TWI879947B - Substituted nitrogen-containing five-membered ring compounds and their applications in medicine - Google Patents

Abstract

The present invention belongs to the field of medicine, and relates to a class of substituted nitrogen-containing five-membered ring compounds and their applications in medicine. Specifically, the present invention relates to a compound as shown in formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug of the compound as shown in formula (I); and also relates to a pharmaceutical composition comprising the compound, and its uses and methods of use. In particular, the compound described in the present invention is a PDE4 inhibitor, which is used to treat PDE4-related diseases, such as atopic dermatitis (AD) or chronic obstructive pulmonary disease (COPD).

Description

Substituted nitrogen-containing five-membered ring compounds and their applications in medicine

The present invention belongs to the field of medicine, and specifically relates to a substituted nitrogen-containing five-membered ring compound, a pharmaceutical composition containing the compound, and its use in medicine and a method of using the compound. In particular, the compound of the present invention is a PDE4 inhibitor, which is used to treat 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. They mainly participate in physiological activities such as energy metabolism, memory, immune response, vision and olfactory formation by activating protein kinase A (PKA) and protein kinase G (PKG). The regulation of their intracellular concentration is mainly determined by the balance between the synthesis of adenylate cyclase and the hydrolysis of phosphodiesterase (PDEs). PDEs can specifically use 3,5-cyclic nucleotides as substrates to catalyze the hydrolysis of intracellular cGMP and cAMP to generate corresponding inactive adenosine 5-phosphate, thereby affecting various metabolic functions of organisms. Therefore, inhibition of PDEs is a very effective way to induce the activity of many cells, affecting the activation of inflammatory cells and immune cells and the contractile response of smooth muscle cells.

So far, 11 gene families of phosphodiesterases (PDEs) have been reported, and each family 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 hydrolyze cAMP, PDE5, PDE6, and PDE9 specifically hydrolyze cGMP, and PDE1, PDE2, PDE3, PDE10, and PDE11 act on both cAMP and cGMP. Among them, PDE4 is mainly distributed in various inflammatory cells, and 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 is mainly focused on immune and inflammatory diseases. Many well-known pharmaceutical companies in the world have taken PDE4 as a target for chronic inflammatory diseases. PDE4 inhibitors exert their anti-inflammatory effects mainly through the following pathways: (1) inhibiting the activity of multiple inflammatory mediators; (2) inhibiting the upregulation and expression of cell adhesion factors; (3) inhibiting the activation of blood leukocytes; (4) inducing cell apoptosis; (5) inducing the production of cytokines with inhibitory activity (such as interleukin-6); (6) inducing the release of catecholamines and endogenous hormones. The first generation of PDE4 inhibitors mainly include theophylline, rolipram and piclamilast. Rolipram has a certain therapeutic effect on nervous system diseases such as Parkinson's disease, depression and anxiety. However, the first generation of PDE4 inhibitors are limited in clinical application due to severe side effects such as nausea and vomiting. The second generation of PDE4 inhibitors include roflumilast and cilomilast. Roflumilast is used to treat COPD and has a certain therapeutic effect on other inflammatory diseases, such as ulcerative colitis and Crohn's disease. The third generation of PDE4 inhibitors, apremilast, has been used to treat autoimmune diseases such as psoriasis, and has fewer side effects and is easier for patients to tolerate. WO/2000/064260 discloses that PDE4 inhibitor Ro 20-1724 1% cream is effective in treating psoriasis. WO 2000/009504 discloses another PDE4 inhibitor CP-80633 (0.5% ointment), which significantly improves the clinical score of atopic dermatitis (erythema, induration and epidermal exfoliation). However, more PDE4 inhibitors that can effectively treat atopic dermatitis are still needed clinically.

The following is a summary of some aspects of the present invention, but is not intended to be limiting. These aspects and other parts are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When there is a discrepancy between the disclosure of this specification and the referenced documents, the disclosure of this specification shall prevail.

The present invention provides a class of compounds with phosphodiesterase-4 (PDE4) inhibitory activity, which are used to prepare drugs for preventing, treating or alleviating respiratory diseases, allergies, inflammations, central nervous system diseases or non-insulin-dependent diabetes mellitus associated with PDE4, such as chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculous fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; wherein bronchitis is acute bronchitis bronchiolitis, chronic bronchitis, allergic bronchitis, diffuse panbronchitis, obstructive bronchitis, allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatic arthritis or psoriatic arthritis, etc.; the compounds of the present invention can well inhibit PDE4 and have excellent physicochemical properties and pharmacokinetic properties.

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

Specifically:

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

in:

^R1 and ^R2 are each independently hydrogen, deuterium, _C1-6 alkyl, C1-6 _halogenated alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, a heterocyclic group consisting of 3-10 atoms, _C6-10 aryl, a heteroaryl group consisting of 5-10 atoms, _C3-8 cycloalkyl- _C1-4 alkylene, _C1-6 alkyl-C(=O)-, _C3-8 cycloalkyl-C(=O)-, a heterocyclic group- _C1-4 alkylene consisting of 3-10 atoms, _C6-10 aryl- _C1-4 alkylene or a heteroaryl- _C1-4 alkylene consisting of 5-10 atoms;

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

^R3 is hydrogen, deuterium, carboxyl, _C1-6 alkyl, C1-6 _halogenated alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, _C6-10 aryl, a heterocyclic group consisting of 3-10 atoms, a heteroaryl group consisting of 5-10 atoms, _C3-8 cycloalkyl- _C1-4 alkylene, _C6-10 aryl- _C1-4 alkylene, a heterocyclic group- _C1-4 alkylene consisting of 3-10 atoms, a heteroaryl-C1-4 alkylene consisting of 5-10 atoms, _C1-6 alkyl-C(=O)-, _C1-6 alkyl-S(=O) _t- , _C1-6 alkoxy-C(=O)-, _{C3-8 cycloalkyl} -C(=O)-, C _3-8 cycloalkyl-S(=O) _t -, heterocyclic group consisting of 3-10 atoms-C(=O)-, heterocyclic group consisting of 3-10 atoms-S(=O) _t -, -C(=O)-NR ^d R ^e , -S(=O) _t -NR ^d R ^e , C _6-10 aryl-C(=O)-, heteroaryl-C(=O)- consisting of 5-10 atoms, 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 halogenated} alkyl, 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-, -NRx-, ^-NRx -C(=O)-, -NRx ^- S(=O) _t- , -NRx ^- C(=O)-NRy-, -NRx ^- C(=O) ^-O- , -S(=O)t-, ^-C (=O) _- or -C(=O)-O-, wherein -NRx-C(=O)-, -NRx ^- S(=O)t-, -NRx ^- C(=O) _-NRy- and ^{-NRx - C} (=O)-O- are each connected to ( _CH2 ) _m at their left end and to (CH2) _n at their right end, and -C(=O)-O- is connected to ( _CH2 ) _m at _its right end and to ( _CH2 ) _n at its left end;

wherein each of ^Rx and ^Ry is independently hydrogen, deuterium, _C1-6 alkyl, C1-6 _halogenated alkyl, _C3-8 cycloalkyl, _C6-10 aryl, a heterocyclic group consisting of 3-10 atoms, a heteroaryl group consisting of 5-10 atoms, a _C3-8 cycloalkyl-C1-6 alkylene group, a _C6-10 aryl- _C1-6 alkylene group, a _heterocyclic group- _{C1-6 alkylene group consisting of 3-10 atoms, a heteroaryl-C1-6} alkylene group consisting of 5-10 atoms, a _C1-6 alkyl-S(=O) _t- , _{a C1-6 alkyl} -C(=O)-, or a _C1-6 alkoxy-C(=O) _-C1-6 alkylene group;

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

each ^R7 is independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, carboxyl, _C1-6 alkyl, C1-6 _halogenated alkyl, _C1-6 alkoxy, _C1-6 alkylamino, -C(=O) ^-NRaRb , -S(=O) _t- ^NRaRb , _C1-6 ^alkyl - ^C (=O)-N( ^Rc )-, _C1-6 alkyl-S(=O) _t -N( ^Rc )-, _C1-6 alkoxy-C(=O)-N( ^Rc )-, _C1-6 alkyl-C(=O)-, _C1-6 alkyl-S(=O) _t- , _C1-6 alkoxy-C(=O)-, _C1-6 alkyl-C(=O)-O-, _C3-8 cycloalkyl, C1-6 _6-10 aryl groups, heterocyclic groups consisting of 3-10 atoms, or heteroaryl groups consisting of 5-10 atoms;

each of ^Ra and ^Rb is independently hydrogen, deuterium, _C1-6 alkyl, C1-6 _halogenated alkyl, _C3-8 cycloalkyl, _C6-10 aryl, a heterocyclic group consisting of 3-10 atoms, a heteroaryl group consisting of 5-10 atoms, a C3-8 cycloalkyl-C1-6 alkylene, a C6-10 aryl- _C1-6 alkylene, a heterocyclic group- _C1-6 alkylene consisting of 3-10 atoms, a heteroaryl-C1-6 alkylene consisting of _5-10 atoms, a C1-6 alkyl-S(=O)t- or a C1-6 alkyl-C(=O)-, wherein each of Ra and Rb is independently hydrogen, deuterium, _C1-6 alkyl, _C1-6 halogenated alkyl, C3-8 cycloalkyl, C6-10 aryl- _C1-6 alkylene, a heterocyclic group- _C1-6 alkylene consisting of 3-10 atoms, a heteroaryl-C1-6 alkylene consisting of 5-10 atoms, a C1-6 alkyl-S(=O) _t- or a _C1-6 alkyl-C(=O)-, wherein each of ^Ra and Rb is independently hydrogen, deuterium, ^b is independently unsubstituted or substituted with 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O) _-NH2 , _C1-6alkoxyC (=O)-, _C1-6alkyl -C(=O)-N( ^Rc )-, _C1-6alkyl -S(=O) _t -N( ^Rc )-, _C1-4alkyl , _{C1-4haloalkyl} , _C1-4alkoxy or _{C1-4alkylamino} ;

Each of R ^d and ^Re is independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 halogenated} alkyl, C _3-8 cycloalkyl, C _6-10 aryl, a heterocyclic group consisting of 3-10 atoms, a heteroaryl group consisting of 5-10 atoms, a C _3-8 cycloalkyl-C _1-6 alkylene, a C _6-10 aryl-C _1-6 alkylene, a heterocyclic group-C _1-6 alkylene consisting of 3-10 atoms, a heteroaryl-C _1-6 alkylene consisting of 5-10 atoms, a C _1-6 alkyl-S(═O) _t - or a C _1-6 alkyl-C(═O)-, wherein each of R ^d and R ^e is independently unsubstituted or substituted with 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O) _-NH2 , _C1-6alkoxyC (=O)-, _C1-6alkyl -C(=O)-N( ^Rc )-, _C1-6alkyl -S(=O) _t -N( ^Rc )-, _C1-4alkyl , _{C1-4haloalkyl} , _C1-4alkoxy or _{C1-4alkylamino} ;

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

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

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

t is 1 or 2;

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

m is 1, 2, 3, or 4.

In some embodiments, the compound of the present invention is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II): (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 same meaning as described in the present invention.

In some embodiments, the compound of the present invention is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (III): (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 same meaning as described in the present invention.

_In some embodiments, ^R1 and ^R2 are each independently hydrogen, deuterium, _{methyl, ethyl, n-propyl, isopropyl, isobutyl, -CH2F, -CHF2 , -CF3 , -CH2CH2F , -CH2CHF2 , -CH2CF3 , -CH2CH2CH2F} , _-CH2CH2CHF2 , _-CH2CH2CF3 , _-CH2Cl , _-CHCl2 , _{-CH = CH2} , _{-CH2CH = CH2} , _-C≡CH , _-CH2 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, piperazinyl, piperidinyl, fluoroinyl, thiofluoroinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C 1-3 alkylene, pyridyl-C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furanyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, pyrazolyl-C _1-3 alkylene, thiazolyl-C _{1-3 -3} alkylene, oxazolyl-C _1-3 alkylene, triazolyl-C _{1-3 alkylene, tetrazolyl-C 1-3 alkylene} , piperazinyl-C _1-3 alkylene, piperidinyl-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;

^R3 is hydrogen, deuterium, carboxyl, _C1-3 alkyl, C1-3 _{halogenated alkyl, C2-4} alkenyl, _C2-4 alkynyl, _{CH3 -} C(=O)-, _CH3CH2 -C(=O)-, _CH3CH2CH2 -C(=O)-, ( _{CH3 ) 2CH -} C(=O)-, CH3 _- S(=O) _2- , _CH3CH2 - _S (=O) _2- , CH3CH2CH2- _S (=O) _2- , ( _{CH3 ) 2CH} - _{S(=O)2- ,} CH3-OC(=O)-, _{CH3CH2 - OC(=O)-, CH3CH2CH2 -} OC(=O)-, ( _{CH3 ) 2CH - 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 ^R6 is independently deuterium, -F, -Cl, -Br, -I, hydroxy, _{amino ,} cyano, oxo, methyl, ethyl _{, n} -propyl, isopropyl, _-CH2F , _-CHF2 , _{-CF3 , -CH2CH2F} , -CH2CHF2 _, -CH2CF3, _-CH2CH2CH2F , _-CH2CH2CHF2 , _-CH2CH2CF3 , _-CH2Cl , _-CHCl2 , _methoxy , ethoxy, _n -propyloxy, methylamino, _{ethylamino ,} or _n -propylamino.

In some embodiments, each of ^Rx and ^Ry is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, _C1-4 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl- _C1-3 alkylene, cyclobutyl- _C1-3 alkylene, cyclopentyl- _C1-3 alkylene, cyclohexyl- _C1-3 alkylene, phenyl, naphthyl, pyridyl, pyrimidyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl- _C1-3 alkylene, naphthyl- _C1-3 alkylene, pyridyl-C1-3 -C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furanyl-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, piperazinyl-C _1-3 alkylene, piperidinyl-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.

In some embodiments, G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein G is unsubstituted or substituted by 1, 2, 3 or 4 R ⁷ ;

each ^R7 is independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, carboxyl, _C1-4 alkyl, C1-4 _halogenated alkyl, _C1-4 alkoxy, _C1-4 alkylamino, -C(=O) ^-NRaRb , -S(=O) _2- ^NRaRb , _C1-4 ^{alkyl -} C(=O)-NH-, _C1-4 alkyl-S(=O) _2- NH-, _C1-4 alkoxy-C(=O)-NH-, _{CH3 -} C(=O)-, _CH3CH2 -C(=O)-, _{CH3CH2CH2 -} C(=O ₎ -, ( _CH3 ) _2CH -C(=O ₎ -, _{CH3CH2CH2CH2 -} C(= _O )-, CH3 _- 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 wherein each ^Ra and ^Rb has the meaning as described in the present invention.

_In some embodiments, each ^Ra and ^Rb is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n _- butyl, _-CH2F , _-CHF2 , _-CF3 , -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, _-CH2CH2CHF2 , _-CH2CH2CF3 , _-CH2Cl , _{-CHCl2 , phenyl , naphthyl} , pyridyl, pyrimidinyl, furanyl _{, thienyl ,} pyrrolyl _, pyrazolyl _, thiazolyl _, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, _phenyl - _C1-3alkylene , naphthyl-C1-3alkylene, -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, piperazinyl-C _1-3 alkylene, piperidinyl-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 - or C _1-3 alkyl _- C(═O)-; wherein each R ^a and R ^b are independently unsubstituted or substituted with 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, 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 The invention is substituted by a N-methylamino, N -ethylamino, N'N -dimethylamino, N'N -diethylamino or N'N -methylethylamino group.

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

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

In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is sodium pyruvate, doxofenadine, tetomilast, talusulast, theophylline, formoterol, salmeterol, fluticasone propionate, rolipram, pyramister, cilomilast, indacaterol, olodaterol, mildenafil, zithromycin, salbutamol, carmoxicillin, budesonide, dipropionic acid, Beclomethasone, triamcinolone acetonide, flunisolide, mometasone furoate, roflenide, cyclosporine, ipratropium bromide, oxtropium bromide, tiotropium bromide, glycopyrrolate, isoflurane, vilanterol, aclidinium bromide, benralizumab, tralokinumab, revatostat, crisabor, fluocinolone acetate, desoxymethasone, mometasone, triamcinolone, betamethasone, alclometasone, desoxonide, hydrogenated Cortisone, clobetasol, halbetasol, diflorasone, meproclat, tacrolimus, pimecrolimus, tazarotene, cyclosporine, apremilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, ibudilast, tofacitinib, JTE-052, baricitinib, upapatinib, WBI-1001, MRX-6, GSK2981278, dulu monoclonal antibody, levitra, nimolizumab, tromirumab, etanercept, adalimumab, infliximab, ustekinumab, secukinumab, omalizumab, CIM-331, golimumab and pegol, tocilizumab, calcipotriol, calcitriol, alitretinoin, VTP-38543, ZPL-389, aprepitant, trodipitant, foviprant, 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 use of the compound or the pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate diseases associated with type 4 phosphodiesterase.

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

Wherein, the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; wherein, bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchitis or obstructive bronchitis;

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

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

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

Wherein, the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; wherein, bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchitis or obstructive bronchitis;

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

In another aspect, the present invention provides the compound or the pharmaceutical composition of the present invention for preventing, treating or alleviating a disease related to type 4 phosphodiesterase in a patient.

In some embodiments, the compound or pharmaceutical composition of the present invention is used to prevent, treat or alleviate a disease associated with type 4 phosphodiesterase in a patient, wherein the disease associated with type 4 phosphodiesterase is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin-dependent diabetes mellitus;

Wherein, the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; wherein bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchitis or obstructive bronchitis;

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

Another aspect of the present invention relates to methods for preparing, isolating and purifying compounds represented by formula (I), (II) or (III).

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

Definitions and General Terms

Certain embodiments of the present invention are now described in detail, and the embodiments are illustrated by the accompanying structural and chemical formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included in the scope of the present invention as defined by the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is in no way limited to the methods and materials described in the present invention. In the event that one or more of the incorporated documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

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

Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by technical personnel in the field to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference as a whole.

Unless otherwise indicated, the following definitions used in the present invention shall apply. For the purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, 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, the entire contents of which are incorporated herein by reference.

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

The term "subject" used in the present invention refers to an animal. Typically, the animal is a mammal. The subject, for example, also refers to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human. The term "patient" used in the present invention refers to a human (including adults and children or other animals). In some embodiments, "patient" refers to a human.

The term "comprising" is an open expression, which includes the contents specified in the present invention but does not exclude other contents.

The term "stereoisomers" refers to compounds that have the same chemical structure but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis/trans) isomers, atropisomers, and so on.

The term "chiral" refers to a molecule that is non-superimposable with its mirror image, whereas "achiral" refers to a molecule that is superimposable with its mirror image.

The term "enantiomers" refers to two nonsuperimposable isomers of a compound that are mirror images of each other.

The term "diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

The stereochemical definitions and conventions used in the present invention generally follow S.P. 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, i.e. they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory and a compound with the prefix (+) or d is dextrorotatory. 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, and this occurs when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

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

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

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

Any racemate of the resulting final product or intermediate can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereoisomeric salts thereof obtained. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. 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, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. 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, 2012). 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible across a low energy barrier. If tautomerism is possible (such as in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerizations and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the tautomerism of pyridine-4-ol and pyridine-4(1H)-one. 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 above general formula compounds, or as the specific examples in the examples, subclasses, and classes of compounds encompassed by the present invention.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by 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 structure can be substituted by one or more substituents selected from a specified group, the substituents may be the same or different at each position.

The term "optionally substituted with" means that the structure is unsubstituted or substituted with one or more substituents described herein. The substituents of 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, heterocyclic, cycloalkyl, alkyl, nitro, aryloxy, heteroaryloxy, oxo, halogenated alkyl, halogenated alkoxy, hydroxyl-substituted alkyl, hydroxyl-substituted alkoxy, amino-substituted alkyl, cyano-substituted alkyl, hydroxyl-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-OC(=O)-, alkyl-S(=O)-, alkyl-S(=O) _2- , hydroxyl-substituted alkyl-S(=O)-, hydroxyl-substituted alkyl-S(=O) _2- , carboxylalkoxy, _NH2 -C(=O)-, NH ₂ -S(=O) ₂ -, aryl-alkylene, heteroaryl-alkylene, heterocyclo-alkylene, cycloalkyl-alkylene, and the like.

In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used in the present invention such as "each ... independently is" and "... each independently is" and "... independently is" can be interchanged and should be broadly understood, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other. For example, the specific options of 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 )" do not affect each other.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of each member of these group types and ranges. For example, the term " _C1 - _C6 alkyl" or " _C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, _C3 alkyl, _C4 alkyl, _C5 alkyl and _C6 alkyl.

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

The term "alkyl" or "alkyl group" used in the present invention refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described in the present invention, wherein the substituents are deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, carboxyl, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio [0063] The following examples include aryl, alkyl, alkenyl, alkynyl, heterocyclic, cycloalkyl, alkyl, nitro, aryloxy, heteroaryloxy, oxo, halogenated alkyl, halogenated alkoxy, 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, _NH2 -C(=O)-, NH2 _- S(=O) _2- , aryl-alkylene, heteroaryl-alkylene, heterocyclic-alkylene, cycloalkyl-alkylene and the like. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In some embodiments, an alkyl group contains 1-12 carbon atoms; in other embodiments, an alkyl group contains 1-6 carbon atoms; in yet other embodiments, an alkyl group contains 1-4 carbon atoms; and in still other embodiments, an 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" means a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; in yet other embodiments, an alkylene group contains 1-3 carbon atoms; in still other embodiments, an alkylene group contains 1-2 carbon atoms. Such examples include methylene ( _-CH2- ), ethylene ( _-CH2CH2- ), propylene _{(-CH2CH2CH2- )} , isopropylene (-CH( _CH3 ) _CH2- ) _, and _the like.

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

The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more 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 yet 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 ) and the like.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means -CO ₂ H or -COOH.

The term "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 ), two deuterium atoms replace two hydrogen atoms in a methyl group to form a di-deuterated methyl group (-CD ₂ H), and three deuterium atoms replace three hydrogen atoms in a methyl group to form a tri-deuterated methyl group (-CD ₃ ).

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

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 in the form of a substituted hydrogen atom on a nitrogen atom in a heterocyclic ring, for example, N (such as N in 3,4-dihydro- 2H -pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl).

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

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

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH 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-butoxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy ( t- BuO, t -butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, —OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (—OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (—OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (—OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (—OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butoxy (—OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butoxy (—OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), and the like.

The term "alkylamino" means that the two hydrogen atoms on the amino group (-NH ₂ ) are independently and optionally substituted with the same or different alkyl groups, including N -alkylamino or N'N -dialkylamino, wherein the alkyl group has the meaning as described 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 yet other embodiments, the alkylamino group contains 1-3 carbon atoms. The alkylamino group can be optionally substituted with one or more substituents described in the present invention.

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 (-N(CH ₂ CH ₃ ) ₂ ), N'N -methylethylamino (- ), N'N -methylisopropylamino ( ),etc.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with _one or _more halogen atoms. _Examples include, but are not _{limited to} , _-CH2F , -CHF2, _-CF3 , -CH2CH2F, _-CH2CHF2 , -CH2CF3, _{-CH2CH2CH2F , -CH2CH2CHF2 , -CH2CH2CF3 , -CH2Cl} , _{-CHCl2 , and the like} .

The term "composed of j-k atoms", wherein each j and k are independently any non-zero natural numbers, and k>j; the "j-k" includes j, k and any natural numbers in between. It typically describes the number of ring-forming atoms in a molecule, where the number of ring-forming atoms in the molecule is j-k, and the atoms include carbon atoms and/or miscellaneous atoms such as O, N, S, and P.

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

The terms "cycloalkylalkyl" or "cycloalkyl-alkylene" are used interchangeably and refer to an alkyl group substituted with one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group have the meanings as described herein, and such examples include, but are not limited to, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene, cyclopentyl-ethylene, cyclohexyl-methylene, cyclohexyl-ethylene, and the like.

The terms "heterocyclic group" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms, wherein the monocyclic, bicyclic or tricyclic ring does not contain an aromatic ring and at least one ring atom is selected from nitrogen, phosphorus, sulfur, boron and oxygen atoms. Unless otherwise specified, the heterocyclic group can be carbon-based or nitrogen-based, and the _-CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to S -oxide. The nitrogen atom of the ring can be optionally oxidized to N -oxide. Examples of heterocyclic groups include, but are not limited to, oxirane, azocyclobutyl, oxazolobutyl, thiocyclobutyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, oxolinyl, thioxolinyl, 1-oxo-thioxolinyl, 1,1-dioxo-thioxolinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxazoloheptanyl. Examples of heterocyclic groups in which the -CH ₂ - group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone and 3,5-dioxopyridinyl. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, cyclobutanesulfonyl and 1,1-dioxothioquinoline. The heterocyclic group may be optionally substituted by one or more substituents described in the present invention.

The term "heterocyclylalkyl" or "heterocyclyl-alkylene" may be used interchangeably to refer to an alkyl group substituted with a heterocyclyl; 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, oxacyclobutane-3-ylmethyl, pyrrolidin-2-ylmethyl, morpholin-4-ylmethyl, and the like.

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbon 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, wherein each ring system contains a ring consisting of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include phenyl, naphthyl and anthracenyl. The aryl groups can be independently and optionally substituted with one or more substituents described herein.

The terms "arylalkyl" or "aryl-alkylene" are used interchangeably and refer to an alkyl group substituted with one or more aryl groups, wherein the aryl and alkyl groups have the meanings described herein. In some embodiments, the arylalkyl group refers to a "lower arylalkyl" group, i.e., an aryl group is attached to a C _1-6 alkyl or alkylene group. In other embodiments, the arylalkyl group refers to a "phenylalkyl" containing a C _1-4 alkyl group. Specific examples include diphenylmethyl, phenylmethylene, and phenylethylene. The aryl group on the arylalkyl or arylalkylene group may be further substituted with a substituent described herein.

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 consisting of 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocyclic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described in the present invention. In some of these embodiments, the 5-10 atom heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S, N or B.

Examples of heteroaryl groups include, but are not limited to, furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N- -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (such as 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), oxazinyl (such as 3-oxazinyl), thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl) , thienyl (such as 2-thienyl, 3-thienyl), pyrazolyl (such as 2-pyrazolyl), isothiazolyl, pyrimidinyl, pyridinyl; also includes the following bicyclic, but is by no means limited to these bicyclic: benzimidazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), , , , , , , or etc.

The term "heteroarylalkyl" or "heteroarylalkylene" can be used interchangeably, and both refer to an alkyl group substituted with one or more heteroaryl groups, wherein the heteroaryl and alkyl groups have the meanings described in the present invention, and such examples include, but are not limited to, imidazol-2-ylmethylene, furan-2-ylethylene, indol-3-ylmethylene, etc.

As described in the present invention, a ring system formed by a substituent connected to the central ring by a bond (as shown in formula c) represents that the substituent can be substituted at any substitutable position on the ring. For example, formula c represents that the substituent R can be substituted singly or polysubstituted at any substitutable position on the C ring, as shown in formula c1 to formula c19.

As described in the present invention, a linker bonded to the ring system (as shown in Formula d) means that the linker bond can be connected to the rest of the molecule at any connectable position on the ring system. Formula d means that any possible connectable 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, ^R4 is -( _CH2 ) _m -L-( _CH2 ) _n -G, wherein the left and right connecting bonds of the L group can be connected to ( _CH2 ) _m and ( _CH2 ) _n interchangeably; for example, when L is -NRx ^- C(=O)-, -NRx-S(=O)t-, -NRx ^- C(=O)-NRy- or -NRx ^- C(=O) _-O- , -(CH2)m-L-(CH2)n-G is defined as the ^left end of L connected to (CH2)m and the right end of L connected to ( _CH2 ) _n , and the left end of L connected to ( _CH2 )n and the right end of L connected to (CH2) _m . The preferred embodiment is: when L is -NRx- ^C (= _O )-, -NRx- _S (=O)t-, -NRx-C(= _O )-NRy- or ^-NRx - _C (=O)-O-, -( _CH2 ) _m -L-( _CH2 )n-G is defined as the left end of L connected to (CH2) _m and the right end of L connected to (CH2)n, and the ^left end of L connected to (CH2)n and the right end of L connected to (CH2) _m. -, -NR ^x -C(=O)-NR ^y - or -NR ^x -C(=O)-O-, the left end of L is connected to (CH ₂ ) _m and the right end of L is connected to (CH ₂ ) _n ; in addition, 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. Among them, the preferred embodiment is that when L is -C(=O)-O-, -(CH ₂ ) _m -L-(CH ₂ ) _n -G is defined as -(CH ₂ ) _m -OC(=O)-G.

The term "prodrug" used in the present invention refers to a compound that is converted into a compound represented by formula (I) or (II) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, see 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.

"Metabolites" refer to products obtained by metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amination, deamination, esterification, degreasing, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.

The term "pharmaceutically acceptable salt" used in the present invention refers to organic salts 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 non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in the literature such as ion exchange methods to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, iodide. Acid salts, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, appletate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, sulfonate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with an appropriate base include salts of alkali metals, alkali earth metals, ammonium and N ⁺ (C _1-4 alkyl) ₄ . The present invention also contemplates quaternary ammonium salts formed from any compound containing a nitrogen group. Water-soluble 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 the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates and aromatic sulfonates.

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

The term "nitrogen oxide" means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N -oxide. Special examples of N -oxides are N -oxides of tertiary amines or N -oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N -oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N -oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

The term "carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combination thereof, which are known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except for the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical composition is covered.

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

Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds, alkaline or acidic moieties by conventional chemical methods. Generally speaking, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., 1985; and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

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

Any structural formula given in the present invention is also intended to represent the isotopically unenriched form of these compounds as well as the isotopically enriched form. An isotopically enriched compound has a structure depicted by the general formula given in the present invention, except that one or more atoms are replaced by atoms with a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, those compounds 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 are present. Such isotopically enriched compounds may be used in metabolic studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including determination of drug or substrate tissue distribution, 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 (II) can be prepared by conventional techniques familiar to those skilled in the art or by using appropriate isotope-labeled reagents as described in the examples and preparation processes of the present invention to replace the unlabeled reagents used originally.

In addition, substitution with heavier isotopes, particularly deuterium (i.e., ² H or D), may provide certain therapeutic advantages resulting 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 considered as a substituent of the compound represented by formula (I) or formula (II). The concentration of such heavier isotopes, particularly deuterium, may be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as _D2O , acetone- _d6 , DMSO - _d6 .

Description of the compounds of the present invention

The present invention relates to novel substituted nitrogen-containing five-membered ring compounds and the use of the compounds in medicine. The compounds of the present invention or the pharmaceutical composition containing the compounds are used as PDE4 inhibitors and have a good therapeutic effect on atopic dermatitis.

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, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I): (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 have the meanings as defined in the present invention.

In some embodiments, ^R1 and ^R2 are each independently hydrogen, deuterium, _C1-6 alkyl, C1-6 _halogenated alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, heterocyclic group consisting of 3-10 atoms, _C6-10 aryl, heteroaryl consisting of 5-10 atoms, _C3-8 cycloalkyl- _C1-4 alkylene, _C1-6 alkyl-C(=O)-, _C3-8 cycloalkyl-C(=O)-, heterocyclic group- _C1-4 alkylene consisting of 3-10 atoms, _C6-10 aryl- _C1-4 alkylene or heteroaryl- _C1-4 alkylene consisting of 5-10 atoms;

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

^R3 is hydrogen, deuterium, carboxyl, _C1-6 alkyl, C1-6 _halogenated alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, _C6-10 aryl, a heterocyclic group consisting of 3-10 atoms, a heteroaryl group consisting of 5-10 atoms, _C3-8 cycloalkyl- _C1-4 alkylene, _C6-10 aryl- _C1-4 alkylene, a heterocyclic group- _C1-4 alkylene consisting of 3-10 atoms, a heteroaryl-C1-4 alkylene consisting of 5-10 atoms, _C1-6 alkyl-C(=O)-, _C1-6 alkyl-S(=O) _t- , _C1-6 alkoxy-C(=O)-, _{C3-8 cycloalkyl} -C(=O)-, C _3-8 cycloalkyl-S(=O) _t -, heterocyclic group consisting of 3-10 atoms-C(=O)-, heterocyclic group consisting of 3-10 atoms-S(=O) _t -, -C(=O)-NR ^d R ^e , -S(=O) _t -NR ^d R ^e , C _6-10 aryl-C(=O)-, heteroaryl-C(=O)- consisting of 5-10 atoms, 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 halogenated} alkyl, 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-, -NRx-, ^-NRx -C(=O)-, -NRx ^- S(=O) _t- , -NRx ^- C(=O)-NRy-, -NRx ^- C(=O) ^-O- , -S(=O)t-, ^-C (=O) _- or -C(=O)-O-, wherein -NRx-C(=O)-, -NRx ^- S(=O)t-, -NRx ^- C(=O) _-NRy- and ^{-NRx - C} (=O)-O- are each connected to ( _CH2 ) _m at their left end and to (CH2) _n at their right end, and -C(=O)-O- is connected to ( _CH2 ) _m at _its right end and to ( _CH2 ) _n at its left end;

wherein each of ^Rx and ^Ry is independently hydrogen, deuterium, _C1-6 alkyl, C1-6 _halogenated alkyl, _C3-8 cycloalkyl, _C6-10 aryl, a heterocyclic group consisting of 3-10 atoms, a heteroaryl group consisting of 5-10 atoms, a _C3-8 cycloalkyl- _C1-6 alkylene, a C6-10 aryl- _C1-6 alkylene, a heterocyclic group consisting of _3-10 atoms- _C1-6 alkylene, a heteroaryl-C1-6 alkylene consisting of 5-10 atoms, _C1-6 alkyl-S(=O) _t- , _C1-6 alkyl-C(=O)- or _C1-6 alkoxy-C(=O) _-C1-6 alkylene; G is _C3-8 cycloalkyl, _C6-10 aryl-C1-6 _6-10 aryl, 3-10 heterocyclic group or 5-10 heteroaryl; wherein G is unsubstituted or substituted by 1, 2, 3 or 4 R ⁷ ;

each ^R7 is independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, carboxyl, _C1-6 alkyl, C1-6 _halogenated alkyl, _C1-6 alkoxy, _C1-6 alkylamino, -C(=O) ^-NRaRb , -S(=O) _t- ^NRaRb , _C1-6 ^alkyl - ^C (=O)-N( ^Rc )-, _C1-6 alkyl-S(=O) _t -N( ^Rc )-, _C1-6 alkoxy-C(=O)-N( ^Rc )-, _C1-6 alkyl-C(=O)-, _C1-6 alkyl-S(=O) _t- , _C1-6 alkoxy-C(=O)-, _C1-6 alkyl-C(=O)-O-, _C3-8 cycloalkyl, C1-6 _6-10 aryl groups, heterocyclic groups consisting of 3-10 atoms, or heteroaryl groups consisting of 5-10 atoms;

each of ^Ra and ^Rb is independently hydrogen, deuterium, _C1-6 alkyl, C1-6 _halogenated alkyl, _C3-8 cycloalkyl, _C6-10 aryl, a heterocyclic group consisting of 3-10 atoms, a heteroaryl group consisting of 5-10 atoms, a C3-8 cycloalkyl-C1-6 alkylene, a C6-10 aryl- _C1-6 alkylene, a heterocyclic group- _C1-6 alkylene consisting of 3-10 atoms, a heteroaryl-C1-6 alkylene consisting of _5-10 atoms, a C1-6 alkyl-S(=O)t- or a C1-6 alkyl-C(=O)-, wherein each of Ra and Rb is independently hydrogen, deuterium, _C1-6 alkyl, _C1-6 halogenated alkyl, C3-8 cycloalkyl, C6-10 aryl- _C1-6 alkylene, a heterocyclic group- _C1-6 alkylene consisting of 3-10 atoms, a heteroaryl-C1-6 alkylene consisting of 5-10 atoms, a C1-6 alkyl-S(=O) _t- or a _C1-6 alkyl-C(=O)-, wherein each of ^Ra and Rb is independently hydrogen, deuterium, ^b is independently unsubstituted or substituted with 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O) _-NH2 , _C1-6alkoxyC (=O)-, _C1-6alkyl -C(=O)-N( ^Rc )-, _C1-6alkyl -S(=O) _t -N( ^Rc )-, _C1-4alkyl , _{C1-4haloalkyl} , _C1-4alkoxy or _{C1-4alkylamino} ;

Each of R ^d and ^Re is independently hydrogen, deuterium, C _1-6 alkyl, C _{1-6 halogenated} alkyl, C _3-8 cycloalkyl, C _6-10 aryl, a heterocyclic group consisting of 3-10 atoms, a heteroaryl group consisting of 5-10 atoms, a C _3-8 cycloalkyl-C _1-6 alkylene, a C _6-10 aryl-C _1-6 alkylene, a heterocyclic group-C _1-6 alkylene consisting of 3-10 atoms, a heteroaryl-C _1-6 alkylene consisting of 5-10 atoms, a C _1-6 alkyl-S(═O) _t - or a C _1-6 alkyl-C(═O)-, wherein each of R ^d and R ^e is independently unsubstituted or substituted with 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O) _-NH2 , _C1-6alkoxyC (=O)-, _C1-6alkyl -C(=O)-N( ^Rc )-, _C1-6alkyl -S(=O) _t -N( ^Rc )-, _C1-4alkyl , _{C1-4haloalkyl} , _C1-4alkoxy or _{C1-4alkylamino} ;

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

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

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

t is 1 or 2;

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

m is 1, 2, 3, or 4.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II): (II);

wherein each of R ¹ , R ² , R ³ , R ^5a , R ^5b , R ^6a , R ^6b , R, L, n and G has the meanings as defined in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (III): (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 same meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (IV) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (IV): (IV);

wherein each of R ¹ , R ² , R ³ , R ^5a , R ^5b , R ^6a , R ^6b , R, L, n and G has the meanings as defined in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (V) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (V): (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 same meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (VI) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (VI): (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 same meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (VII) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (VII): (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 same meaning as described in the present invention.

In some embodiments, ^R1 is hydrogen, deuterium, methyl, ethyl, _{n - propyl ,} isopropyl, isobutyl _, -CH2F _, -CHF2, _-CF3 , _{-CH2CH2F , -CH2CHF2} , _-CH2CF3 , _-CH2CH2CH2F , _-CH2CH2CHF2 , -CH2CH2CF3, _-CH2Cl , _-CHCl2 , _{-CH = CH2} , _{-CH2CH = CH2 ,} -C≡CH _{, -CH2} 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, piperazinyl, piperidinyl, fluoroinyl, thiofluoroinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C 1-3 alkylene, pyridyl-C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furanyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, pyrazolyl-C _1-3 alkylene, thiazolyl-C _{1-3 The invention} may _{be a C 1-3 alkylene group , ...}

In some embodiments, ^R2 is hydrogen, deuterium, methyl, ethyl, _{n - propyl ,} isopropyl, isobutyl _, -CH2F _, -CHF2, _-CF3 , _{-CH2CH2F , -CH2CHF2} , _-CH2CF3 , _-CH2CH2CH2F , _-CH2CH2CHF2 , -CH2CH2CF3, _-CH2Cl , _-CHCl2 , _{-CH = CH2} , _{-CH2CH = CH2 ,} -C≡CH _{, -CH2} 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, piperazinyl, piperidinyl, fluoroinyl, thiofluoroinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C 1-3 alkylene, pyridyl-C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furanyl-C _1-3 alkylene, thienyl-C _1-3 alkylene, pyrrolyl-C _1-3 alkylene, pyrazolyl-C _1-3 alkylene, thiazolyl-C _{1-3 The invention} may _{be a C 1-3 alkylene group , ...}

In some embodiments, R ³ is hydrogen, deuterium, carboxyl, C _1-3 alkyl, C _{1-3 halogenated} alkyl, 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 .

In some embodiments, 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-propyloxy, methylamino, ethylamino, or n-propylamino.

In some embodiments, each ^Rx is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, _C1-4 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl- _{C1-3 alkylene, cyclobutyl-C1-3 alkylene, cyclopentyl-C1-3 alkylene , cyclohexyl-C1-3 alkylene} , phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl- _C1-3 alkylene, naphthyl- _C1-3 alkylene, pyridyl-C1-3 -C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furanyl-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, piperazinyl-C _1-3 alkylene, piperidinyl-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.

In some embodiments, 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, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C _1-3 alkylene, naphthyl-C _1-3 alkylene, pyridyl-C 1-3 -C _1-3 alkylene, pyrimidinyl-C _1-3 alkylene, furanyl-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, piperazinyl-C _1-3 alkylene, piperidinyl-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.

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.

In some embodiments, each R ⁷ is independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, carboxyl, C _1-4 alkyl, C _{1-4 halogenated} 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, , , , , , , , , , , , , , , , , , , , , , , , or wherein each ^Ra and ^Rb has the meanings described in the present invention.

_In some embodiments, each ^Ra and ^Rb is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n _- butyl, _-CH2F , _-CHF2 , _-CF3 , -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, _-CH2CH2CHF2 , _-CH2CH2CF3 , _-CH2Cl , _{-CHCl2 , phenyl , naphthyl} , pyridyl, pyrimidinyl, furanyl _{, thienyl ,} pyrrolyl _, pyrazolyl _, thiazolyl _, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, _phenyl - _C1-3alkylene , naphthyl-C1-3alkylene, -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, piperazinyl-C _1-3 alkylene, piperidinyl-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 - or C _1-3 alkyl _- C(═O)-; wherein each R ^a and R ^b are independently unsubstituted or substituted with 1, 2 or 3 groups 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 The amino group may be substituted with an alkylene group selected from the group consisting of alkylene group, ...

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

In some embodiments, R is hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n- _{propoxy, -CH2F , -CHF2} , -CF3, _-CH2Cl or _-CHCl2 .

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

In some embodiments, the present invention includes but is not limited to compounds having one of the following structures or stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of compounds having one of the following structures: (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 the embodiments are: formula (I), (II), (III), (IV), (V), (VI) and The compound represented by (VII), whose pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, appletate, 2-hydroxypropionate, pyruvate, oxalate, hydroxyacetate, salicylate, glucuronide, galacturonide, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate or a combination thereof.

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

In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, additive, 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, doxofenadine, tetomilast, talusulast, theophylline, formoterol, salmeterol, fluticasone propionate, rolipram, pyramister, cilomilast, indacaterol, olodaterol, mildenafil, zithromycin, salbutamol, carmoxicillin, budesonide, beclomethasone dipropionate , triamcinolone acetonide, flunisolide, mometasone furoate, roflenide, cyclosone, ipratropium bromide, oxtropium bromide, tiotropium bromide, glycopyrrolate, oxadiazine, vilanterol, aclidinium bromide, benralizumab, tralokinumab, revatolide, crisabor, fluocinolone acetate, desoxymethasone, mometasone, triamcinolone, betamethasone, alclometasone, desonesonide, hydrocortisone, clobeta Clobatsol, halbetasol, diflorasone, meproclat, tacrolimus, pimecrolimus, tazarotene, cyclosporine, apremilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, ibudilast, tofacitinib, JTE-052, baricitinib, upatininib, WBI-1001, MRX-6, GSK2981278, durulucab, levitra, nimolizumab, tromirumab, etanercept, adalimumab, infliximab, ustekinumab, secukinumab, omalizumab, CIM-331, golimumab and peg-serine, tocilizumab, calcipotriol, calcitriol, alitretinoin, VTP-38543, ZPL-389, aprepitant, trodipitant, foviprant, 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 use of the compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) or its pharmaceutical composition disclosed in the present invention in the preparation of a drug, wherein the drug is used to prevent, treat or alleviate diseases related to type 4 phosphodiesterase (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 some other embodiments, the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculous fibrosis, pulmonary cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; wherein bronchitis includes acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchitis or obstructive bronchitis;

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

Another aspect of the present invention relates to methods for preparing, isolating and purifying compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII).

Pharmaceutical compositions, preparations and administration of the compounds of the present invention

The present invention provides a pharmaceutical composition comprising a compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) or a single stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate 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 preventive ingredients.

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

As used herein, "pharmaceutically acceptable excipients" means pharmaceutically acceptable materials, mixtures or vehicles that are relevant to the dosage form or consistency of the drug composition. Each excipient must be compatible with the other ingredients of the drug composition when mixed to avoid interactions that would significantly reduce the efficacy of the compounds disclosed herein when administered to a patient and interactions that would result in a drug composition that is not pharmaceutically acceptable. In addition, each excipient must be pharmaceutically acceptable, for example, have a sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, pharmaceutically acceptable excipients may be selected based on their specific functions in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can help produce a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected that can help produce a stable dosage form. Certain pharmaceutically acceptable excipients may be selected that help carry or transport the compounds of the present invention from one organ or part of the body to another organ or part of the body when the drug is administered to the patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

Some examples of suitable molding agents include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gum tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: solvents, propellants, solubilizers, solubilizers, emulsifiers, coloring agents, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesive agents, antioxidants, chelating agents, penetration enhancers, pH Regulators, plasticizers, surfactants, foaming agents, defoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents and filter aids. The skilled person will recognize that some pharmaceutically acceptable excipients can provide more than one function and provide alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation. The compounds of the present invention can be formulated using methods known in the art so that the active ingredient can be released quickly, continuously or delayed after administration to the patient.

The skilled artisan possesses knowledge and skill in the art to enable them to select appropriate pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. In addition, there are a number of resources available to the skilled artisan that describe pharmaceutically acceptable excipients and are useful in selecting appropriate 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).

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

Except for any conventional carriers that are incompatible with the compounds of the present invention because they may interact in a deleterious manner with any other ingredients in the pharmaceutically acceptable composition, its use is contemplated to be within the scope of the present invention.

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

As used in the present invention, "pharmaceutically acceptable carrier" includes any and all solvents and solvent mixtures, coatings, binders, solid carriers, dispersion media, surfactant 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 of pharmaceutically acceptable carriers include those having components selected from the group consisting of lactose, gelatin, sugar alcohols (e.g., starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, colloidal silicon dioxide, carboxymethyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, buffered aqueous solutions, copolyvidone, polysorbate, ethanol, propylene glycol, polyethylene glycol (preferably polyethylene glycol, e.g., PEG400), Tween® 80 (i.e., PEG (20), sorbitan monooleate), DMSO, a mixture of water and a solubilizing agent, for example an aqueous solution of an alcohol such as ethanol and/or a polyethylene glycol such as polyethylene glycol, an ester of a polyol such as glycerol and/or polyethylene glycol with a fatty acid, a surfactant such as an anionic, cationic, nonionic and amphoteric surfactant, a complexing agent such as a cyclodextrin, for example α-cyclodextrin (α-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD), a salt of bile acid or a lipid such as an animal or plant phospholipid, a sizing agent, and an oil such as corn oil, or a mixture of two or more of the aforementioned 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, which forms a lipid-based drug delivery system (DDS) in an aqueous medium. The pharmaceutical composition, in addition to at least one compound of the compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) or a salt thereof, further comprises at least one surfactant. Non-limiting examples of suitable surfactants are as described above. In various embodiments, the lipid-based drug delivery system forms the following structures: (1) liposomes (i.e., dispersed closed bilamellar assemblies of lamellar phase in water); (2) nanoparticles of non-lamellar phase (e.g., cubic, hexagonal, spongy); or (3) micelles, emulsions, microemulsions (i.e., 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 oil (i.e. lipids, e.g. compounds of formula (I) or salts thereof), at least one surfactant, optionally at least one cosolvent and optionally at least one cosurfactant, ideally isotropic, which spontaneously emulsify to form an oil-in-water emulsion when introduced into an aqueous phase under mild agitation. Mild agitation can be provided, for example, by the motility of the stomach.

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

Therefore, 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, solvent or a combination thereof, the process comprising mixing the various ingredients. The pharmaceutical composition comprising a compound disclosed herein can be prepared by mixing at ambient temperature and atmospheric pressure, for example.

The compounds disclosed herein are generally formulated into dosage forms suitable for administration to a patient via a 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, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (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 administration of the compounds of the present invention, such as solid dosage forms of tablets, capsules, granules, tablets and bulk powders. The compounds of the present invention may be administered alone or in combination with various pharmaceutically acceptable carriers and excipients known in the art (e.g., sucrose, mannitol, lactose, starch), including but not limited to suspending agents, solubilizing agents, buffers, binders, disintegrants, preservatives, coloring agents, flavoring agents, lubricants, etc. Timed-release capsules, tablets and gels are also advantageous for administration of the compounds of the present invention.

Various topical formulations can be used for administration of the compounds of the invention, such as lotions, ointments, tinctures, wipes, spirits, powders, creams, oils, pastes, plasters, film coatings 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 delaying agents, disintegrants, emulsifiers, antioxidants, adhesives, binders, viscosity increasing agents, solubilizing agents, dispersants, emulsifiers, lubricants, hygroscopic agents, liposomes, microemulsions and β-cyclodextrin, etc.

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

Inhalable preparations include inhalable powders, metered aerosols containing propellants or inhalable formulations without propellants. For this purpose, the powders (preferably in micronized form) can be administered directly or via nebulizable solutions or suspensions containing them.

To the powdered compounds of the invention may be added a formulator or carrier which is generally non-toxic and chemically inert toward the compounds of the invention, such as lactose or any other additive suitable for improving the respirable fraction.

Inhalation aerosols containing gaseous propellants such as hydrofluorocarbons may contain the compounds of the present invention in solution or dispersed form. Propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optional other excipients.

Propellant-free inhalable formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they may be delivered by spray nebulizers or ultrasonic nebulizers known in the art, or by soft-mist nebulizers such as ^Respimat® .

The term "therapeutically effective amount" as used herein refers to the total amount of active ingredients sufficient to show a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate the symptoms of a disease that is administered or brought into balance in the body. The effective amount required for a particular treatment regimen depends on a variety of factors, including the disease being treated, the severity of the disease, the activity of the specific drug being used, the method of administration, the clearance rate of the specific drug, the duration of treatment, combined medication, age, weight, sex, diet and health of the patient, etc. Other factors to be considered in the art regarding a "therapeutically effective amount" may be found in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8 ^ed ., Pergamon Press, 1990; Remington's Pharmaceutical Sciences, ¹⁷ ed., Mack Publishing Company, Easton, Pa., 1990.

The dosage of the compounds of the invention will depend on a variety of factors, including the specific disease being treated, the severity of the symptoms, the route of administration, the frequency of dosing intervals, the specific compound used, the potency, toxicological properties, and pharmacokinetic characteristics of the compound.

The amount of active ingredient that can be combined with a carrier material to produce a unit dosage form will vary depending on the host being treated and the specific mode of administration. For example, a formulation intended for application to humans may conveniently contain about 5 mg to about 250 mg/kg body weight/day of active agent, compounded with a suitable and convenient amount of carrier material (which may account for about 5% to about 95% of the total composition). Unit dosage forms will generally contain about 1 mg to about 500 mg of active ingredient.

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

The term "administering" refers to providing a therapeutically effective amount of a drug to an individual, and the administration methods include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, etc. The dosage forms include ointments, lotions, tablets, capsules, pills, flying powders, granules, suppositories, pills, tablets, injections, sterile solutions or non-aqueous solutions, suspensions, emulsions, patches, etc. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silicone, potato starch, urea, dextran, etc.).

The preferred route of administration will vary with clinical characteristics, and the dosage must be varied depending on the patient being treated. The physician will determine the appropriate dosage based on the individual patient. The therapeutically effective amount per unit dose depends on body weight, physiological function, and the chosen vaccination regimen. The compound per unit dose refers to the weight of the compound per administration, excluding the weight of the carrier (the drug contains the carrier).

Any suitable route of administration can be used to provide an effective dose of the compound of the present invention to mammals, especially humans. For example, oral administration, rectal administration, parenteral administration, topical administration, ocular administration, nasal administration, pulmonary administration, etc. can be adopted. Dosage forms include tablets, tablets, capsules, creams, ointments, suspensions, dispersions, solutions, aerosols, etc. Preferably, the compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) is administered by inhalation or topical administration.

The pharmaceutical compositions provided by the present invention can be formulated for administration in single or multiple doses. The single dose formulations are packaged in ampoules, vials or syringes. The multiple dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. 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 co-formulated with substances that supplement the intended effect.

In some embodiments, the treatment method of the present invention comprises administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need. Each embodiment of the present invention comprises administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need to treat the disease mentioned in the present invention.

In some embodiments, the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention can be administered once, or several times at different time intervals within a specified time period according to the dosing regimen. For example, once, twice, three times or four times a day. In some embodiments, the drug is administered once a day. In some other embodiments, the drug is administered twice a day. The drug can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosing regimen of the compound of the present invention or a pharmaceutical composition comprising the 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 a skilled person. In addition, the appropriate dosing regimen for the compounds of the invention or pharmaceutical compositions comprising the compounds of the invention, including the duration of implementation of the regimen, 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 concurrent therapies, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such skilled artisans will also understand that the appropriate dosing regimen may require adjustment depending on the individual patient's response to the dosing regimen or as the individual patient's needs change over time.

The compounds of the present invention can be administered simultaneously with, before or after one or more other therapeutic agents. The compounds of the present invention can be administered separately with other therapeutic agents through the same or different administration routes, or in the form of the same pharmaceutical composition. This is selected by a person skilled in the art based on the actual physical conditions of the patient, such as health, age, weight, etc. If formulated as a fixed dose, this combination product uses the compounds of the present invention (within the dosage range described in the present invention) and other pharmaceutically active agents (within their dosage range).

Accordingly, in one aspect, the present invention includes a combination comprising a certain 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 above-mentioned additional therapeutic agents.

The compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) can be used in combination with other drugs for preventing, treating or alleviating diseases or symptoms for which the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) are suitable. These other drugs can be administered simultaneously or sequentially with the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) by their commonly used routes and amounts. When the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) are used simultaneously with one or more other drugs, a pharmaceutical unit dosage form containing such other drugs and the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) is preferred.

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

2-Agonists, such as albuterolamine, formoterol, salmeterol, and carmoxicillin;

Corticosteroids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, flunisolide, mometasone furoate, roflenone, ciclesonide, fluocinolone acetate, desoxymethasone, mometasone, triamcinolone, betamethasone, alclomethasone, desonide, hydrocortisone, and meproclat;

Anticholinergics or antimuscarinic drugs, such as ipratropium bromide, oxitropium bromide, tiotropium bromide, glycopyrrolate, and revatropate;

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

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

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

Topical nonsteroidal anti-inflammatory drugs, 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 therapeutic drugs, such as Dupilumab, Levitra, Nemolizumab, Trakinumab, Etanercept, Adalimumab, Infliximab, Utekinumab, Secukinumab, Omazumilab, CIM-331;

Vitamin D analogs, such as calcipotriol and calcitriol;

Oral retinoic acid derivatives, such as alitretinoin;

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 and trepitant;

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

Oral chymotrypsin inhibitors, such as SUN 13834.

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

The treatment method comprising administering the compound or drug composition of the present invention further comprises administering other anti-chronic obstructive pulmonary disease (COPD) or atopic dermatitis drugs (combination therapy) to the patient, wherein the other anti-chronic obstructive pulmonary disease (COPD) or atopic dermatitis drugs are the drugs in the above-mentioned additional therapeutic agents or their combinations.

The present invention provides a method for treating a lung disease (e.g., COPD, asthma or fibrocystic fibrosis) or an inflammatory disease (e.g., atopic dermatitis or psoriasis) in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of at least one compound of formula (I) or formula (II), or a pharmaceutically acceptable salt or solvent thereof, and at least one compound selected from the following: a steroid (e.g., a glucocorticoid), a calcineurin inhibitor, a PDE4 inhibitor, a JAK kinase inhibitor, a cysteinyl leukotriene antagonist, a nonsteroidal anti-inflammatory drug, a topical ROR agent, an anti-IL4 antibody, an IL-31 antibody, an IL-22 antibody, an IL-33 antibody , IL-12 antibody, IL-23 antibody, IL-17 antibody, IgE antibody, IL-4 antibody, vitamin D analogs, liver X receptor (LXR) selective agonists, histamine H1 antagonists, histamine H3 antagonists, H4 receptor antagonists, NK1 receptor antagonists, CRTH2 receptor antagonists, chymotrypsin inhibitors, 5-lipoxygenase inhibitors, beta-2 adrenergic receptor (adrenoceptor) agonist, alpha-adrenaline receptor agonist, muscarine M1 antagonist, muscarine M3 antagonist, muscarine M2 agonist, NK3 antagonist, LTB4 antagonist, bronchodilator, PDE inhibitor.

Uses of the compounds and pharmaceutical compositions of the present invention

The amount of the compound of the present invention or the compound in the composition of the present invention can be effective to detectably antagonize PDE4 to treat the following diseases: pain (e.g., 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 (e.g., atopic dermatitis, seborrheic dermatitis, contact dermatitis), asthma, chronic obstructive pulmonary disease (COPD), arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxin shock, Gram-negative sepsis, glomerulonephritis, Parkinson's disease, Alzheimer's disease, mild cognitive impairment (MCI), depression, anxiety, ARDS, osteoarthritis, ankylosing spondylitis, multiple sclerosis, gingivitis, periodontitis, pruritus, herpes, CNS tumors, interstitial pneumonia, allergy, crystal-induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, ARDS, pulmonary hypertension, gout, alcoholic liver disease, lupus, cancer, allergic rhinitis, non-allergic rhinitis, autoimmune hemolytic syndrome, autoimmune hepatitis, autoimmune neuropathy lesions, cirrhosis, fibrotic diseases, gastritis, Goodpasture's syndrome, Graves' disease, Gullain-Barre disease, Hashimoto's thyroiditis, HIV-related autoimmune syndrome and blood diseases, lichen planus, myocarditis (including viral myocarditis), neuropathy (including, for example, IgA neuropathy, membranous neuropathy and idiopathic neuropathy), nephritic syndrome, Reiter's syndrome, Sjagellon's syndrome, systemic lupus erythematosus, the method comprising administering to the patient an effective amount of at least one compound represented by formula (I), (II) or (III) or a pharmaceutically acceptable salt or solvent thereof.

General synthesis steps

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

Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of compounds not exemplified in accordance with the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by making some routine modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are set forth 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 Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. and Qingdao Ocean Chemical Factory.

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

The following reactions were generally carried out under positive pressure of nitrogen or argon or in a desiccating tube over anhydrous solvent (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were introduced via syringe. Glassware was dried.

The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The test conditions for hydrogen nuclear magnetic resonance spectroscopy were: at room temperature, a Bruker 400 MHz or 600 MHz nuclear magnetic spectrometer, using CDC1 ₃ , DMSO- d ₆ , CD ₃ OD or acetone- d ₆ as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

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

The purity of the compounds was characterized by Agilent 1260 Preparative HPLC or Calesep Pump 250 Preparative HPLC (column: NOVASEP, 50/80 mm, DAC) with UV detection at 210 nm/254 nm.

The stereo configuration of each chiral compound described in the present invention is resolved using one of the following analytical methods:

Analytical methods:

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

2. Use IA column (manufacturer: Dacello, specification: 4.6 × 250 mm, 5 μm) mobile phase conditions: column temperature 40 ℃, flow rate 1.0 mL/min, 40% ethanol, 60% n-hexane. The following abbreviations are used throughout the present invention: g gram EtOH Ethanol KK Potassium acetate mg mg CDCl ₃ Deuterated chloroform PE Petroleum ether mol More DCM Dichloromethane MsCl Methanesulfonyl chloride h Hours DMF N , N -dimethylformamide TEA Triethylamine min minute DMSO Dimethyl sulfoxide HOAc Acetic acid L Lift THF Tetrahydrofuran CD ₃ OD Deuterated methanol mL, ml mL _BnOH Benzyl alcohol CH ₃ CN Acetonitrile M, mol/L Mole/liter EtOAc, EA Ethyl acetate Pd/C Palladium Carbon DPPA Diphenyl phosphate DIPEA N , N -Diisopropylethylamine _Tf2O Trifluoromethanesulfonic anhydride Pd(dppf)Cl ₂ [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride CDI N , N '-Carbonyldiimidazole HOAT N -Hydroxy-7-nitrobenzotriazole

Synthesis scheme of compound (IA):

Compound (IA) can be prepared by the above synthetic route, wherein ^R1 , ^R2 , ^R3 , X, ^X1 , ^R5a , ^R5b , ^R6a , ^R6b , R, n and G have the same meanings as defined in the present invention. Compound (IA-1) is esterified with HOOC( _CH2 )nG under alkaline or acidic conditions to obtain compound (IA).

Synthesis scheme of compound (IB):

Compound (IB) can be prepared by the above synthetic route, wherein ^R1 , ^R2 , ^R3 , X, ^X1 , ^R5a , R5b, ^R6a , ^R6b , R, n and G have the same meanings as those defined in the present invention. Compound (IB-1) or a salt ^thereof (such as hydrochloride, etc.) is subjected to condensation reaction with HOOC( _CH2 )nG under appropriate conditions to obtain compound (IB).

Synthesis scheme of intermediate N and intermediate N':

Intermediate N can be prepared by an intermediate synthesis method, wherein, unless otherwise specified, ^R1 and ^R2 have the meanings as described in the present invention. Starting material N1 reacts with material BnOH and diphenyl azidophosphate under alkaline conditions to form an amino protecting group to obtain intermediate N2, intermediate N2 undergoes catalytic hydrogenation reduction to obtain intermediate N3, intermediate N3 undergoes diazotization reaction, and then undergoes substitution reaction with potassium iodide to obtain intermediate N; intermediate N removes the corresponding group ^R1 under acidic conditions to obtain intermediate N4, intermediate N4 undergoes substitution reaction with benzyl bromide to obtain intermediate N'.

Specific synthesis method of intermediate N and intermediate N':

The following specific synthesis methods of intermediates N and intermediates N' are merely examples of specific synthesis methods. The synthesis methods of intermediates N and intermediates 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

Dissolve 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (5.0 g, 19.4 mmol) in toluene (25 ml), add DPPA (5.0 mL, 23.0 mmol) and triethylamine (4.3 mL, 31.0 mmol), react at room temperature for 1 h, add benzyl alcohol (3.0 mL, 29.0 mmol), heat to 90 °C and react for 3 h. The solvent was removed by concentration under reduced pressure, and water (100 ml) was added to the residue, followed by extraction 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 obtain 5.01 g of a white solid 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

Dissolve benzyl (3-cyclopropylmethoxy-4-difluoromethoxy)phenyl)carbamate (145 mg, 0.45 mmol) in anhydrous methanol (6 mL), add palladium carbon (50 mg), exclude air, introduce hydrogen, and react at room temperature for 2 h. Filter through diatomaceous earth to remove the catalyst, and concentrate the filtrate 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

Dissolve the compound (3-cyclopropylmethoxy-4-difluoromethoxy)aniline hydrochloride (17 g, 64.0 mmol) in 1,4-dioxane (85 mL) and water (30 mL), stir well and cool to below 0 °C, add concentrated hydrochloric acid (17 mL), cool to -15 °C, add a solution of sodium nitrite (5.3 g, 77.0 mmol) and water (15 mL) dropwise, continue to react for 40 min, add a solution of potassium iodide (13.8 g, 83.1 mmol) and water (15 mL), after the addition is complete, raise the temperature to 0 °C and continue to react for 2 h, add water (200 mL) After stirring evenly, the reaction was stopped. After returning to room temperature, the mixture was extracted with EA (200 mL×2). 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

The compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (4.9 g, 14.0 mmol) was dissolved in acetonitrile (8 mL), and water (10 mL) and concentrated hydrochloric acid (10 mL) were added. The mixture was reacted at 80 °C for 4 h, and sodium hydroxide solution was added to adjust the pH to 5. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: PE/EA (v/v) = 5/1) to obtain 1.8 g of light 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].

Synthesis of Intermediate N': 2-(Benzyloxy)-1-(Difluoromethoxy)-4-iodobenzene

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), and benzyl bromide (2.5 mL, 21.0 mmol) was added. The mixture was reacted at 100 ℃ for 16 h, and the solid was removed by filtration. The filtrate was concentrated, and water (50 mL) was added. The mixture was extracted with EA (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: PE/EA (v/v) = 4/1) to obtain 4.8 g of a light 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).

Synthesis scheme of intermediate M:

The intermediate M can be prepared by the above two synthetic routes, wherein X is a halogen, and R ¹ , R ² and R ³ have the meanings as 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 a substitution reaction is performed to obtain an intermediate M2. The intermediate M2 is subjected to a borylation reaction with diboric acid pinacol ester under alkaline conditions to obtain a compound M3. M3 and intermediate N' (route one) or intermediate N (route two) are subjected to Suzuki coupling to obtain intermediates M4-1 and M4-6, respectively. Among them, route one is that intermediate M4-1 is first subjected to a deprotection and salification reaction to obtain intermediate M4-2, and then under alkaline conditions (such as triethylamine, N,N- In route one, intermediate M4-3 is obtained by substitution reaction under conditions of triethylamine, N,N-diisopropylethylamine, etc., followed by catalytic hydrogenation reduction to obtain intermediate M4-4, and finally substitution reaction occurs under alkaline conditions to obtain intermediate M4-5; route two is that intermediate M4-6 is first catalytically hydrogenated and reduced under the action of palladium carbon to obtain intermediate M4-7, and then deprotected to obtain intermediate M4-8, and finally substitution reaction occurs under alkaline conditions (such as triethylamine, N , N -diisopropylethylamine, etc.) to obtain intermediate M4-9; M4-5 or M4-9 is then subjected to reduction reaction, halogenation reaction, hydriding reaction, hydrogenation reduction, etc. to finally obtain intermediate M.

Specific synthesis method of intermediate M:

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

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

Compound (R) -1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (0.98 g, 4.0 mmol) was dissolved in dichloromethane (15 mL). DIPEA (3.4 mL, 20.5 mmol) and trifluoromethanesulfonic anhydride (1.3 mL, 7.7 mmol) were added at -15 °C. After stirring for 10 min, the mixture was returned to room temperature and the reaction was continued for 18 h. The reaction was stopped and water (50 mL) was added. The mixture was extracted with dichloromethane (5 mL×3). The mixture was 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 a yellow oil with a yield of 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: Synthesis of (R) -1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H -pyrrole-1,2-dicarboxylate

(R) -1-tert-Butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro- 1H -pyrrole-1,2-dicarboxylate (1.3 g, 3.5 mmol), diboric acid pinacol ester (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). The mixture was reacted at 100 °C for 13 h under nitrogen protection. The mixture was cooled to room temperature and filtered. Water (50 mL) was added to the filtrate. EtOAc (5 mL×3) was used to purify the mixture. After extraction, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, concentrated, and separated by silica gel column chromatography (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 1:

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

(R) -1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H -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 1,4-dioxane (20 mL) solution and reacted at 100 °C for 5 h under nitrogen protection. The reaction solution was filtered, water (20 mL) was added to the filtrate, and EtOAc (15 mL×3) was used to purify the mixture. After extraction, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, concentrated, and separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 4/1) to obtain 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: Synthesis of (R) -4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2-carboxylic acid methyl 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), and HCl in ethyl acetate (4 mol/L, 15 mL) was added. The reaction was carried out at room temperature for 1 h, and the solvent was removed to obtain 2.02 g of a light 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: Synthesis of (R) -1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2-carboxylic acid methyl ester

Compound (R) -4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2-carboxylic acid methyl ester hydrochloride (2.0 g, 4.9 mmol) was dissolved in dichloromethane (10 mL), and DIPEA (4.0 mL, 24 mmol) was added. After cooling to 0 °C, acetyl chloride (1.1 g, 14 mmol) was added. The reaction was stopped after stirring at room temperature for 3 h. Water (20 mL×3) was added and stirred. The mixture was 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 a 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-carboxylic acid methyl ester

Compound (R) -1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2-carboxylic acid methyl ester (4.5 g, 11 mmol) was dissolved in methanol (30 mL), 10% Pd/C (450 mg) was added, hydrogen was introduced, and the reaction was carried out at room temperature for 5 h. The mixture was filtered and the filtrate was concentrated to obtain 3.1 g of a light brown liquid with a yield of 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-carboxylic acid methyl ester

Compound (2R) -1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid methyl ester (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, and the mixture was heated at 80 ℃ for 4 h. The solvent was removed under reduced pressure, water (50 mL) was added, and the mixture was 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 1.5 g of light brown liquid with a yield of 100%.

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: Synthesis of 1-((2 R )-4-(4-(difluoromethoxy)-3-isopropyloxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone

Compound (2R) -1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester (560 mg, 1.51 mmol) was dissolved 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. A saturated aqueous sodium chloride solution (20 mL) was added and extracted with EtOAc (20 mL×3). The organic phase was dried over 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: Synthesis of 1-((2 R )-2-(bromomethyl)-4-(4-(difluoromethoxy)-3-isopropyloxyphenyl)pyrrolidin-1-yl)ethanone

The compound 1-((2 R )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (493 mg, 1.44 mmol) was dissolved in EtOAc (20 mL), and triethylamine (442 mg, 4.37 mmol) was added. MsCl (333 mg, 2.91 mmol) was added in an ice bath. After reacting at room temperature for 1 h, lithium bromide (1.26 g, 14.56 mmol) was added. The reaction was continued at room temperature for 8 h. Water (30 mL) was added to stop the reaction. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed to obtain 376 mg of a 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: Synthesis of 1-((2 R )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropyloxyphenyl)pyrrolidin-1-yl)ethanone

The 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, and the reaction was heated at 80°C for 6 h. The mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with EtOAc (10 mL× ₃ ). The organic phase was dried over anhydrous _Na2SO4 , concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 60/1) to obtain 223 mg of a light brown liquid with a yield of 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: Synthesis of 1-((2 R )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropyloxyphenyl)pyrrolidin-1-yl)ethanone

The compound 1-((2 R )-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 introduced, and 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 2 :

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

(R) -1-tert-Butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H -pyrrole-1,2-dicarboxylate (1.15 g, 3.3 mmol), 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (1.1 g, 3.2 mmol), potassium phosphate (2.1 g, 9.9 mmol) and Pd(dppf)Cl ₂ (120 mg, 0.16 mmol) were dissolved in dry 1,4-dioxane (15 mL). The mixture was reacted at 100 °C for 3 h under nitrogen protection. The reaction solution was filtered and water (50 mL) and EtOAc (5 mL×3) were added to the filtrate. After extraction, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 8/1) to obtain 1.13 g of 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: Synthesis of ( 2R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-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 introduced, and the reaction was carried out at room temperature for 7 h. The reaction solution was then filtered and the filtrate was concentrated to obtain 990 mg of a yellow liquid with a yield of 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-carboxylic acid methyl ester hydrochloride

Compound ( 2R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (990 mg, 2.2 mmol) was dissolved in dichloromethane (6 mL). HCl ethyl acetate solution (4 mol/L, 8 mL) was added and stirred at room temperature for 50 min. The solvent was removed to obtain 751 mg of a white solid with a yield of 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: Synthesis of (2R) -1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester

Compound (2R) -4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid 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. The reaction was stopped after stirring at room temperature for 5 h. The organic phase was washed with water (10 mL×3), dried over anhydrous Na ₂ SO ₄ , and the concentrate was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to obtain 186 mg of a light yellow liquid with a yield of 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: Synthesis of 1-((2 R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (800 mg, 2.09 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL), lithium borohydride (445 mg, 20.9 mmol) was added in an ice bath, and ice water (15 mL) was added after reacting at room temperature for 4 h. After concentration, water (30 mL) was added, and the mixture was extracted with EtOAc (20 mL×3). The organic phase was washed with dilute hydrochloric acid (15 mL×1, 1M) and saturated sodium chloride aqueous solution (15 mL×1). The organic phase was dried over anhydrous sodium sulfate, and 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: Synthesis of 1-((2 R )-2-(bromomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

Dissolve the compound 1-((2 R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (520 mg, 1.46 mmol) in EtOAc (20 mL), add triethylamine (525 mg, 5.19 mmol), add MsCl (301 mg, 2.63 mmol) in an ice bath, react at room temperature for 2 h, then add lithium bromide (636 mg, 7.32 mmol), continue to react at room temperature for 12 h, and add water (30 mL). The reaction was stopped, and 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) to obtain 146 mg of a light yellow liquid with a yield of 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: Synthesis of 1-((2 R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

The compound 1-(( 2R )-2-(bromomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (250 mg, 0.60 mmol) was dissolved in DMF (3 mL), sodium azide (388 mg, 5.97 mmol) was added, and the reaction was heated at 90 °C for 2.5 h. The mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with EtOAc (10 mL× ₃ ). The organic phase was dried over anhydrous _Na2SO4 , concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 60/1) to obtain 163 mg of a light brown liquid 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: Synthesis of 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

The compound 1-((2 R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (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), reacted at 50 ℃ 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 a light brown liquid 1.8 g, yield 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] ⁺ .

Embodiment:

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

Compound 1-((2 R )-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). After cooling to 0 °C, DIPEA (90 mg, 0.70 mmol) was added. The mixture was reacted at room temperature for 12 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 50/1) to obtain 23 mg of a white viscous product 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

Compound 3-((((2 R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoic acid methyl ester (23 mg, 0.045 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL), and lithium hydroxide monohydrate (10 mg, 0.24 mmol) was added. The reaction was stopped after 1.5 h at 50 ℃, and dilute hydrochloric acid (1M) was added to adjust the solution pH to 1. THF was removed under reduced pressure, and 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 a light yellow solid with a yield of 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-((2 R )-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). After cooling to 0 °C, DIPEA (116 mg, 0.90 mmol) was added. The mixture was reacted at room temperature for 6 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL). mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 50/1) to obtain 30 mg of a white viscous product 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: Methyl 4-((((2 R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoate

Compound 1-((2 R )-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). After cooling to 0 °C, DIPEA (90 mg, 0.70 mmol) was added. The mixture was reacted at room temperature for 12 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 50/1) to obtain 26 mg of a white viscous product with a yield of 44% and a purity of 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-((((2 R )-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)carbamoyl)benzoic acid methyl ester (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. The reaction was stopped after 1.5 h at 50 ℃, and dilute hydrochloric acid (1M) was added to adjust the solution pH to 1. The tetrahydrofuran was removed under reduced pressure, and 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 a light yellow solid with a yield of 77% and a purity of 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: Methyl 4-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoate

Compound 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (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). After cooling to 0 °C, DIPEA (131 mg, 1.01 mmol) was added. The mixture was then returned to room temperature for reaction for 12 h. Dichloromethane (15 mL) was added, water (10 mL) was added, and extraction with dichloromethane (10 mL×3), the organic phases were combined, 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 a white solid with a yield of 66% and a purity of 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-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoic acid

Compound 4-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoic acid methyl ester (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 at 50 ℃ for 2 h, and dilute hydrochloric acid (1 M) was added to adjust the solution pH to 1. THF was removed under reduced pressure, and the residue was extracted with EtOAc (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 48 mg of a 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)pyrrolidin-2-yl)methyl)- N ⁴ -ethyl- ^N 4 -methylterephthalamide

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). After cooling to 0 °C, DIPEA (62 mg, 0.48 mmol) was added. The mixture was returned to room temperature and the reaction was continued for 12 h. Water (5 mL) was added and stirred. The mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 25/1) to obtain 16 mg of a white solid with a yield of 37% and a purity of 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-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate

Compound 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (40 mg, 0.11 mmol), 5-(methoxycarbonyl)-2-pyridinecarboxylic acid methyl ester (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). After cooling to 0 °C, DIPEA (87 mg, 0.67 mmol) was added. The mixture was returned to room temperature and the reaction was continued for 10 h. Dichloromethane (15 mL) was added and the organic phase was washed with water (10 mL×3), 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) to obtain 40 mg of a light yellow solid with a yield of 68% and a purity of 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-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate hydrochloride

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate (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 mmol) was added. The reaction was stopped at 50 ℃ for 2 h, and dilute hydrochloric acid (1M) was added to adjust the solution pH to 4. THF was removed under reduced pressure, and 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 35 mg of a white solid 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)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dicarboxamide

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate hydrochloride (30 mg, 0.06 mmol), N -ethylmethylamine (10 mg, 0.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (57 mg, 0.30 mmol) and HOAT (16 mg, 0.12 mmol) were dissolved in dichloromethane (5 mL). After cooling to 0 °C, DIPEA (46 mg, 0.36 mmol) was added. The mixture was reacted at room temperature for 6 h. Water (50 mL) was added and stirred. The mixture was extracted with dichloromethane (10 mL×3), 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) = 24/1) to obtain 18 mg of a white solid with a yield of 55% and a purity of 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: Methyl 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))picolinate

Compound 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (40 mg, 0.11 mmol), 2,6-pyridinedicarboxylic acid monomethyl ester (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). After cooling to 0 °C, DIPEA (87 mg, 0.67 mmol) was added. The mixture was then returned to room temperature and the reaction was continued for 7 h. Dichloromethane (15 mL) was added and the organic phase was washed with water (10 mL×3), 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) to obtain 34 mg of a light brown solid with a yield of 58% and a purity of 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-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))picolinic acid hydrochloride

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)picolinic acid methyl ester (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 mmol) was added. The mixture was reacted at 50 °C for 1 h and then cooled to room temperature. Dilute hydrochloric acid (1M) was added to adjust the solution pH to 4. THF was removed under reduced pressure, and the residue was extracted with EtOAc (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 29 mg of a 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)pyrrolidin-2-yl)methyl)- N ⁶ -ethyl- N ⁶ -methylpyridine-2,6-dicarboxamide

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)picolinic acid hydrochloride (30 mg, 0.06 mmol) was dissolved in dry THF (4 mL), CDI (39 mg, 0.24 mmol) was added, and the mixture was reacted at 60 °C for 1 h. N -ethylmethylamine (14 mg, 0.24 mmol) was added and the reaction was continued for 6 h. Water (15 mL) was added and stirred, and the mixture was extracted with EtOAc (5 mL×3), 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) = 30/1) to obtain 14 mg of a light yellow solid with a yield of 43% and a purity of 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)pyrrolidin-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), react at 60 °C for 6 h, cool to room temperature, add water (15 mL), and extract the organic phase with EtOAc (15 mL). mL×3), the organic phases were combined, 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 35 mg of a light brown solid with a yield of 41% and a purity of 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)pyrrolidin-2-yl)methyl)-2-ethoxy-3-fluorobenzamide

Compound 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (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). After cooling to 0 °C, DIPEA (85 mg, 0.66 mmol) was added. After returning to room temperature, the reaction was continued for 8 h. Dichloromethane (15 mL) was added and 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 a light brown solid with a yield of 72% and a purity of 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)pyrrolidin-2-yl)methyl)- N ⁵ -isopropyl- N ⁵ -methylpyridine-2,5-dicarboxamide

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-dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.59 mmol) and HOAT (32 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL). The mixture was cooled to 0 °C and DIPEA (77 mg, 0.60 mmol) was added. The mixture was reacted at room temperature for 12 h. Water (30 mL) was added and 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) to obtain 42 mg of a white solid with a yield of 63% and a purity of 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)pyrrolidin-2-yl)methyl)- N ⁵ -(4-fluorophenyl)- N ⁵ -methylpyridine-2,5-dicarboxamide

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate 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). After cooling to 0 °C, DIPEA (78 mg, 0.60 mmol) was added. The mixture was reacted at room temperature for 12 h. Water (30 mL) was added and extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: EtOAc (v) = 100%) to obtain 48 mg of a white solid with a yield of 66% and a purity of 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)pyrrolidin-2-yl)methyl)- N ⁵ -(2-(dimethylamino)ethyl)- N ⁵ -methylpyridine-2,5-dimethylamide

Compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate 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). The mixture was cooled to 0 °C and DIPEA (77 mg, 0.60 mmol) was added. The mixture was reacted at room temperature for 12 h. Water (30 mL) was added and the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 18/1) to obtain 42 mg of a 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)pyrrolidin-2-yl)methyl)- N ⁵ -methyl- N ⁵ -(2,2,2-trifluoroethyl)pyridine-2,5-dicarboxamide

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 -methyl-2,2,2-trifluoroethylamine hydrochloride (71 mg, 0.47 mmol) and HOAT (33 mg, 0.24 mmol) were dissolved in dichloromethane (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol) and DIPEA (142 mg, 1.10 mmol) were added in an ice bath. The mixture was reacted at room temperature for 4 h. Water (30 mL) was added and 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 separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 54/1) to obtain 32 mg of a 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)pyrrolidin-2-yl)methyl)- N ⁵ -(cyanomethyl)- N ⁵ -methylpyridine-2,5-dicarboxamide

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate hydrochloride (80 mg, 0.16 mmol), 2-(methylamino)acetonitrile hydrochloride (71 mg, 0.84 mmol) and HOAT (43 mg, 0.32 mmol) were dissolved in dichloromethane (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (155 mg, 0.81 mmol) and DIPEA (186 mg, 1.44 mmol) were added in an ice bath. The mixture was reacted at room temperature for 15 h. Water (30 mL) was added and 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 separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 54/1) to obtain 18 mg of a white solid with a yield of 20% and a purity of 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)pyrrolidin-2-yl)methyl)- N ⁵ -(2-amino-2-oxoethyl)- N ⁵ -methylpyridine-2,5-dicarboxamide

Compound 6-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate hydrochloride (60 mg, 0.12 mmol), 2-(methylamino)acetamide hydrochloride (50 mg, 0.40 mmol) and HOAT (33 mg, 0.24 mmol) were dissolved in dichloromethane (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol) and DIPEA (146 mg, 1.13 mmol) were added in an ice bath. The mixture was reacted at room temperature for 3 h. After cooling to room temperature, water (30 mL) was added. After stirring, 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 separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 30/1) to obtain 34 mg of a 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-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-o-methoxybenzamide

Step 1: Synthesis of methyl o-methoxybenzoate

Anhydrous DMF (10 mL) was added to the compound methyl salicylate (1.02 g, 6.68 mmol), and the mixture was stirred at room temperature until completely dissolved. Potassium carbonate (2.79 g, 19.98 mmol) and iodomethane (2.86 g, 20.1 mmol) were then added, and the mixture was heated to 60 °C and stirred for 2 h. The reaction was stopped, and the mixture was concentrated. Water (15 mL) was added, and the mixture was extracted with EtOAc (20 mL×3). The mixture was 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 a yellow oil with a yield of 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-Anisic 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. The mixture was stirred at room temperature for 3 h to stop the reaction. Dilute hydrochloric acid (1 M) was added under an ice bath, and the pH was adjusted to 5-6. The mixture was concentrated and water (10 mL) was added. The mixture was extracted with EtOAc (15 mL×3). The mixture was dried 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 a light blue solid with a yield of 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: Synthesis of 4-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-1-methoxybenzamide

Anhydrous THF (8 mL) was added to the compound 2-methoxybenzoic acid (73.9 mg, 0.49 mmol), and the mixture was stirred at room temperature until dissolved. Then, carbonyldiimidazole (86.5 mg, 0.52 mmol) was added, and the mixture was stirred at room temperature for 1 h. Then, 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (93.2 mg, 0.26 mmol) was added, and the mixture was heated to 60 °C and stirred for 5 h. The reaction was stopped, concentrated, and water (15 mL) was added. The mixture was extracted with EtOAc (30 mL×3). Anhydrous Na ₂ SO ₄ was dried, concentrated, and separated by silica gel column chromatography (eluent PE/EtOAc (v/v) = 1:3) to obtain 91.1 mg of a light brown oil with a yield of 70.9% and a purity of 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-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-1-methylaminobenzamide

Step 1: Synthesis of methyl o-aminobenzoate

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

To the compound methyl o-aminobenzoate (247.1 mg, 1.50 mmol), THF (4 mL) and water (4 mL) were added, followed by potassium hydroxide (142 mg, 2.53 mmol). The mixture was heated to 60 °C and stirred for 22 h to stop the reaction. Dilute hydrochloric acid (1 M) was added under ice bath to adjust the pH to 2-3. The mixture was concentrated and water (10 mL) was added. The mixture was extracted with EtOAc (15 mL×3). The mixture was dried over anhydrous Na ₂ SO ₄ and concentrated to obtain 213.1 mg of a white solid with a yield of 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: Synthesis of 4-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-1-methylaminobenzamide

Anhydrous THF (8 mL) was added to the compound 2-methylaminobenzoic acid (72.1 mg, 0.48 mmol), and the mixture was stirred at room temperature until completely dissolved. Then, carbonyldiimidazole (86.9 mg, 0.53 mmol) was added, and the mixture was stirred at room temperature for 2 h. Then, 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (106.6 mg, 0.30 mmol) was added, and the mixture was heated to 60 °C and stirred for 6 h. The reaction was stopped, concentrated, and water (15 mL) was added. The mixture was extracted with EtOAc (30 mL×3), and anhydrous Na ₂ SO ₄ was dried, concentrated, and separated by silica gel column chromatography (eluent PE:EtOAc (v/v) = 1:3) to obtain 59.3 mg of a light brown oil with a yield of 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-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)piperidine-4-carboxylic acid

Step 1: 1-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)piperidine-4-carboxylic acid methyl ester

The compound 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (100 mg, 0.28 mmol) was dissolved in dry tetrahydrofuran (10 mL), and DIPEA (44 mg, 0.34 mmol) and 4-nitrophenyl chloroformate (62 mg, 0.31 mmol) were added. The mixture was reacted at room temperature for 1.5 h, and methyl piperidine-4-carboxylate (47 mg, 0.32 mmol) was added. The mixture was reacted at room temperature for 14 h, and water (10 mL) was added. The mixture was extracted with EtOAc (5 mL×3), 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 a 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-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)piperidine-4-carboxylic acid

Compound 1-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)piperidine-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 lithium hydroxide monohydrate (52 mg, 1.24 mmol) was added. The reaction was stopped at 50 ℃ for 1.5 h, and dilute hydrochloric acid (1M) was added to adjust the solution pH to 1. THF was removed under reduced pressure, and the residue was extracted with dichloromethane (10 mL×3). The organic phase was dried over anhydrous 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)pyrrolidin-2-yl)methyl)- N ⁴ -ethyl- N ⁴ -methylpiperidin-1,4-dicarboxamide

Compound 1-((((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)piperidine-4-carboxylic acid (90 mg, 0.18 mmol), N -ethylmethylamine (68 mg, 1.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (170 mg, 0.89 mmol) and HOAT (48 mg, 0.35 mmol) were dissolved in dichloromethane (5 mL). After cooling to 0 °C, DIPEA (114 mg, 0.88 mmol) was added. The mixture was reacted at room temperature for 5.5 h. Water (20 mL) was added and 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 a white viscous product with a yield of 73% and a purity of 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-(((2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-3-(1-hydroxy-1,3-dihydrobenzo[ c ][1,2]oxaborolan-5-yl)urea

The compound 2-hydroxymethyl-5-aminophenylboronic acid half ester (47 mg, 0.32 mmol) was dissolved in dry tetrahydrofuran (5 mL), and DIPEA (44 mg, 0.34 mmol) and 4-nitrophenyl chloroformate (62 mg, 0.31 mmol) were added. The mixture was reacted at room temperature for 3.5 h. 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (100 mg, 0.28 mmol) was added. The mixture was reacted at room temperature for 5.5 h. Water (10 mL) was added. The mixture was extracted with EtOAc (5 mL×3), 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 43 mg of a white solid with a yield of 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]oxaborolan-5-yl((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamate

The compound 2-hydroxymethyl-5-hydroxyphenylboronic acid half ester (47 mg, 0.31 mmol) was dissolved in dry tetrahydrofuran (5 mL), and DIPEA (44 mg, 0.34 mmol) and 4-nitrophenyl chloroformate (62 mg, 0.31 mmol) were added. The mixture was reacted at room temperature for 3 h. 1-((2 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (100 mg, 0.28 mmol) was added. The mixture was reacted at room temperature for 5 h. Water (10 mL) was added. The mixture was extracted with EtOAc (5 mL×3), the organic phase 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 a white solid with a yield of 18% and a purity of 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)pyrrolidin-2-yl)methyl)-2-ethoxybenzamide

Step 1: Synthesis of compound ( S) -1-tert-butyl 2-methyl 4-((trifluoromethyl)sulfonyl)oxy- 1H -pyrrole-1,2( 2H , 5H )-dicarboxylate

Dissolve 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) in dichloromethane (50 mL). Add trifluoromethanesulfonic anhydride (10.5 mL, 59.3 mmol) in dichloromethane (20 mL) dropwise at -15 °C and stir at room temperature for 2 h. Dichloromethane (100 mL) was added for dilution, and the organic phase was washed with saturated saline (100 mL × 3), adjusted to pH = 1 with hydrochloric acid (2 mol/L), and then washed with saturated sodium bicarbonate solution (100 mL), dried with anhydrous sodium sulfate, and the concentrated solution was decompressed. The residue was separated by 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: Synthesis of compound ( S) -1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -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 diboron (8.92 g, 35.1 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride 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. The mixture was concentrated under reduced pressure, ethyl acetate (200 mL) was added, 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) to obtain a yellow transparent liquid (10.0 g, yield 97%).

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

Compound ( S) -1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -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)palladium dichloride dichloromethane complex (850 mg, 1.02 mmol) and potassium phosphate (13.0 g, 61.2 mmol) were dissolved in anhydrous 1,4-dioxane (80 mL) and stirred at 100 °C for 3 h under nitrogen protection. The mixture was concentrated under reduced pressure, ethyl acetate (200 mL) was added, 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) to obtain a yellow liquid (8.23 g, yield 86%).

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

Compound ( S) -1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -1H -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 diatomaceous earth and concentrated under reduced pressure to obtain a yellow liquid (3.49 g, yield 93%).

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: Synthesis of compound ( 2S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxymethylpyrrolidine-1-carboxylate

Dissolve compound (2S ) -1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-1,2-dicarboxylate (1.70 g, 3.85 mmol) in anhydrous tetrahydrofuran (20 mL), add lithium borohydride (140 mg, 5.78 mmol) solution in portions, and stir 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 separated by silica gel column chromatography (eluent: 60-90 petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 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: Synthesis of compound ( 2S )-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate

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). A solution of methanesulfonyl chloride in ethyl acetate (7.3 mL, 3.48 mmol, 0.48 mol/L) was slowly added dropwise at 0 °C and stirred at room temperature for 3 h. The solid was filtered off and washed with ethyl acetate (10 mL). The solvent was removed under reduced pressure to obtain a yellow liquid ( 2S )-2-methanesulfonyloxymethyl-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine (1.31 g, yield 99%).

Compound ( 2S )-2-methanesulfonyloxymethyl-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-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. The N , N -dimethylformamide was removed under reduced pressure, and ethyl acetate (50 mL) was added for dilution. The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (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)

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

MS-ESI: m/z 339.20 [M-HCl+H] ⁺ .

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

Dissolve compound ( 2S )-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (880 mg, 2.35 mmol) and triethylamine (992 uL, 7.05 mmol) in dichloromethane (23 mL). Slowly add acetyl chloride (251 uL, 3.52 mmol) at 0 °C and stir 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 and 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 obtain a yellow viscous liquid (702 mg, yield 79%).

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

The compound 1-(( 2S )-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethyl ketone (399 mg, 1.05 mmol) and triphenylphosphine (3413 mg, 1.58 mmol) were dissolved in tetrahydrofuran/water (8 mL, (v/v) = 3/1) and stirred at 50 °C 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 and 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) = 8/1) to obtain a yellow viscous liquid, a solution of hydrogen chloride in dioxane (1 mL, 4 mol/L) was added and stirred evenly, and the solvent was removed under reduced pressure to obtain a yellow viscous liquid (119 mg, yield 29%).

MS-ESI: m/z 355.15 [M-HCl+H] ⁺ .

Step 10: Synthesis of compound N -((( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidin-2-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 dichloromethane (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59 mg, 0.31 mmol) and N , N -diisopropylethylamine (67 uL, 0.41 mmol) were added in an ice bath and 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 and 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 obtain a yellow liquid (19 mg, yield 37%).

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 -methylpyridine-2,5-dicarboxamide

Step 1: Synthesis of compound 6-(((( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)aminoformyl)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-pyridinedicarboxylic acid-5-methyl ester (56 mg, 0.30 mmol) and N -hydroxy-7-azabenzotriazole (70 mg, 0.51 mmol) were dissolved in dichloromethane (10 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 mg, 0.77 mmol) and N , N -diisopropylethylamine (169 uL, 1.02 mmol) were added in an ice bath, and the mixture 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 and 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 obtain a red liquid (75 mg, yield 54%).

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: Synthesis of compound 6-(((( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)aminoformyl)nicotinic acid

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

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: Synthesis of compound N ² -(((2 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dicarboxamide

Compound 6-(((( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)aminocarbonyl)nicotinic acid (60 mg, 0.12 mmol), N -methylethylamine (20 uL, 0.23 mmol) and N -hydroxy-7-azabenzotriazole (32 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36 mmol) and N , N -diisopropylethylamine (78 uL, 0.42 mmol) were added in an ice bath and 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 and 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 obtain a yellow liquid (20 mg, yield 31%).

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] ⁺ .

Example 39: N ² -(((2 R ,4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dicarboxamide

Step 1: Synthesis of compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (11.0 g, 29.43 mmol), pinacol diboron (8.96 g, 35.3 mmol), potassium acetate (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) were dissolved in dry N , N -dimethylformamide (80 mL) solution and reacted at 100 ℃ for 2 h under nitrogen protection. The reaction solution was filtered through diatomaceous earth and then precipitated with 50 mL of ethyl acetate, washed with saturated brine (50 ml × 2), combined 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, yield 99.97%).

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

Compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (5 g, 14.7 mmol), ( R )-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1, 2- ( 2H , 5H )-dicarboxylate (5.00 g, 13.3 mmol, intermediate M), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (Pd(dppf) _{Cl2.CH2Cl2 )} (550 mg, _0.67 mmol), potassium phosphate ( _{K3PO4 )} (7.60 g, 35.8 mmol), dissolved in toluene (50 mL), stirred in an oil bath at 50 °C for 8 h under nitrogen protection. The reaction solution was filtered through diatomaceous earth, 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, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to obtain a light 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: Synthesis of (2 R , 4 S )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1, 2-dicarboxylate

The compound ( R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -1H -pyrrole-1, 2-( 2H , 5H )-dicarboxylate (4.60 g, 10.5 mmol) was dissolved in methanol solution (70 mL), and 10% Pd/C reducing agent (140 mg) was added. After replacing with hydrogen three times, the reaction was stirred at room temperature under hydrogen protection for 3 h. The reaction solution was filtered through diatomaceous earth, 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, yield 99.50%). Synthesis 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: Synthesis of tert-butyl (2 R ,4 S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

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, and lithium borohydride (332 mg, 15.6 mmol) was added under ice bath conditions. After the addition of the raw materials, the mixture was transferred to room temperature for reaction for 1 h. Saturated sodium chloride aqueous solution (30 mL) was added, and the mixture was 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: Synthesis of compound (2 R ,4 S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Compound ( 2R , 4S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.8 g, 4.40 mmol) was dissolved in dichloromethane (20 mL), triethylamine (880 mg, 8.70 mmol) was added, and methanesulfonyl chloride (702 mg, 6.13 mmol) was added in an ice bath. The reaction was carried out at room temperature for 3.5 h, and water (30 mL) was added to stop the reaction. The organic phase was separated, and 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 light yellow liquid (2.1 g, yield 98%).

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: Synthesis of compound (2 R ,4 S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Compound ( 2R , 4S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (2.1 g, 4.30mmol) was dissolved in DMF (11 mL), sodium azide (1.1 g, 17.0 mmol) was added, and the mixture was heated at 80°C for 3.5 h. The mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (10 mL× ₃ ). The organic phase was dried over anhydrous _Na2SO4 , concentrated, and separated on a silica gel column (eluent: PE/EtOAc (v/v) = 8/1) to obtain a colorless liquid (1.6 g, yield 88%).

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

Dissolve the compound ( 2R , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.66 g, 3.79 mmol) in dichloromethane (20 mL) solution, add 3 mol/L HCl in 1,4-dioxane solution (6 mL), stir at room temperature for 2 h, and concentrate under reduced pressure to obtain a colorless liquid (1.40 g, yield 99%).

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: Synthesis of compound 1-((2 R ,4 S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

Dissolve the compound (2 R ,4 S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (1.42 g, 3.79 mmol) in dichloromethane (20 mL), cool in an ice bath, add N , N -diisopropylethylamine (1.9 g, 15.0 mmol) and acetyl chloride (653 mg, 8.32 mmol), stir at room temperature for 1.5 h, stop the reaction, add water (20 mL) and stir for 2 min, separate the organic phase, dry the organic phase with anhydrous Na ₂ SO ₄ , and separate the concentrated solution by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to obtain a light brown liquid (1.29 g, yield 90%).

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: Synthesis of compound 1-((2 R ,4 S )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride

The compound 1-((2 R ,4 S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-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), reacted at 50 ℃ 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) The obtained light brown liquid was added with 1,4-dioxane solution of HCl (2 mL, 4 mol/L), the pH was adjusted to 1, and the product was concentrated under reduced pressure to obtain a light yellow solid (1.14 g, yield 92%).

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: Synthesis of N ² -(((2 R ,4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- ^N 5 -methylpyridine-2,5-dicarboxamide

Compound 1-((2 R ,4 S )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride (660 mg, 1.69 mmol), 5-(ethyl(methyl)aminoformyl)picolinic acid (452 mg, 2.17 mmol) and 1-hydroxybenzotriazole (342 mg, 2.53 mmol) were dissolved in dry N , N -dimethylformamide (15 ml) solution, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (649 mg, 3.39 mmol) was added, and after cooling at 0 °C, N -methylmorpholine (553 mg, 5.47 mmol), transferred to room temperature and stirred for 4 h. Water (150 mL) was added to stop the reaction, and 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 obtain a white solid (632 mg, yield 69 %).

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] ⁺ .

Example 40: N ² -(((2 R ,4 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dicarboxamide

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

Compound ( R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -1H -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. Lithium borohydride (507 mg, 13.4 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 3 h. The reaction was stopped when the raw material was completely reacted. A mixture of ice and water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: PE/EtOAc (v/v) = 5/1) to obtain a white foamy solid (3.78 g, yield 88%).

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: Synthesis of compound (2 R , 4 R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Compound ( R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)-2, 5-dihydro- 1H -pyrrole-1-carboxylic acid tert-butyl ester (2.2 g, 5.3 mmol) and (tricyclohexylphosphine) (1,5-cyclooctadiene) (pyridine) iridium hexafluorophosphate (Crabtrees catalyst) (0.66 g, 0.80 mmol) were dissolved in 90 mL of anhydrous dichloromethane solution and reacted at room temperature for 72 h under a 0.5 MPa hydrogen atmosphere. The reaction was stopped when the raw materials reacted completely. Add 300 mL of saturated brine, extract with dichloromethane (50 mL × 3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrate on a silica gel column (eluent: PE/EtOAc (v/v) = 10/1) to obtain a yellow liquid (1.75 g, yield 76%). Synthesis 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: Synthesis of compound ( 2R , 4R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Dissolve the compound (2 R , 4 R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.7 g, 3.9 mmol) in 30 mL of anhydrous dichloromethane solution. Add methylsulfonyl chloride (MsCl) (1.8 mL, 13.0 mmol) in an ice bath and react at room temperature for 2 h. The reaction is stopped when the raw material reacts completely. A mixture of ice and water was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: PE/EtOAc (v/v) = 5/1) to obtain a light yellow oil (1.95 g, yield 98%).

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: Synthesis of compound (2 R , 4 R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Compound ( 2R , 4R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.8 g, 3.7 mmol) and sodium azide (716 mg, 11.0 mmol) were dissolved in 15 mL N , N -dimethylformamide solution and reacted at 80°C for 4 h. The reaction was stopped when the raw materials were completely reacted. Add 100 mL of water and extract with ethyl acetate (20 mL × 3). Dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrate on a silica gel column (eluent: PE/EtOAc (v/v) = 5/1) to obtain a colorless oil (1.3 g, yield 81%).

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: Synthesis of compound (2 R , 4 R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride

Dissolve the 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) in 30 mL of dichloromethane solution, then add 1, 4-dioxane hydrochloride solution (5 mL), react at room temperature for 1 h, and stop the reaction when the raw material reacts completely. Distill under reduced pressure to remove the solvent, and concentrate to obtain 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: Synthesis of compound 1-((2 R , 4 R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

Dissolve ( 2R , 4R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (4.6 g, 10.0 mmol) in 20 mL of dichloromethane solution. Add triethylamine (0.8 mL, 6.0 mmol) and acetyl chloride (0.1 mL, 3 mmol) in an ice bath. React at room temperature for 1 h. Stop the reaction when the raw material reacts completely. Saturated brine was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: PE/EA (v/v) = 2/1) to obtain a yellow liquid (1.04 g, yield 93%).

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: Synthesis of compound 1-((2 R , 4 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

The compound 1-((2 R , 4 R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (1.0 g, 2.63 mmol) was dissolved in a mixed solvent of 30 mL tetrahydrofuran and 10 mL water, and then triphenylphosphine (1.04 g, 4.0 mmol) was added. The reaction was carried out at 50 ℃ for 2 h. The reaction was stopped when the raw material was completely reacted. Add 30 mL of saturated brine and extract with ethyl acetate (20 mL × 3). Dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrate on a silica gel column (eluent: DCM/MeOH (v/v) = 20/1) to obtain a light brown viscous substance (0.89 g, yield 95%).

MS-ESI: m/z 355.10 [M+H] ⁺ .

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

Dissolve the compound 1-((2 R , 4 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (0.88 g, 2.5 mmol) in 30 mL of dichloromethane solution, then add 1, 4-dioxane hydrochloride solution (2 mL) and react at room temperature for 1 h. When the raw material reacts completely, the reaction is stopped. Distill under reduced pressure to remove the solvent, and the concentrated solution obtains a brown solid (0.95 g, yield 98%).

Step 9: Synthesis of compound N ² -((((2 R , 4 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2, 5 -dimethylamide

Compound 1-((2 R ,4 R )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride (950 mg, 2.43 mmol), 5-(ethyl(methyl)aminoformyl)picolinic acid (603 mg, 2.89 mmol) and 1-hydroxy-7-azobenzotriazole (1.12 g, 7.82 mmol) were dissolved in dichloromethane (40 mL) solution and cooled in an ice bath. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.56 g, 7.72 mmol) and N , N -diisopropylethylamine (1.8 mL, 10.0 mmol), react at room temperature for 1 h. When the raw material reacts completely, stop the reaction, add saturated brine (100 mL), extract with dichloromethane (30 mL × 3), dry the organic phase with anhydrous sodium sulfate, separate and purify by reduced pressure concentrated silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) to obtain a dark red solid (900 mg, yield 68%).

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)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dicarboxamide

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

Dissolve the compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (10.410 g, 26.73 mmol) in anhydrous tetrahydrofuran (62 mL), cool to -20 ℃, add isopropylmagnesium chloride-lithium chloride (22 mL, 29.00 mmol, 1.3 mol/L in THF) dropwise, stir at room temperature for 2 h, stir at -78 ℃ for 0.5 h, add (2 S )-1-tert-butyloxycarbonyl-4-oxoproline methyl ester (5.00 g, 20.60 mmol) in anhydrous tetrahydrofuran (20 mL) dropwise, and stir at -70 ℃ for 2 h. Add saturated ammonium chloride solution (5 mL) to quench the reaction, add ethyl acetate (100 mL) to dilute, wash the organic phase with saturated salt water (100 mL), extract the aqueous phase with ethyl acetate (50 mL × 3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate to obtain a yellow liquid, and purify it by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 4/1) to obtain a yellow transparent liquid (5.21 g, yield 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: Synthesis of compound ( 2S , 4R )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine-2-carboxylic acid

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) and lithium hydroxide monohydrate (560 mg, 22.91 mmol) were dissolved in tetrahydrofuran/water (13 mL, (v/v) = 5/1) and stirred at room temperature for 4 h. Cool in an ice bath for 10 min, add dilute hydrochloric acid (4 mol/L) dropwise to adjust pH = 4, add saturated saline (50 mL), extract with ethyl acetate (100 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 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: Synthesis of compound ( 1R , 4S )-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate

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). Methanesulfonyl chloride (1.3 mL, 17.00 mmol) was slowly added dropwise at 0 °C and stirred at room temperature for 2 h. Dichloromethane (100 mL) was added for dilution, and the organic phase was washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow liquid. Purification was performed by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 5/1) to obtain 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: Synthesis of compound ( 2S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2-carboxylic acid

Dissolve 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) in dichloromethane (85 mL), add a dichloromethane solution (20 mL) of trifluoroacetic acid (5.6 mL, 34.00 mmol) dropwise, and stir 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. It 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: Synthesis of compound ( 2S , 4R )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid

Compound ( 2S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2-carboxylic acid (640 mg, 1.50 mmol) was dissolved in ethanol (31 mL), and Pd/C (520 mg, 10%Pd, 55% _H2O ) and triethylamine (319 uL, 2.29 mmol) were added. The air was excluded and the mixture was stirred at room temperature under hydrogen atmosphere for 17 h. The reaction solution was filtered through diatomaceous earth to remove the solid, and the filtrate was depressurized to remove the solvent 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: Synthesis of compound ( 2S , 4R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

Compound ( 2S , 4R )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic 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). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (622 mg, 3.23 mmol) and N -methylmorpholine (480 uL, 4.30 mmol) were added in an ice bath and stirred at room temperature for 12 h. Dilute with water (50 mL), extract the reaction solution with ethyl acetate (50 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate the residue by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 5/1) to obtain a colorless transparent liquid (764 mg, yield 80.39%).

MS-ESI: m/z 386.05 [M- t -Bu+2H] ⁺ .

Step 7: Synthesis of compound ( 2S , 4R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

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-cooling and stirred at room temperature for 3.5 h. Saturated ammonium chloride (20 mL) was added to quench the lithium borohydride, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined and 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 (518 mg, 1.25 mmol, yield 72.77%).

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

Compound ( 2S , 4R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (212-2) (510 mg, 1.23 mmol) and N,N-diisopropylethylamine (612 uL, 3.70 mmol) were dissolved in dichloromethane (5 mL). Methanesulfonyl chloride (114 uL, 1.85 mmol) was slowly added dropwise at 0 °C and stirred at room temperature for 2 h. 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 yellow liquid (606 mg, yield 99.97%).

MS-ESI: m/z 436.10 [M- t -Bu+2H] ⁺ .

Step 9: Synthesis of compound ( 2S , 4R )-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate

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 anhydrous N , N -dimethylformamide (6 mL) and stirred at 80 °C for 2 h. The N , N -dimethylformamide was removed under reduced pressure, and ethyl acetate (50 mL) was added to the residue for dilution. The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 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: Synthesis of compound ( 2S , 4R )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride

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

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: Synthesis of compound 1-( 2S , 4R )-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

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

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: Synthesis of compound 1-( 2S , 4R )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride

Palladium on carbon (18 mg, 10% Pd, 55% H 2 O) was added to the compound 1-(2 S ,4 S )-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (180 mg, 0.47 mmol) in methanol (5 mL), 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, and the reaction solution was filtered through diatomaceous earth to remove the palladium on carbon. The solvent was removed by reducing the 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: Synthesis of compound N ² -(((2 S ,4 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)- N ⁵ -methyl- N ⁵ -ethylpyridine-2,5-dicarboxamide

Compound 1-( 2S , 4R )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride (150 mg, 0.38 mmol), 5-(ethyl(methyl)aminoformyl)picolinic acid (88 mg, 0.42 mmol) and 1-hydroxybenzotriazole (79 mg, 0.57 mmol) were dissolved in N , N -dimethylformamide (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (111 mg, 0.58 mmol) and N -methylmorpholine (86 uL, 0.77 mmol) were added in an ice bath and 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) to obtain a white solid (118 mg, yield 56.45%).

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)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dicarboxamide

Step 1: Synthesis of compound ( 2S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine - 2-carboxylic acid

Compound ( 2S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -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), and anhydrous tetrahydrofuran (2 mL) were dissolved in anhydrous ethanol (18 mL), the air was excluded, and the mixture was stirred at room temperature under a hydrogen atmosphere (0.8 MPa) for 4 days. The solvent was concentrated, ethyl acetate (50 mL) was added to the residue to dilute it, pH = 1 was adjusted with dilute hydrochloric acid (1 mol/L), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried with 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%). Synthesis 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: Synthesis of compound ( 2S )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

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). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (548 mg, 2.84 mmol) and N -methylmorpholine (430 uL, 3.80 mmol) were added in an ice bath and stirred at room temperature for 13 h. Dilute with water (50 mL), extract the reaction solution with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate the residue by silica gel column chromatography (eluent: PE/AcOEt (v/v) = 5/1) to obtain a colorless transparent liquid (571 mg, yield 68.24 %).

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: Synthesis of compound ( 2S , 4S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

Compound ( 2S )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (540 mg, 1.22 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), lithium borohydride (48 mg, 1.98 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. Saturated ammonium chloride (20 mL) was added to quench the lithium borohydride, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and 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: Synthesis of compound ( 2S , 4S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

Compound ( 2S , 4S )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (260 mg, 0.63 mmol) and N , N -diisopropylethylamine (324 uL, 1.96 mmol) were dissolved in dichloromethane (5 mL), and methanesulfonyl chloride (76 uL, 0.98 mmol) was slowly added dropwise at 0 ℃, and stirred at room temperature for 2 h. 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 yellow liquid (309 mg, yield 99.99%).

MS-ESI: m/z 436.10 [M- t -Bu+2H] ⁺ .

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

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 anhydrous 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, and ethyl acetate (50 mL) was added to the residue for dilution. The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure. 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: Synthesis of compound ( 2S , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (11213-5)

Dissolve the compound ( 2S , 4S )-tert-butyl 2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate (270 mg, 0.62 mmol) in DCM (6 mL), inject a solution of hydrogen chloride in dioxane (1.5 mL, 6.00 mmol, 4 mol/L), and stir at room temperature for 2 h. Remove the solvent under reduced pressure to obtain a yellow solid (270 mg, yield 99.66%).

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: Synthesis of compound 1-( 2S , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (213-6)

Dissolve the compound ( 2S , 4S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (220 mg, 0.59 mmol) and triethylamine (248 uL, 1.76 mmol) in dichloromethane (6 mL). Slowly add acetyl chloride (62 uL, 0.87 mmol) at 0 °C and stir at room temperature 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 (eluent: PE/AcOEt (v/v) = 1/1) to obtain a yellow liquid (171 mg, yield 76.58%).

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: Synthesis of compound 1-( 2S , 4S )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride

Palladium on carbon (34 mg, 10% Pd, 55% H 2 O) was added to the compound 1-(2 S ,4 S )-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (165 mg, 0.43 mmol) in methanol (5 mL), 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, and the reaction solution was filtered through diatomaceous earth to remove palladium on 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: Synthesis of compound N ² -(((2 S ,4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)- N ⁵ -methyl ^{N 5} -ethylpyridine-2,5-dicarboxamide

Compound 1-(2S , 4S )-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride (163 mg, 0.42 mmol), 5-(ethyl(methyl)aminoformyl)picolinic acid (94 mg, 0.45 mmol) and 1-hydroxybenzotriazole (85 mg, 0.62 mmol) were dissolved in N , N -dimethylformamide (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118 mg, 0.62 mmol) and N -methylporoline (92 uL, 0.82 mmol) were added in an ice bath and 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) to obtain a white solid (110 mg, yield 48.43%).

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] ⁺ .

Example 43: N ² -(((2 R ,4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)pyridine-2,5-dicarboxamide

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

Compound 1-((2 R ,4 S )-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-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 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT) (630 mg, 4.63 mmol) were added. The mixture was cooled at 0°C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.75 g, 9.13 mmol) and N , N -diisopropylethylamine (DIPEA) were added. (2.09 g, 16.20 mmol), transferred to room temperature and stirred for 2 h, water (20 mL) was added 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 obtain a white foam (1.01 g, yield 65.90 %).

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: Synthesis of 6-((((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-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 lithium hydroxide monohydrate (440 mg, 10.49 mmol) and aqueous solution (10 mL) were added. The mixture was stirred at 50 °C for 2 h, then cooled to 0 °C, 1 mol/L hydrochloric acid was added dropwise to acidify (pH=3), and extracted with ethyl acetate (20 mL×2). The organic phase was dried over anhydrous sodium sulfate for 30 min and concentrated under reduced pressure. A white solid (943 mg, 95.80 % yield) was obtained.

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: Synthesis of N ² -((((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)pyridine-2, 5-dicarboxamide

Compound 6-((((2R, 4S)-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) were dissolved in dry tetrahydrofuran (20 mL) solvent and cooled at 0 °C. 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, reduced pressure and concentrated the reaction solution, added water (20 mL), extracted with ethyl acetate (20 mL×2), combined the organic phases, dried over anhydrous sodium sulfate for 30 min, reduced pressure and concentrated, purified by silica gel column chromatography (eluent: methanol/dichloromethane (v/v) = 1/10), and obtained a white solid (300 mg, yield 90.45 %).

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] ⁺ .

Example 44: N ² -(((2 R ,4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)- N ⁵ -methylpyridine-2,5-dicarboxamide

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), ammonium hydrochloride (270 mg, 4.00 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (123 mg, 0.90 mmol) were dissolved in dry tetrahydrofuran (20 mL) solvent, transferred to 0 °C, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (360 mg, 1.88 mmol), N , N -diisopropylethylamine (DIPEA) were added. (769 mg, 5.59 mmol), transferred to room temperature and stirred for 6 h. Stop the reaction, reduce pressure and concentrate the reaction solution, dilute with water (20 mL), extract with ethyl acetate (20 mL×2), combine the organic phases, dry with anhydrous sodium sulfate for 30 min, reduce pressure and concentrate, purify by silica gel column chromatography (eluent: methanol/dichloromethane (v/v= 1/10), and obtain a white solid product (300 mg, yield 94.15%).

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-(cyclopropylmethoxyl-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethylpyridine-2,5-dicarboxamide

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) were dissolved in dry DMF (20 mL) solvent, and the mixture was transferred to 0 °C. 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. Stop the reaction, reduce pressure and concentrate the reaction solution, dilute with water (20 mL), extract with ethyl acetate (20 mL), combine the organic phases, dry with anhydrous sodium sulfate for 30 min, reduce pressure and concentrate, purify by silica gel column chromatography (eluent: methanol/dichloromethane (v/v) = 1/10), and obtain a white solid product (300 mg, yield 90.45%).

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] ⁺ .

Example 46: N ² -(((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dicarboxamide

Compound N ² -((((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N ⁵ -ethyl-N ⁵ -methylpyridine-2, 5 -dimethylamide (125 mg, 0.23 mmol, Example 39) was dissolved in acetonitrile (3 mL) solvent, and concentrated hydrochloric acid (1.2 g, 32.91 mmol) was added dropwise, and then stirred at 80 °C for 6 h. The mixture was cooled to room temperature, water was added to dissolve the precipitate, and the mixture was extracted with ethyl acetate (300 mL×3). The organic phase was dried over anhydrous sodium sulfate for 30 min. 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)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dimethylamide

Step 1: 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 -methylpyridine-2,5-dicarboxamide (1245-1)

Compound N ² -((((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dicarboxamide (400 mg, 0.73 mmol) was dissolved in acetonitrile (6 mL), and concentrated hydrochloric acid (3 mL, 36.5%) was added. The mixture was heated at 80 ℃ for 12 h. After the reaction was completed, 30 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 3). Anhydrous sodium sulfate was added to the organic phase for drying, and the solvent was removed by distillation under reduced pressure. The product was separated and purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to give 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: Synthesis of N ² -((((2 R , 4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dicarboxamide (DLR011245)

Compound N ² -((((2 R , 4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethyl- N ⁵ -methylpyridine-2,5-dicarboxamide (180 mg, 0.37 mmol) and 2-iodopropane (94 mg, 0.55 mmol) were dissolved in DMF (10 mL), and potassium carbonate (150 mg, 1.11 mmol) was added. The mixture was heated at 80 °C for 4 h. After the reaction was completed, 50 mL of water was added and the mixture was extracted with ethyl acetate (30 mL×3), anhydrous sodium sulfate was added to the organic phase for drying, the solvent was removed by distillation under reduced pressure, and the product was separated and purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to obtain 130 mg of a 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] ⁺ .

Example 48: N ² -(((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethylpyridine-2,5-dicarboxamide

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

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

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: Synthesis of N ² -(((2 R , 4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-(isopropoxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethylpyridine-2, 5 -dimethylamide

Compound N ² -(((2 R , 4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethylpyridine-2, 5-dicarboxamide (108 mg, 0.23 mmol) was dissolved in N , N -dimethylformamide solvent (10 mL), and anhydrous potassium carbonate (95 mg, 0.69 mmol) and 2-iodopropane (59 mg, 0.35 mmol) were added, and the mixture was stirred at 80 ℃ 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 them over anhydrous sodium sulfate for 30 min, and purify them by silica gel column chromatography (eluent: methanol/dichloromethane (v/v) = 25%) to obtain a light brown solid (100 mg, yield 80.69%).

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)pyrrolidin-2-yl)methyl)- N ⁵ -methylpyridine-2,5-dicarboxamide

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

Dissolve the compound N ² -(((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N ⁵ -methylpyridine-2, 5-dicarboxamide (450 mg, 0.87 mmol, Example 44) in acetonitrile solvent (10 mL), add concentrated hydrochloric acid (1 mL) dropwise, stir 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 over 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: Synthesis of N ² -(((2 R , 4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropyloxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -methylpyridine-2, 5-dimethylamide

Dissolve the compound N ² -(((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -methylpyridine-2,5-dimethylamide (140 mg, 0.3 mmol) in 10 mL of N , N -dimethylamide solvent, add anhydrous potassium carbonate (120 mg, 0.9 mmol) and 2-iodopropane (76 mg, 0.45 mmol), stir at 80 ℃ for 4 h, stop the reaction, cool to room temperature, add water (50 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, and dry the organic phases over anhydrous sodium sulfate for 30 min, and was purified by 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] ⁺ .

Example 50: N ² -(((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)pyridine-2,5-dicarboxamide

Compound 1-((2 R , 4 S )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone hydrochloride (100 mg, 0.26 mmol, Example 58, step 11), 5-aminoformylpicolinic acid (45 mg, 0.26 mmol) and 1-hydroxy-7-azabenzotriazole (71 mg, 0.52 mmol) were dissolved in N , N -dimethylformamide (10 mL) solution. Under ice bath conditions, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and N , N -diisopropylethylamine (100 mg, 0.78 mmol), react at room temperature for 10 h. When the raw material reacted completely, 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 separated and purified by reduced pressure concentrated silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) to obtain a white solid (78 mg, yield 61%).

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] ⁺ .

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

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

Compound ( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (380 mg, 0.92 mmol, Example 39, step 4) was dissolved in N , N -dimethylformamide (10 mL) solvent, and 5-(ethyl(methyl)aminoformyl)picolinic acid (211 mg, 1.01 mmol) and 1-hydroxybenzotriazole (HOBT) (249 mg, 1.84 mmol) were added. The mixture was cooled at 0 °C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (353 g, 1.84 mmol) and N -methylmorpholine (NMM) were added. (279 mg, 2.76 mmol), transferred to room temperature and stirred for 16 h, water (20 mL) was added to stop the reaction, extracted 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 obtain a colorless oily product (287 mg, yield 51.68%).

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

The compound (( 2R , 4S )-1-(tert-butyloxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate (290 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL) solvent, and a solution of hydrochloric acid in 1,4-dioxane (2.4 mL, 9.60 mmol) was added. The mixture was stirred at room temperature for 2 h, the reaction was stopped, the mixture was concentrated under reduced pressure once, and dichloromethane (20 mL) was added to dissolve the mixture, and the mixture was 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: Synthesis of (( 2R , 4S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate

Dissolve the compound (( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate hydrochloride (241 mg, 0.48 mmol) in dichloromethane (10 mL) solvent, cool at 0 °C, add N , N -diisopropylethylamine (DIPEA) (248 mg, 1.92 mmol) and acetyl chloride (75 mg, 0.96 mmol), transfer to room temperature and stir for 1 h. The reaction solution is washed with water (20 mL× 2) The residue was washed and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to obtain a light yellow solid product (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] ⁺ .

Example 52: ((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethylformamido)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), and concentrated sulfuric acid (0.16 mL, 2.99 mmol) was slowly added. The mixture was refluxed at 70 °C for 1 h, cooled to room temperature, and ice water (20 mL) was added. The mixture was stirred until a white solid was completely precipitated, and then filtered. The solid was dissolved in tetrahydrofuran (20 mL), and the organic phase was 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-(ethylaminoformyl)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) were dissolved in dry N , N -dimethylformamide (30 mL) solvent, cooled at 0 °C, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (5.29 g, 27.60 mmol) and N , N -diisopropylethylamine (DIPEA) (5.35 g, 41.40 mmol) were added. The mixture was stirred at room temperature for 27 min. h, stop the reaction, reduce the pressure and concentrate the solvent, add water (30 mL) to dissolve the concentrate, extract with dichloromethane (30 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, reduce the pressure and concentrate, purify by silica gel column chromatography (DCM/MeOH (v/v) = 20/1), and obtain a white solid (1.78 g, yield 61.95 %).

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-(ethylaminoformyl)picolinate

Compound 5-(ethylaminoformyl)picolinic acid methyl ester (1.77 g, 8.50 mmol) was dissolved in tetrahydrofuran (16 mL) solvent, and lithium hydroxide monohydrate (0.37 g, 8.93 mmol) and aqueous solution (2.5 mL) were added. The mixture was stirred at 50 °C for 23 h, cooled to room temperature and filtered. 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

Compound ( 2R , 2S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl 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, and the reaction was stirred at room temperature for 2 h. The reaction was stopped, and the mixture was concentrated under reduced pressure once, and then dichloromethane (20 mL) was added to dissolve it, and the mixture was 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: Synthesis of methyl (( 2R , 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetate

The 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 N , N -diisopropylethylamine (DIPEA) (2.66 g, 20.6 mmol) and acetyl chloride (0.97 g, 12.36 mmol) were added. The mixture was stirred at room temperature 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 obtain a yellow liquid product (1.15 g, yield 70.24%).

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

The compound (( 2R , 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetate (1.15 g, 2.89 mmol) was dissolved in tetrahydrofuran (20 mL) solvent, and lithium hydroxide monohydrate (0.30 g, 7.23 mmol) and aqueous solution (10 mL) were added. The mixture was stirred at 50 °C for 2 h, then cooled to 0 °C, 1 M hydrochloric acid was added dropwise to acidify (pH = 2), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 40 mL). mL×2), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily product (1.00 g, yield 97.37 %).

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: Synthesis of methyl (( 2R , 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)5-(ethylaminoformyl)picolinate

Lithium 5-(ethylaminoformyl)picolinate (168 mg, 0.84 mmol) and hydrochloric acid in 1,4-dioxane (0.28 mL, 1 mmol) were dissolved in N , N -dimethylformamide (5 mL). After stirring until the solution was clear, 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) and N, N-diisopropylethylamine (DIPEA) (325 mg, 2.52 mmol) were added in sequence under ice bath, the mixture was stirred at room temperature for 9 h, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated brine (20 mL×2), and the organic phases were dried over anhydrous sodium sulfate. The concentrated and stirred sample was purified by 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)pyrrolidin-2-yl)methyl 5-(methylaminoformyl)picolinate

Step 1: Synthesis of methyl 5-(methylaminoformyl)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-azabenzotriazole (HOAT) (3.76 g, 27.60 mmol) were dissolved in dry N , N -dimethylformamide (30 mL) solvent, cooled at 0 °C, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (4.97 g, 25.94 mmol) and N , N -diisopropylethylamine (DIPEA) (5.03 g, 38.91 mmol) were added, and the mixture was stirred at room temperature for 17 minutes. h, stop the reaction, reduce the pressure and concentrate the solvent, add water (30 mL) to dissolve the concentrate, extract with dichloromethane (30 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, reduce the pressure and concentrate, and purify by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to obtain a white solid (1.50 g, yield 59.56 %).

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 5-(methylaminoformyl) lithium picolinate

Compound 5-(ethylaminoformyl)picolinic acid 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) were added. The mixture was stirred at 50 °C for 23 h, and then the reaction solution was concentrated and dried under vacuum 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: Synthesis of (( 2R , 4S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)5-(methylaminoformyl)picolinate

Lithium 5-(methylaminoformyl)picolinate (248 mg, 1.33 mmol) and a solution of hydrochloric acid in 1,4-dioxane (0.45 mL, 1.78 mmol) were dissolved in N , N -dimethylformamide (6 mL). After stirring until the solution was clear, 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) and N , N -diisopropylethylamine (DIPEA) (517 mg, 4.00 mmol) were added in sequence under ice bath, the mixture was stirred at room temperature for 24 h, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined and washed with saturated brine (20 mL × 2), and the organic phases were dried over anhydrous sodium sulfate. The sample was concentrated and stirred, and then column chromatography (DCM/MeOH (v/v) = 15/1) was performed 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] ⁺ .

Example 54: ((2 R , 4 S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-carbamoylpicolinate

Step 1: Synthesis of 5-aminoformylpicolinic acid methyl ester

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-nitrobenzotriazole (HOAT) (3.76 g, 27.60 mmol) were dissolved in N , N -dimethylformamide (30 mL) solvent, cooled at 0 °C, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (5.29 g, 27.60 mmol) and N , N -diisopropylethylamine (DIPEA) (5.35 g, 41.40 mmol) were added, and the mixture was stirred at room temperature for 27 min. h, stop the reaction, reduce the pressure and concentrate the solvent, add water (30 mL) to dissolve the concentrate, extract with dichloromethane (30 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, reduce the pressure and concentrate, and purify by silica gel column chromatography (DCM/MeOH (v/v) = 20/1) to obtain a colorless liquid (1.26 g, yield 50.68 %).

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-aminoformylpicolinate

Compound 5-(ethyl(methyl)aminoformyl)picolinic acid methyl ester (249-1) (1.24 g, 6.88 mmol) was dissolved in tetrahydrofuran (20 mL) solvent, and lithium hydroxide monohydrate (0.32 g, 7.57 mmol) and aqueous solution (10 mL) were added. The mixture was stirred at 50 °C for 3.5 h, and then the solvent was removed by concentration under reduced pressure. The mixture was dried under vacuum at 50 °C for 8 h to obtain a white solid product (1.18 g, yield 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: Synthesis of (( 2R , 4S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-aminoformylpicolinic acid

Lithium 5-aminoformylpicolinate (248 mg, 1.44 mmol) and a solution of hydrochloric acid in 1,4-dioxane (0.48 mL, 1.92 mmol) were dissolved in DMF (5 mL). After stirring until the mixture was clear, 1-(( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethyl-1-one (342 mg, 0.96 mmol, Example 52, Step 6), 1-hydroxy-7-azabenzotriazole (HOAT) (196 mg, 1.44 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (460 mg, 2.40 mmol) and N , N -diisopropylethylamine (DIPEA) (558 mg, 4.32 mmol) were added in sequence under ice bath, the mixture was stirred at room temperature for 24 h, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated brine (20 mL×2), and the organic phases were dried over anhydrous sodium sulfate. The sample was concentrated and stirred, and then chromatographed on a silica gel column (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

Add 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (20.00 g, 58.80 mmol) and acetonitrile (80 mL) to a 250 mL two-necked round-bottom flask to dissolve it, then slowly add concentrated hydrochloric acid (40 mL) dropwise, react in an oil bath at 80 °C for 12 h under nitrogen protection, and stop the reaction. 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 obtain a light 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

Add 2-(difluoromethoxy)-5-iodophenol (11.4 g, 39.86 mmol) and N , N -dimethylformamide (55 mL) to a 250 mL single-necked flask to dissolve it, then add potassium carbonate (16.53 g, 119.58 mmol) and 2-iodopropane (10.16 g, 59.79 mmol), stir the reaction at 80 °C for 2 h, and 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 with anhydrous sodium sulfate for 30 min, and concentrate under reduced pressure to obtain a light yellow oily product (12.51 g, yield 95.66%)

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: Synthesis of compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

Compound 1-(difluoromethoxy)-4-iodo-2-isopropoxybenzene (13.7 g, 41.76 mmol), pinacol diborate (11.13 g, 43.85 mmol), potassium acetate (6.15 g, 62.64 mmol), 2-dicyclohexylphosphino-2'-methylbiphenyl (Mephos) (1.52 g, 4.18 mmol) and potassium acetate (470 mg, 2.09 mmol) were dissolved in dry N , N -dimethylformamide (82 mL) solution and reacted at 80 °C for 2 h under nitrogen protection. After the reaction solution was cooled, water (700 mL) was added and mixed, and extracted with ethyl acetate (40 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/PE (v/v) = 1/10) to obtain a brown liquid product (11.4 g, yield 83.19 %).

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

Compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (10.58 g, 32.24 mmol), ( R )-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy) -1H -pyrrole-1, 2-( 2H , 5H )-dicarboxylate (11.0 g, 29.31 mmol, intermediate M2), palladium acetate (160 mg, 0.73 mmol), 2-dicyclohexylphosphino-2'-methylbiphenyl (Mephos) (530 mg, 1.47 mmol), N -methylmorpholine (NMM) (6.52 g, 64.48 mmol) were dissolved in toluene (55 mL) and water (27 mL) solution, under nitrogen protection, react in an 80 ℃ oil bath for 40 min. After the reaction solution was cooled, water (200 mL × 2) was added to wash the organic phase, which 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 a brown liquid (12.4 g, yield 98.98%).

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

The compound ( R )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl) -1H -pyrrole-1,2( 2H , 5H )-dicarboxylate (4.60 g, 10.5 mmol) was dissolved in methanol solution (70 mL), and 10% Pd/C reducing agent (140 mg) was added. After replacing with hydrogen three times, the reaction was stirred at room temperature under hydrogen protection for 3 h. The reaction solution was filtered through diatomaceous earth, 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, yield 99.50%).

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

Dissolve the compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1, 2-dicarboxylate (4.40 g, 10.25 mmol) in dry tetrahydrofuran (22 mL) solution, cool at -5 ℃, add 2 mol/L lithium borohydride tetrahydrofuran solution (5.13 mL), and after the addition of the raw materials, transfer to room temperature and react for 4 h. Saturated aqueous sodium chloride solution (30 mL) was added, and the mixture was 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 obtain a colorless liquid (4.10 g, yield 99.64%).

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 ((2 R ,4 S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methanol hydrochloride

Dissolve the compound (2 R ,4 S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.10 g, 10.21 mmol) in dichloromethane (20 mL) solution, add 4.02 mol/L HCl in 1,4-dioxane (15.2 mL), stir at room temperature for 3 h, and concentrate under reduced pressure to obtain a light brown liquid (3.40 g, yield 98.57%).

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: Synthesis of compound ((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl acetate

The compound ((2 R ,4 S )-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, N , N -diisopropylethylamine (6.50 g, 50.3 mmol) and acetyl chloride (2.21 g, 28.17 mmol) were added, and the reaction was stopped after 1 h at room temperature. Water (50 mL) was added to wash the organic phase, and 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 obtain a brown liquid (3.80 g, yield 98.01%).

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: Synthesis of compound 1-((2 R ,4 S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone

The compound ((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl acetate (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), reacted at 50 ℃ 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: Synthesis of ((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate

Compound 5-(ethyl(methyl)aminoformyl)pyridinecarboxylic acid lithium salt (280 mg, 1.32 mmol) was added to a dry N,N-dimethylformamide (6 ml) solution, 4.02 mol/L HCl in 1,4-dioxane (0.44 mL), 1-((2 R ,4 S )-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-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) were added. mmol), cooled in an ice bath, added N , N -diisopropylethylamine (DIPEA) (510 mg, 3.96 mmol), transferred to room temperature and stirred for 13 h. Add water (50 ml) to quench the reaction, extract the organic phase with ethyl acetate (15 ml × 2), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to obtain a light yellow solid (165 mg, yield 31.87%).

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-(methylaminoformyl)picolinate

Compound 5-(methylaminoformyl)picolinic acid lithium salt (250 mg, 1.32 mmol) was added to a dry N , N -dimethylformamide (6 ml) solution, 4.02 mol/L HCl in 1,4-dioxane (0.44 mL), 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) were added. mmol), cooled in an ice bath, added N , N -diisopropylethylamine (DIPEA) (510 mg, 3.96 mmol), transferred to room temperature and stirred for 14 h. Add water (50 mL) to quench the reaction, extract the organic phase with ethyl acetate (15 mL × 2), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (DCM/MeOH (v/v) = 25/1) to obtain a light yellow solid (157 mg, yield 34.98%).

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-aminoformylpicolinate

Compound 5-aminoformylpyridinecarboxylic acid lithium salt (220 mg, 1.30 mmol) was added to a dry N , N -dimethylformamide (6 mL) solution, 4.02 mol/L HCl in 1,4-dioxane (0.43 mL), 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), cooled in an ice bath, added N , N -diisopropylethylamine (DIPEA) (510 mg, 3.92 mmol), transferred to room temperature and stirred for 14 h. Add water (50 mL) to quench the reaction, extract the organic phase with ethyl acetate (15 mL ethyl acetate 10 mmol), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (DCM/MeOH (v/v) = 15/1) to obtain a light yellow solid (163 mg, yield 36.50%).

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)pyridinamide

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

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

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 g, 142.7 mmol) was added, and the mixture was heated at 80 °C for 4 h. After the reaction, 150 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was dried by adding anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The product was separated and purified by silica gel column chromatography (PE/ EtOAc (v/v) = 100/1) to obtain a light yellow liquid (14.4 g, yield 92%).

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: Synthesis of compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Compound 1-(difluoromethoxy)-4-iodo-2-isopropoxybenzene (14 g, 42.7 mmol), pinacol diborate (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 potassium acetate (0.48 g, 2.13 mmol) were mixed in DMF (70 mL) solution and reacted at 80 °C for 6 h under nitrogen protection. The reaction was stopped and cooled to room temperature. Water (250 mL) was added to the reaction solution, and the mixture was extracted with petroleum ether (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated by silica gel column chromatography (eluent: PE/ EtOAc (v/v) = 100/1) to obtain a brown-yellow liquid (12.6 g, yield 90%).

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

Compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (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) and reacted at 80 °C under nitrogen for 1 h. h, stop the reaction, and cool to room temperature. Add water (100 mL) to the reaction solution, extract with ethyl acetate (30 mL × 3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrate by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 5/1) to obtain a yellow liquid (12.6 g, yield 90%).

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: Synthesis of compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1,2-dicarboxylate

The compound ( R )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl) -1H -pyrrole-1,2( 2H , 5H )-dicarboxylate (12.5 g, 29.2 mmol) and 10% palladium/carbon (2.84 g, 2.92 mmol) were dissolved in 190 mL of methanol and reacted at room temperature for 6 h under a hydrogen atmosphere. The reaction was stopped when the raw materials reacted completely. The palladium carbon was filtered through diatomaceous earth, and the organic phase was concentrated by decompression 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: Synthesis of compound (2 R , 4 S ) 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1,2-dicarboxylate (10 g, 13.3 mmol) was dissolved in 50 mL of anhydrous tetrahydrofuran solution. Under ice bath conditions, lithium borohydride solution (11.6 mL, 2 mol/L) was added and reacted at room temperature for 3 h. The reaction was stopped when the raw material reacted completely. Ice-water mixture was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: PE/EtOAc ( v/v ) = 5/1) to obtain a colorless liquid (8.8 g, yield 94%).

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: Synthesis of compound (2 R , 4 S ) 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-((((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Compound (2 R , 4 S ) tert-butyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (7.0 g, 14.7 mmol) and N , N -diisopropylethylamine (3.6 g, 27.9 mmol) were dissolved in 50 mL of dichloromethane solution. Methylsulfonyl chloride (MsCl) (2.6 g, 22.7 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 2 h. The reaction of the raw materials was completed and the reaction was stopped. Ice-water mixture was added to quench the reaction, and the mixture was 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: Synthesis of compound (2 R , 4 S ) 2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Compound (2 R , 4 S ) 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-((((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (8.0 g, 16.7 mmol) and sodium azide (1.6 g, 25.0 mmol) were dissolved in 40 mL N , N -dimethylformamide solution and reacted at 80 ℃ for 6 h. The reaction was stopped after the reaction of the raw materials was complete. 100 mL of water was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: PE/EA ( v/v ) = 10/1) to obtain a colorless oil (5.0 g, Yield 71%).

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 (2 R , 4 S )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine hydrochloride

Dissolve 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) in 10 mL of dichloromethane solution, then add 1,4-dioxane hydrochloride solution (14 mL, 4.01 mol/L), react at room temperature for 1.5 h, and stop the reaction when the raw material reacts completely. Distill under reduced pressure to remove the solvent, and concentrate to obtain 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: Synthesis of compound 1-((2 R , 4 S )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone

Dissolve the compound (2 R , 4 S )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine hydrochloride (4.4 g, 12.1 mmol) in 20 mL of dichloromethane solution. Add N , N -diisopropylethylamine (6.3 g, 48.5 mmol) and acetyl chloride (1.9 g, 24.3 mmol) in an ice bath. React at room temperature for 1 h. Stop the reaction when the raw materials react completely. Saturated brine was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: PE/EA (v/v) = 1/1) to obtain a yellow liquid (4.2 g, yield 94%).

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: Synthesis of compound 1-((2 R , 4 S )-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone hydrochloride

The compound 1-((2 R , 4 S )-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (4.1 g, 11.1 mmol) was dissolved in 40 mL of methanol, and palladium carbon (0.82 g, 2.23 mmol) and hydrochloric acid (3.6 mL, 4.01 mol/L) were added. The reaction was carried out at room temperature under a 1 MPa hydrogen atmosphere for 2.5 h. The reaction of the raw materials was completed and the reaction was stopped. The reaction solution was filtered through diatomaceous earth, the organic phase was concentrated by decompression, 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: Synthesis of N -((((2 R , 4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)pyridinamide

Compound 1-((2 R , 4 S )-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). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (200 mg, 1.1 mmol) and N , N -diisopropylethylamine (210 mg, 1.6 mmol) were added in turn under ice bath conditions. The reaction was carried out at room temperature for 10 min. h, the raw material reacted completely, the reaction was stopped, saturated brine (50 mL) was added, extracted with dichloromethane (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, separated and purified by reduced pressure concentrated 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-((2 R , 4 S )-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) were dissolved in dichloromethane (10 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150 mg, 0.8 mmol) and N , N -diisopropylethylamine (160 mg, 1.2 mmol) were added in sequence under ice bath conditions. The reaction was carried out at room temperature for 10 minutes. h, the raw material reacted completely, the reaction was stopped, saturated brine (50 mL) was added, extracted with dichloromethane (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, separated and purified by reduced pressure concentrated silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) 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-(ethylaminoformyl)picolinate

Step 1: Synthesis of 2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Compound 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene (10.0 g, 26.59 mmol), pinacol diboron (7.43 g, 29.25 mmol), potassium acetate (5.22 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) were dissolved in N , N -dimethylformamide (100 mL) solution and reacted at 80 ℃ for 8 h under nitrogen protection. The reaction solution was diluted with 100 mL of water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with water (100 mL × 3), dried with 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 yellow solid product (8.90 g, yield 88.97%).

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

Compound 2-(3-(Benzyloxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (739 mg, 1.96 mmol), ( R )-1-tert-butyl 2-methyl 4-((((trifluoromethyl)sulfonyl)methoxy) -1H -pyrrole-1, 2 ( 2H , 5H )-dicarboxylate (700 mg, 1.87 mmol, intermediate M2), sodium acetate (21 mg, 0.09 mmol), 2-dicyclohexylphosphino-2'-methylbiphenyl (Mephos) (68 mg, 0.19 mmol), N -methylmorpholine (NMM) (416 mg, 4.11 mmol) were dissolved in toluene (10 mL) and water (5 mL). The reaction mixture was stirred in an oil bath at 80 °C under nitrogen protection 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 over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc=5:1) to obtain a yellow oily product (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: Synthesis of 1-(tert-butyl) 2-methyl(2 R ,4 S )-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine 1,2-dicarboxylate

The 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, and Pd/C (201 mg, 0.83 mmol) was added. After hydrogen was replaced three times, the reaction was stirred at room temperature under hydrogen protection for 2 h, the reaction was stopped, filtered with diatomaceous earth, 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: Synthesis of 1-(tert-butyl) 2-methyl (2 R , 4 S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)pyrrolidine-1,2-dicarboxylate

The compound 1-(tert-butyl) 2-methyl (2 R , 4 S )-4-(4-(difluoromethoxy)-3-hydroxyphenyl) pyrrolidine 1,2-dicarboxylate (617 mg, 1.59 mmol), potassium carbonate (659 mg, 4.77 mmol) and isobutane bromide (327 mg, 2.39 mmol) were dissolved in N , N -dimethylformamide (10 mL) solvent and stirred at 80 ℃ for 3.5 h. Stop the reaction and cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (20 mL × 2), wash the combined organic phases with water (20 mL × 2), dry the organic phase with anhydrous sodium sulfate, and purify the concentrated sample by column chromatography (PE/ EtOAc (v/v) = 3/1) to obtain a colorless liquid product (600 mg, yield 85.09 %).

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: Synthesis of tert-butyl (2 R ,4 S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

The compound 1-(tert-butyl) 2-methyl (2 R , 4 S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl) pyrrolidine-1,2-dicarboxylate (561 mg, 1.26 mmol) was dissolved in tetrahydrofuran (10 mL) solvent, and lithium borohydride tetrahydrofuran solution (1.26 mL, 2 M) was added under ice bath. The reaction was stirred at room temperature for 1.5 h. The reaction solution was slowly added to ice water (20 mL), and 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 and washed with saturated brine (25 mL × 2) Washing, drying the organic phase with anhydrous sodium sulfate, and purifying the concentrated sample 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 ((2 R ,4 S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)pyrrolidin-2-yl)methanol hydrochloride

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 a solution of hydrochloric acid in 1,4-dioxane (2.9 mL, 4 M) was added. The mixture was stirred at room temperature for 1.5 h, the reaction was stopped, the mixture was concentrated under reduced pressure once, and dichloromethane (20 mL) was added to dissolve the mixture. The mixture was 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-isobutoxyphenyl)pyrrolidin-2-yl)methyl acetate

The compound ((2 R , 4 S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)pyrrolidin-2-yl)methanol hydrochloride (364 mg, 1.03 mmol) was dissolved in dichloromethane (10 mL) solvent and cooled at 0 ℃. N , N -diisopropylethylamine (DIPEA) (666 mg, 5.15 mmol) and acetyl chloride (243 mg, 3.09 mmol) were added and stirred at room temperature 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, yield 75.84%).

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

The compound ((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)pyrrolidin-2-yl)methyl acetate (312 mg, 0.78 mmol) was dissolved in tetrahydrofuran (6 mL) solvent, and lithium hydroxide monohydrate (82 mg, 1.95 mmol) and water (3 mL) were added. The mixture was stirred at 50 °C for 2 h, then cooled to 0 °C, 1 M hydrochloric acid was added dropwise to acidify (pH = 2), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A yellow oily product (280 mg, 100% yield) was obtained.

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: Synthesis of ((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)pyrrolidin-2-yl)methyl 5-(ethylaminoformyl)picolinate

Lithium 5-(ethylaminoformyl)picolinate (147 mg, 0.73 mmol) and hydrochloric acid in 1,4-dioxane (0.24 mL, 4 M) were dissolved in N , N -dimethylformamide (5 mL) solvent and stirred until clear. 1-(( 2R , 4S )-4-(4-(difluoromethoxy)-3-isobutoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one (175 mg, 0.49 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT) (100 mg, 0.73 mmol) were added. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added in sequence under ice-cooling. (235 mg, 1.40 mmol), N , N -diisopropylethylamine (DIPEA) (285 mg, 2.21 mmol), 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, washed with saturated brine (20 mL × 2), and the organic phase was dried over anhydrous sodium sulfate. The concentrated and stirred sample was purified by 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-(ethylaminoformyl)pyridinylcarboxamido)methyl)pyrrolidin-3-yl)-2-(difluoromethoxy)phenylcyclopropylcarboxylate

Compound N ² -((((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethylpyridine-2,5-dicarboxamide (200 mg, 0.42 mmol, Example 48, step 1) was dissolved in N , N -dimethylformamide (10 mL) solvent and stirred until clear. Cyclopropylcarboxylic acid (54 mg, 0.63 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT) (114 mg, 0.84 mmol) were added. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (161 mg, 0.84 mmol) were added in an ice bath. mmol), N , N -diisopropylethylamine (DIPEA) (217 mg, 1.68 mmol), transferred to room temperature and stirred for 18 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), dried over anhydrous sodium sulfate, and the concentrated and stirred sample was purified by 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)aminoformyl)pyridine-2-carboxylic acid (71 mg, 0.34 mmol) and 1-hydroxy-7-azabenzotriazole (93 mg, 0.68 mmol) were dissolved in dichloromethane (10 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg, 0.68 mmol) and N , N -diisopropylethylamine (130 mg, 1.02 mmol) were added in turn under ice bath conditions. The mixture was reacted at room temperature for 2 hours. h, the raw material reacted completely, the reaction was stopped, saturated brine (50 mL) was added, extracted with dichloromethane (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, separated and purified by reduced pressure concentrated silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) to obtain a white solid (32 mg, yield 19%).

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] ⁺ .

Example 63: ((2 R , 4 S )-1-acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-2-yl)methyl 5-(ethylaminoformyl)picolinate

Compound 5-(ethylaminoformyl) lithium 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) was added. After reacting for 10 min, 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) and 1-hydroxy-7-azabenzotriazole (93 mg, 0.68 mmol) were added. Under ice bath conditions, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg, 0.68 mmol) was added in sequence. and N , N -diisopropylethylamine (130 mg, 1.02 mmol), react at room temperature for 2 h. The raw materials reacted completely and the reaction was stopped. Saturated brine (50 mL) was added and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and separated and purified by reduced pressure concentrated silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) 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-dicarboxamide

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), ethyl bromide (4.49 g, 41.17 mmol) and potassium carbonate (11.83 g, 82.35 mmol) were mixed in acetone (25 mL), reacted at 60 ℃ for 10 h, and then diluted with dichloromethane (100 mL). The organic phase was washed with saturated brine (100 mL × 3), dried with anhydrous sodium sulfate, and concentrated by vacuum distillation 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

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 evenly and stirred at 50 ℃ 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 filter cake was washed with water (50 mL × 3), and dried at 60 ℃ in vacuum 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), and toluene (50 mL) to a two-necked flask (100 mL) (Bottle A), stir in an ice bath, slowly add diphenyl phosphate azide (14.50 g, 52.70 mmol), and stir at room temperature for 2 h.

Step 2: Add toluene (50 mL) and benzyl alcohol (5.70 g, 52.70 mmol) to another single-mouth bottle (250 mL) (bottle B), heat to 110 °C, drip the material in bottle A into bottle B, and stir for 2 h. Stop heating and stirring, cool to room temperature, wash the reaction solution with water (100 mL), then with 5% sodium hydroxide aqueous solution (100 mL × 3), dry with anhydrous Na ₂ SO ₄ , and concentrate by vacuum distillation to obtain a yellow solid. Add petroleum ether/ethyl acetate (50 mL, v/v=10/1) to the crude product and stir for 3 h, filter 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

Add (3-ethoxy-4-methoxyphenyl)carbamate (11.50 g, 38.16 mmol), 10% palladium on carbon (0.61 g, 0.57 mmol), and methanol (40 mL) to a high pressure autoclave (1 L), exclude air, introduce hydrogen (0.5 MPa), and stir at room temperature for 2 h. The reaction solution is filtered through diatomaceous earth, and the filtrate is 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

Dissolve the compound 3-ethoxy-4-methoxyaniline (6.40 g, 38.28 mmol) in 1,4-dioxane (30 mL) and water (11 mL), cool to 0 °C, add concentrated hydrochloric acid (9.7 mL, 36% aq), stir evenly, cool to -15 °C, add a solution of sodium nitrite (2.91 g, 42.11 mmol) and water (7 mL) dropwise, control the temperature of addition between -15 °C and -5 °C, return the temperature to -5 °C and stir for 30 min, then add a solution of potassium iodide (8.26 g, 49.76 mmol) and water (12 mL), control the temperature of addition between -15 °C and -5 °C, return the temperature to 0 °C and stir for 30 min. ℃ 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. The organic phase was washed with water (100 mL × 3), dried with 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 used to purify the product to obtain 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-trioxazolidine

3-Ethoxy-4-methoxyiodobenzene (1277-6) (6.24 g, 22.44 mmol), pinacol diborate (5.70 g, 22.44 mmol), potassium acetate (3.30 g, 33.66 mmol), palladium acetate (0.25 g, 1.12 mmol), 2-dicyclohexylphospho-2'-methylbiphenyl (Mephos) (0.82 g, 2.24 mmol) were mixed in N , N -dimethylformamide (36 mL) and stirred at 80 °C for 6 h under nitrogen 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 phase with anhydrous sodium sulfate, and concentrate by reduced pressure rotary evaporation to obtain a brown liquid. Purify by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) to obtain 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: Synthesis of compound ( R )-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl) -1H -pyrrole-1,2( 2H , 5H )-dicarboxylate

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 )-dicarboxylate (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 sodium acetate (0.04 g, 0.18 mmol) were mixed in a mixed solution of toluene (10 mL) and water (5 mL) and reacted at 80 °C under nitrogen for 1 h. h, stop the reaction, and cool to room temperature. Add water (50 mL) to the reaction solution, extract with ethyl acetate (30 mL × 3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrate by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 5/1) to obtain a yellow liquid (1.1 g, yield 44%).

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: Synthesis of compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate

Dissolve the compound ( R )-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl) -1H -pyrrole-1,2( 2H , 5H )-dicarboxylate (2.0 g, 5.30 mmol) and palladium carbon (0.45 g, 5.30 mmol) in 35 mL of methanol. In a hydrogen atmosphere, react at room temperature for 12 h. When the raw materials react completely, stop the reaction. Filter the palladium carbon with diatomaceous earth, and concentrate the organic phase by decompression 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 (2 R , 4 S )-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

Dissolve the 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) in 10 mL of dichloromethane solution, then add 1, 4-dioxane hydrochloride solution (3.94 mL, 4.01 mol/L), react at room temperature for 1.5 h, and stop the reaction when the raw material reacts completely. Distill under reduced pressure to remove the solvent, and concentrate to obtain 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/z280.30 [M+H-HCl] ⁺ .

Step 10: Synthesis of compound (2 R , 4 S )-1-acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester

Dissolve the compound ( 2R , 4S )-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0 g, 3.17 mmol) in 20 mL of dichloromethane solution. Add N , N -diisopropylethylamine (1.64 g, 12.68 mmol) and acetyl chloride (0.50 g, 6.34 mmol) in an ice bath. React at room temperature for 1 h. Stop the reaction when the raw materials react completely. Saturated brine was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: DCM/MeOH (v/v) = 20/1) to obtain a yellow liquid (0.95 g, yield 93%).

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: Synthesis of compound 1-((2 R , 4 S )-4-(3-ethoxy-4-methoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone

Compound (2 R , 4 S )-1-acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester (0.50 g, 1.56 mmol) was dissolved in 15 mL tetrahydrofuran solution. Lithium borohydride solution (1.17 mL, 2 mol/L) was added under ice bath conditions. The reaction was carried out at room temperature for 3 h. The reaction of the raw material was completed and the reaction was stopped. Ice-water mixture was added to quench the reaction, and the product was extracted with ethyl acetate (20 mL × 3). The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated by silica gel column (eluent: PE/EtOAc (v/v) = 5/1) to obtain a colorless liquid (0.42 g, yield 92%).

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: Synthesis of compound ((2 R , 4 S )-1-acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-2-yl)methyl methanesulfonate

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. Methylsulfonyl chloride (MsCl) (0.69 g, 5.98 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 2 h. The reaction of the raw materials was completed and the reaction was stopped. Ice-water mixture was added to quench the reaction, and the mixture was 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, yield 91%).

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: Synthesis of compound 1-((2 R , 4 S )-2-(azidomethyl)-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone

Compound ((2 R , 4 S )-1-acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-2-yl)methyl methanesulfonate (1.5 g, 4.04 mmol) and sodium azide (0.39 g, 6.06 mmol) were dissolved in 10 mL N , N -dimethylformamide solution and reacted at 80 ℃ for 3 h. The reaction was stopped after the reaction of the raw materials was complete. 100 mL of water was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: PE/EtOAc ( v/v ) = 10/1) to obtain a colorless oil (0.95 g, yield 74%).

MS-ESI: m/z 319.20 [M+H] ⁺ .

Step 14: Synthesis of compound 1-((2 R , 4 S )-2-(aminomethyl)-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone hydrochloride

The 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, and palladium carbon (94.0 mg, 0.30 mmol) and hydrochloric acid (0.96 mL, 4.01 mol/L) were added. The reaction was carried out at room temperature for 5 h under a 1 Mpa hydrogen atmosphere. The reaction was stopped when the raw material reacted completely. The reaction solution was filtered through diatomaceous earth, the organic phase was concentrated by decompression, 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-dicarboxamide

Compound 1-((2 R , 4 S )-2-(aminomethyl)-4-(3-ethoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone hydrochloride (100 mg, 0.34 mmol) and 5-(ethylaminoformyl)pyridine-2-carboxylic acid lithium salt (68 mg, 0.34 mmol) were dissolved in N , N -dimethylformamide (10 mL), hydrochloric acid (0.17 mL, 0.68 mmol) was added, and after reacting for 30 min, 1-hydroxy-7-azabenzotriazole (93 mg, 0.68 mmol) was added. Under ice bath conditions, 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 4 h. The raw material reacted completely and the reaction was stopped. Saturated brine (50 mL) was added and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and separated and purified by reduced pressure concentrated silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) 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-(ethylaminoformyl)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, and the organic phase was washed with saturated brine (100 mL × 3), then dried with 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 evenly and stirred at 50 ℃ 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, the filter cake was washed with water (50 mL×3), and vacuum dried at 60 ℃ for 12 h to obtain a white solid (10.36 g, yield 100 %).

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

Step 1 : At room temperature, add 3-isopropoxy-4-methoxybenzoic acid (10.30 g, 48.99 mmol), triethylamine (6.44 g, 663.69 mmol), and toluene (50 ml) to a two-necked flask (Bottle A), stir in an ice bath, slowly add diphenylphosphocyanate (DPPA) (14.83 g, 53.89 mmol) dropwise, and stir 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 flask (bottle B), heat to 110 °C, drip the material in bottle A into bottle B, and stir at constant temperature for 2 h. Stop heating and stirring, cool to room temperature, wash the reaction solution with water (100 mL), then with 5% sodium hydroxide aqueous solution (100 mL×3), dry with anhydrous Na ₂ SO ₄ , and concentrate under reduced pressure to obtain a yellow solid. Add petroleum ether/ethyl acetate (50 mL, v/v = 10:1) to the crude product and stir for 3 h, filter 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

Add (3-isopropoxy-4-methoxyphenyl)carbamate (11.34 g, 35.96 mmol), 10% palladium on carbon (0.51 g, 0.54 mmol), and methanol (40 mL) to the autoclave, replace the hydrogen atmosphere (0.5 MPa), and stir at room temperature for 2 h. The reaction solution was filtered through diatomaceous earth, 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

Dissolve the compound 3-isopropoxy-4-methoxyaniline (6.90 g, 38.07 mmol) in 1, 4-dioxane (30 mL) and water (11 mL), cool to 0 °C, add concentrated hydrochloric acid (9.6 mL, 36% aq), stir evenly, cool to -15 °C, add a solution of sodium nitrite (2.89 g, 41.88 mmol) and water (7 mL) dropwise, control the temperature of addition between -15 °C and -5 °C, return to -5 °C and stir for 30 min, add a solution of potassium iodide (8.22 g, 49.49 mmol) and water (12 mL), control the temperature of addition between -15 °C and -5 °C. ℃, then return to 0 ℃ and stir 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. The organic phase was washed with water (100 mL × 3), dried with 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) was used to purify the product 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-dioxaborolane

3-Isopropoxy-4-methoxyiodobenzene (8.64 g, 26.63 mmol), pinacol diborate (6.76 g, 26.63 mmol), potassium acetate (39.2 g, 39.95 mmol), palladium acetate (0.30 g, 1.33 mmol), and 2-dicyclohexylphospho-2'-methylbiphenyl (Mephos) (0.97 g, 2.66 mmol) were mixed in N , N -dimethylformamide (48 mL) and stirred at 80 °C for 6 h under nitrogen protection. The mixture was cooled to room temperature, water (100 mL) was added to the reaction solution, and the reaction solution was extracted with petroleum ether (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown liquid, which was purified by silica gel column chromatography (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: Synthesis of compound ( R )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl) -1H -pyrrole-1, 2 ( 2H , 5H )-dicarboxylate

Compound ( R )-1-tert-butyl 2-methyl 4-((((trifluoromethyl)sulfonyl)methoxy) -1H -pyrrole-1, 2 ( 2H , 5H )-dicarboxylate (5.50 g, 14.65 mmol, intermediate _M2 ), 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-methylphenyl)phenyl]phosphine (267.00 mg, 0.73 mmol) were dissolved in toluene (30 mL). 4-Methylmorpholine (3.25 g, 32.08 mmol) and water (15 mL) were added to the solvent. Under a nitrogen atmosphere, the mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate for 30 min and purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v) = 3/20) to obtain a brown viscous product (5 g, yield 87.19 %).

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: Synthesis of compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1, 2-dicarboxylate

The compound ( R )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)-1H-pyrrole-1, 2 ( 2H , 5H )-dicarboxylate (5.55 g, 14.18 mmol) was dissolved in methanol (90 mL) solvent, and palladium carbon (0.56 mg, 1.42 mmol) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 4 h. The reaction was stopped, filtered through diatomaceous earth, and concentrated under reduced pressure to obtain a colorless viscous 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 (2 R , 4 S )-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

Dissolve the compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(4-methoxy-3-(propyloxy)phenyl)pyrrolidine-1, 2-dicarboxylate (1.70 g, 4.32 mmol) in dichloromethane (3 mL) solvent, then add hydrogen chloride/1, 4-dioxane (9 mL) solution. After adding the raw materials, stir and react at room temperature for 2 h. Stop the reaction, reduce pressure and concentrate once, then add dichloromethane (20 mL) to dissolve, reduce pressure and concentrate again to obtain a light 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: Synthesis of compound (2 R , 4 S )-1-acetyl-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester

Dissolve the compound (2 R ,4 S )-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.7 g, 5.79 mmol) in dichloromethane (10 mL) solvent, transfer the temperature to 0 °C, slowly add ethyldiisopropylamine (DIPEA) (2.99 g, 23.16 mmol) and acetyl chloride (0.91 g, 11.58 mmol) in sequence, and stir the reaction at room temperature for 2 h. Stop the reaction, wash the reaction solution with water (50 mL×1), extract the organic phase once with dichloromethane (20 mL), combine the organic phases, wash once with saturated brine (50 mL), separate the organic phase, add anhydrous sodium sulfate to dry for 30 min, concentrate under reduced pressure, separate by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 80%), and obtain a light brown viscous product (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 (2 R , 4 S )-2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-ethanone

The 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, and 2 mol/L lithium hydroxide in tetrahydrofuran (95.83 mg, 4.4 mmol) solvent was added dropwise at -5 °C.

After the addition was complete, 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. Ethyl acetate (30 mL) was added and stirred, and the organic phase was separated and concentrated under reduced pressure. The aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was separated and the concentrated liquid was dissolved. Ethyl acetate (20 mL) was added to dissolve completely. The pH was adjusted to 3 with saturated sodium chloride (30 mL) and dilute hydrochloric acid. After drying over anhydrous sodium sulfate, the solution was concentrated under reduced pressure to obtain a colorless viscous liquid (560 mg, yield 82.81%).

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: Synthesis of compound ((2 R , 4 S )-1-acetyl-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidin-2-yl)methyl 5-(acetylamino)picolinate

The compound 6-(acetylamino)pyridine-3-carboxylic acid lithium (130 mg, 0.65 mmol) was dissolved in N , N -dimethylformamide (2 mL) solvent, and hydrochloric acid dioxane solution (36 mg, 0.98 mmol) was added and stirred for 2 min. After the solution was clarified, ( 2R , 4S )-2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-ethanone (200 mg, 0.65 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT) (130 mg, 0.98 mmol) were added. The mixture was cooled at 0 °C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (250 mg, 1.30 mmol) and N- dimethylformamide (EDCI) were added. , N -diisopropylethylamine (DIPEA) (420 mg, 3.25 mmol), stirred at room temperature for 12 h. 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, separate by silica gel column chromatography (eluent: methanol/dichloromethane (v/v) = 1/20), and obtain a light 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-isobutoxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethylpyridine-2,5-dicarboxamide

Compound N ² -((((2 R ,4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)- N ⁵ -ethylpyridine-2,5-dicarboxamide (250 mg, 0.52 mmol, Example 48, step 1) was dissolved in N , N -dimethylformamide (10 mL) solvent and stirred until clear. Potassium carbonate (216 mg, 1.56 mmol) and isobutyl bromide (107 mg, 0.78 mmol) were added in sequence. 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. Ethyl acetate (20 mL × 2) was used to dry the mixture. Extract, combine the organic phases, wash with saturated brine (20 mL×2), dry the organic phase with anhydrous sodium sulfate, and pass the concentrated stirred sample through column chromatography (DCM/MeOH (v/v) = 20/1) to obtain a white solid product (212 mg, yield 76.55 %).

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-aminoformylpicolinate

The compound 6-amidopyridine-3-carboxylic acid lithium (390 mg, 2.28 mmol) was dissolved in N , N -dimethylformamide (2 mL) solvent, and a solution of hydrochloric acid dioxane (62 mg, 1.71 mmol) was added. The mixture was stirred for 2 min. After the solution became clear, (2R, 4S)-2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-ethanone (350 mg, 1.14 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT) (230 mg, 1.17 mmol) were added. The mixture was cooled at 0 °C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (440 mg, 2.28 mmol) and N , N -diisopropylethylamine (DIPEA) (740 mg, 5.7 mmol), stirred at room temperature for 13 h. 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, separate by silica gel column chromatography (eluent: methanol/dichloromethane (v/v) = 1/20), and obtain 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-aminoformylpicolinate

The compound 5-aminoformyl lithium 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. After reacting for 10 min, 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) were added. Under ice bath conditions, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (260 mg, 1.36 mmol) was added in sequence. and N , N -diisopropylethylamine (260 mg, 2.04 mmol), react at room temperature for 2 h. The raw materials reacted completely and the reaction was stopped. Saturated brine (50 mL) was added and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and separated and purified by reduced pressure concentrated silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20/1) 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-(methylaminoformyl)picolinate

The compound 5-(methylaminoformyl) lithium picolinate was dissolved in N, N -dimethylformamide (4 mL) solvent, and a solution of hydrochloric acid dioxane (130 mg, 3.50 mmol) was added. The mixture was stirred for 2 min. After the solution became clear, (2 R , 4 S )-2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-ethanone (715 mg, 2.33 mmol, Example 65, step 11) and 1-hydroxy-7-azabenzotriazole (HOAT) (480 mg, 3.50 mmol) were added. The mixture was cooled at 0 °C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (890 mg, 4.66 mmol) and N, N -diisopropylethylamine (DIPEA) (1.51 g, 1.93 mmol), then add N, N -dimethylformamide (6 mL) solvent, stir and react at 30 ℃ for 4 h. 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, and separate by silica gel column chromatography (eluent: methanol/dichloromethane (v/v) = 1/20) to obtain 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-(ethylaminoformyl)picolinate

Compound 5-(ethylaminoformyl)picolinic acid lithium salt (260 mg, 1.30 mmol) was added to a dry N , N -dimethylformamide (6 ml) solution, 4.02 mol/L HCl in 1,4-dioxane (0.43 mL), 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), cooled in an ice bath, added N , N -diisopropylethylamine (DIPEA) (510 mg, 3.92 mmol), transferred to room temperature and stirred for 16 h. Add water (50 ml) to quench the reaction, extract the organic phase with ethyl acetate (15 mL × 2), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (DCM/MeOH (v/v) = 25/1) to obtain a light yellow solid (319 mg, yield 69.59%).

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-dicarboxamide

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, and the organic phase was washed with saturated brine (100 mL × 3), then dried with 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 evenly and stirred at 50 ℃ 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, the filter cake was washed with water (50 mL×3), and vacuum dried at 60 ℃ for 12 h to obtain a white solid (10.36 g, yield 100 %).

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), and toluene (50 ml) to a two-necked flask (Bottle A), stir in an ice bath, slowly add diphenylphosphohydride (DPPA) (14.83 g, 53.89 mmol) dropwise, and stir 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 flask (bottle B), heat to 110 °C, drip the material in bottle A into bottle B, and stir at constant temperature for 2 h. Stop heating and stirring, cool to room temperature, wash the reaction solution with water (100 mL), then with 5% sodium hydroxide aqueous solution (100 mL×3), dry with anhydrous Na ₂ SO ₄ , and concentrate under reduced pressure to obtain a yellow solid. Add petroleum ether/ethyl acetate (50 mL, v/v = 10:1) to the crude product and stir for 3 h, filter 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

Add (3-isopropoxy-4-methoxyphenyl)carbamate (11.34 g, 35.96 mmol), 10% palladium on carbon (0.51 g, 0.54 mmol), and methanol (40 mL) to the autoclave, replace the hydrogen atmosphere (0.5 MPa), and stir at room temperature for 2 h. The reaction solution was filtered through diatomaceous earth, 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

Dissolve the compound 3-isopropoxy-4-methoxyaniline (6.90 g, 38.07 mmol) in 1, 4-dioxane (30 mL) and water (11 mL), cool to 0 °C, add concentrated hydrochloric acid (9.6 mL, 36% aq), stir evenly, cool to -15 °C, add a solution of sodium nitrite (2.89 g, 41.88 mmol) and water (7 mL) dropwise, control the temperature of addition between -15 °C and -5 °C, return to -5 °C and stir for 30 min, add a solution of potassium iodide (8.22 g, 49.49 mmol) and water (12 mL), control the temperature of addition between -15 °C and -5 °C. ℃, then return to 0 ℃ and stir 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. The organic phase was washed with water (100 mL × 3), dried with 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) was used to purify the product 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-dioxaborolane

3-Isopropoxy-4-methoxyiodobenzene (8.64 g, 26.63 mmol), pinacol diborate (6.76 g, 26.63 mmol), potassium acetate (39.2 g, 39.95 mmol), palladium acetate (0.30 g, 1.33 mmol), and 2-dicyclohexylphospho-2'-methylbiphenyl (Mephos) (0.97 g, 2.66 mmol) were mixed in N , N -dimethylformamide (48 mL) and stirred at 80 °C for 6 h under nitrogen protection. The mixture was cooled to room temperature, water (100 mL) was added to the reaction solution, and the reaction solution was extracted with petroleum ether (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown liquid, which was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 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, pos.ion) m/z: 293.25 [M+H] ⁺ .

Step 7: Synthesis of compound ( R )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl) -1H -pyrrole-1, 2 ( 2H , 5H )-dicarboxylate

Compound ( R )-1-tert-butyl 2-methyl 4-((((trifluoromethyl)sulfonyl)methoxy) -1H -pyrrole-1,2( 2H , 5H )-dicarboxylate (5.50 g, 14.65 mmol, intermediate _M2 ), 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-methylphenyl)phenyl]phosphine (267.00 mg, 0.73 mmol) were dissolved in toluene (30 mL). 4-Methylmorpholine (3.25 g, 32.08 mmol) and water (15 mL) were added to the solvent. Under a nitrogen atmosphere, the mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate for 30 min and purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v) = 3/20) to obtain a brown viscous product (5 g, yield 87.19 %).

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: Synthesis of compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1, 2-dicarboxylate

The compound ( R )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)-1H-pyrrole-1, 2 ( 2H , 5H )-dicarboxylate (5.55 g, 14.18 mmol) was dissolved in methanol (90 mL) solvent, and palladium carbon (0.56 mg, 1.42 mmol) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 4 h. The reaction was stopped, filtered through diatomaceous earth, and concentrated under reduced pressure to obtain a colorless viscous 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: Synthesis of compound (2 R , 4 S )-tert-butyl 2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-carboxylate

Dissolve the compound (2R,4S)-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl) pyrrolidine-1, 2-dicarboxylate (3.00 g, 7.62 mmol) in tetrahydrofuran (10 mL). Add lithium borohydride in tetrahydrofuran (2 mol/L, 0.33 g, 15.24 mmol) at 0 °C and stir the reaction at room temperature for 2 h. The reaction solution was slowly poured into ice water (50 mL) and stirred continuously to generate hydrogen. Ethyl acetate (30 mL) was added and stirred to separate the organic phase. The solution was concentrated under reduced pressure. The aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was separated and the concentrated solution was dissolved. Ethyl acetate (20 mL) was added to dissolve the solution completely. The pH was adjusted to 3 with saturated sodium chloride solution (30 mL) and dilute hydrochloric acid. After drying over anhydrous sodium sulfate, the solution was concentrated under reduced pressure to obtain a colorless viscous liquid (2.95 g, yield 100%).

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: Synthesis of compound (2 R , 4 S )-tert-butyl 4-(3-isopropoxy-4-methoxyphenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

Dissolve the compound ( 2R , 4S )-tert-butyl 2-(hydroxymethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-carboxylate (2.78 g, 7.61 mmol) in dichloromethane solvent (15 mL), add N , N -diisopropylethylamine (DIPEA) (1.57 g, 12.18 mmol), transfer to 0°C and slowly add methanesulfonyl chloride (1.13 g, 9.89 mmol). After 5 minutes, the addition of methanesulfonyl chloride is complete, and transfer to room temperature and stir to react for 1 h. The reaction solution was washed with water (50 mL) once, and then saturated salt water (50 mL) was added. The pH was adjusted to 3 by washing with dilute hydrochloric acid. The organic phase was separated, and the pH was adjusted to 8 by saturated sodium bicarbonate. After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain a brown viscous liquid (3.4 g, yield 100%).

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

Dissolve the compound (2 R , 4 S )-tert-butyl 4-(3-isopropoxy-4-methoxyphenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (3.3 g, 7.44 mmol) in N , N -dimethylformamide solvent (15 mL), add sodium azide (0.63 g, 9.67 mmol), and stir the reaction at 80 ℃ for 3 h. Stop the reaction and pour the reaction solution slowly into water (150 mL) while stirring. Add ethyl acetate (100 mL × 3) for extraction. Combine the organic phases, wash with saturated brine (200 mL × 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify 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 (2 R , 4 S )-2-(azidomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine hydrochloride

Dissolve the compound (2 R , 4 S )-tert-butyl 2-(azidomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1-carboxylate (1.83 g, 4.69 mmol) in dichloromethane (5 mL), add 1, 4-dioxane hydrochloride solution (0.85 g, 23.45 mmol, 5.85 mL), and stir at room temperature for 2 h. Stop the reaction, reduce the pressure and concentrate the reaction solution, add dichloromethane (20 mL) to dissolve, and then reduce the pressure and concentrate to obtain a light yellow viscous product (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: Synthesis of compound 1-((2 R , 4 S )-2-(azidomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone

Dissolve the compound (2 R , 4 S )-2-(azidomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine hydrochloride (1.53 g, 4.68 mmol) in dichloromethane (8 mL) solvent, transfer the temperature to 0 ℃, add N , N -diisopropylethylamine (DIPEA) (2.42 g, 18.72 mmol) and acetyl chloride (0.73 g, 9.36 mmol) in sequence, transfer the temperature to room temperature and stir the reaction for 2 h. The reaction mixture was washed once with water (100 mL), the organic phase was extracted once with dichloromethane (50 mL), the organic phases were combined, and then washed once with saturated brine (100 mL), the organic phase was separated, anhydrous sodium sulfate was added to the organic phase for drying, the organic phase was concentrated under reduced pressure, and silica gel column chromatography (eluent: ethyl acetate/petroleum ether (v/v) = 4/5) was used to obtain a 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: Synthesis of compound 1-((2 R , 4 S )-2-(aminomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone hydrochloride

The compound 1-((2 R ,4 S )-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 the reducing agent palladium carbon (0.15 g, 0.41 mmol) and 1,4-dioxane hydrochloride (0.21 g, 5.86 mmol, 1.46 mL) were added. The mixture was stirred at room temperature in a 1 MPa hydrogen atmosphere for 3 h. The reaction solution was filtered through diatomaceous earth, 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: Synthesis of compound N ² -(((2 R , 4 S )-1-acetyl-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidin-2-yl)methyl)-N ⁵ -ethylpyridine-2, 5-dicarboxamide

The compound 6-(acetylamino)pyridine-3-carboxylic acid lithium (220 mg, 1.09 mmol) was dissolved in N , N -dimethylformamide (5 mL) solvent, and the mixture was cooled to 0°C. Hydrogen chloride 1,4-dioxane solution (40 mg, 1.09 mmol) was added and stirred for 2 min. After the solution was clarified, the mixture was cooled to room temperature. 1-((2 R , 4 S )-2-(aminomethyl)-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethanone hydrochloride (250 mg, 0.73 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT) (150 mg, 1.09 mmol) were added. The mixture was cooled to 0°C and 1-(3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI) (420 mg, 2.19 mmol), N , N -diisopropylethylamine (DIPEA) (570 mg, 4.38 mmol), stirred at room temperature for 15 h. 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, separate by silica gel column chromatography (eluent: methanol/dichloromethane (v/v) = 1/20), and obtain 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-(ethylaminoformyl)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), isobutane bromide (11.28 g, 82.34 mmol) and potassium carbonate (22.76 g, 164.67 mmol) were mixed in N , N -dimethylformamide (50 mL) and stirred at 80 °C for 10 h. Ethyl acetate (200 mL) was added to dilute, and the organic phase was washed with saturated brine (100 mL × 3), dried with anhydrous sodium sulfate, 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), and water (10 mL) were mixed evenly and stirred at 50 ℃ for 2 h. Dilute hydrochloric acid (4 mol/L) was added dropwise to adjust pH=1, and water (100 mL) was added. A large amount of solid was precipitated by stirring, and filtered. The filter cake was washed with water (50 mL × 3), and dried at 60 ℃ in vacuum for 12 h to obtain a green solid (10.35 g, yield 100%).

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), and toluene (50 ml) to a two-necked flask (100 mL) (Bottle A), stir in an ice bath, slowly add diphenyl phosphate azide (13.97 g, 50.77 mmol), and stir at room temperature for 2 h.

Step 2: Add toluene (50 mL) and benzyl alcohol (5.49 g, 50.77 mmol) to another single-mouth bottle (250 mL) (bottle B), heat to 110 °C, drip the material in bottle A into bottle B, and stir for 2 h. Stop heating and stirring, cool to room temperature, wash the reaction solution with water (100 mL), then with 5% sodium hydroxide aqueous solution (100 mL × 3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow solid. Add petroleum ether/ethyl acetate (50 mL, v/v = 10/1) to the crude product and stir for 3 h, filter 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

Add (3-isobutoxy-4-methoxyphenyl)carbamate (10.90 g, 33.09 mmol), 10% palladium on carbon (0.53 g, 0.50 mmol), and methanol (50 mL) to a high pressure autoclave (250 mL). Expel air, introduce hydrogen (0.5 MPa), and stir at room temperature for 2 h. Filter the reaction solution through diatomaceous earth, collect the filtrate, and concentrate it 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

Dissolve the compound 3-isobutoxy-4-methoxyaniline (4.05 g, 20.74 mmol) in 1,4-dioxane (30 mL) and water (11 mL), cool to 0 °C, add concentrated hydrochloric acid (5.3 mL, 36% concentration), stir evenly, cool to -15 °C, add a solution of sodium nitrite (1.57 g, 22.81 mmol) and water (7 mL) dropwise, control the temperature of addition between -15 °C and -5 °C, after the addition is complete, heat to -5 °C and stir for 30 min, add a solution of potassium iodide (4.48 g, 26.96 mmol) and water (12 mL), control the temperature of addition between -15 °C and -5 °C. ℃, after the addition was complete, the temperature was raised to 0 ℃ and stirred for 2 h. Sodium bisulfite (1.08 g, 10.37 mmol) was added and stirred for 1 h to quench the reaction. Petroleum ether (200 mL) was added to the reaction solution, the organic phase was washed with water (100 mL×3), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous liquid. Silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) was used to purify the product 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-dioxaborolane

3-Isobutoxy-4-methoxyiodobenzene (3.60 g, 11.76 mmol), pinacol diborate (2.99 g, 11.76 mmol), potassium acetate (1.73 g, 17.64 mmol), palladium acetate (0.13 g, 0.59 mmol), and 2-dicyclohexylphospho-2'-methylbiphenyl (Mephos) (0.43 g, 1.18 mmol) were mixed in N , N -dimethylformamide (48 mL) and stirred at 80 °C for 6 h under nitrogen 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 phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a brown liquid. Purify by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) to obtain 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: Synthesis of compound ( R) -1-tert-butyl 2-methyl 4-(3-isobutoxy-4-methoxyphenyl) -1H -pyrrole-1,2( 2H , 5H )-dicarboxylate

Compound 2-(3-isobutoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.10 g, 6.86 mmol), ( R )- 1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1 H -pyrrole-1,2(2H,5H)-dicarboxylate (2.57 g, 6.86 mmol), sodium acetate (39 mg, 0.17 mmol), 2-dicyclohexylphosphino-2'-methylbiphenyl (Mephos) (130 mg, 0.34 mmol) and N-methylmorpholine (1.53 g, 15.09 mmol) were dissolved in toluene (10 mL) and water (5 mL) and stirred at 80 ℃ for 1 h under nitrogen protection. The mixture was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, 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 obtain a yellow liquid (2.15 g, yield 77.22%).

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: Synthesis of compound (2R ,4S) -1-tert-butyl 2-methyl 4-(3-isobutoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate

Compound ( R )-1-tert-butyl 2-methyl 4-(3-isobutoxy-4-methoxyphenyl) -1H -pyrrole-1,2( 2H , 5H )-dicarboxylate (2.14 g, 5.28 mmol) and 10% palladium on carbon (200 mg) were added to methanol (30 mL) and stirred for 12 h under a hydrogen atmosphere (1 atm). The solid was filtered off through diatomaceous earth and concentrated under reduced pressure to obtain a colorless transparent liquid (2.02 g, yield 93.88%).

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

Dissolve the compound (2R ,4S) -1-tert-butyl 2-methyl 4-(3-isobutoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (2.02 g, 4.96 mmol) in anhydrous tetrahydrofuran (5 mL), stir in an ice bath for 0.5 h, add lithium borohydride (2.5 mL, 4.96 mmol, 2 mol/L in THF) solution dropwise, and stir at room temperature for 4 h. Saturated ammonium chloride solution (50 mL) was added to quench the reaction, ethyl acetate (100 mL) was added to the residue for dilution, and the residue was washed with saturated ammonium chloride solution (100 mL×2), and the pH was adjusted to 3 with hydrochloric acid (4 mol/L). The residue was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (eluent: 60-90 petroleum ether/ethyl acetate (v/v) = 3/1) to obtain a colorless, transparent, viscous solid (1.70 g, yield 90.32%).

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), and a solution of hydrogen chloride in dioxane (5.0 mL, 20.0 mmol, 4 mol/L) was injected, and stirred at room temperature for 3 h. The solvent was removed under reduced pressure to obtain 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

Dissolve the compound ((2R ,4S) -4-(3-isobutoxy-4-methoxyphenyl)pyrrolidin-2-yl)methanol hydrochloride (1.09 g, 3.90 mmol) and triethylamine (2.02 g, 15.60 mmol) in dichloromethane (5 mL). Slowly add acetyl chloride (610 mg, 7.80 mmol) at 0°C and stir at room temperature for 2 h. Add dichloromethane (50 mL), wash the reaction solution with water (50 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow liquid (1.15 g, 3.16 mmol). Mix the above yellow liquid (1.15 g, 3.16 mmol), lithium hydroxide monohydrate (199 mg, 4.74 mmol), tetrahydrofuran (6 mL), and water (2 mL) evenly, and stir at 50 ℃ for 2 h. Add saturated brine (20 mL), add dilute hydrochloric acid (4 mol/L) dropwise to adjust pH=1, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a yellow liquid (938 mg, yield 92.35%).

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: Synthesis of compound ((2R ,4S) -1-acetyl-4-(3-isobutoxy-4-methoxyphenyl)pyrrolidin-2-yl)methyl 5-(ethylaminoformyl)picolinate

Compound 1-(( 2R,4S) -2-hydroxymethyl-4-(3-isobutoxy-4-methoxyphenyl)pyrrolidin-1-yl)ethyl ketone (151 mg, 0.47 mmol), 5-(ethylaminoformyl)picolinic acid (183 mg, 0.94 mmol) and N -hydroxy-7-azabenzotriazole (160 mg, 1.17 mmol) were dissolved in N , N -dimethylformamide (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg, 1.41 mmol) and N , N -diisopropylethylamine (243, 1.88 mmol) were added in an ice bath and stirred at room temperature for 15 h. Dichloromethane (100 mL) was added to the reaction solution for extraction. The organic phase was washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain a white solid (80 mg, yield 34.21%).

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-(ethylaminoformyl)pyridinylcarboxamido)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 -ethylpyridine-2,5-dicarboxamide (214 mg, 0.45 mmol, Example 48, step 1) was dissolved in N , N -dimethylformamide (10 mL) solvent and stirred until clear. Isobutyric acid (59 mg, 0.68 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT) (123 mg, 0.90 mmol) were added. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (173 mg, 0.90 mmol) were added in an ice bath. mmol), N , N -diisopropylethylamine (DIPEA) (233 mg, 1.80 mmol), transferred to room temperature and stirred for 21 h, water (20 mL) was added to dilute the reaction solution, extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine (20 mL × 2), and the organic phase was dried over anhydrous sodium sulfate. The concentrated and stirred sample was subjected to column chromatography (DCM/MeOH (v/v) = 20/1) to obtain a white solid product (200 mg, yield 81.32%).

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 tests

Biological Examples

The present invention uses the following method to conduct biological tests on the compounds of the present invention: (1) Using the BPS production reagent kit (BPS, Cat. No. 60343), according to the instructions provided by the manufacturer, the fluorescent polarization method is used to detect the inhibitory effect of the compound on the PDE4B2 enzyme. (2) The PDE4B2 enzyme concentration is prepared to 83.33 pg/μL, and the final concentration is 27.78 pg/μL; the substrate FAM-Cyclic-3',5'-AMP concentration is prepared to 300 nM, and the final reaction concentration is 100 nM. The enzyme and substrate dilutions are both diluted using the buffer PDE Assay buffer provided in the reagent kit; the Binding Agent is diluted 100 times using the Binding Agent Diluent provided in the reagent kit and set aside. The reaction system is shown in Table 1. [Table 1] Compounds against PDE4B2 enzyme IC ₅₀ detection system Test sample hole Positive control hole Negative control well Buffer blank well 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 samples 5 μL 0 μL 0 μL 0 μL PDE Assay buffer 0 μL 5 μL 10 μL 15 μL Incubate at 25°C in a constant temperature shaker for 1 h Binding Agent 15 μL 15 μL 15 μL 15 μL 25 ℃, constant temperature oscillator oscillator 1 h

A 384-well plate was used for the test. The experiment set up test sample wells, positive control wells, negative control wells and blank wells. Each sample was tested in duplicate for its inhibitory effect on PDE4B2 enzyme concentration at 10 concentrations. The PDE4B2 enzyme and FAM-Cyclic-3',5'-AMP substrate reaction wells were used as positive controls, the FAM-Cyclic-3',5'-AMP substrate wells were used as negative controls, and the buffer solution wells were used as blank controls. After adding the corresponding samples, enzymes, substrates and buffer to each well in the order of Table 1 , incubate in a 25 ℃ constant temperature incubator for 1 h, then add 15 μL of the prepared Binding Agent to each well, shake on a 25 ℃ constant temperature oscillator for 1 h, and then use PHER Astar FS multifunctional enzyme marker (BMG) to detect at FP485/525 wavelength. Graph Pad Prism 5 software was used to plot the inhibitory effects of compounds on PDE4B2 enzyme at different concentrations and calculate IC ₅₀ .

The inhibitory effect of the compounds of the present invention on the PDE4B2 enzyme was determined according to the above method, and it was found that the compounds of the present invention have an inhibitory effect on the PDE4B2 enzyme, and its IC ₅₀ value is less than 1 μM; it was further found that the IC ₅₀ value of the inhibitory effect of some compounds of the present invention on the PDE4B2 enzyme is less than 500 nM; it was further found that the IC ₅₀ value of the inhibitory effect of some compounds of the present invention on the PDE4B2 enzyme is less than 200 nM. Specifically, the determination results of the inhibitory effect of some compounds of the present invention on the PDE4B2 enzyme are shown in Table 2. [Table 2] Determination results of the inhibitory effect of some compounds of the present invention on the PDE4B2 enzyme Example No. PDE4B2 IC ₅₀ (nM) Example No. PDE4B2 IC ₅₀ (nM) Embodiment 3 59.89 Embodiment 18 29.08 Embodiment 4 45.87 Embodiment 19 10.58 Embodiment 8 19.43 Embodiment 21 5.33 Embodiment 9 11.18 Embodiment 22 7.721 Embodiment 10 38.07 Embodiment 23 10.66 Embodiment 11 7.113 Embodiment 24 36.29 Embodiment 12 23.45 Embodiment 26 62.2 Embodiment 13 56.59 Embodiment 27 22.9 Embodiment 14 39.12 Embodiment 28 11.7 Embodiment 17 2.85 / / Embodiment 39 1.63 Embodiment 57 1.21 Embodiment 40 12.07 Embodiment 58 3.52 Embodiment 43 7.40 Embodiment 59 22.42 Embodiment 44 4.39 Embodiment 60 1.27 Embodiment 45 1.68 Embodiment 62 6.85 Embodiment 47 1.94 Embodiment 63 1.11 Embodiment 48 3.18 Embodiment 64 7.05 Embodiment 49 2.95 Embodiment 65 2.38 Embodiment 50 6.80 Embodiment 66 7.94 Embodiment 51 0.48 Embodiment 67 10.81 Embodiment 52 0.14 Embodiment 68 5.48 Embodiment 53 0.16 Embodiment 69 2.81 Embodiment 54 0.18 Embodiment 70 0.19 Embodiment 55 0.63 Embodiment 71 40.76 Embodiment 56 0.58 Embodiment 72 1.38

Conclusion: The experiment shows that the compounds of the present invention generally have a high inhibitory effect on PDE4B2 enzyme in vitro.

The compound of the present invention has an effect on the PMA-induced acute atopic dermatitis mouse model

Female ICR mice weighing 26-28g were taken. After 7 days of adaptive breeding, they were randomly divided into normal group, model group and each compound group. There were 4 mice in the normal group and 10 mice in each group. Except for the mice in the normal group, the other mice were smeared with 20 μL of PMA solution (dissolved in anhydrous ethanol) with a concentration of 0.25 mg/mL on the right ear for modeling, and the normal group was smeared with the corresponding solvent. Each compound group was given the first drug 30 minutes before modeling and the second drug 15 minutes after modeling. The ears of 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)], and the animals in the normal group and model group were smeared with the corresponding solvent. The animals were killed 6 hours after the second drug administration. The right ear of each animal was cut off and the ear pieces were obtained at a fixed position using an 8 mm ear punch and weighed. The ear pieces were then stored in liquid nitrogen, and then 500 μL of physiological saline was added and homogenized using a homogenizer. After centrifugation, the supernatant was obtained, and the concentrations of IL-1β and IL-6 in the supernatant were detected and normalized to protein concentration.

The specific results are shown in Tables 3 to 7: Effects of the compounds of the present invention on ear thickness, ear weight and ear inflammatory factor secretion in PMA-induced acute atopic dermatitis mice (Mean±SEM, animal data N=4 or N=10) [Table 3] Effects of the 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 set - 10 0.395±0.011 - 41.2±1.2 - Embodiment 9 0.3mg/ear/bid 10 0.308±0.007** 51.1% 26.6±1.8** 50.7% Embodiment 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 set - 10 0.453±0.009 - 36.5±1.0 - Embodiment 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 set - 10 0.391±0.017 - 30.9±0.1 - Embodiment 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 set - 10 0.483±0.009 - 32.3±0.9 - Embodiment 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 ear thickness, ear weight and inflammatory factors in mice (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 set - 10 0.50±0.02 - 41.80±0.21 - Embodiment 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;)

From the above experimental results, it can be seen that compared with the model group, the compounds of the present invention can significantly reduce the ear thickness and ear weight of PMA-induced acute atopic dermatitis mice and the secretion of ear inflammatory factors IL-1β and IL-6 (P < 0.05).

The compound of the present invention has an effect on the OXA-induced chronic atopic dermatitis mouse model

Male Balb/c mice weighing 24-26 g were selected. After 7 days of adaptive breeding, the other animals, except the normal group, were sensitized by applying 40 μL 1% OXA solution (dissolved in acetone) to both ears of the mice on Day 0 and Day 1, and repeated sensitization was performed by applying 40 μL 0.5% OXA solution to both ears of the mice on Day 7 and Day 8. The normal group was applied with the corresponding solvent. Starting from Day 12, except for the normal group, the other animals were stimulated by applying 20 μl 0.5% OXA solution to the right ear of the mice twice a week. The normal group was applied with the corresponding solvent, and the thickness of the right ear was measured 24 hours after each stimulation. Except for the normal group, the rest of the animals were randomly divided into the model group and each compound group according to the ear thickness results on the 13th day, with 5 animals in the normal group and 10 animals in each of the other groups. The drug administration started on Day 14, twice a day, and 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 drug administration group, and the corresponding solvent was applied to the animals in the normal group and model group. On Day 29, the ear thickness was measured and the animals were killed. The right ear of each animal was cut off and an ear piece was obtained at a fixed position using an 8 mm ear punch and weighed. The ear piece was then stored in liquid nitrogen and then 500 μL of physiological saline was added and homogenized using 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 normalized to protein concentration.

The results showed that compared with the model group, the compound of the present invention could significantly reduce the ear thickness and terminal ear weight of OXA-induced chronic atopic dermatitis mice and the secretion of ear inflammatory factors IL-1β, IL-4, IL-5, IL-6 and TNF-α from Day 20 to the end of drug administration (P < 0.01);

It will be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments and may be embodied in other specific forms without departing from its essential characteristics. It is therefore intended that the embodiments be considered in all respects as illustrative and non-restrictive, and that reference should be made to the appended claims rather than to the foregoing embodiments, and that all variations coming within the meaning and range of equivalents of the appended claims are intended to be included in the present invention.

In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in an appropriate manner.

Finally, it should be noted that there are other ways to implement the present invention. Accordingly, the embodiments of the present invention are to be described as examples, but are not limited to the contents described in the present invention, and may also be modified within the scope of the present invention or added in the claims. All publications or patents cited in the present invention will be used as references for the present invention.

Claims (12)

A compound, which is a compound represented by formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by formula (I): (I); wherein: R ¹ and R ² are each independently hydrogen, deuterium, C _1-6 alkyl, C _1-6 halogenated alkyl, C _3-8 cycloalkyl-C _1-4 alkylene, C _1-6 alkyl-C(=O)-, C _3-8 cycloalkyl-C(=O)- or a heterocyclic-C _1-4 alkylene consisting of 3-10 atoms; X and X ¹ are each independently -O-; R ³ is C _1-6 alkyl-C(=O)- or C _1-6 alkyl-S(=O) _t -, 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, hydroxyl, amino, cyano, oxo, C _1-4 alkyl, C _R4 ^is -( _CH2 ) _m -L-( _CH2 ) _n -G; L is -NRx-C(=O)-, -NRx ^- C(=O) _-NRy- , ^{-NRx -} C(=O)-O- or _-C (=O)-O-; wherein each ^Rx and ^Ry is independently hydrogen, deuterium, _C1-6 alkyl or _C1-6 haloalkyl; G is _C3-8 cycloalkyl, _C6-10 aryl, a heterocyclic group consisting of 3-10 atoms or a heteroaryl group consisting of 5-10 atoms; wherein ^G is unsubstituted or substituted by 1, 2, 3 or 4 R7; each ^{R 7} is independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, carboxyl, C _1-6 alkyl, C _1-6 halogenated alkyl, 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)- or C _1-6 alkyl-C(=O)-O-; each of ^Ra and R 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, a heterocyclic group consisting of 3-10 atoms, or a heteroaryl group consisting of 5-10 atoms, wherein each Ra and R ^b are independently unsubstituted or substituted with 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, -C(=O)-NH ₂ , C _1-6 alkoxy C(=O)-, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino; each R ^c is independently hydrogen, deuterium, C _1-3 alkyl or C _1-3 haloalkyl; R is hydrogen or deuterium; R ^{R 5a} , R ^5b , R ^6a and R ^6b are each independently hydrogen or deuterium; t is 1 or 2; n is 0, 1 or 2; m is 1 or 2. The compound as described in claim 1, which is a compound represented by formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by formula (II): (II). The compound as described in claim 1, which is a compound represented by formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by formula (III): (III). The compound of claim 1, wherein: ^R1 and ^R2 are each _{independently} hydrogen, deuterium, methyl, ethyl _, n-propyl, isopropyl, _isobutyl , _-CH2F , _{-CHF2 , -CF3} , -CH2CH2F, -CH2CHF2, _-CH2CF3 , _-CH2CH2CH2F , _-CH2CH2CHF2 , _-CH2CH2CF3 , _{-CH2Cl , -CHCl2 ,} cyclopropylmethylene, cyclopropylethylene, cyclobutylmethylene, cyclobutylethylene, cyclopentylmethylene, cyclopentylethylene, cyclohexylmethylene _, cyclohexylethylene _{, CH3C} ( ₌ O)- _{, CH3CH2C} (= _{O ) - , CH3CH2CH2} C(=O)-, (CH ₃ ) ₂ CHC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, piperazinyl-C _1-3 alkylene, piperidinyl-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 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 - or (CH ₃ ) ₂ CH-S(═O) ₂ -, 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, 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-propyloxy, methylamino, ethylamino or n-propylamino. The compound as described in claim 1, wherein: each of R ^x and R ^y is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl or C _1-4 halogenated alkyl. The compound as claimed in 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, hydroxyl, amino, cyano, oxo, carboxyl, C _1-4 alkyl, C _1-4 halogenated 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 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- or CH ₃ CH ₂ CH ₂ CH ₂ -C(=O)-O-. The compound of claim 1, wherein: each ^Ra and ^Rb is independently hydrogen, deuterium, methyl, ethyl, n-propyl _, isopropyl, n-butyl, _-CH2F , -CHF2, -CF3, -CH2CH2F, -CH2CHF2, _-CH2CF3 , -CH2CH2CH2F, _-CH2CH2CHF2 , _{-CH2CH2CF3 ,} -CH2Cl, _-CHCl2 , _{phenyl, naphthyl, pyridyl, pyrimidyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl , piperazinyl} , piperidinyl, morpholinyl, _{thiomorpholinyl} , tetrahydropyranyl or pyrrolidinyl _; wherein each _{Ra and Rb} is independently _{hydrogen ,} deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, _-CH2F , _-CHF2 , _-CF3 , -CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, phenyl, naphthyl, pyridyl, pyrimidyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, ^{tetrahydropyranyl} or pyrrolidinyl; ^b is independently unsubstituted or substituted with 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, 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, The invention is substituted by an N -ethylamino, N'N -dimethylamino, N'N -diethylamino or N'N -methylethylamino group. The compound as described in claim 1, which is a compound having one of the following structures or a stereoisomer, tautomer or pharmaceutically acceptable salt of a compound having one of the following structures: (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 of any one of claims 1 to 8, optionally further comprising a pharmaceutically acceptable adjuvant. The pharmaceutical composition of claim 9 further comprises an additional therapeutic agent, wherein the additional therapeutic agent is sodium pyruvate, doxofenadine, tetomilast, talusulast, theophylline, formoterol, salmeterol, fluticasone propionate, rolipram, pyramister, cilomilast, indacaterol, olodaterol, mildenafil, zithromycin, salbutamol, carmoxicillin, budesonide, beclomethasone dipropionate, trimethoprim-sulfamethoxazole, pheniramine, pheniramine, succinate ... Amnesol, Flunisolide, Mometasone Furoate, Roflenide, Cyclosporine, Ipratropium Bromide, Oxytropium Bromide, Tiotropium Bromide, Glycopyrrolate, Isopropylamine Bromide, Vilanterol, Aclidinium Bromide, Benralizumab, Tralokinumab, Revatolide, Cresabor, Fluocinolone Acetate, Desoxymethasone, Mometasone, Triamcinolone, Betamethasone, Alclometasone, Desonedonide, Hydrocortisone, Clobetasol, halbetasol, diflorasone, meproclat, tacrolimus, pimecrolimus, tazarotene, cyclosporine, apremilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, ibudilast, tofacitinib, JTE-052, baricitinib, upatininib, WBI-1001, MRX-6, GSK2981278, durulumab , levitra, nimolizumab, tromirumab, etanercept, adalimumab, infliximab, ustekinumab, secukinumab, omalizumab, CIM-331, golimumab and peg-serine, tocilizumab, calcipotriol, calcitriol, alitretinoin, VTP-38543, ZPL-389, aprepitant, trodipitant, foviprant, 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 a compound as described in any one of claims 1 to 8 or a pharmaceutical composition as described in any one of claims 9 to 10 in the preparation of a drug, wherein the drug is used to prevent, treat or alleviate diseases related to type 4 phosphodiesterase. The use as described in claim 11, wherein the disease related to type 4 phosphodiesterase is a respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin-dependent diabetes mellitus; wherein the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculous fibrosis, cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; wherein bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchitis or obstructive bronchitis; Wherein, the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatic arthritis or psoriatic arthritis.