C and stirred for 2 h. Sodium bisulfite (1.08 g, 10.37 mmol) was added and stirred for 1 h to quench the reaction, and petroleum ether (200 mL) was added to the reaction solution, The organic phase was washed with water (100 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous liquid. Purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) to obtain a white solid (3.62 g, yield 56.97%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.20 (dd, J = 8.4, 1.9 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 3.72 (d, J = 6.8 Hz, 2H), 2.20 – 2.10 (m, 1H), 1.03 (d, J = 6.7 Hz, 6H).

GC-MS (EI): 306.0 [M] ⁺ .

Step 6: Synthesis of compound 2-(3-isobutoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

3-isobutoxy-4-methoxyiodobenzene (3.60 g, 11.76 mmol), pinacol diboronate (2.99 g, 11.76 mmol), potassium acetate (1.73 g, 17.64 mmol), palladium acetate ( 0.13 g, 0.59 mmol), 2-dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) (0.43 g, 1.18 mmol) was mixed in N , N -dimethylformamide (48 mL) under nitrogen Stir at 80 °C for 6 h under protection. Cool to room temperature, add water (100 mL) to the reaction solution, extract the reaction solution with petroleum ether (100 mL × 3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a brown liquid, which is subjected to silica gel column chromatography (Petroleum ether/ethyl acetate (v/v)=10/1) and purified to give a yellow liquid (2.16 g, yield 59.98%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.41 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 3.81 (d, J = 6.8 Hz, 2H), 2.22 – 2.12 (m, 1H), 1.34 (s, 12H), 1.04 (d, J = 6.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 307.60 [M+H] ⁺ .

Step 7: Compound (R) - 1- tert-butyl-2-methyl-4- (3-isobutoxy-4-methoxyphenyl) -1 H - pyrrole -1,2 (2 H, 5 H )-Diformate Synthesis

The compound 2-(3-isobutoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxolaborane (2.10 g, 6.86 g mmol), (R) - 1- tert-butyl-2-methyl-4 (((trifluoromethyl) sulfonyl acyl) oxy) -1 H - pyrrole -1,2 (2H, 5H) - dicarboxylic acid Ester (2.57 g, 6.86 mmol), palladium acetate (39 mg, 0.17 mmol), 2-dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) (130 mg, 0.34 mmol) and N-methylmorpholine (1.53 g, 15.09 mmol) was dissolved in toluene (10 mL) and water (5 mL), and stirred at 80 °C for 1 h under nitrogen protection. Concentrated under reduced pressure, added water (100 mL), extracted with ethyl acetate (100 mL × 3), combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: 60- 90 petroleum ether/ethyl acetate (v/v) = 5/1) to give a yellow liquid (2.15 g, 77.22% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.92 (s, 1H), 6.90 – 6.85 (m, 1H), 6.85 – 6.79 (m, 1H), 5.94 – 5.88 (m, 1H), 5.20 – 5.06 (m, 1H), 4.66 – 4.47 (m, 2H), 3.86 (s, 3H), 3.80 – 3.71 (m, 5H), 2.21 – 2.11 (m, 1H), 1.52 (s, 3H), 1.45 (s, 6H), 1.03 (d, J = 6.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 350.15 [M- t- Bu+2H] ⁺ .

Step 8: Compound ( 2R,4S) -1-tert-butyl 2-methyl 4-(3-isobutoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate synthesis

The compound (R) -1- tert-butyl 2-methyl-4- (3-isobutoxy-4-methoxyphenyl) -1 H - pyrrole -1,2 (2 H, 5 H) - Diformate (2.14 g, 5.28 mmol) and 10% palladium on carbon (200 mg) were added to methanol (30 mL) and stirred under hydrogen atmosphere (1 atm) for 12 h. The solid was filtered off through celite and concentrated under reduced pressure to give a colorless transparent liquid (2.02 g, 93.88% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.81 (d, J = 8.0 Hz, 1H), 6.78 – 6.74 (m, 1H), 6.74 – 6.71 (m, 1H), 4.41 – 4.28 (m , 1H), 4.06 – 3.88 (m, 1H), 3.83 (s, 3H), 3.78 – 3.71 (m, 5H), 3.45 – 3.35 (m, 1H), 3.35 – 3.22 (m, 1H), 2.68 – 2.57 (m, 1H), 2.21 – 2.10 (m, 1H), 2.08 – 1.97 (m, 1H), 1.43 (s, 9H), 1.03 (d, J = 6.6 Hz, 6H).

MS (ESI, pos.ion) m/z: 352.20 [M- t- Bu+2H] ⁺ .

Step 9: Synthesis of compound (2R,4S) -1-tert-butyl 2-hydroxymethyl-4-(3-isobutoxy-4-methoxyphenyl)pyrrolidine-1-carboxylate

Compound ( 2R,4S) -1-tert-butyl 2-methyl 4-(3-isobutoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (2.02 g , 4.96 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), placed in an ice bath and stirred for 0.5 h, and a solution of lithium borohydride (2.5 mL, 4.96 mmol, 2 mol/L in THF) was added dropwise, and the solution was stirred at room temperature for 4 h. Add saturated ammonium chloride solution (50 mL) to quench the reaction, add ethyl acetate (100 mL) to the residue to dilute, wash with saturated ammonium chloride solution (100 mL×2), adjust with hydrochloric acid (4 mol/L) pH=3, dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: 60-90 petroleum ether/ethyl acetate (v/v) = 3/1) to obtain colorless and transparent Sticky solid (1.70 g, 90.32% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.82 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.73 (s, 1H), 4.09 – 4.01 ( m, 1H), 4.00 – 3.91 (m, 1H), 3.84 (s, 3H), 3.80 – 3.76 (m, 1H), 3.75 (d, J = 6.8 Hz, 2H), 3.71 – 3.65 (m, 1H) , 3.24 – 3.13 (m, 2H), 2.41 – 2.32 (m, 1H), 2.21 – 2.09 (m, 1H), 1.71 – 1.61 (m, 1H), 1.48 (s, 9H), 1.04 (d, J = 6.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 324.20 [M- t- Bu+2H] ⁺ .

Step 10: Synthesis of Compound ((2R,4S) -4-(3-isobutoxy-4-methoxyphenyl)pyrrolidin-2-yl)methanol hydrochloride

Compound ( 2R,4S) -1-tert-butyl 2-hydroxymethyl-4-(3-isobutoxy-4-methoxyphenyl)pyrrolidine-1-carboxylate (1.50 g, 3.95 mmol) was dissolved in DCM (1 mL), injected into a solution of hydrogen chloride in dioxane (5.0 mL, 20.0 mmol, 4 mol/L), and stirred at room temperature for 3 h. The solvent was removed under reduced pressure to give a yellow solid (1.10 g, 99.68%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.95 – 6.71 (m, 3H), 4.08 – 4.01 (m, 1H), 3.99 – 3.89 (m, 1H), 3.80 (s, 2H), 3.74 (d, J = 6.7 Hz, 2H), 3.68 (s, 3H), 3.55 – 3.43 (m, 1H), 3.37 – 3.16 (m, 1H), 2.41 – 2.30 (m, 1H), 2.18 – 2.08 (m , 1H), 2.06 – 1.95 (m, 1H), 1.01 (d, J = 6.6 Hz, 6H).

MS (ESI, pos.ion) m/z: 280.30 [M-HCl+H] ⁺ .

Step 11: Synthesis of compound 1-(( 2R,4S) -2-hydroxymethyl-4-(3-isobutoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethyl ketone

Compound (( 2R,4S) -4-(3-isobutoxy-4-methoxyphenyl)pyrrolidin-2-yl)methanol hydrochloride (1.09 g, 3.90 mmol), triethylamine (2.02 g, 15.60 mmol) was dissolved in dichloromethane (5 mL), and acetyl chloride (610 mg, 7.80 mmol) was slowly added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 h. Dichloromethane (50 mL) was added, the reaction solution was washed with water (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow liquid (1.15 g, 3.16 mmol). The aforementioned yellow liquid (1.15 g, 3.16 mmol) was ), lithium hydroxide monohydrate (199 mg, 4.74 mmol), tetrahydrofuran (6 mL), and water (2 mL) were mixed uniformly, and stirred at 50 °C for 2 h. Saturated brine (20 mL) was added, diluted hydrochloric acid (4 mol/L) was added dropwise to adjust pH=1, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure A yellow liquid (938 mg, 92.35% yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.82 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.72 (s, 1H), 4.27 – 4.16 ( m, 1H), 3.92 – 3.85 (m, 1H), 3.83 (s, 3H), 3.78 – 3.73 (m, 1H), 3.74 (d, J = 6.6 Hz, 2H), 3.70 – 3.61 (m, 1H) , 3.40 (t, J = 10.8 Hz, 1H), 3.31 – 3.19 (m, 1H), 2.46 – 2.35 (m, 1H), 2.18 – 2.09 (m, 1H), 2.12 (s, 3H), 1.72 – 1.60 (m, 1H), 1.03 (d, J = 6.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 322.20 [M+H] ⁺ .

Step 12: Compound (( 2R,4S) -1-Acetyl-4-(3-isobutoxy-4-methoxyphenyl)pyrrolidin-2-yl)methyl 5-(ethyl Synthesis of Carbamate) Picolinate

Compound 1-(( 2R,4S) -2-hydroxymethyl-4-(3-isobutoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethyl ketone (151 mg, 0.47 mmol), 5-(ethylaminocarbamoyl)pyridine acid (183 mg, 0.94 mmol) and N -hydroxy-7-azabenzotriazole (160 mg, 1.17 mmol) in N , N - dimethylformamide (5 mL), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg, 1.41 mmol) and N in an ice bath, N -diisopropylethylamine (243, 1.88 mmol) was stirred at room temperature for 15 h. Dichloromethane was added to the reaction solution for extraction (100 mL), the organic phase was washed with water (50 mL × 3), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane) Methane/methanol (v/v) = 20/1) gave a white solid (80 mg, 34.21% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.07 (s, 1H), 8.24 (d, J = 7.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 6.86 – 6.74 ( m, 3H), 6.71 – 6.59 (m, 1H), 4.77 – 4.65 (m, 2H), 4.60 – 4.54 (m, 1H), 3.95 – 3.85 (m, 1H), 3.82 (s, 3H), 3.71 ( d, J = 6.6 Hz, 2H), 3.57 – 3.45 (m, 3H), 3.32 – 3.21 (m, 1H), 2.62 – 2.50 (m, 1H), 2.15 – 1.98 (m, 2H), 2.09 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.00 (d, J = 6.6 Hz, 6H).

MS (ESI, pos.ion) m/z: 498.25 [M+H] ⁺ .

Example 73: 5 - ((3 S , 5 R) -1- acetyl-5 - ((5- (acyl-ethylcarbamoyl) pyridine carboxylic acyl amino) methyl) pyrrolidin-3-yl )-2-(difluoromethoxy)phenyl isobutyrate

Compound N ² -((((2 R , 4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl ) - N ⁵ - ethyl pyridine-2,5-acyl amine (214 mg, 0.45 mmol, 48 the procedure of Example 1) was dissolved in was dissolved in N, N - dimethylformamide (10 mL) solvent , stir until clear, then add isobutyric acid (59 mg, 0.68 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (123 mg, 0.90 mmol), and add 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (173 mg, 0.90 mmol), N , N -diisopropylethylamine (DIPEA) (233 mg, 1.80 mmol) ), transferred to room temperature and stirred for 21 h, added water (20 mL) to dilute the reaction solution, extracted with ethyl acetate (20 mL × 2), combined the organic phases, washed with saturated brine (20 mL × 2), The organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated and passed through column chromatography (DCM/MeOH (v/v) = 20/1) to give the product as a white solid (200 mg, 81.32 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.12 – 9.05 (m, 1H), 8.96 (s, 1H), 8.21 (s, 2H), 7.20 – 7.12 (m, 1H), 7.10 – 7.03 (m, 1H), 7.00 – 6.95 (m, 1H), 6.43 (s, 1H), 6.35 (t, J = 73.9 Hz, 1H), 4.34 – 4.25 (m, 1H), 4.04 – 3.97 (m, 1H) ), 3.97 – 3.89 (m, 1H), 3.65 – 3.56 (m, 1H), 3.55 – 3.47 (m, 2H), 3.46 – 3.38 (m, 1H), 3.33 – 3.22 (m, 1H), 2.89 – 2.77 (m, 1H), 2.65 – 2.54 (m, 1H), 2.23 (s, 0.4H), 2.15 (s, 2.6H), 2.01 – 1.87 (m, 1H), 1.31 (d, J = 7.0 Hz, 6H ), 1.27 (t, J = 7.3 Hz, 3H).

MS (ESI, pos.ion) m/z: 547.15 [M+H] ⁺ .

biological test

biological example

The present invention adopts the following methods to conduct biological tests on the compounds of the present invention: (1) Using a BPS production kit (BPS, Cat. No. 60343), according to the instructions provided by the manufacturer, a fluorescence polarization method is used to detect the inhibitory effect of the compounds on PDE4B2 enzyme. (2) The PDE4B2 enzyme concentration was prepared to 83.33 pg/μL, and the final concentration was 27.78 pg/μL; the substrate FAM-Cyclic-3', 5'-AMP concentration was prepared to 300 nM, the final reaction concentration was 100 nM, and the enzyme and The substrate diluents were all used in the kit's own buffer PDE Assay buffer; Binding Agent was 100-fold diluted with the kit's own Binding Agent Diluent for use. The reaction system is shown in Table 1. [Table 1] IC ₅₀ detection system for PDE4B2 enzyme Test sample well Positive control wells Negative control wells Buffer blank control wells PDE4B2 enzyme 5 μL 5 μL 0 μL 0 μL FAM-Cyclic-3', 5'-AMP substrate 5 μL 5 μL 5 μL 0 μL Test sample 5 μL 0 μL 0 μL 0 μL PDE Assay buffer 0 μL 5 μL 10 μL 15 μL Incubate for 1 h at 25°C in a constant temperature shaker box Binding Agent 15 μL 15 μL 15 μL 15 μL 25°C, oven-controlled oscillator for 1 h

A 384-well plate was used for detection. The test sample wells, positive control wells, negative control wells and blank wells were set up in the experiment. Each sample was tested for the inhibitory effect of PDE4B2 enzyme concentration at 10 concentrations by double wells. PDE4B2 enzyme and FAM were used for the detection The -Cyclic-3',5'-AMP substrate reaction well was used as a positive control, the FAM-Cyclic-3',5'-AMP substrate well was used as a negative control, and the buffer well was used as a blank control. After adding corresponding samples, enzymes, substrates and buffers to each well in the order of Table 1 , incubate at 25 °C for 1 h, then add 15 μL of the configured Binding Agent to each well, and shake at 25 °C incubator for 1 hr. After h, detection was performed at the wavelength of FP485/525 using a PHER Astar FS multifunctional microplate reader (BMG). Using Graph Pad Prism 5 software, the inhibitory effects of compounds on PDE4B2 at different concentrations were plotted, and IC _{50 was} calculated.

Measured according to the above-described compounds of the present invention PDE4B2 enzyme inhibition, compounds of this invention have found that inhibition of PDE4B2 enzyme, an IC ₅₀ value of less than 1 μM; further been found, some of the compounds of the present invention the IC inhibition of the enzyme ₅₀ PDE4B2 The value is less than 500 nM; it is further found that the IC ₅₀ value of the inhibitory effect on PDE4B2 enzyme of some compounds of the present invention is less than 200 nM. Specifically, the results of the determination of the inhibitory effect of some compounds of the present invention on the PDE4B2 enzyme are shown in Table 2. [Table 2] Measurement results of the inhibitory effect of some compounds of the present invention on PDE4B2 enzyme Example number PDE4B2 IC ₅₀ (nM) Example number PDE4B2 IC ₅₀ (nM) Example 3 59.89 Example 18 29.08 Example 4 45.87 Example 19 10.58 Example 8 19.43 Example 21 5.33 Example 9 11.18 Example 22 7.721 Example 10 38.07 Example 23 10.66 Example 11 7.113 Example 24 36.29 Example 12 23.45 Example 26 62.2 Example 13 56.59 Example 27 22.9 Example 14 39.12 Example 28 11.7 Example 17 2.85 / / Example 39 1.63 Example 57 1.21 Example 40 12.07 Example 58 3.52 Example 43 7.40 Example 59 22.42 Example 44 4.39 Example 60 1.27 Example 45 1.68 Example 62 6.85 Example 47 1.94 Example 63 1.11 Example 48 3.18 Example 64 7.05 Example 49 2.95 Example 65 2.38 Example 50 6.80 Example 66 7.94 Example 51 0.48 Example 67 10.81 Example 52 0.14 Example 68 5.48 Example 53 0.16 Example 69 2.81 Example 54 0.18 Example 70 0.19 Example 55 0.63 Example 71 40.76 Example 56 0.58 Example 72 1.38

Conclusion: Experiments show that the compounds of the present invention generally have a high inhibitory effect on PDE4B2 enzyme in vitro.

The compounds of the present invention are effective in PMA-induced acute atopic dermatitis mouse model

Female ICR mice, weighing 26-28 g, were randomly divided into normal group, model group and each compound group after 7 days of adaptive feeding, with 4 mice in normal group and 10 mice in each other group. Except for the mice in the normal group, the other mice were smeared with 20 μL of PMA solution (dissolved in absolute ethanol) with a concentration of 0.25 mg/mL on the right ear for modeling, and the normal group was smeared with the corresponding vehicle. The first administration of each compound group was performed 30 minutes before modeling and the second administration was performed 15 minutes after modeling. Animals in each group were smeared with 20 μL of the test drug solution with a concentration of 15 mg/mL [ethanol:acetone]. =1:1(v/v)], the animals in the normal group and model group were smeared with the corresponding vehicle. The animals were sacrificed 6 hours after the second administration. The right ear of each animal was cut off and the ear piece was obtained at a fixed position with an 8 mm ear punch and weighed. Homogenize in a homogenizer, take the supernatant after centrifugation, detect the IL-1β and IL-6 concentrations in the supernatant and normalize the protein concentration.

The specific results are shown in Tables 3-7: Effects of the compounds of the present invention on the ear thickness, ear weight and secretion of inflammatory factors in the PMA-induced acute atopic dermatitis mice (Mean±SEM, animal data N=4 or N=10) [ Table 3] Effects of compounds on mouse ear thickness and ear weight (Mean±Sem) group Dosage N ear thickness ear weight Thickness(mm) Inhibition rate Weight (mg) Inhibition rate normal group - 4 0.200±0.000** - 12.4±0.2** - model group - 10 0.395±0.011 - 41.2±1.2 - Example 9 0.3mg/ear/bid 10 0.308±0.007** 51.1% 26.6±1.8** 50.7% Example 11 0.3mg/ear/bid 10 0.231±0.006** 96.5% 16.2±0.7** 86.8% [continued] IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate -0.064±0.004** - -0.025±0.004** - 0.759±0.217 - 0.398±0.116 - 0.179±0.035** 70.4% 0.122±0.048** 65.4% 0.016±0.013** 90.2% -0.008±0.008** 96.0% [Table 4] Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean±Sem) group Dosage N ear thickness ear weight Thickness(mm) Inhibition rate Weight (mg) Inhibition rate normal group - 4 0.202±0.003** - 13.8±0.4** - model group - 10 0.453±0.009 - 36.5±1.0 - Example 17 0.3mg/ear/bid 10 0.235±0.008** 83.7% 17.5±0.9** 86.8% [continued] IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate -0.034±0.004** - -0.006±0.005** - 0.163±0.022 - 0.114±0.016 - 0.029±0.006** 68.1% 0.009±0.005** 88.0% [Table 5] Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean±Sem) group Dosage N ear thickness ear weight Thickness(mm) Inhibition rate Weight (mg) Inhibition rate normal group - 4 0.210±0.015** - 14.8±0.3** - model group - 10 0.391±0.017 - 30.9±0.1 - Example 27 0.3mg/ear/bid 10 0.234±0.016** 86.8% 19.3±0.2** 72.4% [continued] IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate -0.037±0.017** - -0.059±0.033** - 0.154±0.021** - 0.215±0.021** - 0.003±0.019** 78.9% -0.040±0.020** 93.0% [Table 6] Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean±Sem) group Dosage N ear thickness ear weight Thickness(mm) Inhibition rate Weight (mg) Inhibition rate normal group - 4 0.193±0.002** - 12.8±0.4** - model group - 10 0.483±0.009 - 32.3±0.9 - Example 28 0.3mg/ear/bid 10 0.249±0.016** 80.9% 16.3±1.3** 82.3% [continued] IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate -0.062±0.005** - -0.047±0.003** - 0.230±0.026 - 0.182±0.015 - -0.019±0.017** 85.3% -0.040±0.008** 96.9% [Table 7] Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean±Sem) group Dosage N ear thickness ear weight Thickness(mm) Inhibition rate Weight (mg) Inhibition rate normal group - 4 0.20±0.03** - 15.40±0.28** - model group - 10 0.50±0.02 - 41.80±0.21 - Example 61 0.3mg/ear/bid 10 0.27±0.02** 79% 22.42±0.20** 73% [continued] IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate 0.02±0.09** - 0.00±0.09** - 0.58±0.04 - 0.51±0.04 - 0.28±0.04** 53% 0.17±0.03** 66% (Note: *P<0.05, **P<0.01, vs. model group;)

As can be seen from the above experimental results, compared with the model group, the compounds of the present invention can significantly reduce the ear thickness and ear weight and the secretion of ear inflammatory factors IL-1β and IL-6 in PMA-induced acute atopic dermatitis mice ( P < 0.05).

The compounds of the present invention are effective in OXA-induced chronic atopic dermatitis mouse model

Male Balb/c mice with a body weight of 24-26 g were selected. After 7 days of adaptive feeding, except for the normal group, the other animals were coated with 40 μL of 1% OXA solution (dissolved in acetone) on Day 0 and Day 1. Mice were sensitized on both ears. On Day 7 and Day 8, 40 μL of 0.5% OXA solution was applied to both ears of mice to repeat the sensitization. The normal group was smeared with the corresponding vehicle. From Day 12, except for the normal group, the other animals were challenged with 20 μl of 0.5% OXA solution applied to the right ear of the mice, twice a week, the normal group was applied with the corresponding vehicle, and the thickness of the right ear was measured 24 hours after each challenge . Except for the normal group, the rest of the animals were randomly divided into the model group and each compound group on the 13th day according to the results of ear thickness, with 5 animals in the normal group and 10 animals in each other group. The administration started on Day 14, twice a day, 20 μL of the test drug solution with a concentration of 15 mg/mL [ethanol:acetone=1:1(v/v)] was applied to the ears of the animals in each administration group. Group animals were smeared with the corresponding vehicle. On Day 29, the ear thickness was measured and then sacrificed. The right ear of each animal was cut off and the ear piece was obtained at a fixed position with an 8 mm ear punch and weighed. The ear piece was then stored in liquid nitrogen, and then 500 μL of normal saline was added to homogenize it with a homogenizer. After centrifugation, the supernatant was collected, and the concentrations of IL-1β, IL-4, IL-5, IL-6 and TNF-α in the supernatant were detected and the protein concentration was normalized.

The results show that, compared with the model group, the compounds of the present invention can significantly reduce the ear thickness and end-point ear weight of mice with chronic atopic dermatitis induced by OXA from Day 20 to the end of administration, as well as ear inflammatory factors IL-1β, IL -4. Secretion of IL-5, IL-6 and TNF-α (P<0.01);

It will be apparent to those skilled in the art that this disclosure is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from essential characteristics thereof. Accordingly, it is intended that the various embodiments be regarded in all respects as illustrative and non-restrictive, and reference should be made to the appended claims, rather than to the foregoing embodiments, and, therefore, within the meaning and scope of equivalents in the appended claims All changes within are included in the present invention.

In the description of this specification, reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., means a specific feature described in connection with the embodiment or example, A structure, material, or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms 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 as examples, but are not limited to the content described in the present invention, and may also be modifications made within the scope of the present invention or equivalents added in the claims. All publications or patents cited herein are incorporated herein by reference.

Claims (12)

A compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable compound represented by formula (I) Salts or their prodrugs:

(I); wherein: R ¹ and R ² are each independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, heterocyclyl consisting of 3-10 atoms, C _6-10 aryl, heteroaryl consisting of 5-10 atoms, C _3-8 cycloalkyl-C _1-4 alkylene base, C _1-6 alkyl-C(=O)-, C _3-8 cycloalkyl-C(=O)-, heterocyclyl-C _1-4 alkylene composed of 3-10 atoms, C _6-10 aryl or -C _1-4 alkylene 5-10 heteroaryl group consisting of -C _1-4 alkylene group; X and X ¹ are each independently a bond, -O -, - S -, -N(R ^c )-, -C(=O)- or -S(=O) _t -; R ³ is hydrogen, deuterium, carboxyl, C _1-6 alkyl, C _{1-6 haloalkane} base, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, heterocyclyl consisting of 3-10 atoms, heterocyclic group consisting of 5-10 atoms Aryl, C _3-8 cycloalkyl-C _1-4 alkylene, C _6-10 aryl-C _1-4 alkylene, heterocyclyl-C _1-4 alkylene composed of 3-10 atoms Alkyl, 5-10 atoms of heteroaryl-C _1-4 alkylene, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O) _t- , C _1-6 alkoxy-C(=O)-, C _3-8 cycloalkyl-C(=O)-, C _3-8 cycloalkyl-S(=O) _t- , 3-10 Heterocyclyl-C(=O)- composed of atoms, heterocyclyl-S(=O) _t- composed of 3-10 atoms, -C(=O)-NR ^d R ^e , -S(= O) _t- NR ^d R ^e , C _6-10 aryl-C(=O)-, heteroaryl-C(=O)- composed of 5-10 atoms, C _6-10 aryl-S( =O) _t- or heteroaryl-S(=O) _t- composed of 5-10 atoms, wherein R ³ is unsubstituted or substituted by 1, 2, 3 or 4 R ⁶ ; each R ^{6 is} independent Deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, C _1-4 alkyl, C _{1-4 haloalkyl} , C _1-4 alkoxy, C _1-4 alkylamino or C _1-4 alkyl-C(=O)-N(R ^c )-; R ⁴ is -(CH ₂ ) _m -L-(CH ₂ ) _n -G; L is a bond , -O-, -S-, -NR ^x -, -NR ^x -C(=O)-, -NR ^x -S(=O) _t -, -NR ^x -C(=O)-NR ^y - , -NR ^x -C(=O)-O-, -S(=O) _t -, -C(=O)- or -C(=O)-O-; wherein, each R ^x and R ^{y are} independent is hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _3-8 cycloalkyl, C _6-10 aryl, 3-10 atoms of heterocyclyl, 5-10 atoms of heteroaryl, C _3-8 cycloalkyl-C _1-6 alkylene base, C _6-10 aryl-C _1-6 alkylene, heterocyclyl-C _1-6 alkylene consisting of 3-10 atoms, heteroaryl-C _{1- 6} alkylene, C _1-6 alkyl-S(=O) _t- , C _1-6 alkyl-C(=O)- or C _1-6 alkoxy-C(=O)-C _{1 -6} alkylene; G is C _3-8 cycloalkyl, C _6-10 aryl, heterocyclyl consisting of 3-10 atoms or heteroaryl consisting of 5-10 atoms; wherein G is unsubstituted or substituted by 1, 2, 3 or 4 R ⁷ ; each R ^{7 is} independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, carboxyl, C _{1- 6} alkyl, C _{1-6 haloalkyl} , C _1-6 alkoxy, C _1-6 alkylamino, -C(=O)-NR ^a R ^b , -S(=O) _t -NR ^a R ^b , C _1-6 alkyl-C(=O)-N(R ^c )-, C _1-6 alkyl-S(=O) _t -N(R ^c )-, C _1-6 alkoxy Base-C(=O)-N(R ^c )-, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O) _t- , C _1-6 alkoxy Base-C(=O)-, C _1-6 alkyl-C(=O)-O-, C _3-8 cycloalkyl, C _6-10 aryl, heterocyclic group consisting of 3-10 atoms or a heteroaryl group consisting of 5-10 atoms; each R ^a and R ^{b are} independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} , C _3-8 cycloalkyl, C _6-10 aryl, 3-10 atoms heterocyclyl, 5-10 atoms heteroaryl, C _3-8 cycloalkyl-C _1-6 alkylene, C _6-10 aryl -C _1-6 alkylene group, heterocyclyl group consisting of 3-10 atoms -C _1-6 alkylene group, heteroaryl group consisting of 5-10 atoms -C _1-6 alkylene group, C _{1- 6} alkyl-S(=O) _t- or C _1-6 alkyl-C(=O)-, wherein each R ^a and R ^{b are} independently unsubstituted or by 1, 2 or 3 selected from deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, -C(=O)-NH ₂ , C _1-6 alkoxy C(=O)-, C _1-6 Alkyl-C(=O)-N(R ^c )-, C _1-6 alkyl-S(=O) _t -N(R ^c )-, C _1-4 alkyl, C _{1-4 halo} an alkyl group, C _1-4 alkoxy or C _1-4 alkylamino substituted; each of R ^d and R ^{e are} independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 haloalkyl} base, C _3-8 cycloalkyl, C _6-10 aryl, heterocyclic group consisting of 3-10 atoms, 5-10 atom group Heteroaryl, C _3-8 cycloalkyl-C _1-6 alkylene, C _6-10 aryl-C _1-6 alkylene, heterocyclyl-C _{1 consisting of 3-10 atoms -6} alkylene, heteroaryl-C _1-6 alkylene composed of 5-10 atoms, C _1-6 alkyl-S(=O) _t - or C _1-6 alkyl-C(= O) -, wherein each R ^d and R ^e are independently unsubstituted or substituted with 1, 2 or 3 substituents selected from deuterium, -F, -Cl, -Br, -I , hydroxy, amino, cyano, oxo, -C(=O)-NH ₂ , C _1-6 alkoxy C(=O)-, C _1-6 alkyl-C(=O)-N(R ^c )-, C _1-6 alkyl -S(=O) _t -N(R ^c )-, C _1-4 alkyl, C _{1-4 haloalkyl} , C _1-4 alkoxy or C _1-4 alkylamino group substituted ; Each R ^{c is} independently hydrogen, deuterium, C _1-3 alkyl or C _{1-3 haloalkyl} ; R is hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyanide group, C _1-3 alkyl, C _1-3 alkoxy, C _{1-3 haloalkoxy} group or a C _{1-3 haloalkyl} ^{group; R 5a, R 5b, R} 6a and R ^6b are each independently hydrogen , deuterium, -F, -Cl, -Br, -I , hydroxy, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _{1-3 haloalkoxy} group or a C _{1-3 halo alkyl} group; t is 1 or 2; n is 0,1,2,3 or 4; m is 2, 3 or 4. The compound according to claim 1, which is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of the compound represented by formula (II) , pharmaceutically acceptable salts, their prodrugs:

(II). The compound according to claim 1, which is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite of the compound represented by formula (III) , pharmaceutically acceptable salts, their prodrugs:

(III). The compound of claim 1, wherein: R ¹ and R ² are each independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, isobutyl, -CH ₂ F, -CHF _{2 , -CF 3, -CH 2 CH 2} F, -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, - CH ₂ Cl, -CHCl ₂ , -CH=CH ₂ , -CH ₂ CH=CH ₂ , -C≡CH, -CH ₂ C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo propylmethylene, cyclopropylethylene, cyclobutylmethylene, cyclobutylethylene, cyclopentylmethylene, cyclopentylethylene, cyclohexylmethylene, cyclohexylidene _{ethyl, CH 3 C (= O)} -, CH 3 CH 2 C (= O) -, CH 3 CH 2 CH 2 C (= O) -, (CH 3) 2 CHC (= O) -, cyclopropyloxy base-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl, naphthyl, pyridyl, Pyrimidyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, oxazinyl, quaridinyl, morpholinyl, thiomorpholinyl , tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, pyridyl-C _1-3 alkylene, pyrimidinyl-C _{1- 3} alkylene, furyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, pyrazolyl-C _1-3 alkylene, -C _1-3 alkylene-thiazolyl group, oxazolyl -C _1-3 alkylene, -C _1-3 triazole alkylene group, tetrazol group -C _1-3 alkylene, quack Azinyl-C _1-3 alkylene, ciridinyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene, thiomorpholinyl-C _1-3 alkylene, tetra Hydropyranyl-C _1-3 alkylene or pyrrolidinyl-C _1-3 alkylene; R ³ is hydrogen, deuterium, carboxyl, C _1-3 alkyl, C _{1-3 haloalkyl} , C _2-4 alkenyl, C _2-4 alkynyl, CH ₃ -C(=O)-, CH ₃ CH ₂ -C(=O)-, CH ₃ CH ₂ CH ₂ -C(=O)-, (CH ₃ ) ₂ CH-C(=O)-, CH ₃ -S(=O) ₂ -, CH ₃ CH ₂ -S(=O) ₂ -, CH ₃ CH ₂ CH ₂ -S(=O) ₂ -, (CH ₃ ) ₂ CH-S(=O) ₂ -, CH ₃ -OC(=O)-, CH ₃ CH ₂ -OC(=O)-, CH ₃ CH ₂ CH ₂ -OC(= O)-, (CH ₃ ) ₂ CH-OC(=O)-, -S(=O) ₂ -NH ₂ or -C(=O)-NH ₂ , wherein R ³ is unsubstituted or substituted with 1 ^{, 2, 3 or 4 R 6} ; each R ^{6 is} independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, -CH ₂ F, _{-CHF 2, -CF 3, -CH 2} CH 2 F, -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF _{3, -CH 2 Cl, -CHCl 2} , methoxy, ethoxy, n-propyl group, methylamino, ethylamino, or n-propylamino. The compound of claim 1, wherein: each R ^x and R ^{y is} independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C _{1-4 haloalkyl} , cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-C _1-3 alkylene, cyclobutyl-C _1-3 alkylene, cyclopentyl-C _1-3 alkylene, cyclohexyl -C _1-3 alkylene, phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl , oxazinyl, oxidyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene , pyridyl-C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _{1 -3} alkylene, pyrazolyl-C _1-3 alkylene, thiazolyl-C _1-3 alkylene, oxazolyl-C _1-3 alkylene, triazolyl-C _1-3 Alkylene, tetrazolyl-C _1-3 alkylene, oxazinyl-C _1-3 alkylene, oxidyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene Alkyl, thiomorpholinyl-C _1-3 alkylene, tetrahydropyranyl-C _1-3 alkylene, pyrrolidinyl-C _1-3 alkylene, C _1-3 alkyl- S(=O) ₂ -, C _1-3 alkyl-C(=O)- or C _1-3 alkoxy-C(=O)-C _1-3 alkylene. The compound of claim 1, wherein: G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

; wherein G is unsubstituted or substituted by 1, 2, 3 or 4 R ⁷ ; each R ^{7 is} independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo , carboxyl, C _1-4 alkyl, C _{1-4 haloalkyl} , C _1-4 alkoxy, C _1-4 alkylamino, -C(=O)-NR ^a R ^b , -S(= O) ₂ -NR ^a R ^b , C _1-4 alkyl-C(=O)-NH-, C _1-4 alkyl-S(=O) ₂ -NH-, C _1-4 alkoxy- C (= O) -NH-, CH 3 -C (= O) -, CH 3 CH 2 -C (= O) -, CH 3 CH 2 CH 2 -C (= O) -, (CH 3) 2 CH-C(=O)-, CH ₃ CH ₂ CH ₂ CH ₂ -C(=O)-, CH ₃ -S(=O) ₂ -, CH ₃ CH ₂ -S(=O) ₂ -, CH ₃ CH ₂ CH ₂ -S(=O) ₂ -, (CH ₃ ) ₂ CH-S(=O) ₂ -, CH ₃ OC(=O)-, CH ₃ CH ₂ OC(=O)-, CH ₃ CH ₂ CH ₂ OC(=O)-, (CH ₃ ) ₂ CHO-C(=O)-, CH ₃ CH ₂ CH ₂ CH ₂ OC(=O)-, CH ₃ -C(=O)- _{O-, CH 3 CH 2 -C (} = O) -O-, CH 3 CH 2 CH 2 -C (= O) -O -, (CH 3) 2 CH-C (= O) -O-, CH ₃ CH ₂ CH ₂ CH ₂ -C(=O)-O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

. The compound of claim 1, wherein: each R ^a and R ^{b is} independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ F, -CHF _{2 , -CF 3, -CH 2 CH 2} F, -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, - CH ₂ Cl, -CHCl ₂ , phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, oxazinyl, pyridinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, Pyridyl-C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _{1- 3} alkylene, pyrazolyl-C _1-3 alkylene, thiazolyl-C _1-3 alkylene, oxazolyl-C _1-3 alkylene, triazolyl-C _1-3 alkylene Alkyl, tetrazolyl-C _1-3 alkylene, oxazinyl-C _1-3 alkylene, oxidyl-C _1-3 alkylene, morpholinyl-C _1-3 alkylene base, thiomorpholinyl-C _1-3 alkylene, tetrahydropyranyl-C _1-3 alkylene, pyrrolidinyl-C _1-3 alkylene, C _1-3 alkyl-S (=O) ₂ - or C _1-3 alkyl-C(=O)-; wherein each R ^a and R ^{b are} independently unsubstituted or by 1, 2 or 3 selected from deuterium, -F, -Cl , -Br, -I, hydroxyl, amino, cyano, oxo, -C(=O)-NH ₂ , C _1-3 alkoxy C(=O)-, C _1-3 alkyl-C( =O)-NH-, C _1-3 alkyl-S(=O) _t -NH-, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH ₂ F, -CHF _{2 , -CF 3, -CH 2 CH 2} F, -CH 2 CHF 2, -CH 2 CF 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, - CH ₂ Cl, -CHCl ₂ , methoxy, ethoxy, n-propyloxy, isopropyloxy, N -methylamino, N -ethylamino, N'N -dimethylamino, N 'N -diethylamino or N'N -methylethylamino groups. The compound according to claim 1, which is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmacy compound having one of the following structures On acceptable salts or their prodrugs:

(1),

(2),

(3),

(4),

(5),

(6),

(7),

(8),

(9),

(10),

(11),

(12),

(13),

(14),

(15),

(16),

(17),

(18),

(19),

(20),

(twenty one),

(twenty two),

(twenty three),

(twenty four),

(25),

(26),

(27),

(28),

(29),

(30),

(31),

(32),

(33),

(34),

(35),

(36),

(37),

(38),

(39),

(40),

(41),

(42),

(43),

(44),

(45),

(46),

(47),

(48),

(49),

(50),

(51),

(52),

(53),

(54),

(55),

(56),

(57),

(58),

(59),

(60),

(61),

(62),

(63),

(64),

(65),

(66),

(67),

(68),

(69),

(70),

(71),

(72) or

(73). A pharmaceutical composition, comprising the compound described in any one of claims 1 to 8, optionally, it further comprises at least one of pharmaceutically acceptable carriers, excipients, additives, adjuvants and vehicles A sort of. The pharmaceutical composition of claim 9, further comprising an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, telukast, theophylline, Formoterol, salmeterol, fluticasone propionate, rolipram, piramister, cilomilast, indacaterol, olodaterol, midestane, qifluun, albuterol Amine, camoxirol, budesonide, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, roflunomide, ciclesonide, ipratropium bromide, oxytropium Bromide , mometasone, triamcinolone, betamethasone, aclomethasone, desonide, hydrocortisone, clobetasol, halobetasol, diflurasone, meperclone, tacrolimus Limus, pimecrolimus, tazarotene, cyclosporine, apremilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, ibudilast, tofacitinib , JTE-052, baricitinib, upatinib, WBI-1001, MRX-6, GSK2981278, durumumab, lekinizumab, nimolizumab, tralotinib, Etanercept, adalimumab, infliximab, ustekinumab, sekuginu, omazu, CIM-331, golimumab and pegylated, tocilizumab, Calcipotriol, Calcitriol, Aliretinoin, VTP-38543, ZPL-389, Aprepitant, Tripitant, Faviprant, OC-459, SUN 13834, SB-011, VTP -43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02 or a combination thereof. Use of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to any one of claims 9 to 10 in the preparation of a medicament, wherein the medicament is used for preventing, treating or alleviating and Phosphodiesterase type 4-related diseases. The use according to claim 11, wherein the disease related to phosphodiesterase type 4 is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin-dependent diabetes mellitus; Wherein, the respiratory diseases are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, pulmonary tuberculosis fibrosis, cystic fibrosis, acute respiratory distress syndrome or respiratory tract inflammation; wherein bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis; Wherein, the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatism Arthritis or psoriatic arthritis.